U.S. patent application number 11/072194 was filed with the patent office on 2005-11-03 for tranexamic acid formulations.
This patent application is currently assigned to Xanodyne Pharmaceuticals, Inc.. Invention is credited to Greiwe, Jeffrey S., Heasley, Ralph A., Moore, Keith A..
Application Number | 20050244495 11/072194 |
Document ID | / |
Family ID | 35187376 |
Filed Date | 2005-11-03 |
United States Patent
Application |
20050244495 |
Kind Code |
A1 |
Moore, Keith A. ; et
al. |
November 3, 2005 |
Tranexamic acid formulations
Abstract
Disclosed are modified release oral tranexamic acid formulations
and methods of treatment therewith.
Inventors: |
Moore, Keith A.; (Loveland,
OH) ; Heasley, Ralph A.; (Union, KY) ; Greiwe,
Jeffrey S.; (Ft. Thomas, KY) |
Correspondence
Address: |
DAVIDSON, DAVIDSON & KAPPEL, LLC
485 SEVENTH AVENUE, 14TH FLOOR
NEW YORK
NY
10018
US
|
Assignee: |
Xanodyne Pharmaceuticals,
Inc.
Florence
KY
|
Family ID: |
35187376 |
Appl. No.: |
11/072194 |
Filed: |
March 4, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60550113 |
Mar 4, 2004 |
|
|
|
60592885 |
Jul 30, 2004 |
|
|
|
Current U.S.
Class: |
424/468 ;
514/574 |
Current CPC
Class: |
A61K 9/2013 20130101;
A61K 9/2009 20130101; A61K 31/195 20130101; A61P 15/00 20180101;
A61P 7/04 20180101; A61K 9/2054 20130101; A61K 31/19 20130101; A61K
31/196 20130101; A61K 9/2027 20130101; Y10S 514/951 20130101; A61K
9/2059 20130101 |
Class at
Publication: |
424/468 ;
514/574 |
International
Class: |
A61K 007/16; A61K
009/22; A61K 031/19 |
Claims
What is claimed is:
1. A modified release oral dosage form comprising tranexamic acid
or pharmaceutically acceptable salt thereof and a modified release
material which provides for the modified release of the tranexamic
acid or pharmaceutically acceptable salt thereof from the dosage
form such that the dosage form is suitable for administration on a
two or three times a day basis; said dosage form providing an
in-vitro dissolution release rate of the tranexamic acid or
pharmaceutically acceptable salt thereof, when measured by a USP 27
Apparatus Type II Paddle Method @ 50 RPM in 900 ml water at
37.+-.0.5.degree. C., of less than about 70% by weight tranexamic
acid or pharmaceutically acceptable salt thereof released at about
45 minutes and about 100% by weight of said tranexamic acid or
pharmaceutically acceptable salt thereof released by about 120
minutes.
2. The modified release oral dosage form of claim 1, wherein said
dosage form provides an in-vitro dissolution release rate of the
tranexamic acid or pharmaceutically acceptable salt thereof, when
measured by the USP 27 Apparatus Type II Paddle Method @ 50 RPM in
900 ml water at 37.+-.0.5.degree. C., of about 0% to about 40% by
weight tranexamic acid or pharmaceutically acceptable salt thereof
released at about 15 minutes, from about 20% to about 60% by weight
tranexamic acid or pharmaceutically acceptable salt thereof
released at about 30 minutes, from about 40% to about 65% by weight
tranexamic acid or pharmaceutically acceptable salt thereof
released at about 45 minutes, from about 50% to about 95% by weight
tranexamic acid or pharmaceutically acceptable salt thereof
released at about 60 minutes, and not less than about 60% by weight
tranexamic acid or pharmaceutically acceptable salt thereof
released at about 90 minutes.
3. The modified release oral dosage form of claim 1, wherein the
dosage form releases about 10% to about 25% by weight tranexamic
acid or pharmaceutically acceptable salt thereof every 15 minutes
when measured in vitro utilizing the USP 27 Apparatus Type II
Paddle Method @ 50 RPM in 900 ml water at 37.+-.0.5.degree. C.
4. The modified release oral dosage form of claim 1, wherein the
dosage form releases about 1% tranexamic acid or pharmaceutically
acceptable salt thereof every minute when measured in-vitro
utilizing the USP 27 Apparatus Type II paddle method at 50 RPM in
900 ml water at 37.+-.0.5.degree. C.
5. The modified release oral dosage form of claim 1 which provides
a mean maximum plasma concentration (C.sub.max) of tranexamic acid
of from about 9 to about 14.5 mcg/ml after single dose oral
administration of about 1300 mg of tranexamic acid or
pharmaceutically acceptable salt thereof included in one or more of
said modified release oral dosage form to humans.
6. The modified release oral dosage form of claim 1 which provides
a mean maximum plasma concentration (C.sub.max) of tranexamic acid
of from about 5 to about 25 mcg/ml after steady state oral
administration of about 1300 mg of tranexamic acid or
pharmaceutically acceptable salt thereof included in one or more of
said modified release oral dosage form to humans.
7. The modified release oral dosage form of claim 1 which provides
a mean maximum plasma concentration (C.sub.max) of tranexamic acid
of from about 10 to about 20 mcg/ml after steady state oral
administration of about 1300 mg of tranexamic acid or
pharmaceutically acceptable salt thereof included in one or more of
said modified release oral dosage form to humans.
8. The modified release oral dosage form of claim 1 which provides
mean time to maximum plasma concentration (T.sub.max) at from about
1.0 to about 5.5 hours after oral administration of one or more of
said modified release oral dosage form to humans.
9. The modified release oral dosage form of claim 1, wherein the
dosage form provides a mean transit time of said tranexamic acid of
7.70.+-.0.72 hours when orally administered across a patient
population.
10. The modified release oral dosage form of claim 1, wherein the
dosage form provides a mean absorption time of said tranexamic acid
of 4.18.+-.0.70 hours when orally administered across a patient
population.
11. The modified release oral dosage form of claim 1, which
provides for the reduction of at least one side effect selected
from the group consisting of headache, nausea, vomiting, diarrhea,
constipation, cramping, bloating, and combinations thereof, as
compared to an immediate release oral dosage form containing an
equivalent amount of tranexamic acid or pharmaceutically acceptable
salt thereof, when administered across a same or different
population of patients as said modified release dosage form, and
wherein said immediate release dosage form releases all of said
tranexamic acid or pharmaceutically acceptable salt thereof within
about 45 minutes when measured in vitro utilizing the USP 27
Apparatus Type II Paddle Method @ 50 RPM in 900 ml water at
37.+-.0.5.degree. C.
12. The modified release oral dosage form of claim 1, which
provides a mean transit time of said tranexamic acid which is at
least about 20 minutes longer than the immediate release
formulation when administered across a patient population.
13. The modified release oral dosage form of claim 1, which
provides a mean absorption time of said tranexamic acid which is at
least about 20 minutes longer than the immediate release
formulation when administered across a patient population.
14. The modified release oral dosage form of claim 1, wherein said
dosage form provides less headache, nausea, or combination thereof
in comparision to a therapeutically equivalent amount of tranexamic
acid or pharmaceutically acceptable salt thereof administered
intravenously in five minutes or less when administered across a
patient population.
15. The modified release oral dosage form of claim 1, wherein said
tranexamic acid or pharmaceutically acceptable salt thereof is
included in said dosage form in an amount of from about 375 mg to
about 1 gram.
16. The modified release oral dosage form of claim 1, wherein said
tranexamic acid or pharmaceutically acceptable salt thereof is
included in said dosage form in an amount of about 650 mg.
17. The modified release oral dosage form of claim 1, wherein said
dosage form is selected from the group consisting of one or more
tablets, capsules, granules, powders, pellets, dragees, troches,
non-pareils, and pills.
18. The modified release oral dosage form of claim 1, wherein said
dosage form provides a bioavailability of said tranexamic acid of
greater than 40% when administered to humans.
19. A method of treating a human patient in need of tranexamic acid
therapy comprising administering at least one oral dosage form of
claim 1 to a human patient suffering from menorrhagia, conization
of the cervix, epistaxis, hyphema, hereditary angioneurotic edema,
a patient with a blood coagulation disorder undergoing dental
surgery, or combination thereof.
20. A method of treating a patient in need of tranexamic acid
therapy comprising: orally administering to said patient about 1300
mg of tranexamic acid or pharmaceutically acceptable salt thereof
in at least one oral dosage form comprising said tranexamic acid or
pharmaceutically acceptable salt thereof and a modified release
material which provides a mean maximum plasma concentration
(C.sub.max) of tranexamic acid of from about 5 to about 17.5 mcg/ml
after single dose oral administration to humans.
21. The method of claim 20, wherein said at least one oral dosage
form provides a mean maximum plasma concentration (C.sub.max) of
tranexamic acid of from about 9 to about 14.5 mcg/ml after single
dose oral administration to humans.
22. The method of claim 20, wherein said at least one oral dosage
form provides a mean maximum plasma concentration (C.sub.max) of
tranexamic acid of from about 5 to about 25 mcg/ml after steady
state oral administration to humans.
23. The method of claim 20, wherein said at least one oral dosage
form provides a mean maximum plasma concentration (C.sub.max) of
tranexamic acid of from about 10 to about 20 mcg/ml after steady
state oral administration to humans.
24. The method of claim 20, wherein said at least one oral dosage
form provides a mean time to maximum plasma concentration
(T.sub.max) at from about 1.0 to about 5.5 hours after oral
administration to humans.
25. The method of claim 20, wherein said at least one oral dosage
form is two oral dosage forms.
26. A dose of tranexamic acid comprising two or three unit dosage
forms of a modified release formulation, each unit dosage form of
said modified release formulation comprising about 585 to about 715
mg of tranexamic acid or a pharmaceutically acceptable salt thereof
and a modified release material which provides for the release of
the tranexamic acid or pharmaceutically acceptable salt thereof
from the dosage form such that said dosage form is suitable for
administration two or three times a day.
27. The dose of claim 26, wherein each unit dosage form comprises
about 650 mg of tranexamic acid or pharmaceutically acceptable salt
thereof.
28. The dose of claim 26, wherein the modified release material is
selected from the group consisting of vinyl polymers, phthalic acid
derivatives of vinyl copolymers, hydroxyalkylcelluloses,
alkylcelluloses, cellulose acetates, hydroxyalkylcellulose
acetates, cellulose ethers, alkylcellulose acetates, and partial
esters thereof, and polymers and copolymers of lower alkyl acrylic
acids and lower alkyl acrylates, and partial esters thereof, and
mixtures thereof.
29. The dose of claim 26, wherein the modified release material is
selected from the group consisting of gel-forming polymers,
hydratable polymers, water soluble polymers, water swellable
polymers, and mixtures thereof.
30. The dose of claim 26, wherein the modified release material is
selected from the group consisting of hydroxypropylcellulose,
hydryoxpropylmethylcellulose, carboxymethylcellulose, polyvinyl
alcohol, polyvinylpyrrolidone, methylcellulose, vinyl
acetate/crotonic acid copolymers, methacrylic acid copolymers,
maleic anhydride/methyl vinyl ether copolymers, derivatives
thereof, and mixtures thereof.
31. The dose of claim 26, which provides a mean maximum plasma
concentration (C.sub.max) of tranexamic acid of from about 5 to
about 17.5 mcg/ml after single dose oral administration to
humans.
32. The dose of claim 26, which provides a mean maximum plasma
concentration (C.sub.max) of tranexamic acid of from about 9.0 to
about 14.5 mcg/ml after single dose oral administration to
humans.
33. The dose of claims 26, which provides a mean maximum plasma
concentration (C.sub.max) of tranexamic acid of from about 5 to
about 25 mcg/ml after steady state oral administration to
humans.
34. The dose of claim 26, which provides a mean maximum plasma
concentration (C.sub.max) of tranexamic acid of from about 10
mcg/ml to about 20 mcg/ml after steady state oral administration to
humans.
35. The dose of claim 26, which provides a mean time to maximum
plasma concentration (T.sub.max) of tranexamic acid at from about 1
to about 5.5 hours oral administration to humans.
36. The dose of claim 26, which provides for a reduction in
menstrual blood loss per menstrual cycle by about 20% to 100% after
oral administration to a human patient suffering from heavy
menstrual bleeding.
37. The dose of claim 26, wherein the unit dosage forms provide a
dissolution release rate in-vitro of the tranexamic acid or
pharmaceutically acceptable salt thereof, when measured by the USP
27 Apparatus Type II Paddle Method @ 50 RPM in 900 ml water at
37.+-.0.5.degree. C., of less than about 70% by weight tranexamic
acid released at about 45 minutes.
38. A modified release oral dosage form comprising tranexamic acid
and a modified release material which provides for the modified
release of the tranexamic acid from the dosage form such that the
dosage form is suitable for administration on a two or three times
a day basis, the dosage form providing a reduction of at least one
side effect selected from the group consisting of headache, nausea,
vomiting, diarrhea, constipation, cramping, bloating, and
combinations thereof, as compared to an equivalent amount of
tranexamic acid in an immediate release oral dosage form when
administered across a patient population.
39. The modified release oral dosage form of claim 38, wherein said
side effect is headache or nausea.
40. The modified release oral dosage form of claim 38, which
provides a mean transit time of said tranexamic acid which is at
least about 20 minutes longer than the immediate release
formulation.
41. The modified release oral dosage form of claim 38, which
provides a mean absorption time of said tranexamic acid which is at
least about 20 minutes longer than the immediate release
formulation.
42. A modified release oral dosage form comprising tranexamic acid
or a pharmaceutically acceptable salt thereof and a modified
release excipient, said dosage form providing for the release of
the tranexamic acid or pharmaceutically acceptable salt thereof
which is slower than an immediate release oral dosage form and
faster than a controlled release oral dosage form, such that the
modified release oral dosage form is suitable for administration
two or three times a day.
43. The modified release oral dosage form of claim 42, wherein said
tranexamic acid is included in the dosage form in an amount of from
about 375 mg to about 1 gram.
44. The modified release oral dosage form of claim 42, wherein said
modified release material is selected from the group consisting of
vinyl polymers, phthalic acid derivatives of vinyl copolymers,
hydroxyalkylcelluloses, alkylcelluloses, cellulose acetates,
hydroxyalkylcellulose acetates, cellulose ethers, alkylcellulose
acetates, and partial esters thereof, and polymers and copolymers
of lower alkyl acrylic acids and lower alkyl acrylates, and partial
esters thereof, and mixtures thereof.
45. The modified release oral dosage form of claim 42, wherein the
modified release material is selected from the group consisting of
hydroxypropylcellulose, hydryoxpropylmethylcellulose,
carboxymethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone,
methylcellulose, vinyl acetate/crotonic acid copolymers,
methacrylic acid copolymers, maleic anhydride/methyl vinyl ether
copolymers, derivatives thereof, and mixtures thereof.
Description
[0001] This application claims priority from U.S. Provisional
Application No. 60/550,113, filed Mar. 4, 2004, and U.S.
Provisional Application No. 60/592,885, filed Jul. 30, 2004, the
disclosures of which are both hereby incorporated by reference in
their entireties.
FIELD OF THE INVENTION
[0002] The invention is directed to modified release oral
tranexamic acid formulations that preferably minimize or eliminate
undesirable side effects and methods of treatment with these
formulations.
BACKGROUND OF THE INVENTION
[0003] Tranexamic acid (trans-4-(aminomethyl)cyclohexanecarboxylic
acid, Cyklokapron.RTM. (Pfizer) is an antifibrinolytic agent. That
is, it helps to prevent lysis or dissolution of a fibrin clot which
forms in the normal physiologic process of hemostasis. Its
mechanism of action is as a competitive inhibitor of plasminogen
activation, and as a noncompetitive inhibitor of plasmin; both
plasminogen and plasmin are activators of fibrinolysis and active
clot-lysing agents. Tranexamic acid thus helps to stabilize fibrin
clots, which in turn maintains coagulation and helps to control
bleeding.
[0004] Tranexamic acid is used to control excess bleeding, for
example, excess bleeding that occurs during dental procedures in
hemophiliacs and for heavy bleeding during menstruation
(menorrhagia). Women suffering from menorrhagia are typically
treated orally with 500 mg tranexamic acid tablets administered
three or four times daily with a total daily dose ranging from 3
grams/day (two tablets every eight hours) to 6 grams/day (three
tablets every six hours). However, this treatment may cause adverse
gastrointestinal reactions, including nausea, vomiting, diarrhea,
and cramping, etc. These gastrointestinal side effects are due to
the quantity of tranexamic acid and/or rapid rate of release of
tranexamic acid into the stomach with each dose, as well as the
large quantity of excipients used in the tablet formulation that
are introduced into the stomach. Such side effects, in addition to
the cramping, bloating, pain, and other symptoms that may accompany
menses, are undesirable, and a formulation of tranexamic acid is
needed which will reduce or eliminate these side effects.
SUMMARY OF THE INVENTION
[0005] Formulations of tranexamic acid which minimize or eliminate
the undesirable gastrointestinal side effects in patients on oral
tranexamic acid therapy, e.g. women treated for menorrhagia (heavy
menstrual bleeding) are disclosed. The present invention is
directed in part to a modified release formulation, formulated so
that the release of tranexamic acid thereof from the dosage form
occurs in a designed fashion to prevent a bolus of tranexamic acid
being introduced into the stomach and available for dissolution in
the gastric contents. Such modified release formulations reduce the
concentration of tranexamic acid dissolved in the stomach contents
such as e.g., preventing a large bolus of tranexamic acid being
introduced in the stomach. The beneficial effect of this reduced
tranexamic acid concentration is to lower the amount of tranexamic
acid in the gastric contents so that there are fewer adverse
effects with tranexamic acid therapy. This reduction in adverse
effects preferably results in improved patient compliance with
therapy, because preferably patients will not intentionally miss
taking a dose to avoid these adverse side effects. Physicians will
also preferably be more likely to initiate and maintain tranexamic
acid treatment for their patients because of the reduced patient
complaints.
[0006] It is an object of the invention to provide an oral dosage
form comprising tranexamic acid which is suitable for
administration on a two or three times a day basis to humans.
[0007] It is a further object of the invention to provide a
modified release oral dosage form comprising tranexamic acid and a
modified release material which provides for the modified release
of the tranexamic acid and is suitable for administration on a two
or three times a day basis.
[0008] It is a further object of certain embodiments of the present
invention to provide a modified release oral dosage form comprising
tranexamic acid and a modified release material which minimizes or
eliminates the undesirable gastrointestinal side effects in
patients on oral tranexamic acid therapy while maintaining or
improving the therapeutic effect of tranexamic acid.
[0009] It is a further object of certain embodiments of the present
invention to provide a method of treating a patient suffering from
heavy menstrual bleeding (menorrhagia) by orally administering to
the patient one or more dosage forms comprising tranexamic acid and
a modified release material which provide(s) for therapeutically
effective levels of tranexamic acid suitable for two or three times
a day administration.
[0010] The above advantages and objects and others can be achieved
by virtue of the present invention which is directed in part to a
modified release oral dosage form comprising tranexamic acid or a
pharmaceutically acceptable salt thereof and a modified release
material which provides for the modified release of the tranexamic
acid or pharmaceutically acceptable salt thereof from the dosage
form such that the dosage form is suitable for administration on a
two or three times a day basis; said dosage form providing an
in-vitro dissolution release rate of the tranexamic acid or
pharmaceutically acceptable salt thereof, when measured by a USP 27
Apparatus Type II Paddle Method @ 50 RPM in 900 ml water at
37.+-.0.5.degree. C., of less than about 70% by weight tranexamic
acid or pharmaceutically acceptable salt thereof released at about
45 minutes and about 100% by weight of said tranexamic acid or
pharmaceutically acceptable salt thereof released by about 120
minutes.
[0011] In certain embodiments, the present invention is directed to
a method of treating a patient in need of tranexamic acid or
pharmaceutically acceptable salt thereof therapy comprising
administering to the patient about 1300 mg of tranexamic acid or
pharmaceutically acceptable salt thereof in at least one oral
dosage form comprising said tranexamic acid or pharmaceutically
acceptable salt thereof and a modified release material which
provides a mean maximum plasma concentration (C.sub.max) of
tranexamic acid of from about 5 to about 17.5 mcg/ml, preferably
from about 6.5 to about 15 mcg/ml, more preferably from about 9 to
about 14.5 mcg/ml after single dose oral administration to
humans.
[0012] In certain embodiments, the invention is further directed to
a method of treating a patient in need of tranexamic acid or
pharmaceutically acceptable salt thereof therapy comprising
administering to the patient about 1300 mg of tranexamic acid or
pharmaceutically acceptable salt thereof in at least one oral
dosage form comprising said tranexamic acid or pharmaceutically
acceptable salt thereof and a modified release material which
provides a mean maximum plasma concentration (C.sub.max) of
tranexamic acid of from about 5 to about 25 mcg/ml, preferably from
about 10 to about 20 mcg/ml, more preferably from about 12.5 to
about 17.5 mcg/ml, most preferably about 15 to about 17 mcg/ml
after steady state oral administration to humans.
[0013] In certain embodiments, the modified release oral dosage
form of the present invention provides a mean T.sub.max of
tranexamic acid at from about 1 to about 5.5 hours, preferably at
from about 2 to about 4 hours, more preferably at from about 2 to
about 3.5 hours after oral administration of the dosage form to
humans.
[0014] In certain embodiments, the invention is further directed to
a modified release oral dosage form comprising tranexamic acid or
pharmaceutically acceptable salt thereof and a modified release
material which provides for the modified release of the tranexamic
acid or pharmaceutically acceptable salt thereof from the dosage
form such that the dosage form is suitable for administration on a
two or three times a day basis and the dosage form provides a
dissolution release rate in-vitro of the tranexamic acid or
pharmaceutically acceptable salt thereof when measured by the USP
27 Apparatus Type II Paddle Method @ 50 RPM in 900 ml water at
37.+-.0.5.degree. C. of less than about 40% by weight tranexamic
acid or pharmaceutically acceptable salt thereof released at about
15 minutes, less than about 70% by weight tranexamic acid or
pharmaceutically acceptable salt thereof released at about 45
minutes, and not less than 50% by weight tranexamic acid or
pharmaceutically acceptable salt thereof released at about 90
minutes.
[0015] In certain embodiments, the invention is further directed to
a modified release oral dosage form comprising tranexamic acid or
pharmaceutically acceptable salt thereof and a modified release
material which provides for the modified release of the tranexamic
acid or pharmaceutically acceptable salt thereof from the dosage
form such that the dosage form is suitable for administration on a
two or three times a day basis and the dosage form provides a
dissolution release rate in-vitro of the tranexamic acid or
pharmaceutically acceptable salt thereof when measured by the USP
27 Apparatus Type II Paddle Method @ 50 RPM in 900 ml water at
37.+-.0.5.degree. C. of about 0% to about 40% by weight tranexamic
acid or pharmaceutically acceptable salt thereof released at about
15 minutes, from about 20% to about 60% by weight tranexamic acid
or pharmaceutically acceptable salt thereof released at about 30
minutes, from about 40% to about 65% by weight tranexamic acid or
pharmaceutically acceptable salt thereof released at about 45
minutes, from about 50% to about 90% by weight tranexamic acid or
pharmaceutically acceptable salt thereof release at about 60
minutes, and not less than 60% by weight tranexamic acid or
pharmaceutically acceptable salt thereof released at about 90
minutes.
[0016] In certain embodiments, the invention is further directed to
a modified release oral dosage form comprising tranexamic acid or
pharmaceutically acceptable salt thereof and a modified release
material, which provides for a bioavailability of tranexamic acid
of greater than 40%, from about 41% to about 60%, preferably from
about 42% to about 50%, more preferably about 45% after oral
administration to humans
[0017] In certain embodiments, the present invention is further
directed to a modified release oral dosage form comprising from
about 585 to about 715 mg of tranexamic acid or pharmaceutically
acceptable salt thereof, preferably about 650 mg of tranexamic acid
or pharmaceutically acceptable salt thereof, and a modified release
material which provides for the modified release of the tranexamic
acid or pharmaceutically acceptable salt thereof from the dosage
form such that the dosage form is suitable for administration on a
two or three times a day basis.
[0018] In certain embodiments, the present invention is directed to
a modified release oral dosage form comprising tranexamic acid or
pharmaceutically acceptable salt thereof and a modified release
material which provides for the modified release of the tranexamic
acid or pharmaceutically acceptable salt thereof from the dosage
form such that the dosage form is suitable for administration on a
two or three times a day basis, the dosage form providing a
reduction of at least one side effect selected from the group
consisting of headache, nausea, vomiting, diarrhea, constipation,
cramping, bloating, and combinations thereof, as compared to an
equivalent amount of tranexamic acid or pharmaceutically acceptable
salt thereof in an immediate release oral dosage form when
administered across a patient population.
[0019] In certain embodiments, the present invention is directed to
a modified release oral dosage form comprising tranexamic acid or
pharmaceutically acceptable salt thereof and a modified release
excipient, said dosage form providing for the release of the
tranexamic acid or pharmaceutically acceptable salt thereof which
is slower than an immediate release oral dosage form and faster
than a controlled release oral dosage form, such that the modified
release oral dosage form is suitable for administration two or
three times a day.
[0020] In certain embodiments, the invention is further directed to
a modified release oral dosage form comprising about 650 mg of
tranexamic acid or pharmaceutically acceptable salt thereof and a
modified release material, the dosage form being suitable for oral
administration on a three times a day basis, and the dosage form
providing a mean maximum plasma concentration (C.sub.max) of
tranexamic acid of from about 5 to about 17.5 mcg/ml, preferably
from about 6.5 to about 15 mcg/ml, more preferably from about 9 to
about 14.5 mcg/ml per 1300 mg tranexamic acid after single dose
oral administration to humans.
[0021] In certain embodiments, the invention is further directed to
a modified release oral dosage form comprising about 650 mg of
tranexamic acid or pharmaceutically acceptable salt thereof and a
modified release material, the dosage form being suitable for oral
administration on a twice a day basis, and the dosage form
providing a mean maximum plasma concentration (C.sub.max) of
tranexamic acid of from about 5 to about 40 mcg/ml, preferably from
about 10 to about 30 mcg/ml per 1950 mg tranexamic acid after
single dose oral administration to humans.
[0022] In certain embodiments, the invention is further directed to
a modified release oral dosage form comprising about 650 mg of
tranexamic acid or pharmaceutically acceptable salt thereof and a
modified release material, the dosage form being suitable for oral
administration on a three times a day basis, and the dosage form
providing a mean plasma concentration of tranexamic acid of from
about 5 to about 25 mcg/ml, preferably from about 7.5 to about 15
mcg/ml, more preferably from about 8 to about 10 mcg/ml, most
preferably about 9 mcg/ml per 1300 mg tranexamic acid after steady
state oral administration to humans.
[0023] In certain embodiments, the invention is further directed to
a modified release oral dosage form comprising about 650 mg of
tranexamic acid or pharmaceutically acceptable salt thereof and a
modified release material, the dosage form being suitable for
administration on a three times a day basis, and the dosage form
providing a mean maximum plasma concentration (C.sub.max) of
tranexamic acid of from about 5 to about 25 mcg/ml, preferably from
about 10 to about 20 mcg/ml, more preferably from about 12.5 to
about 17.5 mcg/ml, most preferably about 15 to about 17 mcg/ml per
1300 mg tranexamic acid after steady state oral administration to
humans.
[0024] In certain embodiments, the invention is further directed to
a modified release oral dosage form comprising about 650 mg of
tranexamic acid or pharmaceutically acceptable salt thereof and an
modified release material, the dosage form being suitable for
administration on a three times a day basis, and the dosage form
providing a mean plasma trough concentration of tranexamic acid or
pharmaceutically acceptable salt thereof of from about 2 to about
10 mcg/ml, preferably from about 3 to about 7.5 mcg/ml, more
preferably about 4 to about 7 mcg/ml, most preferably about 5 to
about 6 mcg/ml per 1300 mg tranexamic acid or after steady state
oral administration to humans.
[0025] In certain embodiments, the invention is further directed to
a method of treating a patient with a therapeutically effective
amount of tranexamic acid or pharmaceutically acceptable salt
thereof comprising administering to the patient two dosage forms of
the present invention, each dosage form comprising from about 585
mg to about 715 mg of tranexamic acid or pharmaceutically
acceptable salt thereof, preferably about 650 mg tranexamic acid or
pharmaceutically acceptable salt thereof, and a modified release
material such that the dosage form is suitable for oral
administration on a three times a day basis.
[0026] In certain embodiments, the invention is further directed to
a method of treating a patient with a therapeutically effective
amount of tranexamic acid or pharmaceutically acceptable salt
thereof comprising administering to the patient three dosage forms
of the present invention, each dosage form comprising from about
585 mg to about 715 mg, preferably about 650 mg tranexamic acid or
pharmaceutically acceptable salt thereof, and a modified release
material such that the dosage form is suitable for oral
administration on a twice a day basis.
[0027] In certain embodiments, the invention is directed to a dose
of tranexamic acid or pharmaceutically acceptable salt thereof
comprising two unit dosage forms of a modified release formulation,
each unit dosage form of said modified release formulation
comprising from about 585 mg to about 715 mg, preferably about 650
mg of tranexamic acid or pharmaceutically acceptable salt thereof,
and a modified release material which provides for the release of
the tranexamic acid or pharmaceutically acceptable salt thereof
from the dosage form such that the dose provides a therapeutic
effect when administered three times a day.
[0028] In certain embodiments, the invention is directed to a dose
of tranexamic acid comprising three unit dosage forms of a modified
release formulation, each unit dosage form of said modified release
formulation comprising from about 585 mg to about 715 mg,
preferably about 650 mg of tranexamic acid or pharmaceutically
acceptable salt thereof, and a modified release material which
provides for the release of the tranexamic acid or pharmaceutically
acceptable salt thereof from the dosage form such that the dose
provides a therapeutic effect when administered twice a day.
[0029] In certain preferred embodiments, the invention is further
directed to a modified release oral dosage form including
tranexamic acid or pharmaceutically acceptable salt thereof and a
modified release material which provides for the modified release
of the tranexamic acid or pharmaceutically acceptable salt thereof
from the dosage form such that the dosage form is suitable for
administration on a two or three times a day basis and the dosage
form provides a dissolution release rate in-vitro of the tranexamic
acid or pharmaceutically acceptable salt thereof when measured by
the USP 27 Apparatus Type II Paddle Method @ 50 RPM in 900 ml water
at 37.+-.0.5.degree. C. of about 0% to about 40% by weight
tranexamic acid or pharmaceutically acceptable salt thereof
released at about 15 minutes, from about 20% to about 60% by weight
tranexamic acid or pharmaceutically acceptable salt thereof
released at about 30 minutes, from about 40% to about 80% by weight
tranexamic acid or pharmaceutically acceptable salt thereof
released at about 45 minutes, from about 50% to about 95% by weight
tranexamic acid or pharmaceutically acceptable salt thereof release
at about 60 minutes, and not less than about 60% by weight
tranexamic acid or pharmaceutically acceptable salt thereof
released at about 90 minutes.
[0030] In certain preferred embodiments, the invention is further
directed to a modified release oral dosage form including
tranexamic acid or pharmaceutically acceptable salt thereof and a
modified release material which provides for the modified release
of the tranexamic acid or pharmaceutically acceptable salt thereof
from the dosage form such that the dosage form is suitable for
administration on a two or three times a day basis and the dosage
form provides a dissolution release rate in-vitro of the tranexamic
acid or pharmaceutically acceptable salt thereof when measured by
the USP 27 Apparatus Type II Paddle Method @ 50 RPM in 900 ml water
at 37.+-.0.5.degree. C. of about 14% to about 22% by weight
tranexamic acid or pharmaceutically acceptable salt thereof
released at about 15 minutes, from about 32% to about 50% by weight
tranexamic acid or pharmaceutically acceptable salt thereof
released at about 30 minutes, from about 47% to about 71% by weight
tranexamic acid or pharmaceutically acceptable salt thereof
released at about 45 minutes, from about 61% to about 92% by weight
tranexamic acid or pharmaceutically acceptable salt thereof release
at about 60 minutes, and from about 79% to about 100% by weight
tranexamic acid or pharmaceutically acceptable salt thereof
released at about 90 minutes.
[0031] In certain embodiments, the invention is directed to a
modified release oral dosage form comprising tranexamic acid or
pharmaceutically acceptable salt thereof and an effective amount of
a modified release excipient such that the dosage form releases
from about 10% to about 25% by weight tranexamic acid or
pharmaceutically acceptable salt thereof every 15 minutes when
measured in vitro utilizing the USP 27 Apparatus Type II Paddle
Method @ 50 RPM in 900 ml water at 37.+-.0.5.degree. C. In certain
preferred embodiments, the dosage form releases about 18% to about
23% by weight tranexamic acid or pharmaceutically acceptable salt
thereof every 15 minutes when measured in vitro utilizing the USP
27 Apparatus Type II Paddle Method @ 50 RPM in 900 ml water at
37.+-.0.5.degree. C. Most preferably, the dosage form releases
about 100% of said tranexamic acid or pharmaceutically acceptable
salt thereof within about 120 minutes when measured in vitro
utilizing the USP 27 Apparatus Type II Paddle Method @ 50 RPM in
900 ml water at 37.+-.0.5.degree. C. In certain embodiments, the
dosage form releases about 1% of said tranexamic acid or
pharmaceutically acceptable salt thereof every minute when measured
in vitro utilizing the USP 27 Apparatus Type II Paddle Method @ 50
RPM in 900 ml water at 37.+-.0.5.degree. C.
[0032] In certain preferred embodiments, the modified release oral
dosage form of the invention further provides a mean transit time
of said tranexamic acid of 7.70.+-.0.72 hours when administered
across a patient population.
[0033] In certain preferred embodiments, the modified release oral
dosage form of the invention further provides a mean absorption
time of said tranexamic acid of 4.18.+-.0.70 hours when
administered across a patient population.
[0034] In certain further embodiments, the modified release oral
dosage form of the present invention provides confidence intervals
derived from ln-transformed pharmacokinetic kinetic parameters
AUC.sub.0-t, AUC.sub.inf and C.sub.max for tranexamic acid in
plasma which are within a 80-125% range of an immediate release
formulation including an equivalent amount of tranexamic acid when
administered across a patient population under fasted
conditions.
[0035] In certain embodiments, the invention is further directed to
a modified release oral dosage form comprising tranexamic acid or
pharmaceutically acceptable salt thereof and a modified release
material which provides for the modified release of the tranexamic
acid or pharmaceutically acceptable salt thereof from the dosage
form such that the dosage form is suitable for administration on a
two or three times a day basis and the dosage form provides less
than about 20 percent incidence of headache as a side effect after
single dose oral administration across a patient population.
[0036] In certain embodiments, the invention is further directed to
a modified release oral dosage form comprising tranexamic acid or
pharmaceutically acceptable salt thereof and a modified release
material which provides for the modified release of the tranexamic
acid or pharmaceutically acceptable salt thereof from the dosage
form such that the dosage form is suitable for administration on a
two or three times a day basis and the dosage form provides less
than about 10 percent incidence of nausea as a side effect when
administered across a patient population, less than about 7 percent
incidence of nausea when administered across a patient population,
preferable less than about 5 percent incidence of nausea as a side
effect when administered across a patient population, more
preferably less than about 2 percent incidence of nausea as a side
effect after single dose oral administration across a patient
population.
[0037] In certain embodiments, the modified release oral dosage
form of the present invention provides less CNS side effects (e.g.,
headache), less GI side effects (e.g., nausea), or combination
thereof in comparision to an equivalent amount of tranexamic acid
or pharmaceutically acceptable salt thereof in an immediate release
formulation when administered across a patient population.
Additionally or alternatively, in certain embodiments the dosage
form provides less CNS side effects (e.g., headache), less GI side
effects (e.g., nausea), or combination thereof in comparision to a
therapeutically equivalent amount of tranexamic acid administered
intravenously in five minutes or less across a patient
population.
[0038] In certain embodiments, the modified release oral dosage
form of the present invention provides for the reduction of at
least one side effect as compared to an immediate release oral
dosage form including an equivalent amount of tranexamic acid or
pharmaceutically acceptable salt thereof, when the immediate
release dosage form is administered across a same or different
population of patients as said modified release dosage form, and
wherein said immediate release dosage form releases all of said
tranexamic acid or pharmaceutically acceptable salt thereof within
about 45 minutes when measured in vitro utilizing the USP 27
Apparatus Type II Paddle Method @ 50 RPM in 900 ml water at
37.+-.0.5.degree. C. Such side effects can be for example,
headache, nausea, vomiting, diarrhea, constipation, cramping,
bloating, and combinations thereof
[0039] In certain embodiments, the modified release oral dosage
form of the present invention provides a mean transit time of
tranexamic acid which is at least about 20 minutes longer,
preferably about 30 minutes longer, than an immediate release
formulation including an equivalent amount of tranexamic acid when
administered across a patient population.
[0040] In certain embodiments, the dosage form of the present
invention provides a mean absorption time of tranexamic acid which
is at least about 20 minutes longer, preferably about 30 minutes
longer, than an immediate release formulation including an
equivalent amount of tranexamic acid when administered across a
patient population.
[0041] In certain preferred embodiments, the therapeutically
effective dose of the tranexamic acid or pharmaceutically
acceptable salt thereof is provided via the administration of two
or more dosage units. For example, if the dosage unit comprises 650
mg of tranexamic acid or pharmaceutically acceptable salt thereof
and the dose for administration is about 1300 mg then two dosage
units would be administered to a patient in need of such treatment,
or for example, when the dose for administration is 1950 mg, three
dosage units would be administered.
[0042] In certain preferred embodiments, the invention is further
directed to a method of treating a patient with one or more
modified release oral dosage forms comprising tranexamic acid or
pharmaceutically acceptable salt thereof and a modified release
material, wherein the oral dosage form provides a therapeutically
effective plasma level of tranexamic acid or pharmaceutically
acceptable salt thereof in accordance with a three times a day
(TID) dosing schedule, and the therapeutically effective dose
administered comprises about 1300 mg of tranexamic acid or
pharmaceutically acceptable salt thereof.
[0043] In certain preferred embodiments, the invention is further
directed to a method of treating a patient with one or more
modified release oral dosage forms comprising tranexamic acid or
pharmaceutically acceptable salt thereof and a modified release
material, wherein the oral dosage form provides a therapeutically
effective plasma level of tranexamic acid or pharmaceutically
acceptable salt thereof in accordance with a twice a day (BID)
dosing schedule, and the therapeutically effective dose
administered comprises about 1950 mg of tranexamic acid or
pharmaceutically acceptable salt thereof.
[0044] In certain embodiments, the invention is directed to a
method of providing a tranexamic acid plasma concentration within
the range of about 5 mcg/mL to about 15 mcg/mL by administration of
a modified release formulation of the present invention comprising
tranexamic acid or pharmaceutically acceptable salt thereof and a
modified release material on a three times a day basis to a patient
in need of tranexamic acid or pharmaceutically acceptable salt
thereof treatment.
[0045] In certain embodiments, the invention is further directed to
a method of treating a human patient with heavy menstrual bleeding
(e.g., menorrhagia) comprising administering about 1300 mg of
tranexamic acid or pharmaceutically acceptable salt thereof on a
three times a day basis to the human patient to provide a
tranexamic acid or pharmaceutically acceptable salt thereof plasma
concentration within the range of about 5 mcg/mL to about 15 mcg/mL
after steady state oral administration to a human patient.
[0046] In certain embodiments, the invention is directed to a
method of treating a patient suffering from menorrhagia, conization
of the cervix, epistaxis, hyphema, hereditary angioneurotic edema,
a patient with a blood coagulation disorder undergoing dental
surgery, combinations thereof, and the like, by administering at
least one dosage form of the present invention to the patient in
need in tranexamic acid or pharmaceutically acceptable salt thereof
therapy.
[0047] In certain embodiments, the invention is directed to a
method of treating heavy menstrual bleeding with a therapeutically
effective dose of at least one oral formulation of the present
invention comprising tranexamic acid or pharmaceutically acceptable
salt thereof and a modified release material wherein the menstrual
blood loss per menstrual cycle is reduced by at least about 10 ml,
preferably at least about 20 ml, more preferably at least about 40
ml. In a most preferred embodiment the menstrual blood loss per
menstrual cycle is reduced by greater than or equal to about 50
ml.
[0048] In certain embodiments, the invention is directed to a
method of treating heavy menstrual bleeding with a therapeutically
effective dose of at least one oral formulation of the present
invention comprising tranexamic acid or pharmaceutically acceptable
salt thereof and a modified release material which upon oral
administration to a human female reduces the blood loss per
menstrual cycle by about 35 ml to about 200 ml, preferably about 40
ml to about 175 ml, more preferably from about 50 ml to about 150
ml.
[0049] In certain embodiments, the invention is further directed to
a method of treating heavy menstrual bleeding with a
therapeutically effective dose of at least one oral formulation of
the present invention comprising tranexamic acid or
pharmaceutically acceptable salt thereof and a modified release
material which upon oral administration to a human female reduces
the blood loss per menstrual cycle by about 20% to 100%, preferably
from about 20% to about 70%.
[0050] The menstrual blood loss can be measured by procedures known
in the art. For example, in certain embodiments, the menstrual
blood loss can be determined by a procedure described by (i) L.
Hallbert, et al. in "Determination of Menstrual Blood Loss",
Scandinav. J. Clin. & Lab. Investigation, 244-248, 16, 1964,
wherein the procedure is performed by extracting the menstrual
blood from vaginal tampons and towels with a sodium hydroxide
solution, converting heme chromogens to alkaline hematin, which is
determined spectrophotometrically; or (ii) the menstrual blood loss
can be determined by a procedure described by J. Newton, M.D., et
al., in "A Rapid Method for Measuring Menstrual Blood Loss Using
Automatic Extraction.", Contraception, 269-282, September 1977,
Vol. 16, No. 3, wherein the procedure is based upon the formation
of alkaline haematin after the blood has been extracted from
vaginal tampons and sanitary towels by an automatic Stomacher
Lab-Blender. The disclosures of the aforementioned articles are
hereby incorporated by reference in their entireties.
[0051] In certain embodiments, the modified release material may be
incorporated in a coating applied onto e.g., a tablet comprising
the tranexamic acid or pharmaceutically acceptable salt thereof,
may be incorporated into a matrix with the tranexamic acid or
pharmaceutically acceptable salt thereof, or a combination thereof.
For example, in certain preferred embodiments, the modified release
material is a controlled release material such as a gel-forming or
hydratable polymer which is added to e.g., a matrix composition
comprising the tranexamic acid or pharmaceutically acceptable salt
thereof.
[0052] In certain embodiments, the tranexamic acid for use in the
methods and formulations of the present invention is in the form of
a pharmaceutically acceptable salt thereof. Such salt forms include
for example and without limitation the sodium salt, potassium salt,
calcium salt, magnesium salt and the like; as well as the
hydrochloride, hydrobromide, sulfate, phosphate, formate, acetate,
trifluoroacetate, maleate, tartrate, methanesulfonate,
benzenesulfonate, p-toluenesulfonatemethanesulfonate salt forms,
and the like. Preferably the active ingredient for use in
accordance with the present invention is tranexamic acid.
[0053] An "immediate release oral dosage form" for purposes of the
present invention is a dosage form which releases all of active
ingredient (e.g., tranexamic acid) included therein within about 45
minutes when measured in vitro utilizing the USP 27 Apparatus Type
II Paddle Method @ 50 RPM in 900 ml water at 37.+-.0.5.degree.
C.
[0054] A "modified release oral dosage form" for purposes of the
present invention is an oral dosage form which releases the active
ingredient (e.g., tranexamic acid) included therein in a manner
that is slower than an immediate release oral dosage form and
faster than a controlled release oral dosage form, when the dosage
forms include the same amount of active as the modified release
oral dosage form. One definition of the terms "slower" and "faster"
as used in this application is that they are meant to represent a
statistically significant difference at each measured 15 minute
interval after the start of in-vitro dissolution. In certain
preferred embodiments, the modified release oral dosage form of the
present invention provides an in-vitro dissolution release rate of
tranexamic acid or pharmaceutically acceptable salt thereof, when
measured by a USP 27 Apparatus Type II Paddle Method @ 50 RPM in
900 ml water at 37.+-.0.5.degree. C., of less than about 70% by
weight tranexamic acid or pharmaceutically acceptable salt thereof
released at about 45 minutes and about 100% by weight of said
tranexamic acid or pharmaceutically acceptable salt thereof
released by about 120 minutes.
[0055] A "controlled release oral dosage form" for purposes of the
present invention is a dosage form which releases all of the active
ingredient (e.g., tranexamic acid) included therein after about 4
hours or more when measured in vitro utilizing the USP 27 Apparatus
Type II Paddle Method @ 50 RPM in 900 ml water at 37.+-.0.5.degree.
C.
[0056] The term "C.sub.max" unless otherwise indicated is meant for
purposes of the present invention to mean the maximum plasma
concentration of a medicament achieved after single dose
administration of a dosage form, or the maximum plasma
concentration of a medicament achieved over a dosing interval from
multiple-doses at steady-state in accordance with the present
invention.
[0057] The term "T.sub.max" is meant for purposes of the present
invention to mean the elapsed time from administration of a dosage
form to the time the C.sub.max of the medicament is achieved.
[0058] The term "steady state" means that the amount of the drug
reaching the system is approximately the same as the amount of the
drug leaving the system. Thus, at "steady-state", the patient's
body eliminates the drug at approximately the same rate that the
drug becomes available to the patient's system through absorption
into the blood stream.
[0059] The term "mean" for purposes of the present invention, when
used to define a pharmacokinetic value (e.g., T.sub.max), unless
specified otherwise, represents the arithmetic mean value measured
across a patient or subject population.
[0060] The term "three times a day (TID) basis" for purposes of the
present invention, means that the dosage regimen is to be
administered three times a day, preferably on a schedule of every 8
hours.
[0061] The term "mean transit time" is understood by those skilled
in the art and means the time-point where 63.2% of the total AUC is
attained after oral administration, or 63.2% of the IV dose is
eliminated, as described in Applied Pharmacokinetics, Principles of
Therapeutic Drug Monitoring, Second Edition (1986), edited by
William E. Evans, et al., the disclosure of which is hereby
incorporated by reference in its entirety.
[0062] The term "mean absorption time" is understood by those
skilled in the art and means a quantitative parameter which
summarizes how long, on average, the drug molecule remains
unabsorbed, i.e. persists in its dosage form and in the
gastrointestinal tract, also as described in Applied
Pharmacokinetics Principles of Therapeutic Drug Monitoring, Second
Edition (1986), edited by William E. Evans, et al. Unlike the
absorption rate constants (ka) which can be skewed, the mean
absorption time is not affected by incomplete release of drug from
its dosage form, irregular absorption, lag-time, mixed zero-order
dissolution rates, changing GI motility, GI blood flow, first-pass
effect, etc.
BRIEF DESCRIPTION OF THE FIGURES
[0063] FIG. 1 depicts concentration-time profiles for simulated
administration of the 1.3 g tranexamic acid modified release
formulation of Example 1 at a Q8H (every 8 hours) dosing schedule
of 6:00 AM, 2:00 PM, 10:00 PM comparing it with 1 g administered
Q8H.
[0064] FIG. 2 depicts concentration-time profiles for simulated
administration of the 1.3 g tranexamic acid modified release
formulation of Example 1 at a TID (three times a day) dosing
schedule of 8:00 AM, 2:00PM, 8:00PM comparing it with 1 g
administered TID.
[0065] FIG. 3 depicts mean plasma concentration-time profiles on a
semi-log scale over 36 hours for the study of Example 4.
[0066] FIG. 4 depicts mean plasma concentration-time profiles on a
linear scale over 36 hours for the study of Example 4.
DETAILED DESCRIPTION
[0067] The dosage regimen typically listed for tranexamic acid in
HMB (Heavy Menstrual Bleeding) therapy is 1-1.5 g per dose
administered three-four times a day at the onset of copious
menstrual bleeding and continued for the first 3-5 days of the
menstrual cycle. However, the most frequently reported dosage
regimen of tranexamic acid is an immediate release oral formulation
in which 1 g tranexamic acid is administered four times a day (4 g
per day) for HMB therapy outside of the US. Knowledge of this
common regimen is supported by a careful review of the randomized
controlled trials published in the medical literature, product
labeling from other countries' regulatory authorities having the
product approved for HMB therapy, utilization data from Sweden
(Rybo 1991), correspondence and interviews with non-US clinicians
having experience with the product. That regimen is currently the
dosage being studied by the US Center for Disease Control (CDC) in
women with HMB associated with bleeding disorders.
[0068] The absolute bioavailability of tranexamic acid observed
when administering the European commercial formulation
(Cyklokapron, Kabi AB, Sweden Batch 90288; assay 499 mgm/tablet) to
male subjects is approximately 35% and its elimination correlates
with renal creatinine clearance. Peak serum tranexamic acid
concentrations occur approximately 3 hours after the oral
administration of a European immediate-release tablet formulation
(>85% dissolved at 15 minutes) (Pilbrant, et al., Eur. J. Clin.
Pharmacol, (1981)-20:65-72). By comparison, the in vivo absorption
profile observed with the European immediate-release formulation is
slow and very gradual over 3 hours. Specifically, tranexamic acid
serum concentrations are 9, 41, 73, 88 percent (with food), and 22,
63, 85, and 98 percent (fasting) of maximal absorption at 0.5, 1,
1.5 and 2 hours after a 2 g oral dose, respectively. Although not
wishing to be held to any specific theory, it is presently
hypothesized that tranexamic acid oral absorption appears to be
controlled by a non-dissolution rate limited process, i.e. the rate
and extent of oral absorption is a function of a transmembrane
passage-limited process, in order to explain the disparity between
the time of product dissolution and relatively prolonged tmax (time
to achieve the peak serum concentration).
[0069] Preferably, the goal of the formulation, dose strength and
dosage regimen of the invention, is to provide HMB therapy which
achieves from about 20% to 100% reduction in menstrual blood loss
per menstrual cycle. In accordance with certain embodiments of the
present invention, the preferred tranexamic acid dose of 1.3 g
every 8 hours is predicted to provide an average serum tranexamic
acid concentration comparable to that produced by a 1 g every 6
hour regimen (i.e. 12.4 mcg/mL), with associated peaks and troughs
falling approximately within the therapeutic antifibrinolytic range
(5-15 mcg/mL; Cyklokapron NDA 19-280). In certain embodiments, a
two-compartment oral absorption and elimination simulation model
coupled with pharmacokinetic data (Pilbrant, et al., Eur. J. Clin.
Pharmacol, (1981)-20:65-72), and modified-release tablet
dissolution performance information were used to determine the
preferred lead dosage regimen.
[0070] In immediate release formulations the entire dose and the
soluble components in the dosage form dissolve in gastrointestinal
fluid and present a high concentration of solutes for absorption.
The most frequently reported adverse effects are primarily confined
to the proximal gastrointestinal tract (nausea and vomiting). These
adverse symptoms appear to be related to the drug load presented to
the gastric mucosa, since this effect can be minimized by reducing
the immediate-release oral formulation dose or administering the
product slowly by the intravenous route. In certain embodiments, a
lower incidence of proximal gastrointestinal adverse effects is
obtained with the preferred oral modified release formulation
(e.g., dosed 1.3 g every 8 hours) of the invention, e.g., because
of the modified release properties of the drug product
formulation.
[0071] In certain embodiments, the oral dosage form of the present
invention provides for an increased bioavailability as compared to
immediate release oral dosage forms currently available (e.g.,
Cyclokapron). In certain preferred embodiments the increased
bioavailability allows therapeutic plasma levels of tranexamic acid
to be reached with a lower dose of drug. Preferably, the increased
bioavailability also decreases the amount of tranexamic acid that
remains unabsorbed in the gastrointestinal which leads to decreased
incidence of side effects that are typically associated with
formulations that provide higher levels of unabsorbed tranexamic
acid and prolonged exposure of the gastrointestinal tract to the
higher tranexamic acid levels. Preferably the oral dosage form of
the present invention provides for a bioavailability of tranexamic
acid of greater than 40%, from about 41% to about 60%, preferably
from about 42% to about 50%, more preferably about 45% after oral
administration to humans.
[0072] The modified release oral formulations of tranexamic acid of
the present invention provides a release of the drug which is
slower than that of the immediate release 500 mg Cyklokapron
product current marketed in Canada which provided a mean release
rate of 100% by weight tranexamic acid released by about 15 minutes
when measured utilizing USP 27 Apparatus Type II paddle method @ 50
RPM in 900 ml water at 37.+-.0.5.degree. C.
[0073] In certain embodiments, the modified release oral
formulations may be described as providing a mean transit time
through the proximal gastrointestinal mucosa which takes
approximately one half hour longer than an immediate release
formulation. In other preferred embodiments, the modified release
formulations of the invention provide a rate of release of
(dissolved) tranexamic acid from the dosage form in-vitro which is
approximately 20, 40, 60, 80, and 100 percent of the total dose at
0.25, 0.5, 0.75, 1 and 1.5 hours, respectively. In certain
preferred embodiments, such a release rate in-vitro demonstrates
that the formulations of the present invention provide a relative
reduction in the amount and rate of dissolved tranexamic acid
presented to the proximal gastric mucosa to approximate 20, 40, 60,
80, and 100 percent of the total dose at 0.25, 0.5, 0.75, 1 and 1.5
hours, respectively, after oral administration.
[0074] In certain embodiments, the majority of tranexamic acid
absorption appears to occur slowly distal to the stomach, and
assuming linear pharmacokinetics, the modified release formulation
produces an absorption profile which is comparable to that achieved
with the currently available oral immediate release formulations
used outside the U.S.
[0075] In accordance with the present invention a modified release
tranexamic acid tablet for oral administration is disclosed.
Preferably, the tablet contains at least one material (defined
herein as any substance other than the active, i.e., tranexamic
acid) which minimizes or eliminates the adverse gastrointestinal
side effects in patients, for example, women dosed with oral
tranexamic acid for treatment of menorrhagia.
[0076] The modified release oral dosage forms of tranexamic acid
for purposes of the present invention include formulation
ingredients and/or configurations which are typically utilized for
formulations known in the art as extended, sustained and controlled
release formulations, although modified to provide a desirable
release rate in keeping with the teachings of the present
invention. The modified release formulations preferably decrease
the concentration of tranexamic acid and materials dissolved in the
stomach fluids after dosing by controllably releasing tranexamic
acid over a period of time, as opposed to immediate release
formulations which release the entire dose of tranexamic acid all
at once. The modified release formulations of the present invention
thus minimize or prevent gastrointestinal reactions and side
effects that occur when a dose of tranexamic acid is ingested and
immediately reaches the stomach.
[0077] The modified release dosage forms of the present invention
may be prepared as; tablets, capsules, granules, pellets, powders,
dragees, troches, non-pariels, pills or encapsulated suspension,
and may be packaged into capsules, sachets, etc. Such dosage forms
may be prepared by any formulation technique where release of the
active substance (tranexamic acid) from the dosage form is modified
to occur at a slower rate than from an immediate release product.
In these formulations, tranexamic acid release occurs in the
stomach and/or intestine, but at a slower rate so that a bolus of
dissolved drug does not reach the lining of the stomach and cause
adverse effects, or adverse effects occur with a lower intensity or
frequency because of the lower concentration of tranexamic acid.
Hence, adverse effects are preferably reduced, minimized or
eliminated.
[0078] Methods of preparing modified release formulations are found
in Modified Release Drug Delivery Technology, Rathbone, Hadgraft,
and Roberts, Eds., Drugs and the Pharmaceutical Sciences, Vol. 126,
Marcel Dekker Inc., New York, 2003; Modem Pharmaceutics, Third
Edition, Banker and Rhodes, Eds. Drugs and the Pharmaceutical
Sciences, Vol. 72, Marcel Dekker Inc., New York, 1996; Sustained
and Controlled Release Drug Delivery Systems, Robinson, Ed., Drugs
and the Pharmaceutical Sciences, Vol. 6, Marcel Dekker Inc., NY
1978; Sustained Release Medications, Chemical Technology Review No.
177, Johnson, Ed., Noyes Data Corporation 1980; Controlled Drug
Delivery, Fundamentals and Applications, Second Edition, Robinson
and Lee, Eds., Marcel Dekker Inc., New York, 1987, and-as described
in U.S. Pat. No. 6,548,084, each of these references being
expressly incorporated by reference herein in its entirety.
[0079] Preferably, a modified release form, makes tranexamic acid
available over an extended period of time after ingestion. Modified
release dosage forms coupled with the digestion process and the
absorption process in the gastrointestinal tract cause a reduction
in the amount of tranexamic acid in solution in the
gastrointestinal tract compared to dosing tranexamic acid presented
as a conventional dosage form (e.g., as a solution, or as an
immediate release dosage form). The modified release formulation
may be verified by in vitro dissolution testing and in vivo
bioequivalence documentation, according to Food and Drug
Administration standards, e.g., as set forth at www.fda.gov, 21 CFR
.sctn.314, 320, and also at USP 23 NF 18 .sctn.711, 724. For
example, an in vitro dissolution test such as USP 27 Apparatus Type
II Paddle Method @ 50 RPM in 900 ml water at 37.+-.0.5.degree. C.
may be used to verify the release of the tranexamic acid from the
dosage form.
[0080] Tranexamic acid modified release tablets may be formulated
to provide a dose of tranexamic acid, typically about 500 mg to
about 2 grams from one to two tablets, within about the first one
to two hours after the tablet is ingested. Thus, tranexamic acid
release occurs at a designed rate over a period e.g., about 60
minutes to about 120 minutes. The rate of tranexamic acid release
over this period of time is designed to provide a reduced
concentration of tranexamic acid in the stomach while allowing the
absorption of tranexamic acid to occur throughout the
gastrointestinal tract. Absorption of tranexamic acid typically
begins as soon as tranexamic acid is released from the dosage form
and is dissolved in the gastrointestinal fluids contacting the
membranes which line the gastrointestinal tract. The rate of
release of tranexamic acid from the dosage form and the absorption
of drug by the gastrointestinal mucosa help to maintain low
concentrations of drug in the gastrointestinal fluids. The lowered
concentrations preferably result in lower intensity, frequency,
and/or severity of gastrointestinal adverse side effects. The
designed rate of release of tranexamic acid from the dosage form in
the stomach and the upper small intestine, the natural emptying of
gastric juice containing any dissolved tranexamic acid from the
stomach, and the absorption of tranexamic acid from a larger
segment of the gastrointestinal tract (i.e., both the stomach and
the small intestine, rather than the stomach only or the lower
portion of the small intestine if any modified release dosage form
with a longer release time was used), preferably results in reduced
levels of dissolved tranexamic acid in the region of the
gastrointestinal tract proximal or distal to the dosage form.
Reduced concentrations of tranexamic acid along the
gastrointestinal tract preferably provide a reduction in adverse
gastrointestinal effects associated with oral tranexamic acid
therapy.
[0081] As used herein, alleviation of adverse effects using these
formulations indicates any relief in one or more symptoms, such as
decrease in incidence, severity, or duration of symptoms, and is
not limited to absence of symptoms or elimination of symptoms.
Thus, treatment includes any decrease in incidence, duration,
intensity, frequency, etc. of adverse gastrointestinal symptoms
including, but not limited to, headache, nausea, vomiting,
diarrhea, constipation, cramping, bloating, and combinations
thereof. The formulations may reduce symptoms at any time during
tranexamic acid therapy, but minimized adverse effects are
particularly noted immediately or shortly after dosing, that is,
within the first few hours after dosing. As used herein, adverse
gastrointestinal effects and side effects are used interchangeably
to indicate nontherapeutic effects (i.e., not relating to any
possible beneficial effects due to tranexamic acid), ranging from
unpleasant but tolerable sensations to severe gastrointestinal
symptoms. As used herein, the terms oral formulations, ingestable
formulations, and orally administered formulations are used
interchangeably and include any dosage forms which are ingested by
mouth, including, but not limited to, tablets, pills, liquids,
gelcaps, softgels, dragees, capsules, powders, granules, pellets,
etc.
[0082] Modified release formulations of tranexamic acid include
tablets, pellets, granules, capsules, or other oral dosage forms
prepared in such a way to release tranexamic acid in a designed
manner. In certain embodiments, the modified release material is a
gel-forming polymer, a hydratable polymer, a water soluble polymer,
a water swellable polymer, or mixtures thereof.
[0083] In certain embodiments, modified release tranexamic acid
tablets are prepared by adding a modified release material
comprising a gel-forming or hydratable polymer to a tranexamic
tablet composition. Suitable gel-forming or hydratable polymers
include, but are not limited to, hydroxyproplycellulose,
hydroxypropylmethylcellulose or hypromellose,
carboxymethylcellulose, polyvinyl alcohol, etc. This provides a
compressed tablet that may or may not be film coated. The tablet
releases tranexamic acid by diffusion of tranexamic acid through
the tablet matrix, or by erosion of the tablet matrix, or by a
combination of diffusion from and erosion of the tablet matrix.
Tablets formed with water swellable polymers release tranexamic
acid by diffusion of tranexamic acid through the tablet matrix, or
by erosion of the tablet matrix, or by a combination of diffusion
from and erosion of the tablet matrix. One or more water-soluble
hydrophilic polymer(s) may also be used. These include
polyvinylpyrrolidine, hydroxypropyl cellulose,
hydroxypropylmethylcellulose, now referred to as hypromellose
(e.g., Methocel.TM., Dow Chemical Company), methyl cellulose, vinyl
acetate/crotonic acid copolymers, methacrylic acid copolymers,
maleic anhydride/methyl vinyl ether copolymers, derivatives thereof
and mixtures thereof. In various embodiments, the polymer is
hydroxypropyl cellulose or hydroxypropylmethylcellulose. The
polymer may be hydroxypropyl-methyl cellulose with a viscosity
ranging from about 50 cps to about 200 cps. The polymer may be
hydroxypropyl-methyl cellulose with a viscosity of 100 cps,
commercially available as Methocel.TM. K 100 LV (Dow Chemical
Company). The amount of polymer in the composition may be in the
range of about 5% by weight to about 50% by weight of the
composition. In various embodiments, the polymer is in the range of
about 10% by weight to about 35% by weight of the composition, or
about 10% by weight to about 30% by weight of the composition.
[0084] In certain embodiments the modified release material
comprises a vinyl polymer, phthalic acid derivative of vinyl
copolymer, hydroxyalkylcellulose, alkylcellulose (e.g.,
ethylcellulose), cellulose acetate, hydroxyalkylcellulose acetate,
cellulose ether, alkylcellulose acetate and partial esters thereof,
and polymers and copolymers of lower alkyl acrylic acids and lower
alkyl acrylates and partial esters thereof, or combination thereof.
In preferred embodiments the modified release material comprises
hydroxypropylcellulose, hydryoxpropylmethylcellulose,
carboxymethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone,
methylcellulose, vinyl acetate/crotonic acid copolymers,
methacrylic acid copolymers, maleic anhydride/methyl vinyl ether
copolymers, derivatives thereof, and mixtures thereof. In further
preferred embodiments the modified release material comprises a
polymer such as a methacrylic acid copolymer. These are copolymers
of methacrylic acid with neutral acrylate or methacrylate esters
such as ethyl acrylate or methyl methacrylate.
[0085] In certain embodiments the modified release material
comprises a pH independent binder or film-forming agent such as
hydroxypropyl methycellulose, hydroxypropyl cellulose,
methylcellulose, polyvinylpyrrolidone, neutral poly(meth)acrylate
esters (e.g., the methyl methacrylate/ethyl acrylate copolymers
sold as Eudragit.RTM. (Rohm Pharma), starches, gelatin, sugars such
as glucose, sucrose, and mannitol, silicic acid,
carboxymethylcellulose, and the like, diluents such as lactose,
mannitol, dry starch, microcrystalline cellulose and the like,
surface active agents such as polyoxyethylene sorbitan esters,
sorbitan ethers, and the like, coloring agents, flavoring agents,
lubricants such as talc, calcium stearate, and magnesium stearate,
solid polyethylene glycols, sodium lauryl sulfate, and other
tableting aids. Any combination of the aforementioned binders or
film-forming agents may be included in the modified release
material. The modified release material may be combined with
tranexamic acid to form modified release dosage forms.
[0086] In certain embodiments, the formulation includes tranexamic
acid in the range of about 50% by weight to about 95% or more by
weight of the formulation. In other embodiments, tranexamic acid is
in the range of about 60% by weight to about 90% by weight, or
about 60% by weight to about 80% by weight of the formulation. The
remaining weight may be made up of the modified release material
and additional excipients.
[0087] To prepare modified release tablet formulations, the agent
or modified release material to slow the release of tranexamic acid
may be incorporated into the tablet matrix or coated onto the
tablet surface or both. In certain embodiments, tablet formulations
prepared are formulated by granulating a blend of powders of the
modified release material. The powder blend is formed by combining
portions of the powdered components that make up the tablet. These
powders are intimately mixed by dry-blending. The dry blended
mixture is granulated by wet mixing of a solution of a binding
agent with the powder blend. The time for such wet mixing may be
controlled to influence the dissolution rate of the formulation.
For example, the total powder mix time, that is, the time during
which the powder is granulated, may range from about 1 min to about
10 min, or from about 2 min to about 5 min. Following granulation,
the particles are removed from the granulator and placed in a fluid
bed dryer, a vacuum dryer, a microwave dryer, or a tray dryer for
drying. Drying conditions are sufficient to remove unwanted
granulating solvent, typically water, or to reduce the amount of
granulating solvent to an acceptable level. Drying conditions in a
fluid bed dryer or tray dryer are typically about 50 to 70.degree.
C. The granulate is dried, screened, mixed with additional
excipients such as disintegrating agents, flow agents, or
compression aids and lubricants such as talc, stearic acid, or
magnesium stearate, and compressed into tablets.
[0088] In certain embodiments, the tablet that contains a modified
release material within the tablet matrix may be coated with an
optional film-forming agent. This applied film may aid in
identification, mask an unpleasant taste, allow desired colors and
surface appearance, provide enhanced elegance, aid in swallowing,
aid in enteric coating, etc. The amount of film-forming agent may
be in the range of about 2% tablet weight to about 4% tablet
weight. Suitable film-forming agents are known to one skilled in
the art and include hydroxypropyl cellulose, cellulose ester,
cellulose ether, one or more acrylic polymer(s), hydroxypropyl
methylcellulose, cationic methacrylate copolymers
(diethylaminoethyl)meth- acrylate/methyl-butyl-methacrylate
copolymers such as Eudragit E.RTM. (Rohm Pharma) and the like. The
film-forming agents may optionally contain colorants, plasticizers,
fillers, etc. including, but not limited to, propylene glycol,
sorbitan monooleate, sorbic acid, titanium dioxide, and one or more
pharmaceutically acceptable dye(s).
[0089] In certain embodiments, the tranexamic acid tablets of the
invention are coated with a modified release material. In certain
embodiments, tranexamic acid tablets are formulated by dry
blending, rotary compacting, or wet granulating powders composed of
tranexamic acid and tablet excipients. These powders are compressed
into an immediate release tablet. Coating this immediate release
tablet with a modified release material as described herein renders
this tranexamic acid tablet as a modified release tablet.
[0090] In addition to the modified release material, the
formulations of the invention may also contain suitable quantities
of other materials, e.g. preservatives, diluents (e.g.,
microcrystalline cellulose), lubricants (e.g., stearic acid,
magnesium stearate, and the like), binders (e.g., povidone, starch,
and the like), disintegrants (e.g, croscarmellose sodium, corn
starch, and the like), glidants (e.g., talc, colloidal silicon
dioxide, and the like), granulating aids, colorants, and flavorants
that are conventional in the pharmaceutical art. Specific examples
of pharmaceutically acceptable excipients that may be used to
formulate oral dosage forms are described in the Handbook of
Pharmaceutical Excipients, American Pharmaceutical Association
(2003), incorporated by reference herein.
[0091] The release process may be adjusted by varying the type,
amount, and the ratio of the ingredients to produce the desired
dissolution profile, as known to one skilled in the art. A coating
may be a partially neutralized pH-dependent binder that controls
the rate of tranexamic acid dissolution in aqueous media across the
range of pH in the stomach, which has a pH of about 2, and the
intestine, which has a pH of about 5.5 in its upper region. In
certain embodiments, one or more pH dependent binders may be used
to modify the dissolution profile so that tranexamic acid is
released slowly and continuously as the formulation passes through
the stomach and/or intestines.
[0092] In one embodiment, compressed modified release tablets are
formulated to comply with USP criteria and to be of such a size and
shape to be easy to swallow. The size of the tablet will depend
upon the dose of tranexamic acid that is needed to provide adequate
therapy and the particular formulation and excipients that are
selected to provide the physical properties necessary for tableting
and for modified release. In various embodiments, a compressed
modified release tablet contains from about 500 mg to about 1 gram
of tranexamic acid, or from about 600 mg to about 750 mg of
tranexamic acid. The daily dose of tranexamic acid may be achieved
by taking one or two tablets at each dosing time.
[0093] In certain embodiments, the tranexamic acid included in the
dosage form is from about 375 mg to about 1500 mg, preferably from
about 375 mg to about 1000 mg. In one embodiment, the dose of
tranexamic acid per tablet is in the range of about 500 mg to about
1000 mg for tablets and from about 500 mg to about 1500 mg for a
sachet filled with granules. In another embodiment, the dose of
tranexamic acid is in the range of about 3 grams/day to about 6
grams/day in three or four divided doses. As an example, a total
daily dose of 3 grams tranexamic acid may be divided into three
doses of one tablet each with each tablet containing 1 gram
tranexamic acid, or may be divided into four doses of one tablet
each with each tablet containing 0.75 gram tranexamic acid. As
another example, a total daily dose of 4 gram tranexamic acid may
be divided into three doses of two tablets at each dose with each
tablet containing 0.666 gram tranexamic acid, or may be divided
into four doses of one tablet each with each tablet containing 1
gram tranexamic acid. As another example, a total daily dose of 5
gram tranexamic acid may be divided into three doses of one tablet
each with each tablet containing 1.66 gram tranexamic acid, or may
be divided into four doses of two tablets each with each tablet
containing 0.625 gram tranexamic acid. As another example, a total
daily dose of 6 gram tranexamic acid may be divided into three
doses of two tablets each with each tablet containing 1 gram
tranexamic acid, or may be divided into four doses of two tablets
each with each tablet containing 0.75 gram tranexamic acid. For
ease of swallowing, the dose of tranexamic acid taken at each
dosing time may be delivered by taking multiple tablets. For
example, the 4 gram daily dose may be delivered by taking two
666.67 mg tablets three times a day or two 500 mg tablets four
times a day. Similarly, the 3 gram daily dose may be achieved by
taking two 550 mg tablets three times a day or two 375 mg tablets
four times a day. Alternatively, for ease of reference, a dose of
600 mg, 650 mg, or 700 mg of tranexamic acid per tablet may be
used. In a preferred embodiment, a total daily dose of 3900 mg/day
is administered in three divided doses of 1300 mg of two tablets at
each dose with each tablet containing 650 mg of tranexamic acid.
Alternatively, each dose may be delivered by taking granules
containing the prescribed amount of tranexamic acid presented in a
convenient unit dose package. Such examples are not limiting and
other doses within these ranges will be appreciated by those
skilled in the art.
[0094] Alternatively, modified release tranexamic acid formulations
may be administered by pellets or granules in e.g., a sachet or
capsule. Modified release tranexamic acid pellets or granules may
be prepared by using materials to modify the release of tranexamic
acid from the granule or pellet matrix. Modified release
preparations may also be formulated using coatings to modify the
release of tranexamic acid from the granule or pellet. U.S. Pat.
Nos. 5,650,174; and 5,229,135 each of which is expressly
incorporated by reference herein in its entirety, disclose
variations on fabricating a pellet or nonpareil dosage form.
Spheres are filled into packets, termed sachets, or capsules which
are filled by weight to contain the prescribed dose of drug.
Multiparticulates may be coated with an modified release coating,
as disclosed in U.S. Pat. No. 6,066,339, which is expressly
incorporated by reference herein its entirety. Coated
multiparticulates may be packaged in capsules or sachets. The
formulation of granules or pellets for modified release is
described in Multiparticulate Oral Drug Delivery, Ghebre-Sellassie,
Ed. in Drugs and the Pharmaceutical Sciences, Vol. 65 Marcel Dekker
Inc. NY, 1994 and in the relevant parts of the references for
modified release formulations previously cited and the relevant
portions incorporated herein by reference.
[0095] In certain embodiments, the inventive tranexamic acid
formulations may be used for additional indications other than
menorrhagia, such as conization of the cervix, epistaxis, hyphema,
hereditary angioneurotic edema, a patient with a blood coagulation
disorder undergoing dental surgery, combinations thereof, and the
like.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0096] The invention will be further appreciated with respect to
the following non-limiting examples. Other variations or
embodiments of the invention will also be apparent to one of
ordinary skill in the art from the above descriptions and examples.
Thus, the forgoing embodiments are not to be construed as limiting
the scope of this invention.
EXAMPLE 1
[0097] Modified release 650 mg tranexamic acid tablets were
prepared having the ingredients listed in the Table 1 below:
1TABLE 1 Quantity Quantity per batch per tablet Ingredient (kg)
(mg) Active Ingredient Tranexamic Acid, EP 84.50 650.0 Inactive
Ingredients Microcrystalline Cellulose NF (Avicel PH 101) 5.753
44.25 Colloidal Silicon Dioxide NF 0.0975 0.75 Pregelatinized Corn
Starch, NF 6.435 49.50 Hypromellose, USP (Methocel K3 Premium LV)
19.110 147.00 Povidone, USP (K value range 29-32) 4.680 36.00
Stearic Acid, NF (powder) 2.340 18.00 Magnesium Stearate, NF
(powder) 0.585 4.50 Purified Water USP* 17.550 135.00 *Purified
water is removed during processing
[0098] The formulation of Example 1 was prepared as follows:
[0099] 1. Weigh all ingredients and keep in moisture resistant
containers until ready for use.
[0100] 2. Measure water into a container. Mix povidone at medium
speed until completely dissolved.
[0101] 3. Add tranexamic acid, microcrystalline cellulose (MCC),
pregelatinized corn starch, and colloidal silicon dioxide to the
high shear mixer.
[0102] 4. Mix using impeller only.
[0103] 5. Mix for an additional time (impeller only). Add all of
the povidone solution during this mixing step.
[0104] 6. Mix until adequately granulated (impeller and chopper).
Proceed only when desired granulation has been achieved. Add
additional water if necessary.
[0105] 7. Dry the granulation to moisture content of NMT 1.2%.
[0106] 8. Pass the granulation through the oscillating granulator
equipped with a #30 mesh screen. Weigh the granulation. Add
granulation to the V-Blender.
[0107] 9. Add the hypromellose USP Methocel K3 Premium to the
V-blender. Blend.
[0108] 10. Pass magnesium stearate and stearic acid through
oscillating granulator equipped with a #40 mesh screen. Add
magnesium stearate and stearic acid to the V-blender and blend.
[0109] 11. Perform specified physical property testing. Proceed to
compression.
[0110] 12. Compress tablets to desired weight.
EXAMPLE 2
[0111] In Example 2, immediate release 650 mg tranexamic acid
tablets were prepared having the ingredients listed in Table 2
below:
2TABLE 2 Quantity per batch Quantity per Ingredient (kg) tablet
(mg) Active Ingredient Tranexamic Acid, EP (650 mg/tab) 84.50 650.0
Inactive Ingredients Microcrystalline Cellulose, NF 5.753 44.25
(Avicel PH 101) Microcrystalline Cellulose, NF 10.660 82.00 (Avicel
PH 102) Colloidal Silicon Dioxide, NF 0.0975 0.75 Pregelatinized
Corn Starch, NF 6.435 49.50 Croscarmellose Sodium, NF 19.50 15.00
Povidone, USP (K value range 29-32) 4.680 36.00 Stearic Acid, NF
(powder) 2.340 18.00 Magnesium Stearate, NF (powder) 0.585 4.50
Purified Water, USP* 17.550 135.00 Film Coating (Inactive
Ingredients)** Opadry White YS-1-7003 4.110 -- Purified Water, USP
36.990 -- *Purified water is removed during processing **6 kg
excess prepared to account for losses during transfer
[0112] The formulation of Example 2 was prepared as follows:
[0113] 1. Weigh all ingredients and keep in moisture resistant
containers until ready for use.
[0114] 2. Measure water into a container. Mix povidone at medium
speed until completely dissolved.
[0115] 3. Add tranexamic acid, microcrystalline cellulose (MCC),
pregelatinized corn starch, and colloidal silicon dioxide to the
high shear mixer.
[0116] 4. Mix using impeller only.
[0117] 5. Mix for an additional time (impeller only). Add all of
the povidone solution during this mixing step.
[0118] 6. Mix until adequately granulated (impeller and chopper).
Proceed only when desired granulation has been achieved. Add
additional water if necessary.
[0119] 7. Dry the granulation to moisture content of NMT 1.2%.
[0120] 8. Pass the granulation through the oscillating granulator
equipped with a #30 mesh screen. Weigh the granulation. Add
granulation to the V-Blender.
[0121] 9. Add the croscarmellose sodium and MCC to the V-Blender
and blend.
[0122] 10. Pass magnesium stearate and stearic acid through
oscillating granulator equipped with a #40 mesh screen. Add
magnesium stearate and stearic acid to the V-blender and blend.
[0123] 11. Perform specified physical property testing. Proceed to
compression.
[0124] 12. Compress tablets.
[0125] 12. After compression, spray coat the compressed dosage
forms with the Opadry White in water.
EXAMPLE 3
[0126] In Example 3, modified release 650 mg tranexamic acid
tablets were prepared as in Example 1 and coated with a film
coating similar to the immediate release tablets of Example 2. The
ingredients are listed in Table 3 below:
3TABLE 3 Quantity Quantity per batch per tablet Ingredient (kg)
(mg) Active Ingredient Tranexamic Acid, EP 84.50 650.0 Inactive
Ingredients Microcrystalline Cellulose NF (Avicel PH 101) 5.753
44.25 Colloidal Silicon Dioxide NF 0.0975 0.75 Pregelatinized Corn
Starch, NF 6.435 49.50 Hypromellose, USP (Methocel K3 Premium LV)
19.110 147.00 Povidone, USP (K value range 29-32) 4.680 36.00
Stearic Acid, NF (powder) 2.340 18.00 Magnesium Stearate, NF
(powder) 0.585 4.50 Purified Water USP* 17.550 135.00 Film Coating
(Inactive Ingredients)** Opadry White YS-1-7003 4.305 -- Purified
Water, USP 38.750 -- *Purified water is removed during processing
**6 kg excess prepared to account for losses during transfer
EXAMPLE 4
Bioavailability and Bioequivalence Evaluation
[0127] In Example 4, a comparative, randomized, single dose, 4-way
Crossover Absolute Bioavailability (BA) and Bioequivalence (BE)
study of Tranexamic Acid Tablet Formulations prepared in accordance
with Examples 1 and 2 in Healthy Adult Women Volunteers under
Fasting Conditions was performed. The objective was to assess the
bioequivalence of a 650 mg modified release tablet formulation
prepared in accordance with Example 1 compared to the immediate
release reference tablet formulation of tranexamic acid prepared in
accordance with Example 2, and to determine the bioavailability of
the modified tablet formulation to the approved IV (1 g)
formulation Cyklokapron.RTM. by Pharmacia & Upjohn. The design
was a randomized, 4-way crossover, comparative BE and BA
determination. All oral doses administered were 1.3 g. Twenty-eight
(28) healthy non-smoking adult female volunteer subjects were
enrolled in the study. Sample size was calculated assuming a 25% CV
in AUC.sub.inf. The study endpoints were the 90% confidence
intervals of the ratio of least-squares means of the
pharmacokinetic parameters AUC.sub.0-t, AUC.sub.inf and C.sub.max
of the modified release formulation to the immediate-release
formulation from serum concentration-time data drawn up to 36 hours
after a single dose of drug. In addition, the bioavailability of
the tablet formulations were calculated. Smokers, oral
contraceptive users, those with a previous history of
thromboembolic events and altered vision were excluded from the
study. ECG monitoring was performed before, during and after the
estimated times of peak serum tranexamic acid concentrations
exposure. Adverse events were captured and recorded throughout the
trial period.
[0128] In the study, subjects were randomized to receive single
oral 1.3 g (2.times.650 mg tablets) dose of tranexamic acid in
tablet forms which included a modified release dosage form and an
immediate release dosage form. Subjects were also administered a
single 1 g (10 ml) IV solution of tranexamic acid (100 mg/ml
concentration).
[0129] A summary of the pharmacokinetic results from the study of
Example 4 are listed in the tables below.
4TABLE 4 Summary of Results - Tranexamic Acid in Plasma
Pharmacokinetic Parameters (N = 26) ln AUC 0-t* ln AUCinf* ln Cmax*
(mcg .multidot. h/mL) (mcg .multidot. h/mL) (mcg/mL) Modified
Release formulation Mean 66.703 69.642 11.251088 CV 26.8 27.2 29.1
N 26 24 26 Immediate Release formulation Mean 70.157 72.656
12.260414 CV 16.2 16.4 23.0 N 26 24 26 Least-Squares Mean: Modified
Release 66.935 68.891 11.321919 Immediate Release 70.051 72.411
12.258222 Ratio of 95.6 95.1 92.4 Least-Squares Mean (modified
release/immediate release)% *For ln-transformed parameters, the
antilog of the mean (i.e. the geometric mean) is reported. AUCinf,
kel, half-life and F could not be estimated for some subjects. AUG
0-t is the area under the plasma concentration versus time curve,
from time 0 to the last measurable concentration, as calculated by
the linear trapezoidal method.
[0130]
5TABLE 5 Summary of Results - Tranexamic Acid in Plasma
Pharmacokinetic Parameters (N = 26) Tmax Half-life kel F (h) (h)
(1/h) (%) Modified Release formulation Mean 2.942 11.370 0.06300
44.93 CV 22.7 17.6 19.4 25.3 n 26 26 26 24 Immediate Release
formulation Mean 2.808 11.013 0.06438 46.04 CV 20.8 15.5 15.3 16.1
n 26 24 24 24
[0131]
6TABLE 6 Summary of Results - Tranexamic Acid in Plasma
Pharmacokinetic Parameters (N = 26) Ln AUC 0-t* ln AUCinf* ln Cmax*
(mcg .multidot. h/mL) (mcg .multidot. h/mL) (mcg/mL) 90% Confidence
Intervals (Modified release/Immediate release) % lower limit: 87.8%
87.4% 84.0% upper limit: 104.0% 103.5% 101.6% p-Value (ANOVA)
Modified vs Immediate 0.3721 0.3259 0.1676 Period 0.0704 0.0499
0.0356 Sequence 0.7734 0.7978 0.8207 Intrasubject CV % 18.3 17.4
20.6 *For ln-transformed parameters, the antilog of the mean (i.e.
the geometric mean) is reported. AUCinf, kel, half-life and F could
not be estimated for some subjects.
[0132] Concentration-time profiles for the study of Example 4 are
presented on semi-log and linear scale over 36 hours and are
depicted in FIGS. 3 and 4.
[0133] The following pharmacokinetic parameters in the table below
were calculated for tranexamic acid in plasma for the study of
Example 4.
[0134] MRT: The mean residence time (MRT) after intravenous
administration of tranexamic acid was determined using the
equation,
AUMC/AUC+infusion time/2,
[0135] where the AUMC is the area under the moment-time curve.
[0136] MTT: Following oral administration of the Modified Release
and Immediate Release formulations, the mean transit time (MTT) of
tranexamic acid was calculated by dividing the AUMC by the AUC.
[0137] MAT: The mean absorption time (MAT) for the two formulations
was derived by subtracting the MRT from the MTT.
[0138] Mean (.+-.SD) results are presented in the table below:
7 TABLE 7 IV Modified Release Immediate Release MRT (hours) 3.51
.+-. 0.38 N/A N/A MTT (hours) N/A 7.70 .+-. 0.72 7.21 .+-. 1.01 MAT
(hours) N/A 4.18 .+-. 0.70 3.70 .+-. 0.94
[0139] The mean transit time (MTT) and mean absorption time (MAT)
of the Modified Release formulation of tranexamic acid was
approximately 30 minutes longer than that observed for the
Immediate Release formulation.
[0140] The most frequently reported adverse events from the study
of Example 4 are listed in the table below. The table lists the
number of subjects reporting adverse events, and the percentage of
subjects is in parentheses.
8 TABLE 8 Treatment Modified Immediate Release Release IV solution
(2 .times. 650 mg) (2 .times. 650 mg) (10 .times. 100 mg/ml)
Adverse Events (n = 27) (n = 27) (n = 27) Headache 4 (15%) 7 (26%)
7 (26%) Nausea 0 (0%) 2 (7%) 10 (37%) Dizziness 0 (0%) 0 (0%) 11
(41%) Feeling Hot 0 (0%) 0 (0%) 6 (22%) Nasal Congestion 2 (7%) 1
(4%) 1 (4%) Cough 0 (0%) 0 (0%) 2 (7%) Urine odor abnormal 2 (7%) 0
(0%) 1 (4%)
[0141] Dissolution Results for Immediate Release and Modified
Release Formulations prepared in accordance with Examples 2 and 1
respectively used in the study of Example 4 tested under USP 27
Apparatus Type II Paddle Method @ 50 RPM in 900 ml water at
37.+-.0.5.degree. C. are listed in the tables below.
9TABLE 9 Test Results for the Immediate Release Formulation in
Table 2. % Assay 99.9% Content Uniformity 99.4% RSD 0.7% Unknown
Related NMT 0.2% Each <0.1% Substance Total Related Substances
NMT 2.0% Total <0.1% and Impurities Dissolution Profile 15 min.
58.0% 30 min. 96.0% 45 min. 102.0% 60 min. 104.0%
[0142]
10TABLE 10 Test Results for the Modified Release Formulation in
Table 1 % Assay 99.4% Content Uniformity 98.5% RSD 0.6% Unknown
Related NMT 0.2% Each <0.1% Substance Total Related Substances
NMT 2.0% Total <0.1% and Impurities Dissolution Profile 15 min.
21.0% 30 min. 40.0% 45 min. 58.0% 60 min. 73.0% 90 min. 98.0%
Conclusions
[0143] The ratios of least-squares means and the 90% confidence
intervals derived from the analyses of the ln-transformed
pharmacokinetic parameters AUC.sub.0-t, AUC.sub.inf and C.sub.max
for tranexamic acid in plasma were within the 80-125% Food and Drug
Administration (FDA) acceptance range for the modified release
formulation versus the immediate release formulation under fasting
conditions.
[0144] The absolute bioavailability of the modified release and
immediate release tablet formulations were 44.93% and 46.04%
respectively.
[0145] Based on these results, the modified release tranexamic acid
tablet formulation and the immediate release tranexamic acid
formulation are bioequivalent under fasting conditions.
EXAMPLE 4A
Comparative Example
[0146] Comparative Example 4A, a 500 mg immediate release
tranexamic acid tablet, approved and marketed in Canada under the
name Cyklokapron was obtained and dissolution tested under USP 27
Apparatus Type II Paddle Method @ 50 RPM in 900 ml 7.+-.0.5.degree.
C. The dissolution results are listed in Table 10A below:
11TABLE 10A % dissolved % dissolved % dissolve % dissolved Sample #
in 15 min. in 30 min. in 45 min. in 60 min. 1 102 104 105 106 2 102
104 105 106 3 101 102 102 105 4 99 101 102 103 5 100 102 103 104 6
99 101 102 104 Average 101 102 103 105 % RSD 1.4 1.3 1.4 1.1
EXAMPLE 5
[0147] In Example 5, based on single dose pharmacokinetic
parameters, pharmacokinetic simulations of serum concentrations
were performed to compare dosing the modified release formulation
of Example 4 at every 8 hours (Q8H: at 6:00 AM, 2:00 PM, 10:00 PM)
and dosing three times a day, other than every 8 hours (TID: at
8:00 AM, 2:00 PM, and 10:00 PM). The results are provided in Tables
11-14 below.
12TABLE 11 Tranexamic Acid - Modified Release Formulation Dosage
Regimen Simulation - ORAL 1.3 g q8 hr Time (h) Dose (mcg) Conc.
(mcg/mL) 0 1.30E+06 0 1 0 4.0594 2 0 10.0551 3 0 10.6433 4 0
9.20306 5 0 7.26932 6 0 5.4699 8 1.30E+06 2.89909 9 0 6.15391 10 0
11.5813 11 0 11.7752 12 0 10.0646 13 0 7.94622 14 0 6.02067 15 0
4.4712 16 1.30E+06 3.30248 17 0 6.51406 18 0 11.9097 19 0 12.0794
20 0 10.3495 21 0 8.21523 22 0 6.2761 23 0 4.71463 24 1.30E+06
3.53505 25 0 6.73663 26 0 12.1229 27 0 12.2838 28 0 10.5455 29 0
8.40336 30 0 6.45664 31 0 4.88791 32 1.30E+06 3.70138 33 0 6.89628
34 0 12.2762 35 0 12.4309 36 0 10.6868 37 0 8.53894 38 0 6.5868 39
0 5.01286 40 1.30E+06 3.82133 41 0 7.01144 42 0 12.3867 43 0 12.537
44 0 10.7887 45 0 8.63675 46 0 6.68069 47 0 5.103 48 1.30E+06
3.90786 49 0 7.09451 50 0 12.4665 51 0 12.6136 52 0 10.8621 53 0
8.70731 54 0 6.74842 55 0 5.16802 56 1.30E+06 3.97028 57 0 7.15443
58 0 12.524 59 0 12.6688 60 0 10.9152 61 0 8.7582 62 0 6.79728 63 0
5.21493 64 1.30E+06 4.01531 65 0 7.19766 66 0 12.5655 67 0 12.7087
68 0 10.9534 69 0 8.79492 70 0 6.83253 71 0 5.24877 72 1.30E+06
4.0478 73 0 7.22885 74 0 12.5954 75 0 12.7374 76 0 10.981 77 0
8.82141 78 0 6.85796 79 0 5.27318 80 1.30E+06 4.07124 81 0 7.25135
82 0 12.617 83 0 12.7581 84 0 11.0009 85 0 8.84052 86 0 6.87631 87
0 5.29079 88 1.30E+06 4.08814 89 0 7.26758 90 0 12.6326 91 0
12.7731 92 0 11.0153 93 0 8.8543 94 0 6.88954 95 0 5.3035 96
1.30E+06 4.10034 97 0 7.27929 98 0 12.6439 99 0 12.7839 100 0
11.0256 101 0 8.86425 102 0 6.89909 103 0 5.31266 104 1.30E+06
4.10913 105 0 7.28773 106 0 12.652 107 0 12.7917 108 0 11.0331 109
0 8.87142 110 0 6.90597 111 0 5.31927 112 1.30E+06 4.11548 113 0
7.29382 114 0 12.6578 115 0 12.7973 116 0 11.0385 117 0 8.8766 118
0 6.91094 119 0 5.32404 120 0 4.12006
[0148] Concentration-time profiles are presented over 120 hours for
the modified release formulation in Table 12 and are depicted in
FIG. 1. A 1 g formulation administered q8h is also depicted for
comparison purposes.
13TABLE 12 Cmax, Cmin and Cavg for 1.3 g q8 hr simulation
Simulation at 120 hours Pharmacokinetic Parameter Concentration
Cmax 12.8 mcg/mL Cmin 4.1 mcg/mL Cavg 8.4 mcg/ml
[0149]
14TABLE 13 Tranexamic Acid - Modified Release Formulation Dosage
Regimen Simulation - ORAL 1.3 g TID (8:00 AM, 2:00 PM, and 10:00
PM) Time (h) Dose (mcg) Conc. (mcg/mL) 0 1.30E+06 0 1 0 4.0594 2 0
10.0551 3 0 10.6433 4 0 9.20306 5 0 7.26932 6 1.30E+06 5.4699 8 0
12.9542 9 0 12.7378 10 0 10.7293 11 0 8.40129 12 1.30E+06 6.33141
13 0 8.74352 14 0 13.505 15 0 13.2018 16 0 11.1327 17 0 8.76144 18
0 6.65976 19 0 4.98823 20 0 3.73474 21 0 2.8275 22 0 2.18502 23 0
1.73555 24 1.30E+06 1.42243 25 0 5.26298 26 0 11.104 27 0 11.5807
28 0 10.058 29 0 8.06103 30 1.30E+06 6.21137 31 0 8.76659 32 0
13.6187 33 0 13.3709 34 0 11.334 35 0 8.97998 36 1.30E+06 6.88576
37 0 9.27495 38 0 14.0147 39 0 13.6908 40 0 11.6019 41 0 9.21185 42
0 7.09208 43 0 5.40321 44 0 4.1331 45 0 3.20991 46 0 2.55212 47 0
2.08796 48 1.30E+06 1.76074 49 0 5.58776 50 0 11.4158 51 0 11.88 52
0 10.3453 53 0 8.33688 54 1.30E+06 6.47618 55 0 9.02081 56 0
13.8627 57 0 13.6052 58 0 11.5589 59 0 9.1959 60 1.30E+06 7.09304
61 0 9.47395 62 0 14.2057 63 0 13.8742 64 0 11.778 65 0 9.38036 66
0 7.25433 67 0 5.55898 68 0 4.28264 69 0 3.35346 70 0 2.68993 71 0
2.22026 72 1.30E+06 1.88775 73 0 5.70968 74 0 11.5329 75 0 11.9924
76 0 10.4532 77 0 8.44044 78 1.30E+06 6.57559 79 0 9.11625 80 0
13.9543 81 0 13.6931 82 0 11.6434 83 0 9.27696 84 1.30E+06 7.17086
85 0 9.54865 86 0 14.2775 87 0 13.943 88 0 11.8441 89 0 9.44431 90
0 7.31525 91 0 5.61745 92 0 4.33877 93 0 3.40735 94 0 2.74167 95 0
2.26992 96 1.30E+06 1.93543 97 0 5.75546 98 0 11.5768 99 0 12.0346
100 0 10.4937 101 0 8.47931 102 1.30E+06 6.61292 103 0 9.15208 104
0 13.9887 105 0 13.7261 106 0 11.6751 107 0 9.30739 108 1.30E+06
7.20008 109 0 9.5767 110 0 14.3044 111 0 13.9689 112 0 11.8689 113
0 9.46813 114 0 7.33811 115 0 5.63941 116 0 4.35985 117 0 3.42759
118 0 2.76109 119 0 2.28857 120 0 1.95333
[0150] Concentration-time profiles are presented over 120 hours for
the modified release formulation in Table 14 and are depicted in
FIG. 2. A 1 g formulation administered TID is also depicted for
comparison purposes.
15TABLE 14 Cmax, Cmin and Cavg for 1.3 g TID (8:00 AM, 2:00 PM, and
10:00 PM) Simulation at 120 hours Pharmacokinetic Parameter Conc.
Cmax 12.0, 14.0, 14.3 mcg/mL Cmin 1.9, 6.6, 7.2 mcg/mL Cavg 8.4
mcg/mL
EXAMPLE 6
[0151] In Example 6, a study of a single dose followed by multiple
doses, was performed on healthy non-smoking adult female volunteers
using a modified release formulation prepared in accordance with
Example 1. After an overnight fast, subjects received a single oral
dose of tranexamic acid (1.3 g) on Day 1. Blood samples were taken
before dosing and up to 36 hours post-dose. Subjects received
another single oral dose of tranexamic acid (1.3 g) on the evening
of Day 2, and 3 times a day (every 8 hours) starting on the morning
of Day 3 until the last dose on the morning of Day 7. Blood samples
were taken before the 6th, 9th, 12th and 15th dose (the last dose)
for the determination of C.sub.min, and up to 8 hours after the
last dose, for the determination of drug concentration at
steady-state. Subjects were housed from at least 10 hours before
the 1st dose on Day 1 until after the 8-hour blood draw following
the 15th dose (on Day 7).
[0152] Tranexamic acid is minimally bound (approximately 3%) to
plasma proteins (mainly plasminogen) at "typical" therapeutic
plasma concentrations of approximately 5-15 mg/L. The main route of
elimination of tranexamic acid is renal glomerular filtration.
After oral administration of tranexamic acid (250 or 500 mg) to
healthy adults, between 40-70% of the administered dose is excreted
unchanged in the urine within 24 hours. After IV administration (1
g) 30% of the dose is excreted unchanged in the urine within one
hour, 45-55% within 2-3 hours and 90% within 24 hours.
[0153] The beta elimination half-life of tranexamic acid is 2
hours. Based on published data, the mean C.sub.max and AUC.sub.0-6
pharmacokinetic parameters after a single 1.3 g oral dose of
tranexamic acid are expected to be approximately 65% of those
achieved with a 2 g dose (i.e. .about.10 mg/L and .about.40 mg-h/L,
C.sub.max and AUC.sub.0-6 under fasting conditions,
respectively).
[0154] However, the pharmacokinetics of tranexamic acid were not
adequately characterized in Pilbrant, et al., Eur. J. Clin.
Pharmacol, (1981)-20:65-72, since blood samples were collected for
up to only 6 hours post-dose. In addition, the plasma
concentration-time curves after IV administration showed three
exponential phases, with a gamma elimination half-life of
approximately 7 hours. For this reason, the concentration-time
profile of tranexamic acid was estimated by simulating the data
over 36 hours, after oral administration of a 1.3 g dose under
fasting conditions, using NONMEM. Based on the simulation results,
it would be appropriate to collect blood samples until 36 hours in
order to characterize the AUC, Cmax, tmax, t1/2 and F.
[0155] The objective of this study of Example 6 was to assess the
pharmacokinetic linearity of the test tablet formulation of
tranexamic acid (modified release), after a single oral dose (Day
1) compared to a daily (1.3 g every 8 hours) dosage regimen (Days 2
to 7), under fasting conditions.
[0156] In the study of Example 6, blood samples (1.times.5 mL) were
collected in blood collection tubes containing lithium heparin at
Hour 0 (pre-dose) on Day 1, and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4,
5, 6, 8, 10, 14, 24, 28, 32, and 36 hours post-dose. Blood samples
for Cmin determinations were also collected immediately before the
6th, 9th, 12th, and 15th doses on Days 4, 5, 6, and 7,
respectively, and at the following times after the 15th dose: 0.5,
1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, and 8 hours. Plasma samples were
separated by centrifugation, then frozen at -20.degree.
C..+-.10.degree. C. and kept frozen until assayed at AAI
Development Services in New-Ulm, Germany.
[0157] Noncompartmental Pharmacokinetic Parameters
[0158] Calculations for plasma tranexamic acid were calculated by
noncompartmental methods using the following pharmacokinetic
parameters in Tables 15 and 16:
[0159] Day 1:
16TABLE 15 AUC 0-t: The area under the plasma concentration versus
time curve, from time 0 to the last measurable concentration, as
calculated by the linear trapezoidal method. AUCinf: The area under
the plasma concentration versus time curve from time 0 to infinity.
AUCinf was calculated as the sum of AUC 0-t plus the ratio of the
last measurable plasma concentration to the elimination rate
constant. AUC/AUCinf: The ratio of AUC 0-t to AUCinf. Cmax: Maximum
measured plasma concentration over the time span specified. tmax:
Time of the maximum measured plasma concentration. If the maximum
value occured at more than one time point, tmax was defined as the
first time point with this value. kel: Apparent first-order
terminal elimination rate constant calculated from a semi-log plot
of the plasma concentration versus time curve. This parameter was
calculated by linear least squares regression analysis using the
maximum number of points in the terminal log- linear phase (e.g.
three or more non-zero plasma concentrations). t1/2: The apparent
first-order terminal elimination half-life was calculated as
0.693/kel.
[0160] No value for kel, AUCinf or t1/2 were reported for cases
that did not exhibit a terminal log-linear phase in the
concentration versus time profile.
[0161] Day 7:
17TABLE 16 AUC.tau.: The area under the plasma concentration versus
time curve over the final dosing interval, as calculated by the
linear trapezoidal method. Cmax: Maximum measured plasma
concentration over the final dosing interval. Cmin: Measured plasma
concentration prior to the morning dose. tmax: Time of the maximum
measured plasma concentration over the final dosing interval. If
the maximum value occured at more than one time point, tmax was
defined as the first time point with this value. Flux: Percent
fluctuation was calculated as follows: 1 Flux 1: C max - C min C
ssav .times. 100 where Cssav was calculated as the ratio of AUC
0-.tau. to the dosing interval, .tau.. 2 Flux 2: C max - C min C
min .times. 100
[0162] Compartmental Pharmacokinetic Parameters
[0163] Compartmental analysis was performed on tranexamic acid data
following single and multiple oral administrations of the modified
release (MR) tablet formulation. Multiple compartmental models were
constructed and their ability to fit plasma concentrations of
tranexamic acid were evaluated using a standard two-stage (STS)
approach with ADAPT-II (maximum likelihood analysis). The
discrimination process was performed by computing the Akaike
Information Criterion Test (AIC), the minimum value of the
objective function (OBJ) and by looking at pertinent graphical
representations of goodness of fit (e.g. fitted and observed
concentrations versus time).
[0164] The final analysis was performed using an iterative
two-stage approach with the IT2S.RTM. software. This software uses
a population methodology which allows one to provide robust PK
parameter estimates on an individual subject and population basis.
All relevant pharmacokinetic parameters were calculated and
reported. Concentrations were modeled using a weighting procedure
of W.sub.j=1/S.sub.j.sup.2 where the variance .sigma.j.sup.2 was
calculated for each observation using the equation
.sigma.j.sup.2=(a+b*Y.sub.j).sup.2 where a and b are the intercept
and slope of each variance model. The slope is the residual
variability associated with each concentration (includes the
intra-individual variability and the sum of all experimental
errors), and the intercept is related to the limit of detection of
the analytical assay. All PK parameter estimates were updated
iteratively during the population PK analysis (VARUP, IT2S.RTM.)
until stable values were found. The analysis included the
quantitative estimation of population PK parameters and
interindividual variability of tranexamic acid in plasma.
[0165] Individual profiles of observed vs fitted plasma
concentrations of tranexamic acid were provided for the MR
formulation.
[0166] Statistical Analyses
[0167] Descriptive Statistics
[0168] Descriptive statistics including arithmetic means, standard
deviations and coefficients of variation were calculated on the
individual concentration and pharmacokinetic data. Additionally,
geometric means were calculated for the parameters AUC.sub.0-t,
AUC.sub.inf, and C.sub.max for Day 1 and AUC.tau., C.sub.max and
C.sub.min for Day 7.
[0169] Time Dependence Pharmacokinetic Linearity
[0170] The pharmacokinetic parameter AUC.tau. (Day 7) was compared
against AUC.sub.inf (Day 1) using an analysis of variance (ANOVA)
on the ln-transformed values for tranexamic acid. The ANOVA model
included Group, Day (1 (AUC.sub.inf) and 7 (AUC.tau.)) and the
interaction Day*Group as fixed effects. All the interaction terms
were not statistically significant, at a level of 5%, and were
dropped from the final model. The ANOVA included calculation of
least-squares means (LSM), the difference between Day LSM and the
standard error associated with this difference. The above
statistical analysis was done using the SAS.RTM. GLM procedure.
[0171] The ratio of LSM was calculated using the exponentiation of
the Day LSM from the analysis on the ln-transformed response. The
ratio was expressed as a percentage relative to AUC.sub.inf (Day
1).
[0172] A ninety percent confidence interval for the ratio was
derived by exponentiation of the confidence interval obtained for
the difference between Day LSM resulting from the analysis on the
ln-transformed response. The confidence interval was expressed as a
percentage relative to AUC.sub.inf (Day 1).
[0173] Steady-State Analysis
[0174] A steady-state analysis was performed, on the ln-transformed
pre-dose Cmin concentrations at -72, -48, -24 and 0-hour time
points, using Helmert's contrasts. The ANOVA model included Group,
Time and the interaction Time*Group as fixed effects. In order to
model the correlations within every subject, an appropriate
variance-covariance matrix was chosen among the following:
unstructured (UN), compound symmetry (CS), compound symmetry
heterogeneous (CSH), variance component (VC), autoregressive
(AR(1)), autoregressive heterogeneous (ARH(1)) and autoregressive
moving average (ARMA(1,1)), using the Akaike's Burnham and Anderson
criterion (AICC). All the interaction terms were not statistically
significant, at a level of 5%, and were dropped from the final
model. The ANOVA included also calculation of least-squares means
(LSM) for each pre-dose C.sub.min concentrations. Helmert's
contrasts were constructed such that each time point is compared to
the mean of subsequent time points. There are 3 contrasts
associated to the 4 pre-dose concentration timepoints. They are
listed in Table 17 below:
18TABLE 17 Contrast Tests Compar. 1 Predose Day 4 compared to (mean
predose of Day 5, 6 and 7) Compar. 2 Predose Day 5 compared to
(mean predose of Day 6 and 7) Compar. 3 Predose Day 6 compared to
predose Day 7 (0-hour)
[0175] The above statistical analyses were done using the SAS.RTM.
Mixed procedure.
[0176] Formulae
[0177] The following formulae in Table 18 were used for the ratio
of least-squares means and 90% confidence interval calculations
derived from the ANOVA on the In transformed pharmacokinetic
parameters.
19TABLE 18 Ratio of Least- 100 .times. e.sup.(LSM.sup..sub.Day7
.sup.- LSM.sup..sub.Day1.sup.) squares Means: 90% Confidence 100
.times. e.sup.(LSM.sup..sub.Day7 .sup.- LSM.sup..sub.Day1 .sup..+-.
t.sup..sub.df,0.05 .sup..times. SE.sup..sub.Day7-Day1.sup.)
Interval: Note: LSM.sub.Day7 and LSM.sub.Day1 are the least-squares
means of Day 7 and Day 1, as computed by the LSMEANS statement of
the SAS .RTM. GLM procedure. t.sub.df,.alpha. is the value of the
Student's t distribution with df degrees of freedom (i.e. degrees
of freedom for the error term from the analysis of variance) and a
right-tail fractional area of .alpha. (.alpha. = 0.05).
SE.sub.Day7-Day1 is the standard error of the difference between
the adjusted Day means, as computed by the ESTIMATE statement in
the SAS .RTM. GLM procedure.
[0178] Discussion of Pharmacokinetic Results
[0179] Time Dependence Pharmacokinetic Linearity
[0180] The ANOVA model included Group, Day (1 (AUC.sub.inf) and 7
(AUC.tau.)) and the interaction Day*Group as the fixed effect. All
the interaction terms were not statistically significant, at a
level of 5%, and were dropped from the final model. Pharmacokinetic
linearity was calculated for the formulation using the same
approach as above, but the ANOVA model included Group, Day 1
(AUCinf) and Day 7 (AUC.tau.)) and the interactions Group*Day as
fixed effects and Subject nested within Group as a random
effect.
[0181] The pharmacokinetic linearity results are summarized in the
table below.
20 TABLE 19 90% Confidence Interval Formulation Ratio
AUC.tau./AUCinf Lower Limit Upper Limit MR 97.3 86.5 109.5
[0182] The pharmacokinetic linearity results indicate that the
ratios of least-squares means of AUC.tau. (Day 7) to AUC.sub.inf
(Day 1) and the 90% confidence interval for the MR formulation were
within the 80-125% acceptance range. Based on these results, the
650 mg tranexamic acid modified release tablets exhibited linear
pharmacokinetics following repeated administration (7 days) of a
1.3 g dose under fasting conditions.
[0183] Steady-State Analysis
[0184] For the steady-state analysis, the CS variance-covariance
matrix was chosen to model the correlations within every subject.
Overall, the interaction term (i.e. Time*Group) was not
statistically significant and was removed from the final ANOVA
model. For each formulation, the same approach as above was used,
but the ANOVA models included Group, Time and the interactions
Time*Group as fixed effects.
[0185] A summary of LSM results for the steady-state analysis are
summarized in Table 20A below.
21 TABLE 20A Times LSM derived Formulation Days (hour) from the
ANOVA MR 4 -72 4.90536 5 -48 4.77323 6 -24 5.23678 7 0 5.15389
[0186] Summary of statistical comparisons for the steady-state
analysis are summarized in Table 20B below
22TABLE 20B Formulation Helmert's contrasts P-value MR Predose Day
4 compared to (mean predose of Day 0.4438 5, 6 and 7) Predose Day 5
compared to (mean predose of Day 0.0393 6 and 7) Predose Day 6
compared to predose Day 7 0.7318
[0187] Based on the results above, steady-state plasma
concentration of tranexamic acid were reached on Day 4 (-72-hour),
since the p value for the first contrast was not statistically
significant at a 5% alpha error. It should be noted that the second
comparison [Predose Day 5 compared to (mean of Day 6 and 7)] was
found to be statistically significant.
[0188] The largest difference observed in predose plasma
concentrations of tranexamic acid between the LSM of predose Day 5
compared to Day 6 and 7 was less than 10%, which is not considered
clinically relevant. Moreover, the last contrast was not
statistically significant and the observed difference between the
LSM of predose Day 6 and 7 was less than 2%.
[0189] Compartmental Pharmacokinetic Analysis
[0190] The mean apparent oral clearance (CL/F) of the MR
formulation calculated with compartmental methods was 17.7 L/h (295
mL/min). Based on previous data reported in the literature, the
group of Pilbrant, et al., have determined that the urinary
recovery of tranexamic acid exceeded 95% of the dose administered.
Considering the bioavailability of the MR formulation (Mean F:
44.9%, See Table 5), the systemic clearance (CL) of tranexamic acid
(295 mL/min.times.0.449=123 mL/min) would be close to the
glomerular filtration rate in healthy subjects (125 mL/min)5.
[0191] Using compartmental methods, the mean T1/2.gamma. for the MR
formulation was 16.6 hours. Similar values of terminal elimination
half-life were previously reported in the literature. Pilbrant A.,
et al., Eur. J. Clin. Pharmacol (1981), 20: 65-72.
[0192] Following a single oral dose of 1.3 g of the MR formulation,
the mean plasma concentrations of tranexamic acid observed at 28,
32, and 36 hours were 0.19724, 0.15672, and 0.13624 mcg/mL,
respectively. Considering the therapeutic window of tranexamic acid
(5-15 mcg/mL) and the very low plasma concentration levels observed
at these timepoints, the terminal elimination half-life
(T1/2.gamma.) characterizing the slow decline of plasma
concentrations should not play a clinically significant role in the
frequency of drug administration.
[0193] Pharmacokinetic Conclusions
[0194] The pharmacokinetic linearity results indicate that the
ratios of least-squares means of AUC.tau. (Day 7) to AUCinf (Day 1)
and the 90% confidence interval for the MR formulation were within
the 80-125% acceptance range. Based on these results, the 650 mg
tranexamic acid modified release tablets exhibited linear
pharmacokinetics following repeated administration (7 days) of a
1.3 g dose under fasting conditions.
[0195] Steady-state plasma concentrations of tranexamic acid for
the modified-release tablets were reached on Day 4 (-72-hour),
since the p-value for the first contrast was not statistically
significant at a 5% alpha error.
[0196] The pharmacokinetics of tranexamic acid was properly
described using a three compartment PK model with linear
elimination. The absorption kinetic of the single-dose (Day 1) data
of tranexamic acid for the MR formulation was best described using
a mixed-order rate constant of absorption.
[0197] Plasma Pharmacokinetic Parameters for the modified release
(MR) formulation of Tranexamic Acid on day 1 are listed in Table 21
below.
23TABLE 21 ln AUC.sub.0-t* ln AUC.sub.inf* ln C.sub.max* (mcg
.multidot. h/ml) (mcg .multidot. h/ml) (mcg/ml) T.sub.max (h)
Half-life (h) K.sub.el (1/h) Mean 74.571 76.875 13.176041 3.079
11.078 0.06443 CV % 31.3 30.4 33.1 25.0 16.9 18.3 N 19 19 19 19 19
19 *For ln-transformed parameters, the antilog of the mean (i.e.
the geometric mean) is reported; AUC.sub.0-t = AUC post dose (0-36
hours)
[0198] Plasma Pharmacokinetic Parameters for the modified release
(MR) formulation of Tranexamic Acid on day 7 are listed in Table 22
below.
24TABLE 22 ln AUC.sub..tau.* ln C.sub.max* ln C.sub.min* (mcg
.multidot. h/ml) (mcg/ml) (mcg/ml) T.sub.max (h) Flux 1** (%) Flux
2** (%) Mean 74.791 15.803509 5.157681 2.553 113.16 219.21 CV %
29.0 30.1 31.2 14.4 21.6 44.6 N 19 19 19 19 19 19 *For
ln-transformed parameters, the antilog of the mean (i.e. the
geometric mean) is reported; AUC.sub..tau. = AUC dosing interval (8
hours) **Defined in Table 16
Conclusion
[0199] While the invention herein disclosed has been described by
means of specific embodiments and applications thereof, numerous
modifications and variations could be made thereto by those skilled
in the art without departing from the spirit and scope of the
present invention. Such modifications are understood to be within
the scope of the appended claims.
* * * * *
References