Estrogen compositions for vaginal administration

• US 20070004694A1
• Filed: 06/16/2006
• Published: 01/04/2007
• Est. Priority Date: 06/16/2005
• Status: Active Grant

• Current Assignee: Allergan Therapeutics LLC (Abbvie Incorporated)
• Original Assignee: Warner Chilcott Company Incorporated (Abbvie Incorporated)
• Inventors: Woolfson, David, Malcolm, Karl
• Granted Patent: US 10,016,442 B2
• Time in Patent Office: Days
• US Class Current: 514/182
• CPC Class Codes: A61K 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: A61K 31/565 not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/32 Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers , poly(meth)acrylates, or polyvinyl pyrrolidone
• CPC Class Codes: A61K 9/0034 Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
• CPC Class Codes: A61P 5/30 Oestrogens

Abstract

Pharmaceutical gel compositions containing estrogen for vaginal administration, as well as a method of making the same, are disclosed.

Claims

1. A pharmaceutical gel composition containing estrogen for vaginal administration comprising:

(a) at least one estrogen in an amount of about 0.00001% to about 2% by weight of the composition;

(b) at least one hydrogen-bonding gelation polymer; and

(c) at least one gelation promoter in an amount effective to gel said polymer and to substantially solubilize the estrogen, wherein at least a portion of the estrogen is dissolved in said composition at 15°

C.

2. The pharmaceutical gel composition of claim 1, wherein the at least one estrogen is selected from the group consisting of 17β

-estradiol, mestranol, conjugated estrogens USP, estrone and ethinyl estradiol, and salts, esters and prodrugs of any thereof.

3. The pharmaceutical gel composition of claim 1, wherein the amount of the at least one estrogen is from about 0.0005% to about 0.05% by weight of the composition.

4. The pharmaceutical gel composition of claim 3, wherein the amount of the at least one estrogen is from about 0.00075% to about 0.025% by weight of the composition.

5. The pharmaceutical gel composition of claim 1, wherein the at least one hydrogen-bonding gelation polymer is selected from the group consisting of homopolymers, copolymers and interpolymers having pendant carboxylic acid groups, having pendant anhydrides of dicarboxylic acid groups or having both, and esters of any thereof.

6. The pharmaceutical gel composition of claim 1, wherein the at least one hydrogen-bonding gelation polymer is present in an amount sufficient to form a gel with a viscosity ranging from about 50 Pa·

s to about 1000 Pa·

s at 20°

C.

7. The pharmaceutical gel composition of claim 1, wherein the at least one gelation promoter comprises an aqueous solution of the gelation promoter.

8. The pharmaceutical gel composition of claim 1, wherein the at least one gelation promoter is selected from the group consisting of polyhydric alcohols, polyglycols, and combinations thereof.

9. The pharmaceutical gel composition of claim 8, wherein the polyhydric alcohol is selected from the group consisting of 1,2-butanediol, 1,3-butanediol, 1,4-butanediol, butynediol, butenediol, diethylene glycol, ethylene glycol, glycerol, glycofurol, 1,2-hexanediol, 1,2,6-hexanetriol, 3-methyl-1,5-pentanediol, 2-methyl-1,3-propanediol, 1,9-nonanediol, 1,5-pentanediol, poly(vinyl alcohol), 1,3-propanediol, propylene glycol and combinations thereof.

10. The pharmaceutical gel composition of claim 8, wherein the polyglycol is selected from the group consisting of butyl glycol, butyl diglycol, butyl polyglycol, diethylene glycol monomethyl ether, diethylene glycol dimethyl ether, diethylene glycol monoethyl ether, diethylene glycol diethyl ether, dipropylene glycol, dipropylene glycol dimethyl ether, poloxamers, methyl diglycol, methyl triglycol, methyl tetraglycol, poly(ethylene glycol), poly(oxyethylene) alkyl ethers, poly(oxyethylene) alkyl esters, poly(propylene glycol), tetraethylene glycol dimethyl ether, triethylene glycol, triethyl glycol dimethyl ether, tripropylene glycol, glycol-silane copolymers and combinations thereof.

11. The pharmaceutical gel composition of claim 8, wherein the polyglycol is selected from the group consisting of polyoxyethylene, polyoxypropylene, a copolymer of polyoxyethylene and polyoxypropylene and combinations thereof.

12. The pharmaceutical gel composition of claim 1, wherein at least 50% of the estrogen is dissolved in said composition at 15°

C.

13. The pharmaceutical gel composition of claim 12, wherein at least 60% of the estrogen is dissolved in said composition at 15°

C.

14. The pharmaceutical gel composition of claim 13, wherein at least 90% of the estrogen is dissolved in said composition at 15°

C.

15. The pharmaceutical gel composition of claim 1, further comprising at least one pharmaceutically acceptable excipient.

16. The pharmaceutical gel composition of claim 1, further comprising at least one other active ingredient selected from the group consisting of progestogens and androgens.

17. The pharmaceutical gel composition of claim 16, wherein the progestogen is selected from the group consisting of progestogen, 17-hydroxy progestogen esters, 19-nor-17-hydroxy progestogen esters, norgestrel, norgestimate, desogestrel, demegestone, drospirenone, dydrogesterone, medrogestone, medroxy progesterone, medroxyprogesterone acetate, norethesterone, norethindrone, norethindrone acetate, levonorgestrel, 3-ketodesogestrel, gestodene and combinations thereof.

18. The pharmaceutical gel composition of claim 16, wherein the androgen is selected from the group consisting of testosterone, esters thereof, methyl-testosterone, prodrugs thereof and combinations thereof.

22. A method of vaginal administration of estrogen for a female comprising the step of administering the pharmaceutical gel composition of claim 1 to the vaginal epithelial tissue of the female.

19. A method of making a pharmaceutical gel composition containing estrogen for vaginal administration comprising the step of admixing at least one estrogen in an amount of about 0.00001% to about 2% by weight of the composition, at least one hydrogen-bonding gelation polymer, and at least one gelation promoter or aqueous solution thereof in an amount effective to substantially solubilize the estrogen and to gel the polymer to form the pharmaceutical gel composition, wherein at least a portion of the estrogen is dissolved in the composition at 15°

C.

20. The method of claim 19, wherein the admixing step comprises (a) substantially solubilizing the estrogen in the gelation promoter or in an aqueous solution thereof to form a substantially solubilized estrogen preparation and (b) combining the substantially solubilized estrogen preparation with the hydrogen-bonding gelation polymer to form the pharmaceutical gel composition.

21. A pharmaceutical gel composition made according to the method of claim 19.