U.S. patent application number 14/156863 was filed with the patent office on 2014-07-10 for tanaproget compositions containing ethinyl estradiol.
This patent application is currently assigned to Wyeth LLC. The applicant listed for this patent is Wyeth LLC. Invention is credited to Zafar Ali, Ramarao Chatlapalli, Mohamed Ghorab, Shamim Hasan, Arwinder Nagi.
Application Number | 20140194398 14/156863 |
Document ID | / |
Family ID | 37432377 |
Filed Date | 2014-07-10 |
United States Patent
Application |
20140194398 |
Kind Code |
A1 |
Nagi; Arwinder ; et
al. |
July 10, 2014 |
Tanaproget Compositions Containing Ethinyl Estradiol
Abstract
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.
Inventors: |
Nagi; Arwinder; (Moorpark,
CA) ; Chatlapalli; Ramarao; (Hopewell Junction,
NY) ; Hasan; Shamim; (East Elmhurst, NY) ;
Ali; Zafar; (Danbury, CT) ; Ghorab; Mohamed;
(West Lafayette, IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Wyeth LLC |
Madison |
NJ |
US |
|
|
Assignee: |
Wyeth LLC
Madison
NJ
|
Family ID: |
37432377 |
Appl. No.: |
14/156863 |
Filed: |
January 16, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13292405 |
Nov 9, 2011 |
8664208 |
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14156863 |
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11448965 |
Jun 7, 2006 |
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13292405 |
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60688806 |
Jun 9, 2005 |
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Current U.S.
Class: |
514/171 |
Current CPC
Class: |
A61K 9/1652 20130101;
A61P 15/18 20180101; A61P 15/12 20180101; A61K 31/565 20130101;
A61K 9/1682 20130101; A61K 31/567 20130101; A61P 15/00 20180101;
A61K 9/1623 20130101; A61P 5/24 20180101; A61K 31/538 20130101;
A61K 9/4808 20130101; A61P 35/00 20180101; A61P 13/08 20180101;
A61K 31/00 20130101; A61P 43/00 20180101; A61K 9/2054 20130101;
A61K 31/536 20130101; A61K 9/2018 20130101; A61K 9/2077 20130101;
A61K 31/536 20130101; A61K 2300/00 20130101; A61K 9/2095 20130101;
A61K 2300/00 20130101; A61K 31/56 20130101; A61K 31/565
20130101 |
Class at
Publication: |
514/171 |
International
Class: |
A61K 31/567 20060101
A61K031/567; A61K 31/536 20060101 A61K031/536 |
Claims
1. A method of contraception comprising administering to a female
of child bearing age a product comprising an effective amount of
micronized tanaproget, or a pharmaceutically acceptable salt
thereof, and an effective amount of ethinyl estradiol.
2. The method according to claim 1, wherein said effective amount
of tanaproget is about 100 .mu.g, 200 .mu.g, or 300 .mu.g.
3. The method according to claim 1, wherein said effective amount
of ethinyl estradiol comprises about 20 .mu.g.
4. The method according to claim 1, wherein said ethinyl estradiol
is a 2% triturate in lactose.
5. The method according to claim 1, wherein said product further
comprises microcrystalline cellulose, anhydrous lactose,
croscarmellose sodium, magnesium stearate, or combinations
thereof.
6. A method of hormone replacement therapy comprising administering
to a female in need thereof a product comprising an effective
amount of micronized tanaproget, or a pharmaceutically acceptable
salt thereof, and an effective amount of ethinyl estradiol.
7. The method according to claim 6, wherein said product comprises
about 100 .mu.g, 200 .mu.g, or 300 .mu.g of tanaproget.
8. The method according to claim 6, wherein said product comprises
about 20 .mu.g of ethinyl estradiol.
9. The method according to claim 6, wherein said ethinyl estradiol
is a 2% triturate in lactose.
10. The method according to claim 6, wherein said product further
comprises microcrystalline cellulose, anhydrous lactose,
croscarmellose sodium, and magnesium stearate
11. 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).
Description
BACKGROUND
[0001] Compositions containing tanaproget and ethinyl estradiol are
provided.
[0002] 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.
[0003] Tanaproget,
5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-1-methyl-pyr-
role-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.
[0004] What is needed are compositions containing tanaproget for
contraception and hormone replacement therapy.
SUMMARY OF THE INVENTION
[0005] In one aspect, compositions containing micronized
tanaproget, or a pharmaceutically acceptable salt thereof, and
ethinyl estradiol are provided.
[0006] 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.
[0007] In a further aspect, processes for preparing a composition
containing micronized tanaproget and ethinyl estradiol are
provided.
[0008] In yet another aspect, kits containing a composition which
contains micronized tanaproget and ethinyl estradiol are
provided.
[0009] 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.
[0010] 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.
[0011] Other aspects and advantages of the invention will be
readily apparent from the following detailed description of the
invention.
DETAILED DESCRIPTION OF THE INVENTION
[0012] Effective phaiinaceutical 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.
[0013] 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 in
U.S. Pat. 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.
[0014] Micronized tanaproget prepared as described herein typically
has a particle size of less than about 20 .mu.m, desirably less
than about 15 .mu.m, and more desirably less than about 10 .mu.m.
Specifically, 90% of the particles are less than or equal to about
20 .mu.m and 50% are less than or equal to about 15 .mu.m as
determined by the Malvern method, which is readily understood by
one of skill in the art.
[0015] 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.
[0016] Physiologically acceptable acids include those derived from
inorganic and organic acids. A number of inorganic acids are known
in the art and include hydrochloric, hydrobromic, hydroiodic,
sulfuric, nitric, and phosphoric acids, among others. Similarly, a
variety of organic acids are known in the art and include, without
limitation, lactic, formic, acetic, fumaric, citric, propionic,
oxalic, succinic, glycolic, glucuronic, maleic, furoic, glutamic,
benzoic, anthranilic, salicylic, tartaric, malonic, mallic,
phenylacetic, mandelic, embonic, methanesulfonic, ethanesulfonic,
panthenoic, benzenesulfonic, toluenesulfonic, stearic, sulfanilic,
alginic, and galacturonic acids, among others.
[0017] 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.
[0018] 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.
[0019] 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).
[0020] 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.
[0021] 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 faun a
dry granulation.
[0022] 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.
[0023] A. The Compositions
[0024] 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.
[0025] 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 .mu.g of tanaproget, and desirably, about
100, 200, or 300 .mu.g of tanaproget.
[0026] 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 .mu.g of tanaproget, and desirably
about 105, 210, and 315 .mu.g of tanaproget.
[0027] 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 .mu.g of ethinyl
estradiol.
[0028] 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 .mu.g of ethinyl estradiol.
[0029] 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.
[0030] 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.
[0031] 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 includes about 38.9% wt/wt of the
composition. In yet another example, anhydrous lactose includes
about 38.8% wt/wt of the composition.
[0032] 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.
[0033] 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.
[0034] 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%
wt/wt of magnesium stearate.
[0035] 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.
[0036] 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.
[0037] 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.
[0038] 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 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.
[0039] 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.
[0040] 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-US-00001 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
[0041] Another example of a suitable micronized tanaproget
composition is provided in Table 2.
TABLE-US-00002 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
[0042] A further example of a suitable micronized tanaproget
composition is provided in Table 3.
TABLE-US-00003 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
[0043] Still another example of a suitable micronized tanaproget
composition is provided in Table 4.
TABLE-US-00004 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
[0044] Yet a further example of a suitable micronized tanaproget
composition is provided in Table 5.
TABLE-US-00005 TABLE 5 Component wt/wt Micronized Tanaproget 0.35
Ethinyl Estradiol 0.035 MCC 54.4120 Anhydrous Lactose 38.953
Croscamellose Sodium 6.00 Magnesium Stearate 0.25
[0045] In still another example of a suitable micronized tanaproget
composition is provided in Table 6.
TABLE-US-00006 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
[0046] 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
[0047] 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.
[0048] 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.
[0049] 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.
[0050] 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.
[0051] 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.
[0052] 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 .mu.m. The sizes
of the particles of the composition are typically measured by
passing the solid composition through screens of varying sizes. In
one embodiment, about 8% of the particles are greater than or equal
to about 350 .mu.m. In another embodiment, about 28% of the
particles are greater than or equal to about 180 .mu.m. In a
further embodiment, about 34% of the particles are greater than or
equal to about 150 .mu.m. In still another embodiment, about 39% of
the particles are greater than about 125 .mu.m. In yet another
embodiment, about 49% of the particles are greater than about 89
.mu.m. In a further embodiment, about 64% of the particles are
greater than about 75 .mu.m. In still another embodiment, about 90%
of the particles are greater than about 45 .mu.m.
[0053] 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.
[0054] 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.RTM. B2 Tablet Press, among others.
[0055] 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 capsule prior to adding the
filler. In one example, a tablet containing 0.1 mg of tanaproget
and 20 .mu.g of ethinyl estradiol is encapsulated in a capsule. In
another example, a tablet containing 0.2 mg of tanaproget and 20
.mu.g of ethinyl estradiol is encapsulated in a capsule. In a
further example, a tablet containing 0.3 mg of tanaproget and 20
.mu.g of ethinyl estradiol is encapsulated in a capsule.
[0056] 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 .mu.g of ethinyl estradiol is
encapsulated in a capsule. In another example, a tablet contains
0.2 mg of tanaproget and 20 .mu.g of ethinyl estradiol is
encapsulated in a capsule. In a further example, a tablet contains
0 3 mg of tanaproget and 20 .mu.g of ethinyl estradiol is
encapsulated in a capsule.
[0057] 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.RTM. seal coat. Where applied, the weight
percent of the film coat is generally in the range of 2% wt/wt to
6% wt/wt of the tablet.
[0058] 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.
[0059] B. Stability of the Compositions
[0060] 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.degree. C./50% relative humidity
to about 45.degree. C./75% relative humidity and at temperatures up
to about 25.degree. C.
[0061] In one embodiment, the compositions are stored at reduced
temperatures, and, desirably, at temperatures of about 5.degree. C.
It is also desirable that the compositions be stored in the absence
of water, air, and moisture.
[0062] 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.
[0063] C. Additional Components of the Compositions
[0064] 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 adjustors,
surfactants, fillers, disintegrants, and combinations thereof,
among others.
[0065] 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.
[0066] 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.
[0067] 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.
[0068] Excipients can include, without limitation, silicon dioxide,
starch, calcium carbonate, pectin, and crospovidone (polyplasdone),
among others.
[0069] 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.
[0070] 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.
[0071] Surfactants can include polysorbates, sorbitan esters,
poloxamer, or sodium lauryl sulfate. In one embodiment, the
surfactant is sodium lauryl sulfate.
[0072] 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.
[0073] Additional fillers that can be used in the compositions
include mannitol, calcium phosphate, pregelatinized starch, or
sucrose.
[0074] D. Methods of Using the Compositions
[0075] Further provided are methods of delivering tanaproget to a
patient, where the method includes administering a micronized
tanaproget dosing unit.
[0076] 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 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 .mu.g, about 100 .mu.g, about 200
.mu.g, or about 300 .mu.g.
[0077] 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.
[0078] 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.
[0079] 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 polymers such as
hydroxypropylmethylcellulose, ethyl cellulose, polyvinyl alcohol,
and combinations thereof.
[0080] 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.
[0081] 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.
[0082] 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.
[0083] E. Kits
[0084] 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.TM. 2000 blister packs.
[0085] 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 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.
[0086] Additional components may be co-administered with the
compositions and include antiprogestins, estrogens, and selective
estrogen receptor modulators, among others.
[0087] 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.
[0088] 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.
[0089] 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.
[0090] 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.
[0091] 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.
[0092] 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.
[0093] 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.
[0094] 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.
[0095] 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.
[0096] 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.
[0097] 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.
[0098] The kit can further contain instructions for administering
the tanaproget composition.
[0099] 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.
[0100] 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
[0101] The compositions for this example were manufactured using
the following protocol and using the components of Table 7.
TABLE-US-00007 TABLE 7 Component Function Tanaproget (micronized)
Active ingredient Ethinyl Estradiol (EE) 2% Triturate in Active
ingredient Lactose Microcrystalline Cellulose Filler, Granulation
aid, Disintegrant Croscarmellose Sodium Disintegrant Anhydrous
Lactose Filler Magnesium Stearate Lubricant HPMC Capsule, #1
Reddish Brown Capsule shell
[0102] 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 portion four
and five of MCC and anhydrous lactose in the bag 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.
[0103] 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 anhydrous lactose
were passed through #30 mesh hand screen, transferred to the
PK-Blender, and the material blend.
[0104] 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.degree. C., in the absence of light and moisture
using two desiccant bags between the two poly bags.
[0105] 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.
[0106] 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 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.degree. 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-US-00008 TABLE 8 100 .mu.g Tanaproget/ 200 .mu.g Tanaproget/
300 .mu.g Tanaproget/ 20 .mu.g EE 20 .mu.g EE 20 .mu.g EE Tablet
Tablet Tablet Amount Amount Amount Ingredient (mg) wt/wt (mg) wt/wt
(mg) wt/wt Micronized Tanaproget.sup.a 0.105.sup.c 0.1750.sup.c
0.21.sup.c 0.35.sup.c 0.5250.sup.c 0.3150.sup.c Ethinyl
Estradiol.sup.b 1.05.sup.d 1.75.sup.d 1.05.sup.d 1.75.sup.d
1.75.sup.d 1.05.sup.d Microcrystalline 32.7022 54.5037 32.6472
54.4120 54.3203 32.5922 Cellulose 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 .sup.aIf 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.
.sup.bIf assay of EE is other than 2%, adjust the amount of input
to provide the proper level of EE and adjust the lactose
accordingly. .sup.cIncludes 5% overage of Tanaproget.
.sup.dIncludes 5% overage of EE.
Example 2
Tablets Containing a Composition of Tanaproget and Ethinyl
Estradiol
[0107] This example provides the preparation of tablets containing
a composition containing tanaproget and ethinyl estradiol.
[0108] The blend from Example 1 was compressed using a Stokes.RTM.
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.degree. C., in the absence of light and moisture.
Example 3
Tablets-in-Capsules Containing a Composition of Tanaproget and
Ethinyl Estradiol
[0109] 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 .mu.g, 200 .mu.g, and 300 .mu.g of tanaproget. The
amounts of each component are illustrated in Table 9.
[0110] 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 fowl a final placebo blend.
[0111] 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 (100 .mu.g/20 .mu.g, 200 .mu.g/20 .mu.g, 300
.mu.g/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.
[0112] 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-US-00009 TABLE 9 Ingredient Amount wt/wt Tanaproget/EE Tablet
60 mg 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 77
mg Capsule Quali-V
[0113] All publications cited in this specification and priority
applications, i.e., U.S. patent application Ser. No. 13/292,405,
U.S. patent application Ser. No. 11/448,965, and U.S. Provisional
Patent Application No. 60/688,806, 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.
* * * * *