Transdermal therapeutic system

• US 20030044453A1
• Filed: 08/02/2002
• Published: 03/06/2003
• Est. Priority Date: 01/13/1997
• Status: Abandoned Application

• Current Assignee: Jenapharm GmbH & Co. KG (Bayer AG)
• Original Assignee: Jenapharm GmbH & Co. KG (Bayer AG)
• Inventors: Kopke, Kai, Ahrens, Kathrin, Volkel, Christoph, Dittgen, Michael, Gerecke, Hagen, Fricke, Sabine
• Application Number:
  US10/211,400
• Publication Number:
  US 20030044453A1
• Time in Patent Office: Days
• US Class Current: 424/449
• CPC Class Codes: A61K 9/145 with organic compounds
• CPC Class Codes: A61K 9/7023 Transdermal patches and similar drug-containing composite devices, e.g. cataplasms galenical aspects of iontophoretic devices A61K9/0009; microneedle arrays A61K9/0021; buccal patches A61K9/006
• CPC Class Codes: A61K 9/7038 Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system

Abstract

The invention relates to a transdermal therapeutic system for application to the skin and/or mucosa consisting of at least one active substance in the form of a solid dispersion in combination with at least one destructuring agent and/or at least one structuring agent in a common matrix.

Claims

1. Transdermal therapeutic system for application to the skin and/or mucosa consisting of at least one active substance in the form of a solid dispersion in combination with at least one destructuring agent and/or at least one structuring agent in a common matrix.

2. Transdermal therapeutic system according to claim 1, characterized in that the solid dispersion is a molecular dispersion of the active substance in an inert carrier substance.

3. Transdermal therapeutic system according to claim 2, characterized in that the inert carrier substance is selected from inert carriers known per se for solid dispersions, such as, for example, sucrose, lactose, succinic acid, polyethylene glycols, polyvinyl-pyrrolidone, urea, mannitol, mannitose or mixtures thereof.

4. Transdermal thereapeutic system according to any of claims 1 to 3, characterized in that the destructuring agent is selected from the group of carboxamides such as urea, nicotinamide, succinamide, methylacetamide, ethylacetamide or mixtures thereof.

5. Transdermal therapeutic system according to claim 4, characterized in that the relaxation time is more than 120 ms, preferably more than 150 ms.

6. Transdermal therapeutic system according to any of claims 1 to 5, characterized in that the structuring agent is selected from the group of polyols such as, for example, glycerol, ethylene glycol, propylene glycol, from the group of sugar alcohols such as, for example, sorbitol and/or from the group of sugars such as, for example, sucrose or glucose or mixtures thereof.

7. Transdermal therapeutic system according to claim 6, characterized in that the relaxation time is less than 119 ms, preferably less than 80 ms.

8. Transdermal therapeutic system according to any of the preceding claims, characterized in that the ratio between destructuring agent and structuring agent is from 10:

1 to 1;

10.

9. Transdermal therapeutic system according to claim 8, characterized in that the ratio between destructuring agent and structuring agent is from 2:

1 to 1;

2.

10. Transdermal therapeutic system according to any of the preceding claims, characterized in that the active substance is selected from hormones, immunomodulators, immunosuppressants, antibiotics, cytostatics, diuretics, gastrointestinal agents, cardiovascular agents and neuropharmaceuticals or mixtures thereof.

11. Transdermal therapeutic system according to claim 10, characterized in that the active substance is selected from hormones such as testosterone, estradiol, estriol, norethisterone, dienogest or mixtures thereof.

12. Transdermal therapeutic system according to any of claims 1 to 11, characterized in that the matrix is a sheet-like adhesive piece of material, a plaster, a patch, a gel, an ointment, a cream, an emulsion, an embrocation, a paint or impregnated fabric.

13. Composition for transdermal administration comprising in an amount of at least more than 10% by weight and less than 90% by weight a penetration-enhancing agent of the following formula 1

15. Composition according to claim 13 or 14, where the penetration-enhancing agent of the formula 1 is present in a content of more than 10 to 50% by weight, preferably more than 10 to 25% by weight, most preferably 15 to 25% by weight.

16. Composition according to any of claims 13 to 15, where the penetration-enhancing agent of the formula 1 is Solketal (2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane).

17. Composition according to any of the preceding claims 13 to 16, additionally containing a contact adhesive, preferably a contact adhesive based on mixtures containing (co)polymers based on constituents which are selected from the group of C₁- to C₆-alkyl (meth)acrylates, C₁- to C₅-hydroxyalkyl (meth)acrylates, in particular containing a contact adhesive based on mixtures containing (co)polymers based on constituents selected from the group consisting of vinyl acetate, 2-ethylhexyl acrylate, 2-hydroxyethyl acrylate, glycidyl methacrylate, butyl acrylate, acrylic acid and methyl acrylate.

18. Composition according to any of the preceding claims 13 to 17, characterized in that the other lipophilic penetration-enhancing agent is selected from the group of saturated hydrocarbons with 10 to 30 C atoms, of the optionally unsaturated fatty alcohols with 10 to 30 C atoms, of the saturated or unsaturated, monobasic or polybasic fatty acids with 8 to 30 C atoms and their esters with optionally unsaturated fatty alcohols with 10 to 30 C atoms, and triacylglycerides with fatty acid residues with 8 to 22 C atoms, preferably with 5 to 12 C atoms.

19. Composition according to claim 18, characterized in that the other lipophillic penetration-enhancing agent is selected from the group consisting of dioctylcyclohexane, dodecanol, 2-octyldodecanol, 2-hexyldodecanol, oleyl alcohol, lauric acid, oleic acid, palmitic acid, dioctyl ether, isopropyl myristate, hexyl laurate, cetearyl isononanoate, capric acid, (C₁- to C₂₀-)alkyl caprates, (C₁- to C₂₀-)alkyl oleates, in particular decyl oleate, oleyl oleate, (C₁- to C₂₀-)alkyl docosenoates.

20. Composition according to claim 19, characterized in that the other lipophilic penetration-enhancing agent is ethyl oleate.

21. Composition according to any of the preceding claims 13 to 20, characterized in that the other lipophilic penetration-enhancing agent is present in a relative amount of at least 2% by weight, preferably between 5 and 15% by weight.

22. Composition according to any of the preceding claims 13 to 21, characterized in that another hydrophilic penetration-enhancing agent which preferably has a solubility of at least 5% by weight in water is present.

23. Composition according to claim 22, characterized in that the other hydrophilic penetration-enhancing agent is selected from the group consisting of amides, polyethylene glycols, glycols, pyrrolidones, polymers of pyrrolidone derivatives, in particular nicotinamide or urea.

24. Composition according to any of claims 22 to 23, characterized in that the other hydrophilic penetration-enhancing agent is present in a relative amount of from 1 to 10% by weight, preferably from 2 to 5% by weight.

25. Composition according to any of the preceding claims 13 to 24, characterized in that the active substance is a lipophilic active substance, in particular a steroidal agent.

26. Composition according to claim 25, characterized in that the steroidal agent is a steroid hormone, in particular selected from the group consisting of corticosteroids, sex hormones, preferably oestrogens, gestagens, androgens, in particular from the group consisting of testosterone, estradiol and its derivatives, particularly preferably testosterone, estradiol, ethinylestradiol and norethisterone acetate.

27. Composition according to any of the preceding claims 13 to 26, characterized in that the composition contains the active substance in at least saturated solution, preferably in supersaturated solution.

28. Means for transdermal administration comprising the composition according to any of the preceding claims 13 to 27.

29. Means according to claim 28, characterized in that the means is an emulsion, ointment, cream, lotion or transdermal therapeutic system (TTS).

30. TTS according to claim 28, with an optionally detachable protective layer, at least one contact adhesive matrix layer, in particular a contact adhesive-containing primer layer, and a contact adhesive-containing cutaneous layer, another intermediate layer and an optionally active substance- and/or water vapour-impermeable backing layer.

31. TTS according to claim 30, characterized in that the primer layer and the cutaneous layer project beyond the intermediate layer on all sides.

32. TTS according to either of claims 30 or 31, characterized in that the composition according to any of claims 13 to 27 is present distributed in three compartments, namely the contact adhesive-containing primer layer, the contact adhesive-containing cutaneous layer and the other intermediate layer.

33. Process for producing the TTS according to any of claims 30 to 32, comprising the steps of

producing a first laminate by a first mixture containing the at least one active substance and an optionally cross-linkable contact adhesive being produced and applied to a protective layer carrier material,

producing a second laminate by applying the first mixture to a backing layer carrier material,

a disc being punched out of another carrier material, preferably a nonwoven, and being applied to the first laminate,

and a second mixture containing the penetration-enhancing agent according to formula 1 and the other lipophilic penetration-enhancing agent being applied to the other carrier material,

the second laminate being laminated thereon and single TTS being produced therefrom.

34. Product according to any of claims 13 to 32 for use in replacement therapy, in particular hormone replacement therapy.

35. Product according to claim 34 for use for hypogonadism, anaemia, congenital angioneurotic oedema, impotence, infertility or contraception.

14. Composition for transdermal administration comprising a penetration-enhancing agent of the following formula 1