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Method For Purifying Tanaproget

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

Patent Information

Application #
Filing Date
22 October 2007
Publication Number
22/2008
Publication Type
INA
Invention Field
CHEMICAL
Status
Email
Parent Application
Patent Number
Legal Status
Grant Date
2014-09-29
Renewal Date

Applicants

WYETH
FIVE GIRALDA FARMS, MADISON, NEW JERSEY

Inventors

1. CHATLAPALLI RAMARAO
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

Orders

Section Controller Decision Date

Application Documents

# Name Date
1 4050-KOLNP-2007-FORM 3-1.1.pdf 2011-10-08
1 4050-KOLNP-2007_EXAMREPORT.pdf 2016-06-30
2 4050-KOLNP-2007-ASSIGNMENT-1.1.pdf 2014-10-17
2 4050-kolnp-2007-form 18.pdf 2011-10-08
3 4050-KOLNP-2007-CORRESPONDENCE OTHERS 1.1.pdf 2011-10-08
3 4050-KOLNP-2007-CANCELLED PAGES.pdf 2014-10-17
4 4050-KOLNP-2007-CORRESPONDENCE.pdf 2014-10-17
4 4050-KOLNP-2007-ASSIGNMENT.pdf 2011-10-08
5 4050-KOLNP-2007-DECISION.pdf 2014-10-17
5 04050-kolnp-2007-international search report.pdf 2011-10-08
6 4050-KOLNP-2007-EXAMINATION REPORT.pdf 2014-10-17
6 04050-kolnp-2007-international publication.pdf 2011-10-08
7 4050-KOLNP-2007-FORM 13.pdf 2014-10-17
7 04050-kolnp-2007-gpa.pdf 2011-10-08
8 4050-KOLNP-2007-FORM 18-1.1.pdf 2014-10-17
8 04050-kolnp-2007-form 5.pdf 2011-10-08
9 04050-kolnp-2007-form 3.pdf 2011-10-08
9 4050-KOLNP-2007-GPA.pdf 2014-10-17
10 04050-kolnp-2007-form 1.pdf 2011-10-08
10 4050-KOLNP-2007-GRANTED-ABSTRACT.pdf 2014-10-17
11 04050-kolnp-2007-drawings.pdf 2011-10-08
11 4050-KOLNP-2007-GRANTED-CLAIMS.pdf 2014-10-17
12 04050-kolnp-2007-description complete.pdf 2011-10-08
12 4050-KOLNP-2007-GRANTED-DESCRIPTION (COMPLETE).pdf 2014-10-17
13 04050-kolnp-2007-correspondence others.pdf 2011-10-08
13 4050-KOLNP-2007-GRANTED-DRAWINGS.pdf 2014-10-17
14 04050-kolnp-2007-claims.pdf 2011-10-08
14 4050-KOLNP-2007-GRANTED-FORM 1.pdf 2014-10-17
15 04050-kolnp-2007-abstract.pdf 2011-10-08
15 4050-KOLNP-2007-GRANTED-FORM 2.pdf 2014-10-17
16 4050-KOLNP-2007-(09-10-2012)-PETITION UNDER RULE 137.pdf 2012-10-09
16 4050-KOLNP-2007-GRANTED-FORM 3.pdf 2014-10-17
17 4050-KOLNP-2007-GRANTED-FORM 5.pdf 2014-10-17
17 4050-KOLNP-2007-(09-10-2012)-OTHERS.pdf 2012-10-09
18 4050-KOLNP-2007-(09-10-2012)-FORM-5.pdf 2012-10-09
18 4050-KOLNP-2007-GRANTED-LETTER PATENT.pdf 2014-10-17
19 4050-KOLNP-2007-(09-10-2012)-FORM-3.pdf 2012-10-09
19 4050-KOLNP-2007-GRANTED-SPECIFICATION-COMPLETE.pdf 2014-10-17
20 4050-KOLNP-2007-(09-10-2012)-FORM-2.pdf 2012-10-09
20 4050-KOLNP-2007-INTERNATIONAL PUBLICATION.pdf 2014-10-17
21 4050-KOLNP-2007-(09-10-2012)-FORM-13.pdf 2012-10-09
21 4050-KOLNP-2007-INTERNATIONAL SEARCH REPORT & OTHERS.pdf 2014-10-17
22 4050-KOLNP-2007-(09-10-2012)-FORM-1.pdf 2012-10-09
22 4050-KOLNP-2007-OTHERS.pdf 2014-10-17
23 4050-KOLNP-2007-(09-10-2012)-DRAWINGS.pdf 2012-10-09
23 4050-KOLNP-2007-PETITION UNDER RULE 137.pdf 2014-10-17
24 4050-KOLNP-2007-REPLY TO EXAMINATION REPORT.pdf 2014-10-17
24 4050-KOLNP-2007-(09-10-2012)-DESCRIPTION (COMPLETE).pdf 2012-10-09
25 4050-KOLNP-2007-(05-09-2014)-CLAIMS.pdf 2014-09-05
25 4050-KOLNP-2007-(09-10-2012)-CORRESPONDENCE.pdf 2012-10-09
26 4050-KOLNP-2007-(05-09-2014)-EXAMINATION REPORT REPLY RECEIVED.pdf 2014-09-05
26 4050-KOLNP-2007-(09-10-2012)-CLAIMS.pdf 2012-10-09
27 4050-KOLNP-2007-(05-09-2014)-OTHERS.pdf 2014-09-05
27 4050-KOLNP-2007-(09-10-2012)-ANNEXURE TO FORM 3.pdf 2012-10-09
28 4050-KOLNP-2007-(05-09-2014)-PA.pdf 2014-09-05
28 4050-KOLNP-2007-(09-10-2012)-ABSTRACT.pdf 2012-10-09
29 4050-KOLNP-2007-(22-07-2014)-CORRESPONDENCE.pdf 2014-07-22
29 4050-KOLNP-2007-(28-10-2013)-CORRESPONDENCE.pdf 2013-10-28
30 4050-KOLNP-2007-(28-10-2013)-ANNEXURE TO FORM 3.pdf 2013-10-28
30 4050-KOLNP-2007-(21-07-2014)-CORRESPONDENCE.pdf 2014-07-21
31 4050-KOLNP-2007-(13-06-2014)-CORRESPONDENCE.pdf 2014-06-13
31 4050-KOLNP-2007-(21-04-2014)-OTHERS.pdf 2014-04-21
32 4050-KOLNP-2007-(13-06-2014)-OTHERS.pdf 2014-06-13
32 4050-KOLNP-2007-(21-04-2014)-FORM-3.pdf 2014-04-21
33 4050-KOLNP-2007-(21-04-2014)-CORRESPONDENCE.pdf 2014-04-21
34 4050-KOLNP-2007-(13-06-2014)-OTHERS.pdf 2014-06-13
34 4050-KOLNP-2007-(21-04-2014)-FORM-3.pdf 2014-04-21
35 4050-KOLNP-2007-(13-06-2014)-CORRESPONDENCE.pdf 2014-06-13
35 4050-KOLNP-2007-(21-04-2014)-OTHERS.pdf 2014-04-21
36 4050-KOLNP-2007-(21-07-2014)-CORRESPONDENCE.pdf 2014-07-21
36 4050-KOLNP-2007-(28-10-2013)-ANNEXURE TO FORM 3.pdf 2013-10-28
37 4050-KOLNP-2007-(22-07-2014)-CORRESPONDENCE.pdf 2014-07-22
37 4050-KOLNP-2007-(28-10-2013)-CORRESPONDENCE.pdf 2013-10-28
38 4050-KOLNP-2007-(05-09-2014)-PA.pdf 2014-09-05
38 4050-KOLNP-2007-(09-10-2012)-ABSTRACT.pdf 2012-10-09
39 4050-KOLNP-2007-(05-09-2014)-OTHERS.pdf 2014-09-05
39 4050-KOLNP-2007-(09-10-2012)-ANNEXURE TO FORM 3.pdf 2012-10-09
40 4050-KOLNP-2007-(05-09-2014)-EXAMINATION REPORT REPLY RECEIVED.pdf 2014-09-05
40 4050-KOLNP-2007-(09-10-2012)-CLAIMS.pdf 2012-10-09
41 4050-KOLNP-2007-(05-09-2014)-CLAIMS.pdf 2014-09-05
41 4050-KOLNP-2007-(09-10-2012)-CORRESPONDENCE.pdf 2012-10-09
42 4050-KOLNP-2007-(09-10-2012)-DESCRIPTION (COMPLETE).pdf 2012-10-09
42 4050-KOLNP-2007-REPLY TO EXAMINATION REPORT.pdf 2014-10-17
43 4050-KOLNP-2007-(09-10-2012)-DRAWINGS.pdf 2012-10-09
43 4050-KOLNP-2007-PETITION UNDER RULE 137.pdf 2014-10-17
44 4050-KOLNP-2007-(09-10-2012)-FORM-1.pdf 2012-10-09
44 4050-KOLNP-2007-OTHERS.pdf 2014-10-17
45 4050-KOLNP-2007-(09-10-2012)-FORM-13.pdf 2012-10-09
45 4050-KOLNP-2007-INTERNATIONAL SEARCH REPORT & OTHERS.pdf 2014-10-17
46 4050-KOLNP-2007-INTERNATIONAL PUBLICATION.pdf 2014-10-17
46 4050-KOLNP-2007-(09-10-2012)-FORM-2.pdf 2012-10-09
47 4050-KOLNP-2007-(09-10-2012)-FORM-3.pdf 2012-10-09
47 4050-KOLNP-2007-GRANTED-SPECIFICATION-COMPLETE.pdf 2014-10-17
48 4050-KOLNP-2007-(09-10-2012)-FORM-5.pdf 2012-10-09
48 4050-KOLNP-2007-GRANTED-LETTER PATENT.pdf 2014-10-17
49 4050-KOLNP-2007-(09-10-2012)-OTHERS.pdf 2012-10-09
49 4050-KOLNP-2007-GRANTED-FORM 5.pdf 2014-10-17
50 4050-KOLNP-2007-(09-10-2012)-PETITION UNDER RULE 137.pdf 2012-10-09
50 4050-KOLNP-2007-GRANTED-FORM 3.pdf 2014-10-17
51 04050-kolnp-2007-abstract.pdf 2011-10-08
51 4050-KOLNP-2007-GRANTED-FORM 2.pdf 2014-10-17
52 04050-kolnp-2007-claims.pdf 2011-10-08
52 4050-KOLNP-2007-GRANTED-FORM 1.pdf 2014-10-17
53 04050-kolnp-2007-correspondence others.pdf 2011-10-08
53 4050-KOLNP-2007-GRANTED-DRAWINGS.pdf 2014-10-17
54 04050-kolnp-2007-description complete.pdf 2011-10-08
54 4050-KOLNP-2007-GRANTED-DESCRIPTION (COMPLETE).pdf 2014-10-17
55 04050-kolnp-2007-drawings.pdf 2011-10-08
55 4050-KOLNP-2007-GRANTED-CLAIMS.pdf 2014-10-17
56 04050-kolnp-2007-form 1.pdf 2011-10-08
56 4050-KOLNP-2007-GRANTED-ABSTRACT.pdf 2014-10-17
57 04050-kolnp-2007-form 3.pdf 2011-10-08
57 4050-KOLNP-2007-GPA.pdf 2014-10-17
58 4050-KOLNP-2007-FORM 18-1.1.pdf 2014-10-17
58 04050-kolnp-2007-form 5.pdf 2011-10-08
59 4050-KOLNP-2007-FORM 13.pdf 2014-10-17
59 04050-kolnp-2007-gpa.pdf 2011-10-08
60 4050-KOLNP-2007-EXAMINATION REPORT.pdf 2014-10-17
60 04050-kolnp-2007-international publication.pdf 2011-10-08
61 4050-KOLNP-2007-DECISION.pdf 2014-10-17
61 04050-kolnp-2007-international search report.pdf 2011-10-08
62 4050-KOLNP-2007-ASSIGNMENT.pdf 2011-10-08
62 4050-KOLNP-2007-CORRESPONDENCE.pdf 2014-10-17
63 4050-KOLNP-2007-CANCELLED PAGES.pdf 2014-10-17
63 4050-KOLNP-2007-CORRESPONDENCE OTHERS 1.1.pdf 2011-10-08
64 4050-KOLNP-2007-ASSIGNMENT-1.1.pdf 2014-10-17
64 4050-kolnp-2007-form 18.pdf 2011-10-08
65 4050-KOLNP-2007-FORM 3-1.1.pdf 2011-10-08
65 4050-KOLNP-2007_EXAMREPORT.pdf 2016-06-30

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