Transdermal estradiol/progestogen agent patch and its production

• US 6,153,216 A
• Filed: 09/14/1998
• Issued: 11/28/2000
• Est. Priority Date: 12/22/1995
• Status: Expired due to Fees

• Current Assignee: Rotta Research B.V.
• Original Assignee: Rotta Research B.V.
• Inventors: Cordes, Gunter, Setnikar, Ivo, Santoro, Antonino
• Primary Examiner(s): Clardy, S. Mark
• Assistant Examiner(s): Williamson, Michael A.
• Application Number:
  US09/091,395
• Time in Patent Office: 806 Days
• Field of Search: 424/448, 424/449, 514/731, 514/691, 682/41, 682/60, 604/892.1, 604/307
• US Class Current: 424/449
• CPC Class Codes: A61K 31/569 substituted in position 17 alpha, e.g. ethisterone
• CPC Class Codes: A61K 31/575 substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
• CPC Class Codes: A61K 9/7053 obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
• CPC Class Codes: A61K 9/7061 Polyacrylates
• 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

Abstract

The invention concerns a transdermal patch for the release through the skin of estradiol and a progestogen agent and a process for its production.

Claims

1. A transdermal patch for the release through the skin of estradiol and norethisterone acetate (NETA), consisting of an outer backing layers a matrix and a protective release liner, wherein the backing layer is impermeable to the drugs and supports the matrix, the matrix being a crosslinked pressure-sensitive adhesive copolymer matrix in which the active ingredients are dissolved or dispersed and wherein the matrix is covered by the protective release liner impermeable to the drugs that must be removed immediately before the application of the patch onto the skin, wherein said crosslinked pressure sensitive adhesive copolymer matrix is obtained by radical copolymerization of between 50 to 85% 2-ethylhexyl acrylate, 3.5 to 6.5% hydroxyethyl acrylate, 16 to 35% vinylacetate and up to 0.3% glycidyl methacrylate and, optionally, in the presence of substances including a cross-linking agent and a crystallization preventative, suitable to improve the stability and/or performance of the patch, and wherein estradiol and NETA are present in a supersaturated solid solution.

2. A transdermal patch according to claim 1, characterized in that

the backing layer includes a foil of a material impermeable to the active ingredients and to the adhesive copolymer matrix said material selected from the group consisting of polyester, polyurethane, polyethylene, polypropylene and polyvinylchloride materials;

and/or

the matrix-facing surface ofthe backing layer is lacquered, consisting of epoxy resin, polyaminoamido resins and precipitated calcium carbonate; and

the backing layer has a thickness between 10 to 50 μ

m.

3. A transdermal patch according to claim 1, characterized by said crosslinked pressure-sensitive adhesive matrix obtained by radical copolymerization of

2-ethylhexyl acrylate in a concentration of between 61 to 75%,

hydroxyethyl acrylate in a concentration of between 4.5 to 5.5%,

vinylacetate in a concentration of between 24 to 28%, and

glycidyl methacrylate up to a concentration of 0.1 to 0.2%, calculated as w/w based on the matrix.

4. A transdermal patch according to claim 1, characterized by said cross-linking substances being aluminum acetylacetonate, in quantities of between 0.4 to 0.7%.

5. A transdermal patch according to claim 1, characterized by said crystallization preventative being octyldodecanol, in quantities of between 1.3 to 3.5%.

6. A transdermal patch according to claim 1, characterized by a content of estradiol of between 0.6 to 1.8% (w/w in the adhesive matrix).

7. A transdermal patch according to claim 1, characterized by a content of norethisterone of between 4.0 to 10.0% (w/w in the matrix).

8. A transdermal patch according to claim 1, characterized by a content of other substances up to a concentration in the matrix of 2% suitable to improve the stability and/or the performance of the transdermal patch.

9. A transdermal patch according to claim 1, characterized in that the protective release liner is impermeable to the drugs and is

made of a foil of paper, polyester, polyethylene, polypropylene or polyvinylchloride;

and

having a thickness of 80 to 300 μ

m.

10. A transdermal patch according to claim 9, wherein the foil is coated with silicone on one or both sides.

11. A transdermal patch according to claim 1, characterized by a circular or an oval shape, and/or a surface of 20 to 300 cm² according to the required release rate of the active ingredients.

12. A transdermal patch according to claim 1, characterized in that it is sealed in a sachet made of a humidity impermeable multi-layered foil, and made of sheets of aluminum, paper, polyethylene or polyvinylchloride.

13. A transdermal patch according to claim 12, wherein the humidity impermeable multi-layered foil is made of a sheet of Surlyn®

material.

14. A transdermal patch according to claim 12, characterized in that it is sealed in a sachet together with a desiccant.

15. A transdermal patch according to claim 14, wherein the desiccant is silica gel, sodium sulfate or calcium sulfate.

16. A process for the production of a transdermal patch characterized by the following measures:

a solution ofthe crosslinked pressure-sensitive copolymer matrix and of estradiol and norethisterone acetate (NETA) as active ingredients is spread onto a foil that shall become the release liner, and

the solvents are evaporated, at a temperature of from 35 to 90°

C., at atmospheric pressure or under reduced pressure and then covered by a foil which shall become the backing layer;

or

the solution of the crosslinked pressure-sensitive copolymer matrix and of estradiol and the progestogen agent as active ingredients is spread on a silicone-coated intermediate liner made of paper or polyester,

the solvents are evaporated, at a temperature of from 35 to 90°

C., at atmospheric pressure or under reduced pressure,

a foil that shall become the protective release liner is stuck on the matrix supported by the intermediate liner, and

the matrix is transferred from the intermediate liner to the release liner and a foil that shall become the backing layer is stuck on the matrix supported by the release liner;

or

the solution of the crosslinked pressure-sensitive copolymer matrix and of estradiol and the progestogen agent as active ingredients is spread onto a foil that shall become the backing layer, and

the solvents are evaporated, at a temperature of from 35 to 90°

C., at atmospheric pressure or under reduced pressure and the release liner is stuck on the matrix supported by the backing layer.

17. A process according to claim 16, characterized in that the solvent is evaporated under dry air, at a temperature of from 35 to 90°

C.

18. A process according to claim 16, characterized in that the process is carried out under a flux of dry air.

19. A process according to claim 16, characterized by the following measures:

estradiol and norethisterone acetate (NETA) as active ingredients, octyldodecanol and the cross-linking substance, aluminum acetylacetonate, are dissolved or dispersed in methylethylketone or in a methylethylketone/ethanol mixture in proportions of from 2;

1 to 4;

1 (w/w);

the resulting solution or suspension is mixed, under stirring, with a solution or suspension of the crosslinked pressure-sensitive adhesive copolymers in ethylacetate; and

the resulting mixture is spread onto a foil according to claim 16.

20. A process according to claim 16, characterized in that the resulting patch is sealed into a sachet of a multi-layered humidity impermeable foil, made of a sheet of aluminum, paper, polyethylene or polyvinylchloride.

21. A process according to claim 20, characterized in that the patch is sealed in a sachet together with a desiccant.

22. A process according to claim 20, wherein the multi-layered humidity impermeable foil is made of a sheet of Surlyn®

material.

23. A process according to claim 21, wherein the desiccant is silica gel, sodium sulfate or calcium sulfate.