Transdermal therapeutic system

• US 20050220855A1
• Filed: 04/28/2005
• Published: 10/06/2005
• Est. Priority Date: 08/24/2000
• Status: Abandoned Application

• Current Assignee: Axxonis Pharma AG
• Original Assignee: Axxonis Pharma AG
• Inventors: Tack, Johannes, Horowski, Reinhard, Schenk, Dirk, Windt-Hanke, Fred, Engfer, Adalbert, Gunther, Clemens, Bostedt, Katalin Tisa
• Application Number:
  US11/116,279
• Publication Number:
  US 20050220855A1
• Time in Patent Office: Days
• US Class Current: 424/449
• CPC Class Codes: A61K 31/48 Ergoline derivatives, e.g. lysergic acid, ergotamine
• CPC Class Codes: A61K 9/7061 Polyacrylates
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 15/14 for lactation disorders, e.g. galactorrhoea
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/08 for decreasing, blocking or antagonising the activity of the anterior pituitary hormones
• CPC Class Codes: A61P 5/24 of the sex hormones

Abstract

Use of a transdermal therapeutic system (TTS) comprising a pharmaceutical layer containing at least one matrix having an active ingredient and/or an active ingredient reservoir; a diffusion barrier that is permeable to said active ingredient and arranged on the skin side of the active ingredient reservoir; and an ergoline derivative or salt thereof as an active ingredient for producing an agent for obtaining and maintaining the circadian rhythm under dopamine therapy. The invention relates to the use of a transdermal therapeutic system (TTS) comprising a medicinal layer, which contains at least one matrix comprising an active ingredient and/or an active ingredient reservoir and a diffusion barrier situated on the skin side of the active ingredient reservoir and permeable to active ingredients, in addition to, an ergoline-derivative or physiologically compatible salt with an acid thereof, as an active ingredient, for producing a means for treating the restless-legs-syndrome. 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. The invention concerns a transdermal therapeutic system containing ergoline derivatives, preferably lisuride, with a stabilized ergoline compound. Stabilization of the oxidation sensitive ergoline combination is done through a combination of at least one fat-soluble, radical-trapping antioxidant, preferably Di-tert.-butylmethylphenols, Di-tert.-butylmetoxyphenols, tocopherols or ubichinones and a basic polymer.

Claims

1. Use of a transdermal therapeutic system (TTS) comprising a pharmaceutical layer containing at least one matrix having an active ingredient, and/or an active ingredient reservoir;

a diffusion barrier which is permeable to active ingredients and which is arranged on the skin side of the active ingredient reservoir; and

an ergoline derivative according to Formula I or physiologically compatible salt thereof with an acid,

2. The use according to claim 1 wherein the matrix and/or diffusion barrier are selected so that the transdermal flux F through human skin is in the range from 0.1 to 5.0 μ

g/cm²/h.

3. The use according to claim 1 wherein the ergoline derivative is lisuride or a physiologically compatible salt thereof.

4. The use according to claim 1 wherein a covering layer is provided on the side of the matrix and/or active ingredient reservoir that faces away from the skin.

5. The use according to claim 1 wherein the matrix and/or diffusion barrier comprise as their main matrix component a substance selected from the group consisting of polyacrylate, polyurethane, cellulose ether, silicone, polyvinyl compounds, silicate and mixtures of these substances as well as copolymers of these polymeric compounds, preferably hydrophilic polyacrylate with basic substituents.

6. The use according to claim 1 wherein the diffusion barrier comprises as its main barrier component a synthetic polymer selected from the group consisting of cellulose ester, cellulose ether, silicone, polyolefin and mixtures as well as copolymers of these substances.

7. The use according to claim 1 wherein the matrix and/or the active ingredient reservoir and/or the diffusion barrier contain a penetration-enhancing agent that is preferably selected from the group consisting of C1-C8 aliphatic, cycloaliphatic and aromatic alcohols, saturated and unsaturated C8-18 fatty alcohols, saturated and unsaturated C8-18 fatty acids, hydrocarbons and hydrocarbon mixtures, fatty acid esters from C3-19 fatty acids and C1-6-alkyl monools, dicarboxylic acid diesters from C4-8-dicarboxylic acids and C1-6 alkyl monools, and mixtures of these substances.

8. The use according to claim 1 wherein the matrix and/or the active ingredient reservoir and/or the diffusion barrier contain a crystallization inhibitor that is selected from the group consisting of highly dispersed silicon dioxide or macromolecular substances such as polyvinyl pyrrolidone, polyvinyl alcohols, dextrines, dextranes, sterines, bile acids and, in particular, vinyl pyrrolidone vinylacetate copolymers.

9. The use according to claim 1 wherein the matrix and/or active ingredient reservoir and/or diffusion barrier contain an antioxidant that is selected from the group consisting of sulfur-containing amino acids such as cysteine, methyl donors such as methionine, or antioxidants such as glutathione or sodium hydrogensulfite.

10. Use of a TTS according to claim 1 to produce an agent for the treatment or prevention of premenstrual syndrome wherein the preferred F value is in the range from 0.1 to 0.5 μ

g/cm²/h.

11. Use of a TTS according to claim 1 to produce an agent for lactation inhibition wherein the preferred F value is in the range from 0.1 to 0.5 μ

g/cm²/h.

12. A TTS set for the treatment of circadian disturbances under dopamine therapy wherein the set contains a multitude of TTS elements and wherein said elements are configured for releasing different doses.

13. A TTS set according to claim 12 wherein the TTS elements are separated and wherein each TTS element is configured for a continuously ascending sequence of F ranging from 0.1 to 5 μ

g/cm²/h.

14. The TTS set according to claim 12 wherein the TTS elements are equipped with different active surfaces in a continuous sequence.

15. Use of a transdermal therapeutic system (TTS) comprising a pharmaceutical layer containing at least one matrix having an active ingredient, and/or an active ingredient reservoir;

a diffusion barrier which is permeable to active ingredients and which is arranged on the skin side of the active ingredient reservoir; and

an ergoline derivative according to Formula I or physiologically compatible salt thereof with an acid,

16. The use according to claim 15 wherein the matrix and/or diffusion barrier are selected so that the transdermal flux F through human skin measured as described in Example B1 is in the range from 0.1 to 5.0 μ

g/cm²/h.

17. The use according to claim 15 wherein the ergoline derivative is lisuride or a salt thereof with a physiologically compatible acid.

18. The use according to claim 15 wherein a covering layer is provided on the side of the matrix and/or active ingredient reservoir that faces away from the skin.

19. The use according to claim 15 wherein the matrix and/or diffusion barrier comprise as their main matrix component a substance selected from the group consisting of polyacrylate, polyurethane, cellulose ether, silicone, polyvinyl compounds, silicate and mixtures of these substances as well as copolymers of these polymeric compounds.

20. The use according to claim 15 wherein the diffusion barrier comprises as its main barrier component a synthetic polymer selected from the group consisting of cellulose ester, cellulose ether, silicone, polyolefin and mixtures as well as copolymers of these substances.

21. The use according to claim 15 wherein the matrix and/or the active ingredient reservoir and/or the diffusion barrier contain a penetration-enhancing agent that is preferably selected from the group consisting of C1-C8 aliphatic, cycloaliphatic and aromatic alcohols, saturated and unsaturated C8-18 fatty alcohols, saturated and unsaturated C8-18 fatty acids, hydrocarbons and hydrocarbon mixtures, fatty acid esters from C3-19 fatty acids and C1-6 alkyl monools, dicarboxylic acid diesters from C4-8 dicarboxylic acids and C1-6 alkyl monools, and mixtures of these substances.

22. Use of a TTS according to claim 15 to produce an agent for the treatment or prevention of premenstrual syndrome or its symptoms wherein the preferred F value is in the range from 0.1 to 0.5 μ

g/cm²/h.

23. Use of a TTS according to claim 15 to produce an agent for lactation inhibition wherein the preferred F value is in the range from 0.1 to 0.5 μ

g/cm²/h.

24. 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, where

a) the TTS is applied continuously,

b) within the duration of application in a) the preparation for oral or parenteral dosage is administered.

25. The use according to claim 24 wherein the dopaminergically treatable disease may be a disease from the group consisting of Parkinson'"'"'s disease, parkinsonism, restless legs syndrome, and disturbances of the dopaminergic system.

26. The use according to claim 24 wherein the dopamine agonist is an ergoline derivative according to Formula 1 or a physiologically compatible salt thereof,

27. The use according to claim 24 wherein the dopamine agonist is lisuride or a pharmaceutically compatible salt thereof.

28. The use according to claim 24 wherein the dopamine agonist has a half-life of 0.5 to 4 hours, preferably 1 to 2 hours.

29. The use according to claim 24 wherein the TTS comprises a pharmaceutical layer comprising at least one matrix containing an active ingredient and/or an active ingredient reservoir, and a diffusion barrier on the skin side of said active ingredient reservoir that is permeable to said active ingredient.

30. The use according to claim 29 wherein the matrix and/or diffusion barrier are selected so that the transdermal flux F through human skin is in the range from 0.1 to 5.0 μ

g/cm²/h.

31. The use according to claim 29 wherein a covering layer is provided on the side of the matrix and/or active ingredient reservoir that faces away from the skin.

32. The use according to claim 29 wherein the matrix and/or diffusion barrier comprise as their main matrix component a substance selected from the group consisting of polyacrylate, polyurethane, cellulose ether, silicone, polyvinyl compounds, polyisobutylene compounds, silicate and mixtures of these substances as well as copolymers of these polymeric compounds.

33. The use according to claim 29 wherein the diffusion barrier comprises as its main barrier component a synthetic polymer selected from the group consisting of cellulose ester, cellulose ether, silicone, polyolefin and mixtures as well as copolymers of these substances.

34. The use according to claim 29 wherein the matrix and/or the active ingredient reservoir and/or the diffusion barrier contain a penetration-enhancing agent that is preferably selected from the group consisting of C1-C8 aliphatic, cycloaliphatic and aromatic alcohols, saturated and unsaturated C8-18 fatty alcohols, saturated and unsaturated C8-18 fatty acids, hydrocarbons and hydrocarbon mixtures, fatty acid esters from C3-19 fatty acids and C1-6 alkyl monools, dicarboxylic acid diesters from C4-8 dicarboxylic acids and C1-6 alkyl monools, and mixtures of these substances.

35. The use according to claim 24 wherein a TTS set is provided containing a multitude of TTS elements and wherein these elements are designed for the release of different doses.

36. The use according to claim 24 wherein the preparation in tablet form for oral administration contains 25 to 500 μ

g of the dopaminergic agent per tablet.

37. The use according to claim 24 wherein the preparation in form of an injection or infusion solution for parenteral administration contains 25 to 2000 μ

g of the dopaminergic agent per ml of solution.

38. A combination of a transdermal therapeutic system and an oral and/or parenteral preparation containing one and the same dopamine agonist with a short half-life to produce a pharmaceutical for the treatment of dopaminergic diseases.

39. A medication for transdermal application consisting of an impermeable backing layer, an ergoline compound and possibly a penetration enhancers containing matrix, possibly a diffusion barrier covering the matrix, a layer of adhesive permeable for these substances and a peel-off protective cover, characterized by a stabilization of the ergoline compounds through an antioxidant and a basic polymer.

40. The medication of claim 39, characterized by the antioxidant being a compound, which reacts with free radicals.

41. The medication of claim 39, characterized by the antioxidant being selected from among Di-tert.-butylmethylphenols, Di-tert.-butylmetoxyphenols, tocopherols and/or ubichinones.

42. The medication of claim 39, characterized by the antioxidant being present in amounts of 0.25% to 5% w/w.

43. The medication of claim 39, characterized by the basic polymer being an acrylate copolymer.

44. The medication of claim 39, characterized by the acrylate copolymer being a butyl methacrylate-(2-diamino ethyl)methacrylate-methacrylate-copolymer.

45. The medication of claim 39, characterized by containing basic polymers in the matrix or in the adhesive layer.

46. The medication of claim 39, characterized by the basic polymer containing an adhesiveness enhancer in the matrix or in the adhesive layer.

47. The medication of claim 39, characterized by the adhesiveness enhancer containing resins and/or polyacrylates.

48. The medication of claim 39, characterized by containing 1% to 20% w/w adhesiveness enhancer.

49. The medication of claim 39, characterized by containing 2% to 10% w/w adhesive enhancer.

50. The medication of claim 39, characterized by the ergoline compound being lisuride or proterguride.

51. The administration of the medication of claim 39 for prophylaxis and therapy of diseases treatable with dopaminergics.

52. The administration of the medication of claim 39 for treatment of Parkinson'"'"'s disease, for treatment and prevention of the Restless Legs Syndrome and the Premenstrual Syndrome as well as for lactation inhibition and migraine prophylaxis.