Therapeutical system for transdermal delivery of levonorgestrel

• US 6,555,131 B1
• Filed: 03/09/2000
• Issued: 04/29/2003
• Est. Priority Date: 07/04/1997
• Status: Expired due to Fees

• Current Assignee: Schwarz Pharma Ag (Schwarz Pharma)
• Original Assignee: Schwarz Pharma Ag (Schwarz Pharma)
• Inventors: Wolff, Hans-Michael, Arth, Christoph
• Primary Examiner(s): Azpuru, Carlos
• Assistant Examiner(s): GHALI, ISIS A D
• Application Number:
  US09/462,009
• Time in Patent Office: 1,146 Days
• Field of Search: 424/449, 424/448, 424/443
• US Class Current: 424/449
• CPC Class Codes: A61F 13/00 Bandages or dressings radioactive dressings A61N5/1029; Absorbent pads
• 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 9/7061 Polyacrylates
• CPC Class Codes: A61P 15/12 for climacteric disorders

Abstract

A stable therapeutical transdermal system for the transcutaneous delivery of levonorgestrel, alone or together with other sex steroid hormones, over a long time period is disclosed. A method of producing the transdermal system that avoids the use of solvents and avoids degradation of the steroid hormones also is disclosed.

Claims

1. A transdermal therapeutic system for transcutaneous administration of levonorgestrel and additional optional sex steroids over a period of up to seven days, wherein the system comprises a layer of a steroid-containing matrix composition disposed on a carrier film, said matrix composition comprising a solid solution of (a) a copolymer of ethyl acrylate and methyl methacrylate containing about 5% trimethylammonium ethyl methacrylate chloride as the sole (meth)acrylate copolymer, (b) about 20 weight percent to about 30 weight percent of one or more plasticizers selected from the group consisting of esters of weak organic acids, (c) an optional fatty acid ester, and (d) at least 2 weight percent of levonorgestrel and each optional sex steroid distributed in the matrix composition as a molecular dispersion, wherein the system contains at least one sex steroid hormone which had minimum thermal exposure, and wherein the system is free of an adhesive layer.

3. The system of claims 1 and 2 wherein, with the exception of a release surface on the skin, the system is surrounded by a larger active-ingredient-free skin plaster for attachment at an application site.

4. The system of claims 1 and 2 wherein the steroid-hormone-containing matrix contains citric acid triester as the plasticizer.

5. The system of claims 1 and 2 wherein the steroid-hormone-containing matrix contains an ester of oleic acid or nonanoic acid as the fatty acid ester.

6. The system of claims 1 and 2 wherein the system contains estrogens or gestagens alone or in combination.

7. The system of claims 1 and 2 wherein the carrier film has a metal vapor or oxide coating on the matrix side.

8. The system of claims 1 and 2 wherein the system is free of a rate-controlling polymer layer for delivery of the sex steroids.

9. A method of producing a transdermal therapeutic system of claim 1 or 2 comprising:

(a) forming a solid mixture comprising (i) levonorgestrel and additional optional sex steroids and (ii) a copolymer of ethyl acrylate and methyl methacrylate containing about 5% trimethylammonium ethyl methacrylate chloride as the sole (meth)acrylate copolymer;

(b) forming a liquid mixture comprising at least one plasticizer and an optional fatty acid ester;

(c) continuously melt coextruding the solid mixture of step (a) and the liquid mixture of step (b) at a temperature sufficiently low and for a time sufficiently short to maintain the levonorgestrel and optional sex steroids in a nonmolten form to form a matrix composition, and continuously applying the matrix composition onto a protective film to a thickness of 0.02 to 4 mm; and

(d) applying a carrier film on a surface of the matrix composition opposite from the protective film.

10. The method of claim 9 wherein a larger sex steroid-free plaster is applied to the transdermal therapeutic system to provide a cover layer for attaching the system to skin.

11. The method of claim 9 wherein the optional sex steroid is estradiol.

12. The method of claim 11 wherein the melt coextrusion temperature is about 150°

C.

13. The method of claim 9 wherein the protective film comprises a silicone-coated polyester film.

14. The method of claim 9 wherein the carrier film comprises a polyester film.

2. A transdermal therapeutic system for the transcutaneous administration of levonorgestrel over a period of up to seven days, wherein the system comprises a layer form of a levonorgestrel-containing matrix composition disposed on a carrier film, said matrix composition comprising (a) a copolymer of ethyl acrylate and methyl methacrylate containing about 5% trimethylammonium ethyl methacrylate chloride as the sole (meth)acrylate copolymer, (b) about 20 weight percent to about 30 weight percent of at least one plasticizer selected from the group consisting of esters of weak organic acids, (c) an optional fatty acid ester, and (d) at least 2 weight percent of levonorgestrel distributed in the matrix composition in a molecularly dispersed form, wherein the levonorgestrel had minimum thermal exposure, and wherein the system is free of an adhesive layer.

15. A transdermal therapeutic system for the transcutaneous administration of levonorgestrel and additional optional sex steroids over a period of up to seven days, wherein the system comprises a layer form of a levonorgestrel-containing matrix composition disposed on a carrier film, said matrix composition consisting essentially of (a) a copolymer of ethyl acrylate and methyl methacrylate containing about 5% trimethylammonium ethyl methacrylate polymer as the sole (meth)acrylate copolymer, (b) about 20 weight percent to about 30 weight percent of at least one plasticizer selected from the group consisting of esters of weak organic acids, (c) an optional fatty acid ester, and (d) at least 2 weight percent of levonorgestrel distributed in the matrix composition in a molecularly dispersed form, wherein the levonorgestrel had minimum thermal exposure, and wherein the system is free of an adhesive layer,

said system prepared by a method comprising:

(a) forming a solid mixture comprising the levonorgestrel, optional sex steroids, and the ethyl acrylate and methyl methacrylate copolymer;

(b) forming a liquid mixture comprising at least one plasticizer and an optional fatty acid ester;

(c) continuously melt coextruding the solid mixture of step (a) and the liquid mixture of step (b) at a temperature sufficiently low and for a time sufficiently short to maintain the levonorgestrel in a nonmolten form to form the matrix composition, and continuously applying the matrix composition onto a protective film to a thickness of 0.02 to 4 mm; and

(d) applying a carrier film on a surface of the matrix composition opposite from the protective film.