TRANSDERMAL DELIVERY SYSTEM CONTAINING A DOPAMINE AGONIST

Abstract

The present invention relates to a transdermal delivery system (TDS) comprising at least one dopamine agonist, wherein the at least one dopamine agonist is present in a matrix containing at least one polymer from the class of polybutylene. The present invention also relates to a method for producing the TDS according to the invention and to the use of the TDS according to the invention.

Claims

1. A transdermal delivery system comprising at least one matrix comprising at least one dopamine agonist, an active ingredient-impermeable rear layer, and an optional application-side protective film, wherein the at least one matrix containing the at least one dopamine agonist comprises at least one polybutylene polymer.

2. The transdermal delivery system according to claim 1, wherein the dopamine agonist is rotigotine.

3. The transdermal delivery system according to claim 1, wherein the matrix containing the dopamine agonist also comprises at least one polymer selected from the group consisting of styrene-butadiene co-polymers and styrene-butadiene-styrene co-polymers.

4. The transdermal delivery system according to claim 1, wherein the at least one polybutylene polymer has a molecular weight of at least approximately 20,000 g/mol and/or of and at most approximately 100,000 g/mol.

5. The transdermal delivery system according to claim 1, further comprising a second polybutylene polymer has a molecular weight of at least approximately 500,000 g/mol and at most approximately 3,500,000 g/mol.

6. The transdermal delivery system according to claim 1, wherein a first polybutylene polymer from the at least one polybutylene polymer has a molecular weight of at least approximately 60,000 g/mol and at most approximately 75,000 g/mol, and a second polybutylene has a molecular weight of at least approximately 800,000 g/mol and/or of at most approximately 1,200,000 g/mol.

7. The transdermal delivery system according to claim 1, wherein the ratio of the proportions by weight of a first polybutylene polymer from the at least one polybutylene polymer and of a second polybutylene polymer is approximately 9 to approximately 0.1.

8. The transdermal delivery system according to claim 1, wherein the transdermal delivery system comprises at least one active ingredient-containing matrix, which contains at least one active ingredient.

9. The transdermal delivery system according to claim 1, wherein the at least one matrix contains a polyvinyl pyrrolidone.

10. The transdermal delivery system according to claim 1, wherein the at least one matrix contains a myristic acid isopropyl ester.

11. The transdermal delivery system according to claim 1, wherein the at least one matrix comprises 1-dodecanol.

12. The transdermal delivery system according to claim 1, wherein the at least one matrix comprises a co-polymer formed from vinyl pyrrolidone and vinyl acetate.

13. A method for producing a transdermal delivery system according to claim 1, comprising the steps: providing at least one dopamine agonist-containing matrix containing at least one polybutylene polymer, optionally applying the at least one dopamine agonist-containing matrix to a film in order to obtain a laminate comprising a dopamine agonist-containing matrix, optionally drying the laminate comprising the at least one dopamine agonist-containing matrix, optionally punching out transdermal delivery systems in order to obtain planar active ingredient cores, and optionally packaging transdermal delivery systems.

14. The transdermal delivery system according to claim 2, wherein the transdermal delivery system is obtainable by a method comprising the steps: providing at least one dopamine agonist-containing matrix containing at least one polymer from the class of polybutylenes, in particular polyisobutylenes, optionally applying the at least one dopamine agonist-containing matrix to a film in order to obtain a laminate comprising a dopamine agonist-containing matrix, optionally drying the laminate comprising the at least one dopamine agonist-containing matrix, optionally punching out transdermal delivery systems in order to obtain planar active ingredient cores, and optionally packaging transdermal delivery systems.

15. The transdermal delivery system according to claim 1, wherein the transdermal delivery system is packaged in a bag which contains a desiccant.

16-17. (canceled)

18. The transdermal delivery system according to claim 1, wherein the at least one polybutylene polymer is a polyisobutylene polymer.

19. The transdermal delivery system according to claim 4, wherein the at least one polybutylene polymer has a molecular weight of at least approximately 60,000 g/mol—and at most approximately 75,000 g/mol.

20. The transdermal delivery system according to claim 5, wherein the second polybutylene polymer has a molecular weight of at least approximately 800,000 g/mol and at most approximately 1,200,000 g/mol.

21. The transdermal delivery system according to claim 7, wherein the ratio of the proportions by weight of the first polybutylene polymer from the at least one polybutylene polymer and of the second polybutylene polymer is approximately 7 to approximately 0.5, in particular up to approximately 6 to approximately 1.

22. The transdermal delivery system according to claim 8, wherein the transdermal delivery system comprises at least two active ingredient-containing matricies.

Description

[0127] Further features of the invention result from the following description of practical examples in conjunction with the claims and the figures. It should be noted that the invention is not limited to the embodiments of the described practical examples, but instead is defined by the scope of the accompanying claims. In particular, the individual features in embodiments according to the invention may be implemented in a combination other than in the examples described below. In the following explanation of a number of practical examples of the invention, reference is made to the accompanying drawings. In the drawings:

[0128] FIG. 1 shows a graph illustrating the in vitro permeation of rotigotine base (μg/cm.sup.2) from a transdermal therapeutic system according to the invention as per Example 1 through bare mouse skin. The skin permeation was performed over a period of 24 hours (h).

[0129] FIG. 2 shows a graph illustrating the in vitro permeation of rotigotine base (μg/cm.sup.2) from a transdermal therapeutic system according to the invention as per Example 2 through bare mouse skin. The skin permeation was performed over a period of 24 hours (h).

EXAMPLES

[0130] The production of transdermal therapeutic systems in accordance with the present invention and also the permeation of the active ingredient through the skin performed by said systems will be described hereinafter.

Example 1

[0131] Composition of the TDS according to the invention (based on the dried matrix):

TABLE-US-00001 rotigotine base: 9% by weight PIB adhesive (DT 87-6908): 67% by weight  vinyl pyrrolidone-vinyl acetate 6% by weight co-polymer (Kollidon VA 64): PVP (Kollidon CL-M): 2% by weight isopropyl myristate: 8% by weight 1-dodecanol: 8% by weight

[0132] The solubility enhancer (the vinyl pyrrolidone-vinyl acetate co-polymer (Kollidon VA 64, BASF Germany, Ludwigshafen)) was dissolved in ethanol, and the polyvinyl pyrrolidone (Kollidon CL-M, BTC Europe GmbH, Germany) was stirred in. Rotigotine (Olon, Italy) was dissolved in tetrahydrofuran (THF, VWR, Germany), and isopropyl myristate (AppliChem, Germany) and 1-dodecanol (Sasol, Germany) were added and then homogenised. PIB adhesive (DT 87-6908, Henkel, Germany, mixing ratio of medium- to high-molecular: 85% by weight to 15% by weight) and THF were placed in a further vessel, and the previously prepared mixture was added and homogenised. The coating compound was then applied to a PE film siliconised on one side (Primeliner PET 75 μm 15, Loparex, Netherlands), dried at 60° C. for 15 min., and covered with a PETP film (Hostaphan MN 15 DMF, Mitsubishi Polyester Films, Germany). The resultant weight per unit area in the dried state was 50 mg/10 cm.sup.2.

Example 2

[0133] Composition of the TDS according to the invention (based on the dried matrix):

TABLE-US-00002 rotigotine base: 9% by weight PIB adhesive (DT 87-6908): 46.9% by weight SB adhesive (DT 87-6911): 20.1% by weight vinyl pyrrolidone-vinyl acetate 6% by weight co-polymer (Kollidon VA 64): PVP (Kollidon CL-M): 2% by weight isopropyl myristate: 8% by weight 1-dodecanol: 8% by weight

[0134] The solubility enhancer, (the vinyl pyrrolidone-vinyl acetate co-polymer (Kollidon VA 64, BASF Germany, Ludwigshafen)) was dissolved in ethanol, and the polyvinyl pyrrolidone (Kollidon CL-M, BTC Europe GmbH, Germany) was stirred in. Rotigotine (Olon, Italy) was dissolved in tetrahydrofuran (THF, VWR, Germany), and isopropyl myristate (AppliChem, Germany) and 1-dodecanol (Sasol, Germany) were added and then homogenised. PIB adhesive (DT 87-6908, Henkel, Germany, mixing ratio of medium- to high-molecular: 85% by weight to 15% by weight) and SB adhesive (DT-87-6911, Henkel, Germany) and THF were placed in a further vessel, and the previously prepared mixture was added and homogenised. The coating compound was then applied to a PE film siliconised on one side (Primeliner PET 75 μm 1S, Loparex, Netherlands), dried at 60° C. for 15 min., and covered with a PETP film (Hostaphan MN 15 DMF, Mitsubishi Polyester Films, Germany). The resultant weight per unit area in the dried state was 50 mg/10 cm.sup.2.

Execution of an In Vitro Skin Permeation of the TDS According to Examples 1 and 2:

[0135] In vitro skin permeations were performed on the basis of Franz cells, in which the donor and the acceptor chamber are separated from one another vertically by a mouse skin (bare mouse skin, Harlan Laboratories, Netherlands). For preparation of the donor side, the skin was moistened with acceptor medium (phosphate buffer 50 mM, pH 6) and applied to the opening of the Franz cell (opening area 0.98 cm.sup.2). The TDS according to Example 1 or Example 2 was punched out, in each case in a size of 0.98 cm.sup.2, and applied centrally to the skin.

[0136] A magnetic stir bar was introduced into the acceptor chamber filled with acceptor medium. The cells were sealed shut and fixed on a heatable magnetic stirrer (32° C.). Samples were removed at defined points in time with the aid of an automated device and were then examined by means of HPLC in respect of their rotigotine content. The permeated amounts of rotigotine are shown in FIG. 1 and FIG. 2.