PHARMACEUTICAL FORMULATION FOR CONTRACEPTION AND HORMONE-REPLACEMENT THERAPY

• US 20090081303A1
• Filed: 12/02/2008
• Published: 03/26/2009
• Est. Priority Date: 06/13/2003
• Status: Active Grant

• Current Assignee: Skendi Finance, Ltd.
• Original Assignee: Skendi Finance, Ltd.
• Inventors: Savoir, John Claude, Uribe, Juan Angeles
• Granted Patent: US 8,163,722 B2
• Time in Patent Office: Days
• US Class Current: 424/489
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/565 not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• CPC Class Codes: A61K 31/569 substituted in position 17 alpha, e.g. ethisterone
• CPC Class Codes: A61K 31/57 substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61K 9/006 Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• CPC Class Codes: A61K 9/0063 Periodont
• CPC Class Codes: A61K 9/141 Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers (co) spray-dried products A61K9/16, (co) lyophilised products A61K9/19; the carrier being chemically bound to the active ingredient A61K47/50
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1688 resulting in pure drug agglomerate optionally containing up to 5% of excipient
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/12 for climacteric disorders
• CPC Class Codes: A61P 15/18 Feminine contraceptives
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/24 of the sex hormones
• CPC Class Codes: A61P 5/30 Oestrogens

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.

Claims

1. A method for making a slow release estradiol formulation comprising:

(a) creating particles consisting essentially of estradiol and cholesterol

wherein either or both are in an amorphous or polymorphous form;

(b) exposing said particles to an atmosphere of about 25% RH or less for

at least about 12 hours;

(c) exposing the particles to an atmosphere saturated with acetone and

water for at least about 48 hours at about 50°

to about 65°

C.;

(d) drying the particles at about 35°

to about 50°

C. for about 24 hours or

more; and

(e) recovering said particles;

wherein the EDR of the recovered particles is less than about 15%.

2. The method of claim 1, wherein the estradiol is 17-β

-estradiol.

3. The method of claim 1, wherein the EDR is less than about 10%.

4. The method of claim 1, wherein the EDR is less than about 6%.

5. The method of claim 1, wherein the acetone/water atmosphere is about 72 mole % acetone and about 20 mole % water.

6. A method for making a slow release estradiol formulation comprising:

(a) creating particles consisting essentially of estradiol and cholesterol

wherein either or both are in an amorphous or polymorphous form;

(b) exposing said particles to an atmosphere of about 25% RH or less for

about 24 hours;

(c) exposing the particles to an atmosphere saturated with acetone and

water for about 72 hours at about 60°

C.;

(d) drying the particles at about 45°

C. for about 42 hours; and

(e) recovering said particles;

wherein the EDR of the recovered particles is less than about 6%.

7. The method of claim 6, wherein the estradiol is 17-β

-estradiol.

8. The method of claim 6, wherein the estradiol in the recovered particles is hemicrystalline 17-β

-estradiol that is about 55% amorphous and about 45% crystalline.

9. A method for making a slow release estradiol formulation comprising:

(a) creating particles consisting essentially of estradiol and cholesterol 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 EDR of the recovered particles is less than about 20%.

10. The method of claim 9, wherein the acetone and water mixture is about 95 mole % acetone and about 10 mole % water.

11. The method of claim 9, wherein the ethanol and water mixture is about 95 mole % ethanol and about 5 mole % water.

12. The method of claim 9, wherein step (b) is performed over about 24 hours, and step (c) is performed twice.

13. A method for making a slow release estradiol formulation comprising:

(a) creating particles consisting essentially of estradiol and cholesterol

wherein either or both are in an amorphous or polymorphous form;

(b) exposing said particles to an atmosphere saturated with acetone and

water at about 30°

C. for three consecutive stages of about 24 hours;

(c) exposing said particles to an atmosphere saturated with ethanol and

water for about two hours at about 30°

C.;

(d) drying the particles at about 45°

C. for about 42 hours; and

(e) recovering said particles;

wherein the EDR of the recovered particles is about 18% or less.

14. The method of claim 13, wherein the acetone and water mixture is about 95 mole % acetone and about 5 mole % water.

15. The method of claim 13, wherein the ethanol and water mixture is about 95 mole % ethanol and about 5 mole % water.

16. A pharmaceutical formulation comprising about 5 to about 15 mg 17-β

-estradiol admixed with cholesterol in about a 1;

1 molar ratio, and about 200 to about 500 mg progesterone;

wherein the weight ratio of 17-β

-estradiol to progesterone is about 1;

40;

the 17-β

-estradiol consists of a hemicrystalline form that is about 50-60% amorphous and about 40-50% crystalline; and

the EDR of the formulation is about 20% or less.

17. The pharmaceutical formulation of claim 16, wherein the 17-β

-estradiol consists of a hemicrystalline form that is about 55% amorphous and about 45% crystalline

18. The pharmaceutical formulation of claim 16, wherein the EDR is about 6% or less.

19. The pharmaceutical formulation of claim 16, wherein the estradiol/cholesterol admixture and the progesterone are formulated as microspheres of about 35 to about 75 μ

m diameter.

20. Microspheres of estradiol and cholesterol in about 1:

1 molar ratio having an EDR of about 6% or less.

21. The microspheres of claim 20, having an X-ray crystallographic spectra substantially the same as FIG. 22.

22. The microspheres of claim 20, wherein the estradiol consists of a hemicrystalline form where about 50-60% is amorphous and about 40-50% is crystalline.

23. The microspheres of claim 20, wherein the estradiol is in a hemicrystalline form that is about 55% amorphous and about 45% crystalline.

24. The microspheres of claim 20, wherein the estradiol is 17-β

-estradiol.

25. A pharmaceutical formulation comprising a contraceptive-effective and hormone-replacement-effective amount of 17-β

-estradiol and progesterone in a weight ratio of about 1;

40; and

wherein the 17-β

-estradiol is compounded in discrete particles in admixture with cholesterol.

26. The formulation of claim 25, wherein the weight ratio of 17-β

-estradiol;

progesterone is 9;

400.

27. The formulation of claim 25, wherein the 17-β

-estradiol and cholesterol are compounded in a 1;

1 molar ratio into microspheres, and the progesterone is separately compounded into discrete miscrospheres.

28. The formulation of claim 27, wherein the microspheres have a diameter of between about 25 μ

m and about 105 μ

m.

29. A kit comprising a pharmaceutical formulation, the formulation comprising:

(1) a sterile package comprising a unit dose of a contraceptive-effective and hormone-replacement-effective amount of 17-β

-estradiol and progesterone compounded with cholesterol into a plurality of microspheres; and

(2) a sterile package comprising an aqueous vehicle for suspending the microspheres for parenteral administration.

30. The kit of claim 29, wherein the effective amount of the 17-β

-estradiol is about 9 mg.

31. The kit of claim 29, wherein the effective amount of the progesterone is about 400 mg.

32. The kit of claim 29, further comprising a means for parenterally administering the formulation.