Transdermal Therapeutic System with Fentanyl or Related Substances

Abstract

The invention relates to a transdermal therapeutic system (TTS), comprising a backing layer, which is permeable to the active ingredient, at least one matrix layer, comprising fentanyl or an active agent analogous to fentanyl, based on polyacrylate and a protective layer to be removed before usage, characterized in that the polyacrylate polymer is self-adhesive, free of carboxyl groups, has a saturation solubility for fentanyl of 3 to 20 wt. %, preferably of 4 to 12 and particularly of 5 to 10 wt. % and the layers contain at least 80% of the included active ingredient in a molecularly-dispersed, dissolved form.

Claims

1-9. (canceled)

10. A transdermal therapeutic system (TTS) consisting of: A) an active compound-impermeable back layer; B) one matrix layer based on polyacrylate and comprising fentanyl; and C) a protective film to be removed before use; wherein said polyacrylate: i) is self-adhesive; ii) is free of carboxyl groups, but has at least one hydroxyl group; iii) is prepared from a monomer mixture consisting of: a) esters of acrylic and/or methacrylic acid, which are esters of alcohols having 1 to 8 carbon atoms; and b) 2-hydroxyethyl acrylate or 2-hydroxyethyl methacrylate in amounts of up to 20% by weight; and iv) has a saturation solubility for fentanyl of between 5 and 20 percent by weight; and wherein said one matrix layer contains at least 80 percent by weight of the incorporated fentanyl in molecularly disperse dissolved form.

11. The transdermal therapeutic system (TTS) according to claim 10, wherein the esters of acrylic and/or methacrylic acid according to iii a) are selected from the group consisting of 2-ethylhexyl acrylate, n-octyl acrylate, propyl acrylate, n-butyl acrylate, iso-butyl acrylate and the corresponding methacrylates.

12. The transdermal therapeutic system (TTS) according to claim 10, wherein the fentanyl is present in a concentration of at least 5% by weight in the matrix layer.

13. The transdermal therapeutic system (TTS) according to claim 10, wherein the fentanyl is present in a concentration of at most 20% by weight in the matrix layer.

14. The transdermal therapeutic system (TTS) according to claim 10, wherein the fentanyl is completely dissolved in molecularly disperse form in said polyacrylate.

15. The transdermal therapeutic system (TTS) according to claim 10, wherein the polyacrylate contains free hydroxyl groups that are crosslinked by Al.sup.3+ or Ti.sup.4+.

16. The transdermal therapeutic system (TTS) according to claim 10, wherein the polyacrylate has a saturation solubility for fentanyl of between 5 and 12 percent by weight.

17. The transdermal therapeutic system (TTS) according to claim 16, wherein the polyacrylate has a saturation solubility for fentanyl of between 5 and 10 percent by weight.

18. The transdermal therapeutic system (TTS) according to claim 10, wherein said one matrix layer contain at least one substance which improves the permeation rate through human skin, said substance being selected from the group consisting of glycols, fatty acids, fatty acid esters, fatty alcohols and glycerol esters.

19. The transdermal therapeutic system (TTS) according to claim 10, wherein said one matrix layer contains at least one substance which lowers the solubility of the active compound, said substance being selected from the group consisting of liquid hydrocarbons, liquid paraffin, hydrocarbon resins, polar substances and polyethylene glycols having a molecular weight from 200 to 1000.

20. The transdermal therapeutic system (TTS) according to claim 10, wherein the esters of acrylic and/or methacrylic acid according to iii a) are selected from the group consisting of 2-ethylhexyl acrylate, n-octyl acrylate, propyl acrylate, n-butyl acrylate, iso-butyl acrylate and the corresponding methacrylates; wherein the polyacrylate contains free hydroxyl groups that are crosslinked by Al.sup.3+ or Ti.sup.4+. wherein fentanyl is completely dissolved in molecularly disperse form in said polyacrylate; wherein the one matrix layer contains at least one substance which improves the permeation rate through human skin, said substance being selected from the group consisting of glycols, fatty acids, fatty acid esters, fatty alcohols and glycerol esters; and wherein the one matrix layer contains at least one substance which lower the solubility of the active compound, said substance being selected from the group consisting of liquid hydrocarbons, liquid paraffin, hydrocarbon resins, polar substances and polyethylene glycols having a molecular weight from 200 to 1000.

21. A transdermal therapeutic system (TTS) consisting of: A) an active compound-impermeable back layer; B) at least one matrix layer based on polyacrylate and comprising fentanyl; and C) a protective film to be removed before use; wherein said polyacrylate: i) is self-adhesive; ii) is free of carboxyl groups, but has hydroxyl groups to effect crosslinking; iii) is prepared from a monomer mixture consisting of: a) esters of acrylic and/or methacrylic acid, which are esters of alcohols having 1 to 8 carbon atoms; and b) 2-hydroxyethyl acrylate and/or 2-hydroxyethylmethacrylate; wherein each monomer is present in the monomer mixture; and iv) has a saturation solubility for fentanyl of between 5 and 20 percent by weight; wherein said at least one matrix layer contains at least 80 percent by weight of the incorporated fentanyl in molecularly disperse dissolved form; wherein the amount of 2-hydroxyethyl acrylate and/or 2-hydroxyethylmethacrylate is up to 20% by weight; and wherein said polyacrylate is crosslinked by polyvalent cations that are selected from the group consisting of Al.sup.3+ or Ti.sup.4+.

22. The transdermal therapeutic system (TTS) according to claim 21, wherein the polyacrylate has a saturation solubility for fentanyl of between 5 and 12 percent by weight.

23. The transdermal therapeutic system (TTS) according to claim 22, wherein the polyacrylate has a saturation solubility for fentanyl of between 5 and 10 percent by weight.

24. The transdermal therapeutic system (TTS) according to claim 21, wherein said at least one matrix layer contains at least one substance which lowers the solubility of fentanyl, said substance being selected from the group consisting of liquid hydrocarbons, liquid paraffin, hydrocarbon resins, polar substances and polyethylene glycols having a molecular weight from 200 to 1000.

25. The transdermal therapeutic system (TTS) according to claim 22, wherein said at least one matrix layer contains at least one substance which lowers the solubility of fentanyl, said substance being selected from the group consisting of liquid hydrocarbons, liquid paraffin, hydrocarbon resins, polar substances and polyethylene glycols having a molecular weight from 200 to 1000.

26. The transdermal therapeutic system (TTS) according to claim 23, wherein said at least one matrix layer contains at least one substance which lowers the solubility of fentanyl, said substance being selected from the group consisting of liquid hydrocarbons, liquid paraffin, hydrocarbon resins, polar substances and polyethylene glycols having a molecular weight from 200 to 1000

Description

EXAMPLES

Example 1 (Formulation 1, 2, 4)

[0025] Fentanyl (free base) is dissolved in the solution of the adhesive in heptane/ethyl acetate. The amount of fentanyl is in this case calculated such that, based on the solids content of the adhesive solution, a concentration of 5.0% results. The resulting material is coated using a doctor blade onto a siliconized polyester film protective layer to be removed before use, in a thickness such that, after the removal of the solvent, a weight of the coating of about 80 g/m.sup.2 results. After the removal of the solvent, the dried film is laminated with a thin polyester film (back layer of the TTS), and the finished TTS are stamped out of the complete laminate.

Example 2 (Formulation 3)

[0026] 5.0 g of fentanyl, 15.0 g of polypinene, 10.0 g of glycerol, 15.0 g of dioctylcyclohexane and 110 g of the adhesive solution having a solids content of 50.0% are combined and stirred until the fentanyl has dissolved.

[0027] The resulting material is coated using a doctor blade onto a siliconized polyester film (protective layer to be removed before use) in a thickness such that, after the removal of the solvent, a weight of the coating of about 80 g/m.sup.2 results. After the removal of the solvent, the dried film is laminated with a thin polyester film (back layer of the TTS) and the finished TTS are stamped out of the complete laminate.