U.S. patent application number 13/948762 was filed with the patent office on 2013-12-19 for micronized tanaproget and compositions containing same.
This patent application is currently assigned to Wyeth LLC. The applicant listed for this patent is Wyeth LLC. Invention is credited to Rolland W. Carson, Ramarao Chatlapalli, Mohamed K. Ghorab, Shamim A. Hasan, Arwinder Nagi.
Application Number | 20130337058 13/948762 |
Document ID | / |
Family ID | 37027926 |
Filed Date | 2013-12-19 |
United States Patent
Application |
20130337058 |
Kind Code |
A1 |
Nagi; Arwinder ; et
al. |
December 19, 2013 |
Micronized Tanaproget and Compositions Containing Same
Abstract
The present invention provides compositions, desirably
pharmaceutical compositions, containing micronized tanaproget. The
compositions can also contain microcrystalline cellulose,
croscarmellose sodium, anhydrous lactose, and magnesium stearate;
or can contain microcrystalline cellulose, croscarmellose sodium,
sodium lauryl sulfate, povidone, and magnesium stearate. The
compositions are useful in contraception and hormone replacement
therapy and in the treatment and/or prevention of uterine
myometrial fibroids, benign prostatic hypertrophy, benign and
malignant neoplastic disease, dysfunctional bleeding, uterine
leiomyomata, endometriosis, polycystic ovary syndrome, and
carcinomas and adenocarcinomas of the pituitary, endometrium,
kidney, ovary, breast, colon, and prostate and other
hormone-dependent tumors, and in the preparation of medicaments
useful therefor. Additional uses include stimulation of food
intake.
Inventors: |
Nagi; Arwinder; (Moorpark,
CA) ; Chatlapalli; Ramarao; (Hopewell Junction,
NY) ; Hasan; Shamim A.; (East Elmhurst, NY) ;
Carson; Rolland W.; (Roswell, GA) ; Ghorab; Mohamed
K.; (West Lafayette, IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Wyeth LLC |
Madison |
NJ |
US |
|
|
Assignee: |
Wyeth LLC
Madison
NJ
|
Family ID: |
37027926 |
Appl. No.: |
13/948762 |
Filed: |
July 23, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12975444 |
Dec 22, 2010 |
8513240 |
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13948762 |
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11412022 |
Apr 26, 2006 |
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12975444 |
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60675551 |
Apr 28, 2005 |
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Current U.S.
Class: |
424/452 ;
424/400; 514/228.8 |
Current CPC
Class: |
A61P 15/00 20180101;
A61P 43/00 20180101; A61P 35/00 20180101; A61K 9/4866 20130101;
A61K 9/2018 20130101; A61P 15/18 20180101; A61K 9/2054 20130101;
A61K 9/14 20130101; A61P 5/00 20180101; A61K 9/4808 20130101; A61K
31/536 20130101; A61P 5/34 20180101; A61K 9/141 20130101 |
Class at
Publication: |
424/452 ;
514/228.8; 424/400 |
International
Class: |
A61K 31/536 20060101
A61K031/536; A61K 9/14 20060101 A61K009/14; A61K 9/48 20060101
A61K009/48 |
Claims
1. A pharmaceutical composition comprising micronized tanaproget,
or a pharmaceutically acceptable salt thereof, microcrystalline
cellulose, croscarmellose sodium, sodium lauryl sulfate, povidone,
and magnesium stearate.
2. The composition according to claim 1, wherein said tanaproget
comprises about 0.10% wt/wt of said composition.
3. A pharmaceutical composition for oral administration comprising
about 0.10% wt/wt micronized tanaproget, about 90.15% wt/wt
microcrystalline cellulose, about 6% wt/wt/croscarmellose sodium,
about 2% wt/wt sodium lauryl sulfate, about 1.5% wt/wt povidone,
and about 0.25% wt/wt magnesium stearate.
4. A process for preparing a composition comprising micronized
tanaproget, or a pharmaceutically acceptable salt thereof,
microcrystalline cellulose, croscarmellose sodium, anhydrous
lactose, and magnesium stearate, said process comprising: (a)
combining said micronized tanaproget, or a pharmaceutically
acceptable salt thereof, microcrystalline cellulose, croscarmellose
sodium, anhydrous lactose, and magnesium stearate; and (b)
granulating the mixture of step (a).
5. The process according to claim 4, wherein said composition is
compacted and compressed into a tablet suitable for oral
administration.
6. The process according to claim 5, wherein said tablet is
encapsulated in a capsule.
7. The process according to claim 4, further comprising compacting
said composition, milling the composition, or a combination
thereof.
8. The process according to claim 4, wherein about 86% to about 99%
of said tanaproget is released from said composition after about 90
minutes.
9. A process for preparing a composition of claim 1, said process
comprising: (a) combining said micronized tanaproget,
microcrystalline cellulose, croscarmellose sodium, povidone, sodium
lauryl sulfate, and magnesium stearate; and (b) granulating the
product of step (a).
10. The process according to claim 9, further comprising adding
said composition to a capsule.
11. The process according to claim 10, wherein said capsule is a
hard shell gelatin capsule.
12. A capsule comprising the composition of claim 1.
13. A pharmaceutical kit comprising a daily dosage unit of said
capsule of claim 12.
14. The pharmaceutical kit according to claim 13, comprising a
single phase of a daily dosage of said composition over a 21, 28,
31, or 31-day cycle.
15. The pharmaceutical kit according to claim 14, further
comprising a placebo.
16. The composition according to claim 1, comprising about 0.05 mg
to about 1 mg of tanaproget.
17. A tablet comprising the composition of claim 1.
18. A method of contraception, said method comprising administering
the composition of claim 1 to a female patient.
19. A method of hormone replacement therapy, said method comprising
administering the composition of claim 1 to a patient.
20. A method of treating or preventing uterine myometrial fibroids,
benign prostatic hypertrophy, benign and malignant neoplastic
disease, dysfunctional bleeding, uterine leiomyomata,
endometriosis, polycystic ovary syndrome, and carcinomas and
adenocarcinomas of the pituitary, endometrium, kidney, ovary,
breast, colon, and prostate, said method comprising administering
the composition of claim 1 to a patient.
21. A pharmaceutical composition comprising micronized tanaproget,
or a pharmaceutically acceptable salt thereof, microcrystalline
cellulose, croscarmellose sodium, anhydrous lactose, magnesium
stearate, and a granulating agent.
22. The composition according to claim 21, wherein said granulating
agent is silicon dioxide.
23. The composition according to claim 21, wherein said tanaproget
comprises about 0.08% to about 0.4% wt/wt of said composition.
24. The composition according to claim 21 which degrades less than
about 4% over a period of greater than 1 month at temperatures at
or greater than about 25.degree. C. and a relative humidity at or
greater than about 60%.
25. The composition according to claim 21, wherein the particles of
said micronized tanaproget are less than about 10 .mu.m.
26. The composition according to claim 21, wherein the particles of
said composition are less than about 125 .mu.m.
27. A pharmaceutical composition comprising micronized tanaproget,
or a pharmaceutically acceptable salt thereof, microcrystalline
cellulose, croscarmellose sodium, anhydrous lactose, magnesium
stearate, and silicon dioxide.
28. The composition according to claim 27, wherein said tanaproget
comprises about 0.08% to about 0.4% wt/wt of said composition.
29. The composition according to claim 27 which degrades less than
about 4% over a period of greater than 1 month at temperatures at
or greater than about 25.degree. C. and a relative humidity at or
greater than about 60%.
30. The composition according to claim 27, wherein the particles of
said micronized tanaproget are less than about 10 .mu.m.
31. The composition according to claim 27, wherein the particles of
said composition are less than about 125 .mu.m.
32. A process for preparing a composition of claim 21, said process
comprising: (a) combining said micronized tanaproget, or a
pharmaceutically acceptable salt thereof, microcrystalline
cellulose, croscarmellose sodium, anhydrous lactose, magnesium
stearate, and granulating agent; and (b) granulating the mixture of
step (a).
33. The process according to claim 32, wherein said composition is
compacted and directly compressed into a tablet suitable for oral
administration.
34. The process according to claim 33, wherein said tablet is
encapsulated in a capsule.
35. The process according to claim 32, further comprising
compacting said composition, milling the composition, or a
combination thereof.
36. The process according to claim 32, wherein about 86% to about
99% of said tanaproget is released from said composition after
about 90 minutes.
37. A process for preparing a composition of claim 27, said process
comprising: (a) combining said micronized tanaproget,
microcrystalline cellulose, croscarmellose sodium, anhydrous
lactose, magnesium stearate, and silicon dioxide; and (b)
granulating the product of step (a).
38. The process according to claim 37, wherein said composition is
compacted and directly compressed into a tablet suitable for oral
administration.
39. The process according to claim 38, wherein said tablet is
encapsulated in a capsule.
40. The process according to claim 37, further comprising
compacting said composition, milling the composition, or a
combination thereof.
41. The process according to claim 37, wherein about 86% to about
99% of said tanaproget is released from said composition after
about 90 minutes.
42. A tablet comprising the composition of claim 21.
43. A tablet comprising the composition of claim 27.
44. A pharmaceutical kit comprising a daily dosage unit of said
tablet of claim 42.
45. The pharmaceutical kit according to claim 44, wherein said
daily dosage is about 0.05 mg to about 1 mg.
46. The pharmaceutical kit according to claim 45, wherein said
daily dosage is about 0.05 mg to about 0.3 mg.
47. The pharmaceutical kit according to claim 44, which is for oral
delivery of said tablet over 21 days.
48. The pharmaceutical kit according to claim 44, which is for oral
delivery of said tablet over 28 days.
49. The pharmaceutical kit according to claim 44, which is for oral
delivery of said tablet over 30 days.
50. The pharmaceutical kit according to claim 44, which is for oral
delivery of said tablet over 31 days.
51. A pharmaceutical kit, comprising: (i) a first phase of 14 to 28
daily dosage units of said composition of claim 1; and (ii) a
second phase of 1 to 11 daily dosage units of a progestational
agent.
52. The pharmaceutical kit according to claim 51, comprising a
first phase of 14 to 21 daily dosage units of said composition.
53. The pharmaceutical kit according to claim 51, comprising: (i) a
first phase of 18 to 21 daily dosage units of said composition; and
(ii) a second phase of 1 to 7 daily dose units of said
progestational agent.
54. The pharmaceutical kit according to claim 51, comprising: (i) a
first phase of 21 daily dosage units of said tablet; and (ii) a
second phase of 3 daily dosage units for days 22 to 24 of said
progestational agent.
55. A pharmaceutical kit, comprising: (i) a first phase of 14 to 21
daily dosage units of a progestational agent equal in
progestational activity to about 35 to about 150 .mu.g
levonorgestrel; and (ii) a second phase of 1 to 11 daily dosage
units of said composition of claim 1.
56. The pharmaceutical kit according to claim 55, wherein said
progestational agent is equal in progestational activity to about
35 to about 100 .mu.g levonorgestrel.
57. A pharmaceutical kit comprising a daily dosage unit of said
tablet of claim 55.
Description
BACKGROUND OF THE INVENTION
[0001] Intracellular receptors (IR) form a class of structurally
related gene regulators known as "ligand dependent transcription
factors". The steroid receptor family is a subset of the IR family,
including the progesterone receptor (PR), estrogen receptor (ER),
androgen receptor (AR), glucocorticoid receptor (GR), and
mineralocorticoid receptor (MR).
[0002] The natural hormone, or ligand, for the PR is the steroid
progesterone, but synthetic compounds, such as medroxyprogesterone
acetate or levonorgestrel, have been made which also serve as
ligands. Once a ligand is present in the fluid surrounding a cell,
it passes through the cell membrane via passive diffusion, and
binds to the IR to create a receptor/ligand complex. This complex
binds to specific gene promoters present in the cell's DNA. Once
bound to the DNA, the complex modulates the production of mRNA and
protein encoded by that gene.
[0003] A compound that binds to an IR and mimics the action of the
natural hormone is termed an agonist, whilst a compound which
inhibits the effect of the hormone is an antagonist.
[0004] PR agonists (natural and synthetic) are known to play an
important role in the health of women. PR agonists are used in
birth control compositions, typically in the presence of an ER
agonist, alternatively they may be used in conjunction with a PR
antagonist. ER agonists are used to treat the symptoms of
menopause, but have been associated with a proliferative effect on
the uterus which can lead to an increased risk of uterine cancers.
Co-administration of a PR agonist reduces/ablates that risk.
[0005] Tanaproget,
5-(4,4-dimethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1-methyl-1H--
pyrrole-2-carbonitrile, is a progesterone receptor modulator and is
effective in contraception, hormone replacement therapy, and
treating carcinomas and adenocarcinomas, dysfunctional bleeding,
uterine leiomyomata, endometriosis, and polycystic ovary
syndrome.
[0006] What is needed in the art are compositions containing
tanaproget for administration to a mammalian subject.
SUMMARY OF THE INVENTION
[0007] In one aspect, the present invention provides micronized
tanaproget and compositions containing the same.
[0008] In a further aspect, the present invention provides a
composition containing micronized tanaproget, microcrystalline
cellulose, croscarmellose sodium, anhydrous lactose, and magnesium
stearate.
[0009] In still a further aspect, the present invention provides a
composition containing micronized tanaproget, microcrystalline
cellulose, croscarmellose sodium, sodium lauryl sulfate, povidone,
and magnesium stearate.
[0010] In another aspect, the present invention provides a process
for preparing compositions containing micronized tanaproget.
[0011] In a further aspect, the present invention provides kits
having compositions containing micronized tanaproget.
[0012] Other aspects and advantages of the present invention are
described further in the following detailed description of the
preferred embodiments thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0013] The present invention provides effective pharmaceutical
compositions containing micronized tanaproget. The micronized
tanaproget can be readily formulated into an oral dosage unit, and
is particularly well suited for a directly compressible unit. The
inventors have found that tablets or caplets prepared by direct
compression of, or capsules containing, the micronized tanaproget
compositions of the invention exhibited rapid and complete drug
release, as compared to nonmicronized tanaproget. Thus, the
compositions of the invention provide for fast drug release.
[0014] Briefly, tanaproget is micronized under nitrogen and
conventional micronizing techniques, for example with a Trost or
jet mill, applied to non-micronized tanaproget. One method of
preparation of non-micronized tanaproget is described in U.S. Pat.
No. 6,436,929, and generally in US Patent Application Publication
No. 2005/0272702, published Dec. 8, 2005. However, the invention is
not limited to the method by which the non-micronized tanaproget is
produced.
[0015] In another embodiment, non-micronized tanaproget is purified
by recrystallization. In one embodiment, the tanaproget is
recrystallized from acetone and water. In a further embodiment, the
tanaproget is dissolved in acetone, the acetone solution heated,
water added to the heated acetone solution, and the acetone/water
solution cooled to provide purified tanaproget. This purification
specifically includes dissolving crude tanaproget in acetone and
heating the solution to about 45 to about 51.degree. C. After
circulating the heated solution through a carbon filter for at
least about 4 hours, the filtered solution was concentrated using
procedures known to those of skill in the art. After adding water
to the concentrated solution, in one embodiment at a rate which
does not cool the refluxing acetone solution, the acetone/water
solution was cooled to about -6 to about 0.degree. C. In one
embodiment, the acetone/water solution was cooled at a rate of less
than about 0.5.degree. C./minute. After holding the batch at the
reduced temperature for at least about 3 hours, the precipitated,
purified tanaproget is collected using filtration. The collected
solid is washed with a water/acetone mixture, in one embodiment
washed twice with a 1:1 water/acetone mixture. The washed purified
tanaproget is then dried at less than 35.degree. C. for about 4
hours. Further drying at less than about 50.degree. C. was
performed to remove residual acetone/water as measured by
spectroscopic methods.
[0016] In one embodiment, micronized tanaproget prepared according
to the present invention has a particle size of less than about 20
.mu.m, less than about 15 .mu.m, or less than about 10 .mu.m. In a
further embodiment, 90% of the particles are less than or equal to
about 20 .mu.m and 50% are less than or equal to about 15 .mu.m as
determined by the Malvern method, which is readily understood by
one of skill in the art.
[0017] The micronized tanaproget encompasses tautomeric forms of
tanaproget and salts derived from pharmaceutically or
physiologically acceptable acids, bases, alkali metals and alkaline
earth metals. The present invention also includes derivatives of
tanaproget, including, but not limited to, esters, carbamates,
sulfates, ethers, oximes, carbonates, and the like.
[0018] Physiologically acceptable acids include those derived from
inorganic and organic acids. A number of inorganic acids are known
in the art and include hydrochloric, hydrobromic, hydroiodic,
sulfuric, nitric, and phosphoric acids, among others. Similarly, a
variety of organic acids are known in the art and include, without
limitation, lactic, formic, acetic, fumaric, citric, propionic,
oxalic, succinic, glycolic, glucuronic, maleic, furoic, glutamic,
benzoic, anthranilic, salicylic, tartaric, malonic, mallic,
phenylacetic, mandelic, embonic, methanesulfonic, ethanesulfonic,
panthenoic, benzenesulfonic, toluenesulfonic, stearic, sulfanilic,
alginic, and galacturonic acids, among others.
[0019] Physiologically acceptable bases include those derived from
inorganic and organic bases. A number of inorganic bases are known
in the art and include aluminum, calcium, lithium, magnesium,
potassium, sodium, and zinc sulfate or phosphate compounds, among
others. A number of organic bases are known in the art and include,
without limitation, N,N,-dibenzylethylenediamine, chloroprocaine,
choline, diethanolamine, ethylenediamine, meglumine, and procaine,
among others.
[0020] Physiologically acceptable alkali salts and alkaline earth
metal salts can include, without limitation, sodium, potassium,
calcium and magnesium salts in the form of esters, and
carbamates.
[0021] These salts, as well as the nonmicronized and micronized
tanaproget can be in the form of esters, carbamates and other
conventional "pro-drug" forms, which, when administered in such
form, convert to the active moiety in vivo. In one embodiment, the
prodrugs are esters. See, e.g., B. Testa and J. Caldwell, "Prodrugs
Revisited: The "Ad Hoc" Approach as a Complement to Ligand Design",
Medicinal Research Reviews, 16(3):233-241, ed., John Wiley &
Sons (1996).
[0022] Micronized tanaproget discussed herein also encompasses
"metabolites" which are unique products formed by processing
tanaproget by the cell or patient. In one embodiment, metabolites
are formed in vivo.
[0023] In one embodiment, the compositions of the invention are
prepared by dry mixing micronized tanaproget, based upon the total
weight of the unit dose, with the other components of the
composition.
[0024] As referred to herein below, the term "wt/wt" refers to the
weight of one component based on the total weight of the
composition. In one embodiment, this ratio does not include the
weight of the capsule, the weight of any filler utilized in the
capsule, and seal coating, if so utilized.
A. Composition I of the Invention
[0025] The compositions of the present invention are formulated to
provide rapid release of tanaproget, while simultaneously being
stable under conditions of storage. In one embodiment, Composition
I contains micronized tanaproget, or a pharmaceutically acceptable
salt thereof, microcrystalline cellulose (MCC), croscarmellose
sodium, anhydrous lactose, and magnesium stearate.
[0026] In one embodiment, micronized tanaproget is present in
Composition I of the invention in an amount from 0.08% wt/wt to
0.4% wt/wt of the composition. This amount may be varied, depending
upon the amount of micronized tanaproget to be delivered to a
patient. In another embodiment, an overage of tanaproget is
utilized, e.g., a 5% overage.
[0027] The desired therapeutic regimen can be taken into
consideration when formulating Composition I of the invention. For
example, micronized tanaproget is present in the formulation at
about 0.0875% wt/wt, based upon the total weight of the unit dose.
In another example, micronized tanaproget is present in the
composition at about 0.35% wt/wt based upon the total weight of the
unit dose.
[0028] Composition I also contains microcrystalline cellulose at
about 56% wt/wt of the composition; croscarmellose sodium at about
6% wt/wt of the composition; magnesium stearate at about 0.25%
wt/wt of the composition; and anhydrous lactose at about 37% wt/wt
of the composition.
[0029] In one embodiment, Composition I of the present invention
provides about 0.09% micronized tanaproget, about 56.3% wt/wt of
microcrystalline cellulose, about 37.3% wt/wt of anhydrous lactose,
about 6% wt/wt of croscarmellose sodium, and about 0.25% wt/wt of
magnesium stearate.
[0030] In another embodiment, Composition I of the present
invention provides about 0.35% micronized tanaproget, about 56.2%
wt/wt of microcrystalline cellulose, about 37.1 wt/wt of anhydrous
lactose, about 6% wt/wt of croscarmellose sodium, and about 0.25%
wt/wt of magnesium stearate.
[0031] Without limitation as to the method of preparation of a
composition of the invention, an example of a suitable micronized
tanaproget composition is provided in Table 1.
TABLE-US-00001 TABLE 1 Component % wt/wt Tanaproget, Micronized
0.0875 Microcrystalline Cellulose 56.31 Croscarmellose Sodium 6
Anhydrous Lactose 37.35 Magnesium Stearate 0.25
[0032] Still a further example of a suitable micronized tanaproget
composition is provided in Table 2.
TABLE-US-00002 TABLE 2 Component % wt/wt Tanaproget, Micronized
0.35 Microcrystalline Cellulose 56.23 Croscarmellose Sodium 6
Anhydrous Lactose 37.17 Magnesium Stearate 0.25
[0033] Composition I is typically prepared by combining micronized
tanaproget, or a pharmaceutically acceptable salt thereof,
microcrystalline cellulose (MCC), croscarmellose sodium, anhydrous
lactose, and magnesium stearate and mixing or granulating the
mixture. In one embodiment, Composition I is prepared by dry mixing
or granulating the components therein using techniques such as
roller compaction, slugging, or a combination thereof.
[0034] The term "roller compaction" as used herein refers to a
process by which two or more solid materials are compacted between
two rotating rolls, desirably, counter-rotating rolls, to form
solid ribbons. These ribbons are then subject to further steps
including milling to form a composition of the invention.
[0035] The term "slugging" as using herein refers to a process by
which two or more solid materials are compressed on a press,
typically using presses that are larger than those presses utilized
to prepare large tablets. These tablets are then subject to further
steps including milling to form a composition of the invention.
[0036] The components can also be in extragranular or intragranular
forms, as determined by one of skill in the art and as determined
by the requirements of the process. In one embodiment, the
croscarmellose sodium is in intragranular form. In another
embodiment, the croscarmellose sodium is in extragranular form. In
yet another embodiment, the magnesium stearate is in intragranular
form.
[0037] In addition, a variety of apparatuses can be utilized to
perform the process of the invention and includes bags of small,
medium, and large sizes, screens of varying sizes, and blenders,
among others.
[0038] The process can also include compacting or milling
Composition I, typically using compactors and mills selected by one
of skill in the art. The milling step is typically performed on
particles of varying sizes, i.e., large particles, powders, and
fine powders to obtain a preferential and more uniform particle
size. The milling can include several separating, recycling, and
screening steps to obtain the desired particle sizes.
[0039] In one embodiment, the compositions of the present invention
contain particles of an optimal size to permit dissolution of the
composition, and in a further embodiment, the particles are less
than or equal to about 125 .mu.m. The sizes of the particles of the
composition are typically measured by passing the solid composition
through screens of varying sizes. In one embodiment, about 7% of
the particles are greater than or equal to about 350 .mu.m. In
another embodiment, about 26% of the particles are greater than or
equal to about 180 .mu.m. In a further embodiment, about 31% of the
particles are greater than or equal to about 150 .mu.m. In still
another embodiment, about 36% of the particles are greater than
about 125 .mu.m. In yet another embodiment, about 46% of the
particles are greater than about 89 .mu.m. In a further embodiment,
about 52% of the particles are greater than about 75 .mu.m. In
still another embodiment, about 67% of the particles are greater
than about 45 .mu.m.
[0040] If the particles of the compositions are larger than the
optimal size and if the same have not yet been encapsulated in a
capsule, the same can be subject to further milling and screening
steps, among others, to reduce the particle size.
[0041] The process typically includes compressing the composition
into a form suitable for oral administration and is typically a
tablet or caplet. When compressed into a tablet or caplet, one of
skill in the art would readily be able to select a suitable tablet
press for use in the present invention. However, one example of
such a press includes the Stokes.RTM. B2 Tablet Press, among
others.
[0042] In one embodiment, the tablet prepared according to the
present invention is encapsulated in a capsule. In a further
embodiment, the capsule is a hydroxypropyl methylcellulose
(hypromellose) capsule. The capsule can be optionally sealed with
the tablet therein or a filler can be added to the capsule
containing tablet. In one embodiment, the filler includes MCC,
croscarmellose sodium, and magnesium stearate. In another
embodiment, the tablet is placed in the capsule prior to adding the
filler.
[0043] Optionally, the tablets are film-coated. Suitable
film-coatings are known to those of skill in the art. For example,
the film-coating can be selected from among suitable polymers such
as hydroxpropylmethylcellulose, ethyl cellulose, polyvinyl alcohol,
and combinations thereof. Other suitable film-coatings can be
readily selected by one of skill in the art. In one embodiment, the
tablet is coated with an Opadry.RTM. seal coat. Where applied, the
weight percent of the film coat is generally in the range of 2%
wt/wt to 6% wt/wt of the tablet.
[0044] When prepared according to the present invention, the
tablets, capsules, or tablets-in-capsules containing Composition I
release about 86 to about 99% of tanaproget after about 90 minutes.
In a further embodiment, the composition releases about 85% of the
tanaproget after about 20 minutes.
B. Composition II of the Invention
[0045] In another embodiment, a composition of the present
invention contains micronized tanaproget, or a pharmaceutically
acceptable salt thereof, microcrystalline cellulose, croscarmellose
sodium, sodium lauryl sulfate (SLS), povidone (PVP), and magnesium
stearate.
[0046] In one embodiment, the micronized tanaproget is present in
Composition II of the invention in an amount at about 0.1% wt/wt,
or 0.01% wt/wt, of the composition. This amount may be varied,
depending upon the amount of micronized tanaproget to be delivered
to a patient. The desired therapeutic regimen can be taken into
consideration when formulating a composition of the invention. In
another embodiment, an overage of tanaproget is utilized, e.g., a
5% overage.
[0047] Composition II also contains about 90% wt/wt
microcrystalline cellulose; about 6% wt/wt croscarmellose sodium;
about 2% wt/wt sodium lauryl sulfate; about 1.5% povidone; and
about 0.25% wt/wt magnesium stearate.
[0048] In one embodiment, Composition II of the present invention
typically contains about 0.10% or about 0.1% micronized tanaproget,
about 90% wt/wt microcrystalline cellulose, about 6% wt/wt
croscarmellose sodium, about 2% wt/wt sodium lauryl sulfate, about
1.5% povidone, and about 0.25% wt/wt magnesium stearate.
[0049] Without limitation as to the method of preparation of
Composition II of the invention, an example of a suitable
micronized tanaproget composition is provided in Table 3.
TABLE-US-00003 TABLE 3 Component % wt/wt Tanaproget, Micronized 0.1
Microcrystalline Cellulose 90.15 Croscarmellose Sodium 6.00 Sodium
Lauryl Sulfate 2.0 Povidone 1.5 Magnesium Stearate 0.25
[0050] Composition II is prepared by combining micronized
tanaproget, microcrystalline cellulose, croscarmellose sodium,
povidone, sodium lauryl sulfate, and magnesium stearate; and
granulating. In one embodiment, Composition II is prepared by dry
mixing the components therein. The components of the composition
can also be in extragranular or intragranular forms, as determined
by one of skill in the art and as determined by the requirements of
the process. A variety of apparatuses can be utilized to perform
the process of the invention and includes bags of large, medium,
and large sizes, screens of varying sizes, and blenders, among
others.
[0051] The process can also include compacting or milling
Composition II, typically using compactors and mills selected by
one of skill in the art. The milling step is typically performed on
particles of varying sizes, i.e., large particles, powders, and
fine powders to obtain a more uniform particle size. The milling
can include several separating, recycling, and screening steps to
obtain the desired particle sizes.
[0052] If the particles of the compositions are larger than the
optimal size and if the same have not yet been encapsulated in a
capsule, the same can be subject to further milling and screening
steps, among others, to reduce the particle size.
[0053] In a further embodiment, the compositions of the present
invention can be prepared by diluting the other compositions with
excipients. Useful excipients for dilution include those set forth
below and can include MCC, croscarmellose sodium, and magnesium
stearate.
[0054] For example, compositions containing lesser amounts of
tanaproget are prepared according to the present invention by
diluting compositions containing greater amounts of tanaproget. In
one embodiment, a composition containing 0.05 mg of tanaproget is
prepared by diluting a composition containing 0.075, 0.1, 0.15,
0.2, or 0.3 mg of tanaproget, or by diluting a composition
containing 0.075 or 0.1 mg. In a further embodiment, a composition
containing 0.075 mg tanaproget is prepared by diluting a
composition containing 0.1, 0.15, 0.2, or 0.3 mg of tanaproget. In
another embodiment, a composition containing 0.1 mg of tanaproget
is prepared by diluting a composition containing 0.15, 0.2, or 0.3
mg of tanaproget. In yet a further embodiment, a composition
containing 0.15 mg tanaproget is prepared by diluting a composition
containing 0.2 or 0.3 mg of tanaproget. In still another
embodiment, a composition containing 0.2 mg of tanaproget is
prepared by diluting a composition containing 0.3 mg of tanaproget.
In another embodiment, the compositions of the invention prepared
by diluting compositions containing higher amounts of tanaproget
are diluted with MCC, croscarmellose sodium, and magnesium
stearate.
[0055] The process typically includes adding Composition II to a
capsule, e.g., a hard shell gelatin capsule. Typically, the capsule
is a hydroxypropyl methylcellulose or hypromellose capsule.
[0056] However, Composition II can be compressed into a tablet or
caplet, which can optionally be encapsulated in a capsule. In one
embodiment, the capsule is a hydroxypropyl methylcellulose
(hypromellose) capsule. When compressed into a tablet or caplet,
one of skill in the art would readily be able to select a suitable
tablet press for use in the present invention. However, one example
of such a press includes the Stokes.RTM. B2 Tablet Press, among
others. The capsule can be optionally sealed with the tablet
therein or a filler can be added to the capsule containing tablet.
In one embodiment, the filler includes MCC, croscarmellose sodium,
and magnesium stearate. In another embodiment, the tablet is placed
in the capsule prior to adding the filler.
[0057] If the composition is compressed into a tablet or caplet,
the tablets or caplets can optionally be film-coated. Suitable
film-coatings are known to those of skill in the art. For example,
the film-coating can be selected from among suitable polymers such
as hydroxypropyl methylcellulose, ethyl cellulose, polyvinyl
alcohol, and combinations thereof. Other suitable film-coatings can
be readily selected by one of skill in the art. In one embodiment,
the tablet or caplet is coated with an Opadry.RTM. seal coat. Where
applied, the weight percent of the film coat is generally in the
range of 2% wt/wt to 6% wt/wt of the tablet or caplet.
[0058] When prepared according to the present invention, the
capsules containing Composition II release about 86 to about 99% of
tanaproget after about 90 minutes. In a further embodiment, the
capsules release about 85% of the tanaproget after about 20
minutes.
C. Stability of the Compositions of the Invention
[0059] The compositions of the present invention, including
Compositions I and II, are stable over a period of about 1 month
for samples stored at varying temperatures and humidities. The term
stable as used herein refers to the compositions of the invention
which degrade less than about 4%. Typically, it is the tanaproget
that degrades in the composition. Compositions I and II are stable
at about 20.degree. C./50% relative humidity to about 45.degree.
C./75% relative humidity. In one embodiment, Compositions I and II
degrade less than about 4% over a period of greater than 1 month at
temperatures at or greater than about 25.degree. C. and a relative
humidity at or greater than about 60%. Samples were also stable
over a period of about 2 months at temperatures of about 2 to about
8.degree. C., optionally in the absence of light and moisture.
[0060] In one embodiment, Compositions I and II of the invention
are stored at reduced temperatures, in a further embodiment at
temperatures of about 5.degree. C. It is desirable that the
compositions be stored in the absence of water, air, and
moisture.
D. Additional Components of the Compositions of the Invention
[0061] Other suitable components can be added to Compositions I and
II of the present invention, provided that the same is not already
present, and will be readily apparent to one of skill in the art.
Typically, the additional components are inert and do not interfere
with the function of the required components of the compositions.
The compositions of the present invention can thereby further
include other adjuvants, syrups, elixirs, diluents, binders,
lubricants, surfactants, granulating agents, disintegrating agents,
emollients, metal chelators, pH adjustors, surfactants, fillers,
disintegrants, and combinations thereof, among others.
[0062] Adjuvants can include, without limitation, flavoring agents,
coloring agents, preservatives, and supplemental antioxidants,
which can include vitamin E, ascorbic acid, butylated
hydroxytoluene (BHT) and butylated hydroxyanisole (BHA).
[0063] Binders can include, without limitation, povidone,
cellulose, methylcellulose, hydroxymethylcellulose,
carboxymethylcellulose calcium, carboxymethylcellulose sodium,
hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate,
noncrystalline cellulose, polypropylpyrrolidone,
polyvinylpyrrolidone (povidone, PVP), gelatin, gum arabic and
acacia, polyethylene glycols, starch, sugars such as sucrose,
kaolin, dextrose, and lactose, cholesterol, tragacanth, stearic
acid, gelatin, casein, lecithin (phosphatides), cetostearyl
alcohol, cetyl alcohol, cetyl esters wax, dextrates, dextrin,
glyceryl monooleate, glyceryl monostearate, glyceryl
palmitostearate, polyoxyethylene alkyl ethers, polyoxyethylene
castor oil derivatives, polyoxyethylene stearates, polyvinyl
alcohol, and gelatin, among others. In one embodiment, the binder
is povidone.
[0064] Lubricants can include light anhydrous silicic acid, talc,
stearic acid, sodium lauryl sulfate, magnesium stearate and sodium
stearyl furamate, among others. In one embodiment, the lubricant is
magnesium stearate.
[0065] Granulating agents can include, without limitation, silicon
dioxide, starch, calcium carbonate, pectin, crospovidone, and
polyplasdone, among others.
[0066] Disintegrating agents or disintegrants can include starch,
carboxymethylcellulose, substituted hydroxypropylcellulose, sodium
bicarbonate, calcium phosphate, calcium citrate, sodium starch
glycolate, pregelatinized starch or crospovidone, among others.
[0067] Emollients can include, without limitation, stearyl alcohol,
mink oil, cetyl alcohol, oleyl alcohol, isopropyl laurate,
polyethylene glycol, olive oil, petroleum jelly, palmitic acid,
oleic acid, and myristyl myristate.
[0068] Surfactants can include polysorbates, sorbitan esters,
poloxamer, or sodium lauryl sulfate. In one embodiment, the
surfactant is sodium lauryl sulfate.
[0069] Metal chelators can include physiologically acceptable
chelating agents including edetic acid, malic acid, or fumaric
acid. In one embodiment, the metal chelator is edetic acid.
[0070] pH adjusters can also be utilized to adjust the pH of a
solution containing tanaproget to about 4 to about 6. In one
embodiment, the pH of a solution containing tanaproget is adjusted
to a pH of about 4.6. pH adjustors can include physiologically
acceptable agents including citric acid, ascorbic acid, fumaric
acid, or malic acid, and salts thereof. In one embodiment, the pH
adjuster is citric acid.
[0071] Additional fillers that can be used in the composition of
the present invention include mannitol, calcium phosphate,
pregelatinized starch, or sucrose.
E. Methods of Using the Compositions
[0072] The invention further provides a method of delivering
tanaproget to a patient, where the method includes administering a
micronized tanaproget dosing unit according to the invention.
[0073] The dosage requirements of tanaproget may vary based on the
severity of the symptoms presented and the particular subject being
treated. Treatment can be initiated with small dosages less than
the optimum dose of tanaproget. Thereafter the dosage is increased
until the optimum effect under the circumstances is reached.
Precise dosages will be determined by the administering physician
based on experience with the individual subject treated. In
general, the compositions of this invention are most desirably
administered at a concentration that will generally afford
effective results without causing any unacceptable harmful or
deleterious side effects. For example, an effective amount of
micronized tanaproget is generally, e.g., about 0.05 mg to about 1
mg, about 0.05 mg to about 0.3 mg, about 0.05 mg, about 0.075 mg,
about 0.1 mg, about 0.15 mg, about 0.2 mg, or about 0.3 mg.
[0074] These compositions containing micronized tanaproget are
therefore useful in contraception and hormone replacement therapy.
The compositions are also useful in contraception and the treatment
and/or prevention of uterine myometrial fibroids, benign prostatic
hypertrophy, benign and malignant neoplastic disease, dysfunctional
bleeding, uterine leiomyomata, endometriosis, polycystic ovary
syndrome, and carcinomas and adenocarcinomas of the pituitary,
endometrium, kidney, ovary, breast, colon, and prostate and other
hormone-dependent tumors, and in the preparation of medicaments
useful therefor. Additional uses of the compositions include
stimulation of food intake.
[0075] The compositions of the invention are formed into a suitable
dosing unit for delivery to a patient. Suitable dosing units
include oral dosing units, such as directly compressible tablets,
capsules, powders, suspensions, microcapsules, dispersible powders,
granules, suspensions, syrups, elixirs, and aerosols. In one
embodiment, the compositions of the present invention are
compressed into a tablet, which is optionally added to a capsule,
or the compositions are added directly to a capsule. The
compositions of the invention can also be formulated for delivery
by other suitable routes. These dosing units are readily prepared
using the methods described herein and those known to those of
skill in the art.
[0076] Solid forms, including tablets, caplets, and capsules
containing micronized tanaproget can be formed by dry blending
tanaproget with the components described above. In one embodiment,
the capsules utilized in the present invention include
hydroxypropyl methylcellulose (hypromellose) capsule, or a hard
shell gelatin capsule. In another embodiment, the tablets or
caplets of the present invention that contain tanaproget are
film-coated. Suitable film-coatings are known to those of skill in
the art. For example, the film-coating can be selected from among
polymers such as hydroxypropylmethylcellulose, ethyl cellulose,
polyvinyl alcohol, and combinations thereof.
[0077] A pharmaceutically effective amount of tanaproget can vary
depending on the components of the composition, mode of delivery,
severity of the condition being treated, the patient's age and
weight, and any other active ingredients used in the composition.
The dosing regimen can also be adjusted to provide the optimal
therapeutic response. Several divided doses can be delivered daily,
e.g., in divided doses 2 to 4 times a day, or a single dose can be
delivered. The dose can however be proportionally reduced or
increased as indicated by the exigencies of the therapeutic
situation. In one embodiment, the delivery is on a daily, weekly,
or monthly basis. In another embodiment, the delivery is on a daily
delivery. Daily dosages can also be lowered or raised based on the
periodic delivery.
[0078] It is contemplated that when the compositions of this
invention are used for contraception or hormone replacement
therapy, they can be administered in conjunction with one or more
other progesterone receptor agonists, estrogen receptor agonists,
progesterone receptor antagonists, and selective estrogen receptor
modulators, among others.
[0079] When utilized for treating neoplastic disease, carcinomas,
and adenocarcinomas, they can be administered in conjunction with
one or more chemotherapeutic agents, which can readily be selected
by one of skill in the art.
F. Kits of the Invention
[0080] The present invention also provides kits or packages
containing micronized tanaproget. Kits of the present invention can
include tanaproget and a carrier suitable for administration to a
mammalian subject as discussed above. In one embodiment, the
tablets or capsules are packaged in blister packs, and in a further
embodiment in Ultrx.TM. 2000 blister packs.
[0081] The kits or packages containing the compositions of the
present invention are designed for use in the regimens described
herein. In one embodiment, these kits are designed for daily oral
delivery over 21-day, 28-day, 30-day, or 31-day cycles, among
others, or for one oral delivery per day. When the compositions are
to be delivered continuously, a package or kit can include the
composition in each tablet. When the compositions of the present
invention are to be delivered with periodic discontinuation, a
package or kit can include placebos on those days when the
composition is not delivered.
[0082] Additional components may be co-administered with
Composition I or II of the invention and include progestational
agents, estrogens, and selective estrogen receptor modulators.
[0083] In one embodiment, the kits are also organized to indicate a
single oral formulation or combination of oral formulations to be
taken on each day of the cycle, in a further embodiment including
oral tablets to be taken on each of the days specified, and in
still a further embodiment one oral tablet will contain each of the
combined daily dosages indicated.
[0084] In one embodiment, a kit can include a single phase of a
daily dosage of Composition I or II of the invention over a 21-day,
28-day, 30-day, or 31-day cycle. Alternatively, a kit can include a
single phase of a daily dosage of Composition I or II of the
invention over the first 21 days of a 28-day, 30-day, or 31-day
cycle. A kit can also include a single phase of a daily dosage of
Composition I or II of the invention over the first 28 days of a
30-day or 31-day cycle.
[0085] In a further embodiment, a kit can include a single combined
phase of a daily dosage of Composition I or II of the invention and
a progestational agent over a 21-day, 28-day, 30-day, or 31-day
cycle. Alternatively, a kit can include a single combined phase of
a daily dosage of Composition I or II of the invention and a
progestational agent over the first 21 days of a 28-day, 30-day, or
31-day cycle. A kit can also include a single combined phase of a
daily dosage of Composition I or II of the invention and a
progestational agent over the first 28 days of a 30-day or 31-day
cycle.
[0086] In another embodiment, a 28-day kit can include a first
phase of from 14 to 28 daily dosage units of Composition I or II of
the invention; a second phase of from 1 to 11 daily dosage units of
a progestational agent; and, optionally, a third phase of an orally
and pharmaceutically acceptable placebo for the remaining days of
the cycle.
[0087] In yet a further embodiment, a 28-day kit can include a
first phase of from 14 to 21 daily dosage units of Composition I or
II of the invention; a second phase of from 1 to 11 daily dosage
units of a progestational agent; and, optionally, a third phase of
an orally and pharmaceutically acceptable placebo for the remaining
days of the cycle.
[0088] In another embodiment, a 28-day kit can include a first
phase of from 18 to 21 daily dosage units of Composition I or II of
the invention; a second phase of from 1 to 7 daily dose units of a
progestational agent; and, optionally, an orally and
pharmaceutically acceptable placebo for each of the remaining 0 to
9 days in the 28-day cycle.
[0089] In yet a further embodiment, a 28-day kit can include a
first phase of 21 daily dosage units of Composition I or II of the
invention; a second phase of 3 daily dosage units for days 22 to 24
of a progestational agent; and, optionally, a third phase of 4
daily units of an orally and pharmaceutically acceptable placebo
for each of days 25 to 28.
[0090] In another embodiment, a 28-day kit can include a first
phase of from 14 to 21 daily dosage units of a progestational agent
equal in progestational activity to about 35 to about 150 .mu.g
levonorgestrel, a second phase of from 1 to 11 daily dosage units
of Composition I or II of the invention; and optionally, a third
phase of an orally and pharmaceutically acceptable placebo for the
remaining days of the cycle in which no antiprogestin, progestin or
estrogen is administered.
[0091] In a further embodiment, a 28-day kit can include a first
phase of from 14 to 21 daily dosage units of a progestational agent
equal in progestational activity to about 35 to about 100 .mu.g
levonorgestrel; a second phase of from 1 to 11 daily dosage units
of Composition I or II of the invention; and optionally, a third
phase of an orally and pharmaceutically acceptable placebo for the
remaining days of the cycle in which no antiprogestin, progestin or
estrogen is administered.
[0092] In one embodiment, the daily dosage of tanaproget remains
fixed in each particular phase in which it is delivered. In a
further embodiment, the daily dose units described are to be
delivered in the order described, with the first phase followed in
order by the second and third phases. To help facilitate compliance
with each regimen, in a further embodiment the kits contain the
placebo described for the final days of the cycle.
[0093] A number of packages or kits are known in the art for the
use in dispensing pharmaceutical agents for oral use. In one
embodiment, the package has indicators for each day of the 28-day
cycle, and in a further embodiment is a labeled blister package,
dial dispenser package, or bottle.
[0094] The kit can further contain instructions for administering
the tanaproget compositions of the present invention.
[0095] The following examples are provided to illustrate the
invention and do not limit the scope thereof. One skilled in the
art will appreciate that although specific reagents and conditions
are outlined in the following examples, modifications can be made
which are meant to be encompassed by the spirit and scope of the
invention.
EXAMPLES
Example 1
Preparation of Micronized Tanaproget
[0096] Tanaproget prepared according to US Patent Application
Publication No. 2005/0272702, published Dec. 8, 2005 was milled
using a U-10 Comil mill and thereby micronized using a MC50
Jetpharma Micronizer with an EZFH-1.4 Feeder. Particle size was
tested periodically for a particle size of less than about 15
.mu.m, and desirably less than about 10 .mu.m, being distributed
throughout 50% of the sample. The micronized tanaproget was packed
in triple poly-bagged fiber drums. A desiccant was inserted between
the outermost bags and the atmosphere in the bags replaced with
nitrogen gas.
Example 2
Directly Compressible Tablet Compositions Prepared by Employing
Micronized Tanaproget
[0097] The tablet compositions for this example were manufactured
using the following protocol and using the components of Table
4.
TABLE-US-00004 TABLE 4 Ingredients Function Micronized Tanaproget
Active Microcrystalline Cellulose Filler, Granulation (MCC), NF,
(Avicel PH101) Aid, Disintegrant Anhydrous Lactose Filler
Croscarmellose Sodium Disintegrant NF (Ac-Di-Sol) Magnesium
Stearate Lubricant (Vegetable Source), NF Capsule Shell
Inactive
[0098] Anhydrous lactose and MCC were passed through a mesh screen
and transferred to a 1 cu. ft. PK blender. The blended anhydrous
lactose and MCC were passed through a mesh screen into a suitable
poly bag. Micronized tanaproget was transferred to a suitable
plastic bag. The tanaproget was pre-blended with a portion of the
anhydrous lactose/MCC mixture. The pre-blend containing
tanaproget/anhydrous lactose/MCC was transferred to the blender
containing the remaining portion of anhydrous lactose and MCC and
mixed. An intragranular portion of croscarmellose sodium was passed
through a mesh screen and pre-blend with a portion of anhydrous
lactose and MCC. The pre-blend containing the intrangranular
croscarmellose sodium/anhydrous lactose/MCC was added to the
blender containing the tanaproget and mixed. An intragranular
portion of magnesium stearate was passed through a mesh screen and
pre-blend with a portion of anhydrous lactose and MCC. The
pre-blend containing the intragranular magnesium stearate/anhydrous
lactose/MCC was transferred to the blender containing the
tanaproget and mixed to form an intermediate composition.
[0099] The intermediate composition was compressed using a roller
compactor and then milled using a Fitzmill model D6. The milled
material was passed through a mesh screen, the large particles
separated, and the large particles milled to a powder. The fine
powder produced from the milling was compressed and milled to a
powder. All of the milled powder was thereby combined in a blender.
An extragranular portion of croscarmellose sodium was passed
through a mesh screen and pre-blend with a portion of the combined
milled powder. The pre-blend containing the extragranular
croscarmellose sodium and milled powder was then mixed with the
remaining portion of the combined milled powder. An intragranular
portion of magnesium stearate was passed through a screen and
premixed with a portion of the pre-blend containing the
extragranular croscarmellose sodium and milled powder. The premix
containing the extragranular magnesium stearate was added to the
blender and mixed with the second portion of the pre-blend
containing the extragranular croscarmellose sodium and milled
powder to form the final composition.
[0100] The final composition was then compressed into a tablet
using a Stokes.RTM. B2 Tablet Press, adjusting the press as
necessary. At equally spaced intervals, tablet samples were
obtained and stored in double poly-lined containers, desiccants
were placed between the two bags, and the bags were stored at
reduced temperatures of 2.degree. C. to 8.degree. C. in the absence
of light and moisture. Either the stored tablets or freshly
prepared tablets were then encapsulated. See Table 5 for the
amounts of the components utilized in the four different tablet
strengths.
TABLE-US-00005 TABLE 5 Tablet Strength (mg) 0.05 0.075 0.1 0.15 0.2
0.3 A- A- A- A- A- A- mount % mount % mount % mount % mount % mount
% Component (mg) wt/wt (mg) wt/wt (mg) wt/wt (mg) wt/wt (mg) wt/wt
(mg) wt/wt Micronized 0.05 0.0875 0.075 0.0875 0.105 0.0875 0.158
0.0875 0.210 0.35 0.315 0.35 tanaproget Micro- 33.79 56.31 50.68
56.31 67.57 56.31 101.35 56.31 33.74 56.23 50.61 56.23 crystalline
cellulose Anhydrous 22.42 37.35 33.62 37.35 44.83 37.35 67.24 37.35
22.30 37.17 33.45 37.17 Lactose Croscarmellose 3.60 6.00 5.40 6.00
7.20 6.00 10.80 6.00 3.60 6.00 5.40 6.00 Sodium Magnesium 0.15 0.25
0.225 0.25 0.30 0.25 0.45 0.25 0.15 0.25 0.23 0.25 Stearate
[0101] These compositions include a 5% overage of tanaproget to
compensate for manufacturing loss during blending and
compacting.
[0102] For tablet encapsulation of the 0.075, 0.1, 0.15, 0.2, and
0.3 mg tablets, MCC and croscarmellose sodium were passed through a
screen, added to a 1-20 cubic foot blender without an intensifier
bar installed, and mixed. Magnesium stearate was passed through a
screen and mixed with the blend containing MCC and croscarmellose
sodium to form the filler. Using a capsule filler, each size #1
capsule shell was filled by placing one tablet into one capsule
shell body and flood filling the capsule with the filler. The
filled capsule was then closed.
[0103] See Table 6 for the amounts of the components added to the
inert filler.
TABLE-US-00006 TABLE 6 Tablet Strength (mg) 0.075 0.1 0.15 0.2 0.3
Amount % Amount % Amount % Amount % Amount % Ingredients (mg) wt/wt
(mg) wt/wt (mg) wt/wt (mg) wt/wt (mg) wt/wt Microcrystalline
127.725 97.5 120.90 97.5 108.23 97.5 140.4 97.5 127.72 97.5
cellulose Croscarmellose 2.62 2.0 2.48 2.0 2.22 2.0 2.88 2.0 2.62
2.0 Sodium Magnesium 0.655 0.5 0.62 0.5 0.55 0.5 0.72 0.5 0.655 0.5
Stearate Capsule 1 #1 -- 1 #1 -- 1 #1 -- 1 #1 -- 1 #1 -- Brown
Brown Brown Brown Brown HPMC HPMC HPMC HPMC HPMC shell shell shell
shell shell
[0104] These compositions include a 5% overage of tanaproget to
compensate for manufacturing loss during blending and
compacting.
Example 3
Capsule Compositions Prepared by Employing Micronized
Tanaproget
[0105] The capsule compositions for this example are manufactured
using the following protocol and using the components set forth in
Table 7.
TABLE-US-00007 TABLE 7 Ingredients Function Micronized Tanaproget
Active Microcrystalline Cellulose (MCC), NF, Filler, Granulation
Aid, (Avicel PH101) Disintegrant Croscarmellose Sodium NF
(Ac-Di-Sol) Disintegrant Magnesium Stearate, (Vegetable Source), NF
Filler Povidone, K-17, USP Binder Sodium Lauryl Sulfate (SLS), NF
Surface active agent Capsule Shell Inactive
[0106] Micronized tanaproget was added to a first plastic bag. A
first portion of MCC was combined with the tanaproget and mixed. A
second portion of MCC was combined with the blend of tanaproget and
MCC and mixed. The blend containing both portions of MCC and
tanaproget was passed through a #20 hand screen into a larger bag.
The first plastic bag was rinsed with third and fourth portions of
MCC, the rinsed products passed through the #20 hand screen into
the larger bag, and mixed. A fifth portion of MCC was passed
through a #20 hand screen into the larger plastic bag and mixed. A
sixth portion of MCC was passed through a #20 hand screen into the
larger plastic bag and mixed. A seventh portion of MCC was passed
through a #20 hand screen into a suitable size PK-blender. The
blend in the larger bag was passed through a #20 hand screen into
the PK-blender. Eighth and ninth separate portions of MCC were
utilized to obtain any MCC/tanaproget remaining residue from larger
bag, which residue was passed through a #20 hand screen into the
PK-blender. Croscarmellose sodium was passed through a #20 hand
screen into the PK-blender. SLS was passed through a #20 hand
screen into the PK-blender. Povidone was passed through a #20 hand
screen into the PK-blender. All of the materials in the blender
were mixed without intensifier bar activation.
[0107] A last portion of MCC was passed through a #20 hand screen
into the PK-blender and mixed without the intensifier bar
activation. Magnesium stearate was passed through a #30 mesh screen
and premixed with the blend containing the last portion of MCC,
transferred to the PK-blender, and mixed without intensifier bar
activation to form the final blend.
[0108] The capsules were filled with about 100 mg of the final
blend. The capsules were stored in a poly-lined drum at reduced
temperatures and in the absence of light and moisture.
TABLE-US-00008 TABLE 8 Amount Ingredients (mg) % wt/wt Micronized
Tanaproget 0.10 0.10 Microcrystalline Cellulose 90.15 90.15
Croscarmellose Sodium 6.00 6.00 Sodium Lauryl Sulfate 2.0 2.0
Povidone 1.5 1.5 Magnesium Stearate 0.25 0.25
[0109] All documents and priority applications, including U.S.
patent application Ser. No. 12/975,444, filed Dec. 22, 2010, U.S.
patent application Ser. No. 11/412,022, filed Apr. 26, 2006, and
U.S. Provisional Patent Application No. 60/675,551, filed Apr. 28,
2005, listed in this specification are incorporated herein by
reference. While the invention has been described with reference to
a particularly preferred embodiment, it will be appreciated that
modifications can be made without departing from the spirit of the
invention. Such modifications are intended to fall within the scope
of the appended claims.
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