Abstract:
Micronized tanaproget, purified tanaproget Form I, and micronized, purified tanaproget Form I are provided. Also provided are compositions containing one or more of the prepared tanaproget forms, methods of using one or more of the prepared tanaproget forms, and kits containing one or more of the prepared tanaproget forms.
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Notices, Deadlines & Correspondence
123 HOSNER MOUNTAIN ROAD, HOPEWELL JUNCTION, NEW JERSEY 12533
2. NAGI ARWINDER
9 LOCUST DRIVE, THIELLS, NEW YORK 10984
3. POTOSKI JOHN
3 HARTSHORN LANE, WEST NYACK, NEW YORK 10994
4. HELOM JEAN LOUISE
316 LIBERTY AVENUE, HILLSDALE, NEW JERSEY 07642
5. WILK BOGDAN KAZIMIERZ
6 CONRAD LANE, NEW CUTY, NEW YORK 10956
6. RUBEZHOV ARKADIY ZINOVIY
3 FAWN COURT, WEST NYACK, NEW YORK 10994
7. DRAGAN VLADIMIR
51 NANCY LANE, CHESTER,, NEW YORK 10918
Specification
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 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 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
r
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.
What is needed in the art are other forms of tanaproget for use in
pharmaceutical compositions.
SUMMARY OF THE INVENTION
In one aspect, micronized tanaproget Form I is provided.
In another aspect, purified tanaproget Form I is provided.
In a further aspect, a kit containing purified tanaproget Form I; and a carrier
suitable for administration to a mammalian subject is provided.
In still another aspect, a reference standard of purified tanaproget Form I is
provided.
In yet a further aspect, a method of preparing a pharmaceutical composition
comprising purified tanaproget Form I is provided.
Other aspects and advantages are described further in the following detailed
description of the preferred embodiments thereof.
BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS
Figure 1 provides the proton nuclear magnetic resonance spectrum of a sample
of purified tanaproget Form I.
Figure 2 provides the mass spectrum of a sample of purified tanaproget Form
I.
Figure 3 provides the fourier transform infrared spectrum of a sample of
purified tanaproget Form I.
Figure 4 provides the high performance liquid chromatography spectrum of a
sample of purified tanaproget Form I.
Figure 5 provides the X-ray diffraction pattern of a sample of purified
fahaproget Form I.
Figure 6 provides the differential scanning calorimetry thermogram of a
sample of purified tanaproget Form I.
DETAILED DESCRIPTION OF THE INVENTION
Pharmaceutical compositions containing micronized tanaproget Form I,
purified tanaproget Form I, and micronized and purified tanaproget Form I are
provided and discussed herein.
As used herein, the term "tanaproget" refers to 5-(4,4-dimethyl-2-thioxo-1,4-
dihydro-2H-3,l-benzoxazin-6-yl)-1-methyl-1H-pyrrole-2-carbonitrile.
The term "purified" as used herein preferably refers to tanaproget that contains
less than about 1% impurities. In one example, purified tanaproget contains less than
about 0.5% impurities. In another example, purified tanaproget contains less than or
equal to about 0.36% impurities. Desirably, purified tanaproget is about 99.5% pure.
The term "solvent" as used herein refers to a solvent in which tanaproget has
acceptable, moderate, good, or complete solubility. Similarly, the term "anti-solvent"
as used herein refers to a solvent in which tanaproget has limited, reduced, or no
solubility.
A. Micronized Tanaproget
Tanaproget Form I can be 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 nbn-micronized tanaproget is
described in US Patent No. 6,436,929, and generally in US Patent Application
Publication No. US-2005-0272702-A1, which is hereby incorporated by reference.
However, it isnot limited to the method by which the non-micronized tanaproget
Form I is produced.
Micronized tanaproget Form I typically has a median particle size of less than
about 20 µm, desirably less than about 15 µm, and more desirably less than about 10
µm. Specifically, 90% of the particles are less than or equal to about 20 µm and 50%
are iess than or equal to about 15 µm as determined by the Malvern method, which is
readily understood by one of skill in the art.
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.
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.
In one embodiment, micronized 5-(4,4-dimethyl-2-thioxo-1,4-dihydro-2H-3,l-
benzoxazin-6-yl)-l -methyl-1H-pyrrole-2-carbonitrile Form I which has a particle size
less than about 20 µm is provided.
B. Purification of Tanaproget
Also provided is purified tanaproget Form I that is more suitable for
administration in a pharmaceutical composition. Typically, the unpurified tanaproget
is micronized prior to purification.
The inventors have found that the purified tanaproget Form I provided herein
is stable and less likely to convert to another polymorph during storage of either
purified tanaproget Form I alone or in combination with other agents/excipients.
In one embodiment, tanaproget Form I is purified as described in US Patent
Application Publication No. US-2005-0272702-A1, which is hereby incorporated by
reference. However, it is not limited to the method by which the non-micronized
tanaproget Form I is produced.
In another embodiment, tanaproget Form I is purified by recrystallization. The
recrystallization can be performed using a solvent or solvent system. A number of
solvents can be utilized to purify the tanaproget Form I and include ethyl acetate,
acetone, or a combination thereof. Alternatively, solvent systems can be utilized in
which one reagent of the system is a solvent capable of dissolving the tanaproget
Form I and a second reagent of the solvent system is an anti-solvent. Desirable
solvent/anti-solvent systems that are useful include, without limitation,
acetone/tetrahydrofuran, acetone/methanol, acetone/toluene, and acetone/water.
Desirably, tanaproget Form I is purified by recrystallization from acetone/water.
Typically, tanaproget Form I is purified by dissolving unpurified tanaproget in
hot acetone to form a solution, the acetone solution is concentrated, water is mixed
with the concentrated acetone solution, and the concentrated acetone/water solution is
cooled to room temperature.
In a further embodiment, tanaproget Form I is dissolved in acetone and the
solution is heated 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 is concentrated
using procedures known to those of skill in the art. After adding water to the
concentrated solution, desirably at a rate which does not cool the refhrxing acetone
solution, the acetone/water solution is cooled to about -6 to about 0°C. Desirably, the
acetone/water solution is cooled at a rate of less than about 0.5 °C/minute. After
holding the cooled solution at the reduced temperature for at least about 3 hours, the
precipitated, purified tanaproget Form I is collected using filtration. The collected
solid is washed with a water/acetone mixture, desirably washing the solid twice with a 1:1 water/acetone mixture. The washed purified tanaproget Form I is then dried at
less than 35 °C for about 4 hours. Further drying at less than about 50 °C is
performed to remove residual acetone/water as measured by spectroscopic methods.
Typically, the impurities still present in purified tanaproget Form I include
residual acetone, isopropyl alcohol, or water. In one example, purified tanaproget
Form I contains less than about 0.1 % water. In another example, purified tanaproget
Form I contains less than or equal to about 0.07% water.
In one embodiment, a purified Form I of 5-4,4-dimethyl-2-thioxo-1,4-
dihydro-2H-3,l-ben2»xa2an-6-yl)-1-methyl-1H-pyrole-2-carbonitrile having a
differential scanning calorimetry thermogram having an endotherm with a Tonset at
about 230°C; and an X-ray diffraction peak pattern comprising peaks at 20 of about
6.6°, 10.3°, 14.4°, 19.8°,23.8°, 26.3°, and 29.1° is provided.
C. Characterizing Purified Tanaproget
Purified tanaproget Form I can be characterized using several spectroscopic
techniques including nuclear magnetic resonance (proton and carbon), mass
spectroscopy, infrared spectroscopy, chromatography such as high performance liquid
chromatography, X-ray diffraction, and differential scanning calorimetry, among
others. Desirably, the spectra obtained on purified tanaproget Form I using these
techniques provide evidence that the purified tanaproget Form I contains less than 1%
impurities.
In one embodiment, purified tanaproget Form I provides a proton (1H) nuclear
magnetic resonance (NMR) spectrurnof Figure 1. and a carbon (13C) NMR spectrum
of Figure 2. Desirably, the 1H-NMR spectrum (d6-dimethylsulfoxide) contains
peaks at about 5 3.7,7.0, 6.4,7.5,7.15,7.5,1.7, and 12.3. More desirably, the !H-
NMR spectrum (
Documents
Application Documents
#
Name
Date
1
4050-KOLNP-2007-FORM 3-1.1.pdf
2011-10-08
2
4050-kolnp-2007-form 18.pdf
2011-10-08
3
4050-KOLNP-2007-CORRESPONDENCE OTHERS 1.1.pdf
2011-10-08
4
4050-KOLNP-2007-ASSIGNMENT.pdf
2011-10-08
5
04050-kolnp-2007-international search report.pdf
2011-10-08
6
04050-kolnp-2007-international publication.pdf
2011-10-08
7
04050-kolnp-2007-gpa.pdf
2011-10-08
8
04050-kolnp-2007-form 5.pdf
2011-10-08
9
04050-kolnp-2007-form 3.pdf
2011-10-08
10
04050-kolnp-2007-form 1.pdf
2011-10-08
11
04050-kolnp-2007-drawings.pdf
2011-10-08
12
04050-kolnp-2007-description complete.pdf
2011-10-08
13
04050-kolnp-2007-correspondence others.pdf
2011-10-08
14
04050-kolnp-2007-claims.pdf
2011-10-08
15
04050-kolnp-2007-abstract.pdf
2011-10-08
16
4050-KOLNP-2007-(09-10-2012)-PETITION UNDER RULE 137.pdf