U.S. patent application number 17/182728 was filed with the patent office on 2021-06-10 for novel dosage forms of rofecoxib and related methods.
This patent application is currently assigned to Tremeau Pharmaceuticals, Inc.. The applicant listed for this patent is Tremeau Pharmaceuticals, Inc.. Invention is credited to Travis E. Helm, Bradford C. Sippy, Raymond D. Skwierczynski.
Application Number | 20210169845 17/182728 |
Document ID | / |
Family ID | 1000005418036 |
Filed Date | 2021-06-10 |
United States Patent
Application |
20210169845 |
Kind Code |
A1 |
Sippy; Bradford C. ; et
al. |
June 10, 2021 |
NOVEL DOSAGE FORMS OF ROFECOXIB AND RELATED METHODS
Abstract
The subject matter disclosed herein relates to novel doses and
dosage forms of rofecoxib having a therapeutic benefit.
Inventors: |
Sippy; Bradford C.; (Acton,
MA) ; Skwierczynski; Raymond D.; (Andover, MA)
; Helm; Travis E.; (Acton, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Tremeau Pharmaceuticals, Inc. |
Concord |
MA |
US |
|
|
Assignee: |
Tremeau Pharmaceuticals,
Inc.
Concord
MA
|
Family ID: |
1000005418036 |
Appl. No.: |
17/182728 |
Filed: |
February 23, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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17127970 |
Dec 18, 2020 |
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17182728 |
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PCT/US2020/060152 |
Nov 12, 2020 |
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17127970 |
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16867514 |
May 5, 2020 |
10945992 |
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PCT/US2020/060152 |
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63018136 |
Apr 30, 2020 |
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62934898 |
Nov 13, 2019 |
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63018136 |
Apr 30, 2020 |
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62934898 |
Nov 13, 2019 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/16 20130101; A61K
31/365 20130101; A61K 9/20 20130101 |
International
Class: |
A61K 31/365 20060101
A61K031/365; A61K 9/20 20060101 A61K009/20; A61K 9/16 20060101
A61K009/16 |
Claims
1. A formulation comprising 17.5 mg of rofecoxib, or a
pharmaceutically acceptable salt thereof, wherein the formulation
achieves a mean C.sub.max plasma concentration of more than 180
ng/ml following oral administration of a single dose of the
formulation to a population of healthy adults less than 65 years of
age.
2. The formulation of claim 1, wherein the formulation achieves a
mean C.sub.max plasma concentration of more than 190 ng/ml
following oral administration of a single dose of the formulation
to a population of healthy adults less than 65 years of age.
3. The formulation of claim 2, wherein the formulation achieves a
mean C.sub.max plasma concentration of more than 200 ng/ml
following oral administration of a single dose of the formulation
to a population of healthy adults less than 65 years of age.
4. The formulation of claim 3, wherein the formulation achieves a
mean C.sub.max plasma concentration of about 224 ng/ml following
oral administration of a single dose of the formulation to a
population of healthy adults less than 65 years of age.
5. The formulation of claim 1, wherein the formulation achieves a
mean C.sub.max plasma concentration within 80-125% of 224 ng/ml
following oral administration of a single dose of the formulation
to a population of healthy adults less than 65 years of age.
6. The formulation of claim 1, wherein the formulation achieves a
mean plasma AUC.sub.0-.infin. of more than 3000 h*ng/ml following
oral administration of a single dose of the formulation to a
population of healthy adults less than 65 years of age.
7. The formulation of claim 1, wherein the formulation achieves a
higher mean plasma C.sub.max and a higher mean plasma
AUC.sub.0-.infin. in a population of healthy female adults less
than 65 years of age compared to a population of healthy male
adults less than 65 years of age following oral administration of a
single dose of the formulation.
8. The formulation of claim 1, wherein the formulation achieves a
higher mean plasma AUC.sub.0-.infin. in Caucasian adults less than
65 years of age compared to healthy African American adults less
than 65 years of age following oral administration of a single dose
of the formulation.
9. The formulation of claim 1, wherein the formulation achieves an
arithmetic mean plasma concentration of at least 2.0 ng/ml at 15
minutes following oral administration of a single dose of the
formulation to a population of healthy adults less than 65 years of
age.
10. The formulation of claim 1, wherein the formulation achieves an
arithmetic mean plasma concentration of at least 79 ng/ml at 45
minutes following oral administration of a single dose of the
formulation to a population of healthy adults less than 65 years of
age.
11. The formulation of claim 1, wherein the formulation is a liquid
dosage form.
12. The formulation of claim 11, wherein the liquid dosage form is
a solution.
13. The formulation of claim 11, wherein the liquid dosage form is
a suspension.
14. The formulation of claim 11, wherein the liquid dosage form is
a syrup.
15. The formulation of claim 1, wherein the formulation is a tablet
formulation.
16. The formulation of claim 15, wherein the formulation further
comprises a disintegrant.
17. The formulation of claim 15, wherein the rofecoxib has a d90
particle size in the range of about 10 .mu.m to about 12 .mu.m, a
d50 particle size in the range of about 3 .mu.m to about 4 .mu.m,
and a d10 particle size in the range of about 0.5 .mu.m to about
1.0 .mu.m.
18. A formulation comprising 17.5 mg of rofecoxib, or a
pharmaceutically acceptable salt thereof, wherein the formulation
achieves a mean plasma AUC.sub.0-.infin. of more than 3000 h*ng/ml
following oral administration of a single dose of the formulation
to a population of healthy adults less than 65 years of age.
19. The formulation of claim 18, wherein the formulation achieves a
mean C.sub.max plasma concentration of more than 167 ng/ml
following oral administration of a single dose of the formulation
to a population of healthy adults less than 65 years of age.
20. The formulation of claim 19, wherein the formulation achieves a
mean C.sub.max plasma concentration of more than 180 ng/ml
following oral administration of a single dose of the formulation
to a population of healthy adults less than 65 years of age.
21. The formulation of claim 20, wherein the formulation achieves a
mean C.sub.max plasma concentration of more than 190 ng/ml
following oral administration of a single dose of the formulation
to a population of healthy adults less than 65 years of age.
22. The formulation of claim 21, wherein the formulation achieves a
mean C.sub.max plasma concentration of more than 200 ng/ml
following oral administration of a single dose of the formulation
to a population of healthy adults less than 65 years of age.
23. The formulation of claim 22, wherein the formulation achieves a
mean C.sub.max plasma concentration of about 224 ng/ml following
oral administration of a single dose of the formulation to a
population of healthy adults less than 65 years of age.
24. The formulation of claim 18, wherein the formulation achieves a
mean C.sub.max plasma concentration within 80-125% of 224 ng/ml
following oral administration of a single dose of the formulation
to a population of healthy adults less than 65 years of age.
25. The formulation of claim 18, wherein the formulation achieves a
higher mean plasma C.sub.max and a higher mean plasma
AUC.sub.0-.infin. in a population of healthy female adults less
than 65 years of age compared to a population of healthy male
adults less than 65 years of age following oral administration of a
single dose of the formulation.
26. The formulation of claim 18, wherein the formulation achieves a
higher mean plasma AUC.sub.0-.infin. in Caucasian adults less than
65 years of age compared to healthy African American adults less
than 65 years of age following oral administration of a single dose
of the formulation.
27. The formulation of claim 18, wherein the formulation achieves
an arithmetic mean plasma concentration of at least 2.0 ng/ml at 15
minutes following oral administration of a single dose of the
formulation to a population of healthy adults less than 65 years of
age.
28. The formulation of claim 18, wherein the formulation achieves
an arithmetic mean plasma concentration of at least 79 ng/ml at 45
minutes following oral administration of a single dose of the
formulation to a population of healthy adults less than 65 years of
age.
29. The formulation of claim 18, wherein the formulation is a
liquid dosage form.
30. The formulation of claim 29, wherein the liquid dosage form is
a solution.
31. The formulation of claim 29, wherein the liquid dosage form is
a suspension.
32. The formulation of claim 29, wherein the liquid dosage form is
a syrup.
33. The formulation of claim 18, wherein the formulation is a
tablet formulation.
34. The formulation of claim 33, wherein the formulation further
comprises a disintegrant.
35. The formulation of claim 33, wherein the rofecoxib has a d90
particle size in the range of about 10 .mu.m to about 12 .mu.m, a
d50 particle size in the range of about 3 .mu.m to about 4 .mu.m,
and a d10 particle size in the range of about 0.5 .mu.m to about
1.0 .mu.m.
36. A formulation comprising 17.5 mg of rofecoxib, or a
pharmaceutically acceptable salt thereof, wherein the formulation
achieves an arithmetic mean plasma concentration of at least 2.0
ng/ml at 15 minutes following oral administration of a single dose
of the formulation to a population of healthy adults less than 65
years of age.
37. The formulation of claim 36, wherein the formulation achieves
an arithmetic mean plasma concentration of at least 79 ng/ml at 45
minutes following oral administration of a single dose of the
formulation to a population of healthy adults less than 65 years of
age.
38. The formulation of claim 36, wherein the formulation achieves a
mean C.sub.max plasma concentration of more than 167 ng/ml
following oral administration of a single dose of the formulation
to a population of healthy adults less than 65 years of age.
39. The formulation of claim 38, wherein the formulation achieves a
mean C.sub.max plasma concentration of more than 180 ng/ml
following oral administration of a single dose of the formulation
to a population of healthy adults less than 65 years of age.
40. The formulation of claim 39, wherein the formulation achieves a
mean C.sub.max plasma concentration of more than 190 ng/ml
following oral administration of a single dose of the formulation
to a population of healthy adults less than 65 years of age.
41. The formulation of claim 40, wherein the formulation achieves a
mean C.sub.max plasma concentration of more than 200 ng/ml
following oral administration of a single dose of the formulation
to a population of healthy adults less than 65 years of age.
42. The formulation of claim 41, wherein the formulation achieves a
mean C.sub.max plasma concentration of about 224 ng/ml following
oral administration of a single dose of the formulation to a
population of healthy adults less than 65 years of age.
43. The formulation of claim 36, wherein the formulation achieves a
mean C.sub.max plasma concentration within 80-125% of 224 ng/ml
following oral administration of a single dose of the formulation
to a population of healthy adults less than 65 years of age.
44. The formulation of claim 36, wherein the formulation achieves a
mean plasma AUC.sub.0-.infin. of more than 3000 h*ng/ml following
oral administration of a single dose of the formulation to a
population of healthy adults less than 65 years of age.
45. The formulation of claim 36, wherein the formulation achieves a
higher mean plasma C.sub.max and a higher mean plasma
AUC.sub.0-.infin. in a population of healthy female adults less
than 65 years of age compared to a population of healthy male
adults less than 65 years of age following oral administration of a
single dose of the formulation.
46. The formulation of claim 36, wherein the formulation achieves a
higher mean plasma AUC.sub.0-.infin. in Caucasian adults less than
65 years of age compared to healthy African American adults less
than 65 years of age following oral administration of a single dose
of the formulation.
47. The formulation of claim 36, wherein the formulation is a
liquid dosage form.
48. The formulation of claim 47, wherein the liquid dosage form is
a solution.
49. The formulation of claim 47, wherein the liquid dosage form is
a suspension.
50. The formulation of claim 47, wherein the liquid dosage form is
a syrup.
51. The formulation of claim 36, wherein the formulation is a
tablet formulation.
52. The formulation of claim 51, wherein the formulation further
comprises a disintegrant.
53. The formulation of claim 51, wherein the rofecoxib has a d90
particle size in the range of about 10 .mu.m to about 12 .mu.m, a
d50 particle size in the range of about 3 .mu.m to about 4 .mu.m,
and a d10 particle size in the range of about 0.5 .mu.m to about
1.0 .mu.m.
Description
[0001] This application is a continuation of U.S. application Ser.
No. 17/127,970, filed Dec. 18, 2020, which is a continuation of
International Patent Application No. PCT/US2020/060152, filed Nov.
12, 2020, which claims the benefit of and priority under 35 U.S.C.
.sctn. 119(e) to U.S. application Ser. No. 16/867,514, filed May 5,
2020, which claims the benefit of and priority under 35 U.S.C.
.sctn. 119(e) to each of U.S. Provisional Application No.
63/018,136 filed Apr. 30, 2020 and U.S. Provisional Application No.
62/934,898 filed Nov. 13, 2019, the contents of each of which is
incorporated herein by reference in their entireties.
[0002] All patents, patent applications and publications cited
herein are hereby incorporated by reference in their entirety. The
disclosures of these publications in their entireties are hereby
incorporated by reference into this application.
[0003] This patent disclosure contains material that is subject to
copyright protection. The copyright owner has no objection to the
facsimile reproduction by anyone of the patent document or the
patent disclosure as it appears in the U.S. Patent and Trademark
Office patent file or records, but otherwise reserves any and all
copyright rights.
BACKGROUND OF THE INVENTION
[0004] Rofecoxib is a selective COX-2 inhibitor, nonsteroidal
anti-inflammatory drug (NSAID), that was marketed under the brand
name "VIOXX" until it was withdrawn from the market in at least
2004 over safety concerns. Before being withdrawn from the market,
"VIOXX" was approved in the United States for the following
indications: signs and symptoms of osteoarthritis (OA); signs and
symptoms of rheumatoid arthritis (RA) in adults; signs and symptoms
of pauciarticular or polyarticular course Juvenile Rheumatoid
Arthritis; management of acute pain in adults; treatment of primary
dysmenorrhea; and treatment of migraine attacks with or without
aura in adults.
[0005] "VIOXX" was formulated in 12.5 mg, 25 mg, and 50 mg tablet
dosage forms for oral administration. Rapid and complete absorption
is important to the therapeutic efficacy of a drug. The
bioavailability of solid oral dosages of drugs can be limited by
poor dissolution into aqueous bodily fluids. The bioavailability of
"VIOXX" was previously reported to be 93%, as provided in the
FDA-approved label for the product. As rofecoxib, the active
ingredient in "VIOXX", is a poorly water-soluble molecule, the
reported 93% bioavailability was an exceptionally high value for an
oral solid dosage form.
SUMMARY OF THE INVENTION
[0006] In certain aspects, the subject matter disclosed herein
provides a solid dosage formulation comprising 17.5 mg of rofecoxib
and a pharmaceutically acceptable carrier.
[0007] In some embodiments, the rofecoxib formulation reaches a
median time to Cmax plasma concentration in 4 hours or less
following a single administration of the formulation to human
subjects less than 65 years of age. In some embodiments, the
rofecoxib formulation reaches a median time to Cmax plasma
concentration in 3.5 hours or less following a single
administration of the formulation to human subjects less than 65
years of age. In some embodiments, the rofecoxib formulation
reaches a median time to Cmax plasma concentration in 3 hours or
less following a single administration of the formulation to human
subjects less than 65 years of age. In some embodiments, the
rofecoxib formulation reaches a median time to Cmax plasma
concentration in 2.5 hours or less following a single
administration of the formulation to human subjects less than 65
years of age.
[0008] In certain aspects, the subject matter disclosed herein
provides a solid dosage formulation comprising 17.5 mg of rofecoxib
and a pharmaceutically acceptable carrier, wherein the formulation
achieves a mean Cmax plasma concentration of more than 100 ng/ml
following a single administration of the formulation to human
subjects less than 65 years of age.
[0009] In some embodiments, the rofecoxib formulation achieves a
mean Cmax plasma concentration of more than 150 ng/ml, 167 ng/ml,
or 190 ng/ml. In some embodiments, the rofecoxib formulation
achieves a mean Cmax plasma concentration of more than 200 ng/ml.
In some embodiments, the rofecoxib formulation achieves a mean Cmax
plasma concentration of more than 220 ng/ml. In some embodiments,
the rofecoxib formulation achieves a mean Cmax plasma concentration
of more than 250 ng/ml.
[0010] In certain aspects, the subject matter disclosed herein
provides a solid dosage formulation comprising 17.5 mg of rofecoxib
and a pharmaceutically acceptable carrier, wherein the formulation
achieves a mean AUC.sub.0-.infin. of more than 1750 h*ng/ml
following a single administration of the formulation to human
subjects less than 65 years of age.
[0011] In some embodiments, the rofecoxib formulation achieves a
mean AUC.sub.0-.infin. of more than 2000 h*ng/ml following a single
administration of the formulation to human subjects less than 65
years of age. In some embodiments, the rofecoxib formulation
achieves a mean AUC.sub.0-.infin. of more than 2500 h*ng/ml
following a single administration of the formulation to human
subjects less than 65 years of age. In some embodiments, the
rofecoxib formulation achieves a mean AUC.sub.0-.infin. of more
than 3000 h*ng/ml following a single administration of the
formulation to human subjects less than 65 years of age. In some
embodiments, the rofecoxib formulation achieves a mean
AUC.sub.0-.infin. of more than 3100 h*ng/ml following a single
administration of the formulation to human subjects less than 65
years of age. In some embodiments, the rofecoxib formulation
achieves a mean AUC.sub.0-.infin. of more than 3500 h*ng/ml
following a single administration of the formulation to human
subjects less than 65 years of age.
[0012] In some embodiments, the rofecoxib formulation further
comprises a granular component and an extragranular component,
wherein the granular component comprises an intragranular component
comprising the rofecoxib and one or more disintegrants, and wherein
the extragranular component comprises one or more disintegrants. In
some embodiments, the rofecoxib in the formulation has a d90
particle size from about 10-12 .mu.m, a d50 particle size from
about 3-4 .mu.m, and a d10 particle size from about 0.5-1.0
.mu.m.
[0013] In certain aspects, the subject matter disclosed herein
provides a solid dosage formulation comprising 20 mg of rofecoxib
and a pharmaceutically acceptable carrier.
[0014] In some embodiments, the formulation reaches a median time
to Cmax plasma concentration in 4 hours or less following a single
administration of the formulation to human subjects less than 65
years of age. In some embodiments, the formulation reaches a median
time to Cmax plasma concentration in 3 hours or less following
administration. In some embodiments, the formulation reaches a mean
Cmax plasma concentration in less than 3 hours following
administration. In some embodiments, the formulation reaches a
median time to Cmax plasma concentration in 2.5 hours or less
following administration.
[0015] In certain aspects, the subject matter disclosed herein
provides a solid dosage formulation comprising 20 mg of rofecoxib
and a pharmaceutically acceptable carrier, wherein the formulation
achieves a mean Cmax plasma concentration of more than 150 ng/ml
following a single administration of the formulation to human
subjects less than 65 years of age.
[0016] In some embodiments, the rofecoxib formulation achieves a
mean Cmax plasma concentration of more than 191 ng/ml, 200 ng/ml,
215 ng/ml, or 225 ng/ml following a single administration of the
formulation to human subjects less than 65 years of age. In some
embodiments, the rofecoxib formulation achieves a mean Cmax plasma
concentration of more than 250 ng/ml following a single
administration of the formulation to human subjects less than 65
years of age. In some embodiments, the rofecoxib formulation
achieves a mean Cmax plasma concentration of more than 258 ng/ml
following a single administration of the formulation to human
subjects less than 65 years of age. In some embodiments, the
rofecoxib formulation achieves a mean Cmax plasma concentration of
more than 300 ng/ml following a single administration of the
formulation to human subjects less than 65 years of age.
[0017] In certain aspects, the subject matter disclosed herein
provides a solid dosage formulation comprising 20 mg of rofecoxib
and a pharmaceutically acceptable carrier, wherein the formulation
achieves a mean AUC.sub.0-.infin. of more than 2000 h*ng/ml
following a single administration of the formulation to human
subjects less than 65 years of age.
[0018] In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 2500 h*ng/ml following a single
administration of the formulation to human subjects less than 65
years of age. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 3000 h*ng/ml following a single
administration of the formulation to human subjects less than 65
years of age. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 3400 h*ng/ml following a single
administration of the formulation to human subjects less than 65
years of age. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 3500 h*ng/ml following a single
administration of the formulation to human subjects less than 65
years of age. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 3550 h*ng/ml following a single
administration of the formulation to human subjects less than 65
years of age.
[0019] In some embodiments, the formulation further comprises a
granular component and an extragranular component, wherein the
granular component comprises an intragranular component comprising
the rofecoxib and one or more disintegrants, and wherein the
extragranular component comprises one or more disintegrants. In
some embodiments, the rofecoxib in the formulation has a d90
particle size from about 10-12 .mu.m, a d50 particle size from
about 3-4 .mu.m, and a d10 particle size from about 0.5-1.0
.mu.m.
[0020] In certain aspects, the subject matter disclosed herein
provides a method for treating pain, fever, or inflammation in a
subject by administering a 25 mg solid dosage formulation of
rofecoxib or a pharmaceutically acceptable salt thereof, wherein
the formulation achieves a mean Cmax plasma concentration in less
than 3 hours following a single administration of the formulation
to human subjects less than 65 years of age.
[0021] In some embodiments, the rofecoxib formulation achieves a
median time to Cmax plasma concentration in 2.5 hours or less
following administration of the formulation to human subjects less
than 65 years of age.
[0022] In certain aspects, the subject matter disclosed herein
provides a method for treating pain, fever, or inflammation in a
subject by administering a 25 mg solid dosage formulation of
rofecoxib or a pharmaceutically acceptable salt thereof, wherein
the formulation achieves a mean Cmax plasma concentration of more
than 250 ng/ml following a single administration of the formulation
to human subjects less than 65 years of age.
[0023] In some embodiments, the formulation achieves a mean Cmax
plasma concentration of more than 300 ng/ml following
administration of the formulation to human subjects less than 65
years of age. In some embodiments, the formulation achieves a mean
Cmax plasma concentration of more than 320 ng/ml following
administration of the formulation to human subjects less than 65
years of age. In some embodiments, the formulation achieves a mean
Cmax plasma concentration of more than 350 ng/ml following
administration of the formulation to human subjects less than 65
years of age.
[0024] In certain aspects, the subject matter disclosed herein
provides a method for treating pain, fever, or inflammation in a
subject by administering a 25 mg solid dosage formulation of
rofecoxib or a pharmaceutically acceptable salt thereof, wherein
the formulation achieves a mean AUC.sub.0-.infin. of more than 4250
h*ng/ml following a single administration of the formulation to
human subjects less than 65 years of age.
[0025] In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 4500 h*ng/ml following
administration of the formulation to human subjects less than 65
years of age. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 4700 h*ng/ml following
administration of the formulation to human subjects less than 65
years of age. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 5000 h*ng/ml following
administration of the formulation to human subjects less than 65
years of age. In some embodiments, the formulation further
comprises a granular component and an extragranular component,
wherein the granular component comprises an intragranular component
comprising the rofecoxib and one or more disintegrants, and wherein
the extragranular component comprises one or more
disintegrants.
[0026] In some embodiments, the rofecoxib in the formulation has a
d90 particle size from about 10-12 .mu.m, a d50 particle size from
about 3-4 .mu.m, and a d10 particle size from about 0.5-1.0
.mu.m.
[0027] In certain aspects, the subject matter disclosed herein
provides a method for treating pain, fever, or inflammation in a
subject by administering a 25 mg solid dosage formulation of
rofecoxib or a pharmaceutically acceptable salt thereof, wherein a
single administration of the formulation to human subjects achieves
a mean Cmax plasma concentration of more than 240 ng/ml in less
than 3 hours following administration with a mean AUC.sub.0-.infin.
of more than 4250 h*ng/ml.
[0028] In certain aspects, the subject matter disclosed herein
provides a method for treating pain, fever, or inflammation in a
subject by administering a 17.5 mg solid dosage formulation of
rofecoxib or a pharmaceutically acceptable salt thereof.
[0029] In some embodiments, the rofecoxib formulation achieves a
median time to Cmax plasma concentration in 4 hours or less
following a single administration of the formulation to human
subjects less than 65 years of age. In some embodiments, the
rofecoxib formulation achieves a median time to Cmax plasma
concentration in 3.5 hours or less following administration. In
some embodiments, the rofecoxib formulation achieves a median time
to Cmax plasma concentration in 3 hours or less following
administration. In some embodiments, the rofecoxib formulation
achieves a median time to Cmax plasma concentration in 2.5 hours or
less following administration.
[0030] In certain aspects, the subject matter disclosed herein
provides a method for treating pain, fever, or inflammation in a
subject by administering a 17.5 mg solid dosage formulation of
rofecoxib or a pharmaceutically acceptable salt thereof, wherein a
single administration of the formulation to human subjects less
than 65 years of age achieves a mean Cmax plasma concentration of
more than 100 ng/ml.
[0031] In some embodiments, the rofecoxib formulation achieves a
mean Cmax plasma concentration of more than 150 ng/ml, 167 ng/ml,
or 190 ng/ml. In some embodiments, the rofecoxib formulation
achieves a mean Cmax plasma concentration of more than 200 ng/ml.
In some embodiments, the rofecoxib formulation achieves a mean Cmax
plasma concentration of more than 220 ng/ml. In some embodiments,
the rofecoxib formulation achieves a mean Cmax plasma concentration
of more than 250 ng/ml.
[0032] In certain aspects, the subject matter disclosed herein
provides a method for treating pain, fever, or inflammation in a
subject by administering a 17.5 mg solid dosage formulation of
rofecoxib or a pharmaceutically acceptable salt thereof, wherein a
single administration of the formulation to human subjects less
than 65 years of age achieves a mean AUC.sub.0-.infin. of more than
1750 h*ng/ml.
[0033] In some embodiments, the rofecoxib formulation achieves a
mean AUC.sub.0-.infin. of more than 2000 h*ng/ml. In some
embodiments, the rofecoxib formulation achieves a mean
AUC.sub.0-.infin. of more than 2500 h*ng/ml. In some embodiments,
the rofecoxib formulation achieves a mean AUC.sub.0-.infin. of more
than 3000 h*ng/ml. In some embodiments, the rofecoxib formulation
achieves a mean AUC.sub.0-.infin. of more than 3100 h*ng/ml. In
some embodiments, the rofecoxib formulation achieves a mean
AUC.sub.0-.infin. of more than 3500 h*ng/ml.
[0034] In certain aspects, the subject matter disclosed herein
provides a method for treating pain, fever, or inflammation in a
subject by administering a 17.5 mg solid dosage formulation of
rofecoxib or a pharmaceutically acceptable salt thereof, wherein a
single administration of the formulation to human subjects less
than 65 years of age achieves a mean Cmax plasma concentration
within 80% to 125% of 224 ng/ml.
[0035] In certain aspects, the subject matter disclosed herein
provides a method for treating pain, fever, or inflammation in a
subject by administering a 17.5 mg solid dosage formulation of
rofecoxib or a pharmaceutically acceptable salt thereof, wherein
the formulation reaches a Cmax plasma concentration of least 170
ng/ml in the subject.
[0036] In some embodiments, the formulation reaches a Cmax plasma
concentration level of at least 175 ng/ml. In some embodiments, the
formulation reaches a Cmax plasma concentration level of at least
180 ng/ml. In some embodiments, the formulation reaches a Cmax
plasma concentration level of at least 185 ng/ml. In some
embodiments, the formulation reaches a Cmax plasma concentration
level of at least 190 ng/ml.
[0037] In certain aspects, the subject matter disclosed herein
provides a method for treating pain, fever, or inflammation in a
subject by administering a 17.5 mg solid dosage formulation of
rofecoxib or a pharmaceutically acceptable salt thereof, wherein
the formulation reaches an AUC.sub.0-.infin. of more than 2600
h*ng/ml in the subject.
[0038] In some embodiments, the rofecoxib formulation reaches an
AUC.sub.0-.infin. of more than 2750 h*ng/ml. In some embodiments,
the rofecoxib formulation reaches an AUC.sub.0-.infin. of more than
2900 h*ng/ml. In some embodiments, the rofecoxib formulation
reaches an AUC.sub.0-.infin. of more than 3050 h*ng/ml. In some
embodiments, the rofecoxib formulation reaches an AUC.sub.0-.infin.
of more than 3200 h*ng/ml. In some embodiments, the rofecoxib
formulation reaches an AUC.sub.0-.infin. of more than 3350
h*ng/ml.
[0039] In certain aspects, the subject matter disclosed herein
provides a method for treating pain, fever, or inflammation in a
subject by administering a 20 mg solid dosage formulation of
rofecoxib or a pharmaceutically acceptable salt thereof.
[0040] In some embodiments, the rofecoxib formulation achieves a
median time to Cmax plasma concentration in 4 hours or less
following a single administration of the formulation to human
subjects. In some embodiments, the rofecoxib formulation achieves a
median time to Cmax plasma concentration in 3.5 hours or less
following administration. In some embodiments, the rofecoxib
formulation achieves a median time to Cmax plasma concentration in
3 hours or less following administration. In some embodiments, the
rofecoxib formulation achieves a median time to Cmax plasma
concentration in 2.5 hours or less following administration.
[0041] In certain aspects, the subject matter disclosed herein
provides a method for treating pain, fever, or inflammation in a
subject by administering a 20 mg solid dosage formulation of
rofecoxib or a pharmaceutically acceptable salt thereof, wherein a
single administration of the formulation to human subjects less
than 65 years of age achieves a mean Cmax plasma concentration of
more than 150 ng/ml.
[0042] In some embodiments, the rofecoxib formulation achieves a
mean Cmax plasma concentration of more than 191 ng/ml, 200 ng/ml,
215 ng/ml, or 225 ng/ml. In some embodiments, the rofecoxib
formulation achieves a mean Cmax plasma concentration of more than
250 ng/ml. In some embodiments, the rofecoxib formulation achieves
a mean Cmax plasma concentration of more than 258 ng/ml. In some
embodiments, the formulation achieves a mean Cmax plasma
concentration of more than 300 ng/ml.
[0043] In certain aspects, the subject matter disclosed herein
provides a method for treating pain, fever, or inflammation in a
subject by administering a 20 mg solid dosage formulation of
rofecoxib or a pharmaceutically acceptable salt thereof, wherein a
single administration of the formulation to human subjects less
than 65 years of age achieves a mean AUC.sub.0-.infin. of more than
2000 h*ng/ml.
[0044] In some embodiments, the rofecoxib formulation achieves a
mean AUC.sub.0-.infin. of more than 2500 h*ng/ml. In some
embodiments, the rofecoxib formulation achieves a mean
AUC.sub.0-.infin. of more than 3000 h*ng/ml. In some embodiments,
the rofecoxib formulation achieves a mean AUC.sub.0-.infin. of more
than 3400 h*ng/ml. In some embodiments, the rofecoxib formulation
achieves a mean AUC.sub.0-.infin. of more than 3500 h*ng/ml.
[0045] In certain aspects, the subject matter disclosed herein
provides a method for treating pain, fever, or inflammation in a
subject by administering a 20 mg solid dosage formulation of
rofecoxib or a pharmaceutically acceptable salt thereof, wherein a
single administration of the formulation to human subjects less
than 65 years of age achieves a mean Cmax plasma concentration
within 80% to 125% of 259 ng/ml.
[0046] In certain aspects, the subject matter disclosed herein
provides a method for treating pain, fever, or inflammation in a
subject by administering a 20 mg solid dosage formulation of
rofecoxib or a pharmaceutically acceptable salt thereof, wherein
the formulation reaches a Cmax plasma concentration of least 170
ng/ml in the subject.
[0047] In some embodiments, the rofecoxib formulation reaches a
Cmax plasma concentration level of at least 190 ng/ml. In some
embodiments, the rofecoxib formulation reaches a Cmax plasma
concentration level of at least 205 ng/ml. In some embodiments, the
rofecoxib formulation reaches a Cmax plasma concentration level of
at least 220 ng/ml. In some embodiments, the rofecoxib formulation
reaches a Cmax plasma concentration level of at least 235 ng/ml. In
some embodiments, the rofecoxib formulation reaches a Cmax plasma
concentration level of at least 250 ng/ml.
[0048] In certain aspects, the subject matter disclosed herein
provides a method for treating pain, fever, or inflammation in a
subject by administering a 20 mg solid dosage formulation of
rofecoxib or a pharmaceutically acceptable salt thereof, wherein
the formulation reaches an AUC.sub.0-.infin. of more than 3000
h*ng/ml in the subject.
[0049] In some embodiments, the rofecoxib formulation reaches an
AUC.sub.0-.infin. of more than 3200 h*ng/ml. In some embodiments,
the rofecoxib formulation reaches an AUC.sub.0-.infin. of more than
3300 h*ng/ml. In some embodiments, the rofecoxib formulation
reaches an AUC.sub.0-.infin. of more than 3500 h*ng/ml. In some
embodiments, the rofecoxib formulation reaches an AUC.sub.0-.infin.
of more than 3500 h*ng/ml. In some embodiments, the rofecoxib
formulation reaches an AUC.sub.0-.infin. of more than 3525 h*ng/ml.
In some embodiments, the rofecoxib formulation reaches an
AUC.sub.0-.infin. of 3550 h*ng/ml or more. In some embodiments, the
rofecoxib formulation achieves a mean Cmax plasma concentration
within 80% to 125% of 259 ng/ml and a mean AUC.sub.0-.infin. within
80% to 125% of 3550 h*ng/ml. In some embodiments, the rofecoxib
formulation achieves a mean plasma AUC.sub.0-.infin. of about
2840-4438 h*ng/ml and a mean plasma Cmax of about 207-324 ng/ml
following oral administration of a single dose of the formulation
to a population of healthy adults less than 65 years of age in a
fasted state. In some embodiments, the population of healthy adults
are less than 60 years of age.
[0050] In certain aspects, the subject matter disclosed herein
provides a pharmaceutically acceptable formulation comprising a
granular component and an extragranular component, wherein the
granular component comprises an intragranular component comprising
rofecoxib or a pharmaceutically acceptable salt thereof and one or
more disintegrants, and wherein the extragranular component
comprises one or more disintegrants.
[0051] In some embodiments, the one or more disintegrants in the
granular component is selected from starches, clays, celluloses,
algins, gums, cross-linked polymers, and combinations thereof. In
some embodiments, the one or more disintegrants in the granular
component is selected from croscarmellose, crospovidone, sodium
starch glycolate, and combinations thereof. In some embodiments,
one or more disintegrants in the granular component is
croscarmellose sodium. In some embodiments, the one or more
disintegrants in the granular component is about 1% (w/w) to about
8% (w/w) of the formulation. In some embodiments, the one or more
disintegrants in the granular component is about 1% (w/w) to about
6% (w/w) of the formulation. In some embodiments, the one or more
disintegrants in the granular component is about 1% (w/w) to about
4% (w/w) of the formulation. In some embodiments, the one or more
disintegrants in the extragranular component is selected from
starches, clays, celluloses, algins, gums, cross-linked polymers,
and combinations thereof. In some embodiments, the one or more
disintegrants in the extragranular component is selected from
croscarmellose, crospovidone, sodium starch glycolate, and
combinations thereof. In some embodiments, the one or more
disintegrants in the extragranular component is croscarmellose
sodium.
[0052] In some embodiments, the disintegrant in the extragranular
component is about 1% (w/w) to about 8% (w/w) of the formulation.
In some embodiments, the disintegrant in the extragranular
component is about 1% (w/w) to about 6% (w/w) of the formulation.
In some embodiments, the disintegrant in the extragranular
component is about 1% (w/w) to about 4% (w/w) of the formulation.
In some embodiments, the disintegrant in the granular component and
the disintegrant in the extragranular component are together about
2% (w/w) to about 12% (w/w) of the formulation. In some
embodiments, the disintegrant in the granular component and the
disintegrant in the extragranular component are together about 2%
(w/w) to about 10% (w/w) of the formulation. In some embodiments,
the disintegrant in the granular component and the disintegrant in
the extragranular component are together about 2% (w/w) to about 8%
(w/w) of the formulation. In some embodiments, the ratio of
granular disintegrant to extragranular disintegrant is about 40% to
about 60% (w/w). In some embodiments, the ratio of granular
disintegrant to extragranular disintegrant is about 45% to about
55% (w/w). In some embodiments, the ratio of granular disintegrant
to extragranular disintegrant is about 50% to about 50% (w/w). In
some embodiments, the ratio of granular disintegrant to
extragranular disintegrant is about 55% to about 45% (w/w). In some
embodiments, the ratio of granular disintegrant to extragranular
disintegrant is about 60% to about 40% (w/w).
[0053] In some embodiments, the pharmaceutically acceptable
formulation form further comprises one or more of a diluent, a
binder, a coloring agent, and a lubricant. In some embodiments, at
least a portion of the diluent is in the granular component. In
some embodiments, the diluent is selected from dicalcium phosphate,
calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium
chloride, dry starch, powdered sugar, sorbitol, sucrose, inositol,
and combinations thereof. In some embodiments, the diluent is
selected from lactose, cellulose, or a combination thereof. In some
embodiments, the diluent is selected from lactose monohydrate,
microcrystalline cellulose, or a combination thereof.
[0054] In some embodiments, the lactose monohydrate is about 35%
(w/w) to about 45% (w/w) of the formulation. In some embodiments,
the lactose monohydrate is about 37% (w/w) to about 42% (w/w) of
the formulation. In some embodiments, the lactose monohydrate is
about 39% (w/w) to about 40% (w/w) of the formulation. In some
embodiments, the microcrystalline cellulose is about 35% (w/w) to
about 45% (w/w) of the formulation. In some embodiments, the
microcrystalline cellulose is about 37% (w/w) to about 42% (w/w) of
the formulation. In some embodiments, the microcrystalline
cellulose is about 39% (w/w) to about 40% (w/w) of the formulation.
In some embodiments, the diluent is about 75% (w/w) to about 85%
(w/w) of the formulation. In some embodiments, the diluent is about
77% (w/w) to about 82% (w/w) of the formulation. In some
embodiments, the diluent is about 78% (w/w) to about 80% (w/w) of
the formulation.
[0055] In some embodiments, at least a portion of the binder is in
the granular component. In some embodiments, the binder is selected
from starches, gelatins, sugars, gums, waxes, water, alcohols,
celluloses, and combinations thereof. In some embodiments, the
binder is selected from acacia gum, tragacanth, corn starch, methyl
cellulose, panwar gum, ghatti gum, mucilage of isapol husks,
carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone,
sucrose, glucose, dextrose, molasses, lactose, and combinations
thereof. In some embodiments, the binder is hydroxypropyl
cellulose.
[0056] In some embodiments, the binder is about 1% (w/w) to about
5% (w/w) of the formulation. In some embodiments, the binder is
about 2% (w/w) to about 4% (w/w) of the formulation. In some
embodiments, the binder is about 2.5% (w/w) to about 3.5% (w/w) of
the formulation.
[0057] In some embodiments, at least a portion of the coloring
agent is in the extragranular component. In some embodiments, the
coloring agent is pigment blend yellow. In some embodiments, the
coloring agent is about 0.30% (w/w) to about 0.60% (w/w) of the
formulation.
[0058] In some embodiments, at least a portion of the lubricant is
in the extragranular component. In some embodiments, the lubricant
is selected from talc, magnesium stearate, calcium stearate,
stearic acid, metallic stearate, hydrogenated vegetable oils, and
polyethylene glycol, corn starch, boric acids, sodium chloride,
sodium lauryl sulphate. In some embodiments, the lubricant is
magnesium stearate. In some embodiments, the lubricant is about
0.10% (w/w) to about 1% (w/w) of the formulation. In some
embodiments, the lubricant is about 0.50% (w/w) of the
formulation.
[0059] In some embodiments, the rofecoxib or pharmaceutically
acceptable salt thereof is about 5% (w/w) to about 30% (w/w) of the
formulation. In some embodiments, the rofecoxib or pharmaceutically
acceptable salt thereof is about 10% (w/w) to about 20% (w/w) of
the formulation. In some embodiments, the rofecoxib or
pharmaceutically acceptable salt thereof is about 12% (w/w) to
about 13% (w/w) of the formulation.
[0060] In some embodiments, the formulation comprises about 10 mg
of the rofecoxib or pharmaceutically acceptable salt thereof. In
some embodiments, the formulation comprises about 12.5 mg of the
rofecoxib or pharmaceutically acceptable salt thereof. In some
embodiments, the formulation comprises about 17.5 mg of the
rofecoxib or pharmaceutically acceptable salt thereof. In some
embodiments, the formulation comprises about 20 mg of the rofecoxib
or pharmaceutically acceptable salt thereof. In some embodiments,
the formulation comprises about 25 mg of the rofecoxib or
pharmaceutically acceptable salt thereof.
[0061] In some embodiments, the rofecoxib is substantially pure. In
some embodiments, the rofecoxib is highly pure. In some
embodiments, the highly pure rofecoxib comprises less than about
0.1% total impurities. In some embodiments, the highly pure
rofecoxib comprises less than about 0.075% total impurities. In
some embodiments, the highly pure rofecoxib comprises less than
about 0.050% total impurities. In some embodiments, the highly pure
rofecoxib comprises less than about 0.025% total impurities. In
some embodiments, the highly pure rofecoxib comprises less than
about 0.001% total impurities.
[0062] In some embodiments, the rofecoxib is substantially pure or
highly pure. In some embodiments, the highly pure rofecoxib
comprises less than about 0.10%, 0.05%, 0.02%, or 0.01% of
4-[4-(methylsulphonyl)phenyl]-3-phenyl-2,5-furandione. In some
embodiments, the highly pure rofecoxib comprises less than about
0.10%, 0.05%, 0.02%, or 0.01% of
4-[4-(methylsulfonyl)phenyl]-3-phenyl-5-hydroxyfuran-2-one. In some
embodiments, the highly pure rofecoxib comprises less than about
0.10%, 0.05%, 0.02%, or 0.01% of
4-[4-(methylthio)phenyl]-3-phenyl-2(5H)-furanone. In some
embodiments, the highly pure rofecoxib comprises less than about
0.10%, 0.05%, 0.02%, or 0.01% of
4-[4-(methylsulfinyl)phenyl]-3-phenyl-2(5H)-furanone.
[0063] In some embodiments, the formulation is suitable for oral
administration. In some embodiments, the formulation is a solid
dosage form. In some embodiments, the solid dosage form is an oral
tablet.
[0064] In some embodiments, the oral tablet provides a dissolution
rate of at least about 80% of the rofecoxib or pharmaceutically
acceptable salt thereof by about 15 minutes. In some embodiments,
the oral tablet provides a dissolution rate of at least about 85%
of the rofecoxib or pharmaceutically acceptable salt thereof by
about 15 minutes. In some embodiments, the oral tablet provides a
dissolution rate of at least about 90% of the rofecoxib or
pharmaceutically acceptable salt thereof by about 15 minutes. In
some embodiments, the oral tablet provides a dissolution rate of at
least about 95% of the rofecoxib or pharmaceutically acceptable
salt thereof by about 15 minutes. In some embodiments, the oral
tablet provides a dissolution rate of at least about 100% of the
rofecoxib or pharmaceutically acceptable salt thereof by about 15
minutes.
[0065] In some embodiments, the dissolution rate is measured in
about 1% SDS at a paddle speed of about 50 rpm and at a temperature
of about 37.0.degree. C..+-.0.5.degree. C. In some embodiments, the
dissolution rate is measured in about 1% SDS at a paddle speed of
about 75 rpm and at a temperature of about 37.0.degree.
C..+-.0.5.degree. C. In some embodiments, the dissolution rate is
measured in about 1.5% SDS at a paddle speed of about 50 rpm and at
a temperature of about 37.0.degree. C..+-.0.5.degree. C. In some
embodiments, the dissolution rate is measured in about 1.5% SDS at
a paddle speed of about 75 rpm and at a temperature of about
37.0.degree. C..+-.0.5.degree. C. In some embodiments, the
dissolution rate is measured in about 2% SDS at a paddle speed of
about 50 rpm and at a temperature of about 37.0.degree.
C..+-.0.5.degree. C. In some embodiments, the dissolution rate is
measured in about 2% SDS at a paddle speed of about 75 rpm and at a
temperature of about 37.0.degree. C..+-.0.5.degree. C. In some
embodiments, the dissolution rate is measured using a USP Type II
apparatus. In some embodiments, the dissolution rate is measured
with a USP Type II apparatus using 900 mL of 2% SDS, a paddle speed
of 50 rpm, and a temperature of 37.0.degree. C..+-.0.5.degree..
[0066] In some embodiments, the rofecoxib or pharmaceutically
acceptable salt thereof is formulated into granules and at least
about 35% of the granules are less than about 75 .mu.m. In some
embodiments, the rofecoxib or pharmaceutically acceptable salt
thereof is formulated into granules and at least about 55% of the
granules are less than about 150 .mu.m. In some embodiments, the
rofecoxib or pharmaceutically acceptable salt thereof is formulated
into granules and at least about 75% of the granules are less than
about 250 .mu.m. In some embodiments, the rofecoxib or
pharmaceutically acceptable salt thereof is formulated into
granules and at least about 85% of the granules are less than about
425 .mu.m. In some embodiments, the rofecoxib or pharmaceutically
acceptable salt thereof is formulated into granules and at least
about 90% of the granules are less than about 1000 .mu.m.
[0067] In some embodiments, the formulation is a solid dosage
formulation comprising 12.5 mg, 17.5 mg, 20 mg, or 25 mg of
rofecoxib, and wherein the formulation reaches a median time to
Cmax plasma concentration in 3 hours or less following a single
administration of the formulation to human subjects less than 65
years of age.
[0068] In some embodiments, the formulation reaches a mean Cmax
plasma concentration in less than 3 hours following administration.
In some embodiments, the formulation reaches a mean Cmax plasma
concentration in less than 2.5 hours following administration. In
some embodiments, the formulation reaches a mean Cmax plasma
concentration in less than 2 hours following administration. In
some embodiments, the formulation is a solid dosage formulation
comprising 25 mg of rofecoxib, and wherein a single administration
of the formulation to human subjects less than 65 years of age
achieves a mean Cmax plasma concentration of more than 240 ng/ml.
In some embodiments, the formulation achieves a mean Cmax plasma
concentration of more than 300 ng/ml. In some embodiments, the
formulation achieves a mean Cmax plasma concentration of more than
320 ng/ml. In some embodiments, the formulation achieves a mean
Cmax plasma concentration of more than 350 ng/ml.
[0069] In some embodiments, the formulation is a solid dosage
formulation comprising 25 mg of rofecoxib, and wherein a single
administration of the formulation to human subjects less than 65
years of age achieves a mean AUC.sub.0-.infin. of more than 4500
h*ng/ml. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 4700 h*ng/ml. In some embodiments,
the formulation achieves a mean AUC.sub.0-.infin. of more than 5000
h*ng/ml.
[0070] In some embodiments, the formulation is a solid dosage
formulation comprising 25 mg of rofecoxib, and wherein a single
administration of the formulation in human subjects less than 65
years of age reaches a mean Cmax plasma concentration of more than
240 ng/ml in less than 3 hours following administration with a mean
AUC.sub.0-.infin. of more than 4250 h*ng/ml.
[0071] In certain aspects, the subject matter disclosed herein
provides a solid dosage formulation comprising 10 mg to 50 mg of
rofecoxib and a pharmaceutically acceptable carrier, wherein a
single administration of the formulation in human subjects less
than 65 years of age achieves a mean Cmax plasma concentration from
9.8 ng/ml to 16 ng/ml for each 1 mg of rofecoxib in the
formulation.
[0072] In some embodiments, the formulation achieves a mean Cmax
plasma concentration from 10 ng/ml to 14 ng/ml for each 1 mg of
rofecoxib in the formulation. In some embodiments, the formulation
achieves a mean Cmax plasma concentration from 10 ng/ml to 13 ng/ml
for each 1 mg of rofecoxib in the formulation. In some embodiments,
the formulation achieves a mean Cmax plasma concentration from 80%
to 125% of 12.8 ng/ml. In some embodiments, the formulation
achieves a mean Cmax plasma concentration that is bioequivalent to
12.8 ng/ml. In some embodiments, the formulation achieves a mean
Cmax plasma concentration that is 80% to 125% of 12.8 ng/ml.
[0073] In certain aspects, the subject matter disclosed herein
provides a solid dosage formulation comprising 10 mg to 50 mg of
rofecoxib and a pharmaceutically acceptable carrier, wherein a
single administration of the formulation in human subjects less
than 65 years of age achieves a mean AUC.sub.0-.infin. of 170
h*ng/ml to 235 h*ng/ml for each 1 mg of rofecoxib in the
formulation.
[0074] In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of 170 h*ng/ml to 225 h*ng/ml for each 1 mg of
rofecoxib in the formulation. In some embodiments, the formulation
achieves a mean AUC.sub.0-.infin. of 177 h*ng/ml to 225 h*ng/ml for
each 1 mg of rofecoxib in the formulation. In some embodiments, the
formulation achieves a mean AUC.sub.0-.infin. of 180 h*ng/ml to 225
h*ng/ml for each 1 mg of rofecoxib in the formulation. In some
embodiments, the formulation achieves a mean AUC.sub.0-.infin. of
190 h*ng/ml to 215 h*ng/ml for each 1 mg of rofecoxib in the
formulation.
[0075] In certain aspects, the subject matter disclosed herein
provides a method of inhibiting COX-2 in a subject by administering
the formulations described herein.
[0076] In certain aspects, the subject matter disclosed herein
provides a method of inhibiting COX-2 in a subject by administering
a solid dosage formulation comprising 17.5 mg of rofecoxib.
[0077] In some embodiments, the formulation is a solid dosage
formulation comprising 17.5 mg of rofecoxib, wherein a single
administration of the formulation to human subjects less than 65
years of age achieves a mean Cmax that is equal to or greater than
that reported by Schwartz, J. I., et al. Clin. Drug Invent. 2003,
23 (8): 503-509 for a rofecoxib 25 mg tablet. In some embodiments,
the formulation is a solid dosage formulation comprising 17.5 mg of
rofecoxib, wherein a single administration of the formulation to
human subjects less than 65 years of age achieves a mean Cmax that
is equal to or greater than that reported in the FDA-approved label
for VIOXX for a single 25-mg dose of VIOXX. In some embodiments,
the formulation is a solid dosage formulation comprising 20 mg of
rofecoxib, where a single administration of the formulation to
human subjects less than 65 years of age achieves a mean
AUC.sub.0-.infin. that is equal to or greater than that reported by
Schwartz, J. I., et al. Clin. Drug Invent. 2003, 23 (8): 503-509
for a rofecoxib 25 mg tablet. In some embodiments, the formulation
is a solid dosage formulation comprising 20 mg of rofecoxib, where
a single administration of the formulation to human subjects less
than 65 years of age achieves a mean Cmax that is equal to or
greater than that reported by Schwartz, J. I., et al. Clin. Drug
Invent. 2003, 23 (8): 503-509 for a rofecoxib 25 mg tablet. In some
embodiments, the formulation is a solid dosage formulation
comprising 20 mg of rofecoxib, wherein a single administration of
the formulation to human subjects less than 65 years of age
achieves a mean AUC.sub.0-.infin. that is equal to or greater than
that reported in the FDA-approved label for VIOXX for a single
25-mg dose of VIOXX. In some embodiments, the formulation is a
solid dosage formulation comprising 20 mg of rofecoxib, wherein a
single administration of the formulation to human subjects less
than 65 years of age achieves a mean Cmax that is equal to or
greater than that reported in the FDA-approved label for VIOXX for
a single 25-mg dose of VIOXX.
[0078] In some embodiments, the patient is age 2 or older.
[0079] In certain aspects, the subject matter disclosed herein
provides a method for treating pain, fever, or inflammation in a
patient by administering the formulations as described herein.
[0080] In some embodiments, the human subjects are healthy human
subjects. In some embodiments, the patient is age 2 or older.
[0081] In certain aspects, the subject matter disclosed herein
provides a method for treating pain, fever or inflammation in a
patient population comprising providing a solid dosage formulation
comprising 10 mg to 50 mg of rofecoxib to the patient population
for inhibiting COX-2, wherein the formulation achieves a mean Cmax
plasma concentration of between 80 to 125% of 12.8 ng/ml for each 1
mg of rofecoxib in the formulation following single administration
of the formulation in the patient population. In some embodiments,
the formulation achieves a mean Cmax plasma concentration that is
bioequivalent to 12.8 ng/ml for each 1 mg of rofecoxib in the
formulation. In some embodiments, the formulation achieves a mean
Cmax plasma concentration that is between 80 to 125% of 12.8 ng/ml
for each 1 mg of rofecoxib in the formulation.
[0082] In some embodiments, the subject matter disclosed herein
provides a formulation comprising 12.5 mg to 25 mg of rofecoxib and
a pharmaceutically acceptable carrier, wherein a single
administration of the formulation in human female subjects less
than 65 years of age achieves a mean Cmax plasma concentration that
is at least 5%, 10%, 15%, 20%, 25%, or 30% greater than that
achieved following a single administration of the formulation to
human male subjects less than 65 years of age. In some embodiments,
the subject matter disclosed herein provides a formulation
comprising 12.5 mg to 25 mg of rofecoxib and a pharmaceutically
acceptable carrier, wherein a single administration of the
formulation in human female subjects less than 65 years of age
achieves a mean AUC.sub.0-.infin. that is at least 5%, 10%, 15%,
20%, 25%, or 30% greater than that achieved following a single
administration of the formulation to human male subjects less than
65 years of age.
[0083] In some embodiments, the subject matter disclosed herein
provides a formulation comprising 12.5 mg to 25 mg of rofecoxib and
a pharmaceutically acceptable carrier, wherein a single
administration of the formulation in Caucasian subjects less than
65 years of age achieves a mean AUC.sub.0-.infin. that is greater
than that achieved following a single administration of the
formulation to African American subjects less than 65 years of age.
In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. in Caucasian subjects that is at least 1%, 2%,
5%, 9%, or 10% greater than that achieved following a single
administration of the formulation to African American subjects less
than 65 years of age.
[0084] In some embodiments, the subject matter herein provides a
solid dosage formulation comprising 12.5 mg of rofecoxib, wherein
the formulation achieves a mean plasma concentration of at least
about 0.2 ng/ml, 0.3 ng/ml, 0.4 ng/ml, or 0.5 ng/ml at 15 minutes
following single administration of the formulation to human
subjects less than 65 years of age. In some embodiments, the
subject matter herein provides a solid dosage formulation
comprising 12.5 mg of rofecoxib, wherein the formulation achieves
an arithmetic mean plasma concentration of at least about 0.8
ng/ml, 0.9 ng/ml, or 1.0 ng/ml at 15 minutes following single
administration of the formulation to human subjects less than 65
years of age. In some embodiments, the subject matter herein
provides a solid dosage formulation comprising 17.5 mg of
rofecoxib, wherein the formulation achieves a mean plasma
concentration of at least about 0.3 ng/ml, 0.4 ng/ml, 0.5 ng/ml, or
0.6 ng/ml at 15 minutes following single administration of the
formulation to human subjects less than 65 years of age. In some
embodiments, the subject matter herein provides a solid dosage
formulation comprising 17.5 mg of rofecoxib, wherein the
formulation achieves an arithmetic mean plasma concentration of at
least about 1.8 ng/ml, 2.0 ng/ml, 2.2 ng/ml, or 2.4 ng/ml at 15
minutes following single administration of the formulation to human
subjects less than 65 years of age. In some embodiments, the
subject matter herein provides a solid dosage formulation
comprising 20 mg of rofecoxib, wherein the formulation achieves a
mean plasma concentration of at least about 0.8 ng/ml, 0.9 ng/ml,
1.0 ng/ml, 1.1 ng/ml, or 1.16 ng/ml at 15 minutes following single
administration of the formulation to human subjects less than 65
years of age. In some embodiments, the subject matter herein
provides a solid dosage formulation comprising 20 mg of rofecoxib,
wherein the formulation achieves an arithmetic mean plasma
concentration of at least about 4.6 ng/ml, 5.0 ng/ml, 5.4 ng/ml, or
5.7 ng/ml at 15 minutes following single administration of the
formulation to human subjects less than 65 years of age. In some
embodiments, the subject matter herein provides a solid dosage
formulation comprising a solid dosage formulation comprising 25 mg
of rofecoxib, wherein the formulation achieves a mean plasma
concentration of at least about 1.0 ng/ml, 1.1 ng/ml, 1.2 ng/ml, or
1.3 ng/ml at 15 minutes following single administration of the
formulation to human subjects less than 65 years of age. In some
embodiments, the subject matter herein provides a solid dosage
formulation comprising a solid dosage formulation comprising 25 mg
of rofecoxib, wherein the formulation achieves an arithmetic mean
plasma concentration of at least about 4.6 ng/ml, 5.0 ng/ml, 5.4
ng/ml, or 5.6 ng/ml at 15 minutes following single administration
of the formulation to human subjects less than 65 years of age. In
some embodiments, the subject matter herein provides a solid dosage
formulation comprising 12.5 mg of rofecoxib, wherein the
formulation achieves a mean plasma concentration of at least about
27 ng/ml, 29 ng/ml, 31 ng/ml, or 33 ng/ml at 45 minutes following
single administration of the formulation to human subjects less
than 65 years of age. In some embodiments, the subject matter
herein provides a solid dosage formulation comprising 12.5 mg of
rofecoxib, wherein the formulation achieves an arithmetic mean
plasma concentration of at least about 45 ng/ml, 48 ng/ml, 51
ng/ml, 54 ng/ml, or 56 ng/ml at 45 minutes following single
administration of the formulation to human subjects less than 65
years of age. In some embodiments, the subject matter herein
provides a solid dosage formulation comprising a solid dosage
formulation comprising 17.5 mg of rofecoxib, wherein the
formulation achieves a mean plasma concentration of at least about
45 ng/ml, 47 ng/ml, 49 ng/ml, or 51 ng/ml at 45 minutes following
single administration of the formulation to human subjects less
than 65 years of age. In some embodiments, the subject matter
herein provides a solid dosage formulation comprising a solid
dosage formulation comprising 17.5 mg of rofecoxib, wherein the
formulation achieves an arithmetic mean plasma concentration of at
least about 74 ng/ml, 79 ng/ml, 84 ng/ml, 89 ng/ml, or 93 ng/ml at
45 minutes following single administration of the formulation to
human subjects less than 65 years of age. In some embodiments, the
subject matter herein provides a solid dosage formulation
comprising 20 mg of rofecoxib, wherein the formulation achieves a
mean plasma concentration of at least about 58 ng/ml, 62 ng/ml, 66
ng/ml, 70 ng/ml, or 72 ng/ml at 45 minutes following single
administration of the formulation to human subjects less than 65
years of age. In some embodiments, the subject matter herein
provides a solid dosage formulation comprising 20 mg of rofecoxib,
wherein the formulation achieves an arithmetic mean plasma
concentration of at least about 112 ng/ml, 116 ng/ml, or 121 ng/ml
at 45 minutes following single administration of the formulation to
human subjects less than 65 years of age. In some embodiments, the
subject matter herein provides a solid dosage formulation
comprising 25 mg of rofecoxib, wherein the formulation achieves a
mean plasma concentration of at least about 78 ng/ml, 85 ng/ml, 92
ng/ml, or 97 ng/ml, at 45 minutes following single administration
of the formulation to human subjects less than 65 years of age. In
some embodiments, the subject matter herein provides a solid dosage
formulation comprising 25 mg of rofecoxib, wherein the formulation
achieves an arithmetic mean plasma concentration of at least about
133 ng/ml, 139 ng/ml, 145 ng/ml, 151 ng/ml, or 159 ng/ml at 45
minutes following single administration of the formulation to human
subjects less than 65 years of age.
[0085] In some embodiments, the formulation and methods set forth
herein achieve the recited median time to Cmax, mean Cmax plasma
concentration, and mean AUC.sub.0-.infin. values following the
administration of the formulation to human subjects less than 65
years of age in a single dose pharmacokinetic study. In any of the
embodiments described herein, the human subjects may be in a
fasting state. In any of the embodiments described herein, the
human subjects may be less than 60 years of age. In any of the
embodiments described herein, the human subjects may be a
population of healthy adults less than 65 years or 60 years of
age.
BRIEF DESCRIPTION OF FIGURES
[0086] The patent application contains at least one drawing in
color.
[0087] FIGS. 1A-B show two embodiments of the composition of a
25-mg rofecoxib tablet. FIG. 1A shows the composition of a 25-mg
rofecoxib tablet in prototype batches 1-8. FIG. 1B shows the
composition of a 25-mg rofecoxib tablet.
[0088] FIG. 2 shows process conditions for Process A.sub.1-3 in
manufacturing of batches 1-4.
[0089] FIGS. 3A-B show dissolution profiles of rofecoxib tablets,
batches 1 and 2. FIG. 3A shows dissolution of rofecoxib tablets in
0.1N HCl. FIG. 3B shows dissolution of rofecoxib tablets in at
least 2% SDS.
[0090] FIGS. 4A-B show dissolution profiles of rofecoxib tablets,
batches 3 and 4. FIG. 4A shows dissolution of rofecoxib tablets in
0.1N HCl. FIG. 4B shows dissolution of rofecoxib tablets in at
least 2% SDS.
[0091] FIG. 5 shows process conditions for batches 5-8.
[0092] FIGS. 6A-B shows dissolution profiles for Process B.sub.1 in
manufacturing batches 5-8. FIG. 6A shows dissolution of rofecoxib
tablets in batches 5 and 6. FIG. 6B shows dissolution of rofecoxib
tablets in batches 7 and 8.
[0093] FIG. 7 shows dissolution profiles for batches 5 and 6
[0094] FIG. 8 shows composition of 25-mg rofecoxib tablet in
prototype batches 5-6.
[0095] FIG. 9 shows processes description for the manufacture of
prototype 25-mg rofecoxib tablets.
[0096] FIGS. 10A-B show a flow diagram for rofecoxib tablet
manufacturing Process A.sub.1. FIG. 10A shows manufacture of
rofecoxib granules. FIG. 10B shows manufacture of rofecoxib
tablets.
[0097] FIGS. 11A-B show a flow diagram for rofecoxib tablet
manufacturing Process A.sub.2. FIG. 11A shows manufacture of
rofecoxib granules. FIG. 11B shows manufacture of rofecoxib
tablets.
[0098] FIGS. 12A-B show a flow diagram for rofecoxib tablet
manufacturing Process A.sub.3. FIG. 12A shows manufacture of
rofecoxib granules. FIG. 12B shows manufacture of rofecoxib
tablets.
[0099] FIGS. 13A-B show a flow diagram for rofecoxib tablet
manufacturing Process B.sub.1. FIG. 13A shows manufacture of
rofecoxib granules. FIG. 13B shows manufacture of rofecoxib
tablets.
[0100] FIG. 14 shows granule size distribution across rofecoxib
batches.
[0101] FIGS. 15A-B show dissolution of rofecoxib tablets. FIG. 15A
shows dissolution of rofecoxib tablets in 0.1N HCl for batches 1
and 2. FIG. 15B shows dissolution of rofecoxib tablets in at least
2% SDS for batches 1 and 2.
[0102] FIGS. 16A-B show dissolution of rofecoxib tablets. FIG. 16A
shows dissolution of rofecoxib tablets in 0.1N HCl for batches 3
and 4. FIG. 16B shows dissolution of rofecoxib tablets in at least
2% SDS for batches 3 and 4.
[0103] FIG. 17 shows dissolution versus percent water used in
granulation.
[0104] FIG. 18 shows granule size distribution across rofecoxib
batches.
[0105] FIGS. 19A-B show dissolution of rofecoxib tablets. FIG. 19A
shows dissolution of rofecoxib tablets in at least 2% SDS for
batches 5 and 6. FIG. 19B shows dissolution of rofecoxib tablets in
at least 2% SDS for batches 7 and 8.
[0106] FIGS. 20A-B show dissolution of rofecoxib tablets. FIG. 20A
shows dissolution of rofecoxib tablets in at least 2% SDS for
batches 5 and 6. FIG. 20B shows dissolution of rofecoxib tablets in
at least 2% SDS for batches 5 and 6.
[0107] FIG. 21 shows granule size distribution across rofecoxib
batches.
[0108] FIGS. 22A-B show dissolution of rofecoxib tablets. FIG. 22A
shows dissolution of rofecoxib tablets in at least 2% SDS for
batches 5 and 6 at 75 rpm. FIG. 22B shows dissolution of rofecoxib
tablets in at least 2% SDS for batches 5 and 6 at 50 rpm.
[0109] FIGS. 23A-B show dissolution of rofecoxib tablets. FIG. 23A
shows dissolution of rofecoxib tablets in 1.5% SDS for batches 5
and 6 at 75 rpm. FIG. 23B shows dissolution of rofecoxib tablets in
1.5% SDS for batches 5 and 6 at 50 rpm.
[0110] FIGS. 24A-B show dissolution of rofecoxib tablets. FIG. 24A
shows dissolution of rofecoxib tablets in 1.0% SDS for batches 5
and 6 at 75 rpm. FIG. 24B shows dissolution of rofecoxib tablets in
1.0% SDS for batches 5 and 6 at 50 rpm.
[0111] FIG. 25 shows a summary of fasted AUC.sub.0-.infin. and
C.sub.max in the PK 101 (Example 4) pharmacokinetic study.
[0112] FIG. 26 shows a summary of treatment-emergent adverse events
(101 study only).
[0113] FIG. 27 shows mean fasted concentration versus scheduled
time (101 study only).
[0114] FIG. 28 shows an analysis of AUC.sub.0-.infin. and C.sub.max
compared to historical data (101 study only).
[0115] FIG. 29 shows a scatterplot of AUC.sub.0-.infin. by age (101
study only).
[0116] FIG. 30 shows a scatterplot of Cmax by age (101 study
only).
[0117] FIG. 31 shows extrapolated pharmacokinetic AUC and Cmax
values for dosages other than 25 mg of rofecoxib.
[0118] FIG. 32 shows a summary of subject disposition for all
screened subjects (102 study only).
[0119] FIG. 33 shows demographic and baseline
characteristics--safety (102 study only).
[0120] FIG. 34 shows demographic and baseline
characteristics--safety, BMI (102 study only).
[0121] FIG. 35 shows demographic and baseline characteristics--PK
(102 study only).
[0122] FIG. 36 shows demographic and baseline characteristics--PK,
BMI (102 study only).
[0123] FIG. 37 shows a summary of fasted plasma rofecoxib
concentration (ng/mL)--PK, time points 0.00, 0.25, 0.5 hr (102
study only).
[0124] FIG. 38 shows a summary of fasted plasma rofecoxib
concentration (ng/mL)--PK, time points 0.75, 1, 1.5 hr (102 study
only).
[0125] FIG. 39 shows a summary of fasted plasma rofecoxib
concentration (ng/mL)--PK, time points 2, 3, 4 hr (102 study
only).
[0126] FIG. 40 shows a summary of fasted plasma rofecoxib
concentration (ng/mL)--PK, time points 5, 6, 7.5 hr (102 study
only).
[0127] FIG. 41 shows a summary of fasted plasma rofecoxib
concentration (ng/mL)--PK, time points 9, 12, 15 hr (102 study
only).
[0128] FIG. 42 shows a summary of fasted plasma rofecoxib
concentration (ng/mL)--PK, time points 18, 21, 24 hr (102 study
only).
[0129] FIG. 43 shows a summary of fasted plasma rofecoxib
concentration (ng/mL)--PK, time points 27, 30, 33 hr (102 study
only).
[0130] FIG. 44 shows a summary of fasted plasma rofecoxib
concentration (ng/mL)--PK, time points 36, 39, 42 hr (102 study
only).
[0131] FIG. 45 shows a summary of fasted plasma rofecoxib
concentration (ng/mL)--PK, time points 48, 52, 60 hr (102 study
only).
[0132] FIG. 46 shows a summary of fasted plasma rofecoxib
concentration (ng/mL)--PK, time points 72, 96, 120 hr (102 study
only).
[0133] FIG. 47 shows a summary of fasted AUC.sub.0-.infin. and
C.sub.max (101 and 102 studies)--PK.
[0134] FIG. 48 shows a summary of fasted AUC.sub.0-.infin. (102
study only)--PK.
[0135] FIG. 49 shows a summary of fasted C.sub.max (102 study
only)--PK.
[0136] FIG. 50 shows a summary of fasted AUC.sub.0-.infin. and
C.sub.max by gender (102 study only)--12.5 mg PK.
[0137] FIG. 51 shows a summary of fasted AUC.sub.0-.infin. and
C.sub.max by gender (102 study only)--17.5 mg PK.
[0138] FIG. 52 shows a summary of fasted AUC.sub.0-.infin. and
C.sub.max by gender (102 study only)--20 mg PK.
[0139] FIG. 53 shows a summary of fasted AUC.sub.0-.infin. and
C.sub.max by gender (102 study only)--25 mg PK.
[0140] FIG. 54 shows a summary of fasted AUC.sub.0-.infin. and
C.sub.max by age (102 study only)--12.5 mg PK.
[0141] FIG. 55 shows a summary of fasted AUC.sub.0-.infin. and
C.sub.max by age (102 study only)--17.5 mg PK.
[0142] FIG. 56 shows a summary of fasted AUC.sub.0-.infin. and
C.sub.max by age (102 study only)--20 mg PK.
[0143] FIG. 57 shows a summary of fasted AUC.sub.0-.infin. and
C.sub.max by age (102 study only)--25 mg PK.
[0144] FIG. 58 shows a summary of fasted AUC.sub.0-.infin. and
C.sub.max by race (102 study only)--12.5 mg PK.
[0145] FIG. 59 shows a summary of fasted AUC.sub.0-.infin. and
C.sub.max by race (102 study only)--17.5 mg PK.
[0146] FIG. 60 shows a summary of fasted AUC.sub.0-.infin. and
C.sub.max by race (102 study only)--20 mg PK.
[0147] FIG. 61 shows a summary of fasted AUC.sub.0-.infin. and
C.sub.max by race (102 study only)--25 mg PK.
[0148] FIG. 62 shows a summary of fasted AUC.sub.0-.infin. and
C.sub.max by body weight (102 study only)--12.5 mg PK.
[0149] FIG. 63 shows a summary of fasted AUC.sub.0-.infin. and
C.sub.max by body weight (102 study only)--17.5 mg PK.
[0150] FIG. 64 shows a summary of fasted AUC.sub.0-.infin. and
C.sub.max by body weight (102 study only)--20 mg PK.
[0151] FIG. 65 shows a summary of fasted AUC.sub.0-.infin. and
C.sub.max by body weight (102 study only)--25 mg PK.
[0152] FIG. 66 shows a summary of fasted AUC.sub.0-.infin. and
C.sub.max by ethnicity (102 study only)--12.5 mg PK.
[0153] FIG. 67 shows a summary of fasted AUC.sub.0-.infin. and
C.sub.max by ethnicity (102 study only)--17.5 mg PK.
[0154] FIG. 68 shows a summary of fasted AUC.sub.0-.infin. and
C.sub.max by ethnicity (102 study only)--20 mg PK.
[0155] FIG. 69 shows a summary of fasted AUC.sub.0-.infin. and
C.sub.max by ethnicity (102 study only)--25 mg PK.
[0156] FIG. 70 shows a sensitivity analysis of fasted
AUC.sub.0-.infin. and C.sub.max compared to historical data--PK
(102 study only).
[0157] FIG. 71 shows a summary of fasted T.sub.max and t.sub.1/2
(101 and 102 studies combined)--PK.
[0158] FIG. 72 shows a summary of fasted CL/F and V.sub.d/F (102
study only)--PK.
[0159] FIG. 73 shows an exploratory analysis of fasted
AUC.sub.0-.infin. and C.sub.max to estimate the dose that yields
values equal to those observed in the historical data (102 study
only)--PK.
[0160] FIG. 74 shows a summary of treatment-emergent adverse
events--safety (102 study only).
[0161] FIG. 75 shows incidence of treatment-emergent adverse events
by system organ class and preferred term--safety (102 study
only).
[0162] FIG. 76 shows incidence of related treatment-emergent
adverse events by system organ class and preferred term--safety
(102 study only).
[0163] FIG. 77 shows incidence of serious treatment-emergent
adverse events by system organ class and preferred term--safety
(102 study only).
[0164] FIG. 78 shows incidence of treatment adverse events leading
to study discontinuation by system organ class and preferred term
(102 study only).
[0165] FIG. 79 shows incidence of treatment-emergent adverse events
by system organ class, preferred term, and severity--safety (102
study only).
[0166] FIG. 80 shows arithmetic mean (SD) fasted concentration
versus scheduled time profiles on the linear scale (102 study
only).
[0167] FIG. 81 shows TRM-201 12.5 mg arithmetic mean (SD) fasted
concentration versus scheduled time profiles on the linear scale
(102 study only).
[0168] FIG. 82 shows TRM-201 17.5 mg arithmetic mean (SD) fasted
concentration versus scheduled time profiles on the linear scale
(102 study only).
[0169] FIG. 83 shows TRM-201 20 mg arithmetic mean (SD) fasted
concentration versus scheduled time profiles on the linear scale
(102 study only).
[0170] FIG. 84 shows TRM-201 25 mg arithmetic mean (SD) fasted
concentration versus scheduled time profiles on the linear scale
(102 study only).
[0171] FIG. 85 shows arithmetic mean fasted concentration versus
scheduled time profiles on the linear scale (102 study only).
[0172] FIG. 86 shows geometric mean (SD) fasted concentration
versus scheduled time profile on the semi-logarithmic scale (102
study only).
[0173] FIG. 87 shows TRM-201 12.5 mg geometric mean (SD) fasted
concentration versus scheduled time profiles on the
semi-logarithmic scale (102 study only).
[0174] FIG. 88 shows TRM-201 17.5 mg geometric mean (SD) fasted
concentration versus scheduled time profiles on the
semi-logarithmic scale (102 study only).
[0175] FIG. 89 shows TRM-201 20 mg geometric mean (SD) fasted
concentration versus scheduled time profiles on the
semi-logarithmic scale (102 study only).
[0176] FIG. 90 shows TRM-201 25 mg geometric mean (SD) fasted
concentration versus scheduled time profiles on the
semi-logarithmic scale (102 study only).
[0177] FIG. 91 shows geometric mean fasted concentration versus
scheduled time profiles on the semi-logarithmic scale (102 study
only).
[0178] FIG. 92 shows a scatterplot of fasted AUC.sub.0-.infin. by
age (102 study only).
[0179] FIG. 93 shows a scatterplot of fasted AUC.sub.0-.infin. by
race (102 study only).
[0180] FIG. 94 shows a scatterplot of fasted AUC.sub.0-.infin. by
body weight (102 study only).
[0181] FIG. 95 shows a scatterplot of fasted AUC.sub.0-.infin. by
BMI (102 study only).
[0182] FIG. 96 shows a scatterplot of fasted C.sub.max by age (102
study only).
[0183] FIG. 97 shows a scatterplot of fasted C.sub.max by race (102
study only).
[0184] FIG. 98 shows a scatterplot of fasted C.sub.max by body
weight (102 study only).
[0185] FIG. 99 shows a scatterplot of fasted C.sub.max by BMI (102
study only).
[0186] FIG. 100 shows a scatterplot of fasted AUC.sub.0-.infin. and
C.sub.max (dose-adjusted on raw scale) (102 study only).
[0187] FIG. 101 shows a scatterplot of fasted AUC.sub.0-.infin. and
C.sub.max (not dose-adjusted on natural-log scale) (102 study
only).
[0188] FIGS. 102A-B show a boxplot of fasted AUC.sub.0-.infin. and
Cmax, respectively.
[0189] FIG. 103 shows a comparison of the mean plasma concentration
(ng/L) versus time for TRM-201 20 mg and the 25 mg "VIOXX" tablet
and oral suspension reported in Schwartz, J. I., et al. Clin. Drug
Invent. 2003, 23 (8): 503-509.
[0190] FIG. 104 shows a comparison of the mean plasma concentration
(ng/L) versus time for TRM-201 20 mg and the 25 mg "VIOXX" tablet
reported in Schwartz, J. I., et al. Clin. Drug Invent. 2003, 23
(8): 503-509.
DETAILED DESCRIPTION
Definitions
[0191] The following are definitions of terms used in the present
specification. The initial definition provided for a group or term
herein applies to that group or term throughout the present
specification individually or as part of another group, unless
otherwise indicated. Unless otherwise defined, all technical and
scientific terms used herein have the same meaning as commonly
understood by one of ordinary skill in the art.
[0192] As used herein, "dissolution rate" refers to the proportion
of drug which enters a solution in a given amount of time.
[0193] As used herein, "rofecoxib" refers to the active ingredient
4-[4-(methylsulfonyl)phenyl]-3-phenyl-2(5H)-furanone or a
pharmaceutically acceptable salt, solvate, or co-crystal thereof.
The rofecoxib as described herein may be in amorphous or
crystalline form. The purity of rofecoxib is determined as a
percent (%) area basis, typically as quantified by analytical
chromatography, such as using HPLC, UHPLC or UPLC.
[0194] In some embodiments, the highly pure rofecoxib comprises
less than or equal to about 0.10%, 0.075%, 0.050%, 0.025%, 0.020%,
or 0.001% area basis total impurities. In some embodiments, the
highly pure rofecoxib comprises less than about 0.10%, 0.05%,
0.02%, or 0.01% of
4-[4-(methylsulphonyl)phenyl]-3-phenyl-2,5-furandione. In some
embodiments, the highly pure rofecoxib comprises less than about
0.10%, 0.05%, 0.02%, or 0.01% of
4-[4-(methylthio)phenyl]-3-phenyl-2(5H)-furanone. In some
embodiments, the highly pure rofecoxib comprises less than about
0.10%, 0.05%, 0.02%, or 0.01% of
4-[4-(methylthio)phenyl]-3-phenyl-2(5H)-furanone. In some
embodiments, the highly pure rofecoxib comprises less than about
0.10%, 0.05%, 0.02%, or 0.01% of
4-[4-(methylsulfinyl)phenyl]-3-phenyl-2(5H)-furanone.
[0195] As used herein, "highly pure" means, with respect to an
active ingredient, having less than or equal to about 0.10% area
basis total impurities.
[0196] As used herein, "substantially pure" means, with respect to
an active ingredient, having less than or equal to about 0.50% area
basis total impurities.
[0197] As used herein, "essentially free" means, with respect to an
impurity, having less than about 0.10% area basis of the
impurity.
[0198] As used herein, "free of" means, with respect to an impurity
having an amount of the impurity that is below the limitation of
detection i.e. less than 0.02% area basis of the impurity.
[0199] The term "disintegrant" as used herein includes auxiliary
agents which promote the disintegration of tablets or granulates.
upon contact with liquids.
[0200] The singular forms "a", "an" and "the" include plural
reference unless the context clearly dictates otherwise. The use of
the word "a" or "an" when used in conjunction with the term
"comprising" in the claims and/or the specification may mean "one,"
but it is also consistent with the meaning of "one or more," "at
least one," and "one or more than one."
[0201] As used herein the term "about" is used herein to mean
approximately, roughly, around, or in the region of. When the term
"about" is used in conjunction with a numerical range, it modifies
that range by extending the boundaries above and below the
numerical values set forth. In general, the term "about" is used
herein to modify a numerical value above and below the stated value
by a variance of 20 percent up or down (higher or lower).
[0202] The term "pharmaceutically acceptable salt," as used herein,
refers to the relatively non-toxic, inorganic and organic acid
salts of compounds of the subject matter described herein.
[0203] As used herein, the term "subject" refers to a vertebrate
animal. In one embodiment, the subject is a mammal or a mammalian
species. In one embodiment, the subject is a human. In one
embodiment, the subject is a healthy human adult. In other
embodiments, the subject is a non-human vertebrate animal,
including, without limitation, non-human primates, laboratory
animals, livestock, racehorses, domesticated animals, and
non-domesticated animals. In one embodiment, the term "human
subjects" means a population of healthy human adults. In one
embodiment, the subject is a human that is not hepatically
impaired.
[0204] As used herein, the term "patient" refers to a human or
animal.
[0205] The term "mammal" includes, but is not limited to, a human,
mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human
primate, such as a monkey, chimpanzee, baboon or rhesus. In one
embodiment, the mammal is a human.
[0206] As used herein, the term "effective amount" means an amount
of a pharmaceutically active compound, i.e. a drug active, e.g. a
quinolone carboxylic acid antimicrobial agent or pharmaceutically
acceptable salt or ester thereof, given to a recipient patient
sufficient to elicit biological activity, for example,
anti-infective activity, e.g., anti-microbial activity.
[0207] As used herein, the term "a mean" refers to a geometric mean
unless expressly indicated otherwise. The pharmacokinetic
parameters such as "a mean Cmax" or "a mean AUC" refers to the
geometric mean value of a Cmax or an AUC, unless expressly
indicated otherwise.
[0208] The expression "bioequivalent" or "bioequivalence" is a term
of art and is intended to be defined in accordance with 21 C.F.R.
.sctn. 320.1 and prevailing guidelines from the FDA. Bioequivalence
of different formulation of the same drug substance involves
equivalence with respect to the rate and extent of drug absorption.
The extent and rate of absorption of the test formulation is
compared to a reference formulation in order to determine whether
the two formulations are bioequivalent. In practice, two products
are considered bioequivalent if the 90% confidence interval of the
ratio of a log-transformed exposure measure (AUC and/or Cmax) falls
completely within the range 80-125%.
Compositions of the Present Subject Matter
[0209] In certain aspects, the subject matter disclosed herein
provides a solid dosage formulation comprising 17.5 mg of rofecoxib
and a pharmaceutically acceptable carrier.
[0210] In some embodiments, the rofecoxib formulation reaches a
median time to Cmax plasma concentration in 4 hours or less
following a single administration of the formulation to human
subjects less than 65 years of age. In some embodiments, the
rofecoxib formulation reaches a median time to Cmax plasma
concentration in 3.5 hours or less following a single
administration of the formulation to human subjects less than 65
years of age. In some embodiments, the rofecoxib formulation
reaches a median time to Cmax plasma concentration in 3 hours or
less following a single administration of the formulation to human
subjects less than 65 years of age. In some embodiments, the
rofecoxib formulation reaches a median time to Cmax plasma
concentration in 2.5 hours or less following a single
administration of the formulation to human subjects less than 65
years of age.
[0211] In certain aspects, the subject matter disclosed herein
provides a solid dosage formulation comprising 17.5 mg of rofecoxib
and a pharmaceutically acceptable carrier, wherein the formulation
achieves a mean Cmax plasma concentration of more than 100 ng/ml
following a single administration of the formulation to human
subjects less than 65 years of age.
[0212] In some embodiments, the rofecoxib formulation achieves a
mean Cmax plasma concentration of more than 150 ng/ml, 167 ng/ml,
or 190 ng/ml. In some embodiments, the rofecoxib formulation
achieves a mean Cmax plasma concentration of more than 200 ng/ml.
In some embodiments, the rofecoxib formulation achieves a mean Cmax
plasma concentration of more than 220 ng/ml. In some embodiments,
the rofecoxib formulation achieves a mean Cmax plasma concentration
of more than 250 ng/ml.
[0213] In certain aspects, the subject matter disclosed herein
provides a solid dosage formulation comprising 17.5 mg of rofecoxib
and a pharmaceutically acceptable carrier, wherein the formulation
achieves a mean AUC.sub.0-.infin. of more than 1750 h*ng/ml
following a single administration of the formulation to human
subjects less than 65 years of age.
[0214] In some embodiments, the rofecoxib formulation achieves a
mean AUC.sub.0-.infin. of more than 2000 h*ng/ml following a single
administration of the formulation to human subjects less than 65
years of age. In some embodiments, the rofecoxib formulation
achieves a mean AUC.sub.0-.infin. of more than 2500 h*ng/ml
following a single administration of the formulation to human
subjects less than 65 years of age. In some embodiments, the
rofecoxib formulation achieves a mean AUC.sub.0-.infin. of more
than 3000 h*ng/ml following a single administration of the
formulation to human subjects less than 65 years of age. In some
embodiments, the rofecoxib formulation achieves a mean
AUC.sub.0-.infin. of more than 3100 h*ng/ml following a single
administration of the formulation to human subjects less than 65
years of age. In some embodiments, the rofecoxib formulation
achieves a mean AUC.sub.0-.infin. of more than 3500 h*ng/ml
following a single administration of the formulation to human
subjects less than 65 years of age.
[0215] In some embodiments, the rofecoxib formulation further
comprises a granular component and an extragranular component,
wherein the granular component comprises an intragranular component
comprising the rofecoxib and one or more disintegrants, and wherein
the extragranular component comprises one or more disintegrants. In
some embodiments, the rofecoxib in the formulation has a d90
particle size from about 10-12 .mu.m, a d50 particle size from
about 3-4 .mu.m, and a d10 particle size from about 0.5-1.0
.mu.m.
[0216] In certain aspects, the subject matter disclosed herein
provides a solid dosage formulation comprising 20 mg of rofecoxib
and a pharmaceutically acceptable carrier.
[0217] In some embodiments, the formulation reaches a median time
to Cmax plasma concentration in 4 hours or less following a single
administration of the formulation to human subjects less than 65
years of age. In some embodiments, the formulation reaches a median
time to Cmax plasma concentration in 3 hours or less following
administration. In some embodiments, the formulation reaches a mean
Cmax plasma concentration in less than 3 hours following
administration. In some embodiments, the formulation reaches a
median time to Cmax plasma concentration in 2.5 hours or less
following administration.
[0218] In certain aspects, the subject matter disclosed herein
provides a solid dosage formulation comprising 20 mg of rofecoxib
and a pharmaceutically acceptable carrier, wherein the formulation
achieves a mean Cmax plasma concentration of more than 150 ng/ml
following a single administration of the formulation to human
subjects less than 65 years of age.
[0219] In some embodiments, the rofecoxib formulation achieves a
mean Cmax plasma concentration of more than 191 ng/ml, 200 ng/ml,
215 ng/ml, or 225 ng/ml following a single administration of the
formulation to human subjects less than 65 years of age. In some
embodiments, the rofecoxib formulation achieves a mean Cmax plasma
concentration of more than 250 ng/ml following a single
administration of the formulation to human subjects less than 65
years of age. In some embodiments, the rofecoxib formulation
achieves a mean Cmax plasma concentration of more than 258 ng/ml
following a single administration of the formulation to human
subjects less than 65 years of age. In some embodiments, the
rofecoxib formulation achieves a mean Cmax plasma concentration of
more than 300 ng/ml following a single administration of the
formulation to human subjects less than 65 years of age.
[0220] In certain aspects, the subject matter disclosed herein
provides a solid dosage formulation comprising 20 mg of rofecoxib
and a pharmaceutically acceptable carrier, wherein the formulation
achieves a mean AUC.sub.0-.infin. of more than 2000 h*ng/ml
following a single administration of the formulation to human
subjects less than 65 years of age.
[0221] In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 2500 h*ng/ml following a single
administration of the formulation to human subjects less than 65
years of age. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 3000 h*ng/ml following a single
administration of the formulation to human subjects less than 65
years of age. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 3400 h*ng/ml following a single
administration of the formulation to human subjects less than 65
years of age. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 3500 h*ng/ml following a single
administration of the formulation to human subjects less than 65
years of age. In some embodiments, the rofecoxib formulation
achieves a mean Cmax plasma concentration within 80% to 125% of 259
ng/ml and a mean AUC.sub.0-.infin. within 80% to 125% of 3550
h*ng/ml. In some embodiments, the rofecoxib formulation achieves a
mean plasma AUC.sub.0-.infin. of about 2840-4438 h*ng/ml and a mean
plasma Cmax of about 207-324 ng/ml following oral administration of
a single dose of the formulation to a population of healthy adults
less than 65 years of age in a fasted state. In some embodiments,
the population of healthy adults are less than 60 years of age.
[0222] In some embodiments, the formulation further comprises a
granular component and an extragranular component, wherein the
granular component comprises an intragranular component comprising
the rofecoxib and one or more disintegrants, and wherein the
extragranular component comprises one or more disintegrants. In
some embodiments, the rofecoxib in the formulation has a d90
particle size from about 10-12 .mu.m, a d50 particle size from
about 3-4 .mu.m, and a d10 particle size from about 0.5-1.0
.mu.m.
[0223] In certain aspects, the subject matter disclosed herein
provides a method for treating pain, fever, or inflammation in a
subject by administering a 25 mg solid dosage formulation of
rofecoxib or a pharmaceutically acceptable salt thereof, wherein
the formulation achieves a mean Cmax plasma concentration in less
than 3 hours following a single administration of the formulation
to human subjects less than 65 years of age.
[0224] In some embodiments, the rofecoxib formulation achieves a
median time to Cmax plasma concentration in 2.5 hours or less
following administration of the formulation to human subjects less
than 65 years of age.
[0225] In certain aspects, the subject matter disclosed herein
provides a method for treating pain, fever, or inflammation in a
subject by administering a 25 mg solid dosage formulation of
rofecoxib or a pharmaceutically acceptable salt thereof, wherein
the formulation achieves a mean Cmax plasma concentration of more
than 250 ng/ml following a single administration of the formulation
to human subjects less than 65 years of age.
[0226] In some embodiments, the formulation achieves a mean Cmax
plasma concentration of more than 300 ng/ml following
administration of the formulation to human subjects less than 65
years of age. In some embodiments, the formulation achieves a mean
Cmax plasma concentration of more than 320 ng/ml following
administration of the formulation to human subjects less than 65
years of age. In some embodiments, the formulation achieves a mean
Cmax plasma concentration of more than 350 ng/ml following
administration of the formulation to human subjects less than 65
years of age.
[0227] In certain aspects, the subject matter disclosed herein
provides a method for treating pain, fever, or inflammation in a
subject by administering a 25 mg solid dosage formulation of
rofecoxib or a pharmaceutically acceptable salt thereof, wherein
the formulation achieves a mean AUC.sub.0-.infin. of more than 4250
h*ng/ml following a single administration of the formulation to
human subjects less than 65 years of age.
[0228] In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 4500 h*ng/ml following
administration of the formulation to human subjects less than 65
years of age. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 4700 h*ng/ml following
administration of the formulation to human subjects less than 65
years of age. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 5000 h*ng/ml following
administration of the formulation to human subjects less than 65
years of age. In some embodiments, the formulation further
comprises a granular component and an extragranular component,
wherein the granular component comprises an intragranular component
comprising the rofecoxib and one or more disintegrants, and wherein
the extragranular component comprises one or more
disintegrants.
[0229] In some embodiments, the rofecoxib in the formulation has a
d90 particle size from about 10-12 .mu.m, a d50 particle size from
about 3-4 .mu.m, and a d10 particle size from about 0.5-1.0
.mu.m.
[0230] In certain aspects, the subject matter disclosed herein
provides a method for treating pain, fever, or inflammation in a
subject by administering a 25 mg solid dosage formulation of
rofecoxib or a pharmaceutically acceptable salt thereof, wherein a
single administration of the formulation to human subjects achieves
a mean Cmax plasma concentration of more than 240 ng/ml in less
than 3 hours following administration with a mean AUC.sub.0-.infin.
of more than 4250 h*ng/ml.
[0231] In certain aspects, the subject matter disclosed herein
provides a method for treating pain, fever, or inflammation in a
subject by administering a 17.5 mg solid dosage formulation of
rofecoxib or a pharmaceutically acceptable salt thereof.
[0232] In some embodiments, the rofecoxib formulation achieves a
median time to Cmax plasma concentration in 4 hours or less
following a single administration of the formulation to human
subjects less than 65 years of age. In some embodiments, the
rofecoxib formulation achieves a median time to Cmax plasma
concentration in 3.5 hours or less following administration. In
some embodiments, the rofecoxib formulation achieves a median time
to Cmax plasma concentration in 3 hours or less following
administration. In some embodiments, the rofecoxib formulation
achieves a median time to Cmax plasma concentration in 2.5 hours or
less following administration.
[0233] In certain aspects, the subject matter disclosed herein
provides a method for treating pain, fever, or inflammation in a
subject by administering a 17.5 mg solid dosage formulation of
rofecoxib or a pharmaceutically acceptable salt thereof, wherein a
single administration of the formulation to human subjects less
than 65 years of age achieves a mean Cmax plasma concentration of
more than 100 ng/ml.
[0234] In some embodiments, the rofecoxib formulation achieves a
mean Cmax plasma concentration of more than 150 ng/ml, 167 ng/ml,
or 190 ng/ml. In some embodiments, the rofecoxib formulation
achieves a mean Cmax plasma concentration of more than 200 ng/ml.
In some embodiments, the rofecoxib formulation achieves a mean Cmax
plasma concentration of more than 220 ng/ml. In some embodiments,
the rofecoxib formulation achieves a mean Cmax plasma concentration
of more than 250 ng/ml.
[0235] In certain aspects, the subject matter disclosed herein
provides a method for treating pain, fever, or inflammation in a
subject by administering a 17.5 mg solid dosage formulation of
rofecoxib or a pharmaceutically acceptable salt thereof, wherein a
single administration of the formulation to human subjects less
than 65 years of age achieves a mean AUC.sub.0-.infin. of more than
1750 h*ng/ml.
[0236] In some embodiments, the rofecoxib formulation achieves a
mean AUC.sub.0-.infin. of more than 2000 h*ng/ml. In some
embodiments, the rofecoxib formulation achieves a mean
AUC.sub.0-.infin. of more than 2500 h*ng/ml. In some embodiments,
the rofecoxib formulation achieves a mean AUC.sub.0-.infin. of more
than 3000 h*ng/ml. In some embodiments, the rofecoxib formulation
achieves a mean AUC.sub.0-.infin. of more than 3100 h*ng/ml. In
some embodiments, the rofecoxib formulation achieves a mean
AUC.sub.0-.infin. of more than 3500 h*ng/ml.
[0237] In certain aspects, the subject matter disclosed herein
provides a method for treating pain, fever, or inflammation in a
subject by administering a 17.5 mg solid dosage formulation of
rofecoxib or a pharmaceutically acceptable salt thereof, wherein a
single administration of the formulation to human subjects less
than 65 years of age achieves a mean Cmax plasma concentration
within 80% to 125% of 224 ng/ml.
[0238] In certain aspects, the subject matter disclosed herein
provides a method for treating pain, fever, or inflammation in a
subject by administering a 17.5 mg solid dosage formulation of
rofecoxib or a pharmaceutically acceptable salt thereof, wherein
the formulation reaches a Cmax plasma concentration of least 170
ng/ml in the subject.
[0239] In some embodiments, the formulation reaches a Cmax plasma
concentration level of at least 175 ng/ml. In some embodiments, the
formulation reaches a Cmax plasma concentration level of at least
180 ng/ml. In some embodiments, the formulation reaches a Cmax
plasma concentration level of at least 185 ng/ml. In some
embodiments, the formulation reaches a Cmax plasma concentration
level of at least 190 ng/ml.
[0240] In certain aspects, the subject matter disclosed herein
provides a method for treating pain, fever, or inflammation in a
subject by administering a 17.5 mg solid dosage formulation of
rofecoxib or a pharmaceutically acceptable salt thereof, wherein
the formulation reaches an AUC.sub.0-.infin. of more than 2600
h*ng/ml in the subject.
[0241] In some embodiments, the rofecoxib formulation reaches an
AUC.sub.0-.infin. of more than 2750 h*ng/ml. In some embodiments,
the rofecoxib formulation reaches an AUC.sub.0-.infin. of more than
2900 h*ng/ml. In some embodiments, the rofecoxib formulation
reaches an AUC.sub.0-.infin. of more than 3050 h*ng/ml. In some
embodiments, the rofecoxib formulation reaches an AUC.sub.0-.infin.
of more than 3200 h*ng/ml. In some embodiments, the rofecoxib
formulation reaches an AUC.sub.0-.infin. of more than 3350
h*ng/ml.
[0242] In certain aspects, the subject matter disclosed herein
provides a method for treating pain, fever, or inflammation in a
subject by administering a 20 mg solid dosage formulation of
rofecoxib or a pharmaceutically acceptable salt thereof.
[0243] In some embodiments, the rofecoxib formulation achieves a
median time to Cmax plasma concentration in 4 hours or less
following a single administration of the formulation to human
subjects. In some embodiments, the rofecoxib formulation achieves a
median time to Cmax plasma concentration in 3.5 hours or less
following administration. In some embodiments, the rofecoxib
formulation achieves a median time to Cmax plasma concentration in
3 hours or less following administration. In some embodiments, the
rofecoxib formulation achieves a median time to Cmax plasma
concentration in 2.5 hours or less following administration.
[0244] In certain aspects, the subject matter disclosed herein
provides a method for treating pain, fever, or inflammation in a
subject by administering a 20 mg solid dosage formulation of
rofecoxib or a pharmaceutically acceptable salt thereof, wherein a
single administration of the formulation to human subjects less
than 65 years of age achieves a mean Cmax plasma concentration of
more than 150 ng/ml.
[0245] In some embodiments, the rofecoxib formulation achieves a
mean Cmax plasma concentration of more than 191 ng/ml, 200 ng/ml,
215 ng/ml, or 225 ng/ml. In some embodiments, the rofecoxib
formulation achieves a mean Cmax plasma concentration of more than
250 ng/ml. In some embodiments, the rofecoxib formulation achieves
a mean Cmax plasma concentration of more than 258 ng/ml. In some
embodiments, the formulation achieves a mean Cmax plasma
concentration of more than 300 ng/ml.
[0246] In certain aspects, the subject matter disclosed herein
provides a method for treating pain, fever, or inflammation in a
subject by administering a 20 mg solid dosage formulation of
rofecoxib or a pharmaceutically acceptable salt thereof, wherein a
single administration of the formulation to human subjects less
than 65 years of age achieves a mean AUC.sub.0-.infin. of more than
2000 h*ng/ml.
[0247] In some embodiments, the rofecoxib formulation achieves a
mean AUC.sub.0-.infin. of more than 2500 h*ng/ml. In some
embodiments, the rofecoxib formulation achieves a mean
AUC.sub.0-.infin. of more than 3000 h*ng/ml. In some embodiments,
the rofecoxib formulation achieves a mean AUC.sub.0-.infin. of more
than 3400 h*ng/ml. In some embodiments, the rofecoxib formulation
achieves a mean AUC.sub.0-.infin. of more than 3500 h*ng/ml.
[0248] In certain aspects, the subject matter disclosed herein
provides a method for treating pain, fever, or inflammation in a
subject by administering a 20 mg solid dosage formulation of
rofecoxib or a pharmaceutically acceptable salt thereof, wherein a
single administration of the formulation to human subjects less
than 65 years of age achieves a mean Cmax plasma concentration
within 80% to 125% of 259 ng/ml. In some embodiments, the rofecoxib
formulation achieves a mean Cmax plasma concentration within 80% to
125% of 259 ng/ml and a mean AUC.sub.0-.infin. within 80% to 125%
of 3550 h*ng/ml. In some embodiments, the rofecoxib formulation
achieves a mean plasma AUC.sub.0-.infin. of about 2840-4438 h*ng/ml
and a mean plasma Cmax of about 207-324 ng/ml following oral
administration of a single dose of the formulation to a population
of healthy adults less than 65 years of age in a fasted state. In
some embodiments, the population of healthy adults are less than 60
years of age.
[0249] In certain aspects, the subject matter disclosed herein
provides a method for treating pain, fever, or inflammation in a
subject by administering a 20 mg solid dosage formulation of
rofecoxib or a pharmaceutically acceptable salt thereof, wherein
the formulation reaches a Cmax plasma concentration of least 170
ng/ml in the subject.
[0250] In some embodiments, the rofecoxib formulation reaches a
Cmax plasma concentration level of at least 190 ng/ml. In some
embodiments, the rofecoxib formulation reaches a Cmax plasma
concentration level of at least 205 ng/ml. In some embodiments, the
rofecoxib formulation reaches a Cmax plasma concentration level of
at least 220 ng/ml. In some embodiments, the rofecoxib formulation
reaches a Cmax plasma concentration level of at least 235 ng/ml. In
some embodiments, the rofecoxib formulation reaches a Cmax plasma
concentration level of at least 250 ng/ml.
[0251] In certain aspects, the subject matter disclosed herein
provides a method for treating pain, fever, or inflammation in a
subject by administering a 20 mg solid dosage formulation of
rofecoxib or a pharmaceutically acceptable salt thereof, wherein
the formulation reaches an AUC.sub.0-.infin. of more than 3000
h*ng/ml in the subject.
[0252] In some embodiments, the rofecoxib formulation reaches an
AUC.sub.0-.infin. of more than 3200 h*ng/ml. In some embodiments,
the rofecoxib formulation reaches an AUC.sub.0-.infin. of more than
3300 h*ng/ml. In some embodiments, the rofecoxib formulation
reaches an AUC.sub.0-.infin. of more than 3400 h*ng/ml. In some
embodiments, the rofecoxib formulation reaches an AUC.sub.0-.infin.
of more than 3500 h*ng/ml. In some embodiments, the rofecoxib
formulation reaches an AUC.sub.0-.infin. of more than 3525 h*ng/ml.
In some embodiments, the rofecoxib formulation reaches an
AUC.sub.0-.infin. of 3550 h*ng/ml or more. In some embodiments, the
rofecoxib formulation achieves a mean Cmax plasma concentration
within 80% to 125% of 259 ng/ml and a mean AUC.sub.0-.infin. within
80% to 125% of 3550 h*ng/ml.
[0253] In certain aspects, the subject matter disclosed herein
provides a pharmaceutically acceptable formulation comprising a
granular component and an extragranular component, wherein the
granular component comprises an intragranular component comprising
rofecoxib or a pharmaceutically acceptable salt thereof and one or
more disintegrants, and wherein the extragranular component
comprises one or more disintegrants.
[0254] In some embodiments, the one or more disintegrants in the
granular component is selected from starches, clays, celluloses,
algins, gums, cross-linked polymers, and combinations thereof. In
some embodiments, the one or more disintegrants in the granular
component is selected from croscarmellose, crospovidone, sodium
starch glycolate, and combinations thereof. In some embodiments,
one or more disintegrants in the granular component is
croscarmellose sodium. In some embodiments, the one or more
disintegrants in the granular component is about 1% (w/w) to about
8% (w/w) of the formulation. In some embodiments, the one or more
disintegrants in the granular component is about 1% (w/w) to about
6% (w/w) of the formulation. In some embodiments, the one or more
disintegrants in the granular component is about 1% (w/w) to about
4% (w/w) of the formulation. In some embodiments, the one or more
disintegrants in the extragranular component is selected from
starches, clays, celluloses, algins, gums, cross-linked polymers,
and combinations thereof. In some embodiments, the one or more
disintegrants in the extragranular component is selected from
croscarmellose, crospovidone, sodium starch glycolate, and
combinations thereof. In some embodiments, the one or more
disintegrants in the extragranular component is croscarmellose
sodium.
[0255] In some embodiments, the disintegrant in the extragranular
component is about 1% (w/w) to about 8% (w/w) of the formulation.
In some embodiments, the disintegrant in the extragranular
component is about 1% (w/w) to about 6% (w/w) of the formulation.
In some embodiments, the disintegrant in the extragranular
component is about 1% (w/w) to about 4% (w/w) of the formulation.
In some embodiments, the disintegrant in the granular component and
the disintegrant in the extragranular component are together about
2% (w/w) to about 12% (w/w) of the formulation. In some
embodiments, the disintegrant in the granular component and the
disintegrant in the extragranular component are together about 2%
(w/w) to about 10% (w/w) of the formulation. In some embodiments,
the disintegrant in the granular component and the disintegrant in
the extragranular component are together about 2% (w/w) to about 8%
(w/w) of the formulation. In some embodiments, the ratio of
granular disintegrant to extragranular disintegrant is about 40% to
about 60% (w/w). In some embodiments, the ratio of granular
disintegrant to extragranular disintegrant is about 45% to about
55% (w/w). In some embodiments, the ratio of granular disintegrant
to extragranular disintegrant is about 50% to about 50% (w/w). In
some embodiments, the ratio of granular disintegrant to
extragranular disintegrant is about 55% to about 45% (w/w). In some
embodiments, the ratio of granular disintegrant to extragranular
disintegrant is about 60% to about 40% (w/w).
[0256] In some embodiments, the pharmaceutically acceptable
formulation form further comprises one or more of a diluent, a
binder, a coloring agent, and a lubricant. In some embodiments, at
least a portion of the diluent is in the granular component. In
some embodiments, the diluent is selected from dicalcium phosphate,
calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium
chloride, dry starch, powdered sugar, sorbitol, sucrose, inositol,
and combinations thereof. In some embodiments, the diluent is
selected from lactose, cellulose, or a combination thereof. In some
embodiments, the diluent is selected from lactose monohydrate,
microcrystalline cellulose, or a combination thereof.
[0257] In some embodiments, the lactose monohydrate is about 35%
(w/w) to about 45% (w/w) of the formulation. In some embodiments,
the lactose monohydrate is about 37% (w/w) to about 42% (w/w) of
the formulation. In some embodiments, the lactose monohydrate is
about 39% (w/w) to about 40% (w/w) of the formulation. In some
embodiments, the microcrystalline cellulose is about 35% (w/w) to
about 45% (w/w) of the formulation. In some embodiments, the
microcrystalline cellulose is about 37% (w/w) to about 42% (w/w) of
the formulation. In some embodiments, the microcrystalline
cellulose is about 39% (w/w) to about 40% (w/w) of the formulation.
In some embodiments, the diluent is about 75% (w/w) to about 85%
(w/w) of the formulation. In some embodiments, the diluent is about
77% (w/w) to about 82% (w/w) of the formulation. In some
embodiments, the diluent is about 78% (w/w) to about 80% (w/w) of
the formulation.
[0258] In some embodiments, at least a portion of the binder is in
the granular component. In some embodiments, the binder is selected
from starches, gelatins, sugars, gums, waxes, water, alcohols,
celluloses, and combinations thereof. In some embodiments, the
binder is selected from acacia gum, tragacanth, corn starch, methyl
cellulose, panwar gum, ghatti gum, mucilage of isapol husks,
carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone,
sucrose, glucose, dextrose, molasses, lactose, and combinations
thereof. In some embodiments, the binder is hydroxypropyl
cellulose.
[0259] In some embodiments, the binder is about 1% (w/w) to about
5% (w/w) of the formulation. In some embodiments, the binder is
about 2% (w/w) to about 4% (w/w) of the formulation. In some
embodiments, the binder is about 2.5% (w/w) to about 3.5% (w/w) of
the formulation.
[0260] In some embodiments, at least a portion of the coloring
agent is in the extragranular component. In some embodiments, the
coloring agent is pigment blend yellow. In some embodiments, the
coloring agent is about 0.30% (w/w) to about 0.60% (w/w) of the
formulation.
[0261] In some embodiments, at least a portion of the lubricant is
in the extragranular component. In some embodiments, the lubricant
is selected from talc, magnesium stearate, calcium stearate,
stearic acid, metallic stearate, hydrogenated vegetable oils, and
polyethylene glycol, corn starch, boric acids, sodium chloride,
sodium lauryl sulphate. In some embodiments, the lubricant is
magnesium stearate. In some embodiments, the lubricant is about
0.10% (w/w) to about 1% (w/w) of the formulation. In some
embodiments, the lubricant is about 0.50% (w/w) of the
formulation.
[0262] In some embodiments, the rofecoxib or pharmaceutically
acceptable salt thereof is about 5% (w/w) to about 30% (w/w) of the
formulation. In some embodiments, the rofecoxib or pharmaceutically
acceptable salt thereof is about 10% (w/w) to about 20% (w/w) of
the formulation. In some embodiments, the rofecoxib or
pharmaceutically acceptable salt thereof is about 12% (w/w) to
about 13% (w/w) of the formulation.
[0263] In some embodiments, the formulation comprises about 10 mg
of the rofecoxib or pharmaceutically acceptable salt thereof. In
some embodiments, the formulation comprises about 12.5 mg of the
rofecoxib or pharmaceutically acceptable salt thereof. In some
embodiments, the formulation comprises about 17.5 mg of the
rofecoxib or pharmaceutically acceptable salt thereof. In some
embodiments, the formulation comprises about 20 mg of the rofecoxib
or pharmaceutically acceptable salt thereof. In some embodiments,
the formulation comprises about 25 mg of the rofecoxib or
pharmaceutically acceptable salt thereof.
[0264] In some embodiments, the rofecoxib is substantially pure. In
some embodiments, the rofecoxib is highly pure. In some
embodiments, the highly pure rofecoxib comprises less than about
0.1% total impurities. In some embodiments, the highly pure
rofecoxib comprises less than about 0.075% total impurities. In
some embodiments, the highly pure rofecoxib comprises less than
about 0.050% total impurities. In some embodiments, the highly pure
rofecoxib comprises less than about 0.025% total impurities. In
some embodiments, the highly pure rofecoxib comprises less than
about 0.001% total impurities.
[0265] In some embodiments, the rofecoxib is substantially pure or
highly pure. In some embodiments, the highly pure rofecoxib
comprises less than about 0.10%, 0.05%, 0.02%, or 0.01% of
4-[4-(methylsulphonyl)phenyl]-3-phenyl-2,5-furandione. In some
embodiments, the highly pure rofecoxib comprises less than about
0.10%, 0.05%, 0.02%, or 0.01% of
4-[4-(methylsulfonyl)phenyl]-3-phenyl-5-hydroxyfuran-2-one. In some
embodiments, the highly pure rofecoxib comprises less than about
0.10%, 0.05%, 0.02%, or 0.01% of
4-[4-(methylthio)phenyl]-3-phenyl-2(5H)-furanone. In some
embodiments, the highly pure rofecoxib comprises less than about
0.10%, 0.05%, 0.02%, or 0.01% of
4-[4-(methylsulfinyl)phenyl]-3-phenyl-2(5H)-furanone.
[0266] In some embodiments, the formulation is suitable for oral
administration. In some embodiments, the formulation is a solid
dosage form. In some embodiments, the solid dosage form is an oral
tablet.
[0267] In some embodiments, the oral tablet provides a dissolution
rate of at least about 80% of the rofecoxib or pharmaceutically
acceptable salt thereof by about 15 minutes. In some embodiments,
the oral tablet provides a dissolution rate of at least about 85%
of the rofecoxib or pharmaceutically acceptable salt thereof by
about 15 minutes. In some embodiments, the oral tablet provides a
dissolution rate of at least about 90% of the rofecoxib or
pharmaceutically acceptable salt thereof by about 15 minutes. In
some embodiments, the oral tablet provides a dissolution rate of at
least about 95% of the rofecoxib or pharmaceutically acceptable
salt thereof by about 15 minutes. In some embodiments, the oral
tablet provides a dissolution rate of at least about 100% of the
rofecoxib or pharmaceutically acceptable salt thereof by about 15
minutes.
[0268] In some embodiments, the dissolution rate is measured in
about 1% SDS at a paddle speed of about 50 rpm and at a temperature
of about 37.0.degree. C..+-.0.5.degree. C. In some embodiments, the
dissolution rate is measured in about 1% SDS at a paddle speed of
about 75 rpm and at a temperature of about 37.0.degree.
C..+-.0.5.degree. C. In some embodiments, the dissolution rate is
measured in about 1.5% SDS at a paddle speed of about 50 rpm and at
a temperature of about 37.0.degree. C..+-.0.5.degree. C. In some
embodiments, the dissolution rate is measured in about 1.5% SDS at
a paddle speed of about 75 rpm and at a temperature of about
37.0.degree. C..+-.0.5.degree. C. In some embodiments, the
dissolution rate is measured in about 2% SDS at a paddle speed of
about 50 rpm and at a temperature of about 37.0.degree.
C..+-.0.5.degree. C. In some embodiments, the dissolution rate is
measured in about 2% SDS at a paddle speed of about 75 rpm and at a
temperature of about 37.0.degree. C..+-.0.5.degree. C. In some
embodiments, the dissolution rate is measured using a USP Type II
apparatus. In some embodiments, the dissolution rate is measured
with a USP Type II apparatus using 900 mL of 2% SDS, a paddle speed
of 50 rpm, and a temperature of 37.0.degree. C..+-.0.5.degree..
[0269] In some embodiments, the rofecoxib or pharmaceutically
acceptable salt thereof is formulated into granules and at least
about 35% of the granules are less than about 75 .mu.m. In some
embodiments, the rofecoxib or pharmaceutically acceptable salt
thereof is formulated into granules and at least about 55% of the
granules are less than about 150 .mu.m. In some embodiments, the
rofecoxib or pharmaceutically acceptable salt thereof is formulated
into granules and at least about 75% of the granules are less than
about 250 .mu.m. In some embodiments, the rofecoxib or
pharmaceutically acceptable salt thereof is formulated into
granules and at least about 85% of the granules are less than about
425 .mu.m. In some embodiments, the rofecoxib or pharmaceutically
acceptable salt thereof is formulated into granules and at least
about 90% of the granules are less than about 1000 .mu.m.
[0270] In some embodiments, the formulation is a solid dosage
formulation comprising 12.5 mg, 17.5 mg, 20 mg, or 25 mg of
rofecoxib, and wherein the formulation reaches a median time to
Cmax plasma concentration in 3 hours or less following a single
administration of the formulation to human subjects less than 65
years of age.
[0271] In some embodiments, the formulation reaches a mean Cmax
plasma concentration in less than 3 hours following administration.
In some embodiments, the formulation reaches a mean Cmax plasma
concentration in less than 2.5 hours following administration. In
some embodiments, the formulation reaches a mean Cmax plasma
concentration in less than 2 hours following administration. In
some embodiments, the formulation is a solid dosage formulation
comprising 25 mg of rofecoxib, and wherein a single administration
of the formulation to human subjects less than 65 years of age
achieves a mean Cmax plasma concentration of more than 240 ng/ml.
In some embodiments, the formulation achieves a mean Cmax plasma
concentration of more than 300 ng/ml. In some embodiments, the
formulation achieves a mean Cmax plasma concentration of more than
320 ng/ml. In some embodiments, the formulation achieves a mean
Cmax plasma concentration of more than 350 ng/ml.
[0272] In some embodiments, the formulation is a solid dosage
formulation comprising 25 mg of rofecoxib, and wherein a single
administration of the formulation to human subjects less than 65
years of age achieves a mean AUC.sub.0-.infin. of more than 4500
h*ng/ml. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 4700 h*ng/ml. In some embodiments,
the formulation achieves a mean AUC.sub.0-.infin. of more than 5000
h*ng/ml.
[0273] In some embodiments, the formulation is a solid dosage
formulation comprising 25 mg of rofecoxib, and wherein a single
administration of the formulation in human subjects less than 65
years of age reaches a mean Cmax plasma concentration of more than
240 ng/ml in less than 3 hours following administration with a mean
AUC.sub.0-.infin. of more than 4250 h*ng/ml.
[0274] In certain aspects, the subject matter disclosed herein
provides a solid dosage formulation comprising 10 mg to 50 mg of
rofecoxib and a pharmaceutically acceptable carrier, wherein a
single administration of the formulation in human subjects less
than 65 years of age achieves a mean Cmax plasma concentration from
9.8 ng/ml to 16 ng/ml for each 1 mg of rofecoxib in the
formulation.
[0275] In some embodiments, the formulation achieves a mean Cmax
plasma concentration from 10 ng/ml to 14 ng/ml for each 1 mg of
rofecoxib in the formulation. In some embodiments, the formulation
achieves a mean Cmax plasma concentration from 10 ng/ml to 13 ng/ml
for each 1 mg of rofecoxib in the formulation. In some embodiments,
the formulation achieves a mean Cmax plasma concentration from 80%
to 125% of 12.8 ng/ml.
[0276] In certain aspects, the subject matter disclosed herein
provides a solid dosage formulation comprising 10 mg to 50 mg of
rofecoxib and a pharmaceutically acceptable carrier, wherein a
single administration of the formulation in human subjects less
than 65 years of age achieves a mean AUC.sub.0-.infin. of 170
h*ng/ml to 235 h*ng/ml for each 1 mg of rofecoxib in the
formulation.
[0277] In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of 170 h*ng/ml to 225 h*ng/ml for each 1 mg of
rofecoxib in the formulation. In some embodiments, the formulation
achieves a mean AUC.sub.0-.infin. of 177 h*ng/ml to 225 h*ng/ml for
each 1 mg of rofecoxib in the formulation. In some embodiments, the
formulation achieves a mean AUC.sub.0-.infin. of 180 h*ng/ml to 225
h*ng/ml for each 1 mg of rofecoxib in the formulation. In some
embodiments, the formulation achieves a mean AUC.sub.0-.infin. of
190 h*ng/ml to 215 h*ng/ml for each 1 mg of rofecoxib in the
formulation.
[0278] In certain aspects, the subject matter disclosed herein
provides a method of inhibiting COX-2 in a subject by administering
the formulations described herein.
[0279] In certain aspects, the subject matter disclosed herein
provides a method of inhibiting COX-2 in a subject by administering
a solid dosage formulation comprising 17.5 mg of rofecoxib.
[0280] In some embodiments, the formulation is a solid dosage
formulation comprising 17.5 mg of rofecoxib, wherein a single
administration of the formulation to human subjects less than 65
years of age achieves a mean Cmax that is equal to or greater than
that reported by Schwartz, J. I., et al. Clin. Drug Invent. 2003,
23 (8): 503-509 for a rofecoxib 25 mg tablet. In some embodiments,
the formulation is a solid dosage formulation comprising 17.5 mg of
rofecoxib, wherein a single administration of the formulation to
human subjects less than 65 years of age achieves a mean Cmax that
is equal to or greater than that reported in the FDA-approved label
for VIOXX for a single 25-mg dose of VIOXX. In some embodiments,
the formulation is a solid dosage formulation comprising 17.5 mg of
rofecoxib, wherein the formulation achieves equal or greater
efficacy in the treatment of pain, fever, or inflammation in a
subject than a 25 mg tablet of VIOXX (as approved under U.S. New
Drug Applications 021042 and 021647). In some embodiments, the
formulation is a solid dosage formulation comprising 20 mg of
rofecoxib, where a single administration of the formulation to
human subjects less than 65 years of age achieves a mean
AUC.sub.0-.infin. that is equal to or greater than that reported by
Schwartz, J. I., et al. Clin. Drug Invent. 2003, 23 (8): 503-509
for a rofecoxib 25 mg tablet. In some embodiments, the formulation
is a solid dosage formulation comprising 20 mg of rofecoxib, where
a single administration of the formulation to human subjects less
than 65 years of age achieves a mean Cmax that is equal to or
greater than that reported by Schwartz, J. I., et al. Clin. Drug
Invent. 2003, 23 (8): 503-509 for a rofecoxib 25 mg tablet. In some
embodiments, the formulation is a solid dosage formulation
comprising 20 mg of rofecoxib, wherein a single administration of
the formulation to human subjects less than 65 years of age
achieves a mean AUC.sub.0-.infin. that is equal to or greater than
that reported in the FDA-approved label for VIOXX for a single
25-mg dose of VIOXX. In some embodiments, the formulation is a
solid dosage formulation comprising 20 mg of rofecoxib, wherein a
single administration of the formulation to human subjects less
than 65 years of age achieves a mean Cmax that is equal to or
greater than that reported in the FDA-approved label for VIOXX for
a single 25-mg dose of VIOXX. In some embodiments, the formulation
is a solid dosage formulation comprising 20 mg of rofecoxib,
wherein the formulation achieves equal or greater efficacy in the
treatment of pain, fever, or inflammation in a subject than a 25 mg
tablet of VIOXX (as approved under U.S. New Drug Applications
021042 and 021647).
[0281] In some embodiments, the patient is age 2 or older.
[0282] In certain aspects, the subject matter disclosed herein
provides a method for treating pain, fever, or inflammation in a
patient by administering the formulations as described herein.
[0283] In some embodiments, the human subjects are healthy human
subjects. In some embodiments, the patient is age 2 or older.
[0284] In certain aspects, the subject matter disclosed herein
provides a method for treating pain, fever, or inflammation in a
patient population comprising providing a solid dosage formulation
comprising 10 mg to 50 mg of rofecoxib to the patient population
for inhibiting COX-2, wherein the formulation achieves a mean Cmax
plasma concentration of between 80 to 125% of 12.8 ng/ml for each 1
mg of rofecoxib in the formulation following single administration
of the formulation in the patient population.
Further Embodiments of the Present Subject Matter
[0285] In certain aspects, the subject matter disclosed herein
provides a pharmaceutically acceptable formulation comprising
granules. In some embodiments, the pharmaceutically acceptable
formulation comprises a granular component and an extragranular
component, wherein the granular component comprises an
intragranular component comprising rofecoxib or a pharmaceutically
acceptable salt thereof and one or more disintegrants, and wherein
the extragranular component comprises one or more
disintegrants.
[0286] In some embodiments, the one or more disintegrants in the
granular component is selected from starches, clays, celluloses,
algins, gums, cross-linked polymers, and combinations thereof. In
some embodiments, the one or more disintegrants in the granular
component is selected from croscarmellose, crospovidone, sodium
starch glycolate, and combinations thereof.
[0287] In some embodiments, the one or more disintegrants in the
granular component is croscarmellose sodium. In some embodiments,
the one or more disintegrants in the granular component is about 1%
(w/w) to about 8% (w/w) of the formulation. In some embodiments,
the one or more disintegrants in the granular component is about 1%
(w/w) to about 6% (w/w) of the formulation. In some embodiments,
the one or more disintegrants in the granular component is about 1%
(w/w) to about 4% (w/w) of the formulation.
[0288] In some embodiments, the one or more disintegrants in the
extragranular component is selected from starches, clays,
celluloses, algins, gums, cross-linked polymers, and combinations
thereof. In some embodiments, the one or more disintegrants in the
extragranular component is selected from croscarmellose,
crospovidone, sodium starch glycolate, and combinations thereof. In
some embodiments, the one or more disintegrants in the
extragranular component is croscarmellose sodium. In some
embodiments, the disintegrant in the extragranular component is
about 1% (w/w) to about 8% (w/w) of the formulation. In some
embodiments, the disintegrant in the extragranular component is
about 1% (w/w) to about 6% (w/w) of the formulation. In some
embodiments, the disintegrant in the extragranular component is
about 1% (w/w) to about 4% (w/w) of the formulation.
[0289] In some embodiments, the disintegrant in the granular
component and the disintegrant in the extragranular component are
together about 2% (w/w) to about 12% (w/w) of the formulation. In
some embodiments, the disintegrant in the granular component and
the disintegrant in the extragranular component are together about
2% (w/w) to about 10% (w/w) of the formulation. In some
embodiments, the disintegrant in the granular component and the
disintegrant in the extragranular component are together about 2%
(w/w) to about 8% (w/w) of the formulation.
[0290] In some embodiments, the ratio of granular disintegrant to
extragranular disintegrant is about 40% (w/w) to about 60% (w/w).
In some embodiments, the ratio of granular disintegrant to
extragranular disintegrant is about 45% (w/w) to about 55% (w/w).
In some embodiments, the ratio of granular disintegrant to
extragranular disintegrant is about 50% (w/w) to about 50% (w/w).
In some embodiments the ratio of granular disintegrant to
extragranular disintegrant is about 55% (w/w) to about 45% (w/w).
In some embodiments the ratio of granular disintegrant to
extragranular disintegrant is about 60% (w/w) to about 40%
(w/w).
[0291] In some embodiments, the pharmaceutically acceptable
formulation further comprising one or more of a diluent, a binder,
a coloring agent, and a lubricant. In some embodiments, at least a
portion of the diluent is in the granular component. In some
embodiments, the diluent is selected from dicalcium phosphate,
calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium
chloride, dry starch, powdered sugar, sorbitol, sucrose, inositol,
and combinations thereof. In some embodiments, the diluent is
selected from lactose, cellulose, or a combination thereof. In some
embodiments, the diluent is selected from lactose monohydrate,
microcrystalline cellulose, or a combination thereof.
[0292] In some embodiments, the lactose monohydrate is about 35%
(w/w) to about 45% (w/w) of the formulation. In some embodiments,
the lactose monohydrate is about 37% (w/w) to about 42% (w/w) of
the formulation. In some embodiments, the lactose monohydrate is
about 39% (w/w) to about 40% (w/w) of the formulation.
[0293] In some embodiments, the microcrystalline cellulose is about
35% (w/w) to about 45% (w/w) of the formulation. In some
embodiments, the microcrystalline cellulose is about 37% (w/w) to
about 42% (w/w) of the formulation. In some embodiments, the
microcrystalline cellulose is about 39% (w/w) to about 40% (w/w) of
the formulation.
[0294] In some embodiments, the diluent is about 75% (w/w) to about
85% (w/w) of the formulation. In some embodiments, diluent is about
77% (w/w) to about 82% (w/w) of the formulation. In some
embodiments, the diluent is about 78% (w/w) to about 80% (w/w) of
the formulation.
[0295] In some embodiments, at least a portion of the binder is in
the granular component. In some embodiments, the binder is selected
from starches, gelatins, sugars, gums, waxes, water, alcohols,
celluloses, and combinations thereof. In some embodiments, the
binder is selected from acacia gum, tragacanth, corn starch, methyl
cellulose, panwar gum, ghatti gum, mucilage of isapol husks,
carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone,
sucrose, glucose, dextrose, molasses, lactose, and combinations
thereof. In some embodiments, the binder is hydroxypropyl
cellulose. In some embodiments, the binder is about 1% (w/w) to
about 5% (w/w) of the formulation. In some embodiments, binder is
about 2% (w/w) to about 4% (w/w) of the formulation. In some
embodiments, the binder is about 2.5% (w/w) to about 3.5% (w/w) of
the formulation.
[0296] In some embodiments, at least a portion of the coloring
agent is in the extragranular component. In some embodiments, the
coloring agent is pigment blend yellow. In some embodiments, the
coloring agent is about 0.30% (w/w) to about 0.60% (w/w) of the
formulation.
[0297] In some embodiments, at least a portion of the lubricant is
in the extragranular component. In some embodiments, the lubricant
is selected from talc, magnesium stearate, calcium stearate,
stearic acid, metallic stearate, hydrogenated vegetable oils, and
polyethylene glycol, corn starch, boric acids, sodium chloride,
sodium lauryl sulphate. In some embodiments, the lubricant is
magnesium stearate. In some embodiments, the lubricant is about
0.10% (w/w) to about 1% (w/w) of the formulation. In some
embodiments, the lubricant is about 0.50% (w/w) of the
formulation.
[0298] In some embodiments, the rofecoxib or pharmaceutically
acceptable salt thereof is about 5% (w/w) to about 30% (w/w) of the
formulation. In some embodiments, the rofecoxib or pharmaceutically
acceptable salt thereof is about 10% (w/w) to about 20% (w/w) of
the formulation. In some embodiments, the rofecoxib or
pharmaceutically acceptable salt thereof is about 12% (w/w) to
about 13% (w/w) of the formulation. In some embodiments, the
formulation comprises about 10 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 10.5 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 11 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 11.5 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 12 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 12.5 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 17.5 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 20 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 21 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 22 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 22.5 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 25 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 50 mg of the rofecoxib or
pharmaceutically acceptable salt thereof.
[0299] In some embodiments, the rofecoxib is highly pure. In some
embodiments, the highly pure rofecoxib comprises less than about
0.1% total impurities. In some embodiments, the highly pure
rofecoxib comprises less than about 0.075% total impurities. In
some embodiments, the highly pure rofecoxib comprises less than
about 0.050% total impurities. In some embodiments, the highly pure
rofecoxib comprises less than about 0.025% total impurities. In
some embodiments, the highly pure rofecoxib comprises less than
about 0.001% total impurities.
[0300] In some embodiments, the highly pure rofecoxib comprises
less than about 0.10%, 0.05%, 0.02%, or 0.01% of
4-[4-(methylsulphonyl)phenyl]-3-phenyl-2,5-furandione. In some
embodiments, the highly pure rofecoxib comprises less than about
0.10%, 0.05%, 0.02%, or 0.01% of
4-[4-(methylthio)phenyl]-3-phenyl-2(5H)-furanone. In some
embodiments, the highly pure rofecoxib comprises less than about
0.10%, 0.05%, 0.02%, or 0.01% of
4-[4-(methylthio)phenyl]-3-phenyl-2(5H)-furanone. In some
embodiments, the highly pure rofecoxib comprises less than about
0.10%, 0.05%, 0.02%, or 0.01% of
4-[4-(methylsulfinyl)phenyl]-3-phenyl-2(5H)-furanone.
[0301] In some embodiments, the formulation is suitable for oral
administration. In some embodiments, the formulation is a solid
dosage form. In some embodiments, the solid dosage form is an oral
tablet. In some embodiments, the oral tablet provides a dissolution
rate of at least about 80% of the rofecoxib or pharmaceutically
acceptable salt thereof by about 15 minutes. In some embodiments,
the oral tablet provides a dissolution rate of at least about 85%
of the rofecoxib or pharmaceutically acceptable salt thereof by
about 15 minutes. In some embodiments, the oral tablet provides a
dissolution rate of at least about 90% of the rofecoxib or
pharmaceutically acceptable salt thereof by about 15 minutes. In
some embodiments, the oral tablet provides a dissolution rate of at
least about 95% of the rofecoxib or pharmaceutically acceptable
salt thereof by about 15 minutes. In some embodiments, the oral
tablet provides a dissolution rate of at least about 100% of the
rofecoxib or pharmaceutically acceptable salt thereof by about 15
minutes.
[0302] In some embodiments, the dissolution rate is measured in
about 1% SDS at a paddle speed of about 50 rpm and at a temperature
of about 37.0.degree. C..+-.0.5.degree. C. In some embodiments, the
dissolution rate is measured in about 1% SDS at a paddle speed of
about 75 rpm and at a temperature of about 37.0.degree.
C..+-.0.5.degree. C. In some embodiments, the dissolution rate is
measured in about 1.5% SDS at a paddle speed of about 50 rpm and at
a temperature of about 37.0.degree. C..+-.0.5.degree. C. In some
embodiments, the dissolution rate is measured in about 1.5% SDS at
a paddle speed of about 75 rpm and at a temperature of about
37.0.degree. C..+-.0.5.degree. C. In some embodiments, the
dissolution rate is measured in about 2% SDS at a paddle speed of
about 50 rpm and at a temperature of about 37.0.degree.
C..+-.0.5.degree. C. In some embodiments, the dissolution rate is
measured in about 2% SDS at a paddle speed of about 75 rpm and at a
temperature of about 37.0.degree. C..+-.0.5.degree. C. In some
embodiments, the dissolution rate is measured using a USP Type II
apparatus. In some embodiments, the dissolution rate is measured
with a USP Type II apparatus using 900 mL of 2% SDS, a paddle speed
of 50 rpm, and a temperature of 37.0.degree. C..+-.0.5.degree..
[0303] In some embodiments, the rofecoxib or pharmaceutically
acceptable salt thereof is formulated into granules and at least
about 35% of the granules are less than about 75 .mu.m. In some
embodiments, the rofecoxib or pharmaceutically acceptable salt
thereof is formulated into granules and at least about 55% of the
granules are less than about 150 .mu.m. In some embodiments, the
rofecoxib or pharmaceutically acceptable salt thereof is formulated
into granules and at least about 75% of the granules are less than
about 250 .mu.m. In some embodiments, the rofecoxib or
pharmaceutically acceptable salt thereof is formulated into
granules and at least about 85% of the granules are less than about
425 .mu.m. In some embodiments, the rofecoxib or pharmaceutically
acceptable salt thereof is formulated into granules and at least
about 90% of the granules are less than about 1000 .mu.m.
[0304] In some embodiments, a 17.5 mg solid dosage formulation of
rofecoxib reaches a median time to Cmax plasma concentration in 4
hours or less following single administration of the formulation to
human subjects. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib reaches a median time to Cmax plasma
concentration in 3 hours or less following administration. In some
embodiments, a 17.5 mg solid dosage formulation of rofecoxib
reaches a mean Cmax plasma concentration 2.5 hours following
administration. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib reaches a median time to Cmax plasma
concentration in 2 hours or less following administration. In some
embodiments, a 17.5 mg solid dosage formulation of rofecoxib has a
mean Cmax plasma concentration of more than 100 ng/ml. In some
embodiments, a 17.5 mg solid dosage formulation of rofecoxib has a
mean Cmax plasma concentration of more than 150 ng/ml, 167 ng/ml,
or 190 ng/ml. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib has a mean Cmax plasma concentration of
more than 200 ng/ml. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib has a mean Cmax plasma concentration of
more than 220 ng/ml. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib has a mean Cmax plasma concentration of
more than 250 ng/ml. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib has a mean Cmax plasma concentration of
more than 280 ng/ml. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib has a mean AUC.sub.0-.infin. of more than
1750 h*ng/ml. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib has a mean AUC.sub.0-.infin. of more than
2000 h*ng/ml. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib has a mean AUC.sub.0-.infin. of more than
2500 h*ng/ml. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib has a mean AUC.sub.0-.infin. of more than
3000 h*ng/ml. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib has a mean AUC.sub.0-.infin. of more than
3100 h*ng/ml. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib has a mean AUC.sub.0-.infin. of more than
3500 h*ng/ml. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib has a mean AUC.sub.0-.infin. of more than
4000 h*ng/ml. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib has a mean AUC.sub.0-.infin. of more than
4500 h*ng/ml. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib reaches a Cmax plasma concentration of
least 167 ng/ml, 170 ng/ml, 175 ng/ml, 180 ng/ml, or higher
following single administration of the formulation to a human
subject. In some embodiments, a 17.5 mg solid dosage formulation of
rofecoxib reaches an AUC.sub.0-.infin. of at least 2600 h*ng/ml,
2750 h*ng/ml, 2900 h*ng/ml, 3050 h*ng/ml, 3100 h*ng/ml, 3200
h*ng/ml, 3350 h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml or higher
following single administration of the formulation to a human
subject.
[0305] In some embodiments, a 20 mg solid dosage formulation of
rofecoxib reaches a median time to Cmax plasma concentration in 4
hours or less following single administration of the formulation to
human subjects. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib reaches a median time to Cmax plasma
concentration in 3 hours or less following administration. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib reaches
a median time to Cmax plasma concentration in 2.5 hours or less
following administration. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib reaches a median time to Cmax plasma
concentration in 2 hours or less following administration. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib has a
mean Cmax plasma concentration of more than 150 ng/ml. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib has a
mean Cmax plasma concentration of more than 191 ng/ml, 200 ng/ml,
215 ng/ml, or 225 ng/ml. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib has a mean Cmax plasma concentration of
more than 250 ng/ml. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib has a mean Cmax plasma concentration of
more than 258 ng/ml. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib has a mean Cmax plasma concentration of
more than 300 ng/ml. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib has a mean AUC.sub.0-.infin. of more than
2000 h*ng/ml. In some embodiments, a 20 mg solid dosage formulation
of rofecoxib has a mean AUC.sub.0-.infin. of more than 2500
h*ng/ml. In some embodiments, a 20 mg solid dosage formulation of
rofecoxib has a mean AUC.sub.0-.infin. of more than 3000 h*ng/ml.
In some embodiments, a 20 mg solid dosage formulation of rofecoxib
has a mean AUC.sub.0-.infin. of more than 3400 h*ng/ml. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 3500 h*ng/ml. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 4000 h*ng/ml. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib reaches
a Cmax plasma concentration of least 190 ng/ml, 205 ng/ml, 220
ng/ml, 235 ng/ml, 250 ng/ml, or higher following single
administration of the formulation to a human subject. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib reaches
an AUC.sub.0-.infin. of at least 3000 h*ng/ml, 3200 h*ng/ml, 3350
h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml, 3800 h*ng/ml, 3950 h*ng/ml, or
higher following single administration of the formulation to a
human subject. In some embodiments, the rofecoxib formulation
achieves a mean Cmax plasma concentration within 80% to 125% of 259
ng/ml and a mean AUC.sub.0-.infin. within 80% to 125% of 3550
h*ng/ml. In some embodiments, the rofecoxib formulation achieves a
mean plasma AUC.sub.0-.infin. of about 2840-4438 h*ng/ml and a mean
plasma Cmax of about 207-324 ng/ml following oral administration of
a single dose of the formulation to a population of healthy adults
less than 65 years of age in a fasted state. In some embodiments,
the population of healthy adults are less than 60 years of age.
[0306] In some embodiments, a 25 mg solid dosage formulation of
rofecoxib reaches a mean Cmax plasma concentration in less than 3
hours following single administration of the formulation to human
subjects. In some embodiments, a 25 mg solid dosage formulation of
rofecoxib reaches a mean Cmax plasma concentration in less than 2.5
hours following administration. In some embodiments, a 25 mg solid
dosage formulation of rofecoxib reaches a mean Cmax plasma
concentration in less than 2 hours following administration. In
some embodiments, a 25 mg solid dosage formulation of rofecoxib has
a mean Cmax plasma concentration of more than 240 ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean Cmax plasma concentration of more than 300 ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean Cmax plasma concentration of more than 320 ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean Cmax plasma concentration of more than 350 ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 4250 h*ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 4500 h*ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 4550 h*ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 4700 h*ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib reaches
a mean Cmax plasma concentration of more than 240 ng/ml in median
time of about 3 hours or less following administration with an
AUC.sub.0-.infin. of more than 4250 h*ng/ml.
[0307] In some embodiments, a solid dosage formulation of 10 mg to
50 mg of rofecoxib achieves a mean Cmax plasma concentration from
9.8 ng/ml to 16 ng/ml for each 1 mg of rofecoxib in the formulation
following single administration of the formulation to human
subjects. In some embodiments, the solid dosage formulation of
rofecoxib achieves a mean Cmax plasma concentration from 10 ng/ml
to 14 ng/ml for each 1 mg of rofecoxib in the formulation. In some
embodiments, the solid dosage formulation of rofecoxib achieves a
mean Cmax plasma concentration from 10 ng/ml to 13 ng/ml for each 1
mg of rofecoxib in the formulation. In some embodiments, the solid
dosage formulation of rofecoxib achieves a mean Cmax plasma
concentration from 80% to 125% of 12.8 ng/ml. In some embodiments,
the solid dosage formulation of rofecoxib reaches a mean
AUC.sub.0-.infin. of 170 h*ng/ml to 235 h*ng/ml for each 1 mg of
rofecoxib in the formulation. In some embodiments, the solid dosage
formulation of rofecoxib reaches a mean AUC.sub.0-.infin. of 170
h*ng/ml to 225 h*ng/ml for each 1 mg of rofecoxib in the
formulation. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of 177 h*ng/ml to 225 h*ng/ml for each 1 mg of
rofecoxib in the formulation. In some embodiments, the formulation
achieves a mean AUC.sub.0-.infin. of 180 h*ng/ml to 225 h*ng/ml for
each 1 mg of rofecoxib in the formulation. In some embodiments, the
solid dosage formulation of rofecoxib reaches a mean
AUC.sub.0-.infin. of 190 h*ng/ml to 215 h*ng/ml for each 1 mg of
rofecoxib in the formulation.
[0308] In certain aspects, the subject matter disclosed herein
provides a method for treating pain, fever, or inflammation in a
subject by administering a solid dosage formulation comprising 17.5
mg of rofecoxib or a pharmaceutically acceptable salt thereof. In
some embodiments, the formulation achieves a median time to Cmax
plasma concentration in 4 hours or less following single
administration of the formulation to human subjects. In some
embodiments, the formulation achieves a median time to Cmax plasma
concentration in 3 hours or less following administration. In some
embodiments, the formulation achieves a median time to Cmax plasma
concentration in 2.5 hours or less following administration. In
some embodiments, the formulation achieves a median time to Cmax
plasma concentration in 2 hours or less following administration.
In some embodiments, the formulation achieves a mean Cmax plasma
concentration of more than 100 ng/ml. In some embodiments, the
formulation achieves a mean Cmax plasma concentration of more than
150 ng/ml, 167 ng/ml, or 190 ng/ml. In some embodiments, the
formulation achieves a mean Cmax plasma concentration of more than
200 ng/ml. In some embodiments, the formulation achieves a mean
Cmax plasma concentration of more than 220 ng/ml. In some
embodiments, the formulation achieves a mean Cmax plasma
concentration of more than 250 ng/ml. In some embodiments, the
formulation achieves a mean Cmax plasma concentration of more than
280 ng/ml. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 1750 h*ng/ml. In some embodiments,
the formulation achieves a mean AUC.sub.0-.infin. of more than 2000
h*ng/ml. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 2500 h*ng/ml. In some embodiments,
the formulation achieves a mean AUC.sub.0-.infin. of more than 3000
h*ng/ml. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 3100 h*ng/ml. In some embodiments,
the formulation achieves a mean AUC.sub.0-.infin. of more than 3500
h*ng/ml. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 4000 h*ng/ml. In some embodiments,
the formulation achieves a mean AUC.sub.0-.infin. of more than 4500
h*ng/ml. In some embodiments, the formulation reaches a Cmax plasma
concentration of least 167 ng/ml, 170 ng/ml, 175 ng/ml, 180 ng/ml,
or higher following single administration of the formulation to a
human subject. In some embodiments, the formulation reaches an
AUC.sub.0-.infin. of at least 2600 h*ng/ml, 2750 h*ng/ml, 2900
h*ng/ml, 3050 h*ng/ml, 3200 h*ng/ml, 3350 h*ng/ml, 3500 h*ng/ml,
3650 h*ng/ml or higher following single administration of the
formulation to a human subject.
[0309] In certain aspects, the subject matter disclosed herein
provides a method for treating pain, fever, or inflammation in a
subject by administering a solid dosage formulation comprising 20
mg of rofecoxib or a pharmaceutically acceptable salt thereof. In
some embodiments, the formulation achieves a median time to Cmax
plasma concentration in 4 hours or less following single
administration of the formulation to human subjects. In some
embodiments, the formulation achieves a median time to Cmax plasma
concentration in 3 hours or less following administration. In some
embodiments, the formulation achieves a median time to Cmax plasma
concentration in 2.5 hours or less following administration. In
some embodiments, the formulation achieves a median time to Cmax
plasma concentration in 2 hours or less following administration.
In some embodiments, the formulation achieves a mean Cmax plasma
concentration of more than 150 ng/ml. In some embodiments, the
formulation achieves a mean Cmax plasma concentration of more than
191 ng/ml, 200 ng/ml, 215 ng/ml, or 225 ng/ml. In some embodiments,
the formulation achieves a mean Cmax plasma concentration of more
than 250 ng/ml. In some embodiments, the formulation achieves a
mean Cmax plasma concentration of more than 258 ng/ml. In some
embodiments, the formulation achieves a mean Cmax plasma
concentration of more than 300 ng/ml. In some embodiments, the
formulation achieves a mean AUC.sub.0-.infin. of more than 2000
h*ng/ml. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 2500 h*ng/ml. In some embodiments,
the formulation achieves a mean AUC.sub.0-.infin. of more than 3000
h*ng/ml. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 3400 h*ng/ml. In some embodiments,
the formulation achieves a mean AUC.sub.0-.infin. of more than 3500
h*ng/ml. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 4000 h*ng/ml. In some embodiments,
the formulation reaches a Cmax plasma concentration of least 190
ng/ml, 205 ng/ml, 220 ng/ml, 235 ng/ml, 250 ng/ml, or higher
following single administration of the formulation to a human
subject. In some embodiments, the formulation reaches an
AUC.sub.0-.infin. of at least 3000 h*ng/ml, 3200 h*ng/ml, 3350
h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml, 3800 h*ng/ml, 3950 h*ng/ml, or
higher following single administration of the formulation to a
human subject. In some embodiments, the rofecoxib formulation
achieves a mean Cmax plasma concentration within 80% to 125% of 259
ng/ml and a mean AUC.sub.0-.infin. within 80% to 125% of 3550
h*ng/ml. In some embodiments, the rofecoxib formulation achieves a
mean plasma AUC.sub.0-.infin. of about 2840-4438 h*ng/ml and a mean
plasma Cmax of about 207-324 ng/ml following oral administration of
a single dose of the formulation to a population of healthy adults
less than 65 years of age in a fasted state. In some embodiments,
the population of healthy adults are less than 60 years of age.
[0310] In certain aspects, the subject matter disclosed herein
provides a method for treating pain, fever, or inflammation in a
subject by administering a solid dosage formulation comprising 25
mg of rofecoxib or a pharmaceutically acceptable salt thereof. In
some embodiments, the formulation achieves a mean Cmax plasma
concentration in less than 3 hours following single administration
of the formulation to human subjects. In some embodiments, the
formulation achieves a mean Cmax plasma concentration in less than
2.5 hours following administration. In some embodiments, the
formulation achieves a mean Cmax plasma concentration in less than
2 hours following administration. In some embodiments, the
formulation achieves a mean Cmax plasma concentration of more than
240 ng/ml. In some embodiments, the formulation achieves a mean
Cmax plasma concentration of more than 250 ng/ml. In some
embodiments, the formulation achieves a mean Cmax plasma
concentration of more than 300 ng/ml. In some embodiments, the
formulation achieves a mean Cmax plasma concentration of more than
320 ng/ml. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 4250 h*ng/ml. In some embodiments,
the formulation achieves a mean AUC.sub.0-.infin. of more than 4500
h*ng/ml. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 4550 h*ng/ml. In some embodiments,
the formulation achieves a mean AUC.sub.0-.infin. of more than 4700
h*ng/ml. In some embodiments, the formulation achieves a mean Cmax
plasma concentration of more than 240 ng/ml in less than 3 hours
following administration with a mean AUC.sub.0-.infin. of more than
4250 h*ng/ml.
[0311] In some embodiments, the subject matter disclosed herein
provides a method for treating pain, fever, or inflammation in a
subject by administering a solid dosage formulation of 10 mg to 50
mg of rofecoxib that achieves a mean Cmax plasma concentration from
9.8 ng/ml to 16 ng/ml for each 1 mg of rofecoxib in the formulation
following single administration of the formulation to human
subjects. In some embodiments, the solid dosage formulation of
rofecoxib achieves a mean Cmax plasma concentration from 10 ng/ml
to 14 ng/ml for each 1 mg of rofecoxib in the formulation. In some
embodiments, the solid dosage formulation of rofecoxib achieves a
mean Cmax plasma concentration from 10 ng/ml to 13 ng/ml for each 1
mg of rofecoxib in the formulation. In some embodiments, the solid
dosage formulation of rofecoxib achieves a mean Cmax plasma
concentration from 80% to 125% of 12.8 ng/ml. In some embodiments,
the solid dosage formulation of rofecoxib reaches a mean
AUC.sub.0-.infin. of 170 h*ng/ml to 235 h*ng/ml for each 1 mg of
rofecoxib in the formulation. In some embodiments, the solid dosage
formulation of rofecoxib reaches a mean AUC.sub.0-.infin. of 170
h*ng/ml to 225 h*ng/ml for each 1 mg of rofecoxib in the
formulation. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of 177 h*ng/ml to 225 h*ng/ml for each 1 mg of
rofecoxib in the formulation. In some embodiments, the formulation
achieves a mean AUC.sub.0-.infin. of 180 h*ng/ml to 225 h*ng/ml for
each 1 mg of rofecoxib in the formulation. In some embodiments, the
solid dosage formulation of rofecoxib reaches a mean
AUC.sub.0-.infin. of 190 h*ng/ml to 215 h*ng/ml for each 1 mg of
rofecoxib in the formulation.
[0312] In some embodiments, the subject matter disclosed herein
provides a method for treating pain, fever, or inflammation in a
subject by administering a solid dosage formulation of 10 mg to 50
mg of rofecoxib, wherein a single administration of the formulation
in human female subjects less than 65 years of age achieves a mean
Cmax plasma concentration that is at least 10% greater than that
achieved following a single administration of the formulation to
human male subjects less than 65 years of age. In some embodiments,
the formulation achieves a mean Cmax plasma concentration in human
female subjects that is at least 20% greater than that achieved in
human male subjects. In some embodiments, the formulation achieves
a mean Cmax plasma concentration in human female subjects that is
at least 25% greater than that achieved in human male subjects. In
some embodiments, the formulation comprises 17.5 mg to 25 mg of
rofecoxib. In some embodiments, the formulation comprises 17.5 mg
of rofecoxib. In some embodiments, the formulation comprises 20 mg
of rofecoxib. In some embodiments, the formulation comprises 25 mg
of rofecoxib. In some embodiments, the human female and/or male
subjects meet the eligibility criteria of the PK-101 and/or PK-102
studies set forth in Examples 4 and 6.
[0313] In some embodiments, the subject matter disclosed herein
provides a method for treating pain, fever, or inflammation in a
subject by administering a solid dosage formulation of 10 mg to 50
mg of rofecoxib, wherein a single administration of the formulation
in Caucasian subjects less than 65 years of age achieves a mean
AUC.sub.0-.infin. that is greater than that achieved following a
single administration of the formulation to African American
subjects less than 65 years of age. In some embodiments, the
formulation achieves a mean AUC.sub.0-.infin. in Caucasian subjects
that is at least 1%, 2%, 5%, 9%, or 10% greater than that achieved
following a single administration of the formulation to African
American subjects less than 65 years of age. In some embodiments,
the formulation comprises 17.5 mg to 25 mg of rofecoxib. In some
embodiments, the formulation comprises 17.5 mg of rofecoxib. In
some embodiments, the formulation comprises 20 mg of rofecoxib. In
some embodiments, the formulation comprises 25 mg of rofecoxib. In
some embodiments, the Caucasian and/or African American subjects
meet the eligibility criteria of the PK-101 and/or PK-102 studies
set forth in Examples 4 and 6.
[0314] In some embodiments, the subject matter disclosed herein
provides a method for treating pain, fever, or inflammation in a
subject by administering a solid dosage formulation comprising 12.5
mg of rofecoxib, wherein the formulation achieves a mean plasma
concentration of at least about 0.2 ng/ml, 0.3 ng/ml, 0.4 ng/ml, or
0.5 ng/ml at 15 minutes following single administration of the
formulation to human subjects less than 65 years of age. In some
embodiments, the subject matter disclosed herein provides a method
for treating pain, fever, or inflammation in a subject by
administering a solid dosage formulation comprising 12.5 mg of
rofecoxib, wherein the formulation achieves an arithmetic mean
plasma concentration of at least about 0.8 ng/ml, 0.9 ng/ml, or 1.0
ng/ml at 15 minutes following single administration of the
formulation to human subjects less than 65 years of age. In some
embodiments, the subject matter disclosed herein provides a method
for treating pain, fever, or inflammation in a subject by
administering a solid dosage formulation comprising 17.5 mg of
rofecoxib, wherein the formulation achieves a mean plasma
concentration of at least about 0.3 ng/ml, 0.4 ng/ml, 0.5 ng/ml, or
0.6 ng/ml at 15 minutes following single administration of the
formulation to human subjects less than 65 years of age. In some
embodiments, the subject matter disclosed herein provides a method
for treating pain, fever, or inflammation in a subject by
administering a solid dosage formulation comprising 17.5 mg of
rofecoxib, wherein the formulation achieves an arithmetic mean
plasma concentration of at least about 1.8 ng/ml, 2.0 ng/ml, 2.2
ng/ml, or 2.4 ng/ml at 15 minutes following single administration
of the formulation to human subjects less than 65 years of age. In
some embodiments, the subject matter disclosed herein provides a
method for treating pain, fever, or inflammation in a subject by
administering a solid dosage formulation comprising 20 mg of
rofecoxib, wherein the formulation achieves a mean plasma
concentration of at least about 0.8 ng/ml, 0.9 ng/ml, 1.0 ng/ml,
1.1 ng/ml, or 1.16 ng/ml at 15 minutes following single
administration of the formulation to human subjects less than 65
years of age. In some embodiments, the subject matter disclosed
herein provides a method for treating pain, fever, or inflammation
in a subject by administering a solid dosage formulation comprising
20 mg of rofecoxib, wherein the formulation achieves an arithmetic
mean plasma concentration of at least about 4.6 ng/ml, 5.0 ng/ml,
5.4 ng/ml, or 5.7 ng/ml at 15 minutes following single
administration of the formulation to human subjects less than 65
years of age. In some embodiments, the subject matter disclosed
herein provides a method for treating pain, fever, or inflammation
in a subject by administering a solid dosage formulation comprising
25 mg of rofecoxib, wherein the formulation achieves a mean plasma
concentration of at least about 1.0 ng/ml, 1.1 ng/ml, 1.2 ng/ml, or
1.3 ng/ml at 15 minutes following single administration of the
formulation to human subjects less than 65 years of age. In some
embodiments, the subject matter disclosed herein provides a method
for treating pain, fever, or inflammation in a subject by
administering a solid dosage formulation comprising 25 mg of
rofecoxib, wherein the formulation achieves an arithmetic mean
plasma concentration of at least about 4.6 ng/ml, 5.0 ng/ml, 5.4
ng/ml, or 5.6 ng/ml at 15 minutes following single administration
of the formulation to human subjects less than 65 years of age. In
some embodiments, the subject matter disclosed herein provides a
method for treating pain, fever, or inflammation in a subject by
administering a solid dosage formulation comprising 12.5 mg of
rofecoxib, wherein the formulation achieves a mean plasma
concentration of at least about 27 ng/ml, 29 ng/ml, 31 ng/ml, or 33
ng/ml at 45 minutes following single administration of the
formulation to human subjects less than 65 years of age. In some
embodiments, the subject matter disclosed herein provides a method
for treating pain, fever, or inflammation in a subject by
administering a solid dosage formulation comprising 12.5 mg of
rofecoxib, wherein the formulation achieves an arithmetic mean
plasma concentration of at least about 45 ng/ml, 48 ng/ml, 51
ng/ml, 54 ng/ml, or 56 ng/ml at 45 minutes following single
administration of the formulation to human subjects less than 65
years of age. In some embodiments, the subject matter disclosed
herein provides a method for treating pain, fever, or inflammation
in a subject by administering a solid dosage formulation comprising
17.5 mg of rofecoxib, wherein the formulation achieves a mean
plasma concentration of at least about 45 ng/ml, 47 ng/ml, 49
ng/ml, or 51 ng/ml at 45 minutes following single administration of
the formulation to human subjects less than 65 years of age. In
some embodiments, the subject matter disclosed herein provides a
method for treating pain, fever, or inflammation in a subject by
administering a solid dosage formulation comprising 17.5 mg of
rofecoxib, wherein the formulation achieves an arithmetic mean
plasma concentration of at least about 74 ng/ml, 79 ng/ml, 84
ng/ml, 89 ng/ml, or 93 ng/ml at 45 minutes following single
administration of the formulation to human subjects less than 65
years of age. In some embodiments, the subject matter disclosed
herein provides a method for treating pain, fever, or inflammation
in a subject by administering a solid dosage formulation comprising
20 mg of rofecoxib, wherein the formulation achieves a mean plasma
concentration of at least about 58 ng/ml, 62 ng/ml, 66 ng/ml, 70
ng/ml, or 72 ng/ml at 45 minutes following single administration of
the formulation to human subjects less than 65 years of age. In
some embodiments, the subject matter disclosed herein provides a
method for treating pain, fever, or inflammation in a subject by
administering a solid dosage formulation comprising 20 mg of
rofecoxib, wherein the formulation achieves an arithmetic mean
plasma concentration of at least about 112 ng/ml, 116 ng/ml, or 121
ng/ml at 45 minutes following single administration of the
formulation to human subjects less than 65 years of age. In some
embodiments, the subject matter disclosed herein provides a method
for treating pain, fever, or inflammation in a subject by
administering a solid dosage formulation comprising 25 mg of
rofecoxib, wherein the formulation achieves a mean plasma
concentration of at least about 78 ng/ml, 85 ng/ml, 92 ng/ml, or 97
ng/ml, at 45 minutes following single administration of the
formulation to human subjects less than 65 years of age. In some
embodiments, the subject matter disclosed herein provides a method
for treating pain, fever, or inflammation in a subject by
administering a solid dosage formulation comprising 25 mg of
rofecoxib, wherein the formulation achieves an arithmetic mean
plasma concentration of at least about 133 ng/ml, 139 ng/ml, 145
ng/ml, 151 ng/ml, or 159 ng/ml at 45 minutes following single
administration of the formulation to human subjects less than 65
years of age.
[0315] In certain aspects, the subject matter disclosed herein
provides a solid oral dosage form of a pharmaceutically acceptable
formulation comprising a granular component and an extragranular
component, wherein the granular component comprises an
intragranular component comprising rofecoxib or a pharmaceutically
acceptable salt thereof and one or more disintegrants, and wherein
the extragranular component comprises one or more
disintegrants.
[0316] In some embodiments, the one or more disintegrants in the
granular component is selected from starches, clays, celluloses,
algins, gums, cross-linked polymers, and combinations thereof. In
some embodiments, the one or more disintegrants in the granular
component is selected from croscarmellose, crospovidone, sodium
starch glycolate, and combinations thereof. In some embodiments,
the one or more disintegrants in the granular component is
croscarmellose sodium. In some embodiments, the one or more
disintegrants in the granular component is about 1% (w/w) to about
8% (w/w) of the formulation. In some embodiments, the one or more
disintegrants in the granular component is about 1% (w/w) to about
6% (w/w) of the formulation. In some embodiments, the one or more
disintegrants in the granular component is about 1% (w/w) to about
4% (w/w) of the formulation.
[0317] In some embodiments, the one or more disintegrants in the
extragranular component is selected from starches, clays,
celluloses, algins, gums, cross-linked polymers, and combinations
thereof. In some embodiments, the one or more disintegrants in the
extragranular component is selected from croscarmellose,
crospovidone, sodium starch glycolate, and combinations thereof. In
some embodiments, the one or more disintegrants in the
extragranular component is croscarmellose sodium. In some
embodiments, the disintegrant in the extragranular component is
about 1% (w/w) to about 8% (w/w) of the formulation. In some
embodiments, the disintegrant in the extragranular component is
about 1% (w/w) to about 6% (w/w) of the formulation. In some
embodiments, the disintegrant in the extragranular component is
about 1% (w/w) to about 4% (w/w) of the formulation.
[0318] In some embodiments, the disintegrant in the granular
component and the disintegrant in the extragranular component are
together about 2% (w/w) to about 12% (w/w) of the formulation. In
some embodiments, the disintegrant in the granular component and
the disintegrant in the extragranular component are together about
2% (w/w) to about 10% (w/w) of the formulation. In some
embodiments, the disintegrant in the granular component and the
disintegrant in the extragranular component are together about 2%
(w/w) to about 8% (w/w) of the formulation.
[0319] In some embodiments, the ratio of granular disintegrant to
extragranular disintegrant is about 40% (w/w) to about 60% (w/w).
In some embodiments, the ratio of granular disintegrant to
extragranular disintegrant is about 45% (w/w) to about 55% (w/w).
In some embodiments the ratio of granular disintegrant to
extragranular disintegrant is about 50% (w/w) to about 50% (w/w).
In some embodiments the ratio of granular disintegrant to
extragranular disintegrant is about 55% (w/w) to about 45% (w/w).
In some embodiments the ratio of granular disintegrant to
extragranular disintegrant is about 60% (w/w) to about 40%
(w/w).
[0320] In some embodiments, the solid oral dosage form of the
pharmaceutically acceptable formulation further comprising one or
more of a diluent, a binder, a coloring agent, and a lubricant. In
some embodiments, at least a portion of the diluent is in the
granular component. In some embodiments, the diluent is selected
from dicalcium phosphate, calcium sulfate, lactose, cellulose,
kaolin, mannitol, sodium chloride, dry starch, powdered sugar,
sorbitol, sucrose, inositol, and combinations thereof. In some
embodiments, the diluent is selected from lactose, cellulose, or a
combination thereof. In some embodiments, the diluent is selected
from lactose monohydrate, microcrystalline cellulose, or a
combination thereof.
[0321] In some embodiments, the lactose monohydrate is about 35%
(w/w) to about 45% (w/w) of the formulation. In some embodiments,
the lactose monohydrate is about 37% (w/w) to about 42% (w/w) of
the formulation. In some embodiments, the lactose monohydrate is
about 39% (w/w) to about 40% (w/w) of the formulation.
[0322] In some embodiments, the microcrystalline cellulose is about
35% (w/w) to about 45% (w/w) of the formulation. In some
embodiments, the microcrystalline cellulose is about 37% (w/w) to
about 42% (w/w) of the formulation. In some embodiments, the
microcrystalline cellulose is about 39% (w/w) to about 40% (w/w) of
the formulation.
[0323] In some embodiments, the diluent is about 75% (w/w) to about
85% (w/w) of the formulation. In some embodiments, diluent is about
77% (w/w) to about 82% (w/w) of the formulation. In some
embodiments, the diluent is about 78% (w/w) to about 80% (w/w) of
the formulation.
[0324] In some embodiments, at least a portion of the binder is in
the granular component. In some embodiments, the binder is selected
from starches, gelatins, sugars, gums, waxes, water, alcohols,
celluloses, and combinations thereof. In some embodiments, the
binder is selected from acacia gum, tragacanth, corn starch, methyl
cellulose, panwar gum, ghatti gum, mucilage of isapol husks,
carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone,
sucrose, glucose, dextrose, molasses, lactose, and combinations
thereof. In some embodiments, the binder is hydroxypropyl
cellulose. In some embodiments, the binder is about 1% (w/w) to
about 5% (w/w) of the formulation. In some embodiments, binder is
about 2% (w/w) to about 4% (w/w) of the formulation. In some
embodiments, the binder is about 2.5% (w/w) to about 3.5% (w/w) of
the formulation.
[0325] In some embodiments, at least a portion of the coloring
agent is in the extragranular component. In some embodiments, at
least a portion of the coloring agent is in the intragranular
component. In some embodiments, the coloring agent is pigment blend
yellow. In some embodiments, the coloring agent is about 0.30%
(w/w) to about 0.60% (w/w) of the formulation.
[0326] In some embodiments, at least a portion of the lubricant is
in the extragranular component. In some embodiments, the lubricant
is selected from talc, magnesium stearate, calcium stearate,
stearic acid, metallic stearate, hydrogenated vegetable oils, and
polyethylene glycol, corn starch, boric acids, sodium chloride,
sodium lauryl sulphate. In some embodiments, the lubricant is
magnesium stearate. In some embodiments, the lubricant is about
0.10% (w/w) to about 1% (w/w) of the formulation. In some
embodiments, the lubricant is about 0.50% (w/w) of the
formulation.
[0327] In some embodiments, the rofecoxib or pharmaceutically
acceptable salt thereof is about 5% (w/w) to about 30% (w/w) of the
formulation. In some embodiments, the rofecoxib or pharmaceutically
acceptable salt thereof is about 10% (w/w) to about 20% (w/w) of
the formulation. In some embodiments, the rofecoxib or
pharmaceutically acceptable salt thereof is about 12% (w/w) to
about 13% (w/w) of the formulation. In some embodiments, the
formulation comprises about 10 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 10.5 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 11 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 11.5 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 12 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 12.5 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 17.5 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 20 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 21 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 22 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 22.5 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 25 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 50 mg of the rofecoxib or
pharmaceutically acceptable salt thereof.
[0328] In some embodiments, the rofecoxib is highly pure. In some
embodiments, the highly pure rofecoxib comprises less than about
0.1% total impurities. In some embodiments, the highly pure
rofecoxib comprises less than about 0.075% total impurities. In
some embodiments, the highly pure rofecoxib comprises less than
about 0.050% total impurities. In some embodiments, the highly pure
rofecoxib comprises less than about 0.025% total impurities. In
some embodiments, the highly pure rofecoxib comprises less than
about 0.001% total impurities.
[0329] In some embodiments, the highly pure rofecoxib comprises
less than about 0.10%, 0.05%, 0.02%, or 0.01% of
4-[4-(methylsulphonyl)phenyl]-3-phenyl-2,5-furandione. In some
embodiments, the highly pure rofecoxib comprises less than about
0.10%, 0.05%, 0.02%, or 0.01% of
4-[4-(methylthio)phenyl]-3-phenyl-2(5H)-furanone. In some
embodiments, the highly pure rofecoxib comprises less than about
0.10%, 0.05%, 0.02%, or 0.01% of
4-[4-(methylthio)phenyl]-3-phenyl-2(5H)-furanone. In some
embodiments, the highly pure rofecoxib comprises less than about
0.10%, 0.05%, 0.02%, or 0.01% of
4-[4-(methylsulfinyl)phenyl]-3-phenyl-2(5H)-furanone.
[0330] In some embodiments, the solid oral dosage form is an oral
tablet. In some embodiments, the oral tablet provides a dissolution
rate of at least about 80% of the rofecoxib or pharmaceutically
acceptable salt thereof by about 15 minutes. In some embodiments,
the oral tablet provides a dissolution rate of at least about 85%
of the rofecoxib or pharmaceutically acceptable salt thereof by
about 15 minutes. In some embodiments, the oral tablet provides a
dissolution rate of at least about 90% of the rofecoxib or
pharmaceutically acceptable salt thereof by about 15 minutes. In
some embodiments, the oral tablet provides a dissolution rate of at
least about 95% of the rofecoxib or pharmaceutically acceptable
salt thereof by about 15 minutes. In some embodiments, the oral
tablet provides a dissolution rate of at least about 100% of the
rofecoxib or pharmaceutically acceptable salt thereof by about 15
minutes.
[0331] In some embodiments, the dissolution rate is measured in
about 1% SDS at a paddle speed of about 50 rpm and at a temperature
of about 37.0.degree. C..+-.0.5.degree. C. In some embodiments, the
dissolution rate is measured in about 1% SDS at a paddle speed of
about 75 rpm and at a temperature of about 37.0.degree.
C..+-.0.5.degree. C. In some embodiments, the dissolution rate is
measured in about 1.5% SDS at a paddle speed of about 50 rpm and at
a temperature of about 37.0.degree. C..+-.0.5.degree. C. In some
embodiments, the dissolution rate is measured in about 1.5% SDS at
a paddle speed of about 75 rpm and at a temperature of about
37.0.degree. C..+-.0.5.degree. C. In some embodiments, the
dissolution rate is measured in about 2% SDS at a paddle speed of
about 50 rpm and at a temperature of about 37.0.degree.
C..+-.0.5.degree. C. In some embodiments, the dissolution rate is
measured in about 2% SDS at a paddle speed of about 75 rpm and at a
temperature of about 37.0.degree. C..+-.0.5.degree. C. In some
embodiments, the dissolution rate is measured using a USP Type II
apparatus. In some embodiments, the dissolution rate is measured
with a USP Type II apparatus using 900 mL of 2% SDS, a paddle speed
of 50 rpm, and a temperature of 37.0.degree. C..+-.0.5.degree..
[0332] In some embodiments, the rofecoxib or pharmaceutically
acceptable salt thereof is formulated into granules and at least
about 35% of the granules are less than about 75 .mu.m. In some
embodiments, the rofecoxib or pharmaceutically acceptable salt
thereof is formulated into granules and at least about 55% of the
granules are less than about 150 .mu.m. In some embodiments, the
rofecoxib or pharmaceutically acceptable salt thereof is formulated
into granules and at least about 75% of the granules are less than
about 250 .mu.m. In some embodiments, the rofecoxib or
pharmaceutically acceptable salt thereof is formulated into
granules and at least about 85% of the granules are less than about
425 .mu.m. In some embodiments, the rofecoxib or pharmaceutically
acceptable salt thereof is formulated into granules and at least
about 90% of the granules are less than about 1000 .mu.m.
[0333] In some embodiments, a 17.5 mg solid dosage formulation of
rofecoxib reaches a median time to Cmax plasma concentration in 4
hours or less following single administration of the formulation to
human subjects. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib reaches a median time to Cmax plasma
concentration in 3 hours or less following administration. In some
embodiments, a 17.5 mg solid dosage formulation of rofecoxib
reaches a median time to Cmax plasma concentration in 2.5 hours or
less following administration. In some embodiments, a 17.5 mg solid
dosage formulation of rofecoxib reaches a median time to Cmax
plasma concentration in 2 hours or less following administration.
In some embodiments, a 17.5 mg solid dosage formulation of
rofecoxib has a mean Cmax plasma concentration of more than 100
ng/ml. In some embodiments, a 17.5 mg solid dosage formulation of
rofecoxib has a mean Cmax plasma concentration of more than 150
ng/ml, 167 ng/ml, or 190 ng/ml. In some embodiments, a 17.5 mg
solid dosage formulation of rofecoxib has a mean Cmax plasma
concentration of more than 200 ng/ml. In some embodiments, a 17.5
mg solid dosage formulation of rofecoxib has a mean Cmax plasma
concentration of more than 220 ng/ml. In some embodiments, a 17.5
mg solid dosage formulation of rofecoxib has a mean Cmax plasma
concentration of more than 250 ng/ml. In some embodiments, a 17.5
mg solid dosage formulation of rofecoxib has a mean Cmax plasma
concentration of more than 280 ng/ml. In some embodiments, a 17.5
mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 1750 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 2000 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 2500 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 3000 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 3500 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 4000 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 4500 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib reaches a Cmax plasma
concentration of least 167 ng/ml, 170 ng/ml, 175 ng/ml, 180 ng/ml,
or higher following single administration of the formulation to a
human subject. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib reaches an AUC.sub.0-.infin. of at least
2600 h*ng/ml, 2750 h*ng/ml, 2900 h*ng/ml, 3050 h*ng/ml, 3200
h*ng/ml, 3350 h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml or higher
following single administration of the formulation to a human
subject.
[0334] In some embodiments, a 20 mg solid dosage formulation of
rofecoxib reaches a median time to Cmax plasma concentration in 4
hours or less following single administration of the formulation to
human subjects. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib reaches a median time to Cmax plasma
concentration in 3 hours or less following administration. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib reaches
a median time to Cmax plasma concentration in 2.5 hours or less
following administration. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib reaches a median time to Cmax plasma
concentration in 2 hours or less following administration. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib has a
mean Cmax plasma concentration of more than 150 ng/ml. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib has a
mean Cmax plasma concentration of more than 191 ng/ml, 200 ng/ml,
215 ng/ml, or 225 ng/ml. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib has a mean Cmax plasma concentration of
more than 250 ng/ml. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib has a mean Cmax plasma concentration of
more than 258 ng/ml. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib has a mean Cmax plasma concentration of
more than 300 ng/ml. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib has a mean AUC.sub.0-.infin. of more than
2000 h*ng/ml. In some embodiments, a 20 mg solid dosage formulation
of rofecoxib has a mean AUC.sub.0-.infin. of more than 2500
h*ng/ml. In some embodiments, a 20 mg solid dosage formulation of
rofecoxib has a mean AUC.sub.0-.infin. of more than 3000 h*ng/ml.
In some embodiments, a 20 mg solid dosage formulation of rofecoxib
has a mean AUC.sub.0-.infin. of more than 3400 h*ng/ml. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 3500 h*ng/ml. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 4500 h*ng/ml. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib reaches
a Cmax plasma concentration of least 190 ng/ml, 205 ng/ml, 220
ng/ml, 235 ng/ml, 250 ng/ml, or higher following single
administration of the formulation to a human subject. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib reaches
an AUC.sub.0-.infin. of at least 3000 h*ng/ml, 3200 h*ng/ml, 3350
h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml, 3800 h*ng/ml, 3950 h*ng/ml, or
higher following single administration of the formulation to a
human subject. In some embodiments, the rofecoxib formulation
achieves a mean Cmax plasma concentration within 80% to 125% of 259
ng/ml and a mean AUC.sub.0-.infin. within 80% to 125% of 3550
h*ng/ml. In some embodiments, the rofecoxib formulation achieves a
mean plasma AUC.sub.0-.infin. of about 2840-4438 h*ng/ml and a mean
plasma Cmax of about 207-324 ng/ml following oral administration of
a single dose of the formulation to a population of healthy adults
less than 65 years of age in a fasted state. In some embodiments,
the population of healthy adults are less than 60 years of age.
[0335] In some embodiments, a 25 mg solid dosage formulation of
rofecoxib reaches a mean Cmax plasma concentration in less than 3
hours following single administration of the formulation to human
subjects. In some embodiments, a 25 mg solid dosage formulation of
rofecoxib reaches a mean Cmax plasma concentration in less than 2.5
hours following administration. In some embodiments, a 25 mg solid
dosage formulation of rofecoxib reaches a mean Cmax plasma
concentration in less than 2 hours following administration. In
some embodiments, a 25 mg solid dosage formulation of rofecoxib has
a mean Cmax plasma concentration of more than 240 ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean Cmax plasma concentration of more than 250 ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean Cmax plasma concentration of more than 300 ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean Cmax plasma concentration of more than 320 ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 4250 h*ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 4500 h*ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 4550 h*ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 4700 h*ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib reaches
a mean Cmax plasma concentration of more than 240 ng/ml in a median
time of about 3 hours or less following administration with an
AUC.sub.0-.infin. of more than 4250 h*ng/ml.
[0336] In some embodiments, a solid dosage formulation of 10 mg to
50 mg of rofecoxib achieves a mean Cmax plasma concentration from
9.8 ng/ml to 16 ng/ml for each 1 mg of rofecoxib in the formulation
following single administration of the formulation to human
subjects. In some embodiments, the solid dosage formulation of
rofecoxib achieves a mean Cmax plasma concentration from 10 ng/ml
to 14 ng/ml for each 1 mg of rofecoxib in the formulation. In some
embodiments, the solid dosage formulation of rofecoxib achieves a
mean Cmax plasma concentration from 10 ng/ml to 13 ng/ml for each 1
mg of rofecoxib in the formulation. In some embodiments, the solid
dosage formulation of rofecoxib achieves a mean Cmax plasma
concentration from 80% to 125% of 12.8 ng/ml. In some embodiments,
the solid dosage formulation of rofecoxib reaches a mean
AUC.sub.0-.infin. of 170 h*ng/ml to 235 h*ng/ml for each 1 mg of
rofecoxib in the formulation. In some embodiments, the solid dosage
formulation of rofecoxib reaches a mean AUC.sub.0-.infin. of 170
h*ng/ml to 225 h*ng/ml for each 1 mg of rofecoxib in the
formulation. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of 177 h*ng/ml to 225 h*ng/ml for each 1 mg of
rofecoxib in the formulation. In some embodiments, the formulation
achieves a mean AUC.sub.0-.infin. of 180 h*ng/ml to 225 h*ng/ml for
each 1 mg of rofecoxib in the formulation. In some embodiments, the
solid dosage formulation of rofecoxib reaches a mean
AUC.sub.0-.infin. of 190 h*ng/ml to 215 h*ng/ml for each 1 mg of
rofecoxib in the formulation.
[0337] In certain aspects, the subject matter disclosed herein
provides a solid oral dosage form of a pharmaceutically acceptable
formulation comprising a granular component and an extragranular
component, wherein the granular component comprises an
intragranular component comprising 17.5 mg of rofecoxib or a
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation achieves a median time to Cmax plasma concentration in
4 hours or less following single administration of the formulation
to human subjects. In some embodiments, the formulation achieves a
median time to Cmax plasma concentration in 3 hours or less
following administration. In some embodiments, the formulation
achieves a median time to Cmax plasma concentration in 2.5 hours or
less following administration. In some embodiments, the formulation
achieves a median time to Cmax plasma concentration in 2 hours or
less following administration. In some embodiments, the formulation
achieves a mean Cmax plasma concentration of more than 100 ng/ml.
In some embodiments, the formulation achieves a mean Cmax plasma
concentration of more than 150 ng/ml, 167 ng/ml, or 190 ng/ml. In
some embodiments, the formulation achieves a mean Cmax plasma
concentration of more than 200 ng/ml. In some embodiments, the
formulation achieves a mean Cmax plasma concentration of more than
220 ng/ml. In some embodiments, the formulation achieves a mean
Cmax plasma concentration of more than 250 ng/ml. In some
embodiments, the formulation achieves a mean Cmax plasma
concentration of more than 280 ng/ml. In some embodiments, the
formulation achieves a mean AUC.sub.0-.infin. of more than 1750
h*ng/ml. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 2000 h*ng/ml. In some embodiments,
the formulation achieves a mean AUC.sub.0-.infin. of more than 2500
h*ng/ml. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 3000 h*ng/ml. In some embodiments,
the formulation achieves a mean AUC.sub.0-.infin. of more than 3100
h*ng/ml. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 3500 h*ng/ml. In some embodiments,
the formulation achieves a mean AUC.sub.0-.infin. of more than 4000
h*ng/ml. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 4500 h*ng/ml. In some embodiments,
the formulation reaches a Cmax plasma concentration of least 167
ng/ml, 170 ng/ml, 175 ng/ml, 180 ng/ml, or higher following single
administration of the formulation to a human subject. In some
embodiments, the formulation reaches an AUC.sub.0-.infin. of at
least 2600 h*ng/ml, 2750 h*ng/ml, 2900 h*ng/ml, 3050 h*ng/ml, 3100
h*ng/ml, 3200 h*ng/ml, 3350 h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml or
higher following single administration of the formulation to a
human subject.
[0338] In certain aspects, the subject matter disclosed herein
provides a solid oral dosage form of a pharmaceutically acceptable
formulation comprising a granular component and an extragranular
component, wherein the granular component comprises an
intragranular component comprising 20 mg of rofecoxib or a
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation achieves a median time to Cmax plasma concentration in
4 hours or less following single administration of the formulation
to human subjects. In some embodiments, the formulation achieves a
median time to Cmax plasma concentration in 3 hours or less
following administration. In some embodiments, the formulation
achieves a median time to Cmax plasma concentration in 2.5 hours or
less following administration. In some embodiments, the formulation
achieves a median time to Cmax plasma concentration in 2 hours or
less following administration. In some embodiments, the formulation
achieves a mean Cmax plasma concentration of more than 150 ng/ml.
In some embodiments, the formulation achieves a mean Cmax plasma
concentration of more than 191 ng/ml, 200 ng/ml, 215 ng/ml, or 225
ng/ml. In some embodiments, the formulation achieves a mean Cmax
plasma concentration of more than 250 ng/ml. In some embodiments,
the formulation achieves a mean Cmax plasma concentration of more
than 258 ng/ml. In some embodiments, the formulation achieves a
mean Cmax plasma concentration of more than 300 ng/ml. In some
embodiments, the formulation achieves a mean AUC.sub.0-.infin. of
more than 2000 h*ng/ml. In some embodiments, the formulation
achieves a mean AUC.sub.0-.infin. of more than 2500 h*ng/ml. In
some embodiments, the formulation achieves a mean AUC.sub.0-.infin.
of more than 3000 h*ng/ml. In some embodiments, the formulation
achieves a mean AUC.sub.0-.infin. of more than 3400 h*ng/ml. In
some embodiments, the formulation achieves a mean AUC.sub.0-.infin.
of more than 3500 h*ng/ml. In some embodiments, the formulation
achieves a mean AUC.sub.0-.infin. of more than 4000 h*ng/ml. In
some embodiments, the formulation reaches a Cmax plasma
concentration of least 190 ng/ml, 205 ng/ml, 220 ng/ml, 235 ng/ml,
250 ng/ml, or higher following single administration of the
formulation to a human subject. In some embodiments, the
formulation reaches an AUC.sub.0-.infin. of at least 3000 h*ng/ml,
3200 h*ng/ml, 3350 h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml, 3800
h*ng/ml, 3950 h*ng/ml, or higher following single administration of
the formulation to a human subject. In some embodiments, the
rofecoxib formulation achieves a mean Cmax plasma concentration
within 80% to 125% of 259 ng/ml and a mean AUC.sub.0-.infin. within
80% to 125% of 3550 h*ng/ml. In some embodiments, the rofecoxib
formulation achieves a mean plasma AUC.sub.0-.infin. of about
2840-4438 h*ng/ml and a mean plasma Cmax of about 207-324 ng/ml
following oral administration of a single dose of the formulation
to a population of healthy adults less than 65 years of age in a
fasted state. In some embodiments, the population of healthy adults
are less than 60 years of age.
[0339] In certain aspects, the subject matter disclosed herein
provides a solid oral dosage form of a pharmaceutically acceptable
formulation comprising a granular component and an extragranular
component, wherein the granular component comprises an
intragranular component comprising 25 mg of rofecoxib or a
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation achieves a mean Cmax plasma concentration in less than
3 hours following single administration of the formulation to human
subjects. In some embodiments, the formulation achieves a mean Cmax
plasma concentration in less than 2.5 hours following
administration. In some embodiments, the formulation achieves a
mean Cmax plasma concentration in less than 2 hours following
administration. In some embodiments, the formulation achieves a
mean Cmax plasma concentration of more than 240 ng/ml. In some
embodiments, the formulation achieves a mean Cmax plasma
concentration of more than 300 ng/ml. In some embodiments, the
formulation achieves a mean Cmax plasma concentration of more than
320 ng/ml. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 4250 h*ng/ml. In some embodiments,
the formulation achieves a mean AUC.sub.0-.infin. of more than 4500
h*ng/ml. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 4550 h*ng/ml. In some embodiments,
the formulation achieves a mean AUC.sub.0-.infin. of more than 4700
h*ng/ml. In some embodiments, the formulation achieves a Cmax
plasma concentration of more than 240 ng/ml in about 3 hours
following administration with an AUC.sub.0-.infin. of more than
4250 h*ng/ml.
[0340] The subject matter disclosed herein provides a solid oral
dosage form of a pharmaceutically acceptable formulation comprising
a granular component and an extragranular component, wherein the
granular component comprises an intragranular component comprising
10 mg to 50 mg of rofecoxib or a pharmaceutically acceptable salt
thereof that achieves a mean Cmax plasma concentration from 9.8
ng/ml to 16 ng/ml for each 1 mg of rofecoxib in the formulation
following single administration of the formulation to human
subjects. In some embodiments, the solid dosage formulation of
rofecoxib achieves a mean Cmax plasma concentration from 10 ng/ml
to 14 ng/ml for each 1 mg of rofecoxib in the formulation. In some
embodiments, the solid dosage formulation of rofecoxib achieves a
mean Cmax plasma concentration from 10 ng/ml to 13 ng/ml for each 1
mg of rofecoxib in the formulation. In some embodiments, the solid
dosage formulation of rofecoxib achieves a mean Cmax plasma
concentration from 80% to 125% of 12.8 ng/ml. In some embodiments,
the solid dosage formulation of rofecoxib reaches a mean
AUC.sub.0-.infin. of 170 h*ng/ml to 235 h*ng/ml for each 1 mg of
rofecoxib in the formulation. In some embodiments, the solid dosage
formulation of rofecoxib reaches a mean AUC.sub.0-.infin. of 170
h*ng/ml to 225 h*ng/ml for each 1 mg of rofecoxib in the
formulation. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of 177 h*ng/ml to 225 h*ng/ml for each 1 mg of
rofecoxib in the formulation. In some embodiments, the formulation
achieves a mean AUC.sub.0-.infin. of 180 h*ng/ml to 225 h*ng/ml for
each 1 mg of rofecoxib in the formulation. In some embodiments, the
solid dosage formulation of rofecoxib reaches a mean
AUC.sub.0-.infin. of 190 h*ng/ml to 215 h*ng/ml for each 1 mg of
rofecoxib in the formulation.
[0341] A method for inhibiting COX-2 in a subject in need thereof,
the method comprising administering to the subject a
pharmaceutically acceptable formulation comprising a granular
component and an extragranular component, wherein the granular
component comprises an intragranular component comprising rofecoxib
or a pharmaceutically acceptable salt thereof and one or more
disintegrants, and wherein the extragranular component comprises
one or more disintegrants.
[0342] In some embodiments, the one or more disintegrants in the
granular component is selected from starches, clays, celluloses,
algins, gums, cross-linked polymers, and combinations thereof. In
some embodiments, the one or more disintegrants in the granular
component is selected from croscarmellose, crospovidone, sodium
starch glycolate, and combinations thereof. In some embodiments,
the one or more disintegrants in the granular component is
croscarmellose sodium. In some embodiments, the one or more
disintegrants in the granular component is about 1% (w/w) to about
8% (w/w) of the formulation. In some embodiments, the one or more
disintegrants in the granular component is about 1% (w/w) to about
6% (w/w) of the formulation. In some embodiments, the one or more
disintegrants in the granular component is about 1% (w/w) to about
4% (w/w) of the formulation.
[0343] In some embodiments, the one or more disintegrants in the
extragranular component is selected from starches, clays,
celluloses, algins, gums, cross-linked polymers, and combinations
thereof. In some embodiments, the one or more disintegrants in the
extragranular component is selected from croscarmellose,
crospovidone, sodium starch glycolate, and combinations thereof. In
some embodiments, the one or more disintegrants in the
extragranular component is croscarmellose sodium. In some
embodiments, the disintegrant in the extragranular component is
about 1% (w/w) to about 8% (w/w) of the formulation. In some
embodiments, the disintegrant in the extragranular component is
about 1% (w/w) to about 6% (w/w) of the formulation. In some
embodiments, the disintegrant in the extragranular component is
about 1% (w/w) to about 4% (w/w) of the formulation.
[0344] In some embodiments, the disintegrant in the granular
component and the disintegrant in the extragranular component are
together about 2% (w/w) to about 12% (w/w) of the formulation. In
some embodiments, the disintegrant in the granular component and
the disintegrant in the extragranular component are together about
2% (w/w) to about 10% (w/w) of the formulation. In some
embodiments, the disintegrant in the granular component and the
disintegrant in the extragranular component are together about 2%
(w/w) to about 8% (w/w) of the formulation.
[0345] In some embodiments, the ratio of granular disintegrant to
extragranular disintegrant is about 40% (w/w) to about 60% (w/w).
In some embodiments, the ratio of granular disintegrant to
extragranular disintegrant is about 45% (w/w) to about 55% (w/w).
In some embodiments, the ratio of granular disintegrant to
extragranular disintegrant is about 50% (w/w) to about 50% (w/w).
In some embodiments, the ratio of granular disintegrant to
extragranular disintegrant is about 55% (w/w) to about 45% (w/w).
In some embodiments the ratio of granular disintegrant to
extragranular disintegrant is about 60% (w/w) to about 40%
(w/w).
[0346] In some embodiments, the pharmaceutically acceptable
formulation further comprises one or more of a diluent, a binder, a
coloring agent, and a lubricant. In some embodiments, at least a
portion of the diluent is in the granular component. In some
embodiments, the diluent is selected from dicalcium phosphate,
calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium
chloride, dry starch, powdered sugar, sorbitol, sucrose, inositol,
and combinations thereof. In some embodiments, the diluent is
selected from lactose, cellulose, or a combination thereof. In some
embodiments, the diluent is selected from lactose monohydrate,
microcrystalline cellulose, or a combination thereof.
[0347] In some embodiments, the lactose monohydrate is about 35%
(w/w) to about 45% (w/w) of the formulation. In some embodiments,
the lactose monohydrate is about 37% (w/w) to about 42% (w/w) of
the formulation. In some embodiments, the lactose monohydrate is
about 39% (w/w) to about 40% (w/w) of the formulation.
[0348] In some embodiments, the microcrystalline cellulose is about
35% (w/w) to about 45% (w/w) of the formulation. In some
embodiments, the microcrystalline cellulose is about 37% (w/w) to
about 42% (w/w) of the formulation. In some embodiments, the
microcrystalline cellulose is about 39% (w/w) to about 40% (w/w) of
the formulation.
[0349] In some embodiments, the diluent is about 75% (w/w) to about
85% (w/w) of the formulation. In some embodiments, diluent is about
77% (w/w) to about 82% (w/w) of the formulation. In some
embodiments, the diluent is about 78% (w/w) to about 80% (w/w) of
the formulation.
[0350] In some embodiments, at least a portion of the binder is in
the granular component. In some embodiments, the binder is selected
from starches, gelatins, sugars, gums, waxes, water, alcohols,
celluloses, and combinations thereof. In some embodiments, the
binder is selected from acacia gum, tragacanth, corn starch, methyl
cellulose, panwar gum, ghatti gum, mucilage of isapol husks,
carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone,
sucrose, glucose, dextrose, molasses, lactose, and combinations
thereof. In some embodiments, the binder is hydroxypropyl
cellulose. In some embodiments, the binder is about 1% (w/w) to
about 5% (w/w) of the formulation. In some embodiments, binder is
about 2% (w/w) to about 4% (w/w) of the formulation. In some
embodiments, the binder is about 2.5% (w/w) to about 3.5% (w/w) of
the formulation.
[0351] In some embodiments, at least a portion of the coloring
agent is in the extragranular component. In some embodiments, the
coloring agent is pigment blend yellow. In some embodiments, the
coloring agent is about 0.30% (w/w) to about 0.60% (w/w) of the
formulation.
[0352] In some embodiments, at least a portion of the lubricant is
in the extragranular component. In some embodiments, the lubricant
is selected from talc, magnesium stearate, calcium stearate,
stearic acid, metallic stearate, hydrogenated vegetable oils, and
polyethylene glycol, corn starch, boric acids, sodium chloride,
sodium lauryl sulphate. In some embodiments, the lubricant is
magnesium stearate. In some embodiments, the lubricant is about
0.10% (w/w) to about 1% (w/w) of the formulation. In some
embodiments, the lubricant is about 0.50% (w/w) of the
formulation.
[0353] In some embodiments, the rofecoxib or pharmaceutically
acceptable salt thereof is about 5% (w/w) to about 30% (w/w) of the
formulation. In some embodiments, the rofecoxib or pharmaceutically
acceptable salt thereof is about 10% (w/w) to about 20% (w/w) of
the formulation. In some embodiments, the rofecoxib or
pharmaceutically acceptable salt thereof is about 12% (w/w) to
about 13% (w/w) of the formulation. In some embodiments, the
formulation comprises about 10 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 10.5 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 11 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 11.5 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 12 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 12.5 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 17.5 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 20 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 21 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 22 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 22.5 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 25 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 50 mg of the rofecoxib or
pharmaceutically acceptable salt thereof.
[0354] In some embodiments, the rofecoxib is highly pure. In some
embodiments, the highly pure rofecoxib comprises less than about
0.1% total impurities. In some embodiments, the highly pure
rofecoxib comprises less than about 0.075% total impurities. In
some embodiments, the highly pure rofecoxib comprises less than
about 0.050% total impurities. In some embodiments, the highly pure
rofecoxib comprises less than about 0.025% total impurities. In
some embodiments, the highly pure rofecoxib comprises less than
about 0.001% total impurities.
[0355] In some embodiments, the highly pure rofecoxib comprises
less than about 0.10%, 0.05%, 0.02%, or 0.01% of
4-[4-(methylsulphonyl)phenyl]-3-phenyl-2,5-furandione. In some
embodiments, the highly pure rofecoxib comprises less than about
0.10%, 0.05%, 0.02%, or 0.01% of
4-[4-(methylthio)phenyl]-3-phenyl-2(5H)-furanone. In some
embodiments, the highly pure rofecoxib comprises less than about
0.10%, 0.05%, 0.02%, or 0.01% of
4-[4-(methylthio)phenyl]-3-phenyl-2(5H)-furanone. In some
embodiments, the highly pure rofecoxib comprises less than about
0.10%, 0.05%, 0.02%, or 0.01% of
4-[4-(methylsulfinyl)phenyl]-3-phenyl-2(5H)-furanone.
[0356] In some embodiments, the formulation is suitable for oral
administration. In some embodiments, the formulation is a solid
dosage form. In some embodiments, the solid dosage form is an oral
tablet. In some embodiments, the oral tablet provides a dissolution
rate of at least about 80% of the rofecoxib or pharmaceutically
acceptable salt thereof by about 15 minutes. In some embodiments,
the oral tablet provides a dissolution rate of at least about 85%
of the rofecoxib or pharmaceutically acceptable salt thereof by
about 15 minutes. In some embodiments, the oral tablet provides a
dissolution rate of at least about 90% of the rofecoxib or
pharmaceutically acceptable salt thereof by about 15 minutes. In
some embodiments, the oral tablet provides a dissolution rate of at
least about 95% of the rofecoxib or pharmaceutically acceptable
salt thereof by about 15 minutes. In some embodiments, the oral
tablet provides a dissolution rate of at least about 100% of the
rofecoxib or pharmaceutically acceptable salt thereof by about 15
minutes.
[0357] In some embodiments, the dissolution rate is measured in
about 1% SDS at a paddle speed of about 50 rpm and at a temperature
of about 37.0.degree. C..+-.0.5.degree. C. In some embodiments, the
dissolution rate is measured in about 1% SDS at a paddle speed of
about 75 rpm and at a temperature of about 37.0.degree.
C..+-.0.5.degree. C. In some embodiments, the dissolution rate is
measured in about 1.5% SDS at a paddle speed of about 50 rpm and at
a temperature of about 37.0.degree. C..+-.0.5.degree. C. In some
embodiments, the dissolution rate is measured in about 1.5% SDS at
a paddle speed of about 75 rpm and at a temperature of about
37.0.degree. C..+-.0.5.degree. C. In some embodiments, the
dissolution rate is measured in about 2% SDS at a paddle speed of
about 50 rpm and at a temperature of about 37.0.degree.
C..+-.0.5.degree. C. In some embodiments, the dissolution rate is
measured in about 2% SDS at a paddle speed of about 75 rpm and at a
temperature of about 37.0.degree. C..+-.0.5.degree. C. In some
embodiments, the dissolution rate is measured using a USP Type II
apparatus. In some embodiments, the dissolution rate is measured
with a USP Type II apparatus using 900 mL of 2% SDS, a paddle speed
of 50 rpm, and a temperature of 37.0.degree. C..+-.0.5.degree..
[0358] In some embodiments, the rofecoxib or pharmaceutically
acceptable salt thereof is formulated into granules and at least
about 35% of the granules are less than about 75 .mu.m. In some
embodiments, the rofecoxib or pharmaceutically acceptable salt
thereof is formulated into granules and at least about 55% of the
granules are less than about 150 .mu.m. In some embodiments, the
rofecoxib or pharmaceutically acceptable salt thereof is formulated
into granules and at least about 75% of the granules are less than
about 250 .mu.m. In some embodiments, the rofecoxib or
pharmaceutically acceptable salt thereof is formulated into
granules and at least about 85% of the granules are less than about
425 .mu.m. In some embodiments, the rofecoxib or pharmaceutically
acceptable salt thereof is formulated into granules and at least
about 90% of the granules are less than about 1000 .mu.m.
[0359] In some embodiments, a 17.5 mg solid dosage formulation of
rofecoxib reaches a median time to Cmax plasma concentration in 4
hours or less following single administration of the formulation to
human subjects. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib reaches a median time to Cmax plasma
concentration in 3 hours or less following administration. In some
embodiments, a 17.5 mg solid dosage formulation of rofecoxib
reaches a median time to Cmax plasma concentration in 2.5 hours or
less following administration. In some embodiments, a 17.5 mg solid
dosage formulation of rofecoxib reaches a median time to Cmax
plasma concentration in 2 hours or less following administration.
In some embodiments, a 17.5 mg solid dosage formulation of
rofecoxib has a mean Cmax plasma concentration of more than 100
ng/ml. In some embodiments, a 17.5 mg solid dosage formulation of
rofecoxib has a mean Cmax plasma concentration of more than 150
ng/ml, 167 ng/ml, or 190 ng/ml. In some embodiments, a 17.5 mg
solid dosage formulation of rofecoxib has a mean Cmax plasma
concentration of more than 200 ng/ml. In some embodiments, a 17.5
mg solid dosage formulation of rofecoxib has a mean Cmax plasma
concentration of more than 220 ng/ml. In some embodiments, a 17.5
mg solid dosage formulation of rofecoxib has a mean Cmax plasma
concentration of more than 250 ng/ml. In some embodiments, a 17.5
mg solid dosage formulation of rofecoxib has a mean Cmax plasma
concentration of more than 280 ng/ml. In some embodiments, a 17.5
mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 1750 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 2000 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 2500 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 3000 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 3100 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 3500 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 4000 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 4500 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib reaches a Cmax plasma
concentration of least 167 ng/ml, 170 ng/ml, 175 ng/ml, 180 ng/ml,
or higher following single administration of the formulation to a
human subject. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib reaches an AUC.sub.0-.infin. of at least
2600 h*ng/ml, 2750 h*ng/ml, 2900 h*ng/ml, 3050 h*ng/ml, 3100
h*ng/ml, 3200 h*ng/ml, 3350 h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml or
higher following single administration of the formulation to a
human subject.
[0360] In some embodiments, a 20 mg solid dosage formulation of
rofecoxib reaches a median time to Cmax plasma concentration in 4
hours or less following single administration of the formulation to
human subjects. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib reaches a median time to Cmax plasma
concentration in 3 hours or less following administration. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib reaches
a median time to Cmax plasma concentration in 2.5 hours or less
following administration. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib reaches a median time to Cmax plasma
concentration in 2 hours or less following administration. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib has a
mean Cmax plasma concentration of more than 150 ng/ml. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib has a
mean Cmax plasma concentration of more than 191 ng/ml, 200 ng/ml,
215 ng/ml, or 225 ng/ml. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib has a mean Cmax plasma concentration of
more than 250 ng/ml. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib has a mean Cmax plasma concentration of
more than 258 ng/ml. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib has a mean Cmax plasma concentration of
more than 300 ng/ml. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib has a mean AUC.sub.0-.infin. of more than
2000 h*ng/ml. In some embodiments, a 20 mg solid dosage formulation
of rofecoxib has a mean AUC.sub.0-.infin. of more than 2500
h*ng/ml. In some embodiments, a 20 mg solid dosage formulation of
rofecoxib has a mean AUC.sub.0-.infin. of more than 3000 h*ng/ml.
In some embodiments, a 20 mg solid dosage formulation of rofecoxib
has a mean AUC.sub.0-.infin. of more than 3400 h*ng/ml. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 3500 h*ng/ml. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 4000 h*ng/ml. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib reaches
a Cmax plasma concentration of least 190 ng/ml, 205 ng/ml, 220
ng/ml, 235 ng/ml, 250 ng/ml, or higher following single
administration of the formulation to a human subject. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib reaches
an AUC.sub.0-.infin. of at least 3000 h*ng/ml, 3200 h*ng/ml, 3350
h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml, 3800 h*ng/ml, 3950 h*ng/ml, or
higher following single administration of the formulation to a
human subject. In some embodiments, the rofecoxib formulation
achieves a mean Cmax plasma concentration within 80% to 125% of 259
ng/ml and a mean AUC.sub.0-.infin. within 80% to 125% of 3550
h*ng/ml. In some embodiments, the rofecoxib formulation achieves a
mean plasma AUC.sub.0-.infin. of about 2840-4438 h*ng/ml and a mean
plasma Cmax of about 207-324 ng/ml following oral administration of
a single dose of the formulation to a population of healthy adults
less than 65 years of age in a fasted state. In some embodiments,
the population of healthy adults are less than 60 years of age.
[0361] In some embodiments, a 25 mg solid dosage formulation of
rofecoxib reaches a mean Cmax plasma concentration in less than 3
hours following single administration of the formulation to human
subjects. In some embodiments, a 25 mg solid dosage formulation of
rofecoxib reaches a mean Cmax plasma concentration in less than 2.5
hours following administration. In some embodiments, a 25 mg solid
dosage formulation of rofecoxib reaches a mean Cmax plasma
concentration in less than 2 hours following administration. In
some embodiments, a 25 mg solid dosage formulation of rofecoxib has
a mean Cmax plasma concentration of more than 240 ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean Cmax plasma concentration of more than 250 ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean Cmax plasma concentration of more than 300 ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean Cmax plasma concentration of more than 320 ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 4250 h*ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 4500 h*ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 4700 h*ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 5000 h*ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib reaches
a Cmax plasma concentration of more than 240 ng/ml in a median time
of about 3 hours or less following administration with an
AUC.sub.0-.infin. of more than 4250 h*ng/ml.
[0362] In some embodiments, a 10 mg to 50 mg solid dosage
formulation of rofecoxib achieves a mean Cmax plasma concentration
from 9.8 ng/ml to 16 ng/ml for each 1 mg of rofecoxib in the
formulation following single administration of the formulation to
human subjects. In some embodiments, the solid dosage formulation
of rofecoxib achieves a mean Cmax plasma concentration from 10
ng/ml to 14 ng/ml for each 1 mg of rofecoxib in the formulation. In
some embodiments, the solid dosage formulation of rofecoxib
achieves a mean Cmax plasma concentration from 10 ng/ml to 13 ng/ml
for each 1 mg of rofecoxib in the formulation. In some embodiments,
the solid dosage formulation of rofecoxib achieves a mean Cmax
plasma concentration from 80% to 125% of 12.8 ng/ml. In some
embodiments, the solid dosage formulation of rofecoxib reaches a
mean AUC.sub.0-.infin. of 170 h*ng/ml to 235 h*ng/ml for each 1 mg
of rofecoxib in the formulation. In some embodiments, the solid
dosage formulation of rofecoxib reaches a mean AUC.sub.0-.infin. of
170 h*ng/ml to 225 h*ng/ml for each 1 mg of rofecoxib in the
formulation. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of 177 h*ng/ml to 225 h*ng/ml for each 1 mg of
rofecoxib in the formulation. In some embodiments, the formulation
achieves a mean AUC.sub.0-.infin. of 180 h*ng/ml to 225 h*ng/ml for
each 1 mg of rofecoxib in the formulation. In some embodiments, the
solid dosage formulation of rofecoxib reaches a mean
AUC.sub.0-.infin. of 190 h*ng/ml to 215 h*ng/ml for each 1 mg of
rofecoxib in the formulation.
[0363] In certain aspects, the subject matter disclosed herein
provides a method for inhibiting COX-2 in a subject in need
thereof, the method comprising administering to the subject a solid
dosage formulation comprising 17.5 mg of rofecoxib or a
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation achieves a median time to Cmax plasma concentration in
4 hours or less following single administration of the formulation
to human subjects. In some embodiments, the formulation achieves a
median time to Cmax plasma concentration in 3 hours or less
following administration. In some embodiments, the formulation
achieves a median time to Cmax plasma concentration in 2.5 hours or
less following administration. In some embodiments, the formulation
achieves a median time to Cmax plasma concentration in 2 hours or
less following administration. In some embodiments, the formulation
achieves a mean Cmax plasma concentration of more than 100 ng/ml.
In some embodiments, the formulation achieves a mean Cmax plasma
concentration of more than 150 ng/ml, 167 ng/ml, or 190 ng/ml. In
some embodiments, the formulation achieves a mean Cmax plasma
concentration of more than 200 ng/ml. In some embodiments, the
formulation achieves a mean Cmax plasma concentration of more than
220 ng/ml. In some embodiments, the formulation achieves a mean
Cmax plasma concentration of more than 250 ng/ml. In some
embodiments, the formulation achieves a mean Cmax plasma
concentration of more than 280 ng/ml. In some embodiments, the
formulation achieves a mean AUC.sub.0-.infin. of more than 1750
h*ng/ml. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 2000 h*ng/ml. In some embodiments,
the formulation achieves a mean AUC.sub.0-.infin. of more than 2500
h*ng/ml. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 3000 h*ng/ml. In some embodiments,
the formulation achieves a mean AUC.sub.0-.infin. of more than 3500
h*ng/ml. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 4000 h*ng/ml. In some embodiments,
the formulation achieves a mean AUC.sub.0-.infin. of more than 4500
h*ng/ml. In some embodiments, a 17.5 mg solid dosage formulation of
rofecoxib reaches a Cmax plasma concentration of least 167 ng/ml,
170 ng/ml, 175 ng/ml, 180 ng/ml, or higher following single
administration of the formulation to a human subject. In some
embodiments, a 17.5 mg solid dosage formulation of rofecoxib
reaches an AUC.sub.0-.infin. of at least 2600 h*ng/ml, 2750
h*ng/ml, 2900 h*ng/ml, 3050 h*ng/ml, 3200 h*ng/ml, 3350 h*ng/ml,
3500 h*ng/ml, 3650 h*ng/ml or higher following single
administration of the formulation to a human subject.
[0364] In certain aspects, the subject matter disclosed herein
provides a method for inhibiting COX-2 in a subject in need
thereof, the method comprising administering to the subject a solid
dosage formulation comprising 20 mg of rofecoxib or a
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation achieves a median time to Cmax plasma concentration in
4 hours or less following single administration of the formulation
to human subjects. In some embodiments, the formulation achieves a
median time to Cmax plasma concentration in 3 hours or less
following administration. In some embodiments, the formulation
achieves a mean Cmax plasma concentration in less than 3 hours
following administration. In some embodiments, the formulation
achieves a median time to Cmax plasma concentration in 2.5 hours or
less following administration. In some embodiments, the formulation
achieves a median time to Cmax plasma concentration in 2 hours or
less following administration. In some embodiments, the formulation
achieves a mean Cmax plasma concentration of more than 150 ng/ml.
In some embodiments, the formulation achieves a mean Cmax plasma
concentration of more than 191 ng/ml, 200 ng/ml, 215 ng/ml, or 225
ng/ml. In some embodiments, the formulation achieves a mean Cmax
plasma concentration of more than 250 ng/ml. In some embodiments,
the formulation achieves a mean Cmax plasma concentration of more
than 258 ng/ml. In some embodiments, the formulation achieves a
mean Cmax plasma concentration of more than 300 ng/ml. In some
embodiments, the formulation achieves a mean AUC.sub.0-.infin. of
more than 2000 h*ng/ml. In some embodiments, the formulation
achieves a mean AUC.sub.0-.infin. of more than 2500 h*ng/ml. In
some embodiments, the formulation achieves a mean AUC.sub.0-.infin.
of more than 3000 h*ng/ml. In some embodiments, the formulation
achieves a mean AUC.sub.0-.infin. of more than 3400 h*ng/ml. In
some embodiments, the formulation achieves a mean AUC.sub.0-.infin.
of more than 3500 h*ng/ml. In some embodiments, the formulation
achieves a mean AUC.sub.0-.infin. of more than 4000 h*ng/ml. In
some embodiments, the formulation reaches a Cmax plasma
concentration of least 190 ng/ml, 205 ng/ml, 220 ng/ml, 235 ng/ml,
250 ng/ml, or higher following single administration of the
formulation to a human subject. In some embodiments, the
formulation reaches an AUC.sub.0-.infin. of at least 3000 h*ng/ml,
3200 h*ng/ml, 3350 h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml, 3800
h*ng/ml, 3950 h*ng/ml, or higher following single administration of
the formulation to a human subject.
[0365] In certain aspects, the subject matter disclosed herein
provides a method for inhibiting COX-2 in a subject in need
thereof, the method comprising administering to the subject a solid
dosage formulation comprising 25 mg of rofecoxib or a
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation achieves a mean Cmax plasma concentration in less than
3 hours following single administration of the formulation to human
subjects. In some embodiments, the formulation achieves a mean Cmax
plasma concentration in less than 2.5 hours following
administration. In some embodiments, the formulation achieves a
mean Cmax plasma concentration in less than 2 hours following
administration. In some embodiments, the formulation achieves a
mean Cmax plasma concentration of more than 240 ng/ml. In some
embodiments, the formulation achieves a mean Cmax plasma
concentration of more than 250 ng/ml. In some embodiments, the
formulation achieves a mean Cmax plasma concentration of more than
300 ng/ml. In some embodiments, the formulation achieves a mean
Cmax plasma concentration of more than 320 ng/ml. In some
embodiments, the formulation achieves a mean AUC.sub.0-.infin. of
more than 4250 h*ng/ml. In some embodiments, the formulation
achieves a mean AUC.sub.0-.infin. of more than 4500 h*ng/ml. In
some embodiments, the formulation achieves a mean AUC.sub.0-.infin.
of more than 4550 h*ng/ml. In some embodiments, the formulation
achieves a mean AUC.sub.0-.infin. of more than 4700 h*ng/ml. In
some embodiments, the formulation achieves a Cmax plasma
concentration of more than 240 ng/ml about 3 hours following
administration with an AUC.sub.0-.infin. of more than 4250
h*ng/ml.
[0366] In certain aspects, the subject matter disclosed herein
provides a method for inhibiting COX-2 in a subject in need
thereof, the method comprising administering to the subject a solid
dosage formulation comprising 10 mg to 50 mg of rofecoxib or a
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation achieves a mean Cmax plasma concentration from 9.8
ng/ml to 16 ng/ml for each 1 mg of rofecoxib in the formulation
following single administration of the formulation to human
subjects. In some embodiments, the formulation of rofecoxib
achieves a mean Cmax plasma concentration from 10 ng/ml to 14 ng/ml
for each 1 mg of rofecoxib in the formulation. In some embodiments,
the formulation of rofecoxib achieves a mean Cmax plasma
concentration from 10 ng/ml to 13 ng/ml for each 1 mg of rofecoxib
in the formulation. In some embodiments, the solid dosage
formulation of rofecoxib achieves a mean Cmax plasma concentration
from 80% to 125% of 12.8 ng/ml. In some embodiments, the
formulation of rofecoxib reaches a mean AUC.sub.0-.infin. of 170
h*ng/ml to 235 h*ng/ml for each 1 mg of rofecoxib in the
formulation. In some embodiments, the formulation of rofecoxib
reaches a mean AUC.sub.0-.infin. of 170 h*ng/ml to 225 h*ng/ml for
each 1 mg of rofecoxib in the formulation. In some embodiments, the
formulation achieves a mean AUC.sub.0-.infin. of 177 h*ng/ml to 225
h*ng/ml for each 1 mg of rofecoxib in the formulation. In some
embodiments, the formulation achieves a mean AUC.sub.0-.infin. of
180 h*ng/ml to 225 h*ng/ml for each 1 mg of rofecoxib in the
formulation. In some embodiments, the formulation of rofecoxib
reaches a mean AUC.sub.0-.infin. of 190 h*ng/ml to 215 h*ng/ml for
each 1 mg of rofecoxib in the formulation.
[0367] In certain aspects, a method is provided for inhibiting
COX-2 in patients within a patient population, the method
comprising providing a solid dosage formulation comprising 10 mg to
50 mg of rofecoxib to the patient population, wherein the
formulation achieves a mean Cmax plasma concentration from 9.8
ng/ml to 16 ng/ml for each 1 mg of rofecoxib in the formulation
following single administration of the formulation to the patients
within the patient population. In some embodiments, the solid
dosage formulation of rofecoxib achieves a mean Cmax plasma
concentration from 10 ng/ml to 14 ng/ml for each 1 mg of rofecoxib
in the formulation. In some embodiments, the solid dosage
formulation of rofecoxib achieves a mean Cmax plasma concentration
from 10 ng/ml to 13 ng/ml for each 1 mg of rofecoxib in the
formulation. In some embodiments, the solid dosage formulation of
rofecoxib achieves a mean Cmax plasma concentration from 80% to
125% of 12.8 ng/ml. In some embodiments, the solid dosage
formulation of rofecoxib reaches a mean AUC.sub.0-.infin. of 170
h*ng/ml to 235 h*ng/ml for each 1 mg of rofecoxib in the
formulation. In some embodiments, the solid dosage formulation of
rofecoxib reaches a mean AUC.sub.0-.infin. of 170 h*ng/ml to 225
h*ng/ml for each 1 mg of rofecoxib in the formulation. In some
embodiments, the formulation achieves a mean AUC.sub.0-.infin. of
177 h*ng/ml to 225 h*ng/ml for each 1 mg of rofecoxib in the
formulation. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of 180 h*ng/ml to 225 h*ng/ml for each 1 mg of
rofecoxib in the formulation. In some embodiments, the solid dosage
formulation of rofecoxib reaches a mean AUC.sub.0-.infin. of 190
h*ng/ml to 215 h*ng/ml for each 1 mg of rofecoxib in the
formulation.
[0368] A method for inhibiting COX-2 in a subject in need thereof,
the method comprising administering to the subject a solid dosage
form comprising a granular component and an extragranular
component, wherein the granular component comprises an
intragranular component comprising rofecoxib or a pharmaceutically
acceptable salt thereof and one or more disintegrants, and wherein
the extragranular component comprises one or more
disintegrants.
[0369] In some embodiments, the one or more disintegrants in the
granular component is selected from starches, clays, celluloses,
algins, gums, cross-linked polymers, and combinations thereof. In
some embodiments, the one or more disintegrants in the granular
component is selected from croscarmellose, crospovidone, sodium
starch glycolate, and combinations thereof.
[0370] In some embodiments, the one or more disintegrants in the
granular component is croscarmellose sodium. In some embodiments,
the one or more disintegrants in the granular component is about 1%
(w/w) to about 8% (w/w) of the solid dosage form. In some
embodiments, the one or more disintegrants in the granular
component is about 1% (w/w) to about 6% (w/w) of the solid dosage
form. In some embodiments, the one or more disintegrants in the
granular component is about 1% (w/w) to about 4% (w/w) of the solid
dosage form.
[0371] In some embodiments, the one or more disintegrants in the
extragranular component is selected from starches, clays,
celluloses, algins, gums, cross-linked polymers, and combinations
thereof. In some embodiments, the one or more disintegrants in the
extragranular component is selected from croscarmellose,
crospovidone, sodium starch glycolate, and combinations thereof. In
some embodiments, the one or more disintegrants in the
extragranular component is croscarmellose sodium. In some
embodiments, the disintegrant in the extragranular component is
about 1% (w/w) to about 8% (w/w) of the solid dosage form. In some
embodiments, the disintegrant in the extragranular component is
about 1% (w/w) to about 6% (w/w) of the solid dosage form. In some
embodiments, the disintegrant in the extragranular component is
about 1% (w/w) to about 4% (w/w) of the solid dosage form.
[0372] In some embodiments, the disintegrant in the granular
component and the disintegrant in the extragranular component are
together about 2% (w/w) to about 12% (w/w) of the solid dosage
form. In some embodiments, the disintegrant in the granular
component and the disintegrant in the extragranular component are
together about 2% (w/w) to about 10% (w/w) of the solid dosage
form. In some embodiments, the disintegrant in the granular
component and the disintegrant in the extragranular component are
together about 2% (w/w) to about 8% (w/w) of the solid dosage
form.
[0373] In some embodiments, the ratio of granular disintegrant to
extragranular disintegrant is about 40% (w/w) to about 60% (w/w).
In some embodiments, the ratio of granular disintegrant to
extragranular disintegrant is about 45% (w/w) to about 55% (w/w).
In some embodiments, the ratio of granular disintegrant to
extragranular disintegrant is about 50% (w/w) to about 50% (w/w).
In some embodiments, the ratio of granular disintegrant to
extragranular disintegrant is about 55% (w/w) to about 45% (w/w).
In some embodiments, the ratio of granular disintegrant to
extragranular disintegrant is about 60% (w/w) to about 40%
(w/w).
[0374] In some embodiments, the solid dosage form further
comprising one or more of a diluent, a binder, a coloring agent,
and a lubricant. In some embodiments, at least a portion of the
diluent is in the granular component. In some embodiments, the
diluent is selected from dicalcium phosphate, calcium sulfate,
lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch,
powdered sugar, sorbitol, sucrose, inositol, and combinations
thereof. In some embodiments, the diluent is selected from lactose,
cellulose, or a combination thereof. In some embodiments, the
diluent is selected from lactose monohydrate, microcrystalline
cellulose, or a combination thereof.
[0375] In some embodiments, the lactose monohydrate is about 35%
(w/w) to about 45% (w/w) of the solid dosage form. In some
embodiments, the lactose monohydrate is about 37% (w/w) to about
42% (w/w) of the solid dosage form. In some embodiments, the
lactose monohydrate is about 39% (w/w) to about 40% (w/w) of the
solid dosage form.
[0376] In some embodiments, the microcrystalline cellulose is about
35% (w/w) to about 45% (w/w) of the solid dosage form. In some
embodiments, the microcrystalline cellulose is about 37% (w/w) to
about 42% (w/w) of the solid dosage form. In some embodiments, the
microcrystalline cellulose is about 39% (w/w) to about 40% (w/w) of
the solid dosage form.
[0377] In some embodiments, the diluent is about 75% (w/w) to about
85% (w/w) of the solid dosage form. In some embodiments, diluent is
about 77% (w/w) to about 82% (w/w) of the solid dosage form. In
some embodiments, the diluent is about 78% (w/w) to about 80% (w/w)
of the solid dosage form.
[0378] In some embodiments, at least a portion of the binder is in
the granular component. In some embodiments, the binder is selected
from starches, gelatins, sugars, gums, waxes, water, alcohols,
celluloses, and combinations thereof. In some embodiments, the
binder is selected from acacia gum, tragacanth, corn starch, methyl
cellulose, panwar gum, ghatti gum, mucilage of isapol husks,
carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone,
sucrose, glucose, dextrose, molasses, lactose, and combinations
thereof. In some embodiments, the binder is hydroxypropyl
cellulose. In some embodiments, the binder is about 1% (w/w) to
about 5% (w/w) of the solid dosage form. In some embodiments,
binder is about 2% (w/w) to about 4% (w/w) of the solid dosage
form. In some embodiments, the binder is about 2.5% (w/w) to about
3.5% (w/w) of the solid dosage form.
[0379] In some embodiments, at least a portion of the coloring
agent is in the extragranular component. In some embodiments, the
coloring agent is pigment blend yellow. In some embodiments, the
coloring agent is about 0.30% (w/w) to about 0.60% (w/w) of the
solid dosage form.
[0380] In some embodiments, at least a portion of the lubricant is
in the extragranular component. In some embodiments, the lubricant
is selected from talc, magnesium stearate, calcium stearate,
stearic acid, metallic stearate, hydrogenated vegetable oils, and
polyethylene glycol, corn starch, boric acids, sodium chloride,
sodium lauryl sulphate. In some embodiments, the lubricant is
magnesium stearate. In some embodiments, the lubricant is about
0.10% (w/w) to about 1% (w/w) of the solid dosage form. In some
embodiments, the lubricant is about 0.50% (w/w) of the solid dosage
form.
[0381] In some embodiments, the rofecoxib or pharmaceutically
acceptable salt thereof is about 5% (w/w) to about 30% (w/w) of the
solid dosage form. In some embodiments, the rofecoxib or
pharmaceutically acceptable salt thereof is about 10% (w/w) to
about 20% (w/w) of the solid dosage form. In some embodiments, the
rofecoxib or pharmaceutically acceptable salt thereof is about 12%
(w/w) to about 13% (w/w) of the solid dosage form. In some
embodiments, the solid dosage form comprises about 10 mg of the
rofecoxib or pharmaceutically acceptable salt thereof. In some
embodiments, the solid dosage form comprises about 10.5 mg of the
rofecoxib or pharmaceutically acceptable salt thereof. In some
embodiments, the solid dosage form comprises about 11 mg of the
rofecoxib or pharmaceutically acceptable salt thereof. In some
embodiments, the solid dosage form comprises about 11.5 mg of the
rofecoxib or pharmaceutically acceptable salt thereof. In some
embodiments, the solid dosage form comprises about 12 mg of the
rofecoxib or pharmaceutically acceptable salt thereof. In some
embodiments, the solid dosage form comprises about 12.5 mg of the
rofecoxib or pharmaceutically acceptable salt thereof. In some
embodiments, the solid dosage form comprises about 17.5 mg of the
rofecoxib or pharmaceutically acceptable salt thereof. In some
embodiments, the solid dosage form comprises about 20 mg of the
rofecoxib or pharmaceutically acceptable salt thereof. In some
embodiments, the solid dosage form comprises about 21 mg of the
rofecoxib or pharmaceutically acceptable salt thereof. In some
embodiments, the solid dosage form comprises about 22 mg of the
rofecoxib or pharmaceutically acceptable salt thereof. In some
embodiments, the solid dosage form comprises about 22.5 mg of the
rofecoxib or pharmaceutically acceptable salt thereof. In some
embodiments, the solid dosage form comprises about 25 mg of the
rofecoxib or pharmaceutically acceptable salt thereof. In some
embodiments, the solid dosage form comprises about 50 mg of the
rofecoxib or pharmaceutically acceptable salt thereof.
[0382] In some embodiments, the rofecoxib is highly pure. In some
embodiments, the highly pure rofecoxib comprises less than about
0.1% total impurities. In some embodiments, the highly pure
rofecoxib comprises less than about 0.075% total impurities. In
some embodiments, the highly pure rofecoxib comprises less than
about 0.050% total impurities. In some embodiments, the highly pure
rofecoxib comprises less than about 0.025% total impurities. In
some embodiments, the highly pure rofecoxib comprises less than
about 0.001% total impurities.
[0383] In some embodiments, the highly pure rofecoxib comprises
less than about 0.10%, 0.05%, 0.02%, or 0.01% of
4-[4-(methylsulphonyl)phenyl]-3-phenyl-2,5-furandione. In some
embodiments, the highly pure rofecoxib comprises less than about
0.10%, 0.05%, 0.02%, or 0.01% of
4-[4-(methylthio)phenyl]-3-phenyl-2(5H)-furanone. In some
embodiments, the highly pure rofecoxib comprises less than about
0.10%, 0.05%, 0.02%, or 0.01% of
4-[4-(methylthio)phenyl]-3-phenyl-2(5H)-furanone. In some
embodiments, the highly pure rofecoxib comprises less than about
0.10%, 0.05%, 0.02%, or 0.01% of
4-[4-(methylsulfinyl)phenyl]-3-phenyl-2(5H)-furanone.
[0384] In some embodiments, the solid dosage form is suitable for
oral administration. In some embodiments, the solid dosage form is
an oral tablet. In some embodiments, the oral tablet provides a
dissolution rate of at least about 80% of the rofecoxib or
pharmaceutically acceptable salt thereof by about 15 minutes. In
some embodiments, the oral tablet provides a dissolution rate of at
least about 85% of the rofecoxib or pharmaceutically acceptable
salt thereof by about 15 minutes. In some embodiments, the oral
tablet provides a dissolution rate of at least about 90% of the
rofecoxib or pharmaceutically acceptable salt thereof by about 15
minutes. In some embodiments, the oral tablet provides a
dissolution rate of at least about 95% of the rofecoxib or
pharmaceutically acceptable salt thereof by about 15 minutes. In
some embodiments, the oral tablet provides a dissolution rate of at
least about 100% of the rofecoxib or pharmaceutically acceptable
salt thereof by about 15 minutes.
[0385] In some embodiments, the dissolution rate is measured in
about 1% SDS at a paddle speed of about 50 rpm and at a temperature
of about 37.0.degree. C..+-.0.5.degree. C. In some embodiments, the
dissolution rate is measured in about 1% SDS at a paddle speed of
about 75 rpm and at a temperature of about 37.0.degree.
C..+-.0.5.degree. C. In some embodiments, the dissolution rate is
measured in about 1.5% SDS at a paddle speed of about 50 rpm and at
a temperature of about 37.0.degree. C..+-.0.5.degree. C. In some
embodiments, the dissolution rate is measured in about 1.5% SDS at
a paddle speed of about 75 rpm and at a temperature of about
37.0.degree. C..+-.0.5.degree. C. In some embodiments, the
dissolution rate is measured in about 2% SDS at a paddle speed of
about 50 rpm and at a temperature of about 37.0.degree.
C..+-.0.5.degree. C. In some embodiments, the dissolution rate is
measured in about 2% SDS at a paddle speed of about 75 rpm and at a
temperature of about 37.0.degree. C..+-.0.5.degree. C. In some
embodiments, the dissolution rate is measured using a USP Type II
apparatus. In some embodiments, the dissolution rate is measured
with a USP Type II apparatus using 900 mL of 2% SDS, a paddle speed
of 50 rpm, and a temperature of 37.0.degree. C..+-.0.5.degree..
[0386] In some embodiments, the rofecoxib or pharmaceutically
acceptable salt thereof is formulated into granules and at least
about 35% of the granules are less than about 75 .mu.m. In some
embodiments, the rofecoxib or pharmaceutically acceptable salt
thereof is formulated into granules and at least about 55% of the
granules are less than about 150 .mu.m. In some embodiments, the
rofecoxib or pharmaceutically acceptable salt thereof is formulated
into granules and at least about 75% of the granules are less than
about 250 .mu.m. In some embodiments, the rofecoxib or
pharmaceutically acceptable salt thereof is formulated into
granules and at least about 85% of the granules are less than about
425 .mu.m. In some embodiments, the rofecoxib or pharmaceutically
acceptable salt thereof is formulated into granules and at least
about 90% of the granules are less than about 1000 .mu.m.
[0387] In some embodiments, a 17.5 mg solid dosage formulation of
rofecoxib reaches a median time to Cmax plasma concentration in 4
hours or less following single administration of the formulation to
human subjects. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib reaches a median time to Cmax plasma
concentration in 3 hours or less following administration. In some
embodiments, a 17.5 mg solid dosage formulation of rofecoxib
reaches a median time to Cmax plasma concentration in 2.5 hours or
less following administration. In some embodiments, a 17.5 mg solid
dosage formulation of rofecoxib reaches a median time to Cmax
plasma concentration in 2 hours or less following administration.
In some embodiments, a 17.5 mg solid dosage formulation of
rofecoxib has a mean Cmax plasma concentration of more than 100
ng/ml. In some embodiments, a 17.5 mg solid dosage formulation of
rofecoxib has a mean Cmax plasma concentration of more than 150
ng/ml, 167 ng/ml, or 190 ng/ml. In some embodiments, a 17.5 mg
solid dosage formulation of rofecoxib has a mean Cmax plasma
concentration of more than 200 ng/ml. In some embodiments, a 17.5
mg solid dosage formulation of rofecoxib has a mean Cmax plasma
concentration of more than 220 ng/ml. In some embodiments, a 17.5
mg solid dosage formulation of rofecoxib has a mean Cmax plasma
concentration of more than 250 ng/ml. In some embodiments, a 17.5
mg solid dosage formulation of rofecoxib has a mean Cmax plasma
concentration of more than 280 ng/ml. In some embodiments, a 17.5
mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 1750 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 2000 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 2500 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 3000 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 3100 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 3500 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 4000 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 4500 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib reaches a Cmax plasma
concentration of least 167 ng/ml, 170 ng/ml, 175 ng/ml, 180 ng/ml,
or higher following single administration of the formulation to a
human subject. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib reaches an AUC.sub.0-.infin. of at least
2600 h*ng/ml, 2750 h*ng/ml, 2900 h*ng/ml, 3050 h*ng/ml, 3100
h*ng/ml, 3200 h*ng/ml, 3350 h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml or
higher following single administration of the formulation to a
human subject.
[0388] In some embodiments, a 20 mg solid dosage formulation of
rofecoxib reaches a median time to Cmax plasma concentration in 4
hours or less following single administration of the formulation to
human subjects. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib reaches a median time to Cmax plasma
concentration in 3 hours or less following administration. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib reaches
a median time to Cmax plasma concentration in 2.5 hours or less
following administration. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib reaches a median time to Cmax plasma
concentration in 2 hours or less following administration. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib has a
mean Cmax plasma concentration of more than 150 ng/ml. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib has a
mean Cmax plasma concentration of more than 191 ng/ml, 200 ng/ml,
215 ng/ml, or 225 ng/ml. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib has a mean Cmax plasma concentration of
more than 250 ng/ml. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib has a mean Cmax plasma concentration of
more than 258 ng/ml. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib has a mean Cmax plasma concentration of
more than 300 ng/ml. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib has a mean AUC.sub.0-.infin. of more than
2000 h*ng/ml. In some embodiments, a 20 mg solid dosage formulation
of rofecoxib has a mean AUC.sub.0-.infin. of more than 2500
h*ng/ml. In some embodiments, a 20 mg solid dosage formulation of
rofecoxib has a mean AUC.sub.0-.infin. of more than 3000 h*ng/ml.
In some embodiments, a 20 mg solid dosage formulation of rofecoxib
has a mean AUC.sub.0-.infin. of more than 3400 h*ng/ml. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 3500 h*ng/ml. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 4000 h*ng/ml. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib reaches
a Cmax plasma concentration of least 190 ng/ml, 205 ng/ml, 220
ng/ml, 235 ng/ml, 250 ng/ml, or higher following single
administration of the formulation to a human subject. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib reaches
an AUC.sub.0-.infin. of at least 3000 h*ng/ml, 3200 h*ng/ml, 3350
h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml, 3800 h*ng/ml, 3950 h*ng/ml, or
higher following single administration of the formulation to a
human subject. In some embodiments, the rofecoxib formulation
achieves a mean Cmax plasma concentration within 80% to 125% of 259
ng/ml and a mean AUC.sub.0-.infin. within 80% to 125% of 3550
h*ng/ml. In some embodiments, the rofecoxib formulation achieves a
mean plasma AUC.sub.0-.infin. of about 2840-4438 h*ng/ml and a mean
plasma Cmax of about 207-324 ng/ml following oral administration of
a single dose of the formulation to a population of healthy adults
less than 65 years of age in a fasted state. In some embodiments,
the population of healthy adults are less than 60 years of age.
[0389] In some embodiments, a 25 mg solid dosage formulation of
rofecoxib reaches a mean Cmax plasma concentration in less than 3
hours following single administration of the formulation to human
subjects. In some embodiments, a 25 mg solid dosage formulation of
rofecoxib reaches a mean Cmax plasma concentration in less than 2.5
hours following administration. In some embodiments, a 25 mg solid
dosage formulation of rofecoxib reaches a mean Cmax plasma
concentration in less than 2 hours following administration. In
some embodiments, a 25 mg solid dosage formulation of rofecoxib has
a mean Cmax plasma concentration of more than 240 ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean Cmax plasma concentration of more than 250 ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean Cmax plasma concentration of more than 300 ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean Cmax plasma concentration of more than 320 ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 4250 h*ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 4500 h*ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 4700 h*ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 5000 h*ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib reaches
a mean Cmax plasma concentration of more than 240 ng/ml in a median
time of about 3 hours or less following administration with an
AUC.sub.0-.infin. of more than 4250 h*ng/ml.
[0390] In some embodiments, a 10 mg to 50 mg solid dosage
formulation of rofecoxib achieves a mean Cmax plasma concentration
from 9.8 ng/ml to 16 ng/ml for each 1 mg of rofecoxib in the
formulation following single administration of the formulation to
human subjects. In some embodiments, the solid dosage formulation
achieves a mean Cmax plasma concentration from 10 ng/ml to 14 ng/ml
for each 1 mg of rofecoxib in the formulation. In some embodiments,
the solid dosage formulation achieves a mean Cmax plasma
concentration from 10 ng/ml to 13 ng/ml for each 1 mg of rofecoxib
in the formulation. In some embodiments, the solid dosage
formulation achieves a mean Cmax plasma concentration from 80% to
125% of 12.8 ng/ml. In some embodiments, the solid dosage
formulation reaches a mean AUC.sub.0-.infin. of 170 h*ng/ml to 235
h*ng/ml for each 1 mg of rofecoxib in the formulation. In some
embodiments, the solid dosage formulation reaches a mean
AUC.sub.0-.infin. of 170 h*ng/ml to 225 h*ng/ml for each 1 mg of
rofecoxib in the formulation. In some embodiments, the formulation
achieves a mean AUC.sub.0-.infin. of 177 h*ng/ml to 225 h*ng/ml for
each 1 mg of rofecoxib in the formulation. In some embodiments, the
formulation achieves a mean AUC.sub.0-.infin. of 180 h*ng/ml to 225
h*ng/ml for each 1 mg of rofecoxib in the formulation. In some
embodiments, the solid dosage formulation reaches a mean
AUC.sub.0-.infin. of 190 h*ng/ml to 215 h*ng/ml for each 1 mg of
rofecoxib in the formulation.
[0391] In certain aspects, the subject matter disclosed herein
provides a method for inhibiting COX-2 in a subject in need
thereof, the method comprising administering to the subject a solid
dosage formulation comprising 17.5 mg of rofecoxib or a
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation achieves a median time to Cmax plasma concentration in
4 hours or less following single administration of the formulation
to human subjects. In some embodiments, the formulation achieves a
median time to Cmax plasma concentration in 3 hours or less
following administration. In some embodiments, the formulation
achieves a median time to Cmax plasma concentration in 2.5 hours or
less following administration. In some embodiments, the formulation
achieves a median time to Cmax plasma concentration in 2 hours or
less following administration. In some embodiments, the formulation
achieves a mean Cmax plasma concentration of more than 100 ng/ml.
In some embodiments, the formulation achieves a mean Cmax plasma
concentration of more than 150 ng/ml, 167 ng/ml, or 190 ng/ml. In
some embodiments, the formulation achieves a mean Cmax plasma
concentration of more than 200 ng/ml. In some embodiments, the
formulation achieves a mean Cmax plasma concentration of more than
220 ng/ml. In some embodiments, the formulation achieves a mean
Cmax plasma concentration of more than 250 ng/ml. In some
embodiments, the formulation achieves a mean Cmax plasma
concentration of more than 280 ng/ml. In some embodiments, the
formulation achieves a mean AUC.sub.0-.infin. of more than 1750
h*ng/ml. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 2000 h*ng/ml. In some embodiments,
the formulation achieves a mean AUC.sub.0-.infin. of more than 2500
h*ng/ml. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 3000 h*ng/ml. In some embodiments,
the formulation achieves a mean AUC.sub.0-.infin. of more than 3100
h*ng/ml. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 3500 h*ng/ml. In some embodiments,
the formulation achieves a mean AUC.sub.0-.infin. of more than 4000
h*ng/ml. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 4500 h*ng/ml. In some embodiments,
the formulation reaches a Cmax plasma concentration of least 167
ng/ml, 170 ng/ml, 175 ng/ml, 180 ng/ml, or higher following single
administration of the formulation to a human subject. In some
embodiments, the formulation reaches an AUC.sub.0-.infin. of at
least 2600 h*ng/ml, 2750 h*ng/ml, 2900 h*ng/ml, 3050 h*ng/ml, 3200
h*ng/ml, 3350 h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml or higher
following single administration of the formulation to a human
subject.
[0392] In certain aspects, the subject matter disclosed herein
provides a method for inhibiting COX-2 in a subject in need
thereof, the method comprising administering to the subject a solid
dosage formulation comprising 20 mg of rofecoxib or a
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation achieves a median time to Cmax plasma concentration in
4 hours or less following single administration of the formulation
to human subjects. In some embodiments, the formulation achieves a
median time to Cmax plasma concentration in 3 hours or less
following administration. In some embodiments, the formulation
achieves a median time to Cmax plasma concentration in 2.5 hours or
less following administration. In some embodiments, the formulation
achieves a median time to Cmax plasma concentration in 2 hours or
less following administration. In some embodiments, the formulation
achieves a mean Cmax plasma concentration of more than 150 ng/ml.
In some embodiments, the formulation achieves a mean Cmax plasma
concentration of more than 191 ng/ml, 200 ng/ml, 215 ng/ml, or 225
ng/ml. In some embodiments, the formulation achieves a mean Cmax
plasma concentration of more than 250 ng/ml. In some embodiments, a
20 mg solid dosage formulation of rofecoxib has a mean Cmax plasma
concentration of more than 258 ng/ml. In some embodiments, the
formulation achieves a mean Cmax plasma concentration of more than
300 ng/ml. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 2000 h*ng/ml. In some embodiments,
the formulation achieves a mean AUC.sub.0-.infin. of more than 2500
h*ng/ml. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 3000 h*ng/ml. In some embodiments,
the formulation achieves a mean AUC.sub.0-.infin. of more than 3400
h*ng/ml. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 3500 h*ng/ml. In some embodiments,
the formulation achieves a mean AUC.sub.0-.infin. of more than 4000
h*ng/ml. In some embodiments, the formulation reaches a Cmax plasma
concentration of least 190 ng/ml, 205 ng/ml, 220 ng/ml, 235 ng/ml,
250 ng/ml, or higher following single administration of the
formulation to a human subject. In some embodiments, the
formulation reaches an AUC.sub.0-.infin. of at least 3000 h*ng/ml,
3200 h*ng/ml, 3350 h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml, 3800
h*ng/ml, 3950 h*ng/ml, or higher following single administration of
the formulation to a human subject. In some embodiments, the
rofecoxib formulation achieves a mean Cmax plasma concentration
within 80% to 125% of 259 ng/ml and a mean AUC.sub.0-.infin. within
80% to 125% of 3550 h*ng/ml. In some embodiments, the rofecoxib
formulation achieves a mean plasma AUC.sub.0-.infin. of about
2840-4438 h*ng/ml and a mean plasma Cmax of about 207-324 ng/ml
following oral administration of a single dose of the formulation
to a population of healthy adults less than 65 years of age in a
fasted state. In some embodiments, the population of healthy adults
are less than 60 years of age.
[0393] In certain aspects, the subject matter disclosed herein
provides a method for inhibiting COX-2 in a subject in need
thereof, the method comprising administering to the subject a solid
dosage formulation comprising 25 mg of rofecoxib or a
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation achieves a mean Cmax plasma concentration in less than
3 hours following single administration of the formulation to human
subjects. In some embodiments, the formulation achieves a mean Cmax
plasma concentration in less than 2.5 hours following
administration. In some embodiments, the formulation achieves a
mean Cmax plasma concentration in less than 2 hours following
administration. In some embodiments, the formulation achieves a
mean Cmax plasma concentration of more than 240 ng/ml. In some
embodiments, the formulation achieves a mean Cmax plasma
concentration of more than 250 ng/ml. In some embodiments, the
formulation achieves a mean Cmax plasma concentration of more than
300 ng/ml. In some embodiments, the formulation achieves a mean
Cmax plasma concentration of more than 320 ng/ml. In some
embodiments, the formulation achieves a mean AUC.sub.0-.infin. of
more than 4250 h*ng/ml. In some embodiments, the formulation
achieves a mean AUC.sub.0-.infin. of more than 4500 h*ng/ml. In
some embodiments, the formulation achieves a mean AUC.sub.0-.infin.
of more than 4550 h*ng/ml. In some embodiments, the formulation
achieves a mean AUC.sub.0-.infin. of more than 4700 h*ng/ml. In
some embodiments, the formulation achieves a Cmax plasma
concentration of more than 240 ng/ml about 3 hours following
administration with an AUC.sub.0-.infin. of more than 4250
h*ng/ml.
[0394] In certain aspects, the subject matter disclosed herein
provides a method for inhibiting COX-2 in a subject in need
thereof, the method comprising administering to the subject a solid
dosage formulation comprising 10 mg to 50 mg of rofecoxib or a
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation achieves a mean Cmax plasma concentration from 9.8
ng/ml to 16 ng/ml for each 1 mg of rofecoxib in the formulation
following single administration of the formulation to human
subjects. In some embodiments, the formulation achieves a mean Cmax
plasma concentration from 10 ng/ml to 14 ng/ml for each 1 mg of
rofecoxib in the formulation. In some embodiments, the formulation
achieves a mean Cmax plasma concentration from 10 ng/ml to 13 ng/ml
for each 1 mg of rofecoxib in the formulation. In some embodiments,
the formulation achieves a mean Cmax plasma concentration from 80%
to 125% of 12.8 ng/ml. In some embodiments, the formulation reaches
a mean AUC.sub.0-.infin. of 170 h*ng/ml to 235 h*ng/ml for each 1
mg of rofecoxib in the formulation. In some embodiments, the
formulation reaches a mean AUC.sub.0-.infin. of 177 h*ng/ml to 225
h*ng/ml for each 1 mg of rofecoxib in the formulation. In some
embodiments, the formulation reaches a mean AUC.sub.0-.infin. of
190 h*ng/ml to 215 h*ng/ml for each 1 mg of rofecoxib in the
formulation.
[0395] A method for treating one or more conditions in a subject in
need thereof, the method comprising administering to the subject a
pharmaceutically acceptable formulation comprising a granular
component and an extragranular component, wherein the granular
component comprises an intragranular component comprising rofecoxib
or a pharmaceutically acceptable salt thereof and one or more
disintegrants, and wherein the extragranular component comprises
one or more disintegrants.
[0396] In some embodiments, the one or more disintegrants in the
granular component is selected from starches, clays, celluloses,
algins, gums, cross-linked polymers, and combinations thereof. In
some embodiments, the one or more disintegrants in the granular
component is selected from croscarmellose, crospovidone, sodium
starch glycolate, and combinations thereof.
[0397] In some embodiments, the one or more disintegrants in the
granular component is croscarmellose sodium. In some embodiments,
the one or more disintegrants in the granular component is about 1%
(w/w) to about 8% (w/w) of the formulation. In some embodiments,
the one or more disintegrants in the granular component is about 1%
(w/w) to about 6% (w/w) of the formulation. In some embodiments,
the one or more disintegrants in the granular component is about 1%
(w/w) to about 4% (w/w) of the formulation.
[0398] In some embodiments, the one or more disintegrants in the
extragranular component is selected from starches, clays,
celluloses, algins, gums, cross-linked polymers, and combinations
thereof. In some embodiments, the one or more disintegrants in the
extragranular component is selected from croscarmellose,
crospovidone, sodium starch glycolate, and combinations thereof. In
some embodiments, the one or more disintegrants in the
extragranular component is croscarmellose sodium. In some
embodiments, the disintegrant in the extragranular component is
about 1% (w/w) to about 8% (w/w) of the formulation. In some
embodiments, the disintegrant in the extragranular component is
about 1% (w/w) to about 6% (w/w) of the formulation. In some
embodiments, the disintegrant in the extragranular component is
about 1% (w/w) to about 4% (w/w) of the formulation.
[0399] In some embodiments, the disintegrant in the granular
component and the disintegrant in the extragranular component are
together about 2% (w/w) to about 12% (w/w) of the formulation. In
some embodiments, the disintegrant in the granular component and
the disintegrant in the extragranular component are together about
2% (w/w) to about 10% (w/w) of the formulation. In some
embodiments, the disintegrant in the granular component and the
disintegrant in the extragranular component are together about 2%
(w/w) to about 8% (w/w) of the formulation.
[0400] In some embodiments, the ratio of granular disintegrant to
extragranular disintegrant is about 40% (w/w) to about 60% (w/w).
In some embodiments, the ratio of granular disintegrant to
extragranular disintegrant is about 45% (w/w) to about 55% (w/w).
In some embodiments, the ratio of granular disintegrant to
extragranular disintegrant is about 50% (w/w) to about 50% (w/w).
In some embodiments, the ratio of granular disintegrant to
extragranular disintegrant is about 55% (w/w) to about 45% (w/w).
In some embodiments, the ratio of granular disintegrant to
extragranular disintegrant is about 60% (w/w) to about 40%
(w/w).
[0401] In some embodiments, the pharmaceutically acceptable
formulation further comprising one or more of a diluent, a binder,
a coloring agent, and a lubricant. In some embodiments, at least a
portion of the diluent is in the granular component. In some
embodiments, the diluent is selected from dicalcium phosphate,
calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium
chloride, dry starch, powdered sugar, sorbitol, sucrose, inositol,
and combinations thereof. In some embodiments, the diluent is
selected from lactose, cellulose, or a combination thereof. In some
embodiments, the diluent is selected from lactose monohydrate,
microcrystalline cellulose, or a combination thereof.
[0402] In some embodiments, the lactose monohydrate is about 35%
(w/w) to about 45% (w/w) of the formulation. In some embodiments,
the lactose monohydrate is about 37% (w/w) to about 42% (w/w) of
the formulation. In some embodiments, the lactose monohydrate is
about 39% (w/w) to about 40% (w/w) of the formulation.
[0403] In some embodiments, the microcrystalline cellulose is about
35% (w/w) to about 45% (w/w) of the formulation. In some
embodiments, the microcrystalline cellulose is about 37% (w/w) to
about 42% (w/w) of the formulation. In some embodiments, the
microcrystalline cellulose is about 39% (w/w) to about 40% (w/w) of
the formulation.
[0404] In some embodiments, the diluent is about 75% (w/w) to about
85% (w/w) of the formulation. In some embodiments, diluent is about
77% (w/w) to about 82% (w/w) of the formulation. In some
embodiments, the diluent is about 78% (w/w) to about 80% (w/w) of
the formulation.
[0405] In some embodiments, at least a portion of the binder is in
the granular component. In some embodiments, the binder is selected
from starches, gelatins, sugars, gums, waxes, water, alcohols,
celluloses, and combinations thereof. In some embodiments, the
binder is selected from acacia gum, tragacanth, corn starch, methyl
cellulose, panwar gum, ghatti gum, mucilage of isapol husks,
carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone,
sucrose, glucose, dextrose, molasses, lactose, and combinations
thereof. In some embodiments, the binder is hydroxypropyl
cellulose. In some embodiments, the binder is about 1% (w/w) to
about 5% (w/w) of the formulation. In some embodiments, binder is
about 2% (w/w) to about 4% (w/w) of the formulation. In some
embodiments, the binder is about 2.5% (w/w) to about 3.5% (w/w) of
the formulation.
[0406] In some embodiments, at least a portion of the coloring
agent is in the extragranular component. In some embodiments, the
coloring agent is pigment blend yellow. In some embodiments, the
coloring agent is about 0.30% (w/w) to about 0.60% (w/w) of the
formulation.
[0407] In some embodiments, at least a portion of the lubricant is
in the extragranular component. In some embodiments, the lubricant
is selected from talc, magnesium stearate, calcium stearate,
stearic acid, metallic stearate, hydrogenated vegetable oils, and
polyethylene glycol, corn starch, boric acids, sodium chloride,
sodium lauryl sulphate. In some embodiments, the lubricant is
magnesium stearate. In some embodiments, the lubricant is about
0.10% (w/w) to about 1% (w/w) of the formulation. In some
embodiments, the lubricant is about 0.50% (w/w) of the
formulation.
[0408] In some embodiments, the rofecoxib or pharmaceutically
acceptable salt thereof is about 5% (w/w) to about 30% (w/w) of the
formulation. In some embodiments, the rofecoxib or pharmaceutically
acceptable salt thereof is about 10% (w/w) to about 20% (w/w) of
the formulation. In some embodiments, the rofecoxib or
pharmaceutically acceptable salt thereof is about 12% (w/w) to
about 13% (w/w) of the formulation. In some embodiments, the
formulation comprises about 10 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 10.5 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 11 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 11.5 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 12 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 12.5 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 17.5 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 20 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 21 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 22 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 22.5 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 25 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 50 mg of the rofecoxib or
pharmaceutically acceptable salt thereof.
[0409] In some embodiments, the rofecoxib is highly pure. In some
embodiments, the highly pure rofecoxib comprises less than about
0.1% total impurities. In some embodiments, the highly pure
rofecoxib comprises less than about 0.075% total impurities. In
some embodiments, the highly pure rofecoxib comprises less than
about 0.050% total impurities. In some embodiments, the highly pure
rofecoxib comprises less than about 0.025% total impurities. In
some embodiments, the highly pure rofecoxib comprises less than
about 0.001% total impurities.
[0410] In some embodiments, the highly pure rofecoxib comprises
less than about 0.10%, 0.05%, 0.02%, or 0.01% of
4-[4-(methylsulphonyl)phenyl]-3-phenyl-2,5-furandione. In some
embodiments, the highly pure rofecoxib comprises less than about
0.10%, 0.05%, 0.02%, or 0.01% of
4-[4-(methylthio)phenyl]-3-phenyl-2(5H)-furanone. In some
embodiments, the highly pure rofecoxib comprises less than about
0.10%, 0.05%, 0.02%, or 0.01% of
4-[4-(methylthio)phenyl]-3-phenyl-2(5H)-furanone. In some
embodiments, the highly pure rofecoxib comprises less than about
0.10%, 0.05%, 0.02%, or 0.01% of
4-[4-(methylsulfinyl)phenyl]-3-phenyl-2(5H)-furanone.
[0411] In some embodiments, the formulation is suitable for oral
administration. In some embodiments, the formulation is a solid
dosage form. In some embodiments, the solid dosage form is an oral
tablet. In some embodiments, the oral tablet provides a dissolution
rate of at least about 80% of the rofecoxib or pharmaceutically
acceptable salt thereof by about 15 minutes. In some embodiments,
the oral tablet provides a dissolution rate of at least about 85%
of the rofecoxib or pharmaceutically acceptable salt thereof by
about 15 minutes. In some embodiments, the oral tablet provides a
dissolution rate of at least about 90% of the rofecoxib or
pharmaceutically acceptable salt thereof by about 15 minutes. In
some embodiments, the oral tablet provides a dissolution rate of at
least about 95% of the rofecoxib or pharmaceutically acceptable
salt thereof by about 15 minutes. In some embodiments, the oral
tablet provides a dissolution rate of at least about 100% of the
rofecoxib or pharmaceutically acceptable salt thereof by about 15
minutes.
[0412] In some embodiments, the dissolution rate is measured in
about 1% SDS at a paddle speed of about 50 rpm and at a temperature
of about 37.0.degree. C..+-.0.5.degree. C. In some embodiments, the
dissolution rate is measured in about 1% SDS at a paddle speed of
about 75 rpm and at a temperature of about 37.0.degree.
C..+-.0.5.degree. C. In some embodiments, the dissolution rate is
measured in about 1.5% SDS at a paddle speed of about 50 rpm and at
a temperature of about 37.0.degree. C..+-.0.5.degree. C. In some
embodiments, the dissolution rate is measured in about 1.5% SDS at
a paddle speed of about 75 rpm and at a temperature of about
37.0.degree. C..+-.0.5.degree. C. In some embodiments, the
dissolution rate is measured in about 2% SDS at a paddle speed of
about 50 rpm and at a temperature of about 37.0.degree.
C..+-.0.5.degree. C. In some embodiments, the dissolution rate is
measured in about 2% SDS at a paddle speed of about 75 rpm and at a
temperature of about 37.0.degree. C..+-.0.5.degree. C. In some
embodiments, the dissolution rate is measured using a USP Type II
apparatus. In some embodiments, the dissolution rate is measured
with a USP Type II apparatus using 900 mL of 2% SDS, a paddle speed
of 50 rpm, and a temperature of 37.0.degree. C..+-.0.5.degree..
[0413] In some embodiments, the rofecoxib or pharmaceutically
acceptable salt thereof is formulated into granules and at least
about 35% of the granules are less than about 75 .mu.m. In some
embodiments, the rofecoxib or pharmaceutically acceptable salt
thereof is formulated into granules and at least about 55% of the
granules are less than about 150 .mu.m. In some embodiments, the
rofecoxib or pharmaceutically acceptable salt thereof is formulated
into granules and at least about 75% of the granules are less than
about 250 .mu.m. In some embodiments, the rofecoxib or
pharmaceutically acceptable salt thereof is formulated into
granules and at least about 85% of the granules are less than about
425 .mu.m. In some embodiments, the rofecoxib or pharmaceutically
acceptable salt thereof is formulated into granules and at least
about 90% of the granules are less than about 1000 .mu.m.
[0414] In some embodiments, a 17.5 mg solid dosage formulation of
rofecoxib reaches a median time to Cmax plasma concentration in 4
hours or less following single administration of the formulation to
human subjects. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib reaches a median time to Cmax plasma
concentration in 3 hours or less following administration. In some
embodiments, a 17.5 mg solid dosage formulation of rofecoxib
reaches a median time to Cmax plasma concentration in 2.5 hours or
less following administration. In some embodiments, a 17.5 mg solid
dosage formulation of rofecoxib reaches a median time to Cmax
plasma concentration in 2 hours or less following administration.
In some embodiments, a 17.5 mg solid dosage formulation of
rofecoxib has a mean Cmax plasma concentration of more than 100
ng/ml. In some embodiments, a 17.5 mg solid dosage formulation of
rofecoxib has a mean Cmax plasma concentration of more than 150
ng/ml, 167 ng/ml, or 190 ng/ml. In some embodiments, a 17.5 mg
solid dosage formulation of rofecoxib has a mean Cmax plasma
concentration of more than 200 ng/ml. In some embodiments, a 17.5
mg solid dosage formulation of rofecoxib has a mean Cmax plasma
concentration of more than 220 ng/ml. In some embodiments, a 17.5
mg solid dosage formulation of rofecoxib has a mean Cmax plasma
concentration of more than 250 ng/ml. In some embodiments, a 17.5
mg solid dosage formulation of rofecoxib has a mean Cmax plasma
concentration of more than 280 ng/ml. In some embodiments, a 17.5
mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 1750 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 2000 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 2500 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 3000 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 3100 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 3500 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 4000 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 4500 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib reaches a Cmax plasma
concentration of least 167 ng/ml, 170 ng/ml, 175 ng/ml, 180 ng/ml,
or higher following single administration of the formulation to a
human subject. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib reaches an AUC.sub.0-.infin. of at least
2600 h*ng/ml, 2750 h*ng/ml, 2900 h*ng/ml, 3050 h*ng/ml, 3100
h*ng/ml, 3200 h*ng/ml, 3350 h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml or
higher following single administration of the formulation to a
human subject.
[0415] In some embodiments, a 20 mg solid dosage formulation of
rofecoxib reaches a median time to Cmax plasma concentration in 4
hours or less following single administration of the formulation to
human subjects. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib reaches a median time to Cmax plasma
concentration in 3 hours or less following administration. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib reaches
a median time to Cmax plasma concentration in 2.5 hours or less
following administration. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib reaches a median time to Cmax plasma
concentration in 2 hours or less following administration. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib has a
mean Cmax plasma concentration of more than 150 ng/ml. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib has a
mean Cmax plasma concentration of more than 191 ng/ml, 200 ng/ml,
215 ng/ml, or 225 ng/ml. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib has a mean Cmax plasma concentration of
more than 250 ng/ml. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib has a mean Cmax plasma concentration of
more than 258 ng/ml. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib has a mean Cmax plasma concentration of
more than 300 ng/ml. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib has a mean AUC.sub.0-.infin. of more than
2000 h*ng/ml. In some embodiments, a 20 mg solid dosage formulation
of rofecoxib has a mean AUC.sub.0-.infin. of more than 2500
h*ng/ml. In some embodiments, a 20 mg solid dosage formulation of
rofecoxib has a mean AUC.sub.0-.infin. of more than 3000 h*ng/ml.
In some embodiments, a 20 mg solid dosage formulation of rofecoxib
has a mean AUC.sub.0-.infin. of more than 3400 h*ng/ml. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 3500 h*ng/ml. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 4000 h*ng/ml. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib reaches
a Cmax plasma concentration of least 190 ng/ml, 205 ng/ml, 220
ng/ml, 235 ng/ml, 250 ng/ml, or higher following single
administration of the formulation to a human subject. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib reaches
an AUC.sub.0-.infin. of at least 3000 h*ng/ml, 3200 h*ng/ml, 3350
h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml, 3800 h*ng/ml, 3950 h*ng/ml, or
higher following single administration of the formulation to a
human subject. In some embodiments, the rofecoxib formulation
achieves a mean Cmax plasma concentration within 80% to 125% of 259
ng/ml and a mean AUC.sub.0-.infin. within 80% to 125% of 3550
h*ng/ml. In some embodiments, the rofecoxib formulation achieves a
mean plasma AUC.sub.0-.infin. of about 2840-4438 h*ng/ml and a mean
plasma Cmax of about 207-324 ng/ml following oral administration of
a single dose of the formulation to a population of healthy adults
less than 65 years of age in a fasted state. In some embodiments,
the population of healthy adults are less than 60 years of age.
[0416] In some embodiments, a 25 mg solid dosage formulation of
rofecoxib reaches a mean Cmax plasma concentration in less than 3
hours following single administration of the formulation to human
subjects. In some embodiments, a 25 mg solid dosage formulation of
rofecoxib reaches a mean Cmax plasma concentration in less than 2.5
hours following administration. In some embodiments, a 25 mg solid
dosage formulation of rofecoxib reaches a mean Cmax plasma
concentration in less than 2 hours following administration. In
some embodiments, a 25 mg solid dosage formulation of rofecoxib has
a mean Cmax plasma concentration of more than 240 ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean Cmax plasma concentration of more than 250 ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean Cmax plasma concentration of more than 300 ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean Cmax plasma concentration of more than 320 ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 4250 h*ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 4500 h*ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 4550 h*ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 4700 h*ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib reaches
a Cmax plasma concentration of more than 240 ng/ml in a median time
of about 3 hours or less following administration with an
AUC.sub.0-.infin. of more than 4250 h*ng/ml.
[0417] In some embodiments, a 10 mg to 50 mg solid dosage
formulation of rofecoxib achieves a mean Cmax plasma concentration
from 9.8 ng/ml to 16 ng/ml for each 1 mg of rofecoxib in the
formulation following single administration of the formulation to
human subjects. In some embodiments, a 10 mg to 50 mg solid dosage
formulation achieves a mean Cmax plasma concentration from 10 ng/ml
to 14 ng/ml for each 1 mg of rofecoxib in the formulation. In some
embodiments, a 10 mg to 50 mg solid dosage formulation achieves a
mean Cmax plasma concentration from 10 ng/ml to 13 ng/ml for each 1
mg of rofecoxib in the formulation. In some embodiments, a 10 mg to
50 mg solid dosage formulation achieves a mean Cmax plasma
concentration from 80% to 125% of 12.8 ng/ml. In some embodiments,
a 10 mg to 50 mg solid dosage formulation reaches a mean
AUC.sub.0-.infin. of 170 h*ng/ml to 235 h*ng/ml for each 1 mg of
rofecoxib in the formulation. In some embodiments, a 10 mg to 50 mg
solid dosage formulation reaches a mean AUC.sub.0-.infin. of 170
h*ng/ml to 225 h*ng/ml for each 1 mg of rofecoxib in the
formulation. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of 177 h*ng/ml to 225 h*ng/ml for each 1 mg of
rofecoxib in the formulation. In some embodiments, the formulation
achieves a mean AUC.sub.0-.infin. of 180 h*ng/ml to 225 h*ng/ml for
each 1 mg of rofecoxib in the formulation. In some embodiments, a
10 mg to 50 mg solid dosage formulation reaches a mean
AUC.sub.0-.infin. of 190 h*ng/ml to 215 h*ng/ml for each 1 mg of
rofecoxib in the formulation.
[0418] In certain aspects, the subject matter disclosed herein
provides a method for treating one or more conditions in a subject
in need thereof, the method comprising administering to the subject
a pharmaceutically acceptable formulation comprising a granular
component and an extragranular component, wherein the granular
component comprises an intragranular component comprising a 17.5 mg
of rofecoxib or a pharmaceutically acceptable salt thereof. In some
embodiments, the formulation achieves a median time to Cmax plasma
concentration in 4 hours or less following single administration of
the formulation to human subjects. In some embodiments, the
formulation achieves a median time to Cmax plasma concentration in
3 hours or less following administration. In some embodiments, the
formulation achieves a mean Cmax plasma concentration in less than
2.5 hours following administration. In some embodiments, the
formulation achieves a median time to Cmax plasma concentration in
2 hours or less following administration. In some embodiments, the
formulation achieves a mean Cmax plasma concentration of more than
100 ng/ml. In some embodiments, the formulation achieves a mean
Cmax plasma concentration of more than 150 ng/ml, 167 ng/ml, or 190
ng/ml. In some embodiments, the formulation achieves a mean Cmax
plasma concentration of more than 200 ng/ml. In some embodiments,
the formulation achieves a mean Cmax plasma concentration of more
than 250 ng/ml. In some embodiments, the formulation achieves a
mean Cmax plasma concentration of more than 280 ng/ml. In some
embodiments, the formulation achieves a mean AUC.sub.0-.infin. of
more than 1750 h*ng/ml. In some embodiments, the formulation
achieves a mean AUC.sub.0-.infin. of more than 2000 h*ng/ml. In
some embodiments, the formulation achieves a mean AUC.sub.0-.infin.
of more than 2500 h*ng/ml. In some embodiments, the formulation
achieves a mean AUC.sub.0-.infin. of more than 3000 h*ng/ml. In
some embodiments, the formulation achieves a mean AUC.sub.0-.infin.
of more than 3100 h*ng/ml. In some embodiments, the formulation
achieves a mean AUC.sub.0-.infin. of more than 3500 h*ng/ml. In
some embodiments, the formulation achieves a mean AUC.sub.0-.infin.
of more than 4000 h*ng/ml. In some embodiments, the formulation
achieves a mean AUC.sub.0-.infin. of more than 4500 h*ng/ml.
[0419] In certain aspects, the subject matter disclosed herein
provides a method for treating one or more conditions in a subject
in need thereof, the method comprising administering to the subject
a pharmaceutically acceptable formulation comprising a granular
component and an extragranular component, wherein the granular
component comprises an intragranular component comprising 20 mg of
rofecoxib or a pharmaceutically acceptable salt thereof. In some
embodiments, the formulation achieves a median time to Cmax plasma
concentration in 4 hours or less following single administration of
the formulation to human subjects. In some embodiments, the
formulation achieves a median time to Cmax plasma concentration in
3 hours or less following administration. In some embodiments, the
formulation achieves a median time to Cmax plasma concentration in
2.5 hours or less following administration. In some embodiments,
the formulation achieves a median time to Cmax plasma concentration
in 2 hours or less following administration. In some embodiments,
the formulation achieves a mean Cmax plasma concentration of more
than 150 ng/ml. In some embodiments, the formulation achieves a
mean Cmax plasma concentration of more than 191 ng/ml, 200 ng/ml,
215 ng/ml, or 225 ng/ml. In some embodiments, the formulation
achieves a mean Cmax plasma concentration of more than 250 ng/ml.
In some embodiments, the formulation achieves a mean Cmax plasma
concentration of more than 258 ng/ml. In some embodiments, the
formulation achieves a mean Cmax plasma concentration of more than
300 ng/ml. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 2000 h*ng/ml. In some embodiments,
the formulation achieves a mean AUC.sub.0-.infin. of more than 2500
h*ng/ml. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 3000 h*ng/ml. In some embodiments,
the formulation achieves a mean AUC.sub.0-.infin. of more than 3400
h*ng/ml. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 3500 h*ng/ml. In some embodiments,
the formulation achieves a mean AUC.sub.0-.infin. of more than 4000
h*ng/ml. In some embodiments, the formulation reaches a Cmax plasma
concentration of least 190 ng/ml, 205 ng/ml, 220 ng/ml, 235 ng/ml,
250 ng/ml, or higher following single administration of the
formulation to a human subject. In some embodiments, the
formulation reaches an AUC.sub.0-.infin. of at least 3000 h*ng/ml,
3200 h*ng/ml, 3350 h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml, 3800
h*ng/ml, 3950 h*ng/ml, or higher following single administration of
the formulation to a human subject. In some embodiments, the
rofecoxib formulation achieves a mean Cmax plasma concentration
within 80% to 125% of 259 ng/ml and a mean AUC.sub.0-.infin. within
80% to 125% of 3550 h*ng/ml. In some embodiments, the rofecoxib
formulation achieves a mean plasma AUC.sub.0-.infin. of about
2840-4438 h*ng/ml and a mean plasma Cmax of about 207-324 ng/ml
following oral administration of a single dose of the formulation
to a population of healthy adults less than 65 years of age in a
fasted state. In some embodiments, the population of healthy adults
are less than 60 years of age.
[0420] In certain aspects, the subject matter disclosed herein
provides a method for treating one or more conditions in a subject
in need thereof, the method comprising administering to the subject
a pharmaceutically acceptable formulation comprising a granular
component and an extragranular component, wherein the granular
component comprises an intragranular component comprising 25 mg of
rofecoxib or a pharmaceutically acceptable salt thereof. In some
embodiments, the formulation achieves a mean Cmax plasma
concentration in less than 3 hours following single administration
of the formulation to human subjects. In some embodiments, the
formulation achieves a mean Cmax plasma concentration in less than
2.5 hours following administration. In some embodiments, the
formulation achieves a mean Cmax plasma concentration in less than
2 hours following administration. In some embodiments, the
formulation achieves a mean Cmax plasma concentration of more than
240 ng/ml. In some embodiments, the formulation achieves a mean
Cmax plasma concentration of more than 250 ng/ml. In some
embodiments, the formulation achieves a mean Cmax plasma
concentration of more than 300 ng/ml. In some embodiments, the
formulation achieves a mean Cmax plasma concentration of more than
350 ng/ml. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 4250 h*ng/ml. In some embodiments,
the formulation achieves a mean AUC.sub.0-.infin. of more than 4500
h*ng/ml. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 4550 h*ng/ml. In some embodiments,
the formulation achieves a mean AUC.sub.0-.infin. of more than 4700
h*ng/ml. In some embodiments, the formulation achieves a Cmax
plasma concentration of more than 240 ng/ml in about 3 hours
following administration with an AUC.sub.0-.infin. of more than
4250 h*ng/ml.
[0421] In certain aspects, the subject matter disclosed herein
provides a method for treating one or more conditions in a subject
in need thereof, the method comprising administering to the subject
a pharmaceutically acceptable formulation comprising a granular
component and an extragranular component, wherein the granular
component comprises an intragranular component comprising 10 mg to
50 mg of rofecoxib or a pharmaceutically acceptable salt thereof.
In some embodiments, the formulation achieves a mean Cmax plasma
concentration from 9.8 ng/ml to 16 ng/ml for each 1 mg of rofecoxib
in the formulation following single administration of the
formulation to human subjects. In some embodiments, the formulation
achieves a mean Cmax plasma concentration from 10 ng/ml to 14 ng/ml
for each 1 mg of rofecoxib in the formulation. In some embodiments,
the formulation achieves a mean Cmax plasma concentration from 10
ng/ml to 13 ng/ml for each 1 mg of rofecoxib in the formulation. In
some embodiments, the formulation achieves a mean Cmax plasma
concentration from 80% to 125% of 12.8 ng/ml. In some embodiments,
the formulation reaches a mean AUC.sub.0-.infin. of 170 h*ng/ml to
235 h*ng/ml for each 1 mg of rofecoxib in the formulation. In some
embodiments, the formulation reaches a mean AUC.sub.0-.infin. of
170 h*ng/ml to 225 h*ng/ml for each 1 mg of rofecoxib in the
formulation. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of 177 h*ng/ml to 225 h*ng/ml for each 1 mg of
rofecoxib in the formulation. In some embodiments, the formulation
achieves a mean AUC.sub.0-.infin. of 180 h*ng/ml to 225 h*ng/ml for
each 1 mg of rofecoxib in the formulation. In some embodiments, the
formulation reaches a mean AUC.sub.0-.infin. of 190 h*ng/ml to 215
h*ng/ml for each 1 mg of rofecoxib in the formulation.
[0422] A method for treating one or more conditions in a subject in
need thereof, the method comprising administering to the subject a
solid dosage form comprising a granular component and an
extragranular component, wherein the granular component comprises
an intragranular component comprising rofecoxib or a
pharmaceutically acceptable salt thereof and one or more
disintegrants, and wherein the extragranular component comprises
one or more disintegrants.
[0423] In some embodiments, the one or more disintegrants in the
granular component is selected from starches, clays, celluloses,
algins, gums, cross-linked polymers, and combinations thereof. In
some embodiments, the one or more disintegrants in the granular
component is selected from croscarmellose, crospovidone, sodium
starch glycolate, and combinations thereof.
[0424] In some embodiments, the one or more disintegrants in the
granular component is croscarmellose sodium. In some embodiments,
the one or more disintegrants in the granular component is about 1%
(w/w) to about 8% (w/w) of the solid dosage form. In some
embodiments, the one or more disintegrants in the granular
component is about 1% (w/w) to about 6% (w/w) of the solid dosage
form. In some embodiments, the one or more disintegrants in the
granular component is about 1% (w/w) to about 4% (w/w) of the solid
dosage form.
[0425] In some embodiments, the one or more disintegrants in the
extragranular component is selected from starches, clays,
celluloses, algins, gums, cross-linked polymers, and combinations
thereof. In some embodiments, the one or more disintegrants in the
extragranular component is selected from croscarmellose,
crospovidone, sodium starch glycolate, and combinations thereof. In
some embodiments, the one or more disintegrants in the
extragranular component is croscarmellose sodium. In some
embodiments, the disintegrant in the extragranular component is
about 1% (w/w) to about 8% (w/w) of the solid dosage form. In some
embodiments, the disintegrant in the extragranular component is
about 1% (w/w) to about 6% (w/w) of the solid dosage form. In some
embodiments, the disintegrant in the extragranular component is
about 1% (w/w) to about 4% (w/w) of the solid dosage form.
[0426] In some embodiments, the disintegrant in the granular
component and the disintegrant in the extragranular component are
together about 2% (w/w) to about 12% (w/w) of the solid dosage
form. In some embodiments, the disintegrant in the granular
component and the disintegrant in the extragranular component are
together about 2% (w/w) to about 10% (w/w) of the solid dosage
form. In some embodiments, the disintegrant in the granular
component and the disintegrant in the extragranular component are
together about 2% (w/w) to about 8% (w/w) of the solid dosage
form.
[0427] In some embodiments, the ratio of granular disintegrant to
extragranular disintegrant is about 40% (w/w) to about 60% (w/w).
In some embodiments, the ratio of granular disintegrant to
extragranular disintegrant is about 45% (w/w) to about 55% (w/w).
In some embodiments, the ratio of granular disintegrant to
extragranular disintegrant is about 50% (w/w) to about 50% (w/w).
In some embodiments the ratio of granular disintegrant to
extragranular disintegrant is about 55% (w/w) to about 45% (w/w).
In some embodiments the ratio of granular disintegrant to
extragranular disintegrant is about 60% (w/w) to about 40%
(w/w).
[0428] In some embodiments, the solid dosage form further comprises
one or more of a diluent, a binder, a coloring agent, and a
lubricant. In some embodiments, at least a portion of the diluent
is in the granular component. In some embodiments, the diluent is
selected from dicalcium phosphate, calcium sulfate, lactose,
cellulose, kaolin, mannitol, sodium chloride, dry starch, powdered
sugar, sorbitol, sucrose, inositol, and combinations thereof. In
some embodiments, the diluent is selected from lactose, cellulose,
or a combination thereof. In some embodiments, the diluent is
selected from lactose monohydrate, microcrystalline cellulose, or a
combination thereof.
[0429] In some embodiments, the lactose monohydrate is about 35%
(w/w) to about 45% (w/w) of the solid dosage form. In some
embodiments, the lactose monohydrate is about 37% (w/w) to about
42% (w/w) of the solid dosage form. In some embodiments, the
lactose monohydrate is about 39% (w/w) to about 40% (w/w) of the
solid dosage form.
[0430] In some embodiments, the microcrystalline cellulose is about
35% (w/w) to about 45% (w/w) of the solid dosage form. In some
embodiments, the microcrystalline cellulose is about 37% (w/w) to
about 42% (w/w) of the solid dosage form. In some embodiments, the
microcrystalline cellulose is about 39% (w/w) to about 40% (w/w) of
the solid dosage form.
[0431] In some embodiments, the diluent is about 75% (w/w) to about
85% (w/w) of the solid dosage form. In some embodiments, diluent is
about 77% (w/w) to about 82% (w/w) of the solid dosage form. In
some embodiments, the diluent is about 78% (w/w) to about 80% (w/w)
of the solid dosage form.
[0432] In some embodiments, at least a portion of the binder is in
the granular component. In some embodiments, the binder is selected
from starches, gelatins, sugars, gums, waxes, water, alcohols,
celluloses, and combinations thereof. In some embodiments, the
binder is selected from acacia gum, tragacanth, corn starch, methyl
cellulose, panwar gum, ghatti gum, mucilage of isapol husks,
carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone,
sucrose, glucose, dextrose, molasses, lactose, and combinations
thereof. In some embodiments, the binder is hydroxypropyl
cellulose. In some embodiments, the binder is about 1% (w/w) to
about 5% (w/w) of the solid dosage form. In some embodiments,
binder is about 2% (w/w) to about 4% (w/w) of the solid dosage
form. In some embodiments, the binder is about 2.5% (w/w) to about
3.5% (w/w) of the solid dosage form.
[0433] In some embodiments, at least a portion of the coloring
agent is in the extragranular component. In some embodiments, the
coloring agent is pigment blend yellow. In some embodiments, the
coloring agent is about 0.30% (w/w) to about 0.60% (w/w) of the
solid dosage form.
[0434] In some embodiments, at least a portion of the lubricant is
in the extragranular component. In some embodiments, the lubricant
is selected from talc, magnesium stearate, calcium stearate,
stearic acid, metallic stearate, hydrogenated vegetable oils, and
polyethylene glycol, corn starch, boric acids, sodium chloride,
sodium lauryl sulphate. In some embodiments, the lubricant is
magnesium stearate. In some embodiments, the lubricant is about
0.10% (w/w) to about 1% (w/w) of the solid dosage form. In some
embodiments, the lubricant is about 0.50% (w/w) of the solid dosage
form.
[0435] In some embodiments, the rofecoxib or pharmaceutically
acceptable salt thereof is about 5% (w/w) to about 30% (w/w) of the
solid dosage form. In some embodiments, the rofecoxib or
pharmaceutically acceptable salt thereof is about 10% (w/w) to
about 20% (w/w) of the solid dosage form. In some embodiments, the
rofecoxib or pharmaceutically acceptable salt thereof is about 12%
(w/w) to about 13% (w/w) of the solid dosage form. In some
embodiments, the solid dosage form comprises about 10 mg of the
rofecoxib or pharmaceutically acceptable salt thereof. In some
embodiments, the solid dosage form comprises about 10.5 mg of the
rofecoxib or pharmaceutically acceptable salt thereof. In some
embodiments, the solid dosage form comprises about 11 mg of the
rofecoxib or pharmaceutically acceptable salt thereof. In some
embodiments, the solid dosage form comprises about 11.5 mg of the
rofecoxib or pharmaceutically acceptable salt thereof. In some
embodiments, the solid dosage form comprises about 12 mg of the
rofecoxib or pharmaceutically acceptable salt thereof. In some
embodiments, the solid dosage form comprises about 12.5 mg of the
rofecoxib or pharmaceutically acceptable salt thereof. In some
embodiments, the solid dosage form comprises about 20 mg of the
rofecoxib or pharmaceutically acceptable salt thereof. In some
embodiments, the solid dosage form comprises about 21 mg of the
rofecoxib or pharmaceutically acceptable salt thereof. In some
embodiments, the solid dosage form comprises about 22 mg of the
rofecoxib or pharmaceutically acceptable salt thereof. In some
embodiments, the solid dosage form comprises about 22.5 mg of the
rofecoxib or pharmaceutically acceptable salt thereof. In some
embodiments, the solid dosage form comprises about 25 mg of the
rofecoxib or pharmaceutically acceptable salt thereof. In some
embodiments, the solid dosage form comprises about 50 mg of the
rofecoxib or pharmaceutically acceptable salt thereof.
[0436] In some embodiments, the rofecoxib is highly pure. In some
embodiments, the highly pure rofecoxib comprises less than about
0.1% total impurities. In some embodiments, the highly pure
rofecoxib comprises less than about 0.075% total impurities. In
some embodiments, the highly pure rofecoxib comprises less than
about 0.050% total impurities. In some embodiments, the highly pure
rofecoxib comprises less than about 0.025% total impurities. In
some embodiments, the highly pure rofecoxib comprises less than
about 0.001% total impurities.
[0437] In some embodiments, the highly pure rofecoxib comprises
less than about 0.10%, 0.05%, 0.02%, or 0.01% of
4-[4-(methylsulphonyl)phenyl]-3-phenyl-2,5-furandione. In some
embodiments, the highly pure rofecoxib comprises less than about
0.10%, 0.05%, 0.02%, or 0.01% of
4-[4-(methylthio)phenyl]-3-phenyl-2(5H)-furanone. In some
embodiments, the highly pure rofecoxib comprises less than about
0.10%, 0.05%, 0.02%, or 0.01% of
4-[4-(methylthio)phenyl]-3-phenyl-2(5H)-furanone. In some
embodiments, the highly pure rofecoxib comprises less than about
0.10%, 0.05%, 0.02%, or 0.01% of
4-[4-(methylsulfinyl)phenyl]-3-phenyl-2(5H)-furanone.
[0438] In some embodiments, the solid dosage form is suitable for
oral administration. In some embodiments, the solid dosage form is
an oral tablet. In some embodiments, the oral tablet provides a
dissolution rate of at least about 80% of the rofecoxib or
pharmaceutically acceptable salt thereof by about 15 minutes. In
some embodiments, the oral tablet provides a dissolution rate of at
least about 85% of the rofecoxib or pharmaceutically acceptable
salt thereof by about 15 minutes. In some embodiments, the oral
tablet provides a dissolution rate of at least about 90% of the
rofecoxib or pharmaceutically acceptable salt thereof by about 15
minutes. In some embodiments, the oral tablet provides a
dissolution rate of at least about 95% of the rofecoxib or
pharmaceutically acceptable salt thereof by about 15 minutes. In
some embodiments, the oral tablet provides a dissolution rate of at
least about 100% of the rofecoxib or pharmaceutically acceptable
salt thereof by about 15 minutes.
[0439] In some embodiments, the dissolution rate is measured in
about 1% SDS at a paddle speed of about 50 rpm and at a temperature
of about 37.0.degree. C..+-.0.5.degree. C. In some embodiments, the
dissolution rate is measured in about 1% SDS at a paddle speed of
about 75 rpm and at a temperature of about 37.0.degree.
C..+-.0.5.degree. C. In some embodiments, the dissolution rate is
measured in about 1.5% SDS at a paddle speed of about 50 rpm and at
a temperature of about 37.0.degree. C..+-.0.5.degree. C. In some
embodiments, the dissolution rate is measured in about 1.5% SDS at
a paddle speed of about 75 rpm and at a temperature of about
37.0.degree. C..+-.0.5.degree. C. In some embodiments, the
dissolution rate is measured in about 2% SDS at a paddle speed of
about 50 rpm and at a temperature of about 37.0.degree.
C..+-.0.5.degree. C. In some embodiments, the dissolution rate is
measured in about 2% SDS at a paddle speed of about 75 rpm and at a
temperature of about 37.0.degree. C..+-.0.5.degree. C. In some
embodiments, the dissolution rate is measured using a USP Type II
apparatus. In some embodiments, the dissolution rate is measured
with a USP Type II apparatus using 900 mL of 2% SDS, a paddle speed
of 50 rpm, and a temperature of 37.0.degree. C..+-.0.5.degree..
[0440] In some embodiments, the rofecoxib or pharmaceutically
acceptable salt thereof is formulated into granules and at least
about 35% of the granules are less than about 75 .mu.m. In some
embodiments, the rofecoxib or pharmaceutically acceptable salt
thereof is formulated into granules and at least about 55% of the
granules are less than about 150 .mu.m. In some embodiments, the
rofecoxib or pharmaceutically acceptable salt thereof is formulated
into granules and at least about 75% of the granules are less than
about 250 .mu.m. In some embodiments, the rofecoxib or
pharmaceutically acceptable salt thereof is formulated into
granules and at least about 85% of the granules are less than about
425 .mu.m. In some embodiments, the rofecoxib or pharmaceutically
acceptable salt thereof is formulated into granules and at least
about 90% of the granules are less than about 1000 .mu.m.
[0441] In some embodiments, a 17.5 mg solid dosage formulation of
rofecoxib reaches a median time to Cmax plasma concentration in 4
hours or less following single administration of the formulation to
human subjects. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib reaches a median time to Cmax plasma
concentration in 3 hours or less following administration. In some
embodiments, a 17.5 mg solid dosage formulation of rofecoxib
reaches a median time to Cmax plasma concentration in 2.5 hours or
less following administration. In some embodiments, a 17.5 mg solid
dosage formulation of rofecoxib reaches a median time to Cmax
plasma concentration in 2 hours or less following administration.
In some embodiments, a 17.5 mg solid dosage formulation of
rofecoxib has a mean Cmax plasma concentration of more than 100
ng/ml. In some embodiments, a 17.5 mg solid dosage formulation of
rofecoxib has a mean Cmax plasma concentration of more than 150
ng/ml, 167 ng/ml, or 190 ng/ml. In some embodiments, a 17.5 mg
solid dosage formulation of rofecoxib has a mean Cmax plasma
concentration of more than 200 ng/ml. In some embodiments, a 17.5
mg solid dosage formulation of rofecoxib has a mean Cmax plasma
concentration of more than 220 ng/ml. In some embodiments, a 17.5
mg solid dosage formulation of rofecoxib has a mean Cmax plasma
concentration of more than 250 ng/ml. In some embodiments, a 17.5
mg solid dosage formulation of rofecoxib has a mean Cmax plasma
concentration of more than 280 ng/ml. In some embodiments, a 17.5
mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 1750 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 2000 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 2500 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 3000 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 3100 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 3500 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 4000 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 4500 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib reaches a Cmax plasma
concentration of least 167 ng/ml, 170 ng/ml, 175 ng/ml, 180 ng/ml,
or higher following single administration of the formulation to a
human subject. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib reaches an AUC.sub.0-.infin. of at least
2600 h*ng/ml, 2750 h*ng/ml, 2900 h*ng/ml, 3050 h*ng/ml, 3100
h*ng/ml, 3200 h*ng/ml, 3350 h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml or
higher following single administration of the formulation to a
human subject.
[0442] In some embodiments, a 20 mg solid dosage formulation of
rofecoxib reaches a median time to Cmax plasma concentration in 4
hours or less following single administration of the formulation to
human subjects. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib reaches a median time to Cmax plasma
concentration in 3 hours or less following administration. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib reaches
a median time to Cmax plasma concentration in 2.5 hours or less
following administration. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib reaches a median time to Cmax plasma
concentration in 2 hours or less following administration. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib has a
mean Cmax plasma concentration of more than 150 ng/ml. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib has a
mean Cmax plasma concentration of more than 191 ng/ml, 200 ng/ml,
215 ng/ml, or 225 ng/ml. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib has a mean Cmax plasma concentration of
more than 250 ng/ml. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib has a mean Cmax plasma concentration of
more than 300 ng/ml. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib has a mean AUC.sub.0-.infin. of more than
2000 h*ng/ml. In some embodiments, a 20 mg solid dosage formulation
of rofecoxib has a mean AUC.sub.0-.infin. of more than 2500
h*ng/ml. In some embodiments, a 20 mg solid dosage formulation of
rofecoxib has a mean AUC.sub.0-.infin. of more than 3000 h*ng/ml.
In some embodiments, a 20 mg solid dosage formulation of rofecoxib
has a mean AUC.sub.0-.infin. of more than 3400 h*ng/ml. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 3500 h*ng/ml. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 4000 h*ng/ml. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib reaches
a Cmax plasma concentration of least 190 ng/ml, 205 ng/ml, 220
ng/ml, 235 ng/ml, 250 ng/ml, or higher following single
administration of the formulation to a human subject. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib reaches
an AUC.sub.0-.infin. of at least 3000 h*ng/ml, 3200 h*ng/ml, 3350
h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml, 3800 h*ng/ml, 3950 h*ng/ml, or
higher following single administration of the formulation to a
human subject. In some embodiments, the rofecoxib formulation
achieves a mean Cmax plasma concentration within 80% to 125% of 259
ng/ml and a mean AUC.sub.0-.infin. within 80% to 125% of 3550
h*ng/ml. In some embodiments, the rofecoxib formulation achieves a
mean plasma AUC.sub.0-.infin. of about 2840-4438 h*ng/ml and a mean
plasma Cmax of about 207-324 ng/ml following oral administration of
a single dose of the formulation to a population of healthy adults
less than 65 years of age in a fasted state. In some embodiments,
the population of healthy adults are less than 60 years of age.
[0443] In some embodiments, a 25 mg solid dosage formulation of
rofecoxib reaches a mean Cmax plasma concentration in less than 3
hours following single administration of the formulation to human
subjects. In some embodiments, a 25 mg solid dosage formulation of
rofecoxib reaches a mean Cmax plasma concentration in less than 2.5
hours following administration. In some embodiments, a 25 mg solid
dosage formulation of rofecoxib reaches a mean Cmax plasma
concentration in less than 2 hours following administration. In
some embodiments, a 25 mg solid dosage formulation of rofecoxib has
a mean Cmax plasma concentration of more than 240 ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean Cmax plasma concentration of more than 250 ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean Cmax plasma concentration of more than 300 ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean Cmax plasma concentration of more than 320 ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 4250 h*ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 4500 h*ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 4550 h*ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 4700 h*ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib reaches
a mean Cmax plasma concentration of more than 240 ng/ml in a median
time of about 3 hours or less following administration with an
AUC.sub.0-.infin. of more than 4250 h*ng/ml.
[0444] In certain aspects, a 10 mg to 50 mg solid dosage
formulation of rofecoxib achieves a mean Cmax plasma concentration
from 9.8 ng/ml to 16 ng/ml for each 1 mg of rofecoxib in the
formulation following single administration of the formulation to
human subjects. In some embodiments, the 10 mg to 50 mg solid
dosage formulation of rofecoxib achieves a mean Cmax plasma
concentration from 10 ng/ml to 14 ng/ml for each 1 mg of rofecoxib
in the formulation. In some embodiments, the 10 mg to 50 mg solid
dosage formulation of rofecoxib achieves a mean Cmax plasma
concentration from 10 ng/ml to 13 ng/ml for each 1 mg of rofecoxib
in the formulation. In some embodiments, the 10 mg to 50 mg solid
dosage formulation achieves a mean Cmax plasma concentration from
80% to 125% of 12.8 ng/ml. In some embodiments, the 10 mg to 50 mg
solid dosage formulation of rofecoxib reaches a mean
AUC.sub.0-.infin. of 170 h*ng/ml to 235 h*ng/ml for each 1 mg of
rofecoxib in the formulation. In some embodiments, the 10 mg to 50
mg solid dosage formulation of rofecoxib reaches a mean
AUC.sub.0-.infin. of 170 h*ng/ml to 225 h*ng/ml for each 1 mg of
rofecoxib in the formulation. In some embodiments, the formulation
achieves a mean AUC.sub.0-.infin. of 177 h*ng/ml to 225 h*ng/ml for
each 1 mg of rofecoxib in the formulation. In some embodiments, the
formulation achieves a mean AUC.sub.0-.infin. of 180 h*ng/ml to 225
h*ng/ml for each 1 mg of rofecoxib in the formulation. In some
embodiments, the 10 mg to 50 mg solid dosage formulation of
rofecoxib reaches a mean AUC.sub.0-.infin. of 190 h*ng/ml to 215
h*ng/ml for each 1 mg of rofecoxib in the formulation.
[0445] In certain aspects, the subject matter disclosed herein
provides a method for treating one or more conditions in a subject
in need thereof, the method comprising administering to the subject
a solid dosage form comprising a granular component and an
extragranular component, wherein the granular component comprises
an intragranular component comprising 17.5 mg of rofecoxib or a
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation achieves a median time to Cmax plasma concentration in
4 hours or less following single administration of the formulation
to human subjects. In some embodiments, the formulation achieves a
median time to Cmax plasma concentration in 3 hours or less
following administration. In some embodiments, the formulation
achieves a median time to Cmax plasma concentration in 2.5 hours or
less following administration. In some embodiments, the formulation
achieves a median time to Cmax plasma concentration in 2 hours or
less following administration. In some embodiments, the formulation
achieves a mean Cmax plasma concentration of more than 100 ng/ml.
In some embodiments, the formulation achieves a mean Cmax plasma
concentration of more than 150 ng/ml, 167 ng/ml, or 190 ng/ml. In
some embodiments, the formulation achieves a mean Cmax plasma
concentration of more than 200 ng/ml. In some embodiments, the
formulation achieves a mean Cmax plasma concentration of more than
220 ng/ml. In some embodiments, the formulation achieves a mean
Cmax plasma concentration of more than 250 ng/ml. In some
embodiments, the formulation achieves a mean Cmax plasma
concentration of more than 280 ng/ml. In some embodiments, the
formulation achieves a mean AUC.sub.0-.infin. of more than 1750
h*ng/ml. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 2000 h*ng/ml. In some embodiments,
the formulation achieves a mean AUC.sub.0-.infin. of more than 2500
h*ng/ml. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 3000 h*ng/ml. In some embodiments,
the formulation achieves a mean AUC.sub.0-.infin. of more than 3100
h*ng/ml. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 3500 h*ng/ml. In some embodiments,
the formulation achieves a mean AUC.sub.0-.infin. of more than 4000
h*ng/ml. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 4500 h*ng/ml. In some embodiments,
the formulation reaches a Cmax plasma concentration of least 167
ng/ml, 170 ng/ml, 175 ng/ml, 180 ng/ml, or higher following single
administration of the formulation to a human subject. In some
embodiments, the formulation reaches an AUC.sub.0-.infin. of at
least 2600 h*ng/ml, 2750 h*ng/ml, 2900 h*ng/ml, 3050 h*ng/ml, 3100
h*ng/ml, 3200 h*ng/ml, 3350 h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml or
higher following single administration of the formulation to a
human subject.
[0446] In certain aspects, the subject matter disclosed herein
provides a method for treating one or more conditions in a subject
in need thereof, the method comprising administering to the subject
a solid dosage form comprising a granular component and an
extragranular component, wherein the granular component comprises
an intragranular component comprising 20 mg of rofecoxib or a
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation achieves a median time to Cmax plasma concentration in
4 hours or less following single administration of the formulation
to human subjects. In some embodiments, the formulation achieves a
median time to Cmax plasma concentration in 3 hours or less
following administration. In some embodiments, the formulation
achieves a median time to Cmax plasma concentration in 2.5 hours or
less following administration. In some embodiments, the formulation
achieves a median time to Cmax plasma concentration in 2 hours or
less following administration. In some embodiments, the formulation
achieves a mean Cmax plasma concentration of more than 150 ng/ml.
In some embodiments, the formulation achieves a mean Cmax plasma
concentration of more than 191 ng/ml, 200 ng/ml, 215 ng/ml, or 225
ng/ml. In some embodiments, the formulation achieves a mean Cmax
plasma concentration of more than 250 ng/ml. In some embodiments,
the formulation achieves a mean Cmax plasma concentration of more
than 258 ng/ml. In some embodiments, the formulation achieves a
mean Cmax plasma concentration of more than 300 ng/ml. In some
embodiments, the formulation achieves a mean AUC.sub.0-.infin. of
more than 2000 h*ng/ml. In some embodiments, the formulation
achieves a mean AUC.sub.0-.infin. of more than 2500 h*ng/ml. In
some embodiments, the formulation achieves a mean AUC.sub.0-.infin.
of more than 3000 h*ng/ml. In some embodiments, the formulation
achieves a mean AUC.sub.0-.infin. of more than 3400 h*ng/ml. In
some embodiments, the formulation achieves a mean AUC.sub.0-.infin.
of more than 3500 h*ng/ml. In some embodiments, the formulation
achieves a mean AUC.sub.0-.infin. of more than 4000 h*ng/ml. In
some embodiments, the formulation reaches a Cmax plasma
concentration of least 190 ng/ml, 205 ng/ml, 220 ng/ml, 235 ng/ml,
250 ng/ml, or higher following single administration of the
formulation to a human subject. In some embodiments, the
formulation reaches an AUC.sub.0-.infin. of at least 3000 h*ng/ml,
3200 h*ng/ml, 3350 h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml, 3800
h*ng/ml, 3950 h*ng/ml, or higher following single administration of
the formulation to a human subject. In some embodiments, the
rofecoxib formulation achieves a mean Cmax plasma concentration
within 80% to 125% of 259 ng/ml and a mean AUC.sub.0-.infin. within
80% to 125% of 3550 h*ng/ml. In some embodiments, the rofecoxib
formulation achieves a mean plasma AUC.sub.0-.infin. of about
2840-4438 h*ng/ml and a mean plasma Cmax of about 207-324 ng/ml
following oral administration of a single dose of the formulation
to a population of healthy adults less than 65 years of age in a
fasted state. In some embodiments, the population of healthy adults
are less than 60 years of age.
[0447] In certain aspects, the subject matter disclosed herein
provides a method for treating one or more conditions in a subject
in need thereof, the method comprising administering to the subject
a solid dosage form comprising a granular component and an
extragranular component, wherein the granular component comprises
an intragranular component comprising 25 mg of rofecoxib or a
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation achieves a mean Cmax plasma concentration in less than
3 hours following single administration of the formulation to human
subjects. In some embodiments, the formulation achieves a mean Cmax
plasma concentration in less than 2.5 hours following
administration. In some embodiments, the formulation achieves a
mean Cmax plasma concentration in less than 2 hours following
administration. In some embodiments, the formulation achieves a
mean Cmax plasma concentration of more than 240 ng/ml. In some
embodiments, the formulation achieves a mean Cmax plasma
concentration of more than 250 ng/ml. In some embodiments, the
formulation achieves a mean Cmax plasma concentration of more than
300 ng/ml. In some embodiments, the formulation achieves a mean
Cmax plasma concentration of more than 320 ng/ml. In some
embodiments, the formulation achieves a mean AUC.sub.0-.infin. of
more than 4250 h*ng/ml. In some embodiments, the formulation
achieves a mean AUC.sub.0-.infin. of more than 4500 h*ng/ml. In
some embodiments, the formulation achieves a mean AUC.sub.0-.infin.
of more than 4550 h*ng/ml. In some embodiments, the formulation
achieves a mean AUC.sub.0-.infin. of more than 4700 h*ng/ml. In
some embodiments, the formulation achieves a Cmax plasma
concentration of more than 240 ng/ml in about 3 hours following
administration with an AUC.sub.0-.infin. of more than 4250
h*ng/ml.
[0448] In certain aspects, the subject matter disclosed herein
provides a method for treating one or more conditions in a subject
in need thereof, the method comprising administering to the subject
a solid dosage form comprising a granular component and an
extragranular component, wherein the granular component comprises
an intragranular component comprising 10 mg to 50 mg of rofecoxib
or a pharmaceutically acceptable salt thereof. In some embodiments,
the formulation achieves a mean Cmax plasma concentration from 9.8
ng/ml to 16 ng/ml for each 1 mg of rofecoxib in the formulation
following single administration of the formulation to human
subjects. In some embodiments, the formulation achieves a mean Cmax
plasma concentration from 10 ng/ml to 14 ng/ml for each 1 mg of
rofecoxib in the formulation. In some embodiments, the formulation
achieves a mean Cmax plasma concentration from 10 ng/ml to 13 ng/ml
for each 1 mg of rofecoxib in the formulation. In some embodiments,
the formulation achieves a mean Cmax plasma concentration from 80%
to 125% of 12.8 ng/ml. In some embodiments, the formulation reaches
a mean AUC.sub.0-.infin. of 170 h*ng/ml to 235 h*ng/ml for each 1
mg of rofecoxib in the formulation. In some embodiments, the
formulation reaches a mean AUC.sub.0-.infin. of 170 h*ng/ml to 225
h*ng/ml for each 1 mg of rofecoxib in the formulation. In some
embodiments, the formulation achieves a mean AUC.sub.0-.infin. of
177 h*ng/ml to 225 h*ng/ml for each 1 mg of rofecoxib in the
formulation. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of 180 h*ng/ml to 225 h*ng/ml for each 1 mg of
rofecoxib in the formulation. In some embodiments, the formulation
reaches a mean AUC.sub.0-.infin. of 190 h*ng/ml to 215 h*ng/ml for
each 1 mg of rofecoxib in the formulation.
[0449] A method for enhancing the dissolution profile of a solid
dosage form comprising rofecoxib or a pharmaceutically acceptable
salt thereof, the method comprising providing a pharmaceutically
acceptable formulation comprising a granular component and an
extragranular component, wherein the granular component comprises
an intragranular component comprising rofecoxib or a
pharmaceutically acceptable salt thereof and one or more
disintegrants, and wherein the extragranular component comprises
one or more disintegrants.
[0450] In some embodiments, the one or more disintegrants in the
granular component is selected from starches, clays, celluloses,
algins, gums, cross-linked polymers, and combinations thereof. In
some embodiments, the one or more disintegrants in the granular
component is selected from croscarmellose, crospovidone, sodium
starch glycolate, and combinations thereof. In some embodiments,
the one or more disintegrants in the granular component is
croscarmellose sodium. In some embodiments, the one or more
disintegrants in the granular component is about 1% (w/w) to about
8% (w/w) of the formulation. In some embodiments, the one or more
disintegrants in the granular component is about 1% (w/w) to about
6% (w/w) of the formulation. In some embodiments, the one or more
disintegrants in the granular component is about 1% (w/w) to about
4% (w/w) of the formulation.
[0451] In some embodiments, the one or more disintegrants in the
extragranular component is selected from starches, clays,
celluloses, algins, gums, cross-linked polymers, and combinations
thereof. In some embodiments, the one or more disintegrants in the
extragranular component is selected from croscarmellose,
crospovidone, sodium starch glycolate, and combinations thereof. In
some embodiments, the one or more disintegrants in the
extragranular component is croscarmellose sodium. In some
embodiments, the disintegrant in the extragranular component is
about 1% (w/w) to about 8% (w/w) of the formulation. In some
embodiments, the disintegrant in the extragranular component is
about 1% (w/w) to about 6% (w/w) of the formulation. In some
embodiments, the disintegrant in the extragranular component is
about 1% (w/w) to about 4% (w/w) of the formulation.
[0452] In some embodiments, the disintegrant in the granular
component and the disintegrant in the extragranular component are
together about 2% (w/w) to about 12% (w/w) of the formulation. In
some embodiments, the disintegrant in the granular component and
the disintegrant in the extragranular component are together about
2% (w/w) to about 10% (w/w) of the formulation. In some
embodiments, the disintegrant in the granular component and the
disintegrant in the extragranular component are together about 2%
(w/w) to about 8% (w/w) of the formulation.
[0453] In some embodiments, the ratio of granular disintegrant to
extragranular disintegrant is about 40% (w/w) to about 60% (w/w).
In some embodiments, the ratio of granular disintegrant to
extragranular disintegrant is about 45% (w/w) to about 55% (w/w).
In some embodiments, the ratio of granular disintegrant to
extragranular disintegrant is about 50% (w/w) to about 50% (w/w).
In some embodiments, the ratio of granular disintegrant to
extragranular disintegrant is about 55% (w/w) to about 45% (w/w).
In some embodiments, the ratio of granular disintegrant to
extragranular disintegrant is about 60% (w/w) to about 40%
(w/w).
[0454] In some embodiments, the pharmaceutically acceptable
formulation further comprising one or more of a diluent, a binder,
a coloring agent, and a lubricant. In some embodiments, at least a
portion of the diluent is in the granular component. In some
embodiments, the diluent is selected from dicalcium phosphate,
calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium
chloride, dry starch, powdered sugar, sorbitol, sucrose, inositol,
and combinations thereof. In some embodiments, the diluent is
selected from lactose, cellulose, or a combination thereof. In some
embodiments, the diluent is selected from lactose monohydrate,
microcrystalline cellulose, or a combination thereof.
[0455] In some embodiments, the lactose monohydrate is about 35%
(w/w) to about 45% (w/w) of the formulation. In some embodiments,
the lactose monohydrate is about 37% (w/w) to about 42% (w/w) of
the formulation. In some embodiments, the lactose monohydrate is
about 39% (w/w) to about 40% (w/w) of the formulation.
[0456] In some embodiments, the microcrystalline cellulose is about
35% (w/w) to about 45% (w/w) of the formulation. In some
embodiments, the microcrystalline cellulose is about 37% (w/w) to
about 42% (w/w) of the formulation. In some embodiments, the
microcrystalline cellulose is about 39% (w/w) to about 40% (w/w) of
the formulation.
[0457] In some embodiments, the diluent is about 75% (w/w) to about
85% (w/w) of the formulation. In some embodiments, diluent is about
77% (w/w) to about 82% (w/w) of the formulation. In some
embodiments, the diluent is about 78% (w/w) to about 80% (w/w) of
the formulation.
[0458] In some embodiments, at least a portion of the binder is in
the granular component. In some embodiments, the binder is selected
from starches, gelatins, sugars, gums, waxes, water, alcohols,
celluloses, and combinations thereof. In some embodiments, the
binder is selected from acacia gum, tragacanth, corn starch, methyl
cellulose, panwar gum, ghatti gum, mucilage of isapol husks,
carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone,
sucrose, glucose, dextrose, molasses, lactose, and combinations
thereof. In some embodiments, the binder is hydroxypropyl
cellulose. In some embodiments, the binder is about 1% (w/w) to
about 5% (w/w) of the formulation. In some embodiments, binder is
about 2% (w/w) to about 4% (w/w) of the formulation. In some
embodiments, the binder is about 2.5% (w/w) to about 3.5% (w/w) of
the formulation.
[0459] In some embodiments, at least a portion of the coloring
agent is in the extragranular component. In some embodiments, the
coloring agent is pigment blend yellow. In some embodiments, the
coloring agent is about 0.30% (w/w) to about 0.60% (w/w) of the
formulation.
[0460] In some embodiments, at least a portion of the lubricant is
in the extragranular component. In some embodiments, the lubricant
is selected from talc, magnesium stearate, calcium stearate,
stearic acid, metallic stearate, hydrogenated vegetable oils, and
polyethylene glycol, corn starch, boric acids, sodium chloride,
sodium lauryl sulphate. In some embodiments, the lubricant is
magnesium stearate. In some embodiments, the lubricant is about
0.10% (w/w) to about 1% (w/w) of the formulation. In some
embodiments, the lubricant is about 0.50% (w/w) of the
formulation.
[0461] In some embodiments, the rofecoxib or pharmaceutically
acceptable salt thereof is about 5% (w/w) to about 30% (w/w) of the
formulation. In some embodiments, the rofecoxib or pharmaceutically
acceptable salt thereof is about 10% (w/w) to about 20% (w/w) of
the formulation. In some embodiments, the rofecoxib or
pharmaceutically acceptable salt thereof is about 12% (w/w) to
about 13% (w/w) of the formulation. In some embodiments, the
formulation comprises about 10 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 10.5 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 11 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 11.5 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 12 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 12.5 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 17.5 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 20 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 21 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 22 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 22.5 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 25 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 50 mg of the rofecoxib or
pharmaceutically acceptable salt thereof.
[0462] In some embodiments, the rofecoxib is highly pure. In some
embodiments, the highly pure rofecoxib comprises less than about
0.1% total impurities. In some embodiments, the highly pure
rofecoxib comprises less than about 0.075% total impurities. In
some embodiments, the highly pure rofecoxib comprises less than
about 0.050% total impurities. In some embodiments, the highly pure
rofecoxib comprises less than about 0.025% total impurities. In
some embodiments, the highly pure rofecoxib comprises less than
about 0.001% total impurities.
[0463] In some embodiments, the highly pure rofecoxib comprises
less than about 0.10%, 0.05%, 0.02%, or 0.01% of
4-[4-(methylsulphonyl)phenyl]-3-phenyl-2,5-furandione. In some
embodiments, the highly pure rofecoxib comprises less than about
0.10%, 0.05%, 0.02%, or 0.01% of
4-[4-(methylthio)phenyl]-3-phenyl-2(5H)-furanone. In some
embodiments, the highly pure rofecoxib comprises less than about
0.10%, 0.05%, 0.02%, or 0.01% of
4-[4-(methylthio)phenyl]-3-phenyl-2(5H)-furanone. In some
embodiments, the highly pure rofecoxib comprises less than about
0.10%, 0.05%, 0.02%, or 0.01% of
4-[4-(methylsulfinyl)phenyl]-3-phenyl-2(5H)-furanone.
[0464] In some embodiments, the formulation is suitable for oral
administration. In some embodiments, the formulation is an oral
tablet. In some embodiments, the oral tablet provides a dissolution
rate of at least about 80% of the rofecoxib or pharmaceutically
acceptable salt thereof by about 15 minutes. In some embodiments,
the oral tablet provides a dissolution rate of at least about 85%
of the rofecoxib or pharmaceutically acceptable salt thereof by
about 15 minutes. In some embodiments, the oral tablet provides a
dissolution rate of at least about 90% of the rofecoxib or
pharmaceutically acceptable salt thereof by about 15 minutes. In
some embodiments, the oral tablet provides a dissolution rate of at
least about 95% of the rofecoxib or pharmaceutically acceptable
salt thereof by about 15 minutes. In some embodiments, the oral
tablet provides a dissolution rate of at least about 100% of the
rofecoxib or pharmaceutically acceptable salt thereof by about 15
minutes.
[0465] In some embodiments, the dissolution rate is measured in
about 1% SDS at a paddle speed of about 50 rpm and at a temperature
of about 37.0.degree. C..+-.0.5.degree. C. In some embodiments, the
dissolution rate is measured in about 1% SDS at a paddle speed of
about 75 rpm and at a temperature of about 37.0.degree.
C..+-.0.5.degree. C. In some embodiments, the dissolution rate is
measured in about 1.5% SDS at a paddle speed of about 50 rpm and at
a temperature of about 37.0.degree. C..+-.0.5.degree. C. In some
embodiments, the dissolution rate is measured in about 1.5% SDS at
a paddle speed of about 75 rpm and at a temperature of about
37.0.degree. C..+-.0.5.degree. C. In some embodiments, the
dissolution rate is measured in about 2% SDS at a paddle speed of
about 50 rpm and at a temperature of about 37.0.degree.
C..+-.0.5.degree. C. In some embodiments, the dissolution rate is
measured in about 2% SDS at a paddle speed of about 75 rpm and at a
temperature of about 37.0.degree. C..+-.0.5.degree. C. In some
embodiments, the dissolution rate is measured using a USP Type II
apparatus. In some embodiments, the dissolution rate is measured
with a USP Type II apparatus using 900 mL of 2% SDS, a paddle speed
of 50 rpm, and a temperature of 37.0.degree. C..+-.0.5.degree..
[0466] In some embodiments, the rofecoxib or pharmaceutically
acceptable salt thereof is formulated into granules and at least
about 35% of the granules are less than about 75 .mu.m. In some
embodiments, the rofecoxib or pharmaceutically acceptable salt
thereof is formulated into granules and at least about 55% of the
granules are less than about 150 .mu.m. In some embodiments, the
rofecoxib or pharmaceutically acceptable salt thereof is formulated
into granules and at least about 75% of the granules are less than
about 250 .mu.m. In some embodiments, the rofecoxib or
pharmaceutically acceptable salt thereof is formulated into
granules and at least about 85% of the granules are less than about
425 .mu.m. In some embodiments, the rofecoxib or pharmaceutically
acceptable salt thereof is formulated into granules and at least
about 90% of the granules are less than about 1000 .mu.m.
[0467] In some embodiments, a 17.5 mg solid dosage formulation of
rofecoxib reaches a median time to Cmax plasma concentration in 4
hours or less following single administration of the formulation to
human subjects. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib reaches a median time to Cmax plasma
concentration in 3 hours or less following administration. In some
embodiments, a 17.5 mg solid dosage formulation of rofecoxib
reaches a mean Cmax plasma concentration in less than 2.5 hours
following administration. In some embodiments, a 17.5 mg solid
dosage formulation of rofecoxib reaches a mean Cmax plasma
concentration in less than 2.5 hours following administration. In
some embodiments, a 17.5 mg solid dosage formulation of rofecoxib
has a mean Cmax plasma concentration of more than 100 ng/ml. In
some embodiments, a 17.5 mg solid dosage formulation of rofecoxib
has a mean Cmax plasma concentration of more than 150 ng/ml, 167
ng/ml, or 190 ng/ml. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib has a mean Cmax plasma concentration of
more than 200 ng/ml. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib has a mean Cmax plasma concentration of
more than 220 ng/ml. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib has a mean Cmax plasma concentration of
more than 250 ng/ml. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib has a mean Cmax plasma concentration of
more than 280 ng/ml. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib has a mean AUC.sub.0-.infin. of more than
1750 h*ng/ml. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib has a mean AUC.sub.0-.infin. of more than
2000 h*ng/ml. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib has a mean AUC.sub.0-.infin. of more than
2500 h*ng/ml. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib has a mean AUC.sub.0-.infin. of more than
3000 h*ng/ml. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib has a mean AUC.sub.0-.infin. of more than
3100 h*ng/ml. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib has a mean AUC.sub.0-.infin. of more than
3500 h*ng/ml. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib has a mean AUC.sub.0-.infin. of more than
4000 h*ng/ml. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib has a mean AUC.sub.0-.infin. of more than
4500 h*ng/ml. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib reaches a Cmax plasma concentration of
least 167 ng/ml, 170 ng/ml, 175 ng/ml, 180 ng/ml, or higher
following single administration of the formulation to a human
subject. In some embodiments, a 17.5 mg solid dosage formulation of
rofecoxib reaches an AUC.sub.0-.infin. of at least 2600 h*ng/ml,
2750 h*ng/ml, 2900 h*ng/ml, 3050 h*ng/ml, 3100 h*ng/ml, 3200
h*ng/ml, 3350 h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml or higher
following single administration of the formulation to a human
subject.
[0468] In some embodiments, a 20 mg solid dosage formulation of
rofecoxib reaches a median time to Cmax plasma concentration in 4
hours or less following single administration of the formulation to
human subjects. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib reaches a median time to Cmax plasma
concentration in 3 hours or less following administration. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib reaches
a median time to Cmax plasma concentration in 2.5 hours or less
following administration. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib reaches a median time to Cmax plasma
concentration in 2 hours or less following administration. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib has a
mean Cmax plasma concentration of more than 150 ng/ml. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib has a
mean Cmax plasma concentration of more than 191 ng/ml, 200 ng/ml,
215 ng/ml, or 225 ng/ml. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib has a mean Cmax plasma concentration of
more than 250 ng/ml. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib has a mean Cmax plasma concentration of
more than 258 ng/ml. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib has a mean Cmax plasma concentration of
more than 300 ng/ml. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib has a mean AUC.sub.0-.infin. of more than
2000 h*ng/ml. In some embodiments, a 20 mg solid dosage formulation
of rofecoxib has a mean AUC.sub.0-.infin. of more than 2500
h*ng/ml. In some embodiments, a 20 mg solid dosage formulation of
rofecoxib has a mean AUC.sub.0-.infin. of more than 3000 h*ng/ml.
In some embodiments, a 20 mg solid dosage formulation of rofecoxib
has a mean AUC.sub.0-.infin. of more than 3400 h*ng/ml. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 3500 h*ng/ml. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 4000 h*ng/ml. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib reaches
a Cmax plasma concentration of least 190 ng/ml, 205 ng/ml, 220
ng/ml, 235 ng/ml, 250 ng/ml, or higher following single
administration of the formulation to a human subject. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib reaches
an AUC.sub.0-.infin. of at least 3000 h*ng/ml, 3200 h*ng/ml, 3350
h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml, 3800 h*ng/ml, 3950 h*ng/ml, or
higher following single administration of the formulation to a
human subject. In some embodiments, the rofecoxib formulation
achieves a mean Cmax plasma concentration within 80% to 125% of 259
ng/ml and a mean AUC.sub.0-.infin. within 80% to 125% of 3550
h*ng/ml. In some embodiments, the rofecoxib formulation achieves a
mean plasma AUC.sub.0-.infin. of about 2840-4438 h*ng/ml and a mean
plasma Cmax of about 207-324 ng/ml following oral administration of
a single dose of the formulation to a population of healthy adults
less than 65 years of age in a fasted state. In some embodiments,
the population of healthy adults are less than 60 years of age.
[0469] In some embodiments, a 25 mg solid dosage formulation of
rofecoxib reaches a mean Cmax plasma concentration in less than 3
hours following single administration of the formulation to human
subjects. In some embodiments, a 25 mg solid dosage formulation of
rofecoxib has a mean Cmax plasma concentration of more than 240
ng/ml. In some embodiments, a 25 mg solid dosage formulation of
rofecoxib has a mean Cmax plasma concentration of more than 250
ng/ml. In some embodiments, a 25 mg solid dosage formulation of
rofecoxib has a mean Cmax plasma concentration of more than 300
ng/ml. In some embodiments, a 25 mg solid dosage formulation of
rofecoxib has a mean Cmax plasma concentration of more than 320
ng/ml. In some embodiments, a 25 mg solid dosage formulation of
rofecoxib has a mean AUC.sub.0-.infin. of more than 4250 h*ng/ml.
In some embodiments, a 25 mg solid dosage formulation of rofecoxib
has a mean AUC.sub.0-.infin. of more than 4500 h*ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 4550 h*ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 4700 h*ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib reaches
a mean Cmax plasma concentration of more than 240 ng/ml in about 3
hours following administration with an AUC.sub.0-.infin. of more
than 4250 h*ng/ml.
[0470] In certain aspects, a 10 mg to 50 mg solid dosage
formulation of rofecoxib achieves a mean Cmax plasma concentration
from 9.8 ng/ml to 16 ng/ml for each 1 mg of rofecoxib in the
formulation following single administration of the formulation to
human subjects. In some embodiments, a 10 mg to 50 mg solid dosage
formulation of rofecoxib achieves a mean Cmax plasma concentration
from 10 ng/ml to 14 ng/ml for each 1 mg of rofecoxib in the
formulation. In some embodiments, a 10 mg to 50 mg solid dosage
formulation of rofecoxib achieves a mean Cmax plasma concentration
from 10 ng/ml to 13 ng/ml for each 1 mg of rofecoxib in the
formulation. In some embodiments, a 10 mg to 50 mg solid dosage
formulation of rofecoxib achieves a mean Cmax plasma concentration
from 80% to 125% of 12.8 ng/ml. In some embodiments, a 10 mg to 50
mg solid dosage formulation of rofecoxib reaches a mean
AUC.sub.0-.infin. of 170 h*ng/ml to 235 h*ng/ml for each 1 mg of
rofecoxib in the formulation. In some embodiments, a 10 mg to 50 mg
solid dosage formulation of rofecoxib reaches a mean
AUC.sub.0-.infin. of 170 h*ng/ml to 225 h*ng/ml for each 1 mg of
rofecoxib in the formulation. In some embodiments, a 10 mg to 50 mg
solid dosage formulation achieves a mean AUC.sub.0-.infin. of 177
h*ng/ml to 225 h*ng/ml for each 1 mg of rofecoxib in the
formulation. In some embodiments, a 10 mg to 50 mg solid dosage
formulation achieves a mean AUC.sub.0-.infin. of 180 h*ng/ml to 225
h*ng/ml for each 1 mg of rofecoxib in the formulation. In some
embodiments, a 10 mg to 50 mg solid dosage formulation of rofecoxib
reaches a mean AUC.sub.0-.infin. of 190 h*ng/ml to 215 h*ng/ml for
each 1 mg of rofecoxib in the formulation.
[0471] In certain aspects, the subject matter disclosed herein
provides a method for enhancing the dissolution profile of a solid
dosage form comprising rofecoxib or a pharmaceutically acceptable
salt thereof, the method comprising providing a pharmaceutically
acceptable formulation comprising a granular component and an
extragranular component, wherein the granular component comprises
an intragranular component comprising 17.5 mg of rofecoxib or a
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation achieves a median time to Cmax plasma concentration in
4 hours or less following single administration of the formulation
to human subjects. In some embodiments, the formulation achieves a
median time to Cmax plasma concentration in 3 hours or less
following administration. In some embodiments, the formulation
achieves a median time to Cmax plasma concentration in 2.5 hours or
less following administration. In some embodiments, the formulation
achieves a median time to Cmax plasma concentration in 2 hours or
less following administration. In some embodiments, the formulation
achieves a mean Cmax plasma concentration of more than 100 ng/ml.
In some embodiments, the formulation achieves a mean Cmax plasma
concentration of more than 150 ng/ml, 167 ng/ml, or 190 ng/ml. In
some embodiments, the formulation achieves a mean Cmax plasma
concentration of more than 200 ng/ml. In some embodiments, the
formulation achieves a mean Cmax plasma concentration of more than
220 ng/ml. In some embodiments, the formulation achieves a mean
Cmax plasma concentration of more than 250 ng/ml. In some
embodiments, the formulation achieves a mean Cmax plasma
concentration of more than 280 ng/ml. In some embodiments, the
formulation achieves a mean AUC.sub.0-.infin. of more than 1750
h*ng/ml. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 2000 h*ng/ml. In some embodiments,
the formulation achieves a mean AUC.sub.0-.infin. of more than 2500
h*ng/ml. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 3000 h*ng/ml. In some embodiments,
the formulation achieves a mean AUC.sub.0-.infin. of more than 3100
h*ng/ml. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 3500 h*ng/ml. In some embodiments,
the formulation achieves a mean AUC.sub.0-.infin. of more than 4000
h*ng/ml. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 4500 h*ng/ml. In some embodiments,
the formulation reaches a Cmax plasma concentration of least 167
ng/ml, 170 ng/ml, 175 ng/ml, 180 ng/ml, or higher following single
administration of the formulation to a human subject. In some
embodiments, the formulation reaches an AUC.sub.0-.infin. of at
least 2600 h*ng/ml, 2750 h*ng/ml, 2900 h*ng/ml, 3050 h*ng/ml, 3100
h*ng/ml, 3200 h*ng/ml, 3350 h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml or
higher following single administration of the formulation to a
human subject.
[0472] In certain aspects, the subject matter disclosed herein
provides a method for enhancing the dissolution profile of a solid
dosage form comprising rofecoxib or a pharmaceutically acceptable
salt thereof, the method comprising providing a pharmaceutically
acceptable formulation comprising a granular component and an
extragranular component, wherein the granular component comprises
an intragranular component comprising 20 mg of rofecoxib or a
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation achieves a median time to Cmax plasma concentration in
4 hours or less following single administration of the formulation
to human subjects. In some embodiments, the formulation achieves a
median time to Cmax plasma concentration in 3 hours or less
following administration. In some embodiments, the formulation
achieves a median time to Cmax plasma concentration in 2.5 hours or
less following administration. In some embodiments, the formulation
achieves a median time to Cmax plasma concentration in 2 hours or
less following administration. In some embodiments, the formulation
achieves a mean Cmax plasma concentration of more than 150 ng/ml.
In some embodiments, the formulation achieves a mean Cmax plasma
concentration of more than 191 ng/ml, 200 ng/ml, 215 ng/ml, or 225
ng/ml. In some embodiments, the formulation achieves a mean Cmax
plasma concentration of more than 250 ng/ml. In some embodiments,
the formulation achieves a mean Cmax plasma concentration of more
than 258 ng/ml. In some embodiments, the formulation achieves a
mean Cmax plasma concentration of more than 300 ng/ml. In some
embodiments, the formulation achieves a mean AUC.sub.0-.infin. of
more than 2000 h*ng/ml. In some embodiments, the formulation
achieves a mean AUC.sub.0-.infin. of more than 2500 h*ng/ml. In
some embodiments, the formulation achieves a mean AUC.sub.0-.infin.
of more than 3000 h*ng/ml. In some embodiments, the formulation
achieves a mean AUC.sub.0-.infin. of more than 3400 h*ng/ml. In
some embodiments, the formulation achieves a mean AUC.sub.0-.infin.
of more than 3500 h*ng/ml. In some embodiments, the formulation
achieves a mean AUC.sub.0-.infin. of more than 4000 h*ng/ml. In
some embodiments, the formulation reaches a Cmax plasma
concentration of least 190 ng/ml, 205 ng/ml, 220 ng/ml, 235 ng/ml,
250 ng/ml, or higher following single administration of the
formulation to a human subject. In some embodiments, the
formulation reaches an AUC.sub.0-.infin. of at least 3000 h*ng/ml,
3200 h*ng/ml, 3350 h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml, 3800
h*ng/ml, 3950 h*ng/ml, or higher following single administration of
the formulation to a human subject.
[0473] In certain aspects, the subject matter disclosed herein
provides a method for enhancing the dissolution profile of a solid
dosage form comprising rofecoxib or a pharmaceutically acceptable
salt thereof, the method comprising providing a pharmaceutically
acceptable formulation comprising a granular component and an
extragranular component, wherein the granular component comprises
an intragranular component comprising 25 mg solid dosage
formulation of rofecoxib or a pharmaceutically acceptable salt
thereof. In some embodiments, the formulation achieves a mean Cmax
plasma concentration in less than 3 hours following single
administration of the formulation to human subjects. In some
embodiments, the formulation achieves a mean Cmax plasma
concentration in less than 2.5 hours following administration. In
some embodiments, the formulation achieves a mean Cmax plasma
concentration in less than 2 hours following administration. In
some embodiments, the formulation achieves a mean Cmax plasma
concentration of more than 240 ng/ml. In some embodiments, the
formulation achieves a mean Cmax plasma concentration of more than
250 ng/ml. In some embodiments, the formulation achieves a mean
Cmax plasma concentration of more than 300 ng/ml. In some
embodiments, the formulation achieves a mean Cmax plasma
concentration of more than 320 ng/ml. In some embodiments, the
formulation achieves a mean AUC.sub.0-.infin. of more than 4250
h*ng/ml. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 4500 h*ng/ml. In some embodiments,
the formulation achieves a mean AUC.sub.0-.infin. of more than 4550
h*ng/ml. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 4700 h*ng/ml. In some embodiments,
the formulation achieves a mean Cmax plasma concentration of more
than 240 ng/ml in less than 3 hours following administration with
an AUC.sub.0-.infin. of more than 4250 h*ng/ml.
[0474] In certain aspects, the subject matter disclosed herein
provides a method for enhancing the dissolution profile of a solid
dosage form comprising rofecoxib or a pharmaceutically acceptable
salt thereof, the method comprising providing a pharmaceutically
acceptable formulation comprising a granular component and an
extragranular component, wherein the granular component comprises
an intragranular component comprising 10 mg to 50 mg of rofecoxib
or a pharmaceutically acceptable salt thereof. In some embodiments,
the formulation achieves a mean Cmax plasma concentration from 9.8
ng/ml to 16 ng/ml for each 1 mg of rofecoxib in the formulation
following single administration of the formulation to human
subjects. In some embodiments, the formulation achieves a mean Cmax
plasma concentration from 10 ng/ml to 14 ng/ml for each 1 mg of
rofecoxib in the formulation. In some embodiments, the formulation
achieves a mean Cmax plasma concentration from 10 ng/ml to 13 ng/ml
for each 1 mg of rofecoxib in the formulation. In some embodiments,
the formulation achieves a mean Cmax plasma concentration from 80%
to 125% of 12.8 ng/ml. In some embodiments, the formulation reaches
a mean AUC.sub.0-.infin. of 170 h*ng/ml to 235 h*ng/ml for each 1
mg of rofecoxib in the formulation. In some embodiments, the
formulation reaches a mean AUC.sub.0-.infin. of 170 h*ng/ml to 225
h*ng/ml for each 1 mg of rofecoxib in the formulation. In some
embodiments, the formulation achieves a mean AUC.sub.0-.infin. of
177 h*ng/ml to 225 h*ng/ml for each 1 mg of rofecoxib in the
formulation. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of 180 h*ng/ml to 225 h*ng/ml for each 1 mg of
rofecoxib in the formulation. In some embodiments, the formulation
reaches a mean AUC.sub.0-.infin. of 190 h*ng/ml to 215 h*ng/ml for
each 1 mg of rofecoxib in the formulation.
[0475] A method for manufacturing a solid dosage form comprising
rofecoxib or a pharmaceutically acceptable salt thereof, the method
comprising providing a pharmaceutically acceptable formulation
comprising a granular component and an extragranular component,
wherein the granular component comprises an intragranular component
comprising rofecoxib or a pharmaceutically acceptable salt thereof
and one or more disintegrants, and wherein the extragranular
component comprises one or more disintegrants.
[0476] In some embodiments, the one or more disintegrants in the
granular component is selected from starches, clays, celluloses,
algins, gums, cross-linked polymers, and combinations thereof. In
some embodiments, the one or more disintegrants in the granular
component is selected from croscarmellose, crospovidone, sodium
starch glycolate, and combinations thereof. In some embodiments,
the one or more disintegrants in the granular component is
croscarmellose sodium. In some embodiments, the one or more
disintegrants in the granular component is about 1% (w/w) to about
8% (w/w) of the formulation. In some embodiments, the one or more
disintegrants in the granular component is about 1% (w/w) to about
6% (w/w) of the formulation. In some embodiments, the one or more
disintegrants in the granular component is about 1% (w/w) to about
4% (w/w) of the formulation.
[0477] In some embodiments, the one or more disintegrants in the
extragranular component is selected from starches, clays,
celluloses, algins, gums, cross-linked polymers, and combinations
thereof. In some embodiments, the one or more disintegrants in the
extragranular component is selected from croscarmellose,
crospovidone, sodium starch glycolate, and combinations thereof. In
some embodiments, the one or more disintegrants in the
extragranular component is croscarmellose sodium. In some
embodiments, the disintegrant in the extragranular component is
about 1% (w/w) to about 8% (w/w) of the formulation. In some
embodiments, the disintegrant in the extragranular component is
about 1% (w/w) to about 6% (w/w) of the formulation. In some
embodiments, the disintegrant in the extragranular component is
about 1% (w/w) to about 4% (w/w) of the formulation.
[0478] In some embodiments, the disintegrant in the granular
component and the disintegrant in the extragranular component are
together about 2% (w/w) to about 12% (w/w) of the formulation. In
some embodiments, the disintegrant in the granular component and
the disintegrant in the extragranular component are together about
2% (w/w) to about 10% (w/w) of the formulation. In some
embodiments, the disintegrant in the granular component and the
disintegrant in the extragranular component are together about 2%
(w/w) to about 8% (w/w) of the formulation.
[0479] In some embodiments, the ratio of granular disintegrant to
extragranular disintegrant is about 40% (w/w) to about 60% (w/w).
In some embodiments, the ratio of granular disintegrant to
extragranular disintegrant is about 45% (w/w) to about 55% (w/w).
In some embodiments, the ratio of granular disintegrant to
extragranular disintegrant is about 50% (w/w) to about 50% (w/w).
In some embodiments, the ratio of granular disintegrant to
extragranular disintegrant is about 55% (w/w) to about 45% (w/w).
In some embodiments, the ratio of granular disintegrant to
extragranular disintegrant is about 60% (w/w) to about 40%
(w/w).
[0480] In some embodiments, the pharmaceutically acceptable
formulation further comprising one or more of a diluent, a binder,
a coloring agent, and a lubricant. In some embodiments, at least a
portion of the diluent is in the granular component. In some
embodiments, the diluent is selected from dicalcium phosphate,
calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium
chloride, dry starch, powdered sugar, sorbitol, sucrose, inositol,
and combinations thereof. In some embodiments, the diluent is
selected from lactose, cellulose, or a combination thereof. In some
embodiments, the diluent is selected from lactose monohydrate,
microcrystalline cellulose, or a combination thereof.
[0481] In some embodiments, the lactose monohydrate is about 35%
(w/w) to about 45% (w/w) of the formulation. In some embodiments,
the lactose monohydrate is about 37% (w/w) to about 42% (w/w) of
the formulation. In some embodiments, the lactose monohydrate is
about 39% (w/w) to about 40% (w/w) of the formulation.
[0482] In some embodiments, the microcrystalline cellulose is about
35% (w/w) to about 45% (w/w) of the formulation. In some
embodiments, the microcrystalline cellulose is about 37% (w/w) to
about 42% (w/w) of the formulation. In some embodiments, the
microcrystalline cellulose is about 39% (w/w) to about 40% (w/w) of
the formulation.
[0483] In some embodiments, the diluent is about 75% (w/w) to about
85% (w/w) of the formulation. In some embodiments, diluent is about
77% (w/w) to about 82% (w/w) of the formulation. In some
embodiments, the diluent is about 78% (w/w) to about 80% (w/w) of
the formulation.
[0484] In some embodiments, at least a portion of the binder is in
the granular component. In some embodiments, the binder is selected
from starches, gelatins, sugars, gums, waxes, water, alcohols,
celluloses, and combinations thereof. In some embodiments, the
binder is selected from acacia gum, tragacanth, corn starch, methyl
cellulose, panwar gum, ghatti gum, mucilage of isapol husks,
carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone,
sucrose, glucose, dextrose, molasses, lactose, and combinations
thereof. In some embodiments, the binder is hydroxypropyl
cellulose. In some embodiments, the binder is about 1% (w/w) to
about 5% (w/w) of the formulation. In some embodiments, binder is
about 2% (w/w) to about 4% (w/w) of the formulation. In some
embodiments, the binder is about 2.5% (w/w) to about 3.5% (w/w) of
the formulation.
[0485] In some embodiments, at least a portion of the coloring
agent is in the extragranular component. In some embodiments, the
coloring agent is pigment blend yellow. In some embodiments, the
coloring agent is about 0.30% (w/w) to about 0.60% (w/w) of the
formulation.
[0486] In some embodiments, at least a portion of the lubricant is
in the extragranular component. In some embodiments, the lubricant
is selected from talc, magnesium stearate, calcium stearate,
stearic acid, metallic stearate, hydrogenated vegetable oils, and
polyethylene glycol, corn starch, boric acids, sodium chloride,
sodium lauryl sulphate. In some embodiments, the lubricant is
magnesium stearate. In some embodiments, the lubricant is about
0.10% (w/w) to about 1% (w/w) of the formulation. In some
embodiments, the lubricant is about 0.50% (w/w) of the
formulation.
[0487] In some embodiments, the rofecoxib or pharmaceutically
acceptable salt thereof is about 5% (w/w) to about 30% (w/w) of the
formulation. In some embodiments, the rofecoxib or pharmaceutically
acceptable salt thereof is about 10% (w/w) to about 20% (w/w) of
the formulation. In some embodiments, the rofecoxib or
pharmaceutically acceptable salt thereof is about 12% (w/w) to
about 13% (w/w) of the formulation. In some embodiments, the
formulation comprises about 10 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 10.5 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 11 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 11.5 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 12 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 12.5 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 17.5 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 20 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 21 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 22 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 22.5 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 25 mg of the rofecoxib or
pharmaceutically acceptable salt thereof. In some embodiments, the
formulation comprises about 50 mg of the rofecoxib or
pharmaceutically acceptable salt thereof.
[0488] In some embodiments, the rofecoxib is highly pure. In some
embodiments, the highly pure rofecoxib comprises less than about
0.1% total impurities. In some embodiments, the highly pure
rofecoxib comprises less than about 0.075% total impurities. In
some embodiments, the highly pure rofecoxib comprises less than
about 0.050% total impurities. In some embodiments, the highly pure
rofecoxib comprises less than about 0.025% total impurities. In
some embodiments, the highly pure rofecoxib comprises less than
about 0.001% total impurities.
[0489] In some embodiments, the highly pure rofecoxib comprises
less than about 0.10%, 0.05%, 0.02%, or 0.01% of
4-[4-(methylsulphonyl)phenyl]-3-phenyl-2,5-furandione. In some
embodiments, the highly pure rofecoxib comprises less than about
0.10%, 0.05%, 0.02%, or 0.01% of
4-[4-(methylthio)phenyl]-3-phenyl-2(5H)-furanone. In some
embodiments, the highly pure rofecoxib comprises less than about
0.10%, 0.05%, 0.02%, or 0.01% of
4-[4-(methylthio)phenyl]-3-phenyl-2(5H)-furanone. In some
embodiments, the highly pure rofecoxib comprises less than about
0.10%, 0.05%, 0.02%, or 0.01% of
4-[4-(methylsulfinyl)phenyl]-3-phenyl-2(5H)-furanone.
[0490] In some embodiments, the formulation is suitable for oral
administration. In some embodiments, the formulation is an oral
tablet. In some embodiments, the oral tablet provides a dissolution
rate of at least about 80% of the rofecoxib or pharmaceutically
acceptable salt thereof by about 15 minutes. In some embodiments,
the oral tablet provides a dissolution rate of at least about 85%
of the rofecoxib or pharmaceutically acceptable salt thereof by
about 15 minutes. In some embodiments, the oral tablet provides a
dissolution rate of at least about 90% of the rofecoxib or
pharmaceutically acceptable salt thereof by about 15 minutes. In
some embodiments, the oral tablet provides a dissolution rate of at
least about 95% of the rofecoxib or pharmaceutically acceptable
salt thereof by about 15 minutes. In some embodiments, the oral
tablet provides a dissolution rate of at least about 100% of the
rofecoxib or pharmaceutically acceptable salt thereof by about 15
minutes.
[0491] In some embodiments, the dissolution rate is measured in
about 1% SDS at a paddle speed of about 50 rpm and at a temperature
of about 37.0.degree. C..+-.0.5.degree. C. In some embodiments, the
dissolution rate is measured in about 1% SDS at a paddle speed of
about 75 rpm and at a temperature of about 37.0.degree.
C..+-.0.5.degree. C. In some embodiments, the dissolution rate is
measured in about 1.5% SDS at a paddle speed of about 50 rpm and at
a temperature of about 37.0.degree. C..+-.0.5.degree. C. In some
embodiments, the dissolution rate is measured in about 1.5% SDS at
a paddle speed of about 75 rpm and at a temperature of about
37.0.degree. C..+-.0.5.degree. C. In some embodiments, the
dissolution rate is measured in about 2% SDS at a paddle speed of
about 50 rpm and at a temperature of about 37.0.degree.
C..+-.0.5.degree. C. In some embodiments, the dissolution rate is
measured in about 2% SDS at a paddle speed of about 75 rpm and at a
temperature of about 37.0.degree. C..+-.0.5.degree. C. In some
embodiments, the dissolution rate is measured using a USP Type II
apparatus. In some embodiments, the dissolution rate is measured
with a USP Type II apparatus using 900 mL of 2% SDS, a paddle speed
of 50 rpm, and a temperature of 37.0.degree. C..+-.0.5.degree..
[0492] In some embodiments, the rofecoxib or pharmaceutically
acceptable salt thereof is formulated into granules and at least
about 35% of the granules are less than about 75 .mu.m. In some
embodiments, the rofecoxib or pharmaceutically acceptable salt
thereof is formulated into granules and at least about 55% of the
granules are less than about 150 .mu.m. In some embodiments, the
rofecoxib or pharmaceutically acceptable salt thereof is formulated
into granules and at least about 75% of the granules are less than
about 250 .mu.m. In some embodiments, the rofecoxib or
pharmaceutically acceptable salt thereof is formulated into
granules and at least about 85% of the granules are less than about
425 .mu.m. In some embodiments, the rofecoxib or pharmaceutically
acceptable salt thereof is formulated into granules and at least
about 90% of the granules are less than about 1000 .mu.m.
[0493] In some embodiments, a 17.5 mg solid dosage formulation of
rofecoxib reaches a median time to Cmax plasma concentration in 4
hours or less following single administration of the formulation to
human subjects. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib reaches a median time to Cmax plasma
concentration in 3 hours or less following administration. In some
embodiments, a 17.5 mg solid dosage formulation of rofecoxib
reaches a median time to Cmax plasma concentration in 2.5 hours or
less following administration. In some embodiments, a 17.5 mg solid
dosage formulation of rofecoxib reaches a median time to Cmax
plasma concentration in 2 hours or less following administration.
In some embodiments, a 17.5 mg solid dosage formulation of
rofecoxib has a mean Cmax plasma concentration of more than 150
ng/ml, 167 ng/ml, or 190 ng/ml. In some embodiments, a 17.5 mg
solid dosage formulation of rofecoxib has a mean Cmax plasma
concentration of more than 200 ng/ml. In some embodiments, a 17.5
mg solid dosage formulation of rofecoxib has a mean Cmax plasma
concentration of more than 220 ng/ml. In some embodiments, a 17.5
mg solid dosage formulation of rofecoxib has a mean Cmax plasma
concentration of more than 250 ng/ml. In some embodiments, a 17.5
mg solid dosage formulation of rofecoxib has a mean Cmax plasma
concentration of more than 280 ng/ml. In some embodiments, a 17.5
mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 1750 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 2000 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 2500 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 3000 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 3100 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 3500 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 4000 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 4500 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib reaches a Cmax plasma
concentration of least 167 ng/ml, 170 ng/ml, 175 ng/ml, 180 ng/ml,
or higher following single administration of the formulation to a
human subject. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib reaches an AUC.sub.0-.infin. of at least
2600 h*ng/ml, 2750 h*ng/ml, 2900 h*ng/ml, 3050 h*ng/ml, 3100
h*ng/ml, 3200 h*ng/ml, 3350 h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml or
higher following single administration of the formulation to a
human subject.
[0494] In some embodiments, a 20 mg solid dosage formulation of
rofecoxib reaches a median time to Cmax plasma concentration in 4
hours or less following single administration of the formulation to
human subjects. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib reaches a median time to Cmax plasma
concentration in 3 hours or less following administration. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib reaches
a median time to Cmax plasma concentration in 2.5 hours or less
following administration. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib reaches a median time to Cmax plasma
concentration in 2 hours or less following administration. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib has a
mean Cmax plasma concentration of more than 150 ng/ml. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib has a
mean Cmax plasma concentration of more than 191 ng/ml, 200 ng/ml,
215 ng/ml, or 225 ng/ml. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib has a mean Cmax plasma concentration of
more than 250 ng/ml. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib has a mean Cmax plasma concentration of
more than 258 ng/ml. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib has a mean Cmax plasma concentration of
more than 300 ng/ml. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib has a mean AUC.sub.0-.infin. of more than
2000 h*ng/ml. In some embodiments, a 20 mg solid dosage formulation
of rofecoxib has a mean AUC.sub.0-.infin. of more than 2500
h*ng/ml. In some embodiments, a 20 mg solid dosage formulation of
rofecoxib has a mean AUC.sub.0-.infin. of more than 3000 h*ng/ml.
In some embodiments, a 20 mg solid dosage formulation of rofecoxib
has a mean AUC.sub.0-.infin. of more than 3400 h*ng/ml. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 3500 h*ng/ml. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 4000 h*ng/ml. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib reaches
a Cmax plasma concentration of least 190 ng/ml, 205 ng/ml, 220
ng/ml, 235 ng/ml, 250 ng/ml, or higher following single
administration of the formulation to a human subject. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib reaches
an AUC.sub.0-.infin. of at least 3000 h*ng/ml, 3200 h*ng/ml, 3350
h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml, 3800 h*ng/ml, 3950 h*ng/ml, or
higher following single administration of the formulation to a
human subject. In some embodiments, the rofecoxib formulation
achieves a mean Cmax plasma concentration within 80% to 125% of 259
ng/ml and a mean AUC.sub.0-.infin. within 80% to 125% of 3550
h*ng/ml. In some embodiments, the rofecoxib formulation achieves a
mean plasma AUC.sub.0-.infin. of about 2840-4438 h*ng/ml and a mean
plasma Cmax of about 207-324 ng/ml following oral administration of
a single dose of the formulation to a population of healthy adults
less than 65 years of age in a fasted state. In some embodiments,
the population of healthy adults are less than 60 years of age.
[0495] In some embodiments, a 25 mg solid dosage formulation of
rofecoxib reaches a mean Cmax plasma concentration in less than 3
hours following single administration of the formulation to human
subjects. In some embodiments, a 25 mg solid dosage formulation of
rofecoxib reaches a mean Cmax plasma concentration in less than 2.5
hours following administration. In some embodiments, a 25 mg solid
dosage formulation of rofecoxib reaches a mean Cmax plasma
concentration in less than 2 hours following administration. In
some embodiments, a 25 mg solid dosage formulation of rofecoxib has
a mean Cmax plasma concentration of more than 240 ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean Cmax plasma concentration of more than 250 ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean Cmax plasma concentration of more than 300 ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean Cmax plasma concentration of more than 320 ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 4250 h*ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 4500 h*ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 4550 h*ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 4700 h*ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib reaches
a mean Cmax plasma concentration of more than 240 ng/ml in a median
time of about 3 hours or less following administration with an
AUC.sub.0-.infin. of more than 4250 h*ng/ml.
[0496] In some embodiments, a 10 mg to 50 mg solid dosage
formulation of rofecoxib achieves a mean Cmax plasma concentration
from 9.8 ng/ml to 16 ng/ml for each 1 mg of rofecoxib in the
formulation following single administration of the formulation to
human subjects. In some embodiments, a 10 mg to 50 mg solid dosage
formulation of rofecoxib achieves a mean Cmax plasma concentration
from 10 ng/ml to 14 ng/ml for each 1 mg of rofecoxib in the
formulation. In some embodiments, a 10 mg to 50 mg solid dosage
formulation of rofecoxib achieves a mean Cmax plasma concentration
from 10 ng/ml to 13 ng/ml for each 1 mg of rofecoxib in the
formulation. In some embodiments, a 10 mg to 50 mg solid dosage
formulation of rofecoxib achieves a mean Cmax plasma concentration
from 80% to 125% of 12.8 ng/ml. In some embodiments, a 10 mg to 50
mg solid dosage formulation of rofecoxib reaches a mean
AUC.sub.0-.infin. of 170 h*ng/ml to 235 h*ng/ml for each 1 mg of
rofecoxib in the formulation. In some embodiments, a 10 mg to 50 mg
solid dosage formulation of rofecoxib reaches a mean
AUC.sub.0-.infin. of 170 h*ng/ml to 225 h*ng/ml for each 1 mg of
rofecoxib in the formulation. In some embodiments, a 10 mg to 50 mg
solid dosage formulation of rofecoxib achieves a mean
AUC.sub.0-.infin. of 177 h*ng/ml to 225 h*ng/ml for each 1 mg of
rofecoxib in the formulation. In some embodiments, a 10 mg to 50 mg
solid dosage formulation of rofecoxib achieves a mean
AUC.sub.0-.infin. of 180 h*ng/ml to 225 h*ng/ml for each 1 mg of
rofecoxib in the formulation. In some embodiments, a 10 mg to 50 mg
solid dosage formulation of rofecoxib reaches a mean
AUC.sub.0-.infin. of 190 h*ng/ml to 215 h*ng/ml for each 1 mg of
rofecoxib in the formulation.
[0497] In certain aspects, the subject matter disclosed herein
provides a method for manufacturing a solid dosage form comprising
rofecoxib or a pharmaceutically acceptable salt thereof, the method
comprising providing a pharmaceutically acceptable formulation
comprising a granular component and an extragranular component,
wherein the granular component comprises an intragranular component
comprising 17.5 mg of rofecoxib or a pharmaceutically acceptable
salt thereof. In some embodiments, the formulation achieves a
median time to Cmax plasma concentration in 4 hours or less
following single administration of the formulation to human
subjects. In some embodiments, the formulation achieves a median
time to Cmax plasma concentration in 3 hours or less following
administration. In some embodiments, the formulation achieves a
median time to Cmax plasma concentration in 2.5 hours or less
following administration. In some embodiments, the formulation
achieves a median time to Cmax plasma concentration in 2 hours or
less following administration. In some embodiments, the formulation
achieves a mean Cmax plasma concentration of more than 150 ng/ml,
167 ng/ml, or 190 ng/ml. In some embodiments, the formulation
achieves a mean Cmax plasma concentration of more than 200 ng/ml.
In some embodiments, the formulation achieves a mean Cmax plasma
concentration of more than 220 ng/ml. In some embodiments, the
formulation achieves a mean Cmax plasma concentration of more than
250 ng/ml. In some embodiments, the formulation achieves a mean
Cmax plasma concentration of more than 280 ng/ml. In some
embodiments, the formulation achieves a mean AUC.sub.0-.infin. of
more than 1750 h*ng/ml. In some embodiments, the formulation
achieves a mean AUC.sub.0-.infin. of more than 2000 h*ng/ml. In
some embodiments, the formulation achieves a mean AUC.sub.0-.infin.
of more than 2500 h*ng/ml. In some embodiments, the formulation
achieves a mean AUC.sub.0-.infin. of more than 3000 h*ng/ml. In
some embodiments, the formulation achieves a mean AUC.sub.0-.infin.
of more than 3100 h*ng/ml. In some embodiments, the formulation
achieves a mean AUC.sub.0-.infin. of more than 3500 h*ng/ml. In
some embodiments, the formulation achieves a mean AUC.sub.0-.infin.
of more than 4000 h*ng/ml. In some embodiments, the formulation
achieves a mean AUC.sub.0-.infin. of more than 4500 h*ng/ml. In
some embodiments, the formulation reaches a Cmax plasma
concentration of least 167 ng/ml, 170 ng/ml, 175 ng/ml, 180 ng/ml,
or higher following single administration of the formulation to a
human subject. In some embodiments, the formulation reaches an
AUC.sub.0-.infin. of at least 2600 h*ng/ml, 2750 h*ng/ml, 2900
h*ng/ml, 3050 h*ng/ml, 3100 h*ng/ml, 3200 h*ng/ml, 3350 h*ng/ml,
3500 h*ng/ml, 3650 h*ng/ml or higher following single
administration of the formulation to a human subject.
[0498] In certain aspects, the subject matter disclosed herein
provides a method for manufacturing a solid dosage form comprising
rofecoxib or a pharmaceutically acceptable salt thereof, the method
comprising providing a pharmaceutically acceptable formulation
comprising a granular component and an extragranular component,
wherein the granular component comprises an intragranular component
comprising 20 mg of rofecoxib or a pharmaceutically acceptable salt
thereof. In some embodiments, the formulation achieves a median
time to Cmax plasma concentration in 4 hours or less following
single administration of the formulation to human subjects. In some
embodiments, the formulation achieves a median time to Cmax plasma
concentration in 3 hours or less following administration. In some
embodiments, the formulation achieves a median time to Cmax plasma
concentration in 2.5 hours or less following administration. In
some embodiments, the formulation achieves a median time to Cmax
plasma concentration in 2 hours or less following administration.
In some embodiments, the formulation achieves a mean Cmax plasma
concentration of more than 150 ng/ml. In some embodiments, the
formulation achieves a mean Cmax plasma concentration of more than
191 ng/ml, 200 ng/ml, 215 ng/ml, or 225 ng/ml. In some embodiments,
the formulation achieves a mean Cmax plasma concentration of more
than 250 ng/ml. In some embodiments, the formulation achieves a
mean Cmax plasma concentration of more than 258 ng/ml. In some
embodiments, the formulation achieves a mean Cmax plasma
concentration of more than 300 ng/ml. In some embodiments, the
formulation achieves a mean AUC.sub.0-.infin. of more than 2000
h*ng/ml. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 2500 h*ng/ml. In some embodiments,
the formulation achieves a mean AUC.sub.0-.infin. of more than 3000
h*ng/ml. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 3400 h*ng/ml. In some embodiments,
the formulation achieves a mean AUC.sub.0-.infin. of more than 3500
h*ng/ml. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 4000 h*ng/ml. In some embodiments,
the formulation reaches a Cmax plasma concentration of least 190
ng/ml, 205 ng/ml, 220 ng/ml, 235 ng/ml, 250 ng/ml, or higher
following single administration of the formulation to a human
subject. In some embodiments, the formulation reaches an
AUC.sub.0-.infin. of at least 3000 h*ng/ml, 3200 h*ng/ml, 3350
h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml, 3800 h*ng/ml, 3950 h*ng/ml, or
higher following single administration of the formulation to a
human subject. In some embodiments, the rofecoxib formulation
achieves a mean Cmax plasma concentration within 80% to 125% of 259
ng/ml and a mean AUC.sub.0-.infin. within 80% to 125% of 3550
h*ng/ml. In some embodiments, the rofecoxib formulation achieves a
mean plasma AUC.sub.0-.infin. of about 2840-4438 h*ng/ml and a mean
plasma Cmax of about 207-324 ng/ml following oral administration of
a single dose of the formulation to a population of healthy adults
less than 65 years of age in a fasted state. In some embodiments,
the population of healthy adults are less than 60 years of age.
[0499] In certain aspects, the subject matter disclosed herein
provides a method for manufacturing a solid dosage form comprising
rofecoxib or a pharmaceutically acceptable salt thereof, the method
comprising providing a pharmaceutically acceptable formulation
comprising a granular component and an extragranular component,
wherein the granular component comprises an intragranular component
comprising 25 mg of rofecoxib or a pharmaceutically acceptable salt
thereof. In some embodiments, the formulation achieves a mean Cmax
plasma concentration in less than 3 hours following single
administration of the formulation to human subjects. In some
embodiments, the formulation achieves a mean Cmax plasma
concentration in less than 2.5 hours following administration. In
some embodiments, the formulation achieves a mean Cmax plasma
concentration in less than 2 hours following administration. In
some embodiments, the formulation achieves a mean Cmax plasma
concentration of more than 240 ng/ml. In some embodiments, the
formulation achieves a mean Cmax plasma concentration of more than
250 ng/ml. In some embodiments, the formulation achieves a mean
Cmax plasma concentration of more than 300 ng/ml. In some
embodiments, the formulation achieves a mean Cmax plasma
concentration of more than 320 ng/ml. In some embodiments, the
formulation achieves a mean AUC.sub.0-.infin. of more than 4250
h*ng/ml. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 4500 h*ng/ml. In some embodiments,
the formulation achieves a mean AUC.sub.0-.infin. of more than 4550
h*ng/ml. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of more than 4700 h*ng/ml. In some embodiments,
the formulation achieves a Cmax plasma concentration of more than
240 ng/ml in about 3 hours following administration with an
AUC.sub.0-.infin. of more than 4250 h*ng/ml.
[0500] In certain aspects, the subject matter disclosed herein
provides a method for manufacturing a solid dosage form comprising
rofecoxib or a pharmaceutically acceptable salt thereof, the method
comprising providing a pharmaceutically acceptable formulation
comprising a granular component and an extragranular component,
wherein the granular component comprises an intragranular component
comprising 10 mg to 50 mg of rofecoxib or a pharmaceutically
acceptable salt thereof. In some embodiments, the formulation
achieves a mean Cmax plasma concentration from 9.8 ng/ml to 16
ng/ml for each 1 mg of rofecoxib in the formulation following
single administration of the formulation to human subjects. In some
embodiments, the formulation achieves a mean Cmax plasma
concentration from 10 ng/ml to 14 ng/ml for each 1 mg of rofecoxib
in the formulation. In some embodiments, the formulation achieves a
mean Cmax plasma concentration from 10 ng/ml to 13 ng/ml for each 1
mg of rofecoxib in the formulation. In some embodiments, the
formulation achieves a mean Cmax plasma concentration from 80% to
125% of 12.8 ng/ml. In some embodiments, the formulation reaches a
mean AUC.sub.0-.infin. of 170 h*ng/ml to 235 h*ng/ml for each 1 mg
of rofecoxib in the formulation. In some embodiments, the
formulation reaches a mean AUC.sub.0-.infin. of 177 h*ng/ml to 225
h*ng/ml for each 1 mg of rofecoxib in the formulation. In some
embodiments, the formulation achieves a mean AUC.sub.0-.infin. of
177 h*ng/ml to 225 h*ng/ml for each 1 mg of rofecoxib in the
formulation. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of 180 h*ng/ml to 225 h*ng/ml for each 1 mg of
rofecoxib in the formulation. In some embodiments, the formulation
reaches a mean AUC.sub.0-.infin. of 190 h*ng/ml to 215 h*ng/ml for
each 1 mg of rofecoxib in the formulation.
Methods for Manufacturing of Rofecoxib Tablets
[0501] In some embodiments, the subject matter disclosed herein
provides for a method of manufacture of a 25-mg rofecoxib tablet.
In some embodiments, the rofecoxib tablet is a 5-mg rofecoxib
tablet, 10-mg rofecoxib tablet, 10.5-mg rofecoxib tablet, 11-mg
rofecoxib tablet, 11.5-mg rofecoxib tablet, 12-mg rofecoxib tablet,
12.5-mg rofecoxib tablet, 13-mg rofecoxib tablet, 14-mg rofecoxib
tablet, 15-mg rofecoxib tablet, 16-mg rofecoxib tablet, 17-mg
rofecoxib tablet, 17.5-mg rofecoxib tablet, 18-mg rofecoxib tablet,
19-mg rofecoxib tablet, 20-mg rofecoxib tablet, 21-mg rofecoxib
tablet, 22-mg rofecoxib tablet, 22.5-mg rofecoxib tablet, 25-mg
rofecoxib tablet, 30-mg rofecoxib tablet, 40-mg rofecoxib tablet,
50-mg rofecoxib tablet, or 60-mg rofecoxib tablet.
[0502] In some embodiments, the composition of the 25-mg rofecoxib
tablet and the function of each excipient are as provided in FIGS.
1A-B. In some embodiments, the manufacturing train includes
high-shear wet granulation because the micronized drug substance
could be prone to powder flow issues during scale-up if a direct
compression process was used. Some of the different embodiments of
the manufacturing process described herein are referred to Process
A.sub.1, Process A.sub.2, Process A.sub.3 or Process B.sub.1.
Subscripted numbers denote small differences in the manufacturing
process between embodiments. Letters denote major differences in
the manufacturing process between embodiments.
Process A.sub.1, Process A.sub.2, and Process A.sub.3
[0503] In some embodiments, the manufacturing process can be
Process A.sub.1, Process A.sub.2, or Process A.sub.3, each with
processing conditions as described in FIG. 2. In some embodiments,
Process A.sub.1, Process A.sub.2, or Process A.sub.3 result in
manufacture of batches 1-4. In some embodiments, dissolution
testing of batches is performed in two media: 2% SDS and 0.1N HCl
at 37.0.+-.0.5.degree. C. with a paddle speed of 75 rpm.
Dissolution profiles for batches 1 and 2 are shown in FIGS. 3A-B.
The points shown in the dissolution profiles are an average of
three tablets, and the 75-minute point is an infinity spin in which
the paddle speed was increased to 250 rpm for 15 minutes following
the 60-minute time point. FIG. 3A shows dissolution of rofecoxib
tablets in 0.1N HCl. FIG. 3B shows dissolution of rofecoxib tablets
in at least 2% SDS. The results in both media indicate that
dissolution may be incomplete after 60 minutes, with one exception
being batch 3 in at least 2% SDS. Dissolution profiles for batches
3 and 4 are shown in FIGS. 4A-B. FIG. 4A shows dissolution of
rofecoxib tablets in 0.1N HCl. FIG. 4B shows dissolution of
rofecoxib tablets in at least 2% SDS.
Process B.sub.1
[0504] In some embodiments, the manufacturing process of the
rofecoxib tablets is Process B.sub.1. In some embodiments, Process
B.sub.1 includes croscarmellolose sodium, a disintegrant, as an
intragranular and extragranular component in order to achieve
complete dissolution of rofecoxib. Batches 1-4 according to Process
A.sub.1-3 may include croscarmellolose sodium as an extragranular
component. In some embodiments. the processing conditions of
Process B.sub.1 are shown in FIG. 5. In Process B.sub.1, as
compared to Process A.sub.1-3, the pigment amount can be increased
from 0.30 to 0.60%, while the percentage of the diluents is
decreased to accommodate increases in pigment or croscarmellose
sodium; the ratio of lactose monohydrate to microcrystalline
cellulose can remain at 1:1. In some embodiments, dissolution
testing is performed in at least 2% SDS at 37.0.+-.0.5.degree. C.
with a paddle speed of 75 rpm. Dissolution profiles for rofecoxib
tablets manufactured using Process B.sub.1 in batches 5-8 are shown
in FIGS. 6A-B. The results indicate that intragranular disintegrant
can improve the rate at which rofecoxib dissolves and the extent to
which rofecoxib dissolves. The results also indicate that there is
no advantage to having 8% total disintegrant in the tablet versus
4% total disintegrant. Therefore, in some embodiments, batches 5
and 6 are the lead formulations. Additional dissolution testing of
batches 5 and 6 in at least 2% SDS at 37.0.+-.0.5.degree. C. with a
slower paddle speed of 50 rpm indicate that 50 rpm is an
appropriate paddle speed for the dissolution test as shown in FIG.
7.
[0505] Exemplary batch analysis and dissolution profile is
presented in Table 1 below for 17.5 mg rofecoxib tablets.
TABLE-US-00001 TABLE 1 Batch Analysis for 17.5-mg Rofecoxib Tablets
Lot No. Uniformity of Dosage Forms Dissolution, % Dissolved
(manufacturing Mean Range 10 15 20 30 45 60 process) % w/w % w/w AV
minutes minutes minutes minutes minutes minutes B19056 (B.sub.1)
100.1 99.2-110.9 1.2 89 97 98 100 101 101
[0506] Exemplary batch analysis and dissolution profile is
presented in Table 2 below for 20 mg rofecoxib tablets.
TABLE-US-00002 TABLE 2 Batch Analysis Data for 20-mg Rofecoxib
Tablets Lot No. Uniformity of Dosage Forms Dissolution, % Dissolved
(manufacturing Mean Range 10 15 20 30 45 60 process) % w/w % w/w AV
minutes minutes minutes minutes minutes minutes B19056 (B.sub.1)
99.7 98.8-100.3 1.2 88 85 97 99 100 100
Process B.sub.2
[0507] In some embodiments, the manufacturing process of the
rofecoxib tablets is Process B.sub.2. Process B.sub.2 differs from
Process B.sub.1 in that, in Process B.sub.2, the pigment blend is
added during granulation. As a result, the compositions of the
25-mg rofecoxib tablets manufactured using Processes B.sub.1 and
B.sub.2 are identical, as only the manufacturing step during which
pigment is added differs. Additional dose strengths can be
manufactured by varying the quantities of the first three
components, while keeping the tablet weight constant at 200 mg. The
ratio of microcrystalline cellulose to lactose monohydrate is
maintained at 1:1 in all dose strengths. Exemplary tablets
manufactured according to Process B.sub.2 are set forth in Tables
6B and 18.
Formulation and Process for the PK Study
[0508] In some embodiments, the amount of pigment in the clinical
batch is 0.30%. For example, the color of batches 5-8 is only
slightly darker than the color of batches 1-4, despite having a
greater amount of pigment. Therefore, there may not be any
aesthetic advantage to having 0.60% pigment in the tablet. Batches
5 and 6, even though they contain more pigment than the clinical
batch, are considered representative of the clinical batch because
all were manufactured using Process B1 and because the composition
of the intragranular and extragranular disintegrant is the same as
that for the clinical batch as shown in FIG. 8. Additional dose
strengths can be manufactured by varying the quantities of the
first three components, while keeping the tablet weight constant at
200 mg. The ratio of microcrystalline cellulose to lactose
monohydrate is maintained at 1:1 in all dose strengths.
[0509] Process descriptions for the manufacture of prototype 25-mg
rofecoxib tablets for Process A.sub.1, Process A.sub.2, or Process
A.sub.3, and Process B.sub.1 are shown in FIG. 9. FIGS. 10A-B show
a flow diagram for rofecoxib tablet manufacturing Process A.sub.1.
FIG. 10A shows manufacture of rofecoxib granules. FIG. 10B shows
manufacture of rofecoxib tablets. FIGS. 11A-B show a flow diagram
for rofecoxib tablet manufacturing Process A.sub.2. FIG. 11A shows
manufacture of rofecoxib granules. FIG. 11B shows manufacture of
rofecoxib tablets. FIGS. 12A-B show a flow diagram for rofecoxib
tablet manufacturing Process A.sub.3. FIG. 12A shows manufacture of
rofecoxib granules. FIG. 12B shows manufacture of rofecoxib
tablets. FIGS. 13A-B show a flow diagram for rofecoxib tablet
manufacturing Process B.sub.1. FIG. 13A shows manufacture of
rofecoxib granules. FIG. 13B shows manufacture of rofecoxib
tablets.
[0510] In some embodiments, rofecoxib tablets are administered to
patients at a clinical site and are packaged in multi-use HDPE
bottles that are induction sealed and closed with child resistant
caps. Each bottle may also contain rayon coil USP. In some
embodiments, rofecoxib tablets are manufactured using a
wet-granulation process.
[0511] In some embodiments, rofecoxib tablets are a solid oral
dosage form that is manufactured using equipment with non-reactive
surfaces. In some embodiments, rofecoxib is packaged in standard
containers that do not present compatibility issues.
[0512] The batch formulae for representative 2.3-kg batches of
rofecoxib tablets are shown in Table 3 below. In some embodiments,
other batch sizes are possible.
TABLE-US-00003 TABLE 3 Batch Formula for 25-mg Rofecoxib Tablets
Amount, (g) Components 25 mg 20 mg 17.5 mg 12.5 mg Rofecoxib.sup.a
287.50 230.00 201.25 143.75 Lactose monohydrate 916.55 945.30
959.68 988.43 Microcrystalline cellulose 916.55 945.30 959.68
988.43 Hydroxypropylcellulose 69.00 69.00 69.00 69.00
Croscarmellose sodium 92.00 92.00 92.00 92.00 Pigment blend yellow
6.90 6.90 6.90 6.90 Magnesium stearate 11.50 11.50 11.50 11.50
Water NA.sup.b NA.sup.b NA.sup.b NA.sup.b .sup.aNote that the
amount of rofecoxib may be adjusted for purity and moisture
content. An adjustment can be made to the amounts of lactose
monohydrate and microcrystalline cellulose used to maintain tablet
weight. .sup.bNA = not applicable. The amount of water for
granulation may vary in order to achieve granules; water for
granulation is removed upon drying of the wet mass.
Rofecoxib
[0513] Rofecoxib (also known as TRM-201; RXB-201; and
4-[4-(methylsulfonyl)phenyl]-3-phenyl-2(5H)-furanone) is a
nonsteroidal anti-inflammatory drug that exhibits
anti-inflammatory, analgesic, and antipyretic activities. Without
being bound by theory, the mechanism of action of rofecoxib is
believed to be due to inhibition of prostaglandin synthesis, via
inhibition of cyclooxygenase-2 (COX-2). Additionally, at
therapeutic concentrations in humans, rofecoxib does not inhibit
the cyclooxygenase-1 (COX-1) isoenzyme.
[0514] Rofecoxib is a potent inhibitor of prostaglandin synthesis
in vitro. Prostaglandins are mediators of inflammation. Rofecoxib
concentrations reached during therapy have produced in vivo
effects. Prostaglandins sensitize afferent nerves and potentiate
the action of bradykinin in inducing pain in animal models. Because
rofecoxib is an inhibitor of prostaglandin synthesis, its mode of
action may be due to a decrease of prostaglandins in peripheral
tissues.
[0515] In some embodiments, rofecoxib is indicated: for relief of
the signs and symptoms of osteoarthritis, for relief of the signs
and symptoms of rheumatoid arthritis in adults, for relief of the
signs and symptoms of pauciarticular or polyarticular course
Juvenile Rheumatoid Arthritis (JRA) in patients 2 years and older
and who weigh 10 kg (22 lbs) or more, for the management of acute
pain in adults, for the treatment of primary dysmenorrhea, for the
acute treatment of migraine attacks with or without aura in adults.
In some embodiments, rofecoxib is used to treat lower back pain,
including chronic lower back pain, and psoriatic arthritis.
[0516] The chemical structure of rofecoxib is shown below.
Rofecoxib bears no chiral centers and has a molecular weight of
314.355 g moL.sup.-1.
##STR00001##
[0517] In some embodiments, rofecoxib is a white to off-white to
light yellow powder. In some embodiments, rofecoxib is sparingly
soluble in acetone, slightly soluble in methanol and isopropyl
acetate, very slightly soluble in ethanol, practically insoluble in
octanol, and insoluble in water. In some embodiments, each tablet
of rofecoxib for oral administration contains either 10 mg, 10.5
mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 17.5 mg, 20 mg, 21 mg, 22 mg,
22.5 mg, 25 mg, or 50 mg of rofecoxib and the following inactive
ingredients: croscarmellose sodium, hydroxypropyl cellulose,
lactose, magnesium stearate, microcrystalline cellulose, and yellow
ferric oxide. The 50 mg tablets may also contain red ferric oxide.
In some embodiments, each 5 mL of the oral suspension contains 10
mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 17.5 mg, 20 mg, 21 mg,
22 mg, 22.5 mg 25 mg, or 50 mg of rofecoxib and the following
inactive ingredients: citric acid (monohydrate), sodium citrate
(dihydrate), sorbitol solution, strawberry flavor, xanthan gum, and
purified water. Added as preservatives are sodium methylparaben
about 0.13% and sodium propylparaben about 0.02%.
[0518] In some embodiments, the rofecoxib or pharmaceutically
acceptable salt thereof is about 1%, about 5% (w/w), about 10%
(w/w), about 15% (w/w), about 20% (w/w), about 25% (w/w), about 30%
(w/w), about 35% (w/w), or about 40% (w/w) of the formulation. In
some embodiments, the formulation comprises about 5 mg, about 8 mg,
about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12
mg, about 12.5 mg, about 15 mg, about 17.5 mg, or about 20 mg of
the rofecoxib or pharmaceutically acceptable salt thereof. In some
embodiments, the formulation comprises about 20 mg, 21 mg, 22 mg,
22.5 mg. In some embodiments, the formulation comprises about 23
mg, about 25 mg, about 27 mg, about 30 mg, about 35 mg, or about 40
mg of the rofecoxib or pharmaceutically acceptable salt thereof. In
some embodiments, the formulation comprises about 45 mg, about 47
mg, about 50 mg, about 53 mg, about 55 mg, about 60 mg of the
rofecoxib or pharmaceutically acceptable salt thereof.
[0519] In some embodiments, the pharmaceutically acceptable
formulation as described here includes highly pure rofecoxib, which
is essentially free or free of one or more of the impurities found
in previously available rofecoxib bulk drug product:
4-[4-(methylsulfonyl)phenyl]-3-phenyl-5-hydroxyfuran-2-one; and
4-[4-(methylsulfonyl)phenyl]-3-phenyl-2,5-furandione. In some
embodiments, the pharmaceutically acceptable formulation as
described here includes one or more beneficial rofecoxib
impurities, such as
4-[4-(methylsulfinyl)phenyl]-3-phenyl-2(5H)-furanone.
[0520] In some embodiments, the highly pure rofecoxib comprises
less than about 0.1% total impurities. In some embodiments, the
highly pure rofecoxib comprises less than about 0.075% total
impurities. In some embodiments, the highly pure rofecoxib
comprises less than about 0.050% total impurities. In some
embodiments, the highly pure rofecoxib comprises less than about
0.025% total impurities. In some embodiments, the highly pure
rofecoxib comprises less than about 0.001% total impurities.
[0521] In some embodiments, the highly pure rofecoxib comprises
less than about 0.10%, 0.05%, 0.02%, or 0.01% of
4-[4-(methylsulphonyl)phenyl]-3-phenyl-2,5-furandione. In some
embodiments, the highly pure rofecoxib comprises less than about
0.10%, 0.05%, 0.02%, or 0.01% of
4-[4-(methylthio)phenyl]-3-phenyl-2(5H)-furanone. In some
embodiments, the highly pure rofecoxib comprises less than about
0.10%, 0.05%, 0.02%, or 0.01% of
4-[4-(methylthio)phenyl]-3-phenyl-2(5H)-furanone. In some
embodiments, the highly pure rofecoxib comprises less than about
0.10%, 0.05%, 0.02%, or 0.01% of
4-[4-(methylsulfinyl)phenyl]-3-phenyl-2(5H)-furanone.
[0522] In some embodiments, the rofecoxib as provided herein
contains less than about 0.25%, 0.20%, 0.15%, 0.10%, 0.05%, 0.02%
or 0.01% of 4-[4-(methylthio)phenyl]-3-phenyl-2(5H)-furanone and/or
4-[4-(methylsulfinyl)phenyl]-3-phenyl-2(5H)-furanone as an
impurity. In some embodiments, the rofecoxib as provided herein
contains greater than or equal to about 0.001%, 0.005%, 0.01%,
0.02%, 0.05%, or 0.10%, but in all cases less than or equal to
about 0.15%, of 4-[4-(methylthio)phenyl]-3-phenyl-2(5H)-furanone
and/or 4-[4-(methylsulfinyl)phenyl]-3-phenyl-2(5H)-furanone as an
impurity.
[0523] Purity of the resulting rofecoxib as described herein is
determined as a percent area basis, typically as quantified by
analytical chromatography, such as using HPLC, UHPLC, UPLC or other
analytical means in the art. In some embodiments, the rofecoxib or
pharmaceutically acceptable salt thereof as provided herein is
micronized.
Rofecoxib Pharmacokinetics
[0524] It was surprisingly and unexpectedly discovered that the
bioavailability of "VIOXX" was likely lower than 93%, contrary to
the FDA-approved label, and that the formulations and methods
described herein can achieve a comparable pharmacokinetic profile
to the previously available "VIOXX" tablets after a single
administration, despite containing 80% or less rofecoxib than the
comparable "VIOXX" tablet.
[0525] In some embodiments, a 17.5 mg solid dosage formulation of
rofecoxib reaches a median time to Cmax plasma concentration in 4
hours or less following single administration of the formulation to
human subjects. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib reaches a median time to Cmax plasma
concentration in 3 hours or less following administration. In some
embodiments, a 17.5 mg solid dosage formulation of rofecoxib
reaches a median time to Cmax plasma concentration in 2.5 hours or
less following administration. In some embodiments, a 17.5 mg solid
dosage formulation of rofecoxib reaches a median time to Cmax
plasma concentration in 2 hours or less following administration.
In some embodiments, a 17.5 mg solid dosage formulation of
rofecoxib has a mean Cmax plasma concentration of more than 100
ng/ml. In some embodiments, a 17.5 mg solid dosage formulation of
rofecoxib has a mean Cmax plasma concentration of more than 150
ng/ml, 167 ng/ml, or 190 ng/ml. In some embodiments, a 17.5 mg
solid dosage formulation of rofecoxib has a mean Cmax plasma
concentration of more than 200 ng/ml. In some embodiments, a 17.5
mg solid dosage formulation of rofecoxib has a mean Cmax plasma
concentration of more than 220 ng/ml. In some embodiments, a 17.5
mg solid dosage formulation of rofecoxib has a mean Cmax plasma
concentration of more than 250 ng/ml. In some embodiments, a 17.5
mg solid dosage formulation of rofecoxib has a mean Cmax plasma
concentration of more than 280 ng/ml. In some embodiments, a 17.5
mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 1750 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 2000 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 2500 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 3000 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 3100 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 3500 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 4000 h*ng/ml. In some embodiments, a
17.5 mg solid dosage formulation of rofecoxib has a mean
AUC.sub.0-.infin. of more than 4500 h*ng/ml. In some embodiments, a
17.5 mg solid dosage form of rofecoxib achieves a mean Cmax plasma
concentration within 80% to 125% of 224 ng/ml. In some embodiments,
a 17.5 mg solid dosage form of rofecoxib achieves a mean
AUC.sub.0-.infin. within 80% to 125% of 3110 h*ng/ml. In some
embodiments, a 17.5 mg solid dosage formulation of rofecoxib
reaches a Cmax plasma concentration of least 167 ng/ml, 170 ng/ml,
175 ng/ml, 180 ng/ml, or higher following single administration of
the formulation to a human subject. In some embodiments, a 17.5 mg
solid dosage formulation of rofecoxib reaches an AUC.sub.0-.infin.
of at least 2600 h*ng/ml, 2750 h*ng/ml, 2900 h*ng/ml, 3050 h*ng/ml,
3100 h*ng/ml, 3200 h*ng/ml, 3350 h*ng/ml, 3500 h*ng/ml, 3650
h*ng/ml or higher following single administration of the
formulation to a human subject.
[0526] In certain aspects, the subject matter disclosed herein
provides a method of treating pain, fever, or inflammation in a
subject by administering to the subject a solid dosage formulation
comprising 17.5 mg of rofecoxib or a pharmaceutically acceptable
salt thereof. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib reaches a mean Cmax plasma concentration
in less than 4 hours following single administration of the
formulation to human subjects. In some embodiments, a 17.5 mg solid
dosage formulation of rofecoxib reaches a median time to Cmax
plasma concentration in 3 hours or less following administration.
In some embodiments, a 17.5 mg solid dosage formulation of
rofecoxib reaches a mean Cmax plasma concentration in less than 2.5
hours following administration. In some embodiments, a 17.5 mg
solid dosage formulation of rofecoxib reaches a mean Cmax plasma
concentration in less than 2 hours following administration. In
some embodiments, a 17.5 mg solid dosage formulation of rofecoxib
has a mean Cmax plasma concentration of more than 150 ng/ml, 167
ng/ml, or 190 ng/ml. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib achieves a mean Cmax plasma concentration
of more than 200 ng/ml. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib achieves a mean Cmax plasma concentration
of more than 220 ng/ml. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib achieves a mean Cmax plasma concentration
of more than 250 ng/ml. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib achieves a mean Cmax plasma concentration
of more than 280 ng/ml. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib achieves a mean AUC.sub.0-.infin. of more
than 1750 h*ng/ml. In In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib achieves a mean AUC.sub.0-.infin. of more
than 2000 h*ng/ml. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib achieves a mean AUC.sub.0-.infin. of more
than 2500 h*ng/ml. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib achieves a mean AUC.sub.0-.infin. of more
than 3000 h*ng/ml. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib achieves a mean AUC.sub.0-.infin. of more
than 3100 h*ng/ml. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib achieves a mean AUC.sub.0-.infin. of more
than 3500 h*ng/ml. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib achieves a mean Cmax plasma concentration
of more than 200 ng/ml in less than 3.5 hours following
administration with an AUC.sub.0-.infin. of more than 3000 h*ng/ml.
In some embodiments, a 17.5 mg solid dosage formulation of
rofecoxib as described herein achieves a mean Cmax, Tmax, or
AUC.sub.0-.infin. that is bioequivalent to a 25 mg tablet of VIOXX.
In some embodiments, a 17.5 mg solid dosage formulation of
rofecoxib as described herein achieves efficacy in treating pain,
fever, or inflammation in a subject that is equal to or greater
than a 25 mg tablet of VIOXX. In some embodiments, a 17.5 mg solid
dosage form of rofecoxib achieves a mean Cmax plasma concentration
within 80% to 125% of 224 ng/ml. In some embodiments, a 17.5 mg
solid dosage form of rofecoxib achieves a mean AUC.sub.0-.infin.
within 80% to 125% of 3110 h*ng/ml. In some embodiments, a 17.5 mg
solid dosage formulation of rofecoxib reaches a Cmax plasma
concentration of least 167 ng/ml, 170 ng/ml, 175 ng/ml, 180 ng/ml,
or higher following single administration of the formulation to a
human subject. In some embodiments, a 17.5 mg solid dosage
formulation of rofecoxib reaches an AUC.sub.0-.infin. of at least
2600 h*ng/ml, 2750 h*ng/ml, 2900 h*ng/ml, 3050 h*ng/ml, 3100
h*ng/ml, 3200 h*ng/ml, 3350 h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml or
higher following single administration of the formulation to a
human subject.
[0527] In some embodiments, a 20 mg solid dosage formulation of
rofecoxib reaches a median time to Cmax plasma concentration in 4
hours or less following single administration of the formulation to
human subjects. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib reaches a median time to Cmax plasma
concentration in 3 hours or less following administration. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib reaches
a median time to Cmax plasma concentration in 2.5 hours or less
following administration. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib reaches a median time to Cmax plasma
concentration in 2 hours or less following administration. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib has a
mean Cmax plasma concentration of more than 150 ng/ml. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib has a
mean Cmax plasma concentration of more than 191 ng/ml, 200 ng/ml,
215 ng/ml, or 225 ng/ml. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib has a mean Cmax plasma concentration of
more than 250 ng/ml. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib has a mean Cmax plasma concentration of
more than 258 ng/ml. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib has a mean Cmax plasma concentration of
more than 300 ng/ml. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib has a mean AUC.sub.0-.infin. of more than
2000 h*ng/ml. In some embodiments, a 20 mg solid dosage formulation
of rofecoxib has a mean AUC.sub.0-.infin. of more than 2500
h*ng/ml. In some embodiments, a 20 mg solid dosage formulation of
rofecoxib has a mean AUC.sub.0-.infin. of more than 3000 h*ng/ml.
In some embodiments, a 20 mg solid dosage formulation of rofecoxib
has a mean AUC.sub.0-.infin. of more than 3400 h*ng/ml. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 3500 h*ng/ml. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 4000 h*ng/ml. In some
embodiments, a 20 mg solid dosage form of rofecoxib achieves a mean
Cmax plasma concentration within 80% to 125% of 259 ng/ml. In some
embodiments, a 20 mg solid dosage form of rofecoxib achieves a mean
AUC.sub.0-.infin. within 80% to 125% of 3550 h*ng/ml. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib reaches
a Cmax plasma concentration of least 190 ng/ml, 205 ng/ml, 220
ng/ml, 235 ng/ml, 250 ng/ml, or higher following single
administration of the formulation to a human subject. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib reaches
an AUC.sub.0-.infin. of at least 3000 h*ng/ml, 3200 h*ng/ml, 3350
h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml, 3800 h*ng/ml, 3950 h*ng/ml, or
higher following single administration of the formulation to a
human subject.
[0528] In certain aspects, the subject matter disclosed herein
provides a method of treating pain, fever, or inflammation in a
subject by administering to the subject a solid dosage formulation
comprising 20 mg of rofecoxib or a pharmaceutically acceptable salt
thereof. In some embodiments, a 20 mg solid dosage formulation of
rofecoxib reaches a mean Cmax plasma concentration in less than 4
hours following single administration of the formulation to human
subjects. In some embodiments, a 20 mg solid dosage formulation of
rofecoxib reaches a median time to Cmax plasma concentration 3
hours or less following administration. In some embodiments, a 20
mg solid dosage formulation of rofecoxib reaches a mean Cmax plasma
concentration in less than 2.5 hours following administration. In
some embodiments, a 20 mg solid dosage formulation of rofecoxib
reaches a mean Cmax plasma concentration in less than 2 hours
following administration. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib has a mean Cmax plasma concentration of
more than 150 ng/ml. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib achieves a mean Cmax plasma concentration
of more than 191 ng/ml, 200 ng/ml, 215 ng/ml, or 225 ng/ml. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib achieves
a mean Cmax plasma concentration of more than 250 ng/ml. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib achieves
a mean Cmax plasma concentration of more than 258 ng/ml. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib achieves
a mean Cmax plasma concentration of more than 300 ng/ml. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib achieves
a mean AUC.sub.0-.infin. of more than 2000 h*ng/ml. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib achieves
a mean AUC.sub.0-.infin. of more than 2500 h*ng/ml. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib achieves
a mean AUC.sub.0-.infin. of more than 3000 h*ng/ml. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib achieves
a mean AUC.sub.0-.infin. of more than 3400 h*ng/ml. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib achieves
a mean AUC.sub.0-.infin. of more than 3500 h*ng/ml. In some
embodiments, a 20 mg solid dosage formulation of rofecoxib achieves
a mean Cmax plasma concentration of more than 191 ng/ml, 200 ng/ml,
215 ng/ml, or 225 ng/ml in less than 3.5 hours following
administration with an AUC.sub.0-.infin. of more than 3000 h*ng/ml.
In some embodiments, a 20 mg solid dosage formulation of rofecoxib
as described herein achieves a mean Cmax, Tmax, or
AUC.sub.0-.infin. that is bioequivalent to a 25 mg tablet of VIOXX.
In some embodiments, a 20 mg solid dosage formulation of rofecoxib
as described herein achieves efficacy in treating pain, fever, or
inflammation in a subject that is equal to or greater than a 25 mg
tablet of VIOXX. In some embodiments, a 20 mg solid dosage form of
rofecoxib achieves a mean Cmax plasma concentration within 80% to
125% of 259 ng/ml. In some embodiments, a 20 mg solid dosage form
of rofecoxib achieves a mean AUC.sub.0-.infin. within 80% to 125%
of 3550 h*ng/ml. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib reaches a Cmax plasma concentration of
least 190 ng/ml, 205 ng/ml, 220 ng/ml, 235 ng/ml, 250 ng/ml, or
higher following single administration of the formulation to a
human subject. In some embodiments, a 20 mg solid dosage
formulation of rofecoxib reaches an AUC.sub.0-.infin. of at least
3000 h*ng/ml, 3200 h*ng/ml, 3350 h*ng/ml, 3500 h*ng/ml, 3650
h*ng/ml, 3800 h*ng/ml, 3950 h*ng/ml, or higher following single
administration of the formulation to a human subject.
[0529] In some embodiments, a 25 mg solid dosage formulation of
rofecoxib reaches a mean Cmax plasma concentration in less than 3
hours following single administration of the formulation to human
subjects. In some embodiments, a 25 mg solid dosage formulation of
rofecoxib reaches a mean Cmax plasma concentration in less than 2.5
hours following administration. In some embodiments, a 25 mg solid
dosage formulation of rofecoxib reaches a mean Cmax plasma
concentration in less than 2 hours following administration. In
some embodiments, a 25 mg solid dosage formulation of rofecoxib has
a mean Cmax plasma concentration of more than 240 ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean Cmax plasma concentration of more than 250 ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean Cmax plasma concentration of more than 300 ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean Cmax plasma concentration of more than 320 ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 4250 h*ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 4500 h*ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 4550 h*ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib has a
mean AUC.sub.0-.infin. of more than 4700 h*ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib reaches
a mean Cmax plasma concentration of more than 240 ng/ml in a median
time of about 3 hours or less following administration with an
AUC.sub.0-.infin. of more than 4250 h*ng/ml. In some embodiments, a
25 mg solid dosage form of rofecoxib achieves a mean Cmax plasma
concentration within 80% to 125% of 325 ng/ml. In some embodiments,
a 25 mg solid dosage form of rofecoxib achieves a mean
AUC.sub.0-.infin. within 80% to 125% of 4590 h*ng/ml.
[0530] In certain aspects, the subject matter disclosed herein
provides a method of treating pain, fever, or inflammation in a
subject by administering to the subject a 25 mg solid dosage
formulation of rofecoxib or a pharmaceutically acceptable salt
thereof. In some embodiments, a 25 mg solid dosage formulation of
rofecoxib reaches a mean Cmax plasma concentration in less than 3
hours following administration. In some embodiments, a 25 mg solid
dosage formulation of rofecoxib reaches a mean Cmax plasma
concentration in less than 2.5 hours following administration. In
some embodiments, a 25 mg solid dosage formulation of rofecoxib
reaches a mean Cmax plasma concentration in less than 2 hours
following administration. In some embodiments, a 25 mg solid dosage
formulation of rofecoxib has a mean Cmax plasma concentration of
more than 240 ng/ml. In some embodiments, a 25 mg solid dosage
formulation of rofecoxib achieves a mean Cmax plasma concentration
of more than 250 ng/ml. In some embodiments, a 25 mg solid dosage
formulation of rofecoxib has a mean Cmax plasma concentration of
more than 300 ng/ml. In some embodiments, a 25 mg solid dosage
formulation of rofecoxib achieves a mean Cmax plasma concentration
of more than 320 ng/ml. In some embodiments, a 25 mg solid dosage
formulation of rofecoxib achieves a mean AUC.sub.0-.infin. of more
than 4250 h*ng/ml. In some embodiments, a 25 mg solid dosage
formulation of rofecoxib achieves a mean AUC.sub.0-.infin. of more
than 4500 h*ng/ml. In some embodiments, a 25 mg solid dosage
formulation of rofecoxib achieves a mean AUC.sub.0-.infin. of more
than 4550 h*ng/ml. In some embodiments, a 25 mg solid dosage
formulation of rofecoxib achieves a mean AUC.sub.0-.infin. of more
than 4700 h*ng/ml. In some embodiments, a 25 mg solid dosage
formulation of rofecoxib achieves a Cmax plasma concentration of
more than 240 ng/ml in about 3 hours following administration with
an AUC.sub.0-.infin. of more than 4250 h*ng/ml. In some
embodiments, a 25 mg solid dosage formulation of rofecoxib as
described herein achieves a mean Cmax, Tmax, or AUC.sub.0-.infin.
that is higher than a 25 mg tablet of VIOXX. In some embodiments, a
25 mg solid dosage form of rofecoxib achieves a mean Cmax plasma
concentration within 80% to 125% of 325 ng/ml. In some embodiments,
a 25 mg solid dosage form of rofecoxib achieves a mean
AUC.sub.0-.infin. within 80% to 125% of 4590 h*ng/ml.
[0531] In certain aspects, the subject matter disclosed herein
provides a method of treating pain, fever, or inflammation in a
subject by administering to the subject a solid dosage formulation
comprising 10 mg to 50 mg of rofecoxib or a pharmaceutically
acceptable salt thereof. In some embodiments, the formulation
achieves a mean Cmax plasma concentration from 9.8 ng/ml to 16
ng/ml for each 1 mg of rofecoxib in the formulation. In some
embodiments, the formulation achieves a mean Cmax plasma
concentration from 10 ng/ml to 14 ng/ml for each 1 mg of rofecoxib
in the formulation. In some embodiments, the formulation achieves a
mean Cmax plasma concentration from 10 ng/ml to 13 ng/ml for each 1
mg of rofecoxib in the formulation. In some embodiments, the
formulation achieves a mean Cmax plasma concentration from 80% to
125% of 12.8 ng/ml. In some embodiments, the formulation reaches a
mean AUC.sub.0-.infin. of 170 h*ng/ml to 235 h*ng/ml for each 1 mg
of rofecoxib in the formulation. In some embodiments, the
formulation reaches a mean AUC.sub.0-.infin. of 177 h*ng/ml to 225
h*ng/ml for each 1 mg of rofecoxib in the formulation. In some
embodiments, the formulation achieves a mean AUC.sub.0-.infin. of
177 h*ng/ml to 225 h*ng/ml for each 1 mg of rofecoxib in the
formulation. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of 180 h*ng/ml to 225 h*ng/ml for each 1 mg of
rofecoxib in the formulation. In some embodiments, the formulation
reaches a mean AUC.sub.0-.infin. of 190 h*ng/ml to 215 h*ng/ml for
each 1 mg of rofecoxib in the formulation.
[0532] In some embodiments, a method is provided for treating pain,
fever, or inflammation in patients within a patient population, the
method comprising providing a solid dosage formulation comprising
10 mg to 50 mg of rofecoxib, more specifically 17.5 mg to 25 mg, to
the patient population, wherein the formulation achieves a mean
Cmax plasma concentration from 9.8 ng/ml to 16 ng/ml for each 1 mg
of rofecoxib in the formulation following single administration of
the formulation to the patients within the patient population. In
some embodiments, the solid dosage formulation of rofecoxib
achieves a mean Cmax plasma concentration from 10 ng/ml to 14 ng/ml
for each 1 mg of rofecoxib in the formulation. In some embodiments,
the solid dosage formulation of rofecoxib achieves a mean Cmax
plasma concentration from 10 ng/ml to 13 ng/ml for each 1 mg of
rofecoxib in the formulation. In some embodiments, the solid dosage
formulation of rofecoxib achieves a mean Cmax plasma concentration
from 80% to 125% of 12.8 ng/ml. In some embodiments, the solid
dosage formulation of rofecoxib reaches a mean AUC.sub.0-.infin. of
170 h*ng/ml to 235 h*ng/ml for each 1 mg of rofecoxib in the
formulation. In some embodiments, the solid dosage formulation of
rofecoxib reaches a mean AUC.sub.0-.infin. of 177 h*ng/ml to 225
h*ng/ml for each 1 mg of rofecoxib in the formulation. In some
embodiments, the formulation achieves a mean AUC.sub.0-.infin. of
177 h*ng/ml to 225 h*ng/ml for each 1 mg of rofecoxib in the
formulation. In some embodiments, the formulation achieves a mean
AUC.sub.0-.infin. of 180 h*ng/ml to 225 h*ng/ml for each 1 mg of
rofecoxib in the formulation. In some embodiments, the solid dosage
formulation of rofecoxib reaches a mean AUC.sub.0-.infin. of 190
h*ng/ml to 215 h*ng/ml for each 1 mg of rofecoxib in the
formulation.
[0533] In certain aspects, the subject matter disclosed herein
provides a method of treating pain, fever, or inflammation in a
male or female subject by administering to the subject a solid
dosage formulation comprising 10 mg to 50 mg of rofecoxib or a
pharmaceutically acceptable salt thereof. In some embodiments, a
single administration of a solid dosage formulation comprising 12.5
mg to 25 mg of rofecoxib or a pharmaceutically acceptable salt
thereof to healthy female subjects results in a mean Cmax plasma
concentration that is at least 5%, 10%, 15%, 20%, 25%, or 30%
greater than that resulting from a single administration of the
same formulation to male subjects. In some embodiments, a single
administration of a solid dosage formulation comprising 12.5 mg to
25 mg of rofecoxib or a pharmaceutically acceptable salt thereof to
healthy female subjects results in a mean AUC.sub.0-.infin. that is
at least 5%, 10%, 15%, 20%, 25%, or 30% greater than that resulting
from a single administration of the same formulation to male
subjects.
[0534] In some embodiments, the subject matter disclosed herein
provides a method for treating pain, fever, or inflammation in a
subject by administering a solid dosage formulation of 10 mg to 50
mg of rofecoxib, wherein a single administration of the formulation
in Caucasian subjects less than 65 years of age achieves a mean
AUC.sub.0-.infin. that is greater than that achieved following a
single administration of the formulation to African American
subjects less than 65 years of age. In some embodiments, a single
administration of a solid dosage formulation comprising 12.5 mg to
25 mg of rofecoxib or a pharmaceutically acceptable salt thereof to
Caucasian subjects results in a mean AUC.sub.0-.infin. that is at
least 1%, 2%, 5%, 9%, or 10% greater than that achieved following a
single administration of the formulation to African American
subjects less than 65 years of age. In some embodiments, the
formulation comprises 17.5 mg to 25 mg of rofecoxib. In some
embodiments, the formulation comprises 17.5 mg of rofecoxib. In
some embodiments, the formulation comprises 20 mg of rofecoxib. In
some embodiments, the formulation comprises 25 mg of rofecoxib.
[0535] In some embodiments, the subject matter disclosed herein
provides a method for treating pain, fever, or inflammation in a
subject by administering a solid dosage formulation comprising 12.5
mg of rofecoxib, wherein the formulation achieves a mean plasma
concentration of at least about 0.2 ng/ml, 0.3 ng/ml, 0.4 ng/ml, or
0.5 ng/ml at 15 minutes following single administration of the
formulation to human subjects less than 65 years of age. In some
embodiments, the subject matter disclosed herein provides a method
for treating pain, fever, or inflammation in a subject by
administering a solid dosage formulation comprising 12.5 mg of
rofecoxib, wherein the formulation achieves an arithmetic mean
plasma concentration of at least about 0.8 ng/ml, 0.9 ng/ml, or 1.0
ng/ml at 15 minutes following single administration of the
formulation to human subjects less than 65 years of age. In some
embodiments, the subject matter disclosed herein provides a method
for treating pain, fever, or inflammation in a subject by
administering a solid dosage formulation comprising 17.5 mg of
rofecoxib, wherein the formulation achieves a mean plasma
concentration of at least about 0.3 ng/ml, 0.4 ng/ml, 0.5 ng/ml, or
0.6 ng/ml at 15 minutes following single administration of the
formulation to human subjects less than 65 years of age. In some
embodiments, the subject matter disclosed herein provides a method
for treating pain, fever, or inflammation in a subject by
administering a solid dosage formulation comprising 17.5 mg of
rofecoxib, wherein the formulation achieves an arithmetic mean
plasma concentration of at least about 1.8 ng/ml, 2.0 ng/ml, 2.2
ng/ml, or 2.4 ng/ml at 15 minutes following single administration
of the formulation to human subjects less than 65 years of age. In
some embodiments, the subject matter disclosed herein provides a
method for treating pain, fever, or inflammation in a subject by
administering a solid dosage formulation comprising 20 mg of
rofecoxib, wherein the formulation achieves a mean plasma
concentration of at least about 0.8 ng/ml, 0.9 ng/ml, 1.0 ng/ml,
1.1 ng/ml, or 1.16 ng/ml at 15 minutes following single
administration of the formulation to human subjects less than 65
years of age. In some embodiments, the subject matter disclosed
herein provides a method for treating pain, fever, or inflammation
in a subject by administering a solid dosage formulation comprising
20 mg of rofecoxib, wherein the formulation achieves an arithmetic
mean plasma concentration of at least about 4.6 ng/ml, 5.0 ng/ml,
5.4 ng/ml, or 5.7 ng/ml at 15 minutes following single
administration of the formulation to human subjects less than 65
years of age. In some embodiments, the subject matter disclosed
herein provides a method for treating pain, fever, or inflammation
in a subject by administering a solid dosage formulation comprising
25 mg of rofecoxib, wherein the formulation achieves a mean plasma
concentration of at least about 1.0 ng/ml, 1.1 ng/ml, 1.2 ng/ml, or
1.3 ng/ml at 15 minutes following single administration of the
formulation to human subjects less than 65 years of age. In some
embodiments, the subject matter disclosed herein provides a method
for treating pain, fever, or inflammation in a subject by
administering a solid dosage formulation comprising 25 mg of
rofecoxib, wherein the formulation achieves an arithmetic mean
plasma concentration of at least about 4.6 ng/ml, 5.0 ng/ml, 5.4
ng/ml, or 5.6 ng/ml at 15 minutes following single administration
of the formulation to human subjects less than 65 years of age. In
some embodiments, the subject matter disclosed herein provides a
method for treating pain, fever, or inflammation in a subject by
administering a solid dosage formulation comprising 12.5 mg of
rofecoxib, wherein the formulation achieves a mean plasma
concentration of at least about 27 ng/ml, 29 ng/ml, 31 ng/ml, or 33
ng/ml at 45 minutes following single administration of the
formulation to human subjects less than 65 years of age. In some
embodiments, the subject matter disclosed herein provides a method
for treating pain, fever, or inflammation in a subject by
administering a solid dosage formulation comprising 12.5 mg of
rofecoxib, wherein the formulation achieves an arithmetic mean
plasma concentration of at least about 45 ng/ml, 48 ng/ml, 51
ng/ml, 54 ng/ml, or 56 ng/ml at 45 minutes following single
administration of the formulation to human subjects less than 65
years of age. In some embodiments, the subject matter disclosed
herein provides a method for treating pain, fever, or inflammation
in a subject by administering a solid dosage formulation comprising
17.5 mg of rofecoxib, wherein the formulation achieves a mean
plasma concentration of at least about 45 ng/ml, 47 ng/ml, 49
ng/ml, or 51 ng/ml at 45 minutes following single administration of
the formulation to human subjects less than 65 years of age. In
some embodiments, the subject matter disclosed herein provides a
method for treating pain, fever, or inflammation in a subject by
administering a solid dosage formulation comprising 17.5 mg of
rofecoxib, wherein the formulation achieves an arithmetic mean
plasma concentration of at least about 74 ng/ml, 79 ng/ml, 84
ng/ml, 89 ng/ml, or 93 ng/ml at 45 minutes following single
administration of the formulation to human subjects less than 65
years of age. In some embodiments, the subject matter disclosed
herein provides a method for treating pain, fever, or inflammation
in a subject by administering a solid dosage formulation comprising
20 mg of rofecoxib, wherein the formulation achieves a mean plasma
concentration of at least about 58 ng/ml, 62 ng/ml, 66 ng/ml, 70
ng/ml, or 72 ng/ml at 45 minutes following single administration of
the formulation to human subjects less than 65 years of age. In
some embodiments, the subject matter disclosed herein provides a
method for treating pain, fever, or inflammation in a subject by
administering a solid dosage formulation comprising 20 mg of
rofecoxib, wherein the formulation achieves an arithmetic mean
plasma concentration of at least about 112 ng/ml, 116 ng/ml, or 121
ng/ml at 45 minutes following single administration of the
formulation to human subjects less than 65 years of age. In some
embodiments, the subject matter disclosed herein provides a method
for treating pain, fever, or inflammation in a subject by
administering a solid dosage formulation comprising 25 mg of
rofecoxib, wherein the formulation achieves a mean plasma
concentration of at least about 78 ng/ml, 85 ng/ml, 92 ng/ml, or 97
ng/ml, at 45 minutes following single administration of the
formulation to human subjects less than 65 years of age. In some
embodiments, the subject matter disclosed herein provides a method
for treating pain, fever, or inflammation in a subject by
administering a solid dosage formulation comprising 25 mg of
rofecoxib, wherein the formulation achieves an arithmetic mean
plasma concentration of at least about 133 ng/ml, 139 ng/ml, 145
ng/ml, 151 ng/ml, or 159 ng/ml at 45 minutes following single
administration of the formulation to human subjects less than 65
years of age.
Specific Compositions
[0536] In some embodiments, the subject matter discloses a drug
product including an immediate-release tablet that contains either
12.5-, 17.5-, 20-, or 25-mg rofecoxib. In some embodiments, the
tablets are 7.2-mm in diameter tablets. In some embodiments, the
tablets are off-white to light yellow, round, and uncoated with no
markings. In some embodiments, rofecoxib tablets disclosed herein
are for oral administration. In some embodiments, the drug product
does not comprise a liquisolid, orally disintegrating tablet, rapid
dissolving tablets, or chewable.
[0537] In some embodiments, each rofecoxib tablet for oral
administration contains either 12.5-, 17.5-, 20-, or 25-mg of
rofecoxib. In some embodiments, each rofecoxib tablet also contains
one or more of the following inactive ingredients: croscarmellose
sodium, hydroxypropyl cellulose, lactose, magnesium stearate,
microcrystalline cellulose, and pigment blend yellow. The
quantitative composition of one embodiment of the 25-mg tablet and
the function and compendial status of each component are listed in
FIG. 1.
[0538] In some embodiments, the pigment blend is comprised of three
compendial materials as listed in Table 4 below.
TABLE-US-00004 TABLE 4 Components of the Pigment Blend Components
Reference to Standards.sup.a Titanium dioxide USP-NF, Ph. Eur. Iron
oxide yellow USP-NF Iron oxide red USP-NF USP = United States
Pharmacopeia; NF = National Formulary; Ph. Eur. = European
Pharmacopeia .sup.aWhen referred to a Pharmacopeia, the current
edition of this Pharmacopeia is applied.
[0539] Exemplary excipients used in the manufacture of rofecoxib
are listed in Table 5 below. Water is used only as a granulation
medium.
TABLE-US-00005 TABLE 5 Excipients for Rofecoxib Tablets Excipient
Compendial Reference Croscarmellose sodium USP-NF, Ph. Eur., JP
Hydroxypropylcellulose USP-NF, Ph. Eur., JP Lactose monohydrate
USP-NF, Ph. Eur., JP Magnesium stearate USP-NF, Ph. Eur., JP
Microcrystalline cellulose USP-NF, Ph. Eur., JP Pigment blend
yellow Water USP-NF, Ph. Eur. USP = United States Pharmacopeia; NF
= National Formulary; Ph. Eur. = European Pharmacopeia; JP =
Japanese Pharmacopeia.
[0540] Tables 6A and 6B compare exemplary embodiments of the
composition of each tablet dose strength. In some embodiments, the
tablet weight is 200 mg for each dose strength. In some
embodiments, tablet dose strengths are manufactured by varying the
quantities of the first three components, while maintaining the 1:1
ratio of microcrystalline cellulose to lactose monohydrate.
TABLE-US-00006 TABLE 6A Composition of Rofecoxib Tablets 25-mg
Tablet 20-mg Tablet 17.5-mg Tablet 12.5-mg Tablet % (w/w) % (w/w) %
(w/w) % (w/w) per mg per per mg per per mg per per mg per
Components tablet tablet tablet tablet tablet tablet tablet tablet
Intragranular Rofecoxib.sup.a 12.50 25.0 10.00 20.0 8.75 17.5 6.25
12.5 Lactose monohydrate 39.85 79.7 41.10 82.2 41.725 83.45 42.975
85.95 Microcrystalline cellulose 39.85 79.7 41.10 82.2 41.725 83.45
42.975 85.95 Hydroxypropylcellulose 3.00 6.0 3.00 6.00 3.00 6.0
3.00 6.0 Croscarmellose sodium 2.00 4.0 2.00 4.0 2.00 4.0 2.00 4.0
Water NA.sup.b NA.sup.b NA.sup.b NA.sup.b NA.sup.b NA.sup.b
NA.sup.b NA.sup.b Extragranular Pigment blend yellow 0.30 0.6 0.30
0.6 0.30 0.6 0.30 0.6 Croscarmellose sodium 2.00 4.0 2.00 4.0 2.00
4.0 2.00 4.0 Magnesium stearate 0.50 1.0 0.50 1.0 0.50 1.0 0.50 1.0
Totals 100.00 200.0 100.00 200.0 100.00 200.0 100.00 200.0
.sup.aNote that the amount of rofecoxib may be adjusted for purity
and moisture content. An adjustment will be made to the amounts of
lactose monohydrate and microcrystalline cellulose used to maintain
tablet weight. .sup.bWater for granulation is removed upon drying
of the wet mass.
TABLE-US-00007 TABLE 6B Composition of Rofecoxib Tablets
Manufactured by Process B.sub.2 25-mg Tablet 20-mg Tablet 17.5-mg
Tablet 12.5-mg Tablet % (w/w) % (w/w) % (w/w) % (w/w) per mg per
per mg per per mg per per mg per Components tablet tablet tablet
tablet tablet tablet tablet tablet Intragranular Rofecoxib.sup.3
12.50 25.0 10.00 20.0 8.75 17.5 6.25 12.5 Lactose monohydrate 39.85
79.7 41.10 82.2 41.725 83.45 42.975 85.95 Microcrystalline
cellulose 39.85 79.7 41.10 82.2 41.725 83.45 42.975 85.95
Hydroxypropylcellulose 3.00 6.0 3.00 6.00 3.00 6.0 3.00 6.0
Croscarmellose sodium 2.00 4.0 2.00 4.0 2.00 4.0 2.00 4.0 Water
NA.sup.b NA.sup.b NA.sup.b NA.sup.b NA.sup.b NA.sup.b NA.sup.b
NA.sup.b Pigment blend yellow 0.30 0.6 0.30 0.6 0.30 0.6 0.30 0.6
Extragranular Croscarmellose sodium 2.00 4.0 2.00 4.0 2.00 4.0 2.00
4.0 Magnesium stearate 0.50 1.0 0.50 1.0 0.50 1.0 0.50 1.0 Totals
100.00 200.0 100.00 200.0 100.00 200.0 100.00 200.0 .sup.aNote that
the amount of rofecoxib may be adjusted for purity and moisture
content. An adjustment will be made to the amounts of lactose
monohydrate and microcrystalline cellulose used to maintain tablet
weight. .sup.bWater for granulation is removed upon drying of the
wet mass.
[0541] In some embodiments, rofecoxib is a single crystal form
(Form A), the only structure reported in the Cambridge Structural
Database (Groom C R, Bruno M P, Lightfoot S C, et al. The Cambridge
Structural Database. Acta Cryst. 2016; B72:171-179. (Entry CAXMUJ:
https://www.ccdc.cam.ac.uk/structures/Search?Compound=Rofecoxib&DatabaseT-
oSearch=Published). Rofecoxib is practically insoluble in water
(solubility <0.1 mg/mL). Rofecoxib has no ionizable moieties and
cannot form salts; the solubility of rofecoxib cannot be increased
by changing pH. Therefore, in some embodiments, rofecoxib is
micronized in the final step of the manufacturing process in order
to increase dissolution rate.
Description of Manufacturing Process and Process Controls for
Rofecoxib Tablets
[0542] The specific process used to manufacture rofecoxib granules
and subsequent rofecoxib tablets is Process B1, which is described
below and illustrated in FIG. 1. The process nomenclature consists
of a letter with a subscripted number. The letter is indexed when a
major change is made to the process during development; the
subscripted number is indexed when a minor change is made.
Exemplary Preparation of Rofecoxib Granules:
[0543] Step 1G: Blend lactose monohydrate and rofecoxib.
[0544] Step 2G: Pass the lactose-rofecoxib blend, microcrystalline
cellulose, hydroxypropylcellulose, and croscarmellose sodium
through an appropriate-sized sieve screen as the granulator is
charged.
[0545] Step 3G: Mix the dry powder in the high-shear
granulator.
[0546] Step 4G: Spray the water of granulation onto the contents of
the high-shear granulator while mixing. The target amount of water
of granulation is 32% relative to the mass of the dry powder in the
granulator. The actual amount of water added may vary.
[0547] Step 5G: Discharge the wet granules from the granulator into
a high-speed mill equipped with an appropriate-sized screen. Mill
the wet granules.
[0548] Step 6G: Dry the wet-milled granules into a fluid-bed
drier.
[0549] Step 7G: Mill the dried granules using a high-speed mill
equipped with an appropriate-sized screen.
[0550] Exemplary Preparation of Rofecoxib Tablets:
[0551] Step 1T: Blend croscarmellose sodium and pigment.
[0552] Step 2T: Pass the rofecoxib granules, croscarmellose
sodium-pigment blend, and magnesium stearate through an
appropriate-sized sieve screen as the blender is charged. Note more
than one granulation batch may be used in this step.
[0553] Step 3T: Blend the powders.
[0554] Step 4T: Compress the blended powder into tablets.
[0555] Step 5T: Dedust and metal check the tablets. FIGS. 13A-B
show flow diagrams for rofecoxib tablet manufacturing Process
B.sub.1.
[0556] In some embodiments, e.g. the formation of those tablets
described in Table 6B, the pigment may be added in preparation of
the rofecoxib granules prior to formation of the tablets.
Disintegrants and Dissolution Rate
[0557] Disintegrants included in tablet or granulate formulations
are auxiliary agents which can promote the disintegration of said
tablets or granulates upon contact with liquids and bodily fluids.
Disintegrants are essential excipients in solid formulations
because they can lead to enhanced dissolution of tablets into
coarse fragments and further into smaller particles. Disintegrants
ultimately result in the active ingredients of solid drug
formulations interacting sufficiently with liquids or bodily fluids
and forming a solution. In general, higher tablet densities are
associated with poorer solubility profiles. Therefore, the addition
of disintegrants into tablets promotes their desired rapid
dissolution, or disintegration and dissolution. In some
embodiments, the formulation described herein further includes a
granular component and an extragranular component, wherein the
granular component includes an intragranular component including
the rofecoxib and one or more disintegrants, and wherein the
extragranular component includes one or more disintegrants. In some
embodiments, the rofecoxib in the formulation has a d90 particle
size from about 10-12 .mu.m, a d50 particle size from about 3-4
.mu.m, and a d10 particle size from about 0.5-1.0 .mu.m.
[0558] In some embodiments of the pharmaceutically acceptable
formulation described herein, the one or more disintegrants in the
granular component of the formulation may include starches, clays,
celluloses, algins, gums, cross-linked polymers, croscarmellose,
croscarmellose sodium, crospovidone, sodium starch glycolate, and
combinations thereof. In some embodiments, the one or more
disintegrants in the granular component are about 0.5% (w/w) about
1% (w/w), about 2% (w/w), about 3% (w/w), about 4% (w/w), about 5%
(w/w), about 6% (w/w), about 7% (w/w), about 8% (w/w), about 9%
(w/w), or about 10% (w/w) of the formulation.
[0559] In some embodiments of the pharmaceutically acceptable
formulation described herein, the one or more disintegrants in the
extragranular component may include starches, clays, celluloses,
algins, gums, cross-linked polymers, croscarmellose, croscarmellose
sodium, crospovidone, sodium starch glycolate, and combinations
thereof. In some embodiments, the one or more disintegrants in the
extragranular component are about 0.5% (w/w), about 1% (w/w), about
2% (w/w), about 3% (w/w), about 4% (w/w), about 5% (w/w), about 6%
(w/w), about 7% (w/w), about 8% (w/w), about 9% (w/w), about 10%
(w/w) of the formulation.
[0560] In some embodiments, the disintegrant in the granular
component and the disintegrant in the extragranular component are
together about 1% (w/w), about 2% (w/w), about 3% (w/w), about 4%
(w/w), about 5% (w/w), about 6% (w/w), about 7% (w/w), about 8%
(w/w), about 9% (w/w), about 10% (w/w), about 11% (w/w), about 12%
(w/w), about 13% (w/w), about 14% (w/w), about 15% (w/w) of the
formulation.
[0561] The dissolution rate of a solid formulation such as an oral
tablet refers to the proportion of drug which enters a solution in
a given amount of time. In some embodiments of the pharmaceutically
acceptable formulations described herein, the oral tablet provides
a dissolution rate of at least about 70%, at least about 75%, at
least about 80%, at least about 85%, at least about 90%, at least
about 95%, at least about 100% of the rofecoxib or pharmaceutically
acceptable salt thereof by about 15 minutes.
[0562] In some embodiments, the dissolution rate is measured in
about 1% SDS at a paddle speed of about 40 rpm, about 45 rpm, about
50 rpm, about 55 rpm, about 60 rpm, about 65 rpm, about 70 rpm,
about 75 rpm, about 80 rpm, about 85 rpm, about 90 rpm, about 95
rpm and at a temperature of about 37.0.degree. C..+-.0.5.degree. C.
In some embodiments, the dissolution rate is measured in about 1.5%
SDS at a paddle speed of about 40 rpm, about 45 rpm, about 50 rpm,
about 55 rpm, about 60 rpm, about 65 rpm, about 70 rpm, about 75
rpm, about 80 rpm, about 85 rpm, about 90 rpm, about 95 rpm and at
a temperature of about 37.0.degree. C..+-.0.5.degree. C. In some
embodiments, the dissolution rate is measured in about 2% SDS at a
paddle speed of about 40 rpm, about 45 rpm, about 50 rpm, about 55
rpm, about 60 rpm, about 65 rpm, about 70 rpm, about 75 rpm, about
80 rpm, about 85 rpm, about 90 rpm, about 95 rpm and at a
temperature of about 37.0.degree. C..+-.0.5.degree. C. In some
embodiments, the dissolution rate is measured using a USP Type II
apparatus. In some embodiments, the dissolution rate is measured
with a USP Type II apparatus using 900 mL of 2% SDS, a paddle speed
of 50 rpm, and a temperature of 37.0.degree. C..+-.0.5.degree..
[0563] In some embodiments, the ratio of granular disintegrant to
extragranular disintegrant is about 40% (w/w) to about 60% (w/w).
In some embodiments, the ratio of granular disintegrant to
extragranular disintegrant is about 45% (w/w) to about 55% (w/w).
In some embodiments, the ratio of granular disintegrant to
extragranular disintegrant is about 50% (w/w) to about 50% (w/w).
In some embodiments, the ratio of granular disintegrant to
extragranular disintegrant is about 55% (w/w) to about 45% (w/w).
In some embodiments, the ratio of granular disintegrant to
extragranular disintegrant is about 60% (w/w) to about 40%
(w/w).
Granulation Process and Granules for Oral Formulations
[0564] Granulation is the process of forming of granules from
powders or solid substances, producing a material which has the
consistency or granules. This process is highly used in the
pharmaceutical industry to produce tablets for oral administration
of drugs. The process of granulation generally refers to the
agglomeration of very fine particles into larger granules. The size
of the produced granules depends on their intended subsequent use
and can vary largely from 20 .mu.m to 4 mm.
[0565] In the course of a granulation process, particles from one
or more powder substances can be combined to form a granule. Bonds
can be formed between these particles in the process of granulation
by compression or by using a binding agent. Subsequently, this
allows for tablets or pellets to be formed within specific
pre-determined limits.
[0566] In some embodiments of the pharmaceutically acceptable
formulation described herein, the rofecoxib or pharmaceutically
acceptable salt thereof is formulated into granules and at least
about 20%, at least about 25%, at least about 35%, or at least
about 40% of the granules are less than about 75 .mu.m. In some
embodiments, the rofecoxib or pharmaceutically acceptable salt
thereof is formulated into granules and at least about 40%, at
least about 45%, at least about 50%, at least about 55%, or at
least about 60% of the granules are less than about 150 .mu.m. In
some embodiments, the rofecoxib or pharmaceutically acceptable salt
thereof is formulated into granules and at least about 60%, at
least about 65%, at least about 70%, at least about 75%, or at
least about 80% of the granules are less than about 250 .mu.m. In
some embodiments, the rofecoxib or pharmaceutically acceptable salt
thereof is formulated into granules and at least about 70%, at
least about 75%, at least about 80%, at least about 85%, or at
least about 90% of the granules are less than about 425 .mu.m. In
some embodiments, the rofecoxib or pharmaceutically acceptable salt
thereof is formulated into granules and at least about 80%, at
least about 85%, at least about 90%, at least about 95%, or at
least about 100% of the granules are less than about 1000 .mu.m.
Prior to being formulated into granules, the rofecoxib or
pharmaceutically acceptable salt thereof may be micronized. In some
embodiments, the particle size distribution of the rofecoxib or a
pharmaceutically acceptable salt thereof used in the formulation is
as follows: a) the d90 particle size is less than about 12 .mu.m,
11 .mu.m, 10 .mu.m, 9 .mu.m, 8 .mu.m, 7 .mu.m, 6 .mu.m, 5 .mu.m, or
4 .mu.m; b) the d50 particle size is less than about 4 .mu.m, 3
.mu.m, 2 .mu.m, or 1 .mu.m; and c) the d10 particle size is less
than about 1 .mu.m, 0.9 .mu.m, 0.8 .mu.m, 0.7 .mu.m, 0.6 .mu.m, or
0.5 .mu.m. In some embodiments, the particle size distribution of
the rofecoxib or a pharmaceutically acceptable salt thereof used in
the formulation is as follows: a) the d90 particle size is about
10-12 .mu.m; b) the d50 particle size is about 3-4 .mu.m; and c)
the d10 particle size is about 0.5-1.0 .mu.m.
Additional Components
[0567] The pharmaceutically acceptable formulations presented
herein can further comprise one or more additional components
selected from a wide variety of excipients known in the
pharmaceutical formulation art. According to the desired properties
of the tablet or capsule, any number of ingredients can be
selected, alone or in combination, based upon their known uses in
preparing the compositions of the present invention.
Diluents
[0568] Diluents function as fillers in solid formulations such as
tablets. Fillers increase weight and improve content uniformity of
the solid formulations. In some embodiments of the pharmaceutically
acceptable formulations described herein, at least a portion of one
or more diluents is in the granular component. The one or more
diluents include dicalcium phosphate, calcium sulfate, lactose,
cellulose, kaolin, mannitol, dry starch, powdered sugar, sorbitol,
sucrose, inositol, monohydrate, microcrystalline cellulose, and
combinations thereof.
[0569] In some embodiments, the lactose monohydrate diluent is
about 25% (w/w), 30% (w/w), about 32% (w/w), about 34% (w/w), about
35% (w/w), about 37% (w/w), about 39% (w/w), about 40% (w/w), about
42% (w/w), about 44% (w/w) about 45% (w/w), about 47% (w/w), about
49% (w/w), or about 50% (w/w) of the formulation. In some
embodiments, the microcrystalline cellulose diluent is about 30%
(w/w), about 32% (w/w), about 34% (w/w), about 35% (w/w), about 37%
(w/w), about 39% (w/w), about 40% (w/w), about 42% (w/w), about 44%
(w/w), about 45% (w/w), about 47% (w/w), about 49% (w/w), or about
50% (w/w) of the formulation. In some embodiments, the diluent is
about 70% (w/w), about 72% (w/w), about 74% (w/w), about 75% (w/w),
about 77% (w/w), about 79% (w/w), about 80% (w/w), about 82% (w/w),
about 84% (w/w), about 85% (w/w), about 87% (w/w), or about 89%
(w/w) of the formulation.
Binders
[0570] Binders can be used in the formulation of solid oral dosage
forms to hold the active pharmaceutical ingredient and inactive
ingredients together in a cohesive mix. In some embodiments, at
least a portion of the binder is in the granular component. In some
embodiments, the one or more binder include starches, gelatins,
sugars, gums, waxes, water, alcohols, celluloses, acacia gum,
tragacanth, corn starch, methyl cellulose, panwar gum, ghatti gum,
mucilage of isapol husks, carboxymethylcellulose, methylcellulose,
polyvinylpyrrolidone, sucrose, glucose, dextrose, molasses,
lactose, hydroxypropyl cellulose, and combinations thereof. In some
embodiments, the binder is about 0.5% (w/w), about 1% (w/w), about
1.5% (w/w), about 2% (w/w), about 2.5% (w/w), about 3% (w/w), about
3.5% (w/w), about 4% (w/w) about 4.5% (w/w), about 5% (w/w), about
5.5% (w/w), about 6% (w/w) of the formulation.
Color Agents
[0571] One of the most important reasons for adding coloring agents
to solid oral formulations is to prevent errors and confusion for
patients between different medications. In some embodiments, at
least a portion of the one or more coloring agent is in the
extragranular component. The one or more coloring agents can
include pigment blend yellow. In some embodiments, the coloring
agent is about 0.20% (w/w), about 0.25% (w/w) about 0.30% (w/w),
about 0.35% (w/w), about 0.40% (w/w), about 0.45% (w/w), about
0.50% (w/w), about 0.55% (w/w), about 0.60% (w/w), about 0.65%
(w/w), or about 0.70% (w/w) of the formulation.
Lubricants
[0572] In some embodiments, at least a portion of the lubricant is
in the extragranular component. In some embodiments, the one or
more lubricants include talc, magnesium stearate, calcium stearate,
stearic acid, metallic stearate, hydrogenated vegetable oils, and
polyethylene glycol, corn starch, boric acids, sodium chloride,
sodium lauryl sulphate, magnesium stearate, and any combination
thereof. In some embodiments, the lubricant is about 0.05% (w/w),
about 0.10% (w/w), about 0.20% (w/w), about 0.30% (w/w), about
0.40% (w/w), about 0.50% (w/w), about 0.60% (w/w), about 0.70%
(w/w), about 0.80% (w/w), about 0.90% (w/w), about 1% (w/w), or
about 1.2% (w/w), or about 2% (w/w), or about 3% (w/w) of the
formulation.
Formulation
[0573] In certain aspects, the pharmaceutically acceptable
formulation as provided herein can be formulated as a
pharmaceutically acceptable salt or solvate thereof. In some
embodiments, the pharmaceutically acceptable formulations as
provided herein comprising highly pure rofecoxib or a
pharmaceutically acceptable salt or solvate thereof as provided
herein may include the excipients, and may otherwise be formulated,
as described in U.S. Pat. No. 6,063,811, which is incorporated
herein by reference in its entirety, including but not limited to
the formulations specified in Examples 2, 2a, 2b, and 2c of U.S.
Pat. No. 6,063,811. The term "pharmaceutically acceptable salt," as
used herein, refers to the relatively non-toxic, inorganic and
organic acid salts of compounds of the subject matter described
herein. These salts can be prepared in situ during the final
isolation and purification of the compounds of the subject matter
described herein, or by separately reacting a purified compound of
the subject matter described herein in its free base form with a
suitable organic or inorganic acid, and isolating the salt thus
formed. Representative salts include hydrobromide, hydrochloride,
sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate,
palmitate, stearate, laurate, benzoate, lactate, phosphate,
tosylate, citrate, maleate, fumarate, succinate, tartrate,
napthylate, mesylate, glucoheptonate, lactobionate, and
laurylsulphonate salts, and the like. See, for example, Berge et
al., (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19.
[0574] The pharmaceutically acceptable salts of the compounds
disclosed herein include but are not limited to the conventional
nontoxic salts or quaternary ammonium salts of the compounds, e.g.,
from non-toxic organic or inorganic acids. For example, such
conventional nontoxic salts include those derived from inorganic
acids such as hydrochloride, hydrobromic, sulfuric, sulfamic,
phosphoric, nitric, and the like; and the salts prepared from
organic acids such as acetic, butionic, succinic, glycolic,
stearic, lactic, malic, tartaric, citric, ascorbic, palmitic,
maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic,
sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic,
methanesulfonic, ethane disulfonic, oxalic, isothionic, and the
like.
[0575] In some embodiments, the compounds of the subject matter
described herein may contain one or more acidic functional groups
and, thus, are capable of forming pharmaceutically acceptable salts
with pharmaceutically acceptable bases. The term
"pharmaceutically-acceptable salts" in these instances refers to
the relatively non-toxic, inorganic and organic base addition salts
of compounds of the subject matter described herein. These salts
can likewise be prepared in situ during the final isolation and
purification of the compounds, or by separately reacting the
purified compound in its free acid form with a suitable base, such
as the hydroxide, carbonate or bicarbonate of a
pharmaceutically-acceptable metal cation, with ammonia, or with a
pharmaceutically-acceptable organic primary, secondary, or tertiary
amine. Representative alkali or alkaline earth salts include the
lithium, sodium, potassium, calcium, magnesium, and aluminum salts,
and the like. Representative organic amines useful for the
formation of base addition salts include ethylamine, diethylamine,
ethylenediamine, ethanolamine, diethanolamine, piperazine, and the
like. See, for example, Berge et al., supra.
[0576] Formulations of the subject matter described herein include
but are not limited to those suitable for oral administration. The
formulations may conveniently be presented in unit dosage form and
may be prepared by any methods well known in the art of pharmacy.
The amount of active ingredient which can be combined with a
carrier or excipient material to produce a single dosage form will
vary depending upon the host being treated and the particular mode
of administration. The amount of active ingredient, which can be
combined with a carrier or excipient material to produce a single
dosage form will generally be that amount of the compound which
produces a therapeutic effect. Generally, out of 100%, this amount
will range from about 1% to about 99% of active ingredient,
preferably from about 5% to about 70%, most preferably from about
10% to about 30%.
[0577] Methods of preparing these pharmaceutically acceptable
formulations or compositions include the step of bringing into
association a compound of the subject matter described herein with
the carrier or excipient and, optionally, one or more accessory
ingredients. In general, the formulations are prepared by uniformly
and intimately bringing into association a compound of the subject
matter described herein with liquid carriers or excipients, or
finely divided solid carriers or excipient, or both, and then, if
necessary, shaping the product.
[0578] Formulations of the subject matter described herein suitable
for oral administration may be in the form of capsules, cachets,
pills, tablets, lozenges (using a flavored basis, usually sucrose
and acacia or tragacanth), powders, granules, or as a solution or a
suspension in an aqueous or non-aqueous liquid, or as an
oil-in-water or water-in-oil liquid emulsion, or as an elixir or
syrup, or as pastilles (using an inert base, such as gelatin and
glycerin, or sucrose and acacia), and/or as mouthwashes and the
like, each containing a predetermined amount of a compound of the
subject matter described herein as an active ingredient. A compound
of the subject matter described herein may also be administered as
a bolus, electuary or paste.
[0579] In solid dosage forms of the subject matter described herein
for oral administration (capsules, tablets, pills, dragees,
powders, granules, and the like), the active ingredient is mixed
with one or more pharmaceutically acceptable carriers or
excipients, such as sodium citrate or dicalcium phosphate, and/or
any of the following: fillers or extenders, such as starches,
lactose, sucrose, glucose, mannitol, and/or silicic acid; binders,
such as, for example, carboxymethylcellulose, alginates, gelatin,
polyvinyl pyrrolidone, sucrose, and/or acacia; humectants, such as
glycerol; disintegrating agents, such as agar-agar, calcium
carbonate, potato or tapioca starch, alginic acid, certain
silicates, sodium carbonate, and sodium starch glycolate; solution
retarding agents, such as paraffin; absorption accelerators, such
as quaternary ammonium compounds; wetting agents, such as, for
example, sodium lauryl sulfate, sodium dodecyl sulfate, cetyl
alcohol, glycerol monostearate, and polyethylene oxide-polybutylene
oxide copolymer; absorbents, such as kaolin and bentonite clay;
lubricants, such as talc, calcium stearate, magnesium stearate,
solid polyethylene glycols, sodium lauryl sulfate, and mixtures
thereof; and coloring agents. In the case of capsules, tablets and
pills, the pharmaceutically acceptable formulation may also
comprise buffering agents. Solid pharmaceutically acceptable
formulation of a similar type may also be employed as fillers in
soft and hard-filled gelatin capsules using such excipients as
lactose or milk sugars, as well as high molecular weight
polyethylene glycols and the like.
[0580] A tablet may be made by compression or molding, optionally
with one or more accessory ingredients or excipients. Compressed
tablets may be prepared using binder (for example, gelatin or
hydroxybutylmethyl cellulose), lubricant, inert diluent,
preservative, disintegrant (for example, sodium starch glycolate or
cross-linked sodium carboxymethyl cellulose), surface-active or
dispersing agent. Molded tablets may be made by molding in a
suitable machine a mixture of the powdered compound moistened with
an inert liquid diluent.
[0581] The tablets, and other solid dosage forms of the
pharmaceutically acceptable formulation of the subject matter
described herein, such as dragees, capsules, pills, and granules,
may optionally be scored or prepared with coatings and shells, such
as enteric coatings and other coatings well known in the
pharmaceutical-formulating art. They may also be formulated so as
to provide slow or controlled release of the active ingredient
therein using, for example, hydroxybutylmethyl cellulose in varying
proportions, to provide the desired release profile, other polymer
matrices, liposomes, and/or microspheres. They may be sterilized
by, for example, filtration through a bacteria-retaining filter, or
by incorporating sterilizing agents in the form of sterile solid
formulations, which can be dissolved in sterile water or some other
sterile injectable medium immediately before use. These
formulations may also optionally contain opacifying agents and may
be of a formulation that they release the active ingredient(s)
only, or preferentially, in a certain portion of the
gastrointestinal tract, optionally, in a delayed manner. Examples
of embedding formulations, which can be used include polymeric
substances and waxes. The active ingredient can also be in
micro-encapsulated form, if appropriate, with one or more of the
above-described excipients.
[0582] Liquid dosage forms for oral administration of the compounds
of the subject matter disclosed herein include
pharmaceutically-acceptable emulsions, microemulsions, solutions,
suspensions, syrups, and elixirs. In addition to the active
ingredient, the liquid dosage forms may contain inert diluents
commonly used in the art, such as, for example, water or other
solvents, solubilizing agents and emulsifiers, such as ethyl
alcohol, isobutyl alcohol, ethyl carbonate, ethyl acetate, benzyl
alcohol, benzyl benzoate, butylene glycol, 1,3-butylene glycol,
oils (in particular, cottonseed, groundnut, corn, germ, olive,
castor and sesame oils), glycerol, tetrahydrofuryl alcohol,
polyethylene glycols and fatty acid esters of sorbitan, and
mixtures thereof. Additionally, cyclodextrins, e.g.,
hydroxypropyl-.beta.-cyclodextrin or
sulfobutylether-.beta.-cyclodextrin, may be used to solubilize
compounds.
[0583] Besides inert diluents, the oral formulations can also
include adjuvants such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring, coloring, perfuming, and
preservative agents.
[0584] Suspensions, in addition to the active compounds, may
contain suspending agents as, for example, ethoxylated isostearyl
alcohols, polyoxyethylene sorbitol and sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite,
agar, and tragacanth, and mixtures thereof.
[0585] When the compounds of the subject matter disclosed herein
are administered as pharmaceuticals, to humans and animals, they
can be given per se or as a pharmaceutically acceptable formulation
containing, for example, 0.1% to 99.5% (more preferably, 0.5% to
90%) of active ingredient in combination with a
pharmaceutically-acceptable carrier.
[0586] The compounds and pharmaceutically acceptable formulation of
the subject matter disclosed herein can be employed in combination
therapies, that is, the compounds and pharmaceutically acceptable
formulation can be administered concurrently with, prior to, or
subsequent to, one or more other desired therapeutics or medical
procedures. The particular combination of therapies (therapeutics
or procedures) to employ in a combination regimen will take into
account compatibility of the desired therapeutics and/or procedures
and the desired therapeutic effect to be achieved. It will also be
appreciated that the therapies employed may achieve a desired
effect for the same disorder (for example, the compound of the
subject matter disclosed herein may be administered concurrently
with another anticancer agents).
[0587] In some embodiments, the compounds of the subject matter
disclosed herein may be used to treat arthritic conditions in
mammals (e.g., humans, livestock, and domestic animals), race
horses, birds, lizards, and any other organism which can tolerate
the compounds.
[0588] The subject matter disclosed herein also provides a
pharmaceutical pack or kit comprising one or more containers filled
with one or more of the ingredients of the pharmaceutically
acceptable formulation of the subject matter disclosed herein.
Optionally associated with such container(s) can be a notice in the
form prescribed by a governmental agency regulating the
manufacture, use, or sale of pharmaceuticals or biological
products, which notice reflects approval by the agency of
manufacture, use, or sale for human administration.
[0589] Wetting agents, emulsifiers, and lubricants, such as sodium
lauryl sulfate, magnesium stearate, and polyethylene
oxide-polybutylene oxide copolymer, as well as coloring agents,
release agents, coating agents, sweetening, flavoring and perfuming
agents, preservatives, and antioxidants can also be present in the
pharmaceutically acceptable formulation described herein.
[0590] In one embodiment, the pharmaceutically acceptable
formulation useful according to the methods of the subject matter
described herein can be formulated in any manner suitable for
pharmaceutical use.
[0591] In one embodiment, the formulations of the subject matter
disclosed herein can be administered in pharmaceutically acceptable
solutions, which may routinely contain pharmaceutically acceptable
concentrations of salt, buffering agents, preservatives, compatible
carriers, adjuvants, excipients and optionally other therapeutic
ingredients.
Administration
[0592] Some aspects of the subject matter disclosed herein involve
administering an effective amount of a pharmaceutically acceptable
formulation to a subject to achieve a specific outcome.
[0593] For use in therapy, an effective amount of the compound can
be administered to a subject by any mode allowing the compound to
be taken up by the appropriate target cells. "Administering" the
pharmaceutical acceptable formulation of the subject matter
described herein can be accomplished by any means known to the
skilled artisan.
[0594] The concentration of compounds included in formulations used
in the methods of the subject matter disclosed herein can range
from about 1 nM to about 100 .mu.M. Effective doses are believed to
range from about 10 picomole/kg to about 100 micromole/kg.
[0595] The pharmaceutically acceptable formulation disclosed herein
can be prepared and administered in dose units. Solid dose units
are tablets, capsules, powders, and suppositories. For treatment of
a patient, different doses may be necessary depending on activity
of the compound, manner of administration, purpose of the
administration (i.e., prophylactic or therapeutic), nature and
severity of the disorder, age and body weight of the patient. The
administration of a given dose can be carried out both by single
administration in the form of an individual dose unit or else
several smaller dose units. Repeated and multiple administration of
doses at specific intervals of days, weeks, or months apart are
also contemplated by the subject matter described herein.
[0596] The pharmaceutically acceptable formulation described herein
can be administered per se (neat) or in the form of a
pharmaceutically-acceptable salt. When used in medicine the salts
should be pharmaceutically acceptable, but
non-pharmaceutically-acceptable salts can conveniently be used to
prepare pharmaceutically-acceptable salts thereof. Such salts
include, but are not limited to, those prepared from the following
acids: hydrochloric, hydrobromic, sulphuric, nitric, phosphoric,
maleic, acetic, salicylic, p-toluene sulphonic, tartaric, citric,
methane sulphonic, formic, malonic, succinic,
naphthalene-2-sulphonic, and benzene sulphonic. Also, such salts
can be prepared as alkaline metal or alkaline earth salts, such as
sodium, potassium or calcium salts of the carboxylic acid
group.
[0597] The compounds useful in the subject matter disclosed herein
can be delivered in mixtures of more than two such compounds. A
mixture can further include one or more adjuvants in addition to
the combination of compounds.
[0598] A variety of administration routes may be available. The
particular mode selected will depend, of course, upon the
particular compound selected, the age and general health status of
the subject, the particular condition being treated, and the dosage
required for therapeutic efficacy. The methods of the subject
matter described herein, generally speaking, can be practiced using
any mode of administration that is medically acceptable, meaning
any mode that produces effective levels of response without causing
clinically unacceptable adverse effects. Preferred modes of
administration are discussed above.
[0599] The formulations can conveniently be presented in unit
dosage form and can be prepared by any of the methods well known in
the art of pharmacy. All methods include the step of bringing the
compounds into association with a carrier which constitutes one or
more accessory ingredients. In general, the formulations are
prepared by uniformly and intimately bringing the compounds into
association with a liquid carrier, a finely divided solid carrier,
or both, and then, if necessary, shaping the product.
[0600] Other delivery systems can include time-release, delayed
release, or sustained-release delivery systems. Such systems can
avoid repeated administrations of the compounds, increasing
convenience to the subject and the physician. Many types of release
delivery systems are available and known to those of ordinary skill
in the art. They include polymer base systems such as
poly(lactide-glycolide), copolyoxalates, polycaprolactones,
polyesteramides, polyorthoesters, polyhydroxybutyric acid, and
polyanhydrides. Microcapsules of the foregoing polymers containing
drugs are described in, for example, U.S. Pat. No. 5,075,109.
Delivery systems also include non-polymer systems that are: lipids
including sterols such as cholesterol, cholesterol esters and fatty
acids, or neutral fats such as mono-di-and tri-glycerides; hydrogel
release systems; silastic systems; peptide based systems; wax
coatings; compressed tablets using conventional binders and
excipients; partially fused implants; and the like. Specific
examples include, but are not limited to: (a) erosional systems in
which an agent of the subject matter described herein is contained
in a form within a matrix such as those described in U.S. Pat. Nos.
4,452,775, 4,675,189, and 5,736,152, and (b) diffusional systems in
which an active component permeates at a controlled rate from a
polymer such as described in U.S. Pat. Nos. 3,854,480, 5,133,974
and 5,407,686.
[0601] In one aspect, the pharmaceutically acceptable formulation
of rofecoxib as provided herein can be administered in a variety of
manners, including without limitation, orally. The form in which
the drug will be administered (e.g., tablet, capsule, solution,
suspension, emulsion) will depend on the route by which it is
administered. In one aspect, the subject matter disclosed herein
includes a pharmaceutically acceptable formulation comprising
substantially pure or highly pure rofecoxib as provided herein and
a pharmaceutically acceptable carrier, wherein the pharmaceutically
acceptable formulation is in the form of a tablet, and wherein the
amount of the rofecoxib as provided herein is 10 mg, 10.5 mg, 11
mg, 11.5 mg, 12 mg, 12.5 mg, 20 mg, 21 mg, 22 mg, 22.5 mg, or 25
mg. In another aspect, the subject matter disclosed herein includes
a pharmaceutically acceptable formulation comprising substantially
pure or highly pure rofecoxib as provided herein and a
pharmaceutically acceptable carrier or excipient, wherein the
pharmaceutically acceptable formulation is in the form of a tablet,
and wherein the amount of the rofecoxib as provided herein is about
1 mg, 2 mg, 3 mg, 5 mg, 6.25 mg, 7.5 mg, 10 mg, 10.5 mg, 11 mg,
11.5 mg, 12 mg, 12.5 mg, 20 mg, 21 mg, 22 mg, 22.5 mg, 25 mg, 50
mg, 60 mg, or 70 mg.
[0602] In another aspect, the subject matter disclosed herein
includes a pharmaceutically acceptable formulation comprising
substantially pure or highly pure rofecoxib as provided herein and
a pharmaceutically acceptable carrier or excipient, wherein the
pharmaceutically acceptable formulation is in the form of a tablet,
and wherein the amount of the rofecoxib as provided herein is about
0.10 mg/kg, 0.15 mg/kg, 0.20 mg/kg, 0.25 mg/kg, 0.30 mg/kg, 0.35
mg/kg, 0.40 mg/kg, 0.45 mg/kg, 0.50 mg/kg, 0.55 mg/kg, 0.60 mg/kg,
0.65 mg/kg, or 0.70 mg/kg.
[0603] In one aspect, the pharmaceutically acceptable formulation
comprising rofecoxib as provided herein may be packaged with a set
of instructions warning the patient of cardiovascular and/or
gastrointestinal risks associated with administration of the
formulation.
[0604] The formulations, both for human medical use and veterinary
use, of compounds according to the subject matter described herein
typically include such compounds in association with a
pharmaceutically acceptable carrier.
[0605] As used herein, the phrase "pharmaceutically-acceptable
carrier" includes but is not limited to a
pharmaceutically-acceptable material, formulation or vehicle, such
as a solid filler, diluent, excipient, or encapsulating material,
involved in carrying or transporting the subject pharmaceutical
agent from one organ, or portion of the body, to another organ, or
portion of the body. Each carrier must be "acceptable" in the sense
of being compatible with the other ingredients of the formulation
and not injurious to the patient. Some examples of materials which
can serve as pharmaceutically-acceptable carriers include: sugars,
such as lactose, glucose, and sucrose; starches, such as corn
starch and potato starch; cellulose and its derivatives, such as
sodium carboxymethyl cellulose, ethyl cellulose, and cellulose
acetate; powdered tragacanth; malt; gelatin; and talc; excipients,
such as cocoa butter and suppository waxes. The term "carrier"
denotes an organic or inorganic ingredient, natural or synthetic,
with which the active ingredient is combined to facilitate the
application. The components of the pharmaceutically acceptable
formulation also are capable of being comingled with the compounds
of the present subject matter, and with each other, in a manner
such that there is no interaction which would substantially impair
the desired pharmaceutical efficiency.
[0606] The carrier should be "acceptable" in the sense of being
compatible with compounds of the subject matter described herein
and not deleterious to the recipient. Pharmaceutically acceptable
carriers, in this regard, are intended to include any and all
solvents, dispersion media, coatings, absorption delaying agents,
and the like, compatible with pharmaceutical administration. The
use of such media and agents for pharmaceutically active substances
is known in the art. Except insofar as any conventional media or
agent is incompatible with the active compound, use thereof in the
formulations is contemplated. Supplementary active compounds
(identified or designed according to the subject matter disclosed
herein and/or known in the art) also can be incorporated into the
formulations. The formulations can conveniently be presented in
dosage unit form and can be prepared by any of the methods well
known in the art of pharmacy. In general, some formulations are
prepared by bringing the compound into association with a liquid
carrier or a finely divided solid carrier or both, and then, if
necessary, shaping the product into the desired formulation. A
pharmaceutically acceptable formulation of the subject matter
disclosed herein should be formulated to be compatible with its
intended route of administration. Solutions or suspensions can
include the following components: a sterile diluent such as water,
saline solution, fixed oils, polyethylene glycols, glycerine,
propylene glycol or other synthetic solvents; antibacterial agents
such as benzyl alcohol or methyl parabens; antioxidants such as
ascorbic acid or sodium bisulfite; chelating agents such as
ethylenediaminetetraacetic acid; buffers such as acetates, citrates
or phosphates and agents for the adjustment of tonicity such as
sodium chloride or dextrose. The pH can be adjusted with acids or
bases, such as hydrochloric acid or sodium hydroxide.
[0607] Useful solutions for oral administration can be prepared by
any of the methods well known in the pharmaceutical art, described,
for example, in Remington's Pharmaceutical Sciences, 18th ed. (Mack
Publishing Company, 1990). Formulations of the subject matter
described herein suitable for oral administration can be in the
form of: discrete units such as capsules, gelatin capsules,
sachets, tablets, troches, or lozenges, each containing a
predetermined amount of the drug; a powder or granular formulation;
a solution or a suspension in an aqueous liquid or non-aqueous
liquid; or an oil-in-water emulsion or a water-in-oil emulsion. A
tablet can be made by compressing or molding the drug optionally
with one or more accessory ingredients. Compressed tablets can be
prepared by compressing, in a suitable machine, the drug in a
free-flowing form such as a powder or granules, optionally mixed by
a binder, lubricant, inert diluent, surface active or dispersing
agent. Molded tablets can be made by molding, in a suitable
machine, a mixture of the powdered drug and suitable carrier
moistened with an inert liquid diluent.
[0608] Oral formulations generally include an inert diluent or an
edible carrier. For the purpose of oral therapeutic administration,
the active compound can be incorporated with excipients. Oral
formulation prepared using a fluid carrier for use as a mouthwash
include the compound in the fluid carrier and are applied orally
and swished and expectorated or swallowed. Pharmaceutically
compatible binding agents, and/or adjuvant materials can be
included as part of the formulation. The tablets, pills, capsules,
troches and the like can contain any of the following ingredients,
or compounds of a similar nature: a binder such as microcrystalline
cellulose, gum tragacanth or gelatin; an excipient such as starch
or lactose; a disintegrating agent such as alginic acid, Primogel,
or corn starch; a lubricant such as magnesium stearate or Sterotes;
a glidant such as colloidal silicon dioxide; a sweetening agent
such as sucrose or saccharin; or a flavoring agent such as
peppermint, methyl salicylate, or orange flavoring.
[0609] Oral formulations can be formulated in dosage unit form for
ease of administration and uniformity of dosage. Dosage unit form
refers to physically discrete units suited as unitary dosages for
the subject to be treated; each unit containing a predetermined
quantity of active compound calculated to produce the desired
therapeutic effect in association with the required pharmaceutical
carrier. The specification for the dosage unit forms of the subject
matter disclosed herein are dictated by and directly dependent on
the unique characteristics of the active compound and the
therapeutic effect to be achieved, and the limitations inherent in
the art of compounding such an active compound for the treatment of
individuals.
Methods of Use
[0610] A pharmaceutically acceptable formulation comprising
substantially pure or highly pure rofecoxib as presented herein may
be used in the treatment or prevention of conditions or diseases in
humans.
[0611] In one aspect, the subject matter disclosed herein includes
administering a pharmaceutically acceptable formulation comprising
rofecoxib having a favorable impurity profile to a subject to treat
or prevent a disease or condition, including but not limited to one
of the following: osteoarthritis, rheumatoid arthritis, analgesia,
systemic juvenile idiopathic arthritis, migraine or headaches,
juvenile rheumatoid arthritis, ankylosing spondylitis, acute pain,
and primary dysmenorrhea. In another aspect, the disease or
condition is fibromyalgia. In another aspect, the disease or
condition is lower back pain (e.g. chronic lower back pain). In
another aspect, the disease or condition is psoriatic
arthritis.
[0612] In other aspects, the disease or condition is
pain-associated with a condition caused by a bleeding disorder,
including migraine associated with von Willebrand deficiency. In
another aspect, a patient receiving treatment for migraine
associated with von Willebrand deficiency expresses von Willebrand
factor at a level about 50% below normal.
[0613] In one aspect, the treatment described herein may be
administered to a subject of any age. In another aspect, the
patient is age 2 or older, or age 12 years or older. In another
aspect, the patient is of age 12 to 75 years old, inclusive.
[0614] In one aspect, the subject is a healthy human subject. In
another aspect, the subject is screened for all or certain of the
study protocol inclusion or exclusion criteria described below as
part of the treatment.
[0615] In another aspect, the subject is within a patient
population that has a reduced risk of arterial thrombosis,
cardiovascular thrombotic events, or other serious cardiovascular
disease or events, for example humans with inherited bleeding
disorders or coagulopathies such as hemophilia or von Willebrand
disease, or humans with medically-induced bleeding disorders or
coagulopathies.
[0616] In one aspect, the subject is screened for a history or
current symptoms of cardiovascular disease. In one aspect, if the
patient is determined to have a history or current symptoms of
cardiovascular disease, the patient is not administered the
pharmaceutically acceptable formulation. In another aspect, if it
is determined that the patient does not have a history or current
symptoms of cardiovascular disease, the patient is administered the
pharmaceutically acceptable formulation as further set forth
herein. In yet another aspect, the patient is screened for one or
more risk factors that would increase the likelihood of the patient
having a serious cardiovascular thrombotic event following
administration of the pharmaceutically acceptable formulation as
further set forth herein. In one aspect, if it is determined that
the patient may be safely administered the pharmaceutically
acceptable formulation as further set forth herein without
increasing the likelihood of the patient having a serious
cardiovascular thrombotic event, then the patient is administered
the pharmaceutically acceptable formulation as further set forth
herein.
[0617] In another aspect, the subject is screened for a history or
current symptoms of gastrointestinal bleeding, ulceration, and
perforation. In one aspect, if the patient is determined to have a
history or current symptoms of gastrointestinal bleeding,
ulceration, and perforation, the patient is not administered the
pharmaceutically acceptable formulation. In another aspect, if it
is determined that the patient does not have a history or current
symptoms of gastrointestinal bleeding, ulceration, and perforation,
the patient is administered the pharmaceutically acceptable
formulation as further set forth herein.
[0618] The subject may be screened for a history or current
symptoms of both cardiovascular disease or gastrointestinal
bleeding, ulceration, and perforation, in addition to any of the
study protocol inclusion or exclusion criteria listed below.
[0619] A pharmaceutically acceptable formulation comprising
rofecoxib that is administered for any of the diseases or
conditions described herein may be substantially pure or highly
pure, or may be essentially free of, or free of, one or more of
impurities.
[0620] In another aspect, a pharmaceutically acceptable formulation
comprising rofecoxib as provided herein is administered to a
subject who has mild, moderate, or severe pain or inflammation
associated with a condition caused by a bleeding disorder. Pain may
be measured through any clinically-validated pain assessment
measure. In one aspect, pain is measured through the Pain Intensity
Numerical Rating Scale. In another aspect, pain associated with a
specific condition caused by a bleeding disorder, hemophilic
arthropathy, is measured through the Pain Intensity Numerical
Rating Scale or the Patient Assessment of Arthropathy Pain (Visual
Analog Scale; VAS).
[0621] In one aspect, a pharmaceutically acceptable formulation
comprising rofecoxib as provided herein is administered to a
subject who has pain associated SJIA. In another aspect, a
pharmaceutically acceptable formulation comprising rofecoxib as
provided herein is administered to a subject who has migraine
associated with von Willebrand deficiency, wherein the subject
receiving treatment expresses von Willebrand factor at a level
about 50% below normal.
[0622] In one aspect, the treatment of the subject matter disclosed
herein includes administration of a pharmaceutically acceptable
formulation comprising about 10 mg of rofecoxib as provided herein
per day. In one aspect, the treatment of the subject matter
disclosed herein includes administration of a pharmaceutically
acceptable formulation comprising about 10.5 mg of rofecoxib as
provided herein per day. In one aspect, the treatment of the
subject matter disclosed herein includes administration of a
pharmaceutically acceptable formulation comprising about 11 mg of
rofecoxib as provided herein per day. In one aspect, the treatment
of the subject matter disclosed herein includes administration of a
pharmaceutically acceptable formulation comprising about 11.5 mg of
rofecoxib as provided herein per day. In one aspect, the treatment
of the subject matter disclosed herein includes administration of a
pharmaceutically acceptable formulation comprising about 12 mg of
rofecoxib as provided herein per day. In one aspect, the treatment
of the subject matter disclosed herein includes administration of a
pharmaceutically acceptable formulation comprising about 12.5 mg of
rofecoxib as provided herein per day. In one aspect, the treatment
of the subject matter disclosed herein includes administration of a
pharmaceutically acceptable formulation comprising about 20 mg of
rofecoxib as provided herein per day. In one aspect, the treatment
of the subject matter disclosed herein includes administration of a
pharmaceutically acceptable formulation comprising about 21 mg of
rofecoxib as provided herein per day. In one aspect, the treatment
of the subject matter disclosed herein includes administration of a
pharmaceutically acceptable formulation comprising about 22 mg of
rofecoxib as provided herein per day. In one aspect, the treatment
of the subject matter disclosed herein includes administration of a
pharmaceutically acceptable formulation comprising about 22.5 mg of
rofecoxib as provided herein per day. In another aspect, the
treatment includes the administration of a pharmaceutically
acceptable formulation comprising about 25 mg of rofecoxib as
provided herein per day. In one aspect, the treatment of the
subject matter disclosed herein includes administration of a
pharmaceutically acceptable formulation comprising about 50 mg of
rofecoxib as provided herein per day. In another aspect, the
treatment includes the administration of a pharmaceutically
acceptable formulation comprising about 1 mg, 2 mg, 3 mg, 5 mg,
6.25 mg, 7.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg,
17.5 mg, 20 mg, 21 mg, 21.5 mg, 22.5 mg, 25 mg, 50 mg, 60 mg, or 70
mg of rofecoxib as provided herein per day. Treatment may be
administered once daily in the form of one or more tablets. In
other aspects, the pharmaceutically acceptable formulation
comprising rofecoxib as provided herein is administered two times
or more daily.
[0623] In one aspect, a treatment regimen is provided for the safe
treatment of pain, inflammation, migraine and/or arthritis. The
pain, inflammation, migraine and/or arthritis may be associated
with a disease or condition caused by a bleeding disorder. In one
aspect, the treatment subject is a human patient of any age. In
another aspect, the patient is age 12 years or older.
[0624] The treatment regimen may comprise the administration of an
initial (or first) dose of a pharmaceutically acceptable
formulation comprising 4 mg, 8 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg,
12 mg, 12.5 mg, 17.5 mg, 20 mg, or 25 mg of rofecoxib once daily as
further described herein. The treatment regimen may further
comprise evaluating the subject after administration of the initial
dose to determine if the initial dose was fully, partially, or not
effective at treating the pain, inflammation, migraine and/or
arthritis. In another aspect, the treatment regimen may comprise
determining if the subject could benefit from the administration of
a higher dose of rofecoxib. The evaluation and determining steps
may take place after a single administration of the initial dose
(e.g. two days, three days, one week, two weeks, or longer after
the first administration of the initial dose), or after multiple
administrations of the initial dose, and may be performed by a
physician, physician's assistant, nurse, or other health care
provider. In one aspect, the evaluation and determination steps may
be based on subject-reported outcomes, and may include an
assessment of the benefit of a higher dose of rofecoxib compared to
any potential safety risks associated with that higher dose. For
example, if a subject experiences a clinically meaningful decrease
in pain after administration of the initial dose, it may be
determined that the subject should continue on the initial dose
through the duration of the bleeding episode that caused the
pain.
[0625] The treatment regimen may further comprise the
administration of a subsequent (or second) dose of a
pharmaceutically acceptable formulation comprising 10 mg, 12.5 mg,
17.5 mg, 20 mg, 21 mg, 22 mg, 22.5 mg, 25 mg, 30 mg, 35 mg, 40 mg,
45 mg, or 50 mg of rofecoxib once daily if it was determined that
the initial dose was not effective or only partially effective at
treating the pain, inflammation, migraine and/or arthritis, or if
it is determined that the subject could benefit from a higher daily
dose of rofecoxib to treat the pain, inflammation, migraine and/or
arthritis (e.g. that a higher dose could achieve a greater
reduction in pain in the human). In one aspect, the subsequent dose
is administered if it is determined that the initial dose did not
achieve a clinically meaningful reduction in pain, inflammation,
migraine and/or arthritis in the human. In another aspect, the
subsequent dose is administered if it is determined that the
subsequent dose may increase the effectiveness of the treatment
without increasing the risk of adverse events or other side
effects. In another aspect, a higher dose is not administered if it
is determined that the initial dose was effective at treating the
pain, inflammation, migraine and/or arthritis. In another aspect, a
higher dose is not administered if it is determined that the higher
dose would increase the risk of adverse events or other side
effects in the subject. In another aspect, a higher dose is not
administered if it is determined that the risk of administering the
higher dose (e.g. in terms of adverse events or side effects)
outweigh the benefits (e.g. in terms of effectiveness of treating
the pain, inflammation, migraine and/or arthritis). In another
aspect, the step of not administering a higher dose comprises
instructing the subject not to take a higher dose of the
pharmaceutical composition (e.g. not to take 12.5 mg of the
pharmaceutical composition more than once daily).
[0626] In one aspect, the treatment includes the administration of
pharmaceutically acceptable formulation comprising about 0.10
mg/kg, 0.15 mg/kg, 0.20 mg/kg, 0.25 mg/kg, 0.30 mg/kg, 0.35 mg/kg,
0.40 mg/kg, 0.45 mg/kg, 0.50 mg/kg, 0.55 mg/kg, 0.60 mg/kg, 0.65
mg/kg, or 0.70 mg/kg.
[0627] In one aspect, an effective amount of rofecoxib as provided
herein for treating pain associated with a disease or condition
caused by a bleeding disorder is about 12.5 mg once daily, and, in
another aspects, results fewer side effects or in a reduction of
pain equal to or better than the use of a pharmaceutically
acceptable formulation comprising about 25 mg rofecoxib that is not
substantially pure or highly pure, or essentially free of, or free
of, one or more of the impurities described herein that was present
in previously available rofecoxib bulk drug product. In one aspect,
an effective amount of rofecoxib as provided herein for treating
pain associated with a disease or condition caused by a bleeding
disorder is about 1 mg, 2 mg, 3 mg, 5 mg, 6.25 mg, 7.5 mg, 10 mg,
10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 17.5 mg, 20 mg, 21 mg, 22
mg, 22.5 mg, 25 mg, 50 mg, 60 mg, or 70 mg once daily. As a result,
a subject may not need to be administered the higher quantity of
active ingredient in order to experience a reduction in pain.
[0628] In one aspect, an effective amount rofecoxib as provided
herein for treating pain associated with a disease or condition
caused by a bleeding disorder, pain associated with systemic
juvenile idiopathic arthritis, or migraine associated with von
Willebrand deficiency is about 0.10 mg/kg, 0.15 mg/kg, 0.20 mg/kg,
0.25 mg/kg, 0.30 mg/kg, 0.35 mg/kg, 0.40 mg/kg, 0.45 mg/kg, 0.50
mg/kg, 0.55 mg/kg, 0.60 mg/kg, 0.65 mg/kg, or 0.70 mg/kg.
[0629] In one aspect, the treatment described herein is effective
at treating mild, moderate, or severe pain in a subject without the
co-administration of another pain medication or analgesic.
[0630] In another aspect, the treatment described herein results in
the subject decreasing or discontinuing the use of another pain
medication or analgesic, including rescue medications, during the
course of the treatment when compared to before the initiation of
the treatment. In yet another aspect, the treatment results in the
subject decreasing or discontinuing the use of acetaminophen and/or
opioid medications during the treatment during the course of the
treatment when compared to before the initiation of the
treatment.
[0631] In one aspect, a pharmaceutically acceptable formulation
comprising rofecoxib as provided herein is co-administered with
factor replacement therapy to a subject having a bleeding disorder.
In another aspect, the treatment described herein is administered
to a subject having a bleeding disorder who is being administered
or is taking factor replacement therapy prophylactically. In one
aspect, the a pharmaceutically acceptable formulation comprising 10
mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 17.5 mg, 20 mg, 21 mg,
22 mg, 22.5 mg, or 25 mg rofecoxib as provided herein is
administered once daily to a subject who is also being administered
or is taking factor replacement therapy prophylactically.
[0632] In one aspect, a pharmaceutically acceptable formulation
comprising rofecoxib as provided herein is administered daily and
does not increase risk of cardiovascular diseases and/or
gastrointestinal bleeding, ulceration, or perforation during the
course of the treatment, as determined at 2 weeks, 4 weeks, 8
weeks, 12 weeks, 24 weeks, 52 weeks, and/or two or more years. In
another aspect, the rofecoxib as provided herein may be
administered during the course of the treatment without the use or
co-administration of a gastro-protective agent including but not
limited to an antacid therapy, an H2 antagonist, a proton pump
inhibitor, or misoprostol.
[0633] In another aspect, a pharmaceutically acceptable formulation
comprising rofecoxib as provided herein is administered only on an
as-needed basis, for example when a subject experiences a pain
"flare" described as an increase in pain rating of >1 or a pain
rating of >4 to <9 based on the Pain Intensity Numerical
Rating Scale. In yet another aspect, the pharmaceutically
acceptable formulation comprising rofecoxib as further set forth
herein is not administered as a maintenance therapy,
prophylactically, or for long term use (e.g., >1 year). In one
aspect, a pharmaceutically acceptable formulation comprising
rofecoxib as provided herein is administered only on an as-needed
basis and for short term use, for example, less than one week, two
weeks, three weeks, or four weeks, or until the pain, migraine,
arthritis, inflammation, or other conditions or symptoms subside or
resolve, for example, until there is a clinically significant
improvement in pain rating based on the based on the Pain Intensity
Numerical Rating Scale.
[0634] In another aspect, the subject uses or is co-administered a
gastro-protective agent during the course of treatment with a
pharmaceutically acceptable formulation comprising rofecoxib as
provided herein, which prevents or treats gastrointestinal
bleeding, ulceration, and perforation in the subject.
[0635] In one aspect, the treatment described herein achieves a
reduction in at least 1 from baseline in the Pain Intensity
Numerical Rating Scale. In another aspect, the treatment described
herein achieves a reduction in at least 2, 3, 4, or 5 from baseline
in the Pain Intensity Numerical Rating Scale.
[0636] In one aspect, the reduction in the Pain Intensity Numerical
Rating Scale is achieved within 1, 2, 3, 4, 5, or 6 days, or 1
week, or 2 weeks of first administering the pharmaceutically
acceptable formulation.
[0637] In one aspect, the treatment of a disease or condition by
the administering of a pharmaceutically acceptable formulation
comprising substantially pure or highly pure rofecoxib does not
result in one or more of the following adverse events: upper
respiratory infection, headache, nausea, vomiting, and cough, or
one or more of the following serious adverse events: hemorrhage and
hypotension. In one aspect, the treatment of a disease or condition
caused by a bleeding disorder by the administering of a
pharmaceutically acceptable formulation comprising substantially
pure or highly pure rofecoxib does not result in an increased
number of joint bleeding events. In another aspect, the treatment
of a disease or condition caused by a bleeding disorder by the
administering of a pharmaceutically acceptable formulation
comprising substantially pure or highly pure rofecoxib does not
increase the risk of joint bleeding events. In one aspect, the
treatment of a disease or condition caused by a bleeding disorder
by the administering of a pharmaceutically acceptable formulation
comprising substantially pure or highly pure rofecoxib does not
result in an increase in the amount of factor use in the subject.
In another aspect, the treatment of a disease or condition by the
administering of a pharmaceutically acceptable formulation
comprising substantially pure or highly pure rofecoxib does not
result in an increased risk of side effects (including but not
limited to hemorrhaging, hypotension or serious cardiovascular
thrombotic events) compared to the previously marketed "VIOXX"
product when used in that disease or condition. In another aspect,
a pharmaceutically acceptable formulation comprising substantially
pure or highly pure rofecoxib as provided herein results in greater
efficacy in a disease or condition compared to the previously
marketed "VIOXX" product when used in that disease or condition (as
measured by a clinically-validated measure, such as the Pain
Intensity Numerical Rating Scale).
[0638] In another aspect, the treatment of a disease or condition
by the administering of a pharmaceutically acceptable formulation
comprising highly pure rofecoxib that is essentially free of, or
free of, 4-[4-(methylsulfonyl)phenyl]-3-phenyl-5-hydroxyfuran-2-one
and/or 4-[4-(methylsulfonyl)phenyl]-3-phenyl-2,5-furandione does
not result in one or more of the following adverse events: upper
respiratory infection, headache, nausea, vomiting, and cough, or
one or more of the following serious adverse events: hemorrhage and
hypotension. In another aspect, a pharmaceutically acceptable
formulation comprising highly pure rofecoxib that is essentially
free of, or free of,
4-[4-(methylsulfonyl)phenyl]-3-phenyl-5-hydroxyfuran-2-one and/or
4-[4-(methylsulfonyl)phenyl]-3-phenyl-2,5-furandione as provided
herein results in greater efficacy in a disease or condition, or
reduced side effects (e.g. hemorrhaging, hypotension or serious
cardiovascular thrombotic events) compared to the previously
marketed "VIOXX" product when used in that disease or condition (as
measured by a clinically-validated measure, such as the Pain
Intensity Numerical Rating Scale). The purity of the resulting
rofecoxib described as herein is determined as a percent area
basis, typically as quantified by analytical chromatography, such
as using HPLC, UHPLC, UPLC or other analytical means in the
art.
EXAMPLES
Example 1
[0639] In some embodiments, the pharmaceutically acceptable
formulation described herein relates to a tablet formulation as
shown in Table 7 below:
TABLE-US-00008 TABLE 7 Formulation Percent (w/w) Intragranular
Rofecoxib API Lactose Monohydrate, NF, EP, JP, Fastflo 316 SDM
Microcrystalline Cellulose, NF, EP, JP Avicel PH 101
Hydroxypropylcellulose, NF, EP, JP, Klucel EXF Purified Water, USP,
EP Extragranular Croscarmellose Sodium, NF, EP, JP, (Ac-Di-Sol
SD711) Pigment Blend Yellow (HTS: 3206492000) Magnesium Stearate,
NF, EP, JP, Hyqual Vegetable Source 2257 Total
[0640] In some embodiments the water addition and spray rate in the
granulation process of the pharmaceutically acceptable formulations
as described here are as shown in Table 8 below:
TABLE-US-00009 TABLE 8 B18079 B18080 B18084 B18085 Parameter (Batch
1) (Batch 2) (Batch 3) (Batch 4) Water Addition (%) Spray Rate
(g/min)
[0641] FIG. 14 shows the granule size distribution across batches.
In some embodiments, the granule size distribution is W<75
(34-52% w/w) and W<150 (64-82% w/w).
[0642] FIGS. 15A-B show initial dissolution rates for 25 mg
rofecoxib tablets. FIG. 15A shows dissolution of 25 mg rofecoxib
tablets in 0.1N HCl for batches 1 and 2. FIG. 15B shows dissolution
of 25 mg rofecoxib tablets in at least 2% SDS for batches 1 and 2.
The paddle speed is 75 rpm and the number of tablets dissolved is 3
per batch.
[0643] FIGS. 16A-B show initial dissolution rates for 25 mg
rofecoxib tablets. FIG. 16A shows dissolution of 25 mg rofecoxib
tablets in 0.1N HCl for batches 3 and 4. FIG. 16B shows dissolution
of 25 mg rofecoxib tablets in at least 2% SDS for batches 3 and 4.
The paddle speed is 75 rpm and the number of tablets dissolved is 3
per batch.
[0644] FIG. 17 shows dissolution of 25 mg rofecoxib tablet as a
function of percent water added.
Example 2
[0645] In some embodiments, the pharmaceutically acceptable
formulation described herein relates to a tablet formulation as
shown in Table 9 below:
TABLE-US-00010 TABLE 9 Tablet Formulations Percent (w/w) Batches
Batches Batches 1-4 5-6 6-7 (4 + 0) (2 + 2) (4 + 4) Intragranular
Rofecoxib API 12.50 12.50 12.50 Lactose Monohydrate, NF, EP, 39.85
39.70 37.70 JP, Fastflo 316 SDM Microcrystalline Cellulose, NF,
39.85 39.70 37.70 EP, JP Avicel PH101 Hydroxypropylcellulose, NF,
3.00 3.00 3.00 EP, JP, Klucel EXF Croscarmellose Sodium, NF, EP,
0.00 2.00 4.00 JP, (Ac-Di-Sol SD711) Purified Water, USP, EP NA NA
NA Extragranular Croscarmellose Sodium, NF, EP, 4.00 2.00 4.00 JP,
(Ac-Di-Sol SD711) Pigment Blend Yellow (HTS: 0.30 0.60 0.60
3206492000) Magnesium Stearate, NF, EP, JP, 0.50 0.50 0.50 Hyqual
Vegetable Source 2257 Total 100.00 100.00 100.00
[0646] In some embodiments the water addition, spray rate, and
disintegrant in the granulation process of the pharmaceutically
acceptable formulations as described herein are as shown in Table
10 below:
TABLE-US-00011 TABLE 10 Water Addition, Spray Rate, and
Disintegrant B18090 B18091 B18092 B18093 Parameter (Batch 5) (Batch
6) (Batch 7) (Batch 8) Water Addition (%) Spray Rate (g/min)
Disint
[0647] FIG. 18 shows the granule size distribution across
batches.
[0648] FIGS. 19A-B show dissolution rates for 25 mg rofecoxib
tablets. FIG. 19A shows dissolution of 25 mg rofecoxib tablets in
at least 2% SDS for batches 5 and 6. FIG. 19B shows dissolution of
25 mg rofecoxib tablets in at least 2% SDS for batches 7 and 8. The
paddle speed is 75 rpm and the number of tablets dissolved is 3 per
batch.
[0649] FIGS. 20A-B show dissolution rates for 25 mg rofecoxib
tablets. FIG. 20A shows dissolution of 25 mg rofecoxib tablets in
at least 2% SDS for batches 5 and 6 at 75 rpm paddle speed. FIG.
20B shows dissolution of 25 mg rofecoxib tablets in at least 2% SDS
for batches 5 and 6 at 50 rpm paddle speed. The number of tablets
dissolved is 3 per batch.
[0650] All batches have 0.6% extragranular pigment. Two batches use
26% water during granulation. Batch 5 has 4% total disintegrant: 2%
intragranular and 2% extragranular disintegrant. Batch 7 had 8%
total disintegrant: 4% intragranular and 4% extragranular
disintegrant.
[0651] Two batches will use 32% water during granulation. Batch 6
had 4% total disintegrant: 2% intragranular and 2% extragranular
disintegrant. Batch 8 had 8% total disintegrant: 4% intragranular
and 4% extragranular disintegrant.
[0652] 100% Dissolution in 15 minutes is observed for Batches 5-8
at 75% rpm paddle speed. Previous maximum was 86% dissolved in 15
minutes. Based on the dissolution results and the manufacturing
engineering data, there is no advantage to have 8% disintegrant in
the formulation. Additionally, decreasing the paddle speed to 50
rpm leads to a slightly lower % dissolved (95% LC) at 15 minutes
for Batches 5 and 6.
Example 3
[0653] There was no difference in dissolution profile of the two
lead 25 mg rofecoxib tablet formulations in 1, 1.5, and 2% SDS at
either 50 or 75 rpm paddle speed. All media and paddle speeds
provided acceptable profiles. A conservative approach to the
dissolution profile is advised at this stage of development:
[0654] Medium: 1.5 or 2% SDS
[0655] Paddle speed: 50 rpm
[0656] Eight batches of 25-mg rofecoxib tablets were manufactured.
Amount of water added during granulation is the most critical
parameter:
[0657] Water amount affects granule size
[0658] Low water does not make granules
[0659] Excess water affects tablet properties (hardness,
friability, disintegration, dissolution)
[0660] Water content in the 26-32% range yields acceptable tablet
properties
[0661] Disintegrant location affects dissolution properties in at
least 2% SDS. Extragranular disintegrant (4%) only does not result
in complete dissolution. Intragranular and extragranular
disintegrant result in complete dissolution. No advantage to 8%
total disintegrant over 4% total disintegrant when half is
intragranular. Decreasing the paddle speed to 50 rpm from 75 rpm
led to a slightly lower % rofecoxib dissolved at 15 minutes in at
least 2% SDS.
[0662] In some embodiments, the pharmaceutically acceptable
formulation described herein relates to a tablet formulation as
shown in Table 11 below:
TABLE-US-00012 TABLE 11 A Tablet Formulation Percent (w/w) Batches
Batches Batches 1-4 5-6 6-7 Intragranular (4 + 0) (2 + 2) (4 + 4)
Rofecoxib API 12.50 12.50 12.50 Lactose Monohydrate, NF, EP, 39.85
39.70 37.70 JP, Fastflo 316 SDM Microcrystalline Cellulose, NF,
39.85 39.70 37.70 EP, JP Avicel PH101 Hydroxypropylcellulose, NF,
3.00 3.00 3.00 EP, JP, Klucel EXF Croscarmellose Sodium, NF, EP,
0.00 2.00 4.00 JP, (Ac-Di-Sol SD711) Purified Water, USP, EP NA NA
NA Extragranular Croscarmellose Sodium, NF, EP, 4.00 2.00 4.00 JP,
(Ac-Di-Sol SD711) Pigment Blend Yellow (HTS: 0.30 0.60 0.60
3206492000) Magnesium Stearate, NF, EP, JP, 0.50 0.50 0.50 Hyqual
Vegetable Source 2257 Total 100.00 100.00 100.00
[0663] In some embodiments the water addition, spray rate, and
disintegrant in the granulation process of the pharmaceutically
acceptable formulations as described herein as shown in Table 12
below:
TABLE-US-00013 TABLE 12 Water, Spray Rate, and Disintegrant B18090
B18091 B18092 B18093 Parameter (Batch 5) (Batch 6) (Batch 7) (Batch
8) Water Addition (%) Spray Rate (g/min) Disint
[0664] FIG. 21 shows the granule size distribution across
batches.
[0665] FIGS. 22A-B show dissolution rates for 25 mg rofecoxib
tablets. FIG. 22A shows dissolution of 25 mg rofecoxib tablets in
at least 2% SDS for batches 5 and 6 at 75 rpm paddle speed. FIG.
22B shows dissolution of 25 mg rofecoxib tablets in at least 2% SDS
for batches 5 and 6 at 50 rpm paddle speed. The number of tablets
dissolved is 3 per batch.
[0666] FIGS. 23A-B show dissolution rates for 25 mg rofecoxib
tablets. FIG. 23A shows dissolution of 25 mg rofecoxib tablets in
1.5% SDS for batches 5 and 6 at 75 rpm paddle speed. FIG. 23B shows
dissolution of 25 mg rofecoxib tablets in 1.5% SDS for batches 5
and 6 at 50 rpm paddle speed. The number of tablets dissolved is 3
per batch.
[0667] FIGS. 24A-B show dissolution rates for 25 mg rofecoxib
tablets. FIG. 24A shows dissolution of 25 mg rofecoxib tablets in
1% SDS for batches 5 and 6 at 75 rpm paddle speed. FIG. 24B shows
dissolution of 25 mg rofecoxib tablets in 1% SDS for batches 5 and
6 at 50 rpm paddle speed. The number of tablets dissolved is 3 per
batch.
Example 4
[0668] A Single-Dose, Open-Label, Phase 1, Adaptive Pharmacokinetic
Study of TRM-201 (Rofecoxib) 25 mg Administered to Healthy Subjects
in a Fasting State, with Comparison to Historical Pharmacokinetic
Parameters of Previously Marketed Rofecoxib and a Food-Effect
Substudy ("TRM-201-PK-101" or "101 PK Study")
Study Protocol
[0669] 1. Study Objectives
[0670] 1.1 Primary Objective:
[0671] MAIN Study: To evaluate key PK parameters (AUC.sub.0-28,
C.sub.max) of a single dose of TRM-201 in healthy subjects in
comparison to historical PK parameters (AUC.sub.0-.infin.,
C.sub.max) of previously marketed rofecoxib, both in a fasted
state.
[0672] FOOD-EFFECT Substudy: To assess key pharmacokinetic
parameters (AUC.sub.0-.infin., C.sub.max) of a single dose of
TRM-201 in a fasted and fed state.
[0673] 1.2 Secondary Objectives:
[0674] 1. To assess the safety and tolerability of a single dose of
TRM-201 in healthy subjects.
[0675] 2. Investigational Plan
[0676] 2.1 Study Design
[0677] This is a single-center, open-label, adaptive PK study of
TRM-201 consisting of a MAIN study with a PILOT portion conducted
under a fasted condition, and a two-period crossover, FOOD-EFFECT
substudy under both fasted and fed conditions. The PILOT portion of
the study (21 subjects) will include a single dose of TRM-201 in a
single group to assess the PK of TRM-201 in healthy volunteers
under fasted conditions. Following completion of the PILOT portion
and the decision to move forward, an additional 16 subjects will be
enrolled in the MAIN study and an additional 16 subjects will be
enrolled in the FOOD-EFFECT substudy. The MAIN study will include a
single dose of TRM-201 to assess the PK of TRM-201 in healthy
volunteers under fasted conditions. The FOOD-EFFECT substudy is a
single-dose, two-period crossover study. A single dose of TRM-201
will be given on Day 1 of each dosing period to assess the PK of
TRM-201 in healthy volunteers under both fasted and fed conditions.
Subjects will be randomized 1:1 into the two sequences fasted
followed by fed, and fed followed by fasted.
[0678] The PK data from MAIN study (including the PILOT portion)
will be combined with the PK data from the fasted portion of the
FOOD-EFFECT substudy to form the basis of the comparison to
historical pharmacokinetic parameters of previously marketed
rofecoxib. The PK data from the fed portion of the FOOD-EFFECT
substudy will only be compared with the PK data from the fasted
portion of the FOOD-EFFECT substudy.
PILOT Portion and MAIN Study
[0679] The subjects will be screened in the 28 days before
receiving the single dose of TRM-201. Subjects will check in to the
clinic on the day before dosing, and their eligibility will be
confirmed. Subjects will remain at the clinic from Check-In through
the completion of the end-of-study (EOS) visit on Day 6.
[0680] After Check-In, subjects will fast overnight for at least 10
hours before study drug administration. While fasting, subjects
will have nothing to eat and only water to drink. Water will be
permitted as desired, except for the period between 1 hour before
and 1 hour after study drug dosing (excepting as permitted for
dosing). After the 2-hour PK blood sample, subjects will be allowed
one 250-mL cup of clear apple juice. After the 4-hour PK blood
sample, subjects will be served a light lunch. Following the light
lunch, subjects should receive standardized meals according to the
clinic's standard procedures that are scheduled at consistent times
and at least 15 minutes before or 15 minutes after PK sampling time
points. Blood will be withdrawn for PK analysis at predefined time
points as defined in Table 8. The last time point will be 120 hours
after dosing with study drug. After the 120-hour PK sample, the EOS
procedures will be completed, and subjects will be discharged from
the clinic.
FOOD-EFFECT Substudy
[0681] The subjects will be screened in the 28 days before
receiving the single dose of TRM-201. Subjects will check in to the
clinic on the day before dosing, and their eligibility will be
confirmed. Subjects will remain at the clinic from Check-In through
the completion of the EOS visit on Day 13 of Dosing Period 2.
[0682] After Check-In, subjects will fast overnight for at least 10
hours before study drug administration. In the morning of the
dosing day of Period 1, subjects will be randomized in a 1:1 ratio
within each gender to one of two dosing sequences:
[0683] Dosing sequence fasted/fed (8 subjects)
[0684] Dosing sequence fed/fasted (8 subjects)
Regardless of the dosing sequence assigned, all subjects will
undergo the same assessments, pre- and post-dose.
Fasted Group
[0685] While participating in the fasted portion of the substudy,
subjects will fast overnight for at least 10 hours before study
drug dosing. While fasting, subjects will have nothing to eat and
only water to drink. Water will be permitted as desired, except for
the period between 1 hour before and 1 hour after study drug dosing
(excepting as permitted for dosing). After the 2-hour PK blood
sample, subjects will be allowed one 250-mL cup of clear apple
juice. After the 4-hour PK blood sample, subjects will be served a
light lunch. Following the light lunch, subjects should receive
standardized meals according to the clinic's standard procedures
that are scheduled at consistent times and at least 15 minutes
before or 15 minutes after PK sampling time points.
[0686] Blood will be withdrawn for PK analysis at predefined time
points. The last time point will be 120 hours after dosing with
study drug (Day 6). After the 120-hour PK sample, the EOP
procedures will be completed. Subjects will fast overnight on Day 7
of Dosing Period 1 for at least 10 hours and will commence with
Dosing Period 2 in a fed condition on Day 8.
Fed Group
[0687] While participating in the fed portion of the substudy,
subjects will fast overnight for at least 10 hours before study
drug dosing. While fasting, subjects will have nothing to eat and
only water to drink prior to being fed a high fat breakfast.
Subjects in the fed group will start the high fat breakfast
(defined per the FDA guidance as consisting of two eggs fried in
butter, two strips of bacon, two slices of toast with butter, four
ounces of hash brown potatoes and eight ounces of whole milk) 30
minutes prior to dosing with study drug. After the 4-hour PK blood
sample, subjects will be served a light lunch. Following the light
lunch, subjects should receive standardized meals according to the
clinic's standard procedures that are scheduled at consistent times
and at least 15 minutes before or 15 minutes after PK sampling time
points.
[0688] Blood will be withdrawn for PK analysis at predefined time
points as defined in Table 8. The last time point will be 120 hours
after dosing with study drug (Day 6). After the 120-hour PK sample,
the EOP procedures will be completed. Subjects will fast overnight
on Day 7 of Period 1 for at least 10 hours and will commence with
Dosing Period 2 in a fasted condition on Day 8.
[0689] The time between dosing in Period 1 and 2 is 7 days.
Subjects will complete Period 1 of the FOOD-EFFECT substudy on Day
6, but will remain in the clinic and subsequently be dosed on Day 8
to ensure a full 7-day washout of study drug between Periods 1 and
2.
[0690] The assessments and requirements of Dosing Period 2 are the
same as Dosing Period 1. All assessments done on Dosing Period
2/Day 1 should be done at approximately the same time of day as the
assessments of Dosing Period 1/Day 1.
[0691] A subject's participation in the study is complete after the
EOS visit of Period 2.
[0692] Pharmacokinetic and safety endpoints will be evaluated in
the study.
[0693] 2.1.1 Rationale of Study Design
[0694] A scientific bridge will be established between TRM-201 and
the previously marketed rofecoxib. Because there are presently no
FDA-approved rofecoxib products commercially available globally
with which to conduct a directly comparative
bioavailability/bioequivalence study, the present study is designed
to provide PK data for a cross-study comparison to a published
study (Schwartz, J. I., et al. Clin. Drug Invent. 2003, 23 (8):
503-509; hereafter "the Schwartz study").
[0695] The 25-mg dose of rofecoxib was selected for this study
because it is the anticipated maximum daily dose for the treatment
of HA. The data from the Schwartz study were chosen for comparison
because they represent PK data generated with the labeled version
of rofecoxib at 25 mg. The eligibility criteria for this current PK
study have been selected to mirror the subject demographics and
subgroups (gender, age, body mass index [BMI], race, and ethnicity)
in the Schwartz study.
[0696] The FOOD-EFFECT substudy is a standard 2-period crossover
study evaluating TRM-201 in the fasted and fed states.
[0697] A validated bioanalytical method for rofecoxib will be
developed and used for the PK analyses.
[0698] 3. Subject Selection and Withdrawal Criteria
[0699] 3.1 Selection of Study Population
[0700] A sufficient number of subjects will be screened to ensure
that at least 50 evaluable subjects complete the study.
[0701] In order to mirror the population of subjects in the
Schwartz PK study every effort will be made to enroll subjects in
the following proportion: White or European American (80%), Black
(20%). Of the White subjects enrolled, every effort will be made to
enroll approximately 60% of the subjects who identify themselves as
being of Hispanic or Latino ethnicity.
[0702] Subjects will be enrolled only if they meet all the
inclusion criteria and none of the exclusion criteria and all of
the continuing eligibility criteria. Deviations from the inclusion
and exclusion criteria are not allowed because they can potentially
jeopardize the scientific integrity of the study, regulatory
acceptability, or subject safety. Therefore, adherence to the
criteria as specified in the protocol is essential.
[0703] 3.1.1 Inclusion Criteria
[0704] Inclusion Criteria: [0705] 1. The subject is male or female
and is 18 to 60 years of age, inclusive, at Screening. Similar
numbers of male and female subjects should be enrolled. [0706] 2.
The subject has a BMI at Screening of 18 to 32 kg/m.sup.2,
inclusive, with a minimum weight of 47 kg for women and 66 kg for
men and a maximum weight of 80 kg for women and 90 kg for men.
[0707] 3. The subject is not a smoker (or user of e-cigarettes).
[0708] 4. The investigator considers the subject to be in good
general health as determined by medical history, clinical
laboratory test results, vital sign measurements, 12-lead ECG
results, and physical examination findings at Screening and
Check-in. [0709] 5. All female subjects must have a negative
pregnancy test at Screening. Female subjects of childbearing
potential must also have a negative pregnancy test at Check-in and
must be using an acceptable method of birth control during the
study (i.e., diaphragm with spermicide, intrauterine device, condom
with foam or vaginal spermicide, oral contraceptives, or
abstinence). Women who are surgically sterile (i.e., hysterectomy,
bilateral tubal ligation or bilateral oophorectomy), or
postmenopausal (defined as amenorrhea for 12 consecutive months and
documented serum follicle-stimulating hormone level >40 IU/mL)
are exempt from the adequate contraception requirement. [0710] 6.
The subject agrees to comply with all protocol requirements as well
as the particular requirements and specific Phase 1 unit policies.
[0711] 7. The subject provides written informed consent.
[0712] Exclusion Criteria: [0713] 1. The subject has a history of
relevant drug allergy or food allergy/sensitivity (e.g., allergy to
rofecoxib or excipients of TRM-201, allergy to other NSAIDs, or
gluten intolerance that could preclude consumption of a standard
clinic diet). [0714] 2. A female subject is pregnant or lactating.
[0715] 3. The subject has a history of intolerance or
hypersensitivity to aspirin or any other NSAID. [0716] 4. The
subject has a positive test result for hepatitis B surface antigen,
hepatitis C virus antibody, or human immunodeficiency virus types 1
or 2 antibodies at Screening. [0717] 5. The subject has used any
prescription (excluding hormonal birth control) or OTC medications
including NSAIDs (i.e., ibuprofen, naproxen, and aspirin) as well
as herbal or nutritional supplements, within 14 days before the
study drug dosing. Subjects may have taken acetaminophen (up to 2 g
per day) in the 14 days prior to study drug dosing. [0718] 6. The
subject has any clinically significant abnormalities before dosing
on Day 1 or has a history of disease, including: uncontrolled or
poorly controlled hypertension; asthma or pulmonary disease; major
cardiac ischemic symptoms, events, or interventions such as angina
pectoris, myocardial infarction, acute coronary syndrome,
decompensated congestive heart failure, coronary stent or bypass;
history of cerebrovascular ischemic events (transient ischemic
attack or stroke); major vascular ischemic symptoms such as
intermittent claudication or vascular bypass or replacement
surgery; significant cardiovascular, GI, neurological, endocrine,
or renal disease; hepatic impairment; cholecystectomy; other
condition known to interfere with the absorption, distribution,
metabolism, or excretion of drugs; or clinically significant GI
events. [0719] 7. The subject has a history or presence of any
clinically significant abnormality in vital signs, ECG, or
laboratory tests, or has any medical or psychiatric condition that,
in the opinion of the investigator, may interfere with the study
procedures or compromise subject safety (assessed at Screening and
Check-in). [0720] 8. The subject is a cigarette smoker or has used
nicotine or nicotine-containing products (e.g., snuff, nicotine
patch, nicotine chewing gum, e-cigarettes) within 6 months before
study drug dosing. [0721] 9. The subject has a history of alcohol
abuse or drug addiction within the last year or consumes more than
1 unit (1 unit is equal to approximately 1/2 pint [200 mL] of beer,
1 small glass [100 mL] of wine, or 1 measure [25 mL] of spirits) of
alcohol a day. Alcohol is not allowed within 7 days before study
drug dosing. [0722] 10. The subject has a positive test result for
drugs of abuse, alcohol, or cotinine (indicating active current
smoking) at Screening. [0723] 11. The subject is a habitual and
heavy coffee drinker (more than 4 cups a day, 28 cups a week).
[0724] 12. The subject is involved in strenuous activity or contact
sports within at least 24 hours before study drug dosing. [0725]
13. The subject has donated blood or blood products within at least
30 days before the dose of study drug in this study. [0726] 14. The
subject has received study drug in another investigational study
within at least 30 days (or less than 5 half-lives of the
investigational agent) prior to dosing in this study. [0727] 15.
The subject is not suitable for entry into the study, in the
opinion of the investigator. [0728] 16. The subject is an employee
or family member of the investigator or clinic staff.
[0729] Continuing Eligibility at Check-In [0730] Applies to Day -1
of the PILOT Portion, Day -1 of the MAIN Study and Day -1 of the
First Period of the FOOD-EFFECT Substudy: [0731] 1. Females must
have a negative serum pregnancy test. [0732] 2. All subjects must
have a negative test results for drugs of abuse and alcohol [0733]
3. Subjects must have had no significant changes in overall health
status since screening including the use of medications. [0734] 4.
The subject is involved in strenuous activity or contact sports
within at least 24 hours before study drug dosing.
[0735] Subjects with test results which do not meet the above
inclusion/exclusion criteria may have the relevant test repeated
once if it is thought to represent a laboratory error, a
reversible, clinically insignificant intermittent condition, or is
not consistent with the subject's historical values. If
inclusion/exclusion criteria are not met after the repeat test, the
subject should be considered a screen failure and should not be
enrolled in the study. Subjects may be retested once.
[0736] 3.2 Withdrawal/Discontinuation of Subjects from the
Study
[0737] The duration of the study is defined for each subject as the
date signed written informed consent is provided through the EOS
procedures. Participation in the study is scheduled for a maximum
duration of 34 days for each subject participating in the PILOT
portion or MAIN study (27 days for Screening, 1 day for Check-In
(Day -1), dosing on Day 1, PK blood sampling (Days 1-6), and the
EOS procedures on Day 6) and 41 days for subjects who participate
in the FOOD-EFFECT substudy. Period 1: 27 days for Screening, 1 day
for Check-In (Day -1), dosing on Day 1, PK blood sampling (Days
1-6), EOP on Day 6; Period 2: 1 additional day for study drug
washout (Day 7), dosing on Day 8, PK blood sampling (Days 9-13),
and the EOS procedures on Day 13).
[0738] 3.2.1 Reasons for Withdrawal/Discontinuation
[0739] Subjects may withdraw from the study at any time and for any
reason. Every effort should be made to keep subjects in the study.
The reasons for subjects not completing the study will be recorded.
A subject must be withdrawn/discontinued from the study for any of
the following reasons: [0740] 1. The subject tests positive for
pregnancy. [0741] 2. The subject withdraws consent to participate
in the study. [0742] 3. The subject does not continue to meet the
protocol inclusion or exclusion criteria. [0743] 4. The subject
experiences AEs or an AE that, in the investigator's opinion,
require(s) withdrawal from the study. [0744] 5. The subject is
noncompliant with the protocol. [0745] 6. The investigator decides
to withdraw the subject for any medical reason.
[0746] A subject will also be discontinued if the study is
terminated. Upon occurrence of a serious or intolerable AE, the
investigator will confer with the sponsor. If a subject is
discontinued because of an AE, the event will be followed until it
is resolved or considered clinically stable.
[0747] 3.2.2 Handling of Withdrawals/Discontinuations
[0748] Subjects are free to withdraw from the study at any time
upon request. Subject participation in the study may also be
stopped at any time.
[0749] Each subject in the PILOT portion and MAIN study is
scheduled to receive a single dose of study drug. Subjects who
participate in the FOOD-EFFECT substudy will receive a single dose
of study drug twice, once in a fasted condition and once in a fed
condition. When a subject withdraws from the PILOT portion, MAIN
study, or FOOD-EFFECT substudy, the reason(s) for withdrawal shall
be recorded by the investigator on the relevant page of the
electronic case report form (eCRF). Whenever possible, any subject
who receives a dose of study drug and then withdraws from the study
prematurely will undergo all EOS assessments scheduled for Day 6
(Table 13).
[0750] It is vital to obtain follow-up data on any subject
discontinued because of an AE or serious AE (SAE). In every case,
efforts must be made to undertake protocol-specified, safety,
follow-up procedures.
[0751] 3.2.3 Subject Replacement
[0752] The intent is that subjects will not be replaced unless it
is deemed that a critical number of subjects are not evaluable.
[0753] 4. Study Drug
[0754] This is an open-label PK study. Each subject is scheduled to
receive a single 25-mg dose of TRM-201 in the PILOT portion and the
MAIN study, and a single 25-mg dose of TRM-201 twice in the
FOOD-EFFECT substudy. TRM-201 manufactured and formulated as Batch
5 (B18090) and Batch 6 (B18091), above, will be used in the
study.
[0755] 4.1 Administration of Study Drug
[0756] Study drug will be co-administered orally with approximately
250 mL of room temperature water, and up to an additional 250 mL of
water will be allowed, if necessary, to aid in swallowing the study
drug. Study staff will ensure that at least 250 ml of water is
consumed with the dose of study drug and will perform a hand and
mouth check after dosing to ensure the tablet has been
swallowed.
PILOT Portion and MAIN Study
[0757] After fasting for at least 10 hours overnight (Table 13),
subjects will take, a single dose (1 tablet) of TRM-201 on the
morning of Day 1 administered as described above, supervised by
clinic staff. A hand and mouth check will be performed after dosing
to ensure the tablet has been swallowed. During the period between
1 hour before and 1 hour after study drug dosing, subjects may
drink only the water permitted for study drug administration.
FOOD-EFFECT Substudy
[0758] Subjects will be randomized 1:1 into the two sequences:
fasted followed by fed, and fed followed by fasted. During the
fasted period, subjects will fast and be administered a single dose
of TRM-201 as described above. A hand and mouth check will be
performed after dosing to ensure the tablet has been swallowed.
During the period between 1 hour before and 1 hour after study drug
dosing, subjects may drink only the water permitted for study drug
administration.
[0759] During the fed period, subjects will fast overnight for at
least 10 hours and will take a single dose (1 tablet) of TRM-201 as
described above within at least 30 minutes of starting a high fat
breakfast. A hand and mouth check will be performed after dosing to
ensure the tablet has been swallowed. During the period between 1
hour before and 1 hour after study drug dosing, subjects may drink
only the water permitted for study drug administration.
[0760] 4.2 Identity of Study Drug
[0761] The study drug, TRM-201, is an immediate-release tablet that
contains 25-mg rofecoxib. The 7.25-mm diameter tablets are
off-white, round, and uncoated with no markings. TRM-201 tablets
are for oral administration.
[0762] TRM-201 tablets contain the active ingredient rofecoxib (25
mg) and inactive excipients. Each tablet contains the following
inactive excipients: croscarmellose sodium, hydroxypropyl
cellulose, lactose, magnesium stearate, microcrystalline cellulose,
and yellow ferric oxide. All excipients comply with standards
described in United States Pharmacopeia-National Formulary,
European Pharmacopeia, and Japanese Pharmacopeia.
[0763] 4.3 Management of Clinical Supplies
[0764] 4.3.1 Study Drug Packaging and Storage
[0765] TRM-201 oral tablets will be provided as bulk supply in
high-density polyethylene bottles. All packaging and labeling will
be performed according to Good Manufacturing Practice and Good
Clinical Practice (GCP) rules. The lot number and date of
manufacture for the clinical lot used in the study will be provided
to the clinical site and will be reported in the Clinical Study
Report. All study drug will be labeled with:
[0766] Protocol number
[0767] Sponsor's name and address
[0768] Investigational New Drug statement
[0769] Instructions for use and storage
[0770] All study drug must be stored at 20 to 25.degree. C.
(excursions permitted in the range of 15 to 30.degree. C.), in
accordance with the labeled instructions, in a secure cabinet or
room with access restricted to necessary clinic personnel. The site
will keep a temperature log to establish a record of compliance
with storage conditions.
[0771] The clinical unit pharmacy will prepare the dosing for each
subject according to the schedule of events (Table 13).
[0772] 4.3.2 Study Drug Accountability
[0773] The investigator will maintain accurate records of receipt
of all study drug, including dates of receipt. In addition,
accurate records will be kept regarding when and how much study
drug is dispensed and used by each subject in the study. Reasons
for departure from the expected dispensing regimen must also be
recorded on standard clinic drug accountability and packaging
forms. At the completion of the study, to satisfy regulatory
requirements regarding drug accountability, all study drug will be
reconciled and retained or destroyed according to applicable
regulations.
[0774] 4.4 Method of Assigning Subjects to Treatment
[0775] In the PILOT portion, subjects who meet all inclusion
criteria and none of the exclusion criteria and all of the
continuing eligibility criteria will receive TRM-201 according to
the schedule of events (Table 13). Similar numbers of male and
female subjects should be enrolled. Additional subjects may be
screened to attain the overall demographic parameters of the
subjects enrolled in the Schwartz PK study.
[0776] Once a decision to continue is made after the PILOT portion
is completed, subjects will be screened to enter the MAIN study or
the FOOD-EFFECT substudy. In the MAIN study and FOOD-EFFECT
substudy, subjects who meet all of the inclusion criteria and none
of the exclusion criteria and all of the continuing eligibility
criteria will receive TRM-201 according to the schedule of events
(Table 13).
[0777] Similar numbers of male and female subjects should be
enrolled. Additional subjects may be screened to attain the overall
demographic parameters of the subjects enrolled in the Schwartz PK
study.
[0778] Subjects will be randomized in a 2:1:1 ratio to one of three
groups:
[0779] Main study--fasted (16 subjects)
[0780] FOOD-EFFECT substudy--fasted/fed sequence (8 subjects)
[0781] FOOD-EFFECT substudy--fed/fasted sequence (8 subjects)
[0782] 4.5 Blinding
[0783] This is an open-label study: there is no blinding of study
drug.
[0784] 4.6 Treatment Compliance
[0785] All doses of study drug will be administered in the clinic
under direct observation of clinic staff and will be recorded in
the eCRF. Clinic staff will confirm that the subject has swallowed
the dose of study drug.
[0786] The date and time of study drug dosing will be recorded on
the appropriate page of the eCRF.
[0787] 4.7 Prior and Concomitant Therapy
[0788] The investigator or designee must record the use of prior
medications (all medication taken within at least 28 days before
Screening) and concomitant therapy (including both drug and nondrug
therapies and all prescribed, OTC, and alternative medicines) in
the eCRF. This includes drugs that are used as-needed. Any changes
in concomitant medications will also be recorded in the subject's
eCRF. The minimum requirement is that the drug name and dates of
dosing are to be recorded.
[0789] Use of prescription medications (excluding hormonal birth
control) and OTC medications (except acetaminophen), including
NSAIDs (i.e., ibuprofen, naproxen, and aspirin) as well as herbal
or nutritional supplements (exclusion criterion 5), is prohibited
from 14 days before study drug dosing through the EOS. Use of
acetaminophen is prohibited from Check-In through the EOS.
Violation of these prohibitions will result in the subject's
discontinuation from the study.
[0790] 5. Study Procedures, Assessments, and Endpoints
[0791] Before performing any study procedures, all potential
subjects will sign an informed consent form (ICF). Subjects will
have the opportunity to have any questions answered before signing
the ICF. The investigator must address all questions raised by the
subject. The investigator or designee will also sign the ICF.
[0792] The schedule of events for the study is presented in Table
13. The ECG recordings must precede blood sampling for PK
assessments at the specified time points on Day 1 and at the EOS
visit, and PK blood sampling must occur within the sampling
windows. Timings of PK blood sampling and ECG assessments will be
calculated from time `0`, the time of study drug dosing on Day 1
and complete on Day 6 at the 120 hour PK sample draw and from time
`0`, the time of study drug dosing on Day 8 and complete on Day 13
for subjects who participate in the FOOD-EFFECT substudy.
TABLE-US-00014 TABLE 13 Schedule of Events Phase Period-2 Screening
Check-in Pharmacokinetic Sampling EOP/EOSg Subjects Only Day -28 to
-2 -1 1 2 3 4 5 6 7 Period-2 Days 8 9 10 11 12 13 Informed consent
X Demographics X Medical history X X Viral serology X Serum
follicle-stimulating hormone X (females only) Admission to clinic X
Serum pregnancy test (females only) X X X Urine drug screen
(including alcohol X X and cotinine) Clinical laboratory testing
(blood/urine) X X X Height, weight, and body mass index X weight
weight ONLY ONLY Physical examination.sup.a X X X (EOS ONLY) Vital
sign measurements.sup.b X X X X X X X X 12-Lead ECG
assessment.sup.c X X X X (EOS ONLY) Eligibility assessment (initial
and X X continuing) PILOT, MAIN STUDY and fasted- X X X X X X X X
period meal scheduled.sup.i Study drug administration.sup.e X
FOOD-EFFECT fed-period meal X X X X X X X X schedule.sup.f
Pharmacokinetic sample collection (see X X X X X Table 8) Adverse
event assessment X X X X X X Prior or concomitant medication X X X
X X X X assessment Discharge from clinic X (EOS ONLY)
Abbreviations: ECG, electrocardiogram; EOS, end of study; EOP, end
of period. Note: The order of procedures on each day should follow
the order of presentation in Table 13 (top to bottom). When
procedures overlap or occur at the same time point, all blood
sampling should follow vital signs or ECGs, and PK sampling should
be timed to occur last and as close to the scheduled time window as
possible. Timings of PK blood sampling and electrocardiogram
assessments will be calculated from time "0", the time of study
drug dosing. Period-2 subjects will remain in the clinic and be
dosed on Day 8, 2 days after EOP. .sup.aA full physical examination
will be performed at Screening (at minimum, assessment of skin,
head, ears, eyes, nose, throat, neck, thyroid, lungs, heart,
cardiovascular, abdomen, lymph nodes, and musculoskeletal
system/extremities). A brief physical examination will be performed
at Check-In and EOS (at minimum, assessment of skin, lungs,
cardiovascular system, and abdomen). Interim physical examinations
may be performed at the discretion of the investigator, if
necessary, to evaluate adverse events or clinical laboratory
abnormalities. .sup.bVital signs will include systolic and
diastolic blood pressure, pulse rate, respiratory rate, and oral
body temperature, after the subject has been seated for at least 5
minutes. On Day 1 (and Day 8 of FOOD-EFFECT study), vital signs
will be measured within 120 minutes before study drug dosing and at
the 2-hour, 3-hour and 7.5-hour time points. At these time points
(2 h, 3 h and 7.5 h) only systolic and diastolic blood pressure,
pulse rate and respiratory rate will be assessed. On Days 2 through
6, vital signs will be assessed within 15 minutes before the first
PK blood sample of the day. See Note. .sup.cAfter the subject has
been in the supine position for at least 5 minutes, single 12-lead
ECG recordings will be taken at Screening, Check-in, the 2-hour and
3-hour time point, and EOS. .sup.d For all portions of the study
the fasting period will begin at the day of Check-In, for at least
10 hours overnight before study drug administration and again on
Day 7 for the FOOD-EFFECT study. .sup.eStudy drug will be
administered after vital sign measurements have been completed.
Study drug will be administered with ~250 mL of room temperature
water. Up to an additional ~250 mL of water will be allowed, if
necessary, to aid in swallowing the study drug. Subjects will
maintain an upright position (seated or standing) for at least 4
hours after dosing. Dosing for Period-2 subjects must occur at
least 7 days after Period-1 dosing. .sup.fFOOD-EFFECT substudy -
fed portion: Subjects will fast at least 10 hours overnight. In the
morning prior to study drug administration they will be given a
high-fat breakfast to begin at least 30 minutes prior to dosing.
After the 4-hour PK blood sampling, Subjects should then receive
standardized meals according to the clinic's standard procedures
and scheduled at consistent times. Meal may begin immediately after
a PK timepoint and should end at least 15 minutes before a PK
sampling time point. gFor subjects in the FOOD-EFFECT substudy -
this visit is considered the end of the period (EOP) for Dosing
Period 1 and EOS after Dosing Period 2.
[0793] 5.1 Pharmacokinetic Procedures, Assessments, and
Endpoints
[0794] The time points and windows for PK blood sampling for the
PILOT portion, Main study and FOOD-EFFECT substudy are presented in
Table 14 below. For each sample, approximately 3 mL of blood will
be drawn. The samples may be obtained by a straight stick or via an
in-dwelling intravenous (IV) catheter in a forearm vein. Additional
details for the collection, processing, storage, and shipping of PK
samples will be provided in the study manual.
TABLE-US-00015 TABLE 14 Times and Windows for Pharmacokinetic Blood
Sampling for PILOT portion, Main Study and FOOD-EFFECT substudy
Unit of Time Minutes Hours Timepoint 0.sup.a 15 30 45 1 1.5 2 3 4 5
6 7.5 9 12 15 18 Window (min) .+-.5 min .+-.10 min .+-.15 min
.+-.30 min Unit of Time Hours Timepoint 21 24 27 30 33 36 39 42 48
52 60 72 96 120 Window (min) .+-.30 min .+-.60 min Abbreviation:
min; minutes. .sup.aThe blood sample for time 0 should be taken
within 1 hour before dosing with study drug, and prior to breakfast
in the fed-state period. Note - Samples will be collected after
each rofecoxib dose in the food-effect substudy
[0795] Pharmacokinetic samples will be analyzed using a validated
assay for rofecoxib in human plasma. Assay results and validation
details will be provided in a separate bioanalytical report.
[0796] The following PK parameters for rofecoxib will be calculated
as primary endpoints using standard noncompartmental methods for
both the PILOT portion and MAIN study, and the FOOD-EFFECT
substudy: AUC.sub.0-.infin. and Cmax. Secondary endpoints include
Tmax, and t.sub.1/2. Additional PK parameters (e.g., CL/F, and
V.sub.d/F) will also be calculated using standard noncompartmental
methods.
[0797] 5.2 Safety Assessments
[0798] The timing and frequency of all safety assessments is listed
in the schedule of events (Table 13).
[0799] Safety and tolerability will include monitoring and
recording of AEs, clinical laboratory assessments (hematology,
serum chemistry, and urinalysis), vital sign measurements, 12-lead
ECG assessments, and physical examination findings.
[0800] For all safety assessments, the investigator will determine
whether results are clinically significant, which is defined as any
variation in a result that has medical relevance and may result in
an alteration in medical care (e.g., active observation, diagnostic
measures, or therapeutic measures). If clinical significance is
noted, the result and reason for significance will be documented on
the AE page of the subject's eCRF and the investigator will monitor
the subject until the result has reached the reference range or the
result at Screening, or until the investigator determines that
follow-up is no longer medically necessary.
[0801] Any abnormal laboratory test results (hematology, clinical
chemistry, or urinalysis) or other safety assessments (e.g., ECGs,
vital sign measurements), including those that worsen from
baseline, felt to be clinically significant in the medical and
scientific judgment of the investigator are to be recorded as AEs
or SAEs.
[0802] 5.2.1 Adverse Events
[0803] 5.2.1.1 Definitions of Adverse Events
[0804] The investigator is responsible for reporting all AEs that
are observed or reported during the study, regardless of their
relationship to study drug or their clinical significance. If there
is any doubt as to whether a clinical observation is an AE, the
event should be reported.
[0805] An AE is defined as any untoward medical occurrence in a
subject enrolled into this study regardless of its causal
relationship to study drug. Subjects will be instructed to contact
the investigator at any time after enrollment if any symptoms
develop.
[0806] A treatment-emergent AE (TEAE) is defined as any event not
present before exposure to study drug or any event already present
that worsens in either intensity or frequency after exposure to
study drug.
[0807] 5.2.1 Serious Adverse Events
[0808] An SAE is defined as any event that
[0809] results in death
[0810] is immediately life threatening
[0811] requires inpatient hospitalization or prolongation of
existing hospitalization
[0812] results in persistent or significant
disability/incapacity
[0813] is a congenital anomaly/birth defect
[0814] Important medical events that may not result in death, be
life threatening, or require hospitalization may be considered SAEs
when, based upon appropriate medical judgment, they may jeopardize
the subject or may require medical or surgical intervention to
prevent one of the outcomes listed in this definition. Examples of
such medical events include allergic bronchospasm requiring
intensive treatment in an emergency room or at home, blood
dyscrasias or convulsions that do not result in inpatient
hospitalization, or the development of drug dependency or drug
abuse.
[0815] 5.2.1.3 Eliciting and Documenting Adverse Events
[0816] Adverse events will be assessed from the time of study drug
dosing until all EOS procedures are complete.
[0817] Subjects will be asked a standard nonleading question to
elicit any medically related changes in their well-being.
[0818] In addition to subject observations, AEs identified from any
study data (e.g., laboratory values, physical examination findings,
ECG changes) or identified from review of other documents that are
relevant to subject safety will be documented on the AE page in the
eCRF.
[0819] 5.2.1.4 Reporting Adverse Events
[0820] All AEs reported or observed during the study will be
recorded on the AE page in the eCRF. Information to be collected
includes the following:
[0821] event term
[0822] time of onset
[0823] investigator-specified assessment of severity and
relationship to study drug
[0824] time of resolution of the event
[0825] seriousness
[0826] any required treatment or evaluations
[0827] outcome
[0828] All AEs will be followed to adequate resolution. The Medical
Dictionary for Regulatory Activities (MedDRA; Version 21.1) will be
used to code all AEs.
[0829] 5.2.1.5 Reporting Serious Adverse Events
[0830] Any AE that is considered serious by the investigator or
which meets SAE criteria must be reported to the medical monitor
(i.e., within at least 24 hours) after the clinic staff first learn
about the event. The investigator will assess whether there is a
reasonable possibility that the study drug caused the SAE.
[0831] 5.2.1.6 Suspected Unexpected Serious Adverse Reactions
[0832] The sponsor will promptly evaluate all suspected unexpected
serious adverse reactions (SUSARs) against cumulative product
experience to identify and expeditiously communicate possible new
safety findings to the investigator, IRB, and applicable health
authorities based on applicable legislation.
[0833] To determine reporting requirements for single AE cases, the
sponsor will assess the expectedness of these events using the
TRM-201 investigator's brochure. The sponsor will compare the
severity of each SUSAR, and the cumulative event frequency reported
for the study with the severity and frequency reported in the
TRM-201 investigator's brochure.
[0834] Reporting requirements will also be based on the
investigator's assessment of causality and seriousness, with
allowance for upgrading by the sponsor as needed.
[0835] 5.2.1.7 Assessment of Severity
[0836] The severity, or intensity, of an AE refers to the extent to
which an AE affects the subject's daily activities. The intensity
of the AE will be rated as mild, moderate, or severe using the
following criteria: [0837] Mild: These events require minimal or no
treatment and do not interfere with the subject's daily activities.
[0838] Moderate: These events result in a low level of
inconvenience or require minor therapeutic measures. Moderate
events may cause some interference with normal functioning. [0839]
Severe: These events interrupt a subject's usual daily activity and
may require systemic drug therapy or other treatment. Severe events
are usually incapacitating.
[0840] Changes in the severity of an AE should be documented to
allow an assessment of the duration of the event at each level of
intensity to be performed. Adverse events characterized as
intermittent do not require documentation of onset and duration of
each episode.
[0841] 5.2.1.8 Assessment of Causality
[0842] The investigator's assessment of an AE's relationship to
study drug is part of the documentation process, but it is not a
factor in determining what is or is not reported in the study.
[0843] The investigator will assess causality (i.e., whether there
is a reasonable possibility that the study drug caused the event)
for all AEs and SAEs. The relationship will be classified as
follows: [0844] Not related: There is not a reasonable possibility
of relationship to study drug. The AE does not follow a reasonable
temporal sequence from study drug administration, or can be
reasonably explained by the subject's clinical state or other
factors (e.g., disease under study, concurrent diseases, and
concomitant medications). [0845] Related: There is a reasonable
possibility of relationship to study drug. The AE follows a
reasonable temporal sequence from study drug administration and
cannot be reasonably explained by the subject's clinical state or
other factors (e.g., disease under study, concurrent diseases, or
concomitant medications), represents a known reaction to the study
drug or other drugs in its class, is consistent with the known
pharmacological properties of the study drug (and/or recurs with
re-challenge, if applicable).
[0846] 5.2.1.9 Follow-Up of Subjects Reporting Adverse Events
[0847] All AEs must be reported in detail on the appropriate page
in the eCRF and followed to satisfactory resolution, until the
investigator deems the event to be chronic or not clinically
significant, or until the subject is considered stable.
[0848] 5.2.2 Clinical Laboratory Assessments
[0849] The following clinical laboratory assessments will be
performed:
[0850] Hematology: hematocrit, hemoglobin, mean corpuscular
hemoglobin, mean corpuscular hemoglobin concentration, mean
corpuscular volume, platelet count, red blood cell count, and total
and differential leukocyte count
[0851] Serum Chemistry: Alanine aminotransferase, albumin, alkaline
phosphatase, aspartate aminotransferase, bilirubin (total), blood
urea nitrogen, calcium, carbon dioxide, chloride, total
cholesterol, creatine phosphokinase, creatinine,
gamma-glutamyltransferase, globulin, glucose, lactate
dehydrogenase, phosphorus, potassium, sodium, total protein,
triglycerides, and uric acid
[0852] Urinalysis: Appearance, bilirubin, color, glucose, ketones,
leukocyte esterase, reflex microscopy (performed if dipstick is
positive for protein or the blood value is 1+ or greater; and
includes bacteria, casts, crystals, epithelial cells, red blood
cells, and white blood cells), nitrites, occult blood, pH, protein,
specific gravity, turbidity, and urobilinogen
[0853] Serology: Hepatitis B surface antigen, hepatitis C virus
antibody, and human immunodeficiency virus antibody types 1 and 2
(Screening only)
[0854] Other analyses: All subjects: Urine drug screen (alcohol,
amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine,
cotinine, methylenedioxymethamphetamine, opiates, phencyclidine,
propoxyphene, and tetrahydrocannabinol) Female subjects: serum
Follicle-stimulating hormone, serum and urine .beta.-human
chorionic gonadotropin.
[0855] The clinical laboratory that performs the tests will provide
the reference ranges for all clinical laboratory parameters.
Clinical laboratory tests may be repeated at the discretion of the
investigator, if necessary, for assessment of inclusion and
exclusion criteria or evaluation of clinical laboratory
abnormalities.
[0856] 5.2.3 Vital Sign Measurements
[0857] Vital signs will include systolic and diastolic blood
pressure, pulse rate, respiratory rate, and oral body temperature,
after the subject has been seated for at least 5 minutes. Vital
sign measurements will be conducted within the 120 minutes before
dosing of study drug (applicable on Day 1 only) and 15 minutes
before any blood sampling. A single repeat measurement is permitted
at Screening to determine eligibility and Check-In to confirm
continued eligibility. On Day 1 and Day 8 (Dosing Period 2 of
FOOD-EFFECT study) systolic and diastolic blood pressure, pulse
rate and respiratory rate will be assessed at the 2-hour, 3-hour
and 7.5 hour time points.
[0858] 5.2.4 Electrocardiogram Assessments
[0859] After the subject has been in the supine position for at
least 5 minutes, single 12-lead ECG recordings will be made at
Screening, Check-in, the 2-hour and 3-hour time points, and EOS. A
single repeat measurement is permitted at Screening to determine
eligibility and at Check-In to confirm continued eligibility.
Measurements of the following intervals will be reported: RR
interval, PR interval, QRS width, QT interval, and QTcF and may be
interpreted for abnormality by the ECG machine. Any abnormalities
including rhythm; presence of arrhythmia or conduction defects;
morphology; any evidence of myocardial infarction; or ST-segment,
T-Wave, and U-Wave abnormalities should be assessed for clinical
significance and noted.
[0860] 5.3 Pregnancy
[0861] Pregnancy is not regarded as an AE unless there is a
suspicion that an investigational product may have interfered with
the effectiveness of a contraceptive medication. Any pregnancy that
is detected after study drug administration and during study
participation must be reported using the same procedures as an SAE,
but using a clinical study pregnancy form. The pregnancy must be
followed up (with the subject's consent) to determine outcome
(including spontaneous miscarriage, elective termination, normal
birth, or congenital abnormality) and status of mother and child,
even if the subject was discontinued from the study. Pregnancy
complications and elective terminations for medical reasons should
not be reported as an AE or SAE. Spontaneous miscarriages must be
reported as an SAE.
[0862] Any SAE occurring in association with a pregnancy, brought
to the investigator's attention after the subject has completed the
study, and considered by the investigator as possibly related to
the study treatment, must be promptly reported to the Sponsor.
[0863] 5.3.1 Physical Examination Findings
[0864] A full physical examination will be performed at Screening
(at minimum, assessment of skin, head, ears, eyes, nose, throat,
neck, thyroid, lungs, heart, cardiovascular, abdomen, lymph nodes,
and musculoskeletal system/extremities). A brief physical
examination will be performed at Check-In and at the EOS. At a
minimum, assessment of skin, lungs, cardiovascular system, and
abdomen will be performed. Interim physical examinations may be
performed at the discretion of the investigator, if necessary, to
evaluate AEs or clinical laboratory abnormalities. 5.4 Sample
Collections
[0865] The total amount of blood collected from each subject over
the duration of the study is expected to be approximately 130 mL
(PK samples: 90 mL, clinical laboratory samples: 40 mL) for
subjects participating in the PILOT portion and MAIN study and
approximately 220 mL (PK samples: 180 mL, clinical laboratory
samples: 40 mL) for subjects participating in the FOOD-EFFECT
study. Additional assessments may be required, but the maximum
amount of blood drawn for any subject will not exceed 250 mL.
[0866] 6. Statistical and Analytical Plan
[0867] The interim analysis of the PILOT portion is only for
futility; hence, there is no impact of that interim analysis on the
type-1 error potential for the final analyses (all fasted data from
PILOT portion, MAIN study, and the FOOD-EFFECT substudy
combined).
[0868] 6.1 Sample Size Calculations
[0869] 6.2 Comparability of TRM-201 with Previously Marketed
Rofecoxib
[0870] Consistent with the Schwartz study, the total sample size of
50 evaluable subjects is considered sufficient for the objectives
of the study. Back-calculation of summary statistics from the
Schwartz data yielded natural-log-scale SDs of 0.33 and 0.31 for
AUC.sub.0-.infin. and Cmax, respectively. Power is computed as the
probability that the upper limit of a 90% CI for the geometric mean
ratio (GMR=observed geometric mean from this trial divided by the
historical control value) for these parameters falls below 1.25.
Assuming a natural-log-scale SD equal to 0.33, N=50 has approx. 80%
power if the TRUE underlying geometric mean ratio (GMR)=1.11, and
approximately 90% power if the TRUE underlying GMR=1.08. The
maximum OBSERVED GMR that would reject the null hypothesis is 1.15.
The power for C.sub.max is slightly greater since associated SD is
smaller than that for AUC.sub.0-.infin.; however, for perspective
on actual values for the new formulation, Table 15 shows
AUC.sub.0-.infin. and C.sub.max geometric mean values associated
with the ratios computed from SD=0.33.
TABLE-US-00016 TABLE 15 Power Estimates for Comparability between
TRM-201 and Previously Marketed Rofecoxib Geometric Mean Ratios
Maximum OBS. Fold-Incr for 1.15.sup.a Comparability TRUE Fold-Incr.
for ~80% power 1.11.sup.a TRUE Fold-Incr. for ~90% power 1.08.sup.a
Historical mean 1.25 Times PK Geometric value from the the
historical Parameter Parameter Means Schwartz study mean value
C.sub.max Max. OBS. Geo. Mean for 250 217 C.sub.max 25 mg 271
Comparability TRUE Geo. Mean for ~80% power 241 217 271 TRUE Geo.
Mean for ~90% power 234 217 271 AUC.sub.0-.infin. Max. OBS. Geo.
Mean for 4369 3799 AUC.sub.0-.infin. 25 mg 4749 Comparability TRUE
Geo. Mean for ~80% power 4217 3799 4749 TRUE Geo. Mean for ~90%
power 4103 3799 4749 C.sub.max Max. OBS. Geo. Mean for 281 244
C.sub.max 12.5 mg 305 Comparability dose-adjusted TRUE Geo. Mean
for ~80% power 271 244 to 25 mg 305 TRUE Geo. Mean for ~90% power
264 244 305 Abbreviations: Geo. Mean, geometric mean; Incr,
increase; Max., maximum; OBS., observed. .sup.aFold-increase
expressed relative to the historical mean value
[0871] 6.1.2 Comparison of TRM-201 Under Fed and Fasted
Conditions
[0872] There are not pre-specified bounds for the fed/fasted GMR's
for AUC and Cmax derived from the FOOD-EFFECT substudy. However,
those GMR's and associated 90% CI's will be derived from the
2-period crossover model to estimate the food effect. Koytchev, et
al. reported data from which intra-subject SD's for AUC and Cmax
were back-calculated as 0.11 and 0.14 on the natural-log-scale,
respectively (Koytchev, R. et al., Arzneimittelforschung, 2004,
54(9), 624-628). Conservatively, using the value 0.15 for natural
log-scale within-subject SD, Table 16 below indicates 90% CI's for
GMR, back-transformed from the natural-log calculation scale via a
standard crossover design ANOVA.
TABLE-US-00017 TABLE 16 Power estimates for FOOD-EFFECT Substudy
OBSERVED N = 12 N = 15 GMR 90% LCL 90% UCL 90% LCL 90% UCL 0.5 0.45
0.56 0.45 0.55 0.67 0.60 0.75 0.61 0.74 0.8 0.72 0.89 0.73 0.88 1
0.89 1.12 0.91 1.10 1.25 1.12 1.40 1.13 1.38 1.5 1.34 1.68 1.36
1.65 2 1.79 2.23 1.82 2.20 NOTE: calculations via standard 2-period
crossover design ANOVA assuming natural-log-scale SD = 0.15
[0873] 6.2 Analysis Sets
[0874] The following analysis sets will be used in the statistical
analyses:
[0875] The PK analysis set will include subjects who receive a
single dose of TRM-201 and have sufficient concentration data to
support accurate estimation of at least one PK parameter. Subjects
who experience vomiting within at least 2 times the median Tmax
(approximately 6 hours) after study drug dosing will be excluded
from the PK analysis.
[0876] The PK data from Main study (including the PILOT portion)
will be combined with the PK data from the fasted portion of the
FOOD-EFFECT substudy to form the basis of the comparison to
historical pharmacokinetic parameters of previously marketed
rofecoxib. The PK data from the fed portion of the FOOD-EFFECT
substudy will only be compared with the PK data from the fasted
portion of the FOOD-EFFECT substudy.
[0877] The safety analysis set will include all subjects who
receive at least 1 dose of study drug.
[0878] 6.3 Description of Subgroups to be Analyzed
[0879] The relationship of AUC.sub.0-.infin. and C.sub.max to age
and to BMI will each be assessed via scatter plots and correlation
coefficients. If appropriate, additional modeling of those
relationships may be carried out. Summary statistics for
AUC.sub.0-.infin. and C.sub.max will be provide by gender, age
categories (divided into tertiles), race categories, and ethnicity
categories.
[0880] 6.4 Statistical Analysis Methodology
[0881] Details of all statistical analyses will be described in a
separate statistical analysis plan. All data collected will be
presented in data listings. Data from subjects excluded from an
analysis population will be presented in the data listings but will
not be included in the calculation of summary statistics or
statistical analysis.
[0882] For categorical variables, frequencies and percentages will
be presented. Continuous variables will be summarized using
descriptive statistics (number of subjects, mean, median, SD,
minimum, maximum, geometric mean, natural-log-scale SD).
[0883] Baseline demographic and background variables will be
summarized overall for all subjects. The number of subjects who
enroll in the study and the number and percentage of subjects who
complete the study will be presented. Frequency and percentage of
subjects who withdraw or discontinue from the study, and the reason
for withdrawal or discontinuation, will also be summarized.
Statistical analysis will be performed using SAS software Version
9.4 or later. Continuous variables will be summarized using the
mean, the standard deviation, median, minimum value, and maximum
value. Categorical variables will be summarized using frequency
counts and percentages. Data will be listed in data listings.
[0884] 6.4.1 Analysis of Pharmacokinetic Endpoints
[0885] Individual plasma concentrations for rofecoxib and PK
sampling time deviation data will be presented in a data listing.
Plasma concentration data will be summarized by time point using
the following descriptive statistics: number of subjects,
arithmetic mean, SD, coefficient of variation (CV), geometric mean,
natural-log-scale SD, geometric CV, median, minimum, and maximum.
Individual plasma concentration versus actual time profiles will be
presented on both linear and semilogarithmic scales. Additionally,
arithmetic mean concentration versus scheduled time profiles will
be presented on linear scales and geometric means on
semilogarithmic scales.
[0886] The PK parameters of rofecoxib will be analyzed based on the
actual sampling times. All parameters will be calculated using the
Phoenix.RTM. WinNonlin.RTM. version 6.4 or higher (Certara USA
Inc., Princeton, N.J.) or SAS.RTM. version 9.3 or higher (SAS
Institute Inc., Cary, N.C.). The individual PK parameters will be
presented in data listings.
[0887] 6.4.1.1 PILOT Portion, MAIN Study and FOOD-EFFECT
Substudy
[0888] Summary statistics for the primary PK endpoints,
AUC.sub.0-.infin. and Cmax, will include n, arithmetic mean, CV,
SD, geometric mean, natural-log-scale SD, median, minimum, and
maximum, along with the associated 90% CI computed on the
natural-log-scale and back-transformed to the original measurement
scale. The GMR to historical control values and associated 90% CIs
will be computed on log scale and back-transformed to the ratio
scale; the reference values are from the Schwartz study: 3799
nghr/mL and 217 ng/mL for AUC.sub.0-.infin. and Cmax,
respectively.
[0889] Without being bound by theory, the primary hypotheses for
both AUC.sub.0-.infin. and C.sub.max are: [0890] Null Hypothesis:
the TRUE underlying GMR (new formulation versus historical control)
is at least 1.25 [0891] Alternative Hypothesis: the TRUE underlying
GMR (new formulation versus historical control) is less than
1.25
[0892] These null hypotheses will each be tested via comparing to
1.25 the upper limit of a 90% CI for the geometric mean computed on
the natural-log-scale and back-transformed to the original scale.
If the upper 90% CI lies below 1.25 times the historical control
geometric mean value, the null hypothesis will be rejected, and the
alternative hypothesis will be concluded. The AUC.sub.0-.infin. and
C.sub.max null hypotheses need to be rejected to support a
conclusion that the new formulation is sufficiently similar to the
formulation that yielded the historical control data.
[0893] Sensitivity analyses will be carried out separately for
AUC.sub.0-.infin. and C.sub.max using age- and race-adjusted
geometric means that match the mean age and race distribution of
the historical control data. Secondary analyses similar to the
primary will be carried out in comparison to a lower limit of 0.8
times the respective historical control values.
[0894] The T.sub.max will be summarized by n, arithmetic mean, CV,
SD, median, minimum, maximum, and 90% CI for the median via normal
approximation. Apparent t.sub.1/2 will be summarized by n,
arithmetic mean, CV, SD, harmonic mean, jack-knife SD, median,
minimum, and maximum. The 90% CI for harmonic mean will be computed
on the inverse scale and back-transformed to the actual scale. The
90% CIs for median T.sub.max and harmonic mean t.sub.1/2 will be
compared to their respective historical control values.
[0895] In addition to the proposed statistical approach to
calculate the maximum observed geometric mean ratio for the primary
PK parameters using the traditional bioequivalence reference range
of 1.25, an alternative approach considered incorporating the
variability in the PK parameters observed in the Schwartz study.
The results for the maximum observed geometric mean ratio for
AUC.sub.0-.infin. and C.sub.max that would yield 90% CI<1.33
were similar to those of the proposed approach.
[0896] Summary statistics for the secondary PK endpoints, including
apparent plasma clearance (CL/F) and apparent volume of
distribution (V.sub.d/F) will include n, arithmetic mean, SD, CV,
geometric mean, natural-log-scale SD, median, minimum, maximum,
along with the associated 90% CI computed on the natural-log-scale
and back-transformed to the original measurement scale, as
appropriate.
[0897] 6.4.1.2 FOOD-EFFECT Sub-Study (all PK Parameters from
Subjects Who Received 2 Single Doses, One Fasted, and One Fed)
[0898] The PK parameters computed from the FOOD-EFFECT substudy
will be analyzed via the standard 2-period crossover design ANOVA
including factors for treatment, period, and subject via the same
transformations as for the MAIN study. The same summary statistics
for the FOOD-EFFECT study will be derived from that analysis model
via similar methods as for the MAIN study, however, there are no
pre-specified criteria for the AUC and Cmax GMR 90% CI's.
[0899] 6.4.2 Analysis of Safety Endpoints
[0900] All safety data will be summarized for the PILOT portion,
MAIN study, and FOOD-EFFECT substudy combined. Subjects who
received 2 single doses will be counted once with all of their
safety data combined. The incidence of adverse events will be
presented by the MedDRA system organ class and preferred term,
relationship to the test article, and severity. Descriptive
statistics of clinical laboratory results and vital signs will be
presented, as well as summaries of changes from baseline (from the
Check-in visit(s)) and of clinically notable values.
[0901] All AE data will be presented in a data listing by study
part and within the FOOD-EFFECT substudy by treatment sequence.
TEAEs will be summarized overall, as well as by severity and
relationship to study drug. Serious AEs and AEs leading to
discontinuation of study drug will also be presented in the data
listings and summarized.
[0902] Actual values and changes from Baseline for clinical
laboratory test results, vital sign measurements, and 12-lead ECG
results will be summarized at each time point using descriptive
statistics (number of subjects, mean, SD, median, minimum, and
maximum). Shift tables will be generated for clinical laboratory
test results. Physical examination findings will be presented in a
data listing.
[0903] 6.4.3 Other Analyses
[0904] Summary statistics will be provided for demographics,
medical history, physical examination and social history.
[0905] 6.4.4 Handling of Missing Data
[0906] Plasma concentrations that are below the limit of
quantification (BLQ) will be treated as zero for descriptive
statistics. Mean BLQ concentrations will be presented as BLQ, and
the SD and CV will be reported as not applicable. Missing
concentrations will be excluded from the calculations.
[0907] For the PK analysis, BLQ values will be treated as zero with
the exception that a BLQ value between 2 quantifiable
concentrations will be set as missing. Missing concentrations will
be treated as missing from the PK parameter calculations. If
consecutive BLQ concentrations are followed by quantifiable
concentrations in the terminal phase, those concentrations after
BLQ concentrations will be treated as missing.
[0908] 6.4.5 Interim Analyses
[0909] Samples will be assayed, and PK calculations will be
performed on the samples obtained from the subjects enrolled in the
PILOT study. If substantial differences in the exposure of TRM-201
are observed in the PILOT study compared to the expected historical
data for rofecoxib the study may not continue with the current
formulation of study drug.
[0910] Note that the interim analysis of the PILOT portion is only
for futility; hence, there is no impact of that interim analysis on
the type 1 error potential for the final analyses (all fasted data
from the PILOT portion, MAIN study, and the FOOD-EFFECT substudy
combined).
[0911] B. Results from PK 101 Pharmacokinetic Study
[0912] The Cmax and AUC.sub.0-.infin. values in individual subjects
for a 25 mg dosage of rofecoxib (TRM-201) are presented in Table 17
below.
TABLE-US-00018 TABLE 17 AUC and Cmax values by subject (fasted) AUC
In- Total CL Max Half-Life Time of Vz Obs finity Obs Obs by F Conc
Lambda z CMAX by F Subject (h*ng/mL) (L/h) (ng/mL) (h) (h) (L)
100-001 4789.36 5.22 365 13.56 2 102.08 100-002 4637.44 5.39 243
12.58 1.5 97.84 100-003 2939.58 8.50 194 8.31 5 101.94 100-004
3603.33 6.94 188 11.56 7.5 115.72 100-005 4122.74 6.06 355 7.46 3
65.28 100-006 2441.04 10.24 283 9.77 1.5 144.29 100-007 2956.81
8.46 237 9.01 4 109.95 100-008 3107.86 8.04 259 9.46 4 109.80
100-009 3507.21 7.13 309 12.68 1.5 130.43 100-010 5499.09 4.55 270
9.92 15 65.09 100-011 5010.35 4.99 495 10.71 1.5 77.11 100-012
6291.34 3.97 362 15.07 5 86.39 100-013 3680.45 6.79 249 12.42 3
121.75 100-014 4918.55 5.08 289 14.54 2 106.65 100-015 7556.68 3.31
521 15.76 1.5 75.21 100-016 3031.10 8.25 191 10.13 5 120.51 100-017
4598.78 5.44 332 14.25 3 111.79 100-018 5636.28 4.44 271 14.65 4
93.72 100-019 6316.53 3.96 435 14.60 1.5 83.35 100-020 5933.57 4.21
573 12.70 2 77.19 100-021 4716.13 5.30 287 12.75 3 97.54 100-022
6474.80 3.86 371 12.34 2 68.75 100-023 4255.72 5.87 310 9.94 0.75
84.21 100-024 6666.45 3.75 495 11.73 3 63.45 100-025 5586.21 4.48
423 9.59 2 61.89 100-026 4278.71 5.84 287 10.57 3 89.13 100-027
7541.99 3.31 347 13.79 3 65.97 100-028 3252.18 7.69 233 9.50 3
105.32 100-029 6730.23 3.71 443 11.66 2 62.51 100-030 5578.20 4.48
546 9.19 1.5 59.42 100-031 9821.40 2.55 589 24.75 5 90.88 100-032
4936.93 5.06 381 8.67 3 63.36 100-033 3913.08 6.39 296 10.76 2
99.14 100-034 5323.39 4.70 303 13.14 3 89.03 100-035 3740.84 6.68
331 9.14 2 88.12 100-036 4568.89 5.47 275 12.60 4 99.47 100-037
5274.36 4.74 299 13.49 1.5 92.24 100-038 4317.48 5.79 254 9.69 5
80.93 100-039 10044.52 2.49 401 12.72 1.5 45.67 100-040 5447.91
4.59 392 10.54 1.5 69.79 100-041 4199.46 5.95 358 8.37 3 71.88
100-042 2404.47 10.40 284 5.11 2 76.71 100-043 6742.96 3.71 397
12.50 5 66.85 100-044 5025.11 4.98 302 14.44 4 103.65 100-045
3205.43 7.80 282 11.59 1.5 130.40 100-046 4055.32 6.16 248 9.71 4
86.41 100-047 2522.47 9.91 207 11.42 5 163.24 100-048 5008.86 4.99
370 14.01 2 100.92 100-049 3141.52 7.96 226 8.92 3 102.38 100-050
5703.73 4.38 274 14.60 5 92.34 100-051 4610.93 5.42 294 10.48 1.5
81.95 100-052 6876.95 3.64 366 13.82 5 72.49 100-053 4283.72 5.84
345 9.60 2 80.81
[0913] FIG. 25 shows a summary of fasted AUC.sub.0-.infin. and
C.sub.max observed in the pharmacokinetic study. The geometric mean
(natural-log SD) for the AUC.sub.0-.infin. is 4640 ng*hr/mL. The
geometric mean (natural-log SD) for the Cmax is 318 ng/mL.
[0914] FIG. 26 shows a summary of treatment-emergent adverse events
(TEAE). There were four subjects observed with TEAEs, which
constitutes 7.5% of the cohort. TEAE related to the rofecoxib
treatment were observed in 2 subjects, which constitutes 3.8% of
the cohort. No subjects presented with serious TEAE or TEAE, which
would lead to discontinuation of the study.
[0915] FIG. 27 shows mean fasted concentration of rofecoxib versus
scheduled time. A peak is observed between 2 hours and 5 hours
after a single administration of the rofecoxib (TRM-201)
formulation.
[0916] FIG. 28 shows analysis of AUC.sub.0-.infin. and C.sub.max
compared to historical data derived from Schwartz, J. I., et al.
Clin. Drug Invent. 2003, 23 (8): 503-509. The rofecoxib (TRM-201)
disclosed herein achieves larger AUC.sub.0-.infin. and higher Cmax
than historical data.
[0917] FIG. 29 shows a scatterplot of AUC.sub.0-.infin. by age in
fasted subjects. FIG. 30 shows a scatterplot of Cmax by age in
fasted subjects.
REFERENCES FOR EXAMPLE 4
[0918] Bresalier R S, Sandler R S, Quan H, et al. Cardiovascular
events associated with rofecoxib in a colorectal adenoma
chemoprevention trial. New Engl J Med 2005; 352:1092-102. [0919]
Matthews C Z, Woolf E J, Matuszewski B K. Improved procedure for
the determination of rofecoxib in human plasma involving 96-well
solid-phase extraction and fluorescence detection. J Chromatogr A.
2002; 949(1-2):83-9. [0920] Schwartz J I, Larson P J, Porras A G,
et al. Pharmacokinetic evaluation of rofecoxib: comparison of
tablet and suspension formulations. Clin Drug Invest. 2003;
23(8):503-9. [0921] Tsoukas C, Eyster M E, Shingo S, et al.
Evaluation of the efficacy and safety of etoricoxib in the
treatment of hemophilic arthropathy. Blood. 2006; 107(5):1785-90.
[0922] U.S. Food and Drug Administration. Analysis and
recommendations for agency action regarding nonsteroidal
antiinflammatory drugs and cardiovascular risk. J Pain Palliat Care
Pharmacother. 2005; 19(4):83-97. [0923] VIOXX (rofecoxib) [package
insert]. Merck & Co., Inc. Whitehouse Station, N.J.; 2016. 26
p.
Example 5
[0924] Extrapolated PK Values for Dosages Less than 25 mg of
Rofecoxib.
[0925] FIG. 31 shows extrapolated pharmacokinetic values for 17.5
mg and 20 mg of rofecoxib. For 17.5 mg of rofecoxib, the
AUC.sub.0-.infin. is 3248 h*ng/mL and Cmax is 222.6 ng/mL. For 20
mg of rofecoxib, the AUC.sub.0-.infin. is 3712 h*ng/mL and Cmax is
254.4 ng/mL. These values are extrapolated from the pharmacokinetic
study of Example 4 based on results obtained from a single
administration of 25 mg of rofecoxib in healthy subjects, and
assumes dose linearity across the dosage strengths.
Example 6
[0926] A Single-Dose, Open-Label, Phase 1, Four-Period Crossover
Pharmacokinetic Study of TRM-201 (Rofecoxib) 12.5 mg, 17.5 mg, 20
mg and 25 mg Administered to Healthy Subjects in a Fasting State,
with Comparison to Historical Pharmacokinetic Parameters of
Previously Marketed Rofecoxib ("TRM-201-PK-102" or "102 PK
study")
Introduction
[0927] TRM-201 (rofecoxib) was developed for the treatment of
hemophilic arthropathy (HA). Rofecoxib is a cyclooxygenase-2
(COX-2) selective, non-steroidal anti-inflammatory drug (NSAID)
with analgesic, anti-inflammatory, and anti-pyretic properties. At
therapeutic concentrations, rofecoxib inhibits COX-2 but not
cyclooxygenase 1 (COX-1). The U.S. Food and Drug Administration
(FDA) first approved rofecoxib for marketing in 1999, and rofecoxib
was eventually approved for the following indications in adults:
relief of the signs and symptoms of osteoarthritis, relief of the
signs and symptoms of rheumatoid arthritis, management of acute
pain in adults, treatment of primary dysmenorrhea, and acute
treatment of migraine attacks with or without aura. The approved
doses for osteoarthritis were 12.5 mg/day or 25 mg/day, and the
approved dose for rheumatoid arthritis was 25 mg/day.
[0928] The safety profile was established in over 17,000 patients
in placebo- and active-controlled studies at therapeutic and
supra-therapeutic doses, with some patients having had exposure for
up to 2 years. On 30 Sep. 2004 Merck and Co., Inc. voluntarily
withdrew rofecoxib from all markets worldwide following the
observation of an increased risk of serious adverse cardiovascular
events compared to placebo in a long-term controlled clinical trial
(Bresalier et al 2005).
[0929] In April 2005, FDA issued a memorandum concluding its
Analysis and Recommendations for Agency Action regarding NSAIDs and
cardiovascular risk. Related to rofecoxib, FDA concluded in part
(FDA 2005):
[0930] Along with the other approved COX-2 selective NSAIDs
available at the time (i.e., celecoxib, and valdecoxib), rofecoxib
was associated with an increased risk of serious adverse
cardiovascular events compared to placebo.
[0931] Data from large long-term controlled clinical trials that
have included a comparison of COX 2 selective and non-selective
NSAIDs did not clearly demonstrate that the COX-2 selective agents
confer a greater risk of serious adverse cardiovascular events than
non-selective NSAIDs.
[0932] Along with the other approved COX-2 selective NSAIDs
available at the time (i.e., celecoxib, and valdecoxib), rofecoxib
had demonstrated a reduction in the incidence of gastrointestinal
(GI) ulcers visualized at endoscopy compared to certain
non-selective NSAIDs. Only rofecoxib had been shown to reduce the
risk of serious GI bleeding compared to a non-selective NSAID
(naproxen) following chronic use.
[0933] Should a sponsor seek to resume marketing for rofecoxib, a
supplemental new drug application with revised labeling will be
required. The supplemental application should specifically outline
the sponsor's proposal for revised labeling designed to provide for
safe and effective use of the drug in populations where the
potential benefits of the drug may outweigh potential risks, and
all data and arguments that support resumption of marketing.
[0934] In a two-part study focused on the efficacy of etoricoxib,
another COX-2 inhibitor, in patients with HA, (Tsoukas et al 2006),
rofecoxib (19 subjects) exhibited similar efficacy to etoricoxib
(74 patients) in the 6-month extension of the study (Part 2) for
the primary endpoint (Patient Global Assessment of Arthropathy
Pain) and the two secondary endpoints (Patient Global Assessment of
Arthropathy Disease Status and Investigator Global Assessment of
Arthropathy Disease Status). In the six weeks of Part 1, etoricoxib
provided clinically and statistically significant improvement on
all endpoints versus placebo (P<0.001), including the following
additional endpoints: Patient's Global Assessment of Response to
Therapy, Investigator's Assessment of Response to Therapy, Patient
Discontinuation Due to Lack of Efficacy, and Average Rescue
Acetaminophen Usage per Day.
[0935] In view of preliminary evidence of efficacy of rofecoxib in
treating pain associated with HA, the associated reduction of risk
in GI adverse events (AEs) compared to nonselective NSAIDs, the
comparability of risk of serious cardiovascular events with
rofecoxib to comparably effective doses of nonselective NSAIDs, and
the risks associated with the use of opioids to treat pain in this
patient population, the use of rofecoxib will be evaluated for the
treatment of HA.
[0936] Given that there have been no approved rofecoxib products
available globally since September 2004, the first Phase I study
under an investigational new drug (IND) application was a PK study
(TRM-201-PK-101, as described in Example 4) in healthy volunteers
designed to assess the PK profile of a 25-mg dose of TRM-201, for
comparison to published data for the previously marketed rofecoxib
(see Example 4). Top-line results from the combined dataset of
Fasted subjects from the PILOT, MAIN and FOOD-EFFECT portions of
TRM-201-PK-101 yielded significantly greater exposure to key PK
parameters as compared to historical data reported in literature.
Based on this result and the need to establish a scientific bridge
in order "to rely on the systemic safety findings of Vioxx" and
"demonstrate the exposure of your rofecoxib product is comparable
to, or lower than, that of Vioxx", this second PK study was
conducted. The current study was designed to evaluate a single dose
of TRM-201 at 12.5 mg, 17.5 mg, 20 mg and 25 mg in a four-period
crossover design in 24 subjects in a fasted condition to match the
exposure to that of Vioxx. This study was designed to be evaluated
along with the PK data from the fasted portion of the
TRM-201-PK-101 study to select a dose comparable to the 25-mg dose
of previously marketed rofecoxib based on historical PK
parameters.
[0937] Primary Objectives:
[0938] 1. To evaluate key PK parameters of TRM 201 at doses of 12.5
mg 17.5 mg, 20 mg and 25 mg in healthy subjects and use these data
along with the data from the TRM-201-PK-101 study to compare
TRM-201 to historical PK parameters of previously marketed
rofecoxib, all in a fasted state. The key PK parameters for
rofecoxib were the following: [0939] Area under the plasma
concentration-time curve from time zero to infinity
(AUC.sub.0-.infin.) [0940] Observed maximum plasma concentration
(C.sub.max)
[0941] Secondary Objectives:
[0942] 1. To assess the safety and tolerability of TRM-201 at doses
of 12.5 mg, 17.5 mg, 20 mg and 25 mg in healthy subjects.
[0943] 2. To evaluate additional PK parameters of TRM-201 at doses
of 12.5 mg, 17.5 mg, 20 mg and 25 mg in healthy subjects and use
these data along with the data from the TRM-201-PK-101 study to
compare to historical PK parameters of previously marketed
rofecoxib, all in a fasted state including: [0944] Time to observed
maximum concentration (T.sub.max) [0945] Apparent terminal
elimination half-life (t.sub.1/2)
[0946] Study Population
[0947] A sufficient number of subjects were screened, and 24
subjects were enrolled to ensure that at least 20 evaluable
subjects complete the study. In order to mirror the population of
subjects in the PK study (Schwartz et al. 2003) every effort was
made to enroll subjects in the following proportion: White or
European American (80%), Black (20%). Of the White subjects
enrolled, every effort was made to enroll approximately 60% of the
subjects who identify themselves as being of Hispanic or Latino
ethnicity resulting in an overall percentage approximately 48%
Hispanic or Latino participants in the study. Subjects were
enrolled only if they met all the inclusion criteria and none of
the exclusion criteria and all of the continuing eligibility
criteria. Deviations from the inclusion and exclusion criteria were
not allowed.
[0948] Inclusion Criteria: [0949] 1. The subject was male or female
and was 18 to 60 years of age, inclusive, at Screening. Similar
numbers of male and female subjects were enrolled. [0950] 2. The
subject had a BMI at Screening of 18 to 32 kg/m.sup.2, inclusive,
with a minimum weight of 47 kg for women and 66 kg for men and a
maximum weight of 80 kg for women and 90 kg for men. [0951] 3. The
subject was not a smoker (or user of e-cigarettes). [0952] 4. The
investigator considered the subject was in good general health as
determined by medical history, clinical laboratory test results,
vital sign measurements, 12-lead electrocardiogram (ECG) results,
and physical examination findings at Screening and Check-in. [0953]
5. All female subjects had a negative pregnancy test at Screening.
Female subjects of childbearing potential also had a negative
pregnancy test at Check-in and were using an acceptable method of
birth control during the study (i.e., diaphragm with spermicide,
intrauterine device, condom with foam or vaginal spermicide, oral
contraceptives, or abstinence). Women who were surgically sterile
(i.e., hysterectomy, bilateral tubal ligation or bilateral
oophorectomy), or postmenopausal (defined as amenorrhea for 12
consecutive months and documented serum follicle-stimulating
hormone level >40 IU/mL) were exempt from the adequate
contraception requirement. [0954] 6. The subject agreed to comply
with all protocol requirements as well as the particular
requirements and specific Phase I unit policies. [0955] 7. The
subject provided written informed consent.
[0956] Exclusion Criteria: [0957] 1. The subject had a history of
relevant drug allergy or food allergy/sensitivity (e.g., allergy to
rofecoxib or excipients of TRM-201, allergy to other non-steroidal
anti-inflammatory drugs (NSAIDs), or gluten intolerance that could
preclude consumption of a standard clinic diet). [0958] 2. A female
subject was pregnant or lactating. [0959] 3. The subject had a
history of intolerance or hypersensitivity to aspirin or any other
NSAID. [0960] 4. The subject had a positive test result for
hepatitis B surface antigen, hepatitis C virus antibody, or human
immunodeficiency virus types 1 or 2 antibodies at Screening. [0961]
5. The subject had used any prescription (excluding hormonal birth
control) or over the counter medications (OTC) including NSAIDs
(e.g., ibuprofen, naproxen, and aspirin) as well as herbal or
nutritional supplements, within 14 days before the study drug
dosing. Subjects could have taken acetaminophen (up to 2 g per day)
in the 14 days prior to study drug dosing. [0962] 6. The subject
had any clinically significant abnormalities before dosing on Day 1
or had a history of disease, including: uncontrolled or poorly
controlled hypertension; asthma or pulmonary disease; major cardiac
ischemic symptoms, events, or interventions such as angina
pectoris, myocardial infarction, acute coronary syndrome,
decompensated congestive heart failure, coronary stent or bypass;
history of cerebrovascular ischemic events (transient ischemic
attack or stroke); major vascular ischemic symptoms such as
intermittent claudication or vascular bypass or replacement
surgery; significant cardiovascular, gastrointestinal (GI),
neurological, endocrine, or renal disease; hepatic impairment;
cholecystectomy; other condition known to interfere with the
absorption, distribution, metabolism, or excretion of drugs; or
clinically significant GI events. [0963] 7. The subject had a
history or presence of any clinically significant abnormality in
vital signs, ECG, or laboratory tests, or had any medical or
psychiatric condition that, in the opinion of the investigator,
could interfere with the study procedures or compromise subject
safety (assessed at Screening and Check-in). [0964] 8. The subject
was a cigarette smoker or had used nicotine or nicotine-containing
products (e.g., snuff, nicotine patch, nicotine chewing gum,
e-cigarettes) within 6 months before study drug dosing. [0965] 9.
The subject had a history of alcohol abuse or drug addiction within
the last year or consumes more than 1 unit (1 unit is equal to
approximately 1/2 pint [200 mL] of beer, 1 small glass [100 mL] of
wine, or 1 measure [25 mL] of spirits) of alcohol a day. Alcohol
was not allowed within 7 days before study drug dosing. [0966] 10.
The subject had a positive test result for drugs of abuse, alcohol,
or cotinine (indicating active current smoking) at Screening.
[0967] 11. The subject was a habitual and heavy coffee drinker
(more than 4 cups a day, 28 cups a week). [0968] 12. The subject
was involved in strenuous activity or contact sports within 24
hours before study drug dosing. [0969] 13. The subject had donated
blood or blood products within 30 days before the dose of study
drug in this study. [0970] 14. The subject had received study drug
in another investigational study within 30 days (or less than 5
half-lives of the investigational agent) prior to dosing in this
study. [0971] 15. The subject was not suitable for entry into the
study, in the opinion of the investigator. [0972] 16. The subject
was an employee or family member of the investigator or clinic
staff.
[0973] Continuing Eligibility at Check-in [0974] 1. Females had a
negative serum pregnancy test. [0975] 2. All subjects had a
negative test results for drugs of abuse and alcohol [0976] 3.
Subjects had no significant changes in overall health status since
screening including the use of medications. [0977] 4. The subject
was involved in strenuous activity or contact sports within 24
hours before study drug dosing.
[0978] Subjects with test results which did not meet the above
inclusion/exclusion criteria could have the relevant test repeated
once if it was thought to represent a laboratory error, a
reversible, clinically insignificant intermittent condition, or was
not consistent with the subject's historical values. If
inclusion/exclusion criteria were not met after the repeat test,
the subject was considered a screen failure and was not enrolled in
the study. Subjects were retested once.
[0979] Study Design
[0980] This was a single-center, open-label four-period crossover
PK study of TRM-201. The study included 24 subjects who received
TRM-201 as a single dose of 12.5 mg, 17.5 mg, 20 mg and 25 mg to
assess the PK of TRM-201 in healthy volunteers under fasted
conditions. Subjects were randomized to one of four treatment
sequences. The PK data from the current study along with the data
from the TRM-201-PK-101 study (Example 4) was used to compare to
historical pharmacokinetic parameters of previously marketed
rofecoxib, all in a fasted state.
[0981] The subjects were screened in the 28 days before receiving
the single dose of TRM-201 in the first period. Subjects checked in
to the clinic on the day before dosing for Dosing Period 1, and
their eligibility was confirmed. Subjects remained at the clinic
from Check-In through the completion of the end of study (EOS)
visit on Day 27 of Dosing Period 4. The total duration of the study
was approximately 55 days.
[0982] After Check-In, subjects fasted overnight for at least 10
hours before study drug administration. In the morning of the
dosing day of Period 1, subjects were randomized to one of four
treatment sequences: [0983] Dosing Period 1: ADBC [0984] Dosing
Period 2: BACD [0985] Dosing Period 3: CBDA [0986] Dosing Period 4:
DCAB
[0987] Where A=12.5 mg, B=17.5 mg, C=20 mg and D=25 mg
[0988] Regardless of the dosing sequence assigned, all subjects
underwent the same assessments, pre and post-dose.
[0989] In each of the four dosing periods, subjects fasted
overnight for at least 10 hours before study drug dosing. While
fasting, subjects had nothing to eat and only water to drink. Water
was permitted as desired, except for the period between 1 hour
before and 1 hour after study drug dosing (excepting as permitted
for dosing). After the 2-hour PK blood sample, subjects were
allowed one 250-mL cup of clear apple juice. After the 4-hour PK
blood sample, subjects were served a light lunch. Following the
light lunch, subjects received standardized meals according to the
clinic's standard procedures that were scheduled at consistent
times and at least 15 minutes before or 15 minutes after PK
sampling time points. Blood was withdrawn for PK analysis at
predefined time points. For each dosing period the last time point
was 120 hours after dosing with study drug (Day 6). After the 120
hour PK sample, the EOP procedures was completed, subjects remained
in-clinic for the in-between dose period day (Days 7, 14, and 21)
and began the next dosing period starting with an overnight fast
for at least 10 hours on Day -1 of the subsequent dosing period.
Pharmacokinetic and safety endpoints were evaluated.
[0990] Rationale of Study Design
[0991] The subject matter disclosed herein relates to a scientific
bridge between TRM-201 and the previously marketed rofecoxib in
support of a 505(b)(2) new drug application. Because there are
presently no FDA-approved rofecoxib products commercially available
globally with which to conduct a directly comparative
bioavailability/bioequivalence study, the present study, along with
the data from the TRM-201-PK-101 study, was designed to provide PK
data for a cross-study comparison to a published study (Schwartz et
al. 2003) that was submitted to FDA, accepted by FDA, and used in
the approved package insert for rofecoxib.
[0992] The four doses of rofecoxib (12.5 mg, 17.5 mg, 20 mg and 25
mg) were selected for this study to combine with the 25-mg dose
data from TRM-201-PK-101 to select a dose that is comparable to the
25-mg dose of previously marketed rofecoxib because it is the
anticipated maximum daily dose for the treatment of HA. The data
from the study by Schwartz et al. (2003) were chosen for comparison
because they represent PK data generated with the labeled version
of rofecoxib at 25 mg. The eligibility criteria for this current PK
study were selected to mirror the subject demographics and
subgroups (gender, age, body mass index [BMI], race, and ethnicity)
in both the TRM-201-PK-101 and Schwartz studies. A validated
bioanalytical method for rofecoxib was developed and used for the
PK analyses.
[0993] Administration of Study Drug
[0994] Study drug was co-administered orally with approximately 250
mL of room temperature water, and up to an additional 250 mL of
water was allowed, if necessary, to aid in swallowing the study
drug. Study staff ensured that at least 250 ml of water was
consumed with the dose of study drug and performed a hand and mouth
check after dosing to ensure the tablet was swallowed.
[0995] After fasting for at least 10 hours overnight (Table 19),
subjects took, a single dose (1 tablet) of TRM 201 on the morning
of Day 1 in each of the four Dosing Periods administered as
described above and supervised by clinic staff. During the period
between 1 hour before and 1 hour after study drug dosing, subjects
drank only the water permitted for study drug administration.
[0996] Identity of Study Drug
[0997] The study drug, TRM-201, was an immediate-release tablet
that contained 12.5 mg rofecoxib, 17.5 mg rofecoxib, 20 mg
rofecoxib or 25 mg rofecoxib. The 7.25-mm diameter tablets were
off-white, round, and uncoated with no markings. TRM-201 tablets
were for oral administration.
[0998] TRM-201 tablets contained the active ingredient rofecoxib
(12.5 mg, 17.5 mg, 20 mg or 25 mg) and inactive excipients. Each
tablet contained the following inactive excipients: croscarmellose
sodium, hydroxypropyl cellulose, lactose, magnesium stearate,
microcrystalline cellulose, and yellow pigment. Table 18 shows the
specific formulation of the tablets used in the this study:
TABLE-US-00019 TABLE 18 Composition of Rofecoxib Tablets 25-mg
Tablet 20-mg Tablet 17.5-mg Tablet 12.5-mg Tablet % (w/w) % (w/w) %
(w/w) % (w/w) per mg per per mg per per mg per per mg per
Components tablet tablet tablet tablet tablet tablet tablet tablet
Intragranular Rofecoxib.sup.a 12.50 25.0 10.00 20.0 8.75 17.5 6.25
12.5 Lactose monohydrate 39.85 79.7 41.10 82.2 41.725 83.45 42.975
85.95 Microcrystalline cellulose 39.85 79.7 41.10 82.2 41.725 83.45
42.975 85.95 Hydroxypropylcellulose 3.00 6.0 3.00 6.00 3.00 6.0
3.00 6.0 Croscarmellose sodium 2.00 4.0 2.00 4.0 2.00 4.0 2.00 4.0
Pigment blend yellow 0.30 0.6 0.30 0.6 0.30 0.6 0.30 0.6 Water
NA.sup.b NA.sup.b NA.sup.b NA.sup.b NA.sup.b NA.sup.b NA.sup.b
NA.sup.b Extragranular Croscarmellose sodium 2.00 4.0 2.00 4.0 2.00
4.0 2.00 4.0 Magnesium stearate 0.50 1.0 0.50 1.0 0.50 1.0 0.50 1.0
Totals 100.00 200.0 100.00 200.0 100.00 200.0 100.00 200.0
.sup.aNote that the amount of rofecoxib may be adjusted for purity
and moisture content. An adjustment will be made to the amounts of
lactose monohydrate and microcrystalline cellulose used to maintain
tablet weight. .sup.bWater for granulation is removed upon drying
of the wet mass.
TABLE-US-00020 TABLE 19 Schedule of events Phase In-clinic
between-period Dosing Periods 1, 2, 3 and 4 Screening Check-in day
Pharmacokinetic Sampling EOP/EOS Period 1 Days -28 to -2 -1 NA 1 2
3 4 5 6 Period 2 Days 7 8 9 10 11 12 13 Period 3 Days 14 15 16 17
18 19 20 Period 4 Days 21 22 23 24 25 26 27 Informed consent X
Demographics X Medical history X X Viral serology X Serum
follicle-stimulating X hormone (females only) Admission to clinic X
Serum pregnancy test X X X (females only) Urine drug screen X X
(including alcohol and cotinine) Clinical laboratory testing X X X
(blood/urine) Height, weight, and body X weight weight mass index
ONLY ONLY Physical examination.sup.a X X X (EOS ONLY) Vital sign
measurements.sup.b X X X X X X X X X 12-Lead ECG assessment.sup.c X
X X X (EOS ONLY) Eligibility assessment X X (initial and
continuing) Study meal schedule.sup.d X X X X X X X X Study drug
administration.sup.e X Pharmacokinetic sample X X X X X collection
Adverse event assessment X X X X X X X Prior or concomitant X X X X
X X X X medication assessment Discharge from clinic X (EOS ONLY)
Abbreviations: ECG, electrocardiogram; EOP, end of period; EOS, end
of study. Note: The order of procedures on each day followed the
order of presentation in Table 19 (top to bottom). When procedures
overlapped or occurred at the same time point, all blood sampling
followed vital signs or ECGs, and PK sampling was timed to occur
last and as close to the scheduled time window as possible. Timings
of PK blood sampling and electrocardiogram assessments were
calculated from time "0", the time of study drug dosing. .sup.aA
complete physical examination was performed at Screening (at
minimum, assessment of skin, head, ears, eyes, nose, throat, neck,
thyroid, lungs, heart, cardiovascular, abdomen, lymph nodes, and
musculoskeletal system/extremities). A brief physical examination
was performed at Check-In and EOS (at minimum, assessment of skin,
lungs, cardiovascular system, and abdomen). Interim physical
examinations was performed at the discretion of the investigator,
if necessary, to evaluate adverse events or clinical laboratory
abnormalities. .sup.bVital signs included systolic and diastolic
blood pressure, pulse rate, respiratory rate, and oral body
temperature, after the subject had been seated for at least 5
minutes. On Day 1 of each Dosing Period, vital signs were measured
within 120 minutes before study drug dosing and at the 2-hour,
3-hour and 7.5-hour post dose time points. At these time points (2
h, 3 h and 7.5 h) only systolic and diastolic blood pressure, pulse
rate and respiratory rate were assessed. On Days 2 through 6 of
each dosing period, vital signs were assessed within 15 minutes
before the first PK blood sample of the day. .sup.cAfter the
subject had been in the supine position for at least 5 minutes,
single 12-lead ECG recordings were taken at Screening and Check-in,
and on Dosing Day 1 pre-dose and at the 2-hour and 3-hour post-dose
time point for each of the four dosing periods and at EOS.
.sup.dThe fasting period began at the day of Check-In and on each
in-clinic between Dosing Period Day (Days 7, 14, 21) for at least
10 hours overnight before study drug administration for each
period. .sup.eStudy drug was administered after vital sign
measurements has been completed. Study drug was administered with
~250 mL of room temperature water. Up to an additional ~250 mL of
water were allowed, if necessary, to aid in swallowing the study
drug. Subjects maintained an upright position (seated or standing)
for at least 4 hours after dosing. The dosing for each Dosing
Period for each subject occurred at least 7 days after Period-1
dosing.
[0999] Pharmacokinetic Procedures, Assessments, and Endpoints
[1000] The time points and windows for PK blood sampling were
presented in Table 20 below. For each sample, approximately 3 mL of
blood were drawn. The samples were obtained by a straight stick or
via an in-dwelling intravenous (IV) catheter in a forearm vein.
Additional details for the collection, processing, storage, and
shipping of PK samples were provided in the study manual.
TABLE-US-00021 TABLE 20 Times and Windows for Dosing Period 1, 2, 3
and 4 Pharmacokinetic Blood Sampling Unit of Time Minutes Hours
Timepoint 0.sup.a 15 30 45 1 1.5 2 3 4 5 6 7.5 9 12 15 18 Window
(min) .+-.5 min .+-.10 min .+-.15 min .+-.30 min Unit of Time Hours
Timepoint 21 24 27 30 33 36 39 42 48 52 60 72 96 120 Window (min)
.+-.30 min .+-.60 min Abbreviation: min; minutes. .sup.aThe blood
sample for time 0 were taken within 1 hour before dosing with study
drug.
[1001] Pharmacokinetic samples will be analyzed using a validated
assay for rofecoxib in human plasma. Assay results and validation
details will be provided in a separate bioanalytical report. The
following PK parameters for rofecoxib will be calculated as primary
endpoints using standard noncompartmental methods:
AUC.sub.0-.infin. and C.sub.max. Secondary endpoints include
T.sub.max, and t.sub.1/2. Additional PK parameters (e.g., CL/F, and
V.sub.d/F) will also be calculated using standard noncompartmental
methods.
Safety Assessments
[1002] The timing and frequency of all safety assessments was
listed in the schedule of events (Table 19). Safety and
tolerability included monitoring and recording of AEs, clinical
laboratory assessments (hematology, serum chemistry, and
urinalysis), vital sign measurements, 12-lead ECG assessments, and
physical examination findings. For all safety assessments, the
investigator determined whether results were clinically
significant, which was defined as any variation in a result that
had medical relevance and could have resulted in an alteration in
medical care (e.g., active observation, diagnostic measures, or
therapeutic measures). If clinical significance was noted, the
result and reason for significance were documented. Any abnormal
laboratory test results (hematology, clinical chemistry, or
urinalysis) or other safety assessments (e.g., ECGs, vital sign
measurements), including those that worsen from baseline, felt to
be clinically significant in the medical and scientific judgment of
the investigator were to be recorded as AEs or SAEs.
Adverse Events
[1003] Definitions of Adverse Events
[1004] The investigator was responsible for reporting all AEs that
were observed or reported during the study, regardless of their
relationship to study drug or their clinical significance. If there
was any doubt as to whether a clinical observation was an AE, the
event was reported. An AE was defined as any untoward medical
occurrence in a subject enrolled into this study regardless of its
causal relationship to study drug. Subjects were instructed to
contact the investigator at any time after enrollment if any
symptoms developed. A treatment-emergent AE (TEAE) was defined as
any event not present before exposure to study drug or any event
already present that worsens in either intensity or frequency after
exposure to study drug.
[1005] Serious Adverse Events (SAE)
[1006] An SAE was defined as any event that:
[1007] resulted in death
[1008] was immediately life threatening
[1009] required inpatient hospitalization or prolongation of
existing hospitalization
[1010] resulted in persistent or significant
disability/incapacity
[1011] was a congenital anomaly/birth defect
[1012] Important medical events that did not result in death, were
not life threatening, or did not require hospitalization were
considered SAEs when, based upon appropriate medical judgment, they
jeopardized the subject or required medical or surgical
intervention to prevent one of the outcomes listed in this
definition. Examples of such medical events included allergic
bronchospasm requiring intensive treatment in an emergency room or
at home, blood dyscrasias or convulsions that did not result in
inpatient hospitalization, or the development of drug dependency or
drug abuse.
[1013] Comparability of TRM-201 with Previously Marketed
Rofecoxib
[1014] Consistent with the data of Schwartz et al. (2003) and Trial
TRM-201-PK-101, the total sample size of 20 evaluable subjects was
considered sufficient for the objectives of the study. Power was
computed as the probability that the upper limit of a 90% CI for
the geometric mean ratio (GMR=observed geometric mean from this
trial divided by the historical control value) for these parameters
fell below 1.25. Observed natural-log-scale between-subject SDs
from Trial TRM-201-PK-101 were approximately 0.31 and 0.30 for
AUC.sub.0-.infin. and Cmax, respectively; within-subject SD's from
the food effect sub-study were 0.10 and 0.12, respectively.
Geometric mean AUC and Cmax from the 25 mg formulation in
TRM-201-PK-101 were 4685 nghr/ml and 320 ng/ml, respectively. These
were higher than the corresponding values from Schwartz et al.
(2003), which were 3799 and 217, respectively. Since rofecoxib PK
was found to be linear across the 12.5 to 50-mg dose range (Vioxx
Package Insert), the 20 mg formulation in this trial was estimated
to have AUC-3741 and Cmax-266; for the 17.5 mg formulation,
AUC-3276 and Cmax-238.
[1015] The primary analysis model for data from this trial included
data from this trial and that from the 25-mg dose from
TRM-201-PK-101 (fasted results only), which were combined via mixed
model repeated measures analysis (MMRM) in order to maximize the
precision of the estimates. An MMRM analysis on natural log scale
was simulated for the 25-mg dose (N=50) data using the
between-subject SD of 0.31 from TRM-201-PK-101 and for the
estimated 25-mg and 20-mg data that N=20 subjects were expected to
yield in this study. The purpose of this simulation was to estimate
the SD for the least squares natural log scale mean for the 20-mg
dose. This SD estimate was identical for the 17.5-mg dose since
that expected least squares mean was a constant shift lower than
that for 20 mg; hence, it sufficed to run the simulation only once.
The subject effect data expected for this study was simulated from
the back-calculated variance of the between-subject mean effect
(Var (between-subject-mean)=SDbetween{circumflex over (
)}2-SDwithin{circumflex over ( )}2). For the maximum between- and
within-SD's 0.31 and 0.12, 1000 simulations yielded an effective SD
of 0.21 for the least squares mean of 20 mg, which was used for the
following power calculations.
[1016] Note that if this combined analysis of both PK trials were
not carried out, then the comparison of AUC and Cmax from each dose
in this trial would be based on only N=20 subjects using the
between-subject SD (.about.0.3 or 0.31). The MMRM analysis of both
trials combined leverages the 25 mg vs 20 mg (and 25 mg vs 17 mg,
and 25 mg vs 12.5 mg) difference from this trial which was based on
the within-subject SD .about.0.10 subtracted from the pooled
estimate of the 25 mg AUC or Cmax from N=70 subjects using the
between-subject SD. This yields an effective SD for each of the 20
mg, 17.5 mg, and 12.5 mg comparisons to the historic control
value.
[1017] Power was computed as the probability that the upper limit
of a 90% CI for the geometric mean ratio (GMR=observed geometric
mean from this trial divided by the historical control value) for
these parameters fell below 1.25. Assuming a natural-log-scale SD
equal to 0.21, N=20 had approximately 81% power if the TRUE
underlying geometric mean ratio (GMR)=1.10, and approximately 90%
power if the TRUE underlying GMR=1.08. The maximum OBSERVED GMR
that would reject the null hypothesis is 1.14. Table 21 shows
AUC.sub.0-.infin. and C.sub.max geometric mean values associated
with the ratios computed from the effective SD=0.21.
TABLE-US-00022 TABLE 21 Power Estimates for Comparability between
TRM-201 and Previously Marketed Rofecoxib Geometric Mean Ratios
Maximum OBS. Fold-Increase for 1.15.sup.a Comparability TRUE
Fold-Incr. for ~80% power 1.11.sup.a TRUE Fold-Incr. for ~90% power
1.08.sup.a Historical mean 1.25 Times PK Geometric value from the
historical Parameter Parameter Means Schwartz (2003) mean value
C.sub.max Max. OBS. Geo. Mean for 250 217 C.sub.max 25 mg 271
Comparability TRUE Geo. Mean for ~80% power 241 217 271 TRUE Geo.
Mean for ~90% power 234 217 271 AUC.sub.0-.infin. Max. OBS. Geo.
Mean for 4369 3799 AUC.sub.0-.infin. 25 mg 4749 Comparability TRUE
Geo. Mean for ~80% power 4217 3799 4749 TRUE Geo. Mean for ~90%
power 4103 3799 4749 C.sub.max Max. OBS. Geo. Mean for 281 244
C.sub.max 12.5 mg 305 Comparability dose-adjusted TRUE Geo. Mean
for ~80% power 271 244 to 25 mg 305 TRUE Geo. Mean for ~90% power
264 244 305 Abbreviations; Geo. Mean, geometric mean; Incr.
increase; Max., maximum; OBS., observed. .sup.aFold-increase
expressed relative to the historical mean value
Analysis Sets
[1018] The PK analysis set included subjects who receive a single
dose of TRM-201 and had sufficient concentration data to support
accurate estimation of at least one PK parameter. Subjects who
experience vomiting within 2 times the median T.sub.max
(approximately 6 hours) after study drug dosing will be excluded
from the PK analysis. The safety analysis set will include all
subjects who received at least 1 dose of study drug.
[1019] Description of Subgroups to be Analyzed
[1020] The relationship of AUC.sub.0-.infin. and C.sub.max to age
and to BMI were each assessed via scatter plots and correlation
coefficients. If appropriate, additional modeling of those
relationships may be carried out. Summary statistics for
AUC.sub.0-.infin. and C.sub.max were provide by gender, age
categories (divided into tertiles), race categories, and ethnicity
categories.
[1021] Statistical Analysis Methodology
[1022] For categorical variables, frequencies and percentages were
presented. Continuous variables were summarized using descriptive
statistics (number of subjects, mean, median, SD, minimum, maximum,
geometric mean, natural-log-scale SD). Baseline demographic and
background variables were summarized overall for all subjects. The
number of subjects who enrolled in the study and the number and
percentage of subjects who completed the study were presented.
Frequency and percentage of subjects who withdrew or discontinued
from the study, and the reason for withdrawal or discontinuation,
was also summarized. Statistical analysis was performed using SAS
software Version 9.4 or later. Continuous variables were summarized
using the mean, the standard deviation, median, minimum value, and
maximum value. Categorical variables were summarized using
frequency counts and percentages. Data were listed in data
listings.
[1023] Analysis of Pharmacokinetic Endpoints
[1024] Individual plasma concentrations for rofecoxib and PK
sampling time deviation data will be presented in a data listing.
Plasma concentration data will be summarized by time point using
the following descriptive statistics: number of subjects,
arithmetic mean, SD, coefficient of variation (CV), geometric mean,
natural-log-scale SD, geometric CV, median, minimum, and maximum.
Individual plasma concentration versus actual time profiles were
presented on both linear and semilogarithmic scales. Additionally,
arithmetic mean concentration versus scheduled time profiles were
presented on linear scales and geometric means on semilogarithmic
scales.
[1025] The PK parameters of rofecoxib were analyzed based on the
actual sampling times. All parameters were calculated using the
Phoenix.RTM. WinNonlin.RTM. version 6.4 or higher (Certara USA
Inc., Princeton, N.J.) or SAS.RTM. version 9.3 or higher (SAS
Institute Inc., Cary, N.C.). The individual PK parameters were
presented in data listings. Summary statistics for the primary PK
endpoints, AUC.sub.0-.infin. and C.sub.max, included n, arithmetic
mean, CV, SD, geometric mean, natural-log-scale SD, median,
minimum, and maximum, along with the associated 90% CI computed on
the natural-log-scale and back-transformed to the original
measurement scale. The GMR to historical control values and
associated 90% CIs were computed on log scale and back-transformed
to the ratio scale; the reference values are from Schwartz et al.
(2003): 3799 nghr/mL and 217 ng/mL for AUC.sub.0-.infin. and Cmax,
respectively.
[1026] The primary hypotheses for both AUC.sub.0-.infin. and
C.sub.max for each of the 17.5 mg and 20 mg doses (tested via
step-down approach: AUC followed by Cmax for the 17.5 mg dose,
followed by AUC and Cmax for the 20 mg dose) were: [1027] Null
Hypothesis: the TRUE underlying GMR (new formulation versus
historical control) was at least 1.25 [1028] Alternative
Hypothesis: the TRUE underlying GMR (new formulation versus
historical control) was less than 1.25
[1029] These null hypotheses were each tested via comparing to 1.25
the upper limit of a 90% CI for the geometric mean computed on the
natural-log-scale and back-transformed to the original scale. If
the upper 90% CI lied below 1.25 times the historical control
geometric mean value, the null hypothesis would have been rejected,
and the alternative hypothesis would have been concluded. The
AUC.sub.0-.infin. and C.sub.max null hypotheses needed to be
rejected to support a conclusion that the new formulation was
sufficiently similar to the formulation that yielded the historical
control data. Sensitivity analyses will be carried out separately
for AUC.sub.0-.infin. and Cmax using age- and race-adjusted
geometric means that match the mean age and race distribution of
the historical control data. Secondary analyses similar to the
primary were carried out in comparison to a lower limit of 0.8
times the respective historical control values.
[1030] The T.sub.max was summarized by n, arithmetic mean, CV, SD,
median, minimum, maximum, and 90% CI for the median via normal
approximation. Apparent t.sub.1/2 was summarized by n, arithmetic
mean, CV, SD, harmonic mean, jack-knife SD, median, minimum, and
maximum. The 90% CI for harmonic mean was computed on the inverse
scale and back-transformed to the actual scale. The 90% CIs for
median T.sub.max and harmonic mean t.sub.1/2 was compared to their
respective historical control values. In addition to the proposed
statistical approach to calculate the maximum observed geometric
mean ratio for the primary PK parameters using the traditional
bioequivalence reference range of 1.25, an alternative approach
considered incorporating the variability in the PK parameters
observed in the reference Schwartz et al. (2003) study. The results
for the maximum observed geometric mean ratio for AUC.sub.0-.infin.
and C.sub.max that would yield 90% CI<1.33 were similar to those
of the proposed approach. Summary statistics for the secondary PK
endpoints, including apparent plasma clearance (CL/F) and apparent
volume of distribution (V.sub.d/F) included n, arithmetic mean, SD,
CV, geometric mean, natural-log-scale SD, median, minimum, maximum,
along with the associated 90% CI computed on the natural-log-scale
and back-transformed to the original measurement scale, as
appropriate. An exploratory analysis was carried out to estimate
the dose that yielded values of AUC and Cmax equal to those
observed in the Schwartz (2003) paper. This analysis was carried
out via a linear regression fit in the MMRM analysis of the
log-transformed observations across the 12.5 to 25 mg range of
doses in this study.
[1031] Analysis of Safety Endpoints
[1032] All safety data were summarized. The incidence of adverse
events was presented by the MedDRA system organ class and preferred
term, relationship to the test article, and severity. Descriptive
statistics of clinical laboratory results and vital signs were
presented, as well as summaries of changes from baseline (from the
Check-in visit(s)) and of clinically notable values. All AE data
were presented in a data listing TEAEs were summarized overall, as
well as by severity and relationship to study drug. Serious AEs and
AEs leading to discontinuation of study drug were also presented in
the data listings and summarized. Actual values and changes from
Baseline for clinical laboratory test results, vital sign
measurements, and 12-lead ECG results were summarized at each time
point using descriptive statistics (number of subjects, mean, SD,
median, minimum, and maximum).
Results for Example 6
[1033] As shown in the summary of subjects in FIG. 32, 24 subjects
were administered TRM-201 and all subjects completed the study. The
median age of the tested demographic is 49 years old with
approximately 50% males and females as shown in FIG. 33. The
subjects also included 5 black or African-American subjects and 12
Hispanic or Latino subjects. FIG. 34 shows that the median body
mass index (BMI) of the tested cohort was 26.95 kg/m.sup.2.
[1034] FIG. 35 shows demographic and baseline characteristics of
the cohort tested in the pharmacokinetics (PK) study. FIG. 36 shows
demographic and baseline characteristics of BMI indicator in PK
study. FIGS. 37-46 show the summary of fasted plasma rofecoxib
concentration (ng/mL) across various time points 0 hours and 120
hours following 12.5 mg, 17.5 mg, 20 mg, or 25 mg of TRM-201
administration for the 102 PK study. As shown in FIGS. 37 and 38,
the arithmetic mean plasma concentration for 12.5 mg of TRM-201 at
15 minutes is 1.03 ng/ml and the geometric mean is 0.529 ng/ml. The
arithmetic mean plasma concentration for 17.5 mg of TRM-201 at 15
minutes is 2.42 mg/ml and the geometric mean is 0.669 ng/ml. The
arithmetic mean plasma concentration for 20 mg of TRM-201 at 15
minutes is 5.75 ng/ml and the geometric mean is 1.16 ng/ml. The
arithmetic mean plasma concentration for 25 mg of TRM-201 at 15
minutes is 5.63 ng/ml and the geometric mean is 1.37 ng/ml. The
arithmetic mean plasma concentration for 12.5 mg of TRM-201 at 45
minutes is 56.8 ng/ml and the geometric mean is 33.9 ng/ml. The
arithmetic mean plasma concentration for 17.5 mg of TRM-201 at 45
minutes is 93.0 mg/ml and the geometric mean is 51.6 ng/ml. The
arithmetic mean plasma concentration for 20 mg of TRM-201 at 45
minutes is 121 ng/ml and the geometric mean is 72.6 ng/ml. The
arithmetic mean plasma concentration for 25 mg of TRM-201 at 45
minutes is 159 ng/ml and the geometric mean is 97.6 ng/ml.
[1035] FIG. 47 shows a summary of fasted AUC.sub.0-.infin. and
C.sub.max values for the 101-PK (Example 4) and 102-PK (Example 6)
studies, combining those results for the 25 mg of TRM-201 dosage
across the 101-PK and 102-PK studies. The arithmetic mean
AUC.sub.0-.infin. for 12.5 mg of TRM-201 is 2010 nghr/mL. The
geometric mean AUC.sub.0-.infin. for 12.5 mg of TRM-201 is 1880
nghr/mL. The arithmetic mean AUC.sub.0-.infin. for 17.5 mg of
TRM-201 is 3290 nghr/mL. The geometric mean AUC.sub.0-.infin. for
17.5 mg of TRM-201 is 3110 nghr/mL. The arithmetic mean
AUC.sub.0-.infin. for 20 mg of TRM-201 is 3750 nghr/mL. The
geometric mean AUC.sub.0-.infin. for 20 mg of TRM-201 is 3550
nghr/mL. The arithmetic mean AUC.sub.0-.infin. for 25 mg of TRM-201
is 4810 nghr/mL. The geometric mean AUC.sub.0-.infin. for 25 mg of
TRM-201 is 4590 nghr/mL. The arithmetic mean C.sub.max for 12.5 mg
of TRM-201 is 151 ng/mL. The geometric mean C.sub.max for 12.5 mg
of TRM-201 is 144 ng/mL. The arithmetic mean C.sub.max for 17.5 mg
of TRM-201 is 236 ng/mL. The geometric mean C.sub.max for 17.5 mg
of TRM-201 is 224 ng/mL. The arithmetic mean C.sub.max for 20 mg of
TRM-201 is 277 ng/mL. The geometric mean Cmax for 20 mg of TRM-201
is 259 ng/mL. The arithmetic mean C.sub.max for 25 mg of TRM-201 is
336 ng/mL. The geometric mean C.sub.max for 25 mg of TRM-201 is 325
ng/mL.
[1036] FIG. 48 shows a summary of fasted AUC.sub.0-.infin. for the
102 PK study only. The arithmetic mean AUC.sub.0-.infin. for 12.5
mg of TRM-201 is 2010 nghr/mL. The geometric mean AUC.sub.0-.infin.
for 12.5 mg of TRM-201 is 1880 nghr/mL. The arithmetic mean
AUC.sub.0-.infin. for 17.5 mg of TRM-201 is 3290 nghr/mL. The
geometric mean AUC.sub.0-.infin. for 17.5 mg of TRM-201 is 3110
nghr/mL. The arithmetic mean AUC.sub.0-.infin. for 20 mg of TRM-201
is 3750 nghr/mL. The geometric mean AUC.sub.0-.infin. for 20 mg of
TRM-201 is 3550 nghr/mL. The arithmetic mean AUC.sub.0-.infin. for
25 mg of TRM-201 is 4630 nghr/mL. The geometric mean
AUC.sub.0-.infin. for 25 mg of TRM-201 is 4490 nghr/mL. FIG. 48
also shows values for two model projections (calculated via an MMRM
model) of AUC.sub.0-.infin. geometric means across dosages.
[1037] FIG. 49 shows a summary of fasted C.sub.max for the 102 PK
study only. The arithmetic mean C.sub.max for 12.5 mg of TRM-201 is
151 ng/mL. The geometric mean C.sub.max for 12.5 mg of TRM-201 is
144 ng/mL. The arithmetic mean C.sub.max for 17.5 mg of TRM-201 is
236 ng/mL. The geometric mean C.sub.max for 17.5 mg of TRM-201 is
224 ng/mL. The arithmetic mean C.sub.max for 20 mg of TRM-201 is
277 ng/mL. The geometric mean C.sub.max for 20 mg of TRM-201 is 259
ng/mL. The arithmetic mean C.sub.max for 25 mg of TRM-201 is 349
ng/mL. The geometric mean C.sub.max for 25 mg of TRM-201 is 341
ng/mL.
[1038] FIG. 50 shows a summary of fasted AUC.sub.0-.infin. and
C.sub.max by gender for the 102 PK study only for 12.5 mg of
TRM-201. For males, the arithmetic mean AUC.sub.0-.infin. is 1750
nghr/mL and the arithmetic mean C.sub.max is 132 ng/mL. For males,
the geometric mean AUC.sub.0-.infin. is 1580 nghr/mL and the
geometric mean C.sub.max is 127 ng/mL. For females, the arithmetic
mean AUC.sub.0-.infin. is 2240 nghr/mL and the arithmetic mean
C.sub.max is 168 ng/mL. For females, the geometric mean
AUC.sub.0-.infin. is 2170 nghr/mL and the geometric mean C.sub.max
is 160 ng/mL.
[1039] FIG. 51 shows a summary of fasted AUC.sub.0-.infin. and
C.sub.max by gender for the 102 PK study only for 17.5 mg of
TRM-201. For males, the arithmetic mean AUC.sub.0-.infin. is 2860
nghr/mL and the arithmetic mean C.sub.max is 201 ng/mL. For males,
the geometric mean AUC.sub.0-.infin. is 2710 nghr/mL and the
geometric mean C.sub.max is 196 ng/mL. For females, the arithmetic
mean AUC.sub.0-.infin. is 3650 nghr/mL and the arithmetic mean
C.sub.max is 266 ng/mL. For females, the geometric mean
AUC.sub.0-.infin. is 3490 nghr/mL and the geometric mean C.sub.max
is 251 ng/mL.
[1040] FIG. 52 shows a summary of fasted AUC.sub.0-.infin. and
C.sub.max by gender for the 102 PK study only for 20 mg of TRM-201.
For males, the arithmetic mean AUC.sub.0-.infin. is 3130 nghr/mL
and the arithmetic mean C.sub.max is 234 ng/mL. For males, the
geometric mean AUC.sub.0-.infin. is 2940 nghr/mL and the geometric
mean C.sub.max is 224 ng/mL For females, the arithmetic mean
AUC.sub.0-.infin. is 4270 nghr/mL and the arithmetic mean C.sub.max
is 314 ng/mL. For females, the geometric mean AUC.sub.0-.infin. is
4160 nghr/mL and the geometric mean C.sub.max is 293 ng/mL.
[1041] FIG. 53 shows a summary of fasted AUC.sub.0-.infin. and
C.sub.max by gender for the 102 PK study only for 25 mg of TRM-201.
For males, the arithmetic mean AUC.sub.0-.infin. is 4080 nghr/mL
and the arithmetic mean C.sub.max is 302 ng/mL. For males, the
geometric mean AUC.sub.0-.infin. is 3940 nghr/mL and the geometric
mean C.sub.max is 298 ng/mL. For females, the arithmetic mean
AUC.sub.0-.infin. is 5090 nghr/mL and the arithmetic mean C.sub.max
is 388 ng/mL. For males, the geometric mean AUC.sub.0-.infin. is
5020 nghr/mL and the geometric mean C.sub.max is 382 ng/mL.
[1042] FIG. 54 shows a summary of fasted AUC.sub.0-.infin. and
C.sub.max by age for the 102 PK study only for 12.5 mg of TRM-201.
For 18-40 years, the arithmetic mean AUC.sub.0-.infin. is 1680
nghr/mL and the arithmetic mean C.sub.max is 164 ng/mL. For 18-40
years, the geometric mean AUC.sub.0-.infin. is 1570 nghr/mL and the
geometric mean C.sub.max is 156 ng/mL. For 41-52 years, the
arithmetic mean AUC.sub.0-.infin. is 2090 nghr/mL and the
arithmetic mean C.sub.max is 140 ng/mL. For 41-52 years, the
geometric mean AUC.sub.0-.infin. is 1880 nghr/mL and the geometric
mean C.sub.max is 133 ng/mL. For 53-60 years, the arithmetic mean
AUC.sub.0-.infin. is 2270 nghr/mL and the arithmetic mean C.sub.max
is 150 ng/mL. For 53-60 years, the geometric mean AUC.sub.0-.infin.
is 2240 nghr/mL and the geometric mean C.sub.max is 143 ng/mL.
[1043] FIG. 55 shows a summary of fasted AUC.sub.0-.infin. and
C.sub.max by age for the 102 PK study only for 17.5 mg of TRM-201.
For 18-40 years, the arithmetic mean AUC.sub.0-.infin. is 2820
nghr/mL and the arithmetic mean C.sub.max is 237 ng/mL. For 18-40
years, the geometric mean AUC.sub.0-.infin. is 2750 nghr/mL and the
geometric mean C.sub.max is 229 ng/mL. For 41-52 years, the
arithmetic mean AUC.sub.0-.infin. is 3520 nghr/mL and the
arithmetic mean C.sub.max is 232 ng/mL. For 41-52 years, the
geometric mean AUC.sub.0-.infin. is 3160 nghr/mL and the geometric
mean C.sub.max is 213 ng/mL. For 53-60 years, the arithmetic mean
AUC.sub.0-.infin. is 3510 nghr/mL and the arithmetic mean Cmax is
239 ng/mL. For 53-60 years, the geometric mean AUC.sub.0-.infin. is
3470 nghr/mL and the geometric mean C.sub.max is 230 ng/mL.
[1044] FIG. 56 shows a summary of fasted AUC.sub.0-.infin. and
C.sub.max by age for the 102 PK study only for 20 mg of TRM-201.
For 18-40 years, the arithmetic mean AUC.sub.0-.infin. is 3580
nghr/mL and the arithmetic mean C.sub.max is 308 ng/mL. For 18-40
years, the geometric mean AUC.sub.0-.infin. is 3420 nghr/mL and the
geometric mean C.sub.max is 289 ng/mL. For 41-52 years, the
arithmetic mean AUC.sub.0-.infin. is 3730 nghr/mL and the
arithmetic mean C.sub.max is 262 ng/mL. For 41-52 years, the
geometric mean AUC.sub.0-.infin. is 3360 nghr/mL and the geometric
mean C.sub.max is 242 ng/mL. For 53-60 years, the arithmetic mean
AUC.sub.0-.infin. is 3940 nghr/mL and the arithmetic mean Cmax is
260 ng/mL. For 53-60 years, the geometric mean AUC.sub.0-.infin. is
3880 nghr/mL and the geometric mean C.sub.max is 249 ng/mL.
[1045] FIG. 57 shows a summary of fasted AUC.sub.0-.infin. and
C.sub.max by age for the 102 PK study only for 25 mg of TRM-201.
For 18-40 years, the arithmetic mean AUC.sub.0-.infin. is 4140
nghr/mL and the arithmetic mean C.sub.max is 366 ng/mL. For 18-40
years, the geometric mean AUC.sub.0-.infin. is 4050 nghr/mL and the
geometric mean C.sub.max is 356 ng/mL. For 41-52 years, the
arithmetic mean AUC.sub.0-.infin. is 4810 nghr/mL and the
arithmetic mean C.sub.max is 326 ng/mL. For 41-52 years, the
geometric mean AUC.sub.0-.infin. is 4580 nghr/mL and the geometric
mean C.sub.max is 321 ng/mL. For 53-60 years, the arithmetic mean
AUC.sub.0-.infin. is 4940 nghr/mL and the arithmetic mean C.sub.max
is 354 ng/mL. For 53-60 years, the geometric mean AUC.sub.0-.infin.
is 4880 nghr/mL and the geometric mean C.sub.max is 347 ng/mL.
[1046] FIG. 58 shows a summary of fasted AUC.sub.0-.infin. and
C.sub.max by race for the 102 PK study only for 12.5 mg of TRM-201.
For Black or African-American subjects, the arithmetic mean
AUC.sub.0-.infin. is 1660 nghr/mL and the arithmetic mean C.sub.max
is 143 ng/mL. For Black or African-American subjects, the geometric
mean AUC.sub.0-.infin. is 1590 nghr/mL and the geometric mean
C.sub.max is 142 ng/mL. For White subjects, the arithmetic mean
AUC.sub.0-.infin. is 2110 nghr/mL and the arithmetic mean C.sub.max
is 153 ng/mL. For White subjects, the geometric mean
AUC.sub.0-.infin. is 1960 nghr/mL and the geometric mean C.sub.max
is 144 ng/mL.
[1047] FIG. 59 shows a summary of fasted AUC.sub.0-.infin. and
C.sub.max by race for the 102 PK study only for 17.5 mg of TRM-201.
For Black or African-American subjects, the arithmetic mean
AUC.sub.0-.infin. is 2840 nghr/mL and the arithmetic mean C.sub.max
is 217 ng/mL. For Black or African-American subjects, the geometric
mean AUC.sub.0-.infin. is 2800 nghr/mL and the geometric mean
C.sub.max is 211 ng/mL. For White subjects, the arithmetic mean
AUC.sub.0-.infin. is 3400 nghr/mL and the arithmetic mean C.sub.max
is 241 ng/mL. For White subjects, the geometric mean
AUC.sub.0-.infin. is 3200 nghr/mL and the geometric mean C.sub.max
is 228 ng/mL.
[1048] FIG. 60 shows a summary of fasted AUC.sub.0-.infin. and
C.sub.max by race for the 102 PK study only for 20 mg of TRM-201.
For Black or African-American subjects, the arithmetic mean
AUC.sub.0-.infin. is 3380 nghr/mL and the arithmetic mean C.sub.max
is 298 ng/mL. For Black or African-American subjects, the geometric
mean AUC.sub.0-.infin. is 3300 nghr/mL and the geometric mean
C.sub.max is 295 ng/mL. For White subjects, the arithmetic mean
AUC.sub.0-.infin. is 3850 nghr/mL and the arithmetic mean Cmax is
271 ng/mL. For White subjects, the geometric mean AUC.sub.0-.infin.
is 3610 nghr/mL and the geometric mean C.sub.max is 250 ng/mL.
[1049] FIG. 61 shows a summary of fasted AUC.sub.0-.infin. and
C.sub.max by race for the 102 PK study only for 25 mg of TRM-201.
For Black or African-American subjects, the arithmetic mean
AUC.sub.0-.infin. is 3990 nghr/mL and the arithmetic mean C.sub.max
is 340 ng/mL. For Black or African-American subjects, the geometric
mean AUC.sub.0-.infin. is 3940 nghr/mL and the geometric mean
C.sub.max is 339 ng/mL. For White subjects, the arithmetic mean
AUC.sub.0-.infin. is 4800 nghr/mL and the arithmetic mean C.sub.max
is 351 ng/mL. For White subjects, the geometric mean
AUC.sub.0-.infin. is 4650 nghr/mL and the geometric mean C.sub.max
is 341 ng/mL.
[1050] FIG. 62 shows a summary of fasted AUC.sub.0-.infin. and
C.sub.max by body weight for the 102 PK study only for 12.5 mg of
TRM-201. For 47-70 kg, the arithmetic mean AUC.sub.0-.infin. is
1850 nghr/mL and the arithmetic mean C.sub.max is 175 ng/mL. For
47-70 kg, the geometric mean AUC.sub.0-.infin. is 1690 nghr/mL and
the geometric mean C.sub.max is 165 ng/mL. For 70.1-77 kg, the
arithmetic mean AUC.sub.0-.infin. is 2500 nghr/mL and the
arithmetic mean C.sub.max is 155 ng/mL. For 70.1-77 kg, the
geometric mean AUC.sub.0-.infin. is 2420 nghr/mL and the geometric
mean C.sub.max is 147 ng/mL. For 77.1-90 kg, the arithmetic mean
AUC.sub.0-.infin. is 1790 nghr/mL and the arithmetic mean C.sub.max
is 127 ng/mL. For 77.1-90 kg, the geometric mean AUC.sub.0-.infin.
is 1690 nghr/mL and the geometric mean C.sub.max is 125 ng/mL.
[1051] FIG. 63 shows a summary of fasted AUC.sub.0-.infin. and
C.sub.max by body weight for the 102 only for 17.5 mg of TRM-201.
For 47-70 kg, the arithmetic mean AUC.sub.0-.infin. is 3180 nghr/mL
and the arithmetic mean C.sub.max is 261 ng/mL. For 47-70 kg, the
geometric mean AUC.sub.0-.infin. is 2930 nghr/mL and the geometric
mean C.sub.max is 242 ng/mL. For 70.1-77 kg, the arithmetic mean
AUC.sub.0-.infin. is 3890 nghr/mL and the arithmetic mean C.sub.max
is 254 ng/mL. For 70.1-77 kg, the geometric mean AUC.sub.0-.infin.
is 3730 nghr/mL and the geometric mean C.sub.max is 246 ng/mL. For
77.1-90 kg, the arithmetic mean AUC.sub.0-.infin. is 2910 nghr/mL
and the arithmetic mean C.sub.max is 200 ng/mL. For 77.1-90 kg, the
geometric mean AUC.sub.0-.infin. is 2850 nghr/mL and the geometric
mean C.sub.max is 194 ng/mL.
[1052] FIG. 64 shows a summary of fasted AUC.sub.0-.infin. and
C.sub.max by body weight for the 102 PK study only for 20 mg of
TRM-201. For 47-70 kg, the arithmetic mean AUC.sub.0-.infin. is
3650 nghr/mL and the arithmetic mean C.sub.max is 336 ng/mL. For
47-70 kg, the geometric mean AUC.sub.0-.infin. is 3340 nghr/mL and
the geometric mean C.sub.max is 307 ng/mL. For 70.1-77 kg, the
arithmetic mean AUC.sub.0-.infin. is 4500 nghr/mL and the
arithmetic mean C.sub.max is 259 ng/mL. For 70.1-77 kg, the
geometric mean AUC.sub.0-.infin. is 4400 nghr/mL and the geometric
mean C.sub.max is 248 ng/mL. For 77.1-90 kg, the arithmetic mean
AUC.sub.0-.infin. is 3250 nghr/mL and the arithmetic mean C.sub.max
is 238 ng/mL. For 77.1-90 kg, the geometric mean AUC.sub.0-.infin.
is 3170 nghr/mL and the geometric mean C.sub.max is 231 ng/mL.
[1053] FIG. 65 shows a summary of fasted AUC.sub.0-.infin. and
C.sub.max by body weight for the 102 PK study only for 25 mg of
TRM-201. For 47-70 kg, the arithmetic mean AUC.sub.0-.infin. is
4450 nghr/mL and the arithmetic mean C.sub.max is 385 ng/mL. For
47-70 kg, the geometric mean AUC.sub.0-.infin. is 4310 nghr/mL and
the geometric mean C.sub.max is 376 ng/mL. For 70.1-77 kg, the
arithmetic mean AUC.sub.0-.infin. is 5470 nghr/mL and the
arithmetic mean C.sub.max is 371 ng/mL. For 70.1-77 kg, the
geometric mean AUC.sub.0-.infin. is 5410 nghr/mL and the geometric
mean C.sub.max is 368 ng/mL. For 77.1-90 kg, the arithmetic mean
AUC.sub.0-.infin. is 4130 nghr/mL and the arithmetic mean C.sub.max
is 299 ng/mL. For 77.1-90 kg, the geometric mean AUC.sub.0-.infin.
is 4040 nghr/mL and the geometric mean C.sub.max is 294 ng/mL.
[1054] FIG. 66 shows a summary of fasted AUC.sub.0-.infin. and
C.sub.max by ethnicity for the 102 PK study only for 12.5 mg of
TRM-201. For Hispanic or Latino subjects, the arithmetic mean
AUC.sub.0-.infin. is 2210 nghr/mL and the arithmetic mean C.sub.max
is 157 ng/mL. For Hispanic or Latino subjects, the geometric mean
AUC.sub.0-.infin. is 2090 nghr/mL and the geometric mean C.sub.max
is 146 ng/mL. For non-Hispanic or non-Latino subjects, the
arithmetic mean AUC.sub.0-.infin. is 1820 nghr/mL and the
arithmetic mean C.sub.max is 146 ng/mL. For non-Hispanic or
non-Latino subjects, the geometric mean AUC.sub.0-.infin. is 1680
nghr/mL and the geometric mean C.sub.max is 141 ng/mL.
[1055] FIG. 67 shows a summary of fasted AUC.sub.0-.infin. and
C.sub.max by ethnicity for the 102 PK study only for 17.5 mg of
TRM-201. For Hispanic or Latino subjects, the arithmetic mean
AUC.sub.0-.infin. is 3520 nghr/mL and the arithmetic mean C.sub.max
is 258 ng/mL. For Hispanic or Latino subjects, the geometric mean
AUC.sub.0-.infin. is 3330 nghr/mL and the geometric mean C.sub.max
is 243 ng/mL. For non-Hispanic or non-Latino subjects, the
arithmetic mean AUC.sub.0-.infin. is 3050 nghr/mL and the
arithmetic mean C.sub.max is 214 ng/mL. For non-Hispanic or
non-Latino subjects, the geometric mean AUC.sub.0-.infin. is 2910
nghr/mL and the geometric mean C.sub.max is 207 ng/mL.
[1056] FIG. 68 shows a summary of fasted AUC.sub.0-.infin. and
C.sub.max by ethnicity for the 102 PK study only for 20 mg of
TRM-201. For Hispanic or Latino subjects, the arithmetic mean
AUC.sub.0-.infin. is 3840 nghr/mL and the arithmetic mean C.sub.max
is 281 ng/mL. For Hispanic or Latino subjects, the geometric mean
AUC.sub.0-.infin. is 3630 nghr/mL and the geometric mean C.sub.max
is 258 ng/mL. For non-Hispanic or non-Latino subjects, the
arithmetic mean AUC.sub.0-.infin. is 3660 nghr/mL and the
arithmetic mean C.sub.max is 272 ng/mL. For non-Hispanic or
non-Latino subjects, the geometric mean AUC.sub.0-.infin. is 3470
nghr/mL and the geometric mean C.sub.max is 260 ng/mL.
[1057] FIG. 69 shows a summary of fasted AUC.sub.0-.infin. and
C.sub.max by ethnicity for the 102 PK study only for 25 mg of
TRM-201. For Hispanic or Latino subjects, the arithmetic mean
AUC.sub.0-.infin. is 4980 nghr/mL and the arithmetic mean C.sub.max
is 358 ng/mL. For Hispanic or Latino subjects, the geometric mean
AUC.sub.0-.infin. is 4870 nghr/mL and the geometric mean C.sub.max
is 351 ng/mL. For non-Hispanic or non-Latino subjects, the
arithmetic mean AUC.sub.0-.infin. is 4280 nghr/mL and the
arithmetic mean C.sub.max is 340 ng/mL. For non-Hispanic or
non-Latino subjects, the geometric mean AUC.sub.0-.infin. is 4150
nghr/mL and the geometric mean C.sub.max is 331 ng/mL.
[1058] FIG. 70 shows a sensitivity analysis of fasted
AUC.sub.0-.infin. and C.sub.max compared to historical data. The
geometric mean ratio AUC.sub.0-.infin. of TRM-201 17.5 mg to
historical data for the 25 mg VIOXX product is 0.819. The geometric
mean ratio C.sub.max of TRM-201 17.5 mg to historical data for the
25 mg VIOXX product is 1.03. The geometric mean ratio
AUC.sub.0-.infin. of TRM-201 20 mg to historical data for the 25 mg
VIOXX product is 0.934. The geometric mean ratio C.sub.max of
TRM-201 20 mg to historical data for the 25 mg VIOXX product is
1.19. The AUC.sub.0-.infin. and C.sub.max data for the 25 mg VIOXX
product were obtained from Schwartz, J. I., et al. Clin. Drug
Invent. 2003, 23 (8): 503-509.
[1059] FIG. 71 shows a summary of fasted T.sub.max and t.sub.1/2
for the 101 and 102 PK studies combined. The median time at which
the C.sub.max is observed (T.sub.max) for 12.5 mg of TRM-201 is
2.00 hours. The median T.sub.max for 17.5 mg of TRM-201 is 2.00
hours. The T.sub.max for 20 mg of TRM-201 is 2.00 hours. The
T.sub.max for 25 mg of TRM-201 is 2.50 hours. The median t.sub.1/2
for 12.5 mg of TRM-201 is 12 hours. The t.sub.1/2 is generally
comparable across dosages. The median t.sub.1/2 for 17.5 mg of
TRM-201 is 11.7 hours. The median t.sub.1/2 for 20 mg of TRM-201 is
12.2 hours. The median t.sub.1/2 for 25 mg of TRM-201 is 11.6
hours.
[1060] FIG. 72 shows a summary of fasted CL/F and V.sub.d/F for the
102 PK study only. FIG. 73 shows exploratory analysis of fasted
AUC.sub.0-.infin. and C.sub.max to estimate the dose that yields
values equal to those observed in the historical data (for the 102
PK study only). FIG. 74 shows summary of treatment-emergent adverse
events (TEAE). A total of three subjects exhibited a TEAE in the
102 PK study. One of these subjects was administered 12.5 mg of
TRM-201 and the other two subjects were administered 25 mg of
TRM-201. No subjects exhibited related TEAE, serious TEAE, TEAE
leading to study discontinuation, or severe TEAE.
[1061] FIG. 75 shows incidence of treatment-emergent adverse events
(TEAE) by system organ class and preferred term. At 12.5 mg of
TRM-201, the TEAE in preferred term was constipation. At 25 mg of
TRM-201, the TEAE in preferred term was ear discomfort and
headache.
[1062] FIG. 76 shows no incidence of related TEAE at any dosage.
FIG. 77 shows no incidence of serious TEAE at any dosage. FIG. 78
shows no incidence of TEAE leading to study discontinuation at any
dosage. FIG. 79 shows incidence of TEAE by system organ class,
preferred term, and severity. All reported TEAE were mild.
[1063] FIG. 80 shows arithmetic mean (SD) fasted rofecoxib
concentration across scheduled time profiles on the linear scale.
The peak rofecoxib concentration was observed between 0 and 5 hours
following administration for all dosages. FIGS. 81-84 show
arithmetic mean (SD) fasted rofecoxib concentration across
scheduled time profiles on the linear scale presented by
dosage.
[1064] FIG. 85 shows arithmetic mean fasted concentration across
scheduled time profiles on the linear scale across dosages without
standard deviations.
[1065] FIG. 86 shows geometric mean (SD) fasted concentration
across scheduled time profile on the semi-logarithmic scale. The
peak rofecoxib concentration was observed between 0 and 5 hours
following administration for all dosages. FIGS. 87-90 show
geometric mean (SD) fasted concentration of rofecoxib across
scheduled time profiles on the semi-logarithmic scale broken down
by concentration.
[1066] FIG. 91 shows geometric mean fasted concentration versus
scheduled time profiles on the semi-logarithmic scale for all
dosages without standard deviations.
[1067] FIG. 92 shows a scatterplot of fasted AUC.sub.0-.infin.
values by age and by TRM-201 dosage. FIG. 93 shows a scatterplot of
fasted AUC.sub.0-.infin. values by race and by TRM-201 dosage. FIG.
94 shows a scatterplot of fasted AUC.sub.0-.infin. values by body
weight and by TRM-201 dosage. FIG. 95 shows a scatterplot of fasted
AUC.sub.0-.infin. values by BMI and by TRM-201 dosage.
[1068] FIG. 96 shows a scatterplot of fasted C.sub.max values by
age and by TRM-201 dosage. FIG. 97 shows a scatterplot of fasted
C.sub.max values by race and by TRM-201 dosage. FIG. 98 shows a
scatterplot of fasted C.sub.max values by body weight and by
TRM-201 dosage. FIG. 99 shows a scatterplot of fasted C.sub.max
values by BMI and by TRM-201 dosage.
[1069] FIG. 100 shows a scatterplot of fasted AUC.sub.0-.infin. and
C.sub.max values, dose-adjusted on raw scale, for each TRM-201
dosage. FIG. 101 shows a scatterplot of fasted AUC.sub.0-.infin.
and C.sub.max values, not dose-adjusted on natural-log scale, for
each TRM-201 dosage. FIGS. 102A-B show a boxplot of fasted
AUC.sub.0-.infin. and C.sub.max indices, respectively, for each
dosage.
[1070] FIGS. 103-104 show a comparison of the mean plasma
concentration (ng/L) versus time for TRM-201 20 mg and the 25 mg
"VIOXX" tablet and oral suspension products reported in Schwartz,
J. I., et al. Clin. Drug Invent. 2003, 23 (8): 503-509.
Unexpected Results
[1071] The FDA-approved label for the "VIOXX" product provided that
"[t]he pharmaco-kinetics of rofecoxib are comparable in men and
women," and that "[m]eta-analysis of pharmacokinetic studies has
suggested a slightly (10-15%) higher AUC of rofecoxib in Blacks and
Hispanics as compared to Caucasians." See the "VIOXX" label at p.
2.
[1072] In some embodiments, the subject matter disclosed herein
relates to the surprising and unexpected discovery that certain of
the formulations and methods described herein can achieve different
pharmacokinetic profiles in men and women following single
administration of the same amount of rofecoxib, contrary to what
was described in the FDA-approved label for the "VIOXX" product. It
was also surprisingly and unexpectedly discovered that certain of
the formulations and methods described herein can achieve a higher
AUC in Caucasian subjects than African American subjects following
single administration of the formulations comprising rofecoxib as
described herein.
REFERENCES FOR EXAMPLE 6
[1073] Bresalier R S, Sandler R S, Quan H, et al. Cardiovascular
events associated with rofecoxib in a colorectal adenoma
chemoprevention trial. New Engl J Med 2005; 352:1092-102. [1074]
Matthews C Z, Woolf E J, Matuszewski B K. Improved procedure for
the determination of rofecoxib in human plasma involving 96-well
solid-phase extraction and fluorescence detection. J Chromatogr A.
2002; 949(1-2):83-9. [1075] Schwartz J I, Larson P J, Porras A G,
et al. Pharmacokinetic evaluation of rofecoxib: comparison of
tablet and suspension formulations. Clin Drug Invest. 2003;
23(8):503-9. [1076] Tsoukas C, Eyster M E, Shingo S, et al.
Evaluation of the efficacy and safety of etoricoxib in the
treatment of hemophilic arthropathy. Blood. 2006; 107(5):1785-90.
[1077] U.S. Food and Drug Administration. Analysis and
recommendations for agency action regarding nonsteroidal
antiinflammatory drugs and cardiovascular risk. J Pain Palliat Care
Pharmacother. 2005; 19(4):83-97. [1078] Vioxx (rofecoxib) [package
insert]. Merck & Co., Inc. Whitehouse Station, N.J.; 2016.
Example 7--Bioanalytical Method to Measure Rofecoxib Plasma
Concentrations
Introduction
[1079] In order to support clinical studies with TRM-201
(rofecoxib), a method was developed for the determination of
rofecoxib in human plasma by LC-MS/MS. This method was validated in
accordance with the FDA Good Laboratory Practice Regulations (GLP)
as set forth in Title 21 of the U.S. Code of Federal Regulations
Part 58 as well as FDA Guidance for Industry: Bioanalytical Method
Validation, May 2018. A summary of the validated method is provided
in Table 22.
TABLE-US-00023 TABLE 22 Validation Summary for Rofecoxib Report
Title Validation of a Method for the Determination of Rofecoxib in
Human Plasma by LC-MS/MS Analyte Name Rofecoxib Internal Standard
(IS) Rolccoxib-d.sub.5 Analytical Method Type LC-MS/MS Extraction
Method Liquid-liquid Sample Volume 100 .mu.L QC Concentrations 0.5,
1.5, 20, 200, and 400 ng/mL Standard Curve Concentrations 0.5, 1,
5, 10, 50, 100, 450, and 500 ng/mL Lower Limit Of Quantitation 0.5
ng/mL Upper Limit Of Quantitation 500 ng/mL Mean Recovery of
Analyte (%) 92.6 Mean Recovery of Internal 92.7 Standard (%)
Variation of Matrix Effect from .ltoreq.2.6 Six Lots ofMatrix (%
CV) Sensitivity Analyte response [LLOQ/zero calibrator (i.e. Blank
+ IS)] > five LLOQ QC Intra-run Precision 2.0 to 7.8 Range (%
CV) LLOQ QC Intra-run Accuracy -11.8 to -1.8 Range (% RE)
Analytical QC Intra-run Precision 0.8 to 6.6 Range (% CV)
Analytical QC Intra-run Accuracy -4.0 to 3.0 Range (% RE) LLOQ QC
Inter-run Precision 7.3 (% CV) LLOQ QC Inter-run Accuracy -5.2 (%
RE) Analytical QC Inter-run Precision 3.0 to 4.9 Range (% CV)
Analytical QC Inter-run Accuracy -2.5 to 0.7 Range (% RE) Stock
Solution Stability in 202 Days at -20.degree. C. Dimethyl Sulfoxide
17 Hours at Ambient Temperature Processed Sample Stability 174
Hours at 4.degree. C. Benchtop Stability in Plasma 26 Hours at
Ambient Temperature Freeze/Thaw Stability in Plasma 5 Cycles at
-20.degree. C. and -70.degree. C. Benchtop Stability in Whole 2
Hours in an Ice Bath when Blood Centrifuged at 4.degree. C. or
Ambient Temperature Long-term Storage Stability in 184 Days at
-20.degree. C. and -70.degree. C. Plasma Dilution Integrity 1000
ng/mL diluted 20-fold Selectivity .ltoreq.20.0% LLOQ for analyte;
.ltoreq.5.0% for IS Spike-in Selectivity Meets Acceptance Criteria
2% Hemolyzed Plasma Test No impact on assay performance Lipemic
Plasma Test No impact on assay performance Batch Size Test 192
Injections Carryover <20% LLOQ (Rofecoxib) <5% Carryover IS
(Rofecoxib-d.sub.5)
EQUIVALENTS
[1080] The invention can be embodied in other specific forms
without departing from the spirit or essential characteristics
thereof. The foregoing embodiments are therefore to be considered
in all respects illustrative rather than limiting on the invention
described herein.
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References