Transdermal therapeutic system containing estradiol

• US 6,521,250 B2
• Filed: 03/10/2000
• Issued: 02/18/2003
• Est. Priority Date: 05/06/1993
• Status: Expired due to Term

• Current Assignee: LTS Lohmann Therapie-Systeme GmbH, Merck Patent GmbH (Merck & Co., Inc.)
• Original Assignee: LTS Lohmann Therapie-Systeme GmbH, Merck Patent GmbH (Merck & Co., Inc.)
• Inventors: Seibertz, Frank, Lichtenberger, Rainer, Horstmann, Michael, Meconi, Reinhold
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): HOWARD, SHARON LEE
• Application Number:
  US09/522,925
• Publication Number:
  US 20020012691A1
• Time in Patent Office: 1,075 Days
• Field of Search: 424/443, 424/448, 424/449
• 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 able derivatives alone or combined with gestagens consisting of a 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. A transdermal therapeutic system for the controlled release of estradiol or a pharmaceutically acceptable derivative thereof, said system comprising a backing layer;

an active-substance-containing reservoir which is bonded to the backing layer and which comprises pressure sensitive adhesive and estradiol or a pharmaceutically acceptable derivative thereof combined with a gestagen; and

a removable protective layer, wherein the pressure sensitive adhesive comprises

(a) a styrene-isoprene block copolymer, and

(b) a hydrogenated resin acid or its derivatives in an amount of 55-92% wt.

2. The transdermal therapeutic system according to claim 1, wherein the pressure sensitive adhesive comprises the hydrogenated resin acid or its derivatives in an amount of 60-90% wt.

3. The transdermal therapeutic system according to claim 1, wherein the pressure sensitive adhesive comprises the hydrogenated resin acid or its derivatives in an amount of 70-88% wt.

4. The transdermal therapeutic system according to claim 1, wherein the active-substance-containing reservoir comprises the active substances estradiol and levonorgestrel, as the gestagen, wherein the polymer is styrene-isoprene block copolymer.

5. The transdermal therapeutic system according to claim 1, wherein the derivatives of the hydrogenated acid resins are esters selected from the group consisting of methyl ester, glycerol ester, pentaerythritol ester, pentaerythritol ester modified with maleic add, glycerol ester modified with maleic acid, and triethylene glycol ester.

6. The transdermal therapeutic system according to claim 1, wherein the concentration of estradiol or its pharmaceutically acceptable derivatives in the active-substance-containing reservoir is between 0.2 and 2 percent by weight.

7. The transdermal therapeutic system according to claim 6, wherein the concentration of the estradiol or its pharmaceutically acceptable derivative in the active-substance-containing reservoir is between 0.7 and 1.4 percent by weight.

8. The transdermal therapeutic system according to claim 4, wherein the concentration of levonorgestrel in the active-substance-containing reservoir is between 0.1 and 1.6 percent by weight.

9. The transdermal therapeutic system according to claim 1, wherein the active-substance-containing reservoir has a layer thickness between 30 and 300 μ

m.

10. The transdermal therapeutic system according to claim 9, wherein the thickness of the active-substance-containing reservoir is between 70 and 120 μ

m.

11. The transdermal therapeutic system according to claim 4, wherein the amount of styrene-isoprene block copolymer in the active-substance-containing reservoir is 10 to 45 percent by weight.

12. The transdermal therapeutic system according to claim 11, wherein the amount of the styrene-isoprene block copolymer in the active-substance-containing reservoir is 15 to 33 percent by weight.

13. The transdermal therapeutic system according to claim 1, wherein at least one of the active substances, levonorgestrel as the gestagen or estradiol or its pharmaceutically acceptable derivative is present partially in suspension.

14. The transdermal therapeutic system according to claim 11, wherein part of the estradiol is present in the form of estradiol crystals, with the estradiol crystals substantially consisting of precipitated estradiol anhydrate.

15. The transdermal therapeutic system according to claim 11, wherein the hydrogenated resin acid or its derivative comprises esters of hydrogenated colophony.

16. The transdermal therapeutic system according to claim 1, wherein the reservoir comprises estradiol or a pharmaceutically acceptable derivative of estradiol in combination with a gestagen in a concentration totaling 2-15% wt., wherein the molar ratio of estradiol or its pharmaceutically acceptable derivative to the gestagen is 1:

1 to 1;

10.

17. The transdermal therapeutic system according to claim 1, wherein the reservoir comprises at least one component selected from the group consisting of an anti-ageing agent, a plasticizer, an antioxidant, and an absorption improver, with the plasticizer being contained in a concentration of 0-5% wt. and the anti-ageing agent being contained in a concentration of 0.1% wt.

18. The transdermal therapeutic system according to claim 1, wherein the pressure sensitive adhesive is a solvent-based pressure sensitive adhesive.

19. The transdermal therapeutic system according to claim 1, wherein the pressure sensitive adhesive is a hot-melt pressure sensitive adhesive.

20. The transdermal therapeutic system according to claim 11, wherein the reservoir consists of a plurality of layers.

21. The transdermal therapeutic system according to claim 1, wherein 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 claim 21, wherein a membrane which controls the active substance release is located between the reservoir and the additional pressure sensitive adhesive layer.

23. A process for the production of a transdermal therapeutic system as defined in claim 11, which comprises:

kneading a mixture of a hydrogenated resin acid or its derivatives at an elevated temperature until homogenization is achieved, incorporating the active substances and the polymer at the solution temperature, coating a removable protective layer with the resulting active-substance-containing adhesive mass after homogenization, and laminating a backing layer.

24. A method for the therapeutic treatment of a human or an animal which comprises applying to the skin of said human or animal a transdermal therapeutic system as defined in claim 11, in the form of a patch.