Combination of a transdermal therapeutic system and an oral and/or parenteral preparation containing dopamine agonists for the treatment of dopaminergic disease states

• US 7,258,871 B2
• Filed: 08/24/2001
• Issued: 08/21/2007
• Est. Priority Date: 10/20/2000
• Status: Expired due to Fees

• Current Assignee: Axxonis Pharma AG
• Original Assignee: NeuroBiotec GmbH
• Inventors: Tack, Johannes, Horowski, Reinhard
• Primary Examiner(s): Hartley; Michael G.
• Assistant Examiner(s): Oh; Simon J.
• Application Number:
  US10/362,182
• Publication Number:
  US 20040092544A1
• Time in Patent Office: 2,188 Days
• Field of Search: 424/400, 424/443, 424/447, 424/448, 424/464, 424/451
• US Class Current: 424/443
• CPC Class Codes: A61K 31/48 Ergoline derivatives, e.g. lysergic acid, ergotamine
• CPC Class Codes: A61K 9/7061 Polyacrylates
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs

Abstract

The invention relates to the use of a dopamine agonist in the form of an agent consisting of at least two spatially discrete compositions, of which one is a transdermal therapeutic system (TTS) containing the dopaminergic agent and another one or more are preparations for oral and/or parenteral application containing that same dopaminergic agent for the treatment of dopaminergically treatable diseases with the following elements: a) the TTS is continuously applied, b) within the duration of application in a) the composition for oral or parenteral dosage is administered.

Claims

1. A method of treating Parkinson'"'"'s disease, Pakinsonism, and Restless Legs Syndrome, the method comprising the step of administering two or more discrete compositions of a dopamine agonist, wherein said discrete compositions comprise a first composition and a second composition,

wherein said first composition comprises a transdermal therapeutic system (TTS) containing first dopamine agonist and

wherein said second composition comprises a second preparation of said first dopamine agonist, wherein said second preparation is selected from the group consisting of an oral preparation of the first dopamine agonist, a parenteral preparation of the first dopamine agonist, and mixtures thereof,

wherein the second composition is administered within the duration of the administration of the first composition.

2. The method of claim 1, wherein the first dopamine agonist is an ergoline derivative according to Formula 1 or a physiologically compatible salt thereof,

3. The method of claim 1, wherein the first dopamine agonist is selected from the group consisting of lisuride, pharmaceutically compatible salt lisuride, and mixtures thereof.

4. The method of claim 1, wherein the first dopamine agonist has a half-life of from about 0.5 hours to about 4 hours.

5. The method of claim 1, wherein the TTS comprises a pharmaceutical layer comprising at least one matrix containing the first dopamine agonist.

6. The method of claim 5 wherein the matrix is selected so that the transdermal flux F through human skin is in the range from about 0.1 μ

g/cm²/h to about 5.0 μ

g/cm₂/h.

7. The method of claim 1, wherein the TTS further comprises two or more TTS elements and wherein said TTS elements are configured to release different doses of the first dopamine agonists.

8. The method of claim 1, wherein the second preparation is an oral preparation of the first dopamine agonist, wherein said oral preparation is in tablet form for oral administration, and further wherein the tablet contains from about 25μ

g to about 500 μ

g of the first dopamine agonist.

9. The method of claim 1, wherein the second preparation is a parenteral preparation of the first dopamine agonist, wherein said parenteral preparation is selected from the group consisting of an injection solution and an infusion solution, and further wherein the concentration of the first dopamine agonist in said injection solution or said infusion solution is from about 25 μ

g to about 2000 μ

g of the first dopamine agonist per ml of solution.

11. The method of claim 5, wherein the pharmaceutical layer further comprises a diffusion barrier that is permeable to said first dopamine agonist, wherein said diffusion barrier is on the skin side of the matrix.

12. The method of claim 5 or claim 11, wherein the matrix further comprises a penetration-enhancing agent, wherein said penetration-enhancing agent is selected from the group consisting of:

1,2-propane diol, menthol, dexpanthenol, benzyl alcohol, lauryl alcohol, isocetyl alcohol, cetyl alcohol, mineral oil, lauric acid, isopalmitic acid, isostearic acid, oleic acid;

methyl ester, ethyl ester, 2-hydroxyethyl ester, glycerol ester, propyl ester, isopropyl ester, butyl ester, sec. butyl ester of lauric acid, isobutyl ester of lauric acid, myristic acid, stearic acid and palmitic acid.

13. The method of claim 5 or claim 11, wherein the matrix further comprises a penetration-enhancing agent, wherein said penetration-enhancing agent is selected from the group consisting of:

dimethyl isosorbide, isopropyl myristate and lauryl alcohol.

14. The method of claim 5 or claim 11, wherein the matrix further comprises a penetration-enhancing agent, wherein said penetration-enhancing agent is lauryl alcohol.

15. The method of claim 1, wherein the TTS comprises a pharmaceutical layer comprising an active ingredient reservoir containing the first dopamine agonist and a diffusion barrier that is permeable to said first dopamine agonist, wherein said diffusion barrier is on the skin side of the active ingredient reservoir.

16. The method of claim 11 or claim 15, wherein the diffusion barrier is selected so that the transdermal flux F through human skin is in the range from about 0.1 μ

g/cm²/h to about 5.0 μ

g/cm²/h.

17. The method of claim 15, wherein the active ingredient reservoir and the diffusion barrier are selected so that the transdermal flux F through human skin is in the range from about 0.1 μ

g/cm²/h to about 5.0 μ

g/cm²/h.

18. The method of claim 15, wherein the diffusion barrier further comprises a main barrier component, wherein said main barrier component is substance selected from the group consisting of a polyacrylate, a polyurethane, a cellulose ether, a silicone, a polyvinyl compound, a polyisobutylene compound, a silicate, copolymers of these substances, and mixtures thereof.

19. The method of claim 15, wherein the active ingredient reservoir further comprises a penetration-enhancing agent, wherein the penetration-enhancing agent is selected from the group consisting of:

a C1-C8 aliphatic alcohol, a cycloaliphatic alcohol, an aromatic alcohol, a saturated C8-18 fatty alcohol, an unsaturated C8-18 fatty acid, a hydrocarbon, a hydrocarbon mixture, a fatty acid ester from C3-19 fatty acids and C1-6 alkyl monools, a dicarboxylic acid diester from C4-8 dicarboxylic acids and C1-6 alkyl monools, and mixtures thereof.

20. The method of claim 11 or claim 15, wherein the diffusion barrier further comprises a penetration-enhancing agent, wherein the penetration-enhancing agent is selected from the group consisting of:

a C1-C8 aliphatic alcohol, a cycloaliphatic alcohol, an aromatic alcohol, a saturated C8-18 fatty alcohol, an unsaturated C8-18 fatty acid, a hydrocarbon, a hydrocarbon mixture, a fatty acid ester from C3-19 fatty acids and C1-6 alkyl monools, a dicarboxylic acid diester from C4-8 dicarboxylic acids and C1-6 alkyl monools, and mixtures thereof.

21. The method of claim 11 or claim 15, wherein the active ingredient reservoir further comprises a penetration-enhancing agent, wherein said penetration-enhancing agent is selected from the group consisting of:

1,2-propane diol, menthol, dexpanthenol, benzyl alcohol, lauryl alcohol, isocetyl alcohol, cetyl alcohol, mineral oil, lauric acid, isopalmitic acid, isostearic acid, oleic acid;

methyl ester, ethyl ester, 2-hydroxyethyl ester, glycerol ester, propyl ester, isopropyl ester, butyl ester, sec. butyl ester of laurie acid, isobutyl ester of lauric acid, myristic acid, stearic acid and palmitic acid.

22. The method of claim 15, wherein the active ingredient reservoir further comprises a penetration-enhancing agent, wherein said penetration-enhancing agent is selected from the group consisting of:

dimethyl isosorbide, isopropyl myristate and lauryl alcohol.

23. The method of claim 15, wherein the active ingredient reservoir further comprises a penetration-enhancing agent, wherein said penetration-enhancing agent is lauryl alcohol.

24. The method of claim 11 or claim 15, wherein the diffusion barrier further comprises a penetration-enhancing agent, wherein said penetration-enhancing agent is selected from the group consisting of:

1,2-propane diol, menthol, dexpanthenol, benzyl alcohol, lauryl alcohol, isocetyl alcohol, cetyl alcohol, mineral oil, laurie acid, isopalmitic acid, isostearic acid, oleic acid;

methyl ester, ethyl ester, 2-hydroxyethyl ester, glycerol ester, propyl ester, isopropyl ester, butyl ester, sec. butyl ester of laurie acid, isobutyl ester of lauric acid, myristic acid, stearic acid and palmitic acid.

25. The method of claim 11 or claim 15, wherein the diffusion barrier further comprises a penetration-enhancing agent, wherein said penetration-enhancing agent is selected from the group consisting of:

dimethyl isosorbide, isopropyl myristate and lauryl alcohol.

26. The method of claim 11 or claim 15, wherein the diffusion barrier further comprises a penetration-enhancing agent, wherein said penetration-enhancing agent is lauryl alcohol.

27. The method of claim 1, wherein the TTS further comprises two or more TTS elements and wherein each TTS element is separated from the other and located in a different area of the TTS.

28. The method of claim 1, wherein the TTS further comprises two or more TTS elements and wherein said TTS elements are configured to provide a continuous ascending sequence of flux F values.

29. The method of claim 1, wherein the TTS further comprises two or more TTS elements and wherein said TTS elements are configured to provide a stepwise sequence of flux F values.

30. The method of claim 5 or claim 11, wherein the matrix is selected so that the transdermal flux F through human skin is in the range from about 0.1 μ

g/cm²/h to about 5.0 μ

g/ cm²/h.

31. The method of claim 11, wherein the matrix and the diffusion barrier are selected so that the transdermal flux F through human skin is in the range from about 0.1 μ

g/cm²/h to about 5.0 μ

g/cm²/h.

32. The method of claim 1, wherein the first dopamine agonist has a half-life of from about 1 hour to about 2 hours.

33. The method of claim 5 or claim 15, wherein the TTS further comprises a covering layer, and wherein the covering layer is located on the side of the matrix or active ingredient reservoir that faces away from the skin.

34. The method of claim 5 or claim 11 wherein the matrix further comprises a main matrix component, wherein said main matrix component is a substance selected from the group consisting of a polyacrylate, a polyurethane, a cellulose ether, a silicone, a polyvinyl compound, a polyisobutylene compound, a silicate, copolymers of these substances, and mixtures thereof.

35. The method of claim 11 or claim 15, wherein the diffusion barrier further comprises a main barrier component, wherein said main barrier component is a substance selected from the group consisting of a cellulose ester, a cellulose ether, a silicone, a polyolefin, copolymers of these substances and mixtures thereof.

36. The method of claim 5 or claim 11 wherein the matrix further comprises a penetration-enhancing agent, wherein the penetration-enhancing agent is selected from the group consisting of a C1-C8 aliphatic alcohol, a cycloaliphatic alcohol, an aromatic alcohol, a saturated C8-18 fatty alcohol, an unsaturated C8-1 8 fatty acid, a hydrocarbon, a hydrocarbon mixture, a fatty acid ester from C3-19 fatty acids and C 1-6 alkyl monools, a dicarboxylic acid diester from C4-8 dicarboxylic acids and C1-6 alkyl monools, and mixtures thereof.

10. A pharmaceutical combination for the treatment of Parkinson'"'"'s disease, Pakinsonism, and Restless Legs Syndrome the combination comprising a transdermal therapeutic system containing a first dopamine agonist and a second preparation of said first dopamine agonist, wherein said second preparation is selected from the group consisting of an oral preparation of the first dopamine agonist, a parenteral preparation of the first dopamine agonist, and mixtures thereof, and wherein the first dopamine agonist has a short half-life.