MICRONIZED TANAPROGET AND COMPOSITIONS
CONTAINING SAME
BACKGROUND OF THE INVENTION
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).
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.
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.
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.
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.
1

What is needed in the art are compositions containing tanaproget for
administration to a mammalian subject.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides micronized tanaproget and
compositions containing the same.
In a further aspect, the present invention provides a composition containing
micronized tanaproget, microcrystalline cellulose, croscarmellose sodium, anhydrous
lactose, and magnesium stearate.
In still a further aspect, the present invention provides a composition
containing micronized tanaproget, microcrystalline cellulose, croscarmellose sodium,
sodium lauryl sulfate, povidone, and magnesium stearate.
In another aspect, the present invention provides a process for preparing
compositions containing micronized tanaproget.
In a further aspect, the present invention provides kits having compositions
containing micronized tanaproget.
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
The present invention provides effective pharmaceutical compositions
containing micronized tanaproget. The micronized tanaproget can be readily
formulated into an oral dosage unit, and is particularly well suited for a directly
compressible unit. The inventors have found that tablets or caplets prepared by direct
compression of, or capsules containing, the micronized tanaproget compositions of
the invention exhibited rapid and complete drug release, as compared to
nonmicronized tanaproget. Thus, the compositions of the invention provide for fast
drug release.
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
2

described in US Patent No. 6,436,929, and generally in US Patent Application
Publication No. 2005/0272702, published December 8,2005. However, the
invention is not limited to the method by which the non-micronized tanaproget is
produced.
m another embodiment, non-micronized tanaproget is purified by
recrystallization. In one embodiment, the tanaproget is recrystallized from acetone
and water. In a further embodiment, the tanaproget is dissolved in acetone, the
acetone solution heated, water added to the heated acetone solution, and the
acetone/water solution cooled to provide purified tanaproget. This purification
specifically includes dissolving crude tanaproget in acetone and heating the solution
to about 45 to about 51°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°C. In one
embodiment, the acetone/water solution was cooled at a rate of less than about
0.5°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°C for about 4 hours. Further drying at less than about 50°C was performed
to remove residual acetone/water as measured by spectroscopic methods.
In one embodiment, micronized tanaproget prepared according to the present
invention has a particle size of less than about 20 /mi, less than about 15 /zm, or less
than about 10 /im. In a further embodiment, 90% of the particles are less than or
equal to about 20 /on. and 50% are less than or equal to about 15 /xm 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. The present invention also includes derivatives of
3

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
limitation, lactic, formic, acetic, furnaric, 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, 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.
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. In
one embodiment, metabolites are formed in vivo.
4

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.
As referred to herein below, the term "wt/wt" refers to the weight of one
component based on the total weight of the composition. In one embodiment, this
ratio does not include the weight of the capsule, the weight of any filler utilized in the
capsule, and seal coating, if so utilized.
A. Composition I of the Invention
The compositions of the present invention are formulated to provide rapid
release of tanaproget, while simultaneously being stable under conditions of storage.
In one embodiment, Composition I contains micronized tanaproget, or a
pharmaceutically acceptable salt thereof, microcrystalline cellulose (MGC),
croscarmellose sodium, anhydrous lactose, and magnesium stearate.
In one embodiment, micronized tanaproget is present in Composition I of the
invention in an amount from 0.08% wt/wt to 0.4% wt/wt of the composition. This
amount may be varied, depending upon the amount of micronized tanaproget to be
delivered to a patient. In another embodiment, an overage of tanaproget is utilized,
e.g., a 5% overage.
The desired therapeutic regimen can be taken into consideration when
formulating Composition I of the invention. For example, micronized tanaproget is
present in the formulation at about 0.0875% wt/wt, based upon the total weight of the
unit dose. In another example, micronized tanaproget is present in the composition at
about 0.35% wt/wt based upon the total weight of the unit dose.
Composition I also contains microcrystalline cellulose at about 56% wt/wt of
the composition; croscarmellose sodium at about 6% wt/wt of the composition;
magnesium stearate at about 0.25% wt/wt of the composition; and anhydrous lactose
at about 37% wt/wt of the composition.
In one embodiment, Composition I of the present invention provides about
0.09% micronized tanaproget, about 56.3% wt/wt of microcrystalline cellulose, about
5

37.3% wt/wt of anhydrous lactose, about 6% wt/wt of croscarmellose sodium, and
about 0.25% wt/wt of magnesium stearate.
In another embodiment, Composition I of the present invention provides
about 0.35% micronized tanaproget, about 56.2% wt/wt of microcrystalline cellulose,
about 37.1 wt/wt of anhydrous lactose, about 6% wt/wt of croscarmellose sodium,
and about 0.25% wt/wt of magnesium stearate.
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 1

Component % wt/wt
Tanaproget, Micronized 0.0875
Microcrystalline Cellulose 56.31
I Croscarmellose Sodium 6
I Anhydrous Lactose 37.35
| Magnesium Stearate 0.25
Still a further example of a suitable micronized tanaproget composition is
provided in Table 2.
Table 2

Component % wt/wt
Tanaproget, Micronized 0.35
Microcrystalline Cellulose 56.23
Croscarmellose Sodium 6
1 Anhydrous Lactose 37.17
1 Magnesium Stearate 0.25
Composition I is typically prepared by combining micronized tanaproget, or a
phannaceutically acceptable salt thereof, microcrystalline cellulose (MCC),
croscarmellose sodium, anhydrous lactose, and magnesium stearate and mixing or
granulating the mixture. In one embodiment, Composition I is prepared by dry
mixing or granulating the components therein using techniques such as roller
compaction, slugging, or a combination thereof.
6

The term "roller compaction" as used herein refers to a process by which two
or more solid materials are compacted between two rotating rolls, desirably, counter-
rotating rolls, to form solid ribbons. These ribbons are then subject to further steps
including milling to form a composition of the invention.
The term "slugging" as using herein refers to a process by which two or more
solid materials are compressed on a press, typically using presses that are larger than
those presses utilized to prepare large tablets. These tablets are then subject to
further steps including milling to form a composition of the invention.
The components can also be in extragranular or intragranular forms, as
determined by one of skill in the art and as determined by the requirements of the
process. In one embodiment, the croscarmellose sodium is in intragranular form. In
another embodiment, the croscarmellose sodium is in extragranular form. In yet
another embodiment, the magnesium stearate is in intragranular form.
In addition, a variety of apparatuses can be utilized to perform the process of
the invention and includes bags of small, medium, and large sizes, screens of varying
sizes, and blenders, among others.
The process can also include compacting or milling Composition I, typically
using compactors and mills selected by one of skill in the art. The milling step is
typically performed on particles of varying sizes, i.e., large particles, powders, and
fine powders to obtain a preferential and more uniform particle size. The milling can
include several separating, recycling, and screening steps to obtain the desired
particle sizes.
In one embodiment, the compositions of the present invention contain
particles of an optimal size to permit dissolution of the composition, and in a further
embodiment, the particles are less than or equal to about 125 /mi. The sizes of the
particles of the composition are typically measured by passing the solid composition
through screens of varying sizes. In one embodiment, about 7% of the particles are
greater than or equal to about 350 pan. In another embodiment, about 26% of the
particles are greater than or equal to about 180 jurn. In a farther embodiment, about
31% of the particles are greater than or equal to about 150 jam. In still another
embodiment, about 36% of the particles are greater than about 125 jxm. In yet
7

another embodiment, about 46% of the particles are greater than about 89 pan.. In a
further embodiment, about 52% of the particles are greater than about 75 jum. In still
another embodiment, about 67% of the particles are greater than about 45 /nm.
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 in the present invention. However, one example of such a press
includes the Stokes® B2 Tablet Press, among others.
In one embodiment, the tablet prepared according to the present invention is
encapsulated in a capsule. In a further embodiment, the capsule is a hydroxypropyl
methylcellulose (hypromellose) capsule. The capsule can be optionally sealed with
the tablet therein or a filler can be added to the capsule containing tablet. In one
embodiment, the filler includes MCC, croscarmellose sodium, and magnesium
stearate. In another embodiment, the tablet is placed in the capsule prior to adding
the filler.
Optionally, the tablets are film-coated. Suitable film-coatings are known to
those of skill in the art. For example, the film-coating can be selected from among
suitable polymers such as hydroxpropylmethylcellulose, ethyl cellulose, polyvinyl
alcohol, and combinations thereof. Other suitable film-coatings can be readily
selected by one of skill in the art. In one embodiment, the tablet is coated with an
Opadry® 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 according to the present invention, the tablets, capsules, or
tablets-in-capsules containing Composition I release about 86 to about 99% of
tanaproget after about 90 minutes. In a further embodiment, the composition releases
about 85% of the tanaproget after about 20 minutes.
8

B. Composition II of the Invention
In another embodiment, a composition of the present invention contains
micronized tanaproget, or apharmaceutically acceptable salt thereof, microcrystalline
cellulose, croscarmellose sodium, sodium lauryl sulfate (SLS), povidone (PVP), and
magnesium stearate.
In one embodiment, the micronized tanaproget is present in Composition II of
the invention in an amount at about 0.1% wt/wt, or 0.01% wt/wt, of the composition.
This amount maybe varied, depending upon the amount of micronized tanaproget to
be delivered to a patient. The desired therapeutic regimen can be taken into
consideration when formulating a composition of the invention. In another
embodiment, an overage of tanaproget is utilized, e.g., a 5% overage.
Composition II also contains about 90% wt/wt microcrystalUne cellulose;
about 6% wt/wt croscarmellose sodium; about 2% wt/wt sodium lauryl sulfate; about
1.5% povidone; and about 0.25% wt/wt magnesium stearate.
In one embodiment, Composition II of the present invention typically
contains about 0.10% or about 0.1% micronized tanaproget, about 90% wt/wt
microcrystalline cellulose, about 6% wt/wt croscarmellose sodium, about 2% wt/wt
sodium lauryl sulfate, about 1.5% povidone, and about 0.25% wt/wt magnesium
stearate.
Without limitation as to the method of preparation of Composition II of the
invention, an example of a suitable micronized tanaproget composition is provided in
Table 3.
Table 3

Component % wt/wt
Tanaproget, Micronized 0.1
Microcrystalline Cellulose 90.15
Croscarmellose Sodium 6.00
Sodium Lauryl Sulfate 2.0
Povidone 1.5
Magnesium Stearate 0.25 1
Composition II is prepared by combining micronized tanaproget,
microcrystalline cellulose, croscarmellose sodium, povidone, sodium lauryl sulfate,
9

and magnesium stearate; and granulating. In one embodiment, Composition II is
prepared by dry mixing the components therein. The components of the composition
can also be in extragranular or intragranular forms, as determined by one of skill in
the art and as.determined by the requirements of the process. A variety of
apparatuses can be utilized to perform the process of the invention and includes bags
of large, medium, and large sizes, screens of varying sizes, and blenders, among
others.
The process can also include compacting or milling Composition II, typically
using compactors and mills selected by one of skill in the art. The milling step is
typically performed on particles of varying sizes, i.e., large particles, powders, and
fine powders to obtain a more uniform particle size. The milling can include several
separating, recycling, and screening steps to obtain the desired particle sizes.
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.
In a further embodiment, the compositions of the present invention can be
prepared by diluting the other compositions with excipients. Useful excipients for
dilution include those set forth below and can include MCC, croscarmellose sodium,
and magnesium stearate.
For example, compositions containing lesser amounts of tanaproget are
prepared according to the present invention by diluting compositions containing
greater amounts of tanaproget. In one embodiment, a composition containing 0.05
mg of tanaproget is prepared by diluting a composition containing 0.075, 0.1, 0.15,
0.2, or 0.3 mg of tanaproget, or by diluting a composition containing 0.075 or 0.1
mg. In a further embodiment, a composition containing 0.075 mg tanaproget is
prepared by diluting a composition containing 0.1,0.15,0.2, or 0.3 mg of tanaproget.
In another embodiment, a composition containing 0.1 mg of tanaproget is prepared
by diluting a composition containing 0.15,0.2, or 0.3 mg of tanaproget. In yet a
further embodiment, a composition containing 0.15 mg tanaproget is prepared by
diluting a composition containing 0.2 or 0.3 mg of tanaproget. In still another
embodiment, a composition containing 0.2 mg of tanaproget is prepared by diluting a
10

composition containing 0.3 mg of tanaproget. In another embodiment, the
compositions of the invention prepared by diluting compositions containing higher
amounts of tanaproget are diluted with MCC, croscarmellose sodium, and
magnesium stearate.
The process typically includes adding Composition II to a capsule, e.g., a
hard shell gelatin capsule. Typically, the capsule is a hydroxypropyl methylcellulose
or hypromellose capsule.
However, Composition II can be compressed into a tablet or caplet, which
can optionally be encapsulated in a capsule. In one embodiment, the capsule is a
hydroxypropyl methylcellulose (hypromellose) capsule. When compressed into a
tablet or caplet, one of skill in the art would readily be able to select a suitable tablet
press for use in the present invention. However, one example of such a press
includes the Stokes® B2 Tablet Press, among others. The capsule can be optionally
sealed with the tablet therein or a filler can be added to the capsule containing tablet.
In one embodiment, the filler includes MCC, croscarmellose sodium, and magnesium
stearate. In another embodiment, the tablet is placed in the capsule prior to adding
the filler.
If the composition is compressed into a tablet or caplet, the tablets or caplets
can optionally be film-coated. Suitable film-coatings are known to those of skill in
the art. For example, the film-coating can be selected from among suitable polymers
such as hydroxpropyl methylcellulose, ethyl cellulose, polyvinyl alcohol, and
combinations thereof. Other suitable film-coatings can be readily selected by one of
skill in the art. In one embodiment, the tablet or caplet is coated with an Opadry®
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.
When prepared according to the present invention, the capsules containing
Composition II release about 86 to about 99% of tanaproget after about 90 minutes.
In a further embodiment, the capsules release about 85% of the tanaproget after about
20 minutes.
11

C. Stability of the Compositions of the Invention
The compositions of the present invention, including Compositions I and H,
are stable over a period of about 1 month for samples stored at varying temperatures
and humidities. The term stable as used herein refers to the compositions of the
invention which degrade less than about 4%. Typically, it is the tanaproget that
degrades in the composition. Compositions I and II are stable at about 20°C/50%
relative humidity to about 45°C/75% relative humidity. In one embodiment,
Compositions I and II degrade less than about 4% over a period of greater than 1
month at temperatures at or greater than about 25°C and a relative humidity at or
greater than about 60%. Samples were also stable over a period of about 2 months at
temperatures of about 2 to about 8 °C, optionally in the absence of light and moisture.
In one embodiment, Compositions I and II of the invention are stored at
reduced temperatures, in a further embodiment at temperatures of about 5°C. It is
desirable that the compositions be stored in the absence of water, air, and moisture.
D. Additional Components of the Compositions of the Invention
Other suitable components can be added to Compositions I and II of the
present invention, provided that the same is not already present, and will be readily
apparent to one of skill in the art. Typically, the additional components are inert and
do not interfere with the function of the required components of the compositions.
The compositions of the present invention can thereby further include other
adjuvants, syrups, elixirs, diluents, binders, lubricants, surfactants, granulating
agents, disintegrating agents, emollients, metal chelators, pH adjustors, surfactants,
fillers, disintegrants, and combinations thereof, among others.
Adjuvants can include, without limitation, flavoring agents, coloring agents,
preservatives, and supplemental antioxidants, which can include vitamin E, ascorbic
acid, butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA).
Binders can include, without limitation, povidone, cellulose, methylcellulose,
hydroxymethylcellulose, carboxymethylcellulose calcium, carboxymethylcellulose
sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate,
noncrystalline cellulose, polypropylpyrrolidone, polyvinylpyrrolidone (povidone,
12

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.
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.
Granulating agents can include, without limitation, silicon dioxide, starch,
calcium carbonate, pectin, crospovidone, and 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 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.
Additional fillers that can be used in the composition of the present invention
include mannitol, calcium phosphate, pregelatinized starch, or sucrose.
13

E. Methods of Using the Compositions
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.
The dosage requirements of tanaproget may vary based on the severity of the
symptoms presented and the particular subject being treated. Treatment can be
initiated with small dosages less than the optimum dose of tanaproget. Thereafter the
dosage is increased until the optimum effect under the circumstances is reached.
Precise dosages will be determined by the administering physician based on
experience with the individual subject treated. In general, the compositions of this
invention are most desirably administered at a concentration that will generally
afford effective results without causing any unacceptable harmful or deleterious side
effects. For example, an effective amount of micronized tanaproget is generally, e.g.,
about 0.05 mg to about 1 mg, about 0.05 mg to about 0.3 mg, about 0.05 mg, about
0.075 mg, about 0.1 mg, about 0.15 mg, about 0.2 mg, or about 0.3 mg.
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.
The compositions of the invention are formed into a suitable dosing unit for
delivery to a patient. Suitable dosing units include oral dosing units, such as directly
compressible tablets, capsules, powders, suspensions, microcapsules, dispersible
powders, granules, suspensions, syrups, elixirs, and aerosols. In one embodiment, the
compositions of the present invention are compressed into a tablet, which is
optionally added to a capsule, or the compositions are added directly to a capsule.
The compositions of the invention can also be formulated for delivery by other
14

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 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.
A pharmaceuticaUy 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.
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.
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.
15

F. Kits of the Invention
The present invention also provides kits or packages containing micronized
tanaproget. Kits of the present invention can include tanaproget and a carrier suitable
for adniinistration to a mammalian subject as discussed above. In one embodiment,
the tablets or capsules are packaged in blister packs, and in a further embodiment in
Ultrx™ 2000 blister packs.
The kits or packages containing the compositions of the present invention are
designed for use in the regimens described herein. In one embodiment, these kits are
designed for daily oral delivery over 21-day, 28-day, 30-day, or 31-day cycles,
among others, or for one oral delivery per day. When the compositions are to be
delivered continuously, a package or kit can include the composition in each tablet.
When the compositions of the present invention are to be delivered with periodic
discontinuation, a package or kit can include placebos on those days when the
composition is not delivered.
Additional components may be co-administered with Composition I or II of
the invention and include progestational agents, estrogens, and selective estrogen
receptor modulators.
In one embodiment, the kits are also organized to indicate a single oral
formulation or combination of oral formulations to be taken on each day of the cycle,
in a further embodiment including oral tablets to be taken on each of the days
specified, and in still a further embodiment one oral tablet will contain each of the
combined daily dosages indicated.
In one embodiment, a kit can include a single phase of a daily dosage of
Composition I or II of the invention over a 21-day, 28-day, 30-day, or 31-day cycle.
Alternatively, a kit can include a single phase of a daily dosage of Composition I or
II of the invention over the first 21 days of a 28-day, 30-day, or 31-day cycle. A kit
can also include a single phase of a daily dosage of Composition I or II of the
invention over the first 28 days of a 30-day or 31-day cycle.
In a further embodiment, a kit can include a single combined phase of a daily
dosage of Composition I or II of the invention and a progestational agent over a 21-
day, 28-day, 30-day, or 31-day cycle. Alternatively, a kit can include a single
16

combined phase of a daily dosage of Composition I or II of the invention and a
progestational agent over the first 21 days of a 28-day, 30-day, or 31-day cycle. A
kit can also include a single combined phase of a daily dosage of Composition I or II
of the invention and a progestational agent over the first 28 days of a 30-day or 31-
day cycle.
In another embodiment, a 28-day kit can include a first phase of from 14 to
28 daily dosage units of Composition I or II of the invention; a second phase of from
1 to 11 daily dosage units of a progestational agent; and, optionally, a third phase of
an orally and pharmaceutically acceptable placebo for the remaining days of the
cycle.
In yet a further embodiment, a 28-day kit can include a first phase of from 14
to 21 daily dosage units of Composition I or n 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.
In another embodiment, a 28-day kit can include a first phase of from 18 to
21 daily dosage units of Composition I or II of the invention; a second phase of from
1 to 7 daily dose units of a progestational agent; and, optionally, an orally and
pharmaceutically acceptable placebo for each of the remaining 0 to 9 days in the 28-
day cycle.
In yet a further embodiment, a 28-day kit can include a first phase of 21 daily-
dosage units of Composition I or II of the invention; a second phase of 3 daily dosage
units for days 22 to 24 of a progestational agent; and, optionally, a third phase of 4
daily units of an orally and pharmaceutically acceptable placebo for each of days 25
to 28.
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 ug levonorgestrel, a second phase of from 1 to 11 daily dosage
units of Composition I or II of the invention; and optionally, a third phase of an
orally and pharmaceutically acceptable placebo for the remaining days of the cycle in
which no antiprogestin, progestin or estrogen is administered.
17

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 jig levonorgestrel; a second phase of from 1 to 11 daily dosage
units of Composition I or II of the invention; and optionally, a third phase of an
orally and pharmaceutically acceptable placebo for the remaining days of the cycle in
which no antiprogestin, progestin or estrogen is administered.
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.
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.
The kit can further contain instructions for administering the tanaproget
compositions of the present invention.
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
Tanaproget prepared according to US Patent Application Publication No.
2005/0272702, published December 8,2005 was milled using a U-10 Comil mill and
thereby micronized using a MC50 Jetpharma Micronizer with an EZFH-1.4 Feeder.
Particle size was tested periodically for a particle size of less than about 15 /xm, and
18

desirably less than about 10 /an, being distributed throughout 50% of the sample.
The micronized tanaproget was packed in triple poly-bagged fiber drums. A
desiccant was inserted between the outermost bags and the atmosphere in the bags
replaced with nitrogen gas.
Example 2 - Directly Compressible Tablet Compositions Prepared By
Employing Micronized Tanaproget
The tablet compositions for this example were manufactured using the
following protocol and using the components of Table 4.
Table 4

*" '- '-==sitJ -1-1 •*=- ""
Ingredients Function
Micronized Tanaproget Active
Microcrystalline Cellulose
(MCC), NF, (Avicel PHI 01) Filler, Granulation
Aid, Disintegrant
1 Anhydrous Lactose Filler
Croscarmellose Sodium
NF (Ac-Di-Sol) Disintegrant
Magnesium Stearate
(Vegetable Source), NF Lubricant
Capsule Shell Inactive
Anhydrous lactose and MCC were passed through a mesh screen and
transferred to a 1 cu. ft. PK blender. The blended anhydrous lactose and MCC were
passed through a mesh screen into a suitable poly bag. Micronized tanaproget was
transferred to a suitable plastic bag. The tanaproget was pre-blended with a portion
of the anhydrous lactose/MCC mixture. The pre-blend containing
tanaproget/anhydrous lactose/MCC was transferred to the blender containing the
remaining portion of anhydrous lactose and MCC and mixed. An intragranular
portion of croscarmellose sodium was passed through a mesh screen and pre-blend
with a portion of anhydrous lactose and MCC. The pre-blend containing the
intrangranular croscarmellose sodium/anhydrous lactose/MCC was added to the
blender containing the tanaproget and mixed. An intragranular portion of
magnesium stearate was passed through a mesh screen and pre-blend with a portion
of anhydrous lactose and MCC. The pre-blend containing the intragranular
19

magnesium stearate/anhydrous lactose/MCC was transferred to the blender
containing the tanaproget and mixed to form an intermediate composition.
The intermediate composition was compressed using a roller compactor and
then milled using a Fitzmill model D6. The milled material was passed through a
mesh screen, the large particles separated, and the large particles milled to a powder.
The fine powder produced from the milling was compressed and milled to a powder.
All of the milled powder was thereby combined in a blender. An extragranular
portion of croscarmellose sodium was passed through a mesh screen and pre-blend
with a portion of the combined milled powder. The pre-blend containing the
extragranular croscarmellose sodium and milled powder was then mixed with the
remaining portion of the combined milled powder. An intragranular portion of
magnesium stearate was passed through a screen and premixed with a portion of the
pre-blend containing the extragranular croscarmellose sodium and milled powder.
The premix containing the extragranular magnesium stearate was added to the
blender and mixed with the second portion of the pre-blend containing the
extragranular croscarmellose sodium and milled powder to form the final
composition.
The final composition was then compressed into a tablet using a Stokes® B2
Tablet Press, adjusting the press as necessary. At equally spaced intervals, tablet
samples were obtained and stored in double poly-lined containers, desiccants were
placed between the two bags, and the bags were stored at reduced temperatures of
2°C to 8°C in the absence of light and moisture. Either the stored tablets or freshly
prepared tablets were then encapsulated. See Table 5 for the amounts of the
components utilized in the four different tablet strengths.
20

Table 5

Tablet Strength (mg)

0.05 0.075 0.1 0.15 0.2 0.3
Component Amount %
wt/wt Amount
(niE) %
wt/wt Amount
falR) %
wt/wt Amount
(iriR) %
wt/wt Amount
(mE) %
wt/wt Amount
fmg) %
wt/wt
Micronized
tanaproget 0.05 0.0875 0.075 0.0875 0.105 0.0875 0.158 0.0875 0.210 0.35 0315 0.35
Macrocrystalline
cellulose 33.79 56.31 50.68 56.31 67.57 56.31 101.35 56.31 33.74 56.23 50.61 56.23
Anhydrous
Lactose 22.42 37.35 33.62 37.35 44.83 37.35 67.24 37.35 22.30 37.17 33.45 37.17
Croscarmellosc
Sodium 3.60 6.00 5.40 6.00 7.20 6.00 10.80 6.00 3.60 6.00 5.40 6.00
Magnesium
Stearate 0.15 0.25 0.225 0.25 0.30 0.25 0.45 0.25 0.15 0.25 0.23 0.25
_
These compositions include a 5% overage of tanaproget to compensate for
manufacturing loss during blending and compacting.
For tablet encapsulation of the 0.075,0.1,0.15,0.2, and 0.3 mg tablets, MCC
and croscarmellose sodium were passed through a screen, added to a 1-20 cubic foot
blender without an intensifier bar installed, and mixed. Magnesium stearate was
passed through a screen and mixed with the blend containing MCC and
croscarmellose sodium to form the filler. Using a capsule filler, each size #1 capsule
shell was filled by placing one tablet into one capsule shell body and flood filling the
capsule with the filler. The filled capsule was then closed.
See Table 6 for the amounts of the components added to the inert filler.
Table 6

Tablet Strength (mg)

0.075 0.1 0.15 0.2 0.3
Ingredients Amount
(mg) %
wt/wt Amount
(mg) %
wt/wt Amount
(mg) %
wt/wt Amount
(mg) %
wt/wt Amount
(mg) % I
wt/wt
Microcrystalline
cellulose 127.725 97.5 120.90 97.5 108.23 97.5 140.4 97.5 127.72 97.5
Croscarmellose
Sodium 2.62 2.0 2.48 2.0 2.22 2.0 2.88 2.0 2.62 2.0
1 Magnesium
Stearate 0.655 0.5 0.62 0.5 0.55 0.5 0.72 0.5 0.655 0.5
Capsule 1#1
Brown
HPMC
shell ._ 1#1
Brown
HPMC
shell -- 1#1
Brown
HPMC
shell ... 1#1
Brown
HPMC
shell ... 1#1
Brown
HPMC
shell -
These compositions include a 5% overage of tanaproget to compensate for
manufacturing loss during blending and compacting.
21

Example 3 - Capsule Compositions Prepared By Employing Micronized
Tanaproget
The capsule compositions for this example are manufactured using the
following, protocol and using the components set forth in Table 7.
Table 7

Ingredients Function
Micronized Tanaproget Active
Microcrystalline Cellulose (MCC), NF,
(AvicelPHlOl) Filler, Granulation Aid,
Disintegrant
Croscarmellose Sodium NF (Ac-Di-Sol) Disintegrant
Magnesium Stearate, (Vegetable Source), NF Filler
Povidone, K-17,USP Binder
Sodium Lauryl Sulfate (SLS), NF Surface active agent
Capsule Shell Inactive
Micronized tanaproget was added to a first plastic bag. A first portion of
MCC was combined with the tanaproget and mixed. A second portion of MCC was
combined with the blend of tanaproget and MCC and mixed. The blend containing
both portions of MCC and tanaproget was passed through a #20 hand screen into a
larger bag. The first plastic bag was rinsed with third and fourth portions of MCC,
the rinsed products passed through the #20 hand screen into the larger bag, and
mixed. A fifth portion of MCC was passed through a #20 hand screen into the larger
plastic bag and mixed. A sixth portion of MCC was passed through a #20 hand
screen into the larger plastic bag and mixed. A seventh portion of MCC was passed
through a #20 hand screen into a suitable size PK-blender. The blend in the larger
bag was passed through a #20 hand screen into the PK-blender. Eighth and ninth
separate portions of MCC were utilized to obtain any MCC/tanaproget remaining
residue from larger bag, which residue was passed through a #20 hand screen into the
PK-blender. Croscarmellose sodium was passed through a #20 hand screen into the
PK-blender. SLS was passed through a #20 hand screen into the PK-blender.
Povidone was passed through a #20 hand screen into the PK-blender. All of the
materials in the blender were mixed without intensifier bar activation.
22

A last portion of MCC was passed through a #20 hand screen into the PK-
blender and mixed without the intensifier bar activation. Magnesium stearate was
passed through a #30 mesh screen and premixed with the blend containing the last
portion of MCC, transferred to the PK-blender, and mixed without intensifier bar
activation to form the final blend.
The capsules were filled with about 100 mg of the final blend. The capsules
were stored in a poly-lined drum at reduced temperatures and in the absence of light
and moisture.
Table 8

1 Ingredients Amount
(mg) %
wt/wt
1 Micronized Tanaproget 0.10 0.10
Microcrystalline Cellulose 90.15 90.15
Croscarmellose Sodium 6.00 6.00
Sodium Lauryl Sulfate 2.0 2.0
Povidone 1.5 1.5
Magnesium Stearate 0.25 0.25
All documents listed in this specification are incorporated herein by
reference. While the invention has been described with reference to a particularly
preferred embodiment, it will be appreciated that modifications can be made without
departing from the spirit of the invention. Such modifications are intended to fall
within the scope of the appended claims.
23

CLAIMS:
1. A pharmaceutical composition comprising micronized tanaproget, or a
pharmaceutically acceptable salt thereof, microcrystalline cellulose, croscarmellose
sodium, anhydrous lactose, and magnesium stearate.
2. The composition according to claim 1, wherein said tanaproget
comprises about 0.08% to about 0.4% wt/wt of said composition.
3. The composition according to claims 1 or 2, wherein said tanaproget
comprises about 0.35% wt/wt of said composition.
4. The composition according to claims 1 or 2, wherein said tanaproget
comprises about 0.0875% wt/wt of said composition.
5. The composition according to any of claims 1-4, wherein said
microcrystalline cellulose comprises about 56% wt/wt of said composition.
6. The composition according to any of claims 1-5, wherein said
anhydrous lactose comprises about 37% wt/wt of said composition.
7. The composition according to any of claims 1-6, wherein said
croscarmellose sodium comprises about 6% wt/wt of said composition.
8. The composition according to any of claims 1-7, wherein said
magnesium stearate comprises about 0.25% wt/wt of said composition.
9. A pharmaceutical composition comprising micronized tanaproget, or a
pharmaceutically acceptable salt thereof, microcrystalline cellulose, croscarmellose
sodium, sodium lauryl sulfate, povidone, and magnesium stearate.
24

10. The composition according to claim 9, wherein said microcrystalline
cellulose comprises about 90% wt/wt of said composition.
11. The composition according to claims 9 or 10, wherein said
croscarmellose sodium comprises about 6% wt/wt of said composition.
12. The composition according to any of claims 9-11, wherein said
sodium lauryl sulfate comprises about 2% wt/wt of said composition.
13. The composition according to any of claims 9-12, wherein said
povidone comprises about 1.5% wt/wt of said composition.
14. The composition according to any of claims 9-13, wherein said
magnesium stearate comprises about 0.25% wt/wt of said composition.
15. The composition according to any of claims 9-14, wherein said
tanaproget comprises about 0.10% wt/wt of said composition.
16. A pharmaceutical composition for oral administration comprising
about 0.0875% wt/wt micronized tanaproget, about 56.31% wt/wt microcrystalline
cellulose, about 6% wt/wt croscarmellose sodium, about 37.35% wt/wt anhydrous
lactose, and about 0.25% wt/wt magnesium stearate.
17. A pharmaceutical composition for oral administration comprising
about 0.35% wt/wt micronized tanaproget, about 56.23% wt/wt microcrystalline
cellulose, about 6% wt/wt croscarmellose sodium, about 37.17% wt/wt anhydrous
lactose, and about 0.25% wt/wt magnesium stearate.
25

18. A pharmaceutical composition for oral adrninistration comprising
about 0.10% wt/wt micronized tanaproget, about 90.15% wt/wt microcrystalline
cellulose, about 6% wt/wt/ croscarmellose sodium, about 2% wt/wt sodium lauryl
sulfate, about 1.5% wt/wt povidone, and about 0.25% wt/wt magnesium stearate.
19. The composition according to any of claims 1-18 which degrades less
than about 4% over a period of greater than 1 month at temperatures at or greater
than about 25°C and a relative humidity at or greater than about 60%.
20. The composition according to any of claims 1-19, wherein the
particles of said micronized tanaproget are less than about 10 fim.
21. The composition according to any of claims 1-19, wherein the
particles of said composition are less than about 125 /mi.
22. A process for preparing a composition comprising micronized
tanaproget, or a pharmaceutically acceptable salt thereof, comprising the steps of:

(a) combining said micronized tanaproget, or a pharmaceutically
acceptable salt thereof, microcrystalline cellulose, croscarmellose sodium, anhydrous
lactose, and magnesium stearate; and
(b) granulating the mixture of step (a).

23. The process according to claim 22, wherein said croscarmellose
sodium is intragranular.
24. The process according to claim 22, wherein said croscarmellose
sodium is extragranular.
25. The process according to any of claims 22-24, wherein said
magnesium stearate is intragranular.
26

26. The process according to any of claims 22-25, wherein said
composition is compacted and compressed into a tablet suitable for oral
administration.
27. The process according to claim 26, wherein said tablet is encapsulated
in a capsule.
28. The process according to any of claims 22-25, further comprising
compacting said composition, milling the composition, or a combination thereof.
29. The process according to any of claims 22-28, wherein about 86% to
about 99% of said tanaproget is released from said composition after about 90
minutes.
30. A process for preparing a composition comprising micronized
tanaproget, or a pharmaceutically acceptable salt thereof, comprising:

(a) combining said tanaproget, microcrystalline cellulose, croscarmellose
sodium, povidone, sodium lauryl sulfate, and magnesium stearate; and
(b) granulating the product of step (a).

31. The process according to claim 30, further comprising adding said
composition to a capsule.
32. The process according to claim 31, wherein said capsule is a hard
shell gelatin capsule.
33. A capsule comprising the composition of any of claims 1-21.
34. A pharmaceutical kit comprising a daily dosage unit of said capsule of
claim 33.
27

The present invention provides compositions, desirably pharmaceutical compositions, containing micronized tanaproget. The compositions can also contain microcrystalline cellulose, croscarmellose sodium, anhydrous lactose, and magnesium stearate; or can contain microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, povidone, and
magnesium stearate. The compositions are useful in contraception and hormone replacement therapy and in the treatment and/or
prevention of uterine myometrial fibroids, benign prostatic hypertrophy, benign and malignant neoplastic disease, dysfunctional
bleeding, uterine leiomyomata, endometriosis, polycystic ovary syndrome, and carcinomas and adenocarcinomas of the pituitary,
endometrium, kidney, ovary, breast, colon, and prostate and other hormone-dependent tumors, and in the preparation of medicaments useful therefor. Additional uses include stimulation of food intake.