COMMERCIAL SCALE PRODUCTION METHODS FOR TRANSDERMAL HORMONE FORMULATIONS

• US 20120046264A1
• Filed: 08/17/2011
• Published: 02/23/2012
• Est. Priority Date: 08/17/2010
• Status: Abandoned Application

• Current Assignee: ANI Pharmaceuticals, Inc.
• Original Assignee: BioSante Pharmaceuticals, Inc.
• Inventors: Simes, Stephen, Lieb, Linda
• Application Number:
  US13/212,051
• Publication Number:
  US 20120046264A1
• Time in Patent Office: Days
• US Class Current: 514/180
• CPC Class Codes: A61K 31/565 not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• CPC Class Codes: A61K 31/566 having an oxo group in position 17, e.g. estrone
• CPC Class Codes: A61K 31/568 substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
• 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 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/18 Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• CPC Class Codes: A61K 47/183 Amino acids, e.g. glycine, EDTA or aspartame
• 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 9/0014 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: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives

Abstract

Methods for commercial production of transdermal formulations comprising a hormone compound are provided. In particular, methods for commercial scale production under an inert atmosphere of a transdermal formulation comprising a therapeutically effective amount of a hormone, preferably a testosterone compound, useful for the treatment of hypoactive sexual desire disorder (HSDD) in postmenopausal women are provided.

Claims

1. A method for commercial scale production under an inert atmosphere of a transdermal formulation comprising a therapeutically effective amount of a hormone, the method comprising the steps of:

dissolving a polyalcohol in an amount between 1% and 10% by weight of the formulation and a permeation enhancer in an amount between 1% and 30% by weight of the formulation in an alkanol in an inert atmosphere to form a stirred solution;

adding the therapeutically effective amount of the hormone to the stirred solution to form a hormone solution;

adding purified water to the hormone solution to form a hydroalcoholic mixture;

adding to the hydroalcoholic mixture a sequestering agent in an amount between 0.03% and 0.09% by weight of the formulation to form a second solution;

adding a gelling agent to the second solution in an amount between 0.5% and 10% by weight of the formulation to form a primary compounding solution having viscosity between 16,000 and 40,000 cps; and

adding a pH regulator in an amount between 0.2% and 0.5% by weight of the formulation to the primary compounding solution to adjust the pH to between 5 and 7 to form the transdermal hormone formulation.

2. The method according to claim 1, further comprising collecting the transdermal hormone formulation.

3. The method according to claim 1, wherein the hormone is an estrogen selected from the group consisting of estrogen, 17-beta-estradiol and esters thereof, ethinylestradiol, estriol (trihydroxyestrin), estrone, conjugated estrogens, in particular premarin, sodium estrone sulfate, 8(9)-dehydroestradiol derivatives, 17alfa-dihydroequilin, equilenin, 17alfa-dihydroequilenin, esterified estrogens, and equilin.

4. The method according to claim 1, wherein the hormone is a progesterone selected from the group consisting of progesterone, norethisterone acetate, norgestrel, levonorgestrel, gestodene, CPA, chlormadinone acetate, drospirorenone, and 3-ketodesogestrel.

5. The method according to claim 1, wherein the hormone is a testosterone compound selected from the group consisting of testosterone (17-β

-hydroxyandrostenone), testosterone enanthate, testosterone propionate, testosterone decanoate, testosterone cypionate, methyl testosterone, testolactone, oxymetholone, fluoxymesterone and enanthate, propionate, cypionate, phenylacetate, acetate, isobutyrate, buciclate, heptanoate, decanoate, undecanoate, caprate and isocaprate esters of testosterone and 4-dihydrotestosterone.

6. The method according to claim 5, wherein the therapeutically effective amount of the testosterone compound is between about 0.50% and 2.00% by weight of the formulation.

7. The method according to claim 6, wherein the therapeutically effective amount of the testosterone compound is between about 0.75% and 1.25% by weight of the formulation.

8. The method according to claim 7, wherein the therapeutically effective amount of the testosterone compound is about 1.00% by weight of the formulation.

9. The method accordingly to claim 8, wherein the testosterone compound is testosterone.

10. The method according to claim 1, wherein the alkanol is a C₂ to C₄ alcohol selected from the group consisting of ethanol, isopropanol, and n-propanol, and is present in an amount between 35% and 55% by weight of the formulation.

11. The method according to claim 1, wherein the polyalcohol is propylene glycol, butylene glycol, hexylene glycol, or ethylene glycol,

12. The method according to claim 1, wherein the permeation enhancer is diethylene glycol monoethyl ether, diethylene glycol monomethyl ether, or mixtures thereof.

13. The method according to claim 1, wherein the sequestering agent is an edetic acid in the form of edentate disodium.

14. The method according to claim 1, wherein the gelling agent is a polyacrylic acid Carbomer selected from the group consisting of Carbomer, Carbopol 980 or 940 NF, 981 or 941 NF, 1382 or 1342 NF, and 5984 or 934 NF.

15. The method according to claim 1, wherein the pH regulator is triethanolamine, tromethamine, tetrahydroxypropylethylendiamine, or a NaOH solution.

16. The method according to claim 9, wherein the alkanol is a C₂ to C₄ alcohol selected from the group consisting of ethanol, isopropanol, and n-propanol, the polyalcohol is polypropylene glycol, the permeation enhancer is diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, or mixtures thereof, the gelling agent is Carbomer, Carbopol 980, and the pH regulator is triethanolamine.

17. The method according to claim 15, which further comprises transferring the collected transdermal testeosterone formulation to a holding vessel.

18. The method according to claim 15, which further comprises transferring the harvested transdermal testeosterone formulation to a metered dosage device.

19. The method according to claim 18, wherein the metered dosage device accurately controls the administration of testosterone compound by dispensing a precise amount of testosterone for self administration upon a transdermal surface of the subject.

20. A method for producing under an inert atmosphere a 500 kilogram batch of a transdermal formulation comprising a therapeutically effective amount of a testosterone compound, the method comprising the steps of:

dissolving 5.0 kilograms of a testosterone compound, 25 kilograms of propylene glycol and 30 kilograms diethylene glycol monoethyl ether in 223 kg of stirred 200 proof ethanol to form a stirred solution;

adding 168 kg purified water to the stirred solution to form a hydroalcoholic mixture;

adding to the hydroalcoholic mixture while stirring 300 grams of edetate disodium dissolved in 10 kg purified water to form a second solution;

adding 6.0 kilograms of Carbomer Carbopol 980 to the second solution to form a third solution having viscosity between 22,000 and 25,000 cps;

adding 7.64 kilograms of triethanolamine to the third solution to adjust the pH to between 5 and 7 to form the transdermal testosterone formulation; and

collecting about 500 kilograms of the transdermal testosterone formulation.