Title of Invention	"A METHOD FOR MAKING A SLOW RELEASE ESTRADIOL FORMULATION"
Abstract	The present invention provides slow release estradiol-progesterone formulations that can be used in either contraception or hormone replacement therapies. The formulations comprise shaped particles of estradiol that is in a hemicrystalline form that exhibits especially low dissolution rates. The shaped particles comprise estradiol compounded in a 1:1 molar ratio with cholesterol, and are administered in combination with progesterone. The slow release formulations of the present invention afford the dual advantages of a low dose estradiol formulation with a low frequency administration regimen. The formulations can be parenterally administered once a month or less often.

Title of Invention

"A METHOD FOR MAKING A SLOW RELEASE ESTRADIOL FORMULATION"

Abstract

The present invention provides slow release estradiol-progesterone formulations that can be used in either contraception or hormone replacement therapies. The formulations comprise shaped particles of estradiol that is in a hemicrystalline form that exhibits especially low dissolution rates. The shaped particles comprise estradiol compounded in a 1:1 molar ratio with cholesterol, and are administered in combination with progesterone. The slow release formulations of the present invention afford the dual advantages of a low dose estradiol formulation with a low frequency administration regimen. The formulations can be parenterally administered once a month or less often.

Full Text	A method for making a slow release estradiol formulation comprising: (a) creating particles consisting essentially of estradiol and cholesterol in mole ratio of 3:1 to 1:3 and wherein either or both are in an amorphous or polymorphous form; (b) exposing said particles to an atmosphere saturated with acetone and water; (c) repeating step (b); (d) exposing said particles to an atmosphere saturated with ethanol and water; (e) drying the particles; and (f) recovering said particles; wherein the Estradiol Dissolution Rate of the recovered particles is less than 20 %. I CLAIM: 1. A method for making a slow release estradiol formulation comprising: (a) creating particles consisting essentially of estradiol and cholesterol in mole ratio of 3:1 to 1:3 and wherein either or both are in an amorphous or polymorphous form; (b) exposing said particles to an atmosphere saturated with acetone and water; (c) repeating step (b); (d) exposing said particles to an atmosphere saturated with ethanol and water; (e) drying the particles; and (f) recovering said particles; wherein the Estradiol Dissolution Rate of the recovered particles is less than 20 %. 2. The method as claimed in claim 1, wherein the acetone and water mixture is 65 mole % to 80 mole % acetone and 20 mole % to 35 mole % water. 3. The method as claimed in claim 1, wherein the ethanol and water mixture is 95 - 99 mole % ethanol and 5-1 mole % water. 4. The method as claimed in claim 1, wherein step (b) is performed over at least 24 hours, and step (c) is performed twice. 5. A method for making a slow release estradiol formulation comprising: (a) creating particles consisting essentially of estradiol and cholesterol in mole ratio of 1:1 and wherein either or both are in an amorphous or polymorphous form; (b) exposing said particles to an atmosphere saturated with acetone and water for three consecutive stages; (c) exposing said particles to an atmosphere saturated with ethanol and water; (d) drying the particles at 40 - 50°C for at least 24 hours; and (e) recovering said particles; wherein the Estradiol Dissolution Rate of the recovered particles is 18% or less. 6. The method as claimed in claim 5, wherein the acetone and water mixture is 70 - 75 mole % acetone and 25 - 30 mole % water. 7. The method as claimed in claim 5, wherein the ethanol and water mixture is 95 - 99 mole % ethanol and 5-1 mole % water. 8. A pharmaceutical formulation in unit dose form comprising: (a) 5 mg to 15 mg 17-p-estradiol admixed with cholesterol in a molar ratio of 3:1 to 1:3; and (b) 200 mg to 500 mg progesterone, wherein the weight ratio of 17-p-estradiol to progesterone is between 1:13 to 1:100; and wherein the 17-p-estradiol consists of a hemicrystalline form that is 50-60% amorphous and 40-50% crystalline; and the Estradiol Dissolution Rate of the formulation is 20% or less. 9. The pharmaceutical formulation as claimed in claim 8, wherein the 17-p-estradiol consists of a hemicrystalline form that is 55% amorphous and 45% crystalline. 10. The pharmaceutical formulation as claimed in claim 8, wherein the Estradiol Dissolution Rate is 6% or less. 11. The pharmaceutical formulation as claimed in claim 8, wherein the estradiol/ cholesterol admixture and the progesterone are formulated as microspheres of 35 to 75 nm diameter. 12. Microspheres of estradiol and cholesterol in 1:1 molar ratio having an Estradiol Dissolution Rate of 6% or less. 13. The microspheres as claimed in claim 12., having an X-ray crystallographic spectra substantially the same as Figure 22. 14. The microspheres as claimed in claim 12, wherein the estradiol consists of a hemicrystalline form where 50-60% is amorphous and 40-50% is crystalline. 15. The microspheres as claimed in claim 12, wherein the estradiol is in a hemicrystalline form that is 55% amorphous and 45% crystalline. 16. The microspheres as claimed in claim 12, wherein the estradiol is 17- p-estradiol. 17. A pharmaceutical formulation comprising a contraceptive-effective and hormone-replacement-effective amount of 17-ß-estradiol and progesterone in a weight ratio .of from 1:13 to 1:100; and wherein the 17-ß-estradiol is compounded in discrete particles in admixture with cholesterol. 18. The formulation as claimed in claim 17, wherein the weight ratio of 17-p-estradiol:progesterone is 9:400. 19. The formulation as claimed in claim 17, wherein the 17-ß-estradiol and cholesterol are compounded in a 1:1 molar ratio into microspheres, and the progesterone is separately compounded into discrete microspheres. 20. The formulation as claimed in claim 19, wherein the microspheres have a diameter of between 25 µm and 105 µm. 21. The method as claimed in claim 1, wherein the molar ratio of estradiol to cholesterol is from 1:2 to 2:1. 22. The method as claimed in claim 1, wherein the molar ratio of estradiol to cholesterol is 1:1. 23. The method as claimed in claim 1, further comprising exposing said particles to an atmosphere saturated with ethanol and water. 24. The method as claimed in claim 1, wherein the step of exposing the particles to an atmosphere saturated with acetone and water occurs over 72 hours at 60°C. 25. The method as claimed in claim 1, wherein the mole ratio of estradiol to cholesterol is 1:1. 26. The formulation as claimed in claim 8, wherein the mole ratio of 17-ß estradiol to cholesterol is 1:1. 27. The formulation as claimed in claim 8, wherein the weight ratio of 17- ß-estradiol to progesterone is 9:400. 28. The formulation as claimed in claim 8, comprising 9 mg of 17-ß- estradiol and 400 mg of progesterone. 29. The formulation as claimed in claim 8, wherein the 17-ß-estradiol and cholesterol are in admixture in discrete particles, and the progesterone is in separate and discrete particles. 30. The formulation as claimed in claim 8, wherein the estradiol/cholesterol particles and the progesterone particles are all in the form of microspheres having diameter of 25 µm to 125 µm. 31. The formulation as claimed in claim 30, wherein the microspheres have a diameter of 35 µm to 75 µm. 32. A method for making a slow release estradiol formulation substantially as herein described with reference to foregoing description. 33. A pharmaceutical formulation in unit dose form substantially as herein described with reference to foregoing description.

Full Text

A method for making a slow release estradiol formulation comprising:
(a) creating particles consisting essentially of estradiol and
cholesterol in mole ratio of 3:1 to 1:3 and wherein either or both are in an
amorphous or polymorphous form;
(b) exposing said particles to an atmosphere saturated with
acetone and water;
(c) repeating step (b);
(d) exposing said particles to an atmosphere saturated with
ethanol and water;
(e) drying the particles; and
(f) recovering said particles;
wherein the Estradiol Dissolution Rate of the recovered particles is less than 20 %.

I CLAIM:
1. A method for making a slow release estradiol formulation comprising:
(a) creating particles consisting essentially of estradiol and
cholesterol in mole ratio of 3:1 to 1:3 and wherein either or both are in an
amorphous or polymorphous form;
(b) exposing said particles to an atmosphere saturated with
acetone and water;
(c) repeating step (b);
(d) exposing said particles to an atmosphere saturated with
ethanol and water;
(e) drying the particles; and
(f) recovering said particles;
wherein the Estradiol Dissolution Rate of the recovered particles is less than 20 %.
2. The method as claimed in claim 1, wherein the acetone and water
mixture is 65 mole % to 80 mole % acetone and 20 mole % to 35 mole %
water.
3. The method as claimed in claim 1, wherein the ethanol and water
mixture is 95 - 99 mole % ethanol and 5-1 mole % water.
4. The method as claimed in claim 1, wherein step (b) is performed over
at least 24 hours, and step (c) is performed twice.
5. A method for making a slow release estradiol formulation comprising:

(a) creating particles consisting essentially of estradiol and
cholesterol in mole ratio of 1:1 and wherein either or both are in an
amorphous or polymorphous form;
(b) exposing said particles to an atmosphere saturated with
acetone and water for three consecutive stages;
(c) exposing said particles to an atmosphere saturated with
ethanol and water;
(d) drying the particles at 40 - 50°C for at least 24 hours; and
(e) recovering said particles;
wherein the Estradiol Dissolution Rate of the recovered particles is 18% or less.
6. The method as claimed in claim 5, wherein the acetone and water
mixture is 70 - 75 mole % acetone and 25 - 30 mole % water.
7. The method as claimed in claim 5, wherein the ethanol and water
mixture is 95 - 99 mole % ethanol and 5-1 mole % water.
8. A pharmaceutical formulation in unit dose form comprising:
(a) 5 mg to 15 mg 17-p-estradiol admixed with cholesterol in
a molar ratio of 3:1 to 1:3; and
(b) 200 mg to 500 mg progesterone,
wherein the weight ratio of 17-p-estradiol to progesterone is between 1:13 to 1:100; and wherein the 17-p-estradiol consists of a hemicrystalline form that is 50-60% amorphous and 40-50% crystalline; and the Estradiol Dissolution Rate of the formulation is 20% or less.
9. The pharmaceutical formulation as claimed in claim 8, wherein the
17-p-estradiol consists of a hemicrystalline form that is 55% amorphous
and 45% crystalline.
10. The pharmaceutical formulation as claimed in claim 8, wherein the
Estradiol Dissolution Rate is 6% or less.
11. The pharmaceutical formulation as claimed in claim 8, wherein the
estradiol/ cholesterol admixture and the progesterone are formulated as
microspheres of 35 to 75 nm diameter.

12. Microspheres of estradiol and cholesterol in 1:1 molar ratio having an
Estradiol Dissolution Rate of 6% or less.
13. The microspheres as claimed in claim 12., having an X-ray
crystallographic spectra substantially the same as Figure 22.
14. The microspheres as claimed in claim 12, wherein the estradiol
consists of a hemicrystalline form where 50-60% is amorphous and 40-50%
is crystalline.
15. The microspheres as claimed in claim 12, wherein the estradiol is in a
hemicrystalline form that is 55% amorphous and 45% crystalline.
16. The microspheres as claimed in claim 12, wherein the estradiol is 17-
p-estradiol.
17. A pharmaceutical formulation comprising a contraceptive-effective and
hormone-replacement-effective amount of 17-ß-estradiol and progesterone
in a weight ratio .of from 1:13 to 1:100; and wherein the 17-ß-estradiol is
compounded in discrete particles in admixture with cholesterol.
18. The formulation as claimed in claim 17, wherein the weight ratio of
17-p-estradiol:progesterone is 9:400.
19. The formulation as claimed in claim 17, wherein the 17-ß-estradiol
and cholesterol are compounded in a 1:1 molar ratio into microspheres, and
the progesterone is separately compounded into discrete microspheres.
20. The formulation as claimed in claim 19, wherein the microspheres
have a diameter of between 25 µm and 105 µm.
21. The method as claimed in claim 1, wherein the molar ratio of estradiol
to cholesterol is from 1:2 to 2:1.
22. The method as claimed in claim 1, wherein the molar ratio of estradiol
to cholesterol is 1:1.
23. The method as claimed in claim 1, further comprising exposing said
particles to an atmosphere saturated with ethanol and water.
24. The method as claimed in claim 1, wherein the step of exposing the
particles to an atmosphere saturated with acetone and water occurs over 72
hours at 60°C.
25. The method as claimed in claim 1, wherein the mole ratio of estradiol
to cholesterol is 1:1.
26. The formulation as claimed in claim 8, wherein the mole ratio of 17-ß
estradiol to cholesterol is 1:1.
27. The formulation as claimed in claim 8, wherein the weight ratio of 17-
ß-estradiol to progesterone is 9:400.
28. The formulation as claimed in claim 8, comprising 9 mg of 17-ß-
estradiol and 400 mg of progesterone.
29. The formulation as claimed in claim 8, wherein the 17-ß-estradiol and
cholesterol are in admixture in discrete particles, and the progesterone is in
separate and discrete particles.
30. The formulation as claimed in claim 8, wherein the
estradiol/cholesterol particles and the progesterone particles are all in the
form of microspheres having diameter of 25 µm to 125 µm.
31. The formulation as claimed in claim 30, wherein the microspheres
have a diameter of 35 µm to 75 µm.
32. A method for making a slow release estradiol formulation
substantially as herein described with reference to foregoing description.
33. A pharmaceutical formulation in unit dose form substantially as
herein described with reference to foregoing description.

Documents:

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Patent Number

278115

Indian Patent Application Number

2777/DELNP/2009

PG Journal Number

52/2016

Publication Date

16-Dec-2016

Grant Date

14-Dec-2016

Date of Filing

27-Apr-2009

Name of Patentee

SKENDI FINANCE LTD.

Applicant Address

AKARA BUILDING, 24 DE CASTRO STREET, WICKHAMS CAY I ROAD TOWN, TORTOLA BRITISH VIRGIN ISLANDS

Inventors:

#	Inventor's Name	Inventor's Address
1	JOHN CLAUDE SAVOIR	AV. PROGRESO #44, COYOACAN, MEXICO 04100, MEXICO.
2	JUAN ANGELES URIBE	VALLE DE CUERNO 81, VALLE DE ARAGON, NEZAHUALCOYOTL, MEXICO 57000, MEXICO.

PCT International Classification Number

A61K 9/14

PCT International Application Number

PCT/IB2004/001930

PCT International Filing date

2004-06-10

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	60/477,939	2003-06-13	U.S.A.