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TANAPROGET COMPOSITIONS CONTAINING ETHINYL
ESTRADIOL
Compositions containing tanaproget and ethinyl estradiol are provided.
BACKGROUND OF THE INVENTION
Progesterone receptor (PR) modulators (natural and synthetic) are known to
play an important role in the health of women and are often are used in birth control
compositions and for hormone replacement therapy.
Tanaproget, 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1 -benzoxazin-6-yl)-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.
What is needed are compositions containing tanaproget for contraception and
hormone replacement therapy.
SUMMARY OF THE INVENTION
In one aspect, compositions containing micronized tanaproget, or a
pharmaceutically acceptable salt thereof, and ethinyl estradiol are provided.
In another aspect, compositions containing micronized tanaproget, or a
pharmaceutically acceptable salt thereof, ethinyl estradiol, microcrystalline cellulose,
anhydrous lactose, croscarmellose sodium, and magnesium stearate are provided.
In a further aspect, processes for preparing a composition containing
micronized tanaproget and ethinyl estradiol are provided.
In yet another aspect, kits containing a composition which contains
micronized tanaproget and ethinyl estradiol are provided.
In still a further aspect, methods of contraception are provided and include
administering a composition containing micronized tanaproget and ethinyl estradiol to
female in need thereof.
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In another aspect, methods of hormone replacement therapy are provided and
include administering a composition containing micronized tanaproget and ethinyl
estradiol to a female in need thereof.
Other aspects and advantages of the invention will be readily apparent from
the following detailed description of the invention.
DETAILED DESCRIPTION OF THE INVENTION
Effective pharmaceutical compositions containing micronized tanaproget and
ethinyl estradiol are described. The composition can be readily formulated into an
oral dosage unit, and is particularly well suited for a directly compressible unit.
Briefly, tanaproget is micronized, desirably under nitrogen and by means of
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 hi US Patent No. 6,436,929, and generally in US Patent Application
Publication No. US-2005-0272702-A1, which is hereby incorporated by reference.
However, the invention is not limited to the method by which the non-micronized
tanaproget is produced.
Micronized tanaproget prepared as described herein typically has a particle
size of less than about 20 μn, desirably less than about 15 μm, and more desirably
less than about 10 μm. Specifically, 90% of the particles are less than or equal to
about 20 jum and 50% are less than or equal to about 15 /μm as determined by the
Malvern method, which is readily understood by one of skill in the art.
The micronized tanaproget encompasses tautomeric forms of tanaproget and
salts derived from pharmaceutically or physiologically acceptable acids, bases, alkali
metals and alkaline earth metals. Also provided are derivatives of tanaproget,
including, but not limited to, esters, carbamates, sulfates, ethers, oximes, carbonates,
and the like.
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
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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.
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, Uthium, 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.
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.
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).
Micronized tanaproget discussed herein also encompasses "metabolites"
which are unique products formed by processing tanaproget by the cell or patient.
Desirably, metabolites are formed in vivo.
In one embodiment, the compositions are prepared by dry mixing micronized
tanaproget, based upon the total weight of the unit dose, with the other components of
the composition to form a dry granulation.
As referred to herein below, the term "wt/wt" refers to the weight of one
component based on the total weight of the composition. Typically, 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.
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A. The Compositions
The compositions described herein are formulated to provide rapid release of
tanaproget and ethinyl estradiol, while simultaneously being stable under conditions
of storage. In one embodiment, the composition contains micronized tanaproget and
ethinyl estradiol. In another embodiment, the composition contains micronized
tanaproget, ethinyl estradiol, microcrystalline cellulose (MCC), anhydrous lactose,
croscarmellose sodium, and magnesium stearate.
Suitably, micronized tanaproget is present in the composition in an amount
from about 0.01% wt/wt to about 1% wt/wt. In one example, the composition
contains micronized tanaproget in an amount of about 0.1% to about 0.6% wt/wt. In a
further example, the composition contains micronized tanaproget in an amount of
about 0.17% to about 1% wt/wt. In another example, the composition contains
tanaproget in an amount of about 0.17% wt/wt. In a further example, the composition
contains tanaproget in an amount of about 0.35% wt/wt. In yet another example, the
composition contains tanaproget in an amount of about 0.52% wt/wt. This amount
may be varied, depending upon the amount of micronized tanaproget to be delivered
to a patient. In one embodiment, the compositions contain about 100 to about 300 μg
of tanaproget, and desirably, about 100,200, or 300 μg of tanaproget.
Typically, an excess of tanaproget is utilized, and desirably a 5% excess, over
the amount of tanaproget that is required for the composition. In another
embodiment, when the compositions contain an excess of tanaproget, the
compositions contain about 105 to about 315 μg of tanaproget, and desirably about
105,210, and 315 μg of tanaproget.
Ethinyl estradiol is also present in the compositions described herein. Ethinyl
estradiol can be added to the composition as an individual component or can be added
with one or more excipients. In one example, ethinyl estradiol is added to the
composition as an individual component and includes about 0.03 to about 0.05%
wt/wt of the composition. In another example, ethinyl estradiol is added to the
composition as an individual component and includes about 0.035% wt/wt of the
composition. In one embodiment, the compositions contain about 20 μg of ethinyl
estradiol.
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Typically, an excess of ethinyl estradiol is utilized, and desirably a 5% excess,
over the amount of ethinyl estradiol that is required for the composition. In another
embodiment, the compositions contain about 21 μg of ethinyl estradiol.
Ethinyl estradiol can also be added in combination with other excipients, and
desirably as a mixture with anhydrous lactose. In one embodiment, the source of the
ethinyl estradiol is a triturate which contains 2% ethinyl estradiol in anhydrous
lactose, whereby the ethinyl estradiol includes about 2% wt/wt of the triturate in
anhydrous lactose. The term "triturate", as used herein, refers to a composition
containing fine particles and/or powder. In one example, the composition contains the
ethinyl estradiol 2% triturate in lactose in an amount of about 1 to about 2% wt/wt of
the composition. In another example, the composition contains about ethinyl estradiol
2% triturate in lactose at an amount of about 1.75% wt/wt of the composition. This
amount may be varied, depending upon the amount of ethinyl estradiol to be delivered
to a patient.
The composition can also include microcrystalline cellulose. Typically, the
microcrystalline cellulose includes about 30 to about 60% wt/wt of the composition.
In one example, MCC includes about 30 to about 56% wt/wt of the composition. In a
further example, MCC includes about 54% wt/wt of the composition. In another
example, MCC includes about 54.5% wt/wt of the composition. In a further example,
MCC includes about 54.4% wt/wt of the composition. In still another example, MCC
includes about 54.3% wt/wt of the composition.
Anhydrous lactose can also be included in the compositions described herein.
Typically, the anhydrous lactose includes about 30 to about 56% wt/wt of the
composition. In one example, anhydrous lactose includes about 37% wt/wt of the
composition. In a further example, anhydrous lactose includes about 38% wt/wt of
the composition. In another example, anhydrous lactose includes about 39% of the
composition. In a still further example, anhydrous lactose includes about 37.3%
wt/wt of the composition. In yet a further example, anhydrous lactose includes about
37.2% wt/wt of the composition. In still another example, anhydrous lactose includes
about 37.15% wt/wt of the composition. In a further example, anhydrous lactose
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includes about 38.9% wt/wt of the composition. In yet another example, anhydrous
lactose includes about 38.8% wt/wt of the composition.
The compositions can further include croscarmellose sodium. Typically,
croscarmellose sodium includes about 2 to about 6% wt/wt of the composition. In
one example, croscarmellose sodium includes about 6% wt/wt of the composition.
Magnesium stearate can also be included in the compositions. Typically,
magnesium stearate includes about 0.25 to about 0.5% wt/wt of the composition. In
one example, magnesium stearate includes about 0.25% wt/wt of the composition.
In one embodiment, a composition includes about 0.175% wt/wt of
micronized tanaproget, or a pharmaceutically acceptable salt thereof, about 0.035%
wt/wt of ethinyl estradiol, about 54.5% wt/wt of microcrystalline cellulose, about
37.3% wt/wt of anhydrous lactose, about 6% wt/wt of croscarmellose sodium, and
about 0.25%o wt/wt of magnesium stearate.
In another embodiment, a composition includes about 0.35% wt/wt of
micronized tanaproget, or a pharmaceutically acceptable salt thereof, about 0.035%
wt/wt of ethinyl estradiol, about 54.4% wt/wt of microcrystalline cellulose, about
37.2% wt/wt of anhydrous lactose, about 6% wt/wt of croscarmellose sodium, and
about 0.25% wt/wt of magnesium stearate.
In a further embodiment, a composition includes about 0.525% wt/wt of
micronized tanaproget, or a pharmaceutically acceptable salt thereof, about 0.035%
wt/wt of ethinyl estradiol, about 54.3% wt/wt of microcrystalline cellulose, about
37.15% wt/wt/ of anhydrous lactose, about 6% wt/wt of croscarmellose sodium, and
about 0.25% wt/wt of magnesium stearate.
In still another embodiment, a composition includes about 0.525% wt/wt of
micronized tanaproget, or a pharmaceutically acceptable salt thereof, about 0.035%
wt/wt of ethinyl estradiol, about 54.5% wt/wt of MCC, about 39% wt/wt of anhydrous
lactose, about 6% wt/wt of croscarmellose sodium, and about 0.25% wt/wt of
magnesium stearate.
In yet a further embodiment, a composition includes about 0.35% wt/wt of
micronized tanaproget, about 0.035% wt/wt of ethinyl estradiol, about 54.4% wt/wt of
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MCC, about 39.0% wt/wt of anhydrous lactose, about 6% wt/wt of croscarmellose
sodium, and about 0.25% wt/wt of magnesium stearate.
In still another embodiment, a composition includes about 0.5250% wt/wt of
micronized tanaproget, about 0.035% wt/wt of ethinyl estradiol, about 54.3% wt/wt of
MCC, about 38.9% wt/wt of anhydrous lactose, about 6% wt/wt of croscarmellose
sodium, and about 0.25% wt/wt of magnesium stearate.
Without limitation as to the method of preparation of a composition described
herein, an example of a suitable micronized tanaproget composition is provided in
Table 1.
Table 1

Component % wt/wt
Micronized Tanaproget 0.1750
Ethinyl Estradiol (EE) 2% Triturate in Anhydrous Lactose 1.75
MCC 54.5037
Lactose Anhydrous 37.3213
Croscarmellose Sodium 6.00
Magnesium stearate 0.25
Another example of a suitable micronized tanaproget composition is provided
in Table 2.
Table 2

Component % wt/wt
Micronized Tanaproget 0.35
Ethinyl Estradiol 2% Triturate in Anhydrous Lactose 1.75
MCC 54.4120
Anhydrous Lactose 37.238
Croscarmellose Sodium 6.00
Magnesium Stearate 0.25
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A further example of a suitable micronized tanaproget composition is provided
in Table 3.
Table 3

Component % wt/wt
Micronized Tanaproget 0.5250
Ethinyl Estradiol 2% Triturate in Anhydrous Lactose 1.75
MCC 54.3203
Anhydrous Lactose 37.1547
Croscarmellose Sodium 6.00
Magnesium Stearate 0.25
Still another example of a suitable micronized tanaproget composition is
provided in Table 4.
Table 4

Component %wt/wt
Micronized Tanaproget 0.1750
Ethinyl Estradiol 0.035
MCC 54.5037
Lactose Anhydrous 39.0363
Croscarmellose Sodium 6.00
Magnesium stearate 0.25
Yet a further example of a suitable micronized tanaproget composition is
provided in Table 5.
Table 5

Component % wt/wt
Micronized Tanaproget 0.35
Ethinyl Estradiol 0.035
MCC 54.4120
Anhydrous Lactose 38.953
1 Croscarmellose Sodium 6.00
| Magnesium Stearate 0.25
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In still another example of a suitable micronized tanaproget composition is
provided in Table 6.
Table 6

Component % wt/wt
Micronized Tanaproget 0.5250
Ethinyl Estradiol 0.035
MCC 54.3203
Anhydrous Lactose 38.8697
Croscarmellose Sodium 6.00
Magnesium Stearate 0.25
The compositions are typically prepared by combining micronized tanaproget,
or a pharmaceutically acceptable salt thereof, ethinyl estradiol, MCC, croscarmellose
sodium, anhydrous lactose, and magnesium stearate and mixing or granulating the
mixture. Desirably, the compositions are prepared by dry mixing or granulating the
components therein using techniques such as roller compaction, slugging, or a
combination thereof to form a dry granulation
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.
The term "slugging" as used 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.
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 addition, a variety of apparatuses can be utilized to perform the process
described herein and includes bags of small, medium, and large sizes, screens of
varying sizes, and blenders, among others.
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The process can also include compacting 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 preferential and more uniform particle size. The milling can
include several separating, recycling, and screening steps to obtain the desired particle
sizes.
The compositions desirably contain particles of an optimal size to permit
dissolution of the composition, and more desirably, the particles are less than or equal
to about 100 μm. 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 8% of the particles are greater than or equal to about 350 μm. In
another embodiment, about 28% of the particles are greater than or equal to about 180
μm. In a further embodiment, about 34% of the particles are greater than or equal to
about 150 μm. In still another embodiment, about 39% of the particles are greater
than about 125 μm. In yet another embodiment, about 49% of the particles are greater
than about 89 μm. In a further embodiment, about 64% of the particles are greater
than about 75 μm. In still another embodiment, about 90% of the particles are greater
than about 45 μm.
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.
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 herein. However, one example of such a press includes the
Stokes® B2 Tablet Press, among others.
In one embodiment, the tablet prepared as described herein is encapsulated in
a capsule. Desirably, the capsule is a hydroxypropyl methylcellulose or hypromellose
capsule. The capsule can be optionally sealed with the tablet therein or a filler can be
added to the capsule containing tablet. Typically, the filler includes MCC,
croscarmellose sodium, and magnesium stearate. Desirably, the tablet is placed in the
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capsule prior to adding the filler. In one example, a tablet containing 0.1 mg of
tanaproget and 20 μg of ethinyl estradiol is encapsulated in a capsule. In another
example, a tablet containing 0.2 mg of tanaproget and 20 μg of ethinyl estradiol is
encapsulated in a capsule. In a further example, a tablet containing 0.3 mg of
tanaproget and 20 μg of ethinyl estradiol is encapsulated in a capsule.
In another embodiment, the tablets prepared as described herein are utilized
without encapsulation. In one example, a tablet contains 0.1 mg of tanaproget and 20
μg of ethinyl estradiol is encapsulated in a capsule. In another example, a tablet
contains 0.2 mg of tanaproget and 20 μg of ethinyl estradiol is encapsulated in a
capsule. In a further example, a tablet contains 0.3 mg of tanaproget and 20 μg of
ethinyl estradiol is encapsulated in a capsule.
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. Typically, the tablet is coated with an Opadry® 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.
When prepared as described herein, the tablets, capsules, or tablets-in-capsules
containing a composition release about 94 to about 100% of tanaproget after about 15
minutes.
B. Stability of the Compositions
The compositions described herein 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 which degrade less than about 1%. Typically, it is
the tanaproget that degrades in the composition. Desirably, the composition is stable
at about 20°C/50% relative humidity to about 45°C/75% relative humidity and at
temperatures up to about 25° C.
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In one embodiment, the compositions are stored at reduced temperatures, and,
desirably, at temperatures of about 5 °C. It is also desirable that the compositions be
stored in the absence of water, air, and moisture.
In another embodiment, the compositions are stored at room temperature.
Typically, a stabilizer such as cysteine, sodium thiosulfate, or a combination thereof is
added to the composition in order to maintain its stability at room temperature.
C. Additional Components of the Compositions
Other suitable components can be added to the compositions, 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 can thereby
further include other adjuvants, syrups, elixirs, diluents, excipients, binders,
lubricants, surfactants, granulating agents, disintegrating agents, emollients, metal
chelators, pH adjusters, surfactants, fillers, disintegrants, and combinations thereof,
among others.
Adjuvants can include, without limitation, flavoring agents, coloring agents,
preservatives, and supplemental antioxidants, which can include vitamin E, ascorbic
acid, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), cysteine,
and sodium thiosulfate.
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.
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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.
Excipients can include, without limitation, silicon dioxide, starch, calcium
carbonate, pectin, and crospovidone (polyplasdone), among others.
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.
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.
Surfactants can include polysorbates, sorbitan esters, poloxamer, or sodium
lauryl sulfate. In one embodiment, the surfactant is sodium lauryl sulfate.
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.
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 adjusters 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.
Additional fillers that can be used in the compositions include mannitol,
calcium phosphate, pregelatinized starch, or sucrose.
D. Methods of Using the Compositions
Further provided are methods of delivering tanaproget to a patient, where the
method includes administering a micronized tanaproget dosing unit.
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
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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 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 100 to about
300 fig, about 100 fig, about 200 fig, or about 300 fig.
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. Additional uses of the
compositions include stimulation of food intake.
The compositions 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. Desirably,
the compositions 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 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.
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 include hydroxypropyl methylcellulose,
hypromellose capsule, or a hard shell gelatin capsule. The tablets or caplets that
contain tanaproget are optionally film-coated. Suitable film-coatings are known to
those of skill in the art. For example, the film-coating can be selected from among
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polymers such as hydroxypropylmethylcellulose, ethyl cellulose, polyvinyl alcohol,
and combinations thereof.
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. However, daily dosages can
be lowered or raised based on the periodic delivery.
It is contemplated that when the compositions 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.
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.
E. Kits
Also provided are kits or packages containing tablets, caplets, or capsules
containing micronized tanaproget and ethinyl estradiol. The kits can include tablets,
caplets, or capsules containing tanaproget and ethinyl estradiol and a carrier suitable
for administration to a mammalian subject as discussed above. Typically, the tablets,
caplets, or capsules are packaged in blister packs, and desirably Ultrx™ 2000 blister
packs
The kits or packages containing the compositions are designed for use in the
regimens described herein. These kits are desirably designed for daily oral delivery
over 21-day, 28-day, 30-day, or 31-day cycles, among others, and more desirably for
one oral delivery per day. When the compositions are to be delivered continuously, a
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package or kit can include the composition in each tablet or caplet. When the
compositions of are to be delivered with periodic discontinuation, a package or kit can
include placebos on those days when the composition is not delivered.
Additional components may be co-administered with the compositions and
include antiprogestins, estrogens, and selective estrogen receptor modulators, among
others.
The kits are also desirably organized to indicate a single oral formulation or
combination of oral formulations to be taken on each day of the cycle, desirably
including oral tablets or caplets to be taken on each of the days specified, and more
desirably one oral tablet or caplet will contain each of the combined daily dosages
indicated.
In one embodiment, a kit can include a single phase of a daily dosage of the
composition 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 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 over the first 28 days of a 30-day or 31-day cycle.
In a further embodiment, a kit can include a single combined phase of a daily
dosage of the composition and an antiprogestin 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 and an antiprogestin 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 and an antiprogestin over the first 28 days of a 30-day or 31-day cycle.
In another embodiment, a 28-day kit can include a first phase of from 14 to 28
daily dosage units of the composition; and a second phase of from 0 to 7 daily dosage
units of an orally and pharmaceutically acceptable placebo, wherein the total number
of the daily dosage units is 28.
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; a second phase of from 0 to 7 daily
dosage units of an orally and pharmaceutically acceptable placebo.
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In another embodiment, a 28-day kit can include a first phase of from 18 to 21
daily dosage units of the composition; a second phase of from 0 to 7 daily dose units
of a pharmaceutically acceptable placebo.
In still a further embodiment, a 28-day kit can include a first phase of 14 daily
dosage units of the composition; and a third phase of 14 daily units of an orally and
pharmaceutically acceptable placebo.
In yet another embodiment, a 28-day kit can include a first phase of 17 daily
dosage units of the composition; and a third phase of 11 daily units of an orally and
pharmaceutically acceptable placebo.
In yet a further embodiment, a 28-day kit can include a first phase of 21 daily
dosage units of the composition; and a third phase of 7 daily units of an orally and
pharmaceutically acceptable placebo.
Desirably, the daily dosage of tanaproget remains fixed in each particular
phase in which it is delivered. It is further preferable that 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, it is also preferred that the kits contain the placebo described for the final
days of the cycle.
A number of packages or kits are known in the art for the use in dispensing
pharmaceutical agents for oral use. Desirably, the package has indicators for each day
of the 28-day cycle, and more desirably is a labeled blister package, dial dispenser
package, or bottle.
The kit can further contain instructions for administering the tanaproget
composition.
Also provided is a product containing micronized tanaproget, or a
pharmaceutically acceptable salt thereof, and ethinyl estradiol as a combined
preparation for simultaneous, separate or sequential use in the provision of
contraception to a female of child bearing age or the provision of hormone
replacement therapy to a female in need thereof.
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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 - Compositions Containing Micronized Tanaproget and Ethinyl
Estradiol
The compositions for this example were manufactured using the following
protocol and using the components of Table 7.
Table 7

Component Function j
Tanaproget (micronized) Active ingredient
Ethinyl Estradiol (EE) 2% Triturate in
Lactose Active ingredient
Macrocrystalline Cellulose Filler, Granulation aid,
Disintegrant
Croscarmellose Sodium Disintegrant 1
Anhydrous Lactose Filler
Magnesium Stearate Lubricant
HPMC Capsule, #1 Reddish Brown Capsule shell
MCC and anhydrous lactose were passed through a 30 mesh hand screen,
transferred to a PK-Blender equipped with intensifier bar (pin bar), and blend for 1
minute without intensifier bar activated. A second portion of MCC and anhydrous
lactose was passed through a #30 mesh hand screen into a suitable size plastic bag and
blend for 1 minute. A third portion of MCC was passed through #30 mesh screen into
a smaller plastic bag and the bag was shaken for 15 seconds. Tanaproget was added
to the bag containing the third portion of MCC and blend for 1 minute. A third
portion of anhydrous lactose was passed through a # 30 mesh hand screen into the bag
containing MCC and tanaproget and blend for 1 minute. The blended material was
then passed through a #30 mesh hand screen into the larger bag containing the second
portion of MCC and anhydrous lactose. The emptied bag was rinsed twice by mixing
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portion four and five of MCC and anhydrous lactose in the hag for 1 minute. The
rinses were passed through the # 30 mesh screen that was used to screen the
tanaproget and was transferred into the larger bag containing tanaproget and the third
portion of MCC and anhydrous lactose. A sixth portion of MCC and anhydrous
lactose was passed through the #30 mesh hand screen that was used for the two rinses
and was transferred into the plastic bag containing tanaproget and the third portions of
MCC and anhydrous lactose. The bag blended to form a pre-blend. The pre-blend
was transferred to the PK-Blender containing the first portions of MCC and
anhydrous lactose. The emptied bag that contained the preblend was rinsed twice
with portions seven and eight of MCC and anhydrous lactose that were passed
through a #30 mesh hand screen into the bag shaken for 2 minutes. The rinses were
transferred into the PK-blender.
A ninth portion of MCC and anhydrous lactose was passed through a #30
mesh hand screen into a plastic bag and the material was blend. Ethinyl estradiol
2.0% Triturate was passed through a #30 mesh screen into the plastic bag that had
contained the ninth portion of MCC and anhydrous lactose and mixed. A tenth
portion of MCC and anhydrous lactose was passed through a #30 mesh hand screen,
transferred to the same plastic bag containing the ethinyl estradiol together with the
ninth portions of MCC and anhydrous lactose, and the materials were mixed. An
eleventh portion of MCC and anhydrous lactose were passed through a #30 mesh
hand screen, transferred to the plastic bag containing the ethinyl estradiol, the material
mixed, and was transferred to the PK-blender. Croscarmellose sodium was passed
through #30 mesh hand screen directly into the plastic bag that contained the eleventh
portion of MCC and anhydrous lactose. A twelve portion of MCC and anhydrous
lactose were passed through a #30 mesh hand screen directly into the plastic bag
containing the croscarmellose sodium, the bag was shaken, and the shaken material
was transferred to the PK-Blender. A thirteenth portion of MCC and anhydrous
lactose was passed through a #30 mesh hand screen directly to the plastic bag that had
contained the twelve portion of MCC/anhydrous lactose/croscarmellose sodium, was
shaken, and was transferred to the PK-Blender. Fourteenth portions of MCC and
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anhydrous lactose were passed through #30 mesh hand screen, transferred to the PK-
Blender, and the material blend.
An intra-granular portion of magnesium stearate was passed through #30 mesh
hand screen into a plastic bag, the screen was rinsed with approximately equal portion
from the blend from the blender, and this pre-blend was blended. The pre-blend
containing the intra-granular portion of magnesium stearate was transferred to the PK
Blender and mixed. The blend was discharged from the PK Blender into a double
poly-lined container. If not utilized immediately, the blend was stored under reduced
temperatures of about 2 to about 8°C, in the absence of light and moisture using two
desiccant bags between the two poly bags.
The tanaproget blend was compacted into ribbons using a roller compactor.
The compacted ribbons were milled using a FitzMill, Model D through a # 33 plate,
low speed and knives forward. The milled material was sieved using a #30 mesh
screen and the material on top of the screen and plate of the Fitz-Mill were collected.
The materials that passed through the #30 mesh screen were then passed through a
#120 mesh screen. The material retained on the #120 mesh screen was stored in a
plastic bag. The powder that passed through the #120 mesh screen was compacted
using the roller compactor, the compacted ribbons were milled using Fitz-Mill Model
D through a # 33 plate at low speed and knives forward. The milled material was
passed through a #30 mesh screen and the material retained on the #30 mesh screen
was combined with the milled material retained on the plate of the Fitz-Mill. All of
the material that retained on top of the screen and plate of the Fitz-mill was collected,
hand milled using a mortar and pestle, and passed through a #30 mesh screen. All of
the materials that passed through the #30 mesh screens were combined and half of this
combined material was transferred to a PK-Blender.
An extragranular portion of croscarmellose sodium was passed through a #30
mesh screen into a plastic bag, the screen was rinsed with a portion of the material
that had passed through the #30 mesh screens and transferred to the bag, the blend in
the bag mixed, and the blended material transferred to the PK-Blender. The
remaining portion of the material that passed through the #30 mesh screens was
transferred to the PK-Blender and the material mixed. An extragranular portion of
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magnesium stearate was passed through a #30 mesh screen into a plastic bag, the
screen rinsed with a portion of the material from the blender, and the bag blend to
form a pre-mix. The premix was transferred to the PK-Blender and blend for 2 min.
The blended pre-mix was discharged from the PK-blender into a double poly-lined
container(s) and stored under reduced temperatures of about 2 to about 8 °C, in the
absence of light and moisture using desiccants between the two poly bags. See, Table
8 for the total amounts of the components utilized in the composition.
Table 8

100/ig Tanaproget/
20//g EE
Tablet 200//g Tanaproget /
20/zg EE
Tablet 300^g Tanaproget/
20/ig EE
Tablet
Ingredient Amount
(mg) % wt/wt Amount
(mg) % wt/wt Amount
(mg) % wt/wt
Micronized Tanaprogeta 0.105° 0.1750° 0.21° 0.35° 0.5250 ° 0.3150°
Ethinyl Estradiol^ 1.05" 1.75 d 1.05 d 1.75" 1.75" 1.05"
Macrocrystalline
Cellulose 32.7022 54.5037 32.6472 54.4120 54.3203 32.5922
Anhydrous Lactose 22.3928 37.3213 22.3428 37.238 37.1547 22.2928
Croscarmellose Sodium 3.60 6.00 3.60 6.00 6.00 3.60
Magnesium Stearate 0.15 0.25 0.15 0.25 0.25 0.15
Total 60 mg 100 60 mg 100 60 mg 100
If assay is other than 100.0%, adjust the amount of input to provide the proper level of tanaproget and
adjust the input of Lactose Anhydrous accordingly.
If assay of EE is other than 2%, adjust the amount of input to provide the proper level of EE and
adjust the lactose accordingly.
Includes 5% overage of Tanaproget
Includes 5% overage of EE.
Example 2 - Tablets Containing a Composition of Tanaproget and Ethinyl
Estradiol
This example provides the preparation of tablets containing a composition
containing tanaproget and ethinyl estradiol.
The blend from Example 1 was compressed using a Stokes® Tablet
Compressor, adjusting the press as required. The tablets were stored in double
polylined container with two desiccants bags placed between the two bags and stored
under refrigeration at about 2-8° C, in the absence of light and moisture.
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Example 3 - Tablets-in-Capsules Containing a Composition of Tanaproget
and Ethinyl Estradiol
This example provides the preparation of tablets-in-capsules containing
compositions containing tanaproget and ethinyl estradiol. This example is useful for
the preparation of tablets containing 100 /Ag, 200 /xg, and 300 tig of tanaproget. The
amounts of each component are illustrated in Table 9.
MCC and croscarmellose sodium were passed through #20 mesh screen,
added to a PK-blender without an intensifier bar installed, and blend for 15 minutes.
Magnesium stearate was passed through #30 mesh screen and pre-mixed with a
portion of the MCC/croscarmellose blend. The magnesium stearate preblend was
added to the PK-blender and blend for 2 minutes to form a final placebo blend.
Using a capsule filler, formatted for size #1 capsule shell, a reddish brown
opaque HPMC capsule shell was filled by placing one (1) tanaproget/EE
(lOO^g/20/^g, 200yUg/20jUg, 300Jug/20^g) tablet into one capsule shell body and flood
filling with approximately 144 mg of the placebo blend into each capsule shell. The
filled #1 reddish brown capsule body was closed using the #1 reddish brown opaque
HPMC shell caps. The filled capsules were stored in poly-lined containers, in the
absence of moisture, light and humidity.
Any of the final blend that was not immediately utilized for tablet
encapsulation was added into a poly-lined container and stored at room temperature in
the absence of moisture.
Table 9

Ingredient Amount % wt/wt
Tanaproget/EE Tablet 60 mg 1 Tablet
MCC 140.4 mg 97.5
Croscarmellose Sodium 2.88 mg 2.0
Magnesium Stearate 0.72 mg 0.5
Size #1 HPMC Caps Opaque Brown 4P
Quali-V 77 mg 1 Capsule
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All publications cited in this specification are incorporated herein by reference
herein. 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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What is Claimed Is:
1. A pharmaceutical composition comprising an effective amount of
micronized tanaproget, or a pharmaceutically acceptable salt thereof, and an effective
amount of ethinyl estradiol.
2. The composition according to claim 1, further comprising
rnicrocrystalline cellulose, anhydrous lactose, croscarmellose sodium, and magnesium
stearate
3. The composition according to claim 1 or claim 2, wherein said
tanaproget comprises about 0.1% to about 1% wt/wt of said composition.
4. The composition according to claim 3, wherein said tanaproget
comprises about 0.17% to about 0.53% wt/wt of said composition.
5. The composition according to claim 3, wherein said tanaproget
comprises about 0.17% wt/wt of said composition.
6. The composition according to claim 3, wherein said tanaproget
comprises about 0.35% wt/wt of said composition.
7. The composition according to claim 3, wherein said tanaproget
comprises about 0.52% wt/wt of said composition.
8. The composition according to any one of claims 1 to 7 which
comprises about 100 to about 300 μg of tanaproget.
9. The composition according to any one of claims 1 to 8, wherein said
ethinyl estradiol comprises about 0.03 to about 0.05% wt/wt of said composition.
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10. The composition according to claim 9, wherein said ethinyl estradiol
comprises about 0.035% wt/wt of said composition.
11. The composition according to any one of claims 1 to 9, wherein said
ethinyl estradiol is a 2% triturate in lactose.
12. The composition according to claim 11, wherein said ethinyl estradiol
2% triturate in lactose comprises about 1.75% of said composition.
13. The composition according to any one of claims 1 to 12 which
comprises about 20 μg of ethinyl estradiol.
14. The composition according to any one of claims 1 to 13 which
degrades less than about 1% over a period of greater than 1 month at temperatures up
to about 25 ° C and a relative humidity up to about 60%.
15. The composition according to claim 14, wherein said temperature is
about 5 °C.
16. The composition according to any one of claims 2 to 15, wherein said
microcrystalline cellulose comprises about 30 to about 56% wt/wt of said
composition.
17. The composition according to claim 16, wherein said microcrystalline
cellulose comprises about 54% wt/wt of said composition.
18. The composition according to any one of claims 2 to 17, wherein said
anhydrous lactose comprises about 30 to about 56% wt/wt of said composition
19. The composition according to claim 18, wherein said anhydrous
lactose comprises about 37% wt/wt of said composition.
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20. The composition according to any one of claims 2 to 19, wherein said
croscarmellose sodium comprises about 2 to about 6% wt/wt of said composition.
21. The composition according to claim 20, wherein said croscarmellose
sodium comprises about 6% wt/wt of said composition.
22. The composition according to any one of claims 2 to 21, wherein said
magnesium stearate comprises about 0.25 to about 0.5% wt/wt of said composition.
23. The composition according to claim 22, wherein said magnesium state
comprises about 0.25% wt/wt of said composition.
24. The composition according to any one of claims 1 to 23 which is
formulated as a tablet.
25. The composition according to claim 24, wherein said tablet comprises
about 100 μg, 200 μg, or 300 μg of tanaproget.
26. The composition according to claim 24, wherein said tablet comprises
about 20 /ig of ethinyl estradiol.
27. A pharmaceutical composition comprising about 0.175% wt/wt of
micronized tanaproget, or a pharmaceuticalry acceptable salt thereof, about 0.035%
wt/wt of ethinyl estradiol, about 54.5% 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.
28. A pharmaceutical composition comprising about 0.35% wt/wt of
micronized tanaproget, or a pharmaceutically acceptable salt thereof, about 0.035%
wt/wt of ethinyl estradiol, about 54.4% wt/wt of microcrystalline cellulose, about
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37.2% wt/wt of anhydrous lactose, about 6% wt/wt of croscarmellose sodium, and
about 0.25% wt/wt of magnesium stearate.
29. A pharmaceutical composition comprising about 0.525% wt/wt of
micronized tanaproget, or a pharmaceutically acceptable salt thereof, about 0.035%
wt/wt of ethinyl estradiol, about 54.3% 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.
30. A process for preparing an oral composition comprising micronized
tanaproget, or a pharmaceutically acceptable salt thereof, comprising:

(a) mixing said micronized tanaproget, or a pharmaceutically acceptable
salt thereof, and ethinyl estradiol; and
(b) granulating the product of step (a).

31. The process according to claim 30, wherein step (a) further comprises
microcrystalline cellulose, croscarmellose sodium, anhydrous lactose, and magnesium
stearate.
32. The process according to claim 30 or claim 31, wherein step (b) is a
dry granulation.
33. The process according to any one of claims 30 to 32, further
comprising compacting said composition, milling the composition, or a combination
thereof.
34. The process according to any one of claims 30 to 33, wherein said
about 94 to about 100% of tanaproget is released from said oral composition after
about 15 minutes.
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35. The process according to any one of claims 30 to 34, wherein said
composition is compacted and compressed into a tablet suitable for oral
administration.
36. The process according to any one of claims 25 to 34, wherein said
tablet is encapsulated in a capsule.
37. A pharmaceutical kit comprising a daily dosage unit of said tablet of
claim 35 or said capsule of claim 36.
38. A pharmaceutically useful kit which comprises

(a) a first phase of 14 to 21 daily dosage units of a formulation comprising
tanaproget and ethinyl estradiol; and
(b) a second phase of 0 to 7 daily dosage units of an orally and
pharmaceutically acceptable placebo;
wherein the total number of the daily dosage units is 28.
39. The kit according to claim 38, further comprising an antiprogestin.
40. The kit according to claim 38 or claim 39, wherein the first phase
comprises 14 daily dosage units.
41. The kit according to claim 38 or claim 39, wherein the first phase
comprises 17 daily dosage units.
42. The kit according to claim 38 or claim 39, wherein the first phase
comprises 21 daily dosage units.
43. The kit according to any one of claims 38 to 42, wherein said
formulation comprises about 100 /ig, 200 μg, or 300 μg of tanaproget.
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44. The kit according to any one of claims 38 to 43, wherein said
formulation comprises about 20 μg of ethinyl estradiol.
45. A method of contraception comprising administering to a female of
child bearing age a composition of any of claims 1 to 29.
46. A method of hormone replacement therapy comprising administering
to a female in need thereof a composition of any of claims 1 to 29.
47. A product comprising micronized tanaproget, or a pharmaceutically
acceptable salt thereof, and ethinyl estradiol as a combined preparation for
simultaneous, separate or sequential use in the provision of contraception to a female
of child bearing age or the provision of hormone replacement therapy to a female in
need thereof.
29

Compositions containing micronized tanaproget, or a pharmaceutically acceptable salt thereof, and ethinyl estradiol and methods of preparing the same are provided. Also provided are kits containing the compositions, methods of contraception and hormone replacement therapy including administering a composition containing micronized tanaproget and ethinyl estradiol.