U.S. patent application number 14/293070 was filed with the patent office on 2014-11-06 for micronized tanaproget, compositions, and methods of preparing the same.
This patent application is currently assigned to Wyeth LLC. The applicant listed for this patent is Wyeth LLC. Invention is credited to Ramarao Chatlapalli, Dhaval Gaglani, Mohamed Ghorab, Shamim Hasan, Arwinder Nagi.
Application Number | 20140328925 14/293070 |
Document ID | / |
Family ID | 37023145 |
Filed Date | 2014-11-06 |
United States Patent
Application |
20140328925 |
Kind Code |
A1 |
Nagi; Arwinder ; et
al. |
November 6, 2014 |
MICRONIZED TANAPROGET, COMPOSITIONS, AND METHODS OF PREPARING THE
SAME
Abstract
The present invention provides compositions, desirably
pharmaceutical compositions, containing micronized tanaproget. The
compositions can also contain microcrystalline cellulose,
croscarmellose sodium, anhydrous lactose, magnesium stearate,
micronized edetate calcium disodium hydrous, and micronized sodium
thiosulfate pentahydrate. 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; (East Elmhurst, NY) ;
Ghorab; Mohamed; (West Lafayette, IN) ; Gaglani;
Dhaval; (Gaithersburg, MD) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Wyeth LLC |
Madison |
NJ |
US |
|
|
Assignee: |
Wyeth LLC
Madison
NJ
|
Family ID: |
37023145 |
Appl. No.: |
14/293070 |
Filed: |
June 2, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13890523 |
May 9, 2013 |
8772271 |
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14293070 |
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12752520 |
Apr 1, 2010 |
8450312 |
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13890523 |
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11411523 |
Apr 26, 2006 |
7767668 |
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12752520 |
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60675550 |
Apr 28, 2005 |
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Current U.S.
Class: |
424/489 ;
514/230.5 |
Current CPC
Class: |
A61K 31/536 20130101;
A61P 5/36 20180101; A61P 13/00 20180101; A61P 15/12 20180101; A61P
5/00 20180101; A61P 15/18 20180101; A61P 5/34 20180101; A61K 9/2077
20130101; A61K 9/2013 20130101; A61K 9/2018 20130101; A61K 9/167
20130101; A61P 35/00 20180101; A61K 9/0002 20130101; A61P 15/08
20180101; A61K 9/2054 20130101; A61P 15/00 20180101; A61K 9/16
20130101 |
Class at
Publication: |
424/489 ;
514/230.5 |
International
Class: |
A61K 9/16 20060101
A61K009/16; A61K 31/536 20060101 A61K031/536 |
Claims
1. A method of contraception, hormone replacement therapy,
stimulating food intake, or treating or preventing (i)
endometriosis, (ii) uterine myometrial fibroids, (iii) benign
prostatic hypertrophy, (iv) benign and malignant neoplastic
disease, (v) dysfunctional bleeding, (vi) uterine leiomyomata,
(vii) polycystic ovary syndrome or (viii) carcinomas and
adenocarcinomas of the pituitary, endometrium, kidney, ovary,
breast, colon, prostate, or other hormone dependent tumors in a
patient in need thereof, said method comprising administering a
composition comprising an intragranulation comprising micronized
tanaproget or a pharmaceutically acceptable salt thereof,
microcrystalline cellulose, croscarmellose sodium, anhydrous
lactose, magnesium stearate, micronized edetate calcium disodium
hydrous, and micronized sodium thiosulfate pentahydrate to said
patient.
2. The method according to claim 1, wherein the particles of said
micronized tanaproget are less than about 10 .mu.m.
3. The method according to claim 1, wherein the particles of said
micronized sodium thiosulfate pentahydrate are less than about 31
.mu.m.
4. The method according to claim 1, wherein the particles of said
micronized edetate calcium disodium hydrous are less than about 35
.mu.m.
5. The method according to claim 1, which degrades less than about
3% 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%.
6. The method according to claim 1, wherein said tanaproget
comprises about 0.15% to about 0.50% wt/wt of said composition.
7. The method according to claim 1, wherein said tanaproget
comprises about 0.15% wt/wt of said composition.
8. The method according to claim 1, wherein said tanaproget
comprises about 0.23% wt/wt of said composition.
9. The method according to claim 1, wherein said tanaproget
comprises about 0.31% wt/wt of said composition.
10. The method according to claim 1, wherein said tanaproget
comprises about 0.5% wt/wt of said composition.
11. The method according to claim 1, wherein said microcrystalline
cellulose comprises about 30 to about 50% wt/wt of said
composition.
12. The method according to claim 1, said composition further
comprising extragranular croscarmellose sodium.
13. The method according to claim 12, wherein said intragranular
and extragranular croscarmellose sodium comprises about 2 to about
6% wt/wt of said composition.
14. The method according to claim 1, said composition further
comprising extragranular magnesium stearate.
15. The method according to claim 1, wherein said intragranular and
extragranular magnesium stearate comprises about 0.25 to about 0.5%
wt/wt of said composition.
16. The method according to claim 1, wherein said anhydrous lactose
comprises about 54% to about 55% wt/wt of said composition.
17. The method according to claim 1, wherein said micronized
edetate calcium disodium hydrous comprises about 0.05 to about
0.15% wt/wt of said composition.
18. The method according to claim 1, wherein said micronized sodium
thiosulfate pentahydrate comprises about 0.25 to about 0.75% wt/wt
of said composition.
19. The method according to claim 1, wherein the particles of said
composition are less than about 100 .mu.m.
20. The method according to claim 1, wherein said composition is
administered to said female as a tablet.
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)-1H-methyl-py-
rrole-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 compositions
containing micronized tanaproget or a pharmaceutically acceptable
salt thereof, microcrystalline cellulose, croscarmellose sodium,
anhydrous lactose, magnesium stearate, micronized edetate calcium
disodium hydrous, and micronized sodium thiosulfate
pentahydrate.
[0008] In still a further aspect, the present invention provides
processes for preparing compositions containing micronized
tanaproget.
[0009] 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
[0010] 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 non-micronized tanaproget. Thus, the
compositions of the invention provide for fast drug release.
[0011] 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.
[0012] In another embodiment, non-micronized tanaproget is purified
by recrystallization. In one embodiment, non-micronized 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.
[0013] 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.
[0014] 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.
[0015] 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.
[0016] 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.
[0017] 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.
[0018] 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).
[0019] 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.
[0020] 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. In another embodiment, the compositions of the
invention are prepared by wet mixing micronized tanaproget, based
upon the total weight of the unit dose, with the other components
of the composition.
[0021] As referred to herein below, the term "wt/wt" refers to the
weight of one component based on the total weight of the components
utilized in the composition. In one embodiment, wt/wt refers to the
weight of one component based on the total weight of the
composition. In another embodiment, wt/wt refers to the weight of
one component based on the total weight of the final tablet or
caplet. 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.
[0022] The Composition of the Invention
[0023] 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, the
composition contains micronized tanaproget, or a pharmaceutically
acceptable salt thereof, microcrystalline cellulose (MCC),
croscarmellose sodium, anhydrous lactose, magnesium stearate,
micronized edetate calcium disodium hydrous (EDTA), and micronized
sodium thiosulfate pentahydrate. In a further embodiment, the
tanaproget is intragranular. In still a further embodiment, the
tanaproget, MCC, anhydrous lactose, EDTA, and sodium thiosulfate
pentahydrate are intragranular.
[0024] In one embodiment, micronized tanaproget is present in the
composition of the invention in an amount from 0.15% to about 0.50%
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 the composition of the invention. In another
embodiment, an overage of tanaproget is utilized, e.g., a 5%
overage. For example, micronized tanaproget is present in the
formulation at about 0.15% wt/wt based upon the total weight of the
unit dose. In another example, micronized tanaproget is present in
the composition at about 0.23% wt/wt based upon the total weight of
the unit dose. In a further example, micronized tanaproget is
present in the composition at about 0.31% wt/wt based upon the
total weight of the unit dose. In yet another example, micronized
tanaproget is present in the composition at about 0.5% wt/wt based
upon the total weight of the unit dose.
[0025] The composition also includes microcrystalline cellulose
(MCC), in one embodiment at about 30 to about 50% wt/wt of the
composition. In one example, MCC is present in the composition at
about 30% wt/wt. In another example, MCC is present in the
composition at about 40% wt/wt. In a further example, MCC is
present in the composition at about 50% wt/wt.
[0026] The composition also includes croscarmellose sodium, in one
embodiment at about 2 to about 6% wt/wt of the composition, in
extragranular and/or intragranular forms. In one example,
croscarmellose sodium is present at about 2% wt/wt of the
composition. In another example, croscarmellose sodium is present
at about 4% wt/wt of the composition. In a further example,
croscarmellose sodium is present at about 6% wt/wt of the
composition.
[0027] The composition further includes one or more of an
"antioxidant". By the term "antioxidant" is meant a compound that
is capable or inhibiting or retarding the degradation of the
composition of the present invention. In one embodiment, the
antioxidant inhibits or retards the degradation of the tanaproget
in the composition. Examples of antioxidants that are useful in the
present invention include sodium thiosulfate, sodium metabisulfite,
cysteine, methionine, vitamin E, and edetate calcium disodium
hydrous (EDTA). In a further embodiment, the antioxidant is
micronized prior to use in the present invention.
[0028] In one embodiment, the compositions of the invention include
EDTA, which is present at about 0.05 to 0.15% wt/wt of the
composition, or about 0.05, 0.10, or 0.15% wt/wt of the
composition. In one embodiment, the EDTA is micronized and 90% of
the particles are less than or equal to about 35 .mu.m, 50% are
less than or equal to about 11 .mu.m, and 10% are less than or
equal to 3 .mu.m as determined by the Malvern method, which is
readily understood by one of skill in the art.
[0029] In one embodiment, sodium thiosulfate pentahydrate is
present in the composition at about 0.25 to about 0.75% wt/wt, or
about 0.25, 0.50 (or 0.5), or 0.75% wt/wt. In one embodiment, the
sodium thiosulfate pentahydrate is micronized and 90% of the
particles are less than or equal to about 31 .mu.m, 50% are less
than or equal to about 13 .mu.m, and 10% are less than or equal to
4 .mu.m as determined by the Malvern method, which is readily
understood by one of skill in the art.
[0030] In one example, the composition includes EDTA at about 0.25%
wt/wt and sodium thiosulfate at about 0.25% wt/wt. In another
example, the composition includes EDTA at about 0.10% wt/wt and
sodium thiosulfate at about 0.50% wt/wt. In a further example, the
composition includes EDTA at about 0.15% wt/wt and sodium
thiosulfate at about 0.75% wt/wt.
[0031] The composition of the invention also includes anhydrous
lactose, typically at about 54 to about 55% wt/wt of the
composition. In one example, anhydrous lactose is present at about
54% wt/wt of the composition. In a further example, anhydrous
lactose is present at about 55% wt/wt of the composition. In
another example, anhydrous lactose is present at about 54.8% wt/wt
of the composition. In a further example, anhydrous lactose is
present at about 54.79% wt/wt of the composition. In still another
example, anhydrous lactose is present at about 54.71% wt/wt of the
composition. In yet a further example, anhydrous lactose is present
at about 54.56% wt/wt of the composition.
[0032] The composition of the invention further includes magnesium
stearate, in one embodiment at about 0.25 to about 0.5% wt/wt. In a
further embodiment, the composition contains about 0.25% wt/wt of
magnesium stearate. In another embodiment, the composition contains
about 0.375% wt/wt of magnesium stearate. In another embodiment,
the composition contains about 0.5% wt/wt of magnesium stearate. In
still another embodiment, the composition contains about 0.37%
wt/wt of magnesium stearate. The magnesium stearate can be present
in intragranular and/or extragranular forms.
[0033] In one embodiment, a composition of the invention includes
microcrystalline cellulose at about 40% wt/wt of the composition;
croscarmellose sodium at about 4% wt/wt of the composition;
intragranular magnesium stearate at about 0.37% wt/wt of the
composition; intragranular anhydrous lactose at about 54 to about
55% wt/wt of the composition; intragranular micronized edetate
calcium disodium hydrous at about 0.10% wt/wt of the composition;
and intragranular micronized sodium thiosulfate pentahydrate at
about 0.5% wt/wt of the composition.
[0034] In another embodiment, the composition can further contain
intragranular microcrystalline cellulose at about 40% wt/wt of the
composition; intragranular croscarmellose sodium at about 2% wt/wt
of the composition; intragranular magnesium stearate at about 0.19%
wt/wt of the composition; intragranular anhydrous lactose at about
54 to about 55% wt/wt of the composition; intragranular micronized
edetate calcium disodium hydrous at about 0.10% wt/wt of the
composition; and intragranular micronized sodium thiosulfate
pentahydrate at about 0.5% wt/wt of the composition. The
composition can further contain extragranular croscarmellose sodium
at about 2% wt/wt of the composition and extragranular magnesium
stearate at about 0.19% wt/wt of the composition.
[0035] In a further embodiment, the composition of the present
invention provides about 0.15% wt/wt micronized tanaproget, about
40% wt/wt microcrystalline cellulose, about 54.87% wt/wt anhydrous
lactose, about 4% wt/wt croscarmellose sodium, about 0.38% wt/wt
magnesium stearate, about 0.1% wt/wt micronized EDTA, and about
0.5% wt/wt micronized sodium thiosulfate pentahydrate.
[0036] In still another embodiment, the composition of the present
invention provides about 0.23% wt/wt micronized tanaproget, about
40% wt/wt microcrystalline cellulose, about 54.79% wt/wt anhydrous
lactose, about 4% wt/wt croscarmellose sodium, about 0.38% wt/wt
magnesium stearate, about 0.1% wt/wt micronized EDTA, and about
0.5% wt/wt micronized sodium thiosulfate pentahydrate.
[0037] In a further embodiment, the composition of the present
invention provides about 0.31% wt/wt micronized tanaproget, about
40% wt/wt microcrystalline cellulose, about 54.71% wt/wt anhydrous
lactose, about 4% wt/wt croscarmellose sodium, about 0.38% wt/wt
magnesium stearate, about 0.1% wt/wt micronized EDTA, and about
0.5% wt/wt micronized sodium thiosulfate pentahydrate.
[0038] In still another embodiment, the composition of the present
invention provides about 0.46% wt/wt micronized tanaproget, about
40% wt/wt microcrystalline cellulose, about 54.56% wt/wt anhydrous
lactose, about 4% wt/wt croscarmellose sodium, about 0.38% wt/wt
magnesium stearate, about 0.1% wt/wt micronized EDTA, and about
0.5% wt/wt of micronized sodium thiosulfate pentahydrate.
[0039] 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 Intragranular micronized
tanaproget 0.1546 MCC 40.00 anhydrous lactose 54.8706 EDTA 0.10
micronized sodium thiosulfate 0.5 pentahydrate micronized
croscarmellose sodium 2.00 magnesium stearate 0.1875 Extragranular
croscarmellose sodium 2.00 magnesium stearate 0.1875
[0040] Still a further example of a suitable micronized tanaproget
composition is provided in Table 2.
TABLE-US-00002 TABLE 2 Component % wt/wt Intragranular micronized
tanaproget 0.2316 MCC 40.00 anhydrous lactose 54.7935 EDTA 0.10
micronized sodium 0.5 thiosulfate pentahydrate micronized
croscarmellose 2.00 sodium magnesium stearate 0.1875 Extragranular
croscarmellose sodium 2.00 magnesium stearate 0.1875
[0041] Another example of a suitable micronized tanaproget
composition is provided in Table 3.
TABLE-US-00003 TABLE 3 Component % wt/wt Intragranular micronized
tanaproget 0.3088 MCC 40.00 anhydrous lactose 54.7163 EDTA 0.10
micronized sodium 0.5 thiosulfate pentahydrate micronized
croscarmellose 2.00 sodium magnesium stearate 0.1875 Extragranular
croscarmellose sodium 2.00 magnesium stearate 0.1875
[0042] Yet a further example of a suitable micronized tanaproget
composition is provided in Table 4.
TABLE-US-00004 TABLE 4 Component % wt/wt Intragranular micronized
tanaproget 0.4632 MCC 40.00 anhydrous lactose 54.5619 EDTA 0.10
micronized sodium 0.5 thiosulfate pentahydrate micronized
croscarmellose 2.00 sodium magnesium stearate 0.1875 Extragranular
croscarmellose sodium 2.00 magnesium stearate 0.1875
[0043] The composition of the invention is prepared by mixing
micronized tanaproget, microcrystalline cellulose, croscarmellose
sodium, micronized sodium thiosulfate pentahydrate, anhydrous
lactose, micronized edetate calcium disodium hydrous, and magnesium
stearate. In one embodiment, the composition is prepared by wet
mixing the components therein with water. The components of the
composition can also be in extragranular or intragranular forms, as
determined by one of skill in the art and the requirements of the
process.
[0044] 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.
[0045] The process can also include compacting and/or milling the
composition, 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 preferred and more uniform particle size.
The milling can include several separating, recycling, and
screening steps to obtain the desired particle sizes. Drying is
generally perfoinied using suitable drying instrument selected by
one of skill in the art such as a fluid bed dryer.
[0046] In a further embodiment, the compositions of the present
invention can be prepared by diluting the compositions with
excipients. Useful excipients for dilution include those set forth
below and can include MCC, croscarmellose sodium, and magnesium
stearate.
[0047] Compositions containing lesser amounts of tanaproget can
prepared according to the present invention by diluting
compositions containing greater amounts of tanaproget. In one
embodiment, a composition containing 0.01 mg of tanaproget is
prepared by diluting a composition containing 0.1, 0.15, 0.2, or
0.3 mg of tanaproget, and desirably by diluting a composition
containing 0.10 mg. 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,
magnesium stearate, and lactose.
[0048] In one embodiment, the compositions of the present invention
contain particles of an optimal size to permit dissolution of the
composition, e.g., the particles are less than or equal to about
100 .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 36% of the particles are
greater than or equal to about 180 .mu.m. In another embodiment,
about 46% of the particles are greater than or equal to about 125
.mu.m. In a further embodiment, about 75% of the particles are
greater than or equal to about 45 .mu.m. In still another
embodiment, about 25% of the particles are less than about 45
.mu.m.
[0049] 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.
[0050] 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
or caplet press for use in the present invention. One example of
such a press includes the Stokes.RTM. B2 Tablet Press, among
others.
[0051] The tablet prepared according to the present invention can
be optionally encapsulated in a capsule. In one 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 extragranular croscarmellose sodium
and magnesium stearate. In a further embodiment, the tablet is
placed in the capsule prior to adding the filler.
[0052] Optionally, the tablets or caplets 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 or caplet is coated with an Opadry.TM. seal coat. In a
further embodiment, the tablet or caplet is coated with an
Opadry.TM. Blue 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. In one embodiment, the weight percent of the film
coat is about 3.5% wt/wt of the tablet or caplet. Drying of the
coating is accomplished by conventional means, e.g., with a fluid
bed dryer.
[0053] When prepared according to the present invention, the
tablets, caplets, capsules, or tablets-in-capsules containing the
composition release about 86 to about 99% of tanaproget after about
90 minutes. In a further embodiment, 85% of the tanaproget, or
about 90%, is released in about 15 minutes.
[0054] B. Stability of the Compositions of the Invention
[0055] The compositions of the present invention 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 3%.
Typically, it is the tanaproget that degrades in the composition.
In one embodiment, the compositions are stable at about 20.degree.
C./50% relative humidity to about 45.degree. C./75% relative
humidity. In another embodiment, the compositions of the invention
degrade less than about 3% 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%.
[0056] The compositions of the invention can be stored at reduced
temperatures, and in one embodiment, at temperatures of about
5.degree. C. The compositions can also be stored in the absence of
water, air, and moisture. However, storage at room temperature,
among other atmospheric conditions, does not affect the overall
stability of the compositions.
[0057] C. Additional Components of the Compositions of the
Invention
[0058] Other suitable components can be added to the compositions
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.
[0059] Adjuvants can include, without limitation, flavoring agents,
coloring agents, preservatives, and supplemental antioxidants,
which can include ascorbic acid, butylated hydroxytoluene (BHT) and
butylated hydroxyanisole (BHA).
[0060] Binders can include, without limitation, 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.
[0061] 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.
[0062] Granulating agents can include, without limitation, silicon
dioxide, starch, calcium carbonate, pectin, crospovidone, and
polyplasdone, among others.
[0063] 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.
[0064] 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.
[0065] Surfactants can include polysorbates, sorbitan esters,
poloxamer, or sodium lauryl sulfate. In one embodiment, the
surfactant is sodium lauryl sulfate.
[0066] 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.
[0067] 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.
[0068] Additional fillers that can be used in the composition of
the present invention include mannitol, calcium phosphate,
pregelatinized starch, or sucrose.
[0069] D. Methods of Using the Compositions
[0070] 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.
[0071] 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 1 mg, about 0.15
mg, about 0.2 mg, or about 0.3 mg.
[0072] 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.
[0073] 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 a directly compressible tablets,
caplets, 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 or caplet, 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.
[0074] 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. More desirable tablet or caplet
weights include tablets or caplets of about 100 mg, about 150 mg,
about 200 mg, or about 300 mg. However, tablets or caplets of
lesser or greater weights can be utilized as determined by one of
skill in the art.
[0075] 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.
[0076] 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.
[0077] 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.
[0078] E. Kits of the Invention
[0079] 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, caplets, or capsules are packaged in blister packs, and in
a further embodiment, Ultrx.TM. 2000 blister packs.
[0080] 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 or caplet. 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.
[0081] Additional components may be co-administered with the
composition of the invention and include progestational agents,
estrogens, and selective estrogen receptor modulators.
[0082] In one embodiment, the kits are 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 or caplets to be taken on each of the days specified,
and in still a further embodiment one oral tablet or caplet will
contain each of the combined daily dosages indicated.
[0083] In one embodiment, a kit can include a single phase of a
daily dosage of the composition 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 the composition 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 the
composition of the invention over the first 28 days of a 30-day or
31-day cycle.
[0084] In a further embodiment, a kit can include a single combined
phase of a daily dosage of the composition 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 the composition 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 the composition of the invention and a
progestational agent over the first 28 days of a 30-day or 31-day
cycle.
[0085] In another embodiment, a 28-day kit can include a first
phase of from 14 to 28 daily dosage units of the composition 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.
[0086] In yet a further embodiment, a 28-day kit can include a
first phase of from 14 to 21 daily dosage units of the composition
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 another embodiment, a 28-day kit can include a first
phase of from 18 to 21 daily dosage units of the composition 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.
[0088] In yet a further embodiment, a 28-day kit can include a
first phase of 21 daily dosage units of the composition 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.
[0089] 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 the composition 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.
[0090] 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 the composition 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 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.
[0092] 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.
[0093] The kit can further contain instructions for administering
the tanaproget compositions of the present invention.
[0094] 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
[0095] Tanaproget was 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 a 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
Preparation of Compositions and Tablets Containing Micronized
Tanaproget
[0096] This example provides the preparation of tablets containing
micronized tanaproget using the components of Table 5.
TABLE-US-00005 TABLE 5 Component Function Specification Micronized
tanaproget Active ingredient In-house Microcrystalline Cellulose
Filler, Granulation NF aid, Disintegrant Anhydrous Lactose Filler
NF Sodium thiosulfate pentahydrate Antioxidant USP Edetate Calcium
Disodium Hydrous Antioxidant USP Croscarmellose Sodium Disintegrant
NF Magnesium Stearate Lubricant NF/EP Opadry .TM. II Blue Coating
material In-house
[0097] Tablets containing micronized tanaproget were prepared
according to the following granulation. See, Table 6. If the total
wt/wt % of the components exceeded 100%, the amount of anhydrous
lactose was adjusted by reducing or increasing the amount of
anhydrous lactose in the composition.
TABLE-US-00006 TABLE 6 Tablet Strength (mg) 100 150 200 300 Amount
Amount Amount Amount Component (mg) % wt/wt (mg) % wt/wt (mg) %
wt/wt (mg) % wt/wt Intragranular Micronized 0.1051 0.1546 0.1575
0.2316 0.210 0.3088 0.315 0.4632 tanaproget MCC 27.20 40.00 27.20
40.00 27.20 40.00 27.20 40.00 Anhydrous 37.312 54.8706 37.260
54.7935 37.207 54.7163 37.102 54.5619 lactose EDTA 0.068 0.10 0.068
0.10 0.068 0.10 0.068 0.10 micronized sodium 0.34 0.5 0.34 0.5 0.34
0.5 0.34 0.5 thiosulfate pentahydrate micronized 1.36 2.00 1.36
2.00 1.36 2.00 1.36 2.00 croscarmellose sodium magnesium 0.1275
0.1875 0.1275 0.1875 0.1275 0.1875 0.1275 0.1875 stearate
Extragranular Croscarmellose 1.36 2.00 1.36 2.00 1.36 2.00 1.36
2.00 sodium Magnesium 0.1275 0.1875 0.1275 0.1875 0.1275 0.1875
0.1275 0.1875 stearate Total (Core Tablet 68.00 100.00 68.00 100.00
68.00 100.00 68.00 100.00 Weight) Opardy II Blue 2.38 3.5 2.38 3.5
2.38 3.5 2.38 3.5 Purified Water* -- qs -- qs -- qs -- qs *Not
present in final dosage form.
[0098] Microcrystalline Cellulose (MCC) and anhydrous lactose were
mixed in a suitable size PK-Blender equipped with intensifier bar
for 1 minute without activating the intensifier bar. A second
portion of anhydrous lactose was added to a canister and the
canister was rotated for 1 minute to dust the walls of the canister
with the anhydrous lactose. Micronized tanaproget, sodium
thiosulfate and EDTA were added to the canister and mixed for 1
minute. The content of the canister was then emptied into the
PK-blender. A portion of anhydrous lactose was used to rinse the
emptied canister for 1 minute and was then transferred to the
PK-blender. Croscarmellose sodium was added to the PK-blender. The
remaining MCC and anhydrous lactose were added to the PK-blender.
The blender was mixed, for a certain amount of time at an
appropriate mixing speed, depending on the size of the blender,
with and without the intensifier bar [e.g., 20 revolutions per
minute (rpm) for 13 minutes with intensifier bar inactivated,
followed by 4 minutes with the intensifier bar activated, and
followed by 1 minute with the intensifier bar inactivated].
Intragranular magnesium stearate was added to the PK-Blender and
mixed for 2 minutes without the intensifier bar activated. The
blend from step 8 was discharged from the PK Blender into a double
poly-lined container. The blend was then compacted and milled using
an Alexanderwerk roller compactor. The milled material was
transferred to a suitable size PK-Blender and mixed for 1 minute.
Extragranular croscarmellose sodium was added to the PK-blender and
mixed for 10 minutes without the intensifier bar activated.
Extragranular magnesium stearate was added to the blender and mixed
for 2 minutes without the intensifier bar activated. The blend was
discharged from the PK-blender into a tarred double poly-lined
container. The tablets were thereby prepared by compressing the
final blend into 68 mg tablets using a rotary tablet press equipped
with 7/32'' (0.2187'') round modified concave tooling.
[0099] The tablets were coated using a film coat suspension by
first preparing an Opadry.TM. II Blue suspension by slowly adding
the Opadry.TM. II Blue to water with continuous agitation. The
tablets were loaded into an appropriate size pan of a coating
machine and a sufficient film-coat suspension was applied to
provide around 3.5% average dry-coat weight per tablet.
Example 3
Variation of MCC, Croscarmellose Sodium, and Magnesium Stearate
Concentrations in Tanaproget Compositions
[0100] In this Example, ten (10) compositions containing
tanaproget, EDTA, sodium thiosulfate, anhydrous lactose and varying
amounts of MCC, croscarmellose sodium, and magnesium stearate were
prepared according to the procedure set forth in Example 2 and
using the components set forth in Tables 7 and 8. The remaining
portion of the composition was adjusted using anhydrous lactose to
obtain a total % wt/wt of 100 as noted in Table 8.
TABLE-US-00007 TABLE 7 Component % wt/wt Micronized tanaproget
0.1546 EDTA 0.10 micronized sodium 0.5 thiosulfate pentahydrate
Purified Water* qs *Not present in final dosage form.
TABLE-US-00008 TABLE 8 % wt/wt Croscarmellose Magnesium Anhydrous
Run MCC Sodium Stearate Lactose 1 40 4 0.375 54.87 2 30 6 0.5
62.745 3 50 2 0.5 46.745 4 50 6 0.5 42.745 5 30 2 0.5 66.745 6 30 6
0.25 63.0 7 50 6 0.25 43.0 8 40 4 0.375 54.87 9 50 2 0.25 47.0 10
30 2 0.25 77.0
Example 4
Variation of Excipient Concentration in Tanaproget Compositions
[0101] In this Example, twelve (12) compositions containing fixed
amounts of tanaproget and EDTA and varying amounts of MCC,
croscarmellose sodium, magnesium stearate, sodium thiosulfate,
anhydrous lactose, and cysteine were prepared using the components
set forth in Table 9 and the procedure set forth below.
[0102] 50% of the MCC and 40% of the anhydrous lactose were passed
through a #40 mess screen, transferred to a PK-Blender, and mixed
for 1 minute. 10% of the lactose was added to a bag and mixed with
sodium thiosulfate, cysteine, and EDTA, passed through a #40 mesh
screen and added to the PK blender containing the MCC. Tanaproget
was added to another bag, mixed, passed through a #40 mesh screen,
and added to the PK blender. 10% of the lactose was passed through
a #40 screen, used to rinse the bag that contained the tanaproget,
and added to the PK-blender. The croscarmellose sodium was passed
through a #40 screen and added to the blender. The remaining MCC
and lactose were also passed through a #40 screen and added to the
blender.
[0103] The material in the blender was blended for 12 minutes
without the intensifier bar, followed by 3 minutes with the
intensifier bar, and then an additional 1 minute without the
intensifier bar. Magnesium stearate was passed through a #40
screen, added to the blender, and mixed. The blend from the
PK-blender was then roller compacted and milled using an
Alexanderwerk roller compactor and mill running.
[0104] The compacted and milled granulation was transferred to a
PK-blender and mixed. Extragranular croscarmellose sodium was
passed through a #40 mesh screen, added to the PK blender, and
mixed. Extragranular magnesium stearate was passed through a #40
mesh screen, added to the PK-blender, and mixed to form the final
blend.
[0105] The blend was compressed into 68 mg tablets using an
instrumented Korsh XL100 tablet press with 7/32'' modified concave
B tooling. The tablets were also coated with a 20% Opadry II blue
dispersion.
TABLE-US-00009 TABLE 9 Run (% wt/wt) Component 1 2 3 4 5 6 7 8 9 10
11 12 Intragranular Micronized 0.1545 0.1545 0.1545 0.1545 0.1545
0.1545 0.1545 0.1545 0.1545 0.1545 0.1545 0.1545 tanaproget MCC
40.00 30.00 50.00 50.00 30.00 30.00 50.00 40.00 50.00 30.00 40.00
40.00 Anhydrous 54.3705 62.2455 46.2455 42.2455 66.2455 62.4955
42.4955 54.3705 46.4955 66.4955 54.9205 53.8205 lactose micronized
0.50 0.50 0.50 0.50 0.50 0.50 0.50 0.50 0.50 0.50 0.25 0.75
L-cysteine micronized 0.10 0.10 0.10 0.10 0.10 0.10 0.10 0.10 0.10
0.10 0.10 0.10 EDTA Disodium 0.50 0.50 0.50 0.50 0.50 0.50 0.50
0.50 0.50 0.50 0.25 0.75 thiosulfate Croscarmellose 2.00 3.00 1.00
3.00 1.00 3.00 3.00 2.00 1.0 1.00 2.00 2.00 sodium Magnesium 0.188
0.25 0.25 0.25 0.25 0.125 0.125 0.188 0.125 0.125 0.188 0.188
stearate Extragranular Croscarmellose 2.00 3.00 1.00 3.00 1.00 3.00
3.00 2.00 1.00 1.00 2.00 2.00 sodium Magnesium 0.187 0.25 0.25 0.25
0.25 0.125 0.125 0.187 0.125 0.125 0.187 0.187 stearate Opadry Blue
-- -- -- -- -- -- -- 3.00 -- -- 3.00 3.00
Example 5
Variation of Antioxidant Concentrations in Tanaproget
Compositions
[0106] In this Example, three (3) compositions containing
micronized tanaproget, MCC, croscarmellose sodium, and magnesium
stearate and varying amounts of sodium thiosulfate and EDTA were
prepared according to the procedure set forth in Example 2 and
using the components set forth in Tables 10 and 11. The remaining
portion of the composition was adjusted using anhydrous lactose to
obtain a total % wt/wt of 100 as noted in Table 11.
TABLE-US-00010 TABLE 10 Component % wt/wt Micronized tanaproget
0.1546 MCC 40 magnesium stearate 0.375 croscarmellose sodium 4
Purified Water* qs *Not present in final dosage form.
TABLE-US-00011 TABLE 11 % wt/wt Sodium Anhydrous Run Thiosulfate
EDTA Lactose 1 0.25 0.05 55.17 2 0.5 0.1 54.87 3 0.75 0.15
54.57
[0107] All documents listed in this specification and priority
applications including U.S. patent application Ser. No. 13/890,523,
filed May 9, 2013, U.S. patent application Ser. No. 12/752,520,
filed Apr. 1, 2010, U.S. patent application Ser. No. 11/411,523,
filed Apr. 26, 2006, and U.S. Provisional Patent Application No.
60/675,550, filed Apr. 28, 2005 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.
* * * * *