Transdermal Therapeutic system containing estradiol

• US 20020012691A1
• Filed: 03/10/2000
• Published: 01/31/2002
• Est. Priority Date: 05/06/1993
• Status: Active Grant

• Current Assignee: Frank Seibertz, Michael Horstmann, Rainer Lichtenberger, Reinhold Meconi
• Original Assignee: Frank Seibertz, Michael Horstmann, Rainer Lichtenberger, Reinhold Meconi
• Inventors: Seibertz, Frank, Horstmann, Michael, Meconi, Reinhold, Lichtenberger, Rainer
• Granted Patent: US 6,521,250 B2
• Time in Patent Office: Days
• US Class Current: 424/443
• CPC Class Codes: A61K 31/565 not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• CPC Class Codes: A61K 9/7053 obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
• CPC Class Codes: A61K 9/7069 obtained otherwise than by reactions only involving carbon to carbon unsaturated bonds, e.g. polysiloxane, polyesters, polyurethane, polyethylene oxide
• CPC Class Codes: A61K 9/7076 the adhesive comprising ingredients of undetermined constitution or reaction products thereof, e.g. rosin or other plant resins
• CPC Class Codes: A61P 5/30 Oestrogens

Abstract

An active-substance-containing transdermal therapeutic system for the controlled release of estradiol or its pharmaceutically acceptable derivatives alone or combined with gestagens consisting of a backing layer, an active-substance-containing reservoir which is bonded thereto and produced by using pressure sensitive adhesives, and a removable protective layer is characterized by the fact that the pressure sensitive adhesive comprises esters of colophony.

Claims

1. An active-substance-containing transdermal therapeutic system for the controlled release of estradiol or its pharmaceutically acceptable derivatives alone or combined with gestagens consisting of a backing layer, an active-substance-containing reservoir which is bonded thereto and produced by using pressure sensitive adhesives, and a removable protective layer, characterized in that the pressure sensitive adhesive comprises esters of colophony.

2. The transdermal therapeutic system according to claim 1 comprising the active substances estradiol and levonorgestrel, characterized in that the active layer of the system comprises a styrene-isoprene block copolymer and hydrogenated resin acids or their derivatives in addition to the active substances.

3. The transdermal therapeutic system according to claim 1 characterized in that the pressure sensitive adhesive comprises esters of colophony at a proportion of 55-92%-wt.

4. The transdermal therapeutic system according to claim 1 characterized in that the pressure sensitive adhesive comprises esters of colophony at a proportion of 60-90%-wt.

5. The transdermal therapeutic system according to claim 1 characterized in that the pressure sensitive adhesive comprises esters of colophony at a proportion of 70-88%-wt.

6. The transdermal therapeutic system according to any one of claims 1 to 5 characterized in that esters of colophony are selected from the group consisting of methyl ester, glycerol ester, pentaerythritol ester, pentaerythritol ester modified with maleic acid, glycerol ester modified with maleic acid, and triethylene glycol ester.

7. The transdermal therapeutic system according to claim 1 or 2 characterized in that the concentration of estradiol in the active layer amounts to between 0.2 and 2 percent by weight, preferably between 0.7 and 1.4 percent by weight.

8. The transdermal therapeutic system according to claim 1 or 2 characterized in that the concentration of levonorgestrel in the active layer amounts to between 0.1 and 1.6 percent by weight.

13. The transdermal therapeutic system according to one or several of claims 1 to 12 characterized in that the pressure sensitive adhesive comprises esters of hydrogenated colophony.

14. The transdermal therapeutic system according to one or several of claims 1 to 13 characterized in that the pressure sensitive adhesive comprises polymers.

15. The transdermal therapeutic system according to one or several of claims 1 to 14 characterized in that the pressure sensitive adhesive comprises polymers at a concentration of 6-25%-wt. and that these are selected from the group consisting of styrene-butadiene-styrene block copolymers, styrene-isoprene-styrene block copolymers, styrene-ethylene-butylene-styrene block copolymers, ethylene-vinyl acetate copolymers, polyvinyl pyrrolidone, and cellulose derivatives, as well as polymers based on acrylic acid and methacrylic acid derivatives.

16. The transdermal therapeutic system according to one or several of claims 1 to 15 characterized in that the reservoir comprises estradiol or its pharmaceutically acceptable derivatives alone or in combination with gestagens at a concentration totalling 2-15%-wt., that is at a molar ratio of 1:

1 to 1;

10.

17. The transdermal therapeutic system according to one or several of claims 1 to 16 characterized in that the reservoir comprises at least one component from the group consisting of anti-ageing agents, plasticizers, antioxidants, and absorption improvers, with the plasticizer being contained at a concentration of 0-5%-wt. and the anti-ageing agent being contained at a concentration of 0.1%-wt.

18. The transdermal therapeutic system according to one or several of claims 1 to 17 characterized in that the pressure sensitive adhesive is a solvent-based pressure sensitive adhesive.

19. The transdermal therapeutic system according to one or several of claims 1 to 18 characterized in that the pressure sensitive adhesive is a hot-melt pressure sensitive adhesive.

20. The transdermal therapeutic system according to one or several of claims 1 to 19 characterized in that the reservoir consists of several layers.

21. The transdermal therapeutic system according to one or several of claims 1 to 20 characterized in that the reservoir is provided with an additional pressure sensitive adhesive layer or with a pressure sensitive adhesive edge.

22. The transdermal therapeutic system according to one or several of claims 1 to 21 characterized in that a membrane which controls the active substance release is located between the reservoir and the pressure sensitive adhesive layer.

23. A process for the production of a transdermal therapeutic system as defined in any one of the preceding claims, characterized in that it comprises the following steps:

kneading the mixture of esters of colophony at an elevated temperature until homogenization, incorporating active substance(s) and at least one polymer at the solution temperature, coating a removable protective layer with the active-substance-containing adhesive mass after homogenization, and laminating the backing layer.

24. The use of the active-substance-containing patch according to any one of claims 1 to 22 for therapeutic purposes in human and veterinary medicine

9. The transdermal therapeutic system according to one or several of the preceding claims characterized in that the layer thickness of the active layer amounts to between 30 and 300 μ

m, preferably between 70 and 120 μ

m.

10. The transdermal therapeutic system according to one or sever of the preceding claims characterized in that the proportion of styrene-isoprene block copolymer in the active layer amounts to 10 to 45 percent by weight, preferably 15 to 33 percent by weight.

11. The transdermal therapeutic system according to one or several of the preceding claims characterized in that it comprises one or both of the combination partners, levonorgestrel or estradiol, partially in suspension.

12. The transdermal therapeutic system according to one or several of the preceding claims characterized in that part of the estradiol is present in the transdermal therapeutic system in the form of estradiol crystals, with the estradiol crystals substantially consisting of precipitated estradiol anhydrate.