Pharmaceutical formulation for contraception and hormone-replacement therapy

• US 7,589,082 B2
• Filed: 06/10/2004
• Issued: 09/15/2009
• Est. Priority Date: 06/13/2003
• Status: Expired due to Fees

• Current Assignee: Skendi Finance, Ltd.
• Original Assignee: Skendi Finance, Ltd.
• Inventors: Uribe, Juan Angeles, Savoir, John Claude
• Primary Examiner(s): HUI, SAN MING R
• Application Number:
  US10/864,470
• Publication Number:
  US 20050025827A1
• Time in Patent Office: 1,923 Days
• Field of Search: 514/170, 424/401
• US Class Current: 514/170
• 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 effecting simultaneous contraception and hormone replacement therapy in a female mammal comprising administering to said mammal a pharmaceutical formulation comprising particles of 17-β

-estradiol and cholesterol in about a 1;

1 molar ratio, and particles of progesterone;

wherein the weight ratio of 17-β

-estradiol to progesterone is about 1;

40, and wherein the 17-β

-estradiol is about 50-60% amorphous and about 40-50% crystalline.

2. The method of claim 1, wherein the pharmaceutical formulation has an EDR of about 10% or less.

3. The method of claim 1, wherein the pharmaceutical formulation has an EDR of about 6% or less.

4. The method of claim 1, wherein the pharmaceutical formulation comprises about 5 to about 15 mg of 17-β

-estradiol and about 300 to about 500 mg progesterone.

5. The method of claim 1, wherein the 17-β

-estradiol of the pharmaceutical formulation is about 55% amorphous and about 45% crystalline.

6. The method of claim 1, wherein the administration is by intramuscular injection.

7. The method of claim 1, wherein the formulation is administered about once a month or less frequently.

8. The method of claim 1, wherein the formulation is administered about once every other month.

9. The method of claim 1, wherein the mammal is a human.

10. A method for simultaneous contraception and hormone-replacement, the method comprising administering to a mammal in need of such therapy a pharmaceutical formulation comprising about 5 to about 15 mg 17-β

-estradiol that is 50-60% amorphous and 40-50% crystalline, and about 300 to about 500 mg progesterone.

11. The method of claim 10, wherein the administration of the pharmaceutical formulation is repeated at about one month.

12. The method of claim 10, wherein the pharmaceutical formulation is administered by intramuscular injection.

13. The method of claim 10, wherein the mammal is a human.

14. The method of claim 10, wherein the formulation comprises an aqueous suspension of microspheres consisting essentially of 17-β

-estradiol and cholesterol, and microspheres consisting essentially of progesterone.

15. The method of claim 14, wherein the 17-β

-estradiol and cholesterol are in a molar ratio of about 1;

1, and the weight ratio of 17-β

-estradiol to progesterone is about 9;

400.

16. A method for simultaneous contraception and hormone-replacement, the method comprising administering to a mammal a pharmaceutical formulation comprising particles consisting essentially of 17-β

-estradiol and cholesterol, and particles consisting essentially of progesterone; and

wherein the 17-β

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

40, and wherein the 17-β

-estradiol is 50-60% amorphous.

17. The method of claim 16, wherein the administration of the pharmaceutical formulation is repeated after about one complete menstrual cycle of the subject.

18. The method of claim 16, wherein the pharmaceutical formulation is administered by intramuscular injection.

19. The method of claim 16, wherein the mammal is a human and the administration of the formulation is repeated at about one month.

20. The method of claim 16, wherein the particles are microspheres having a diameter of between about 35 μ

m to about 75 μ

m.