Transdermal therapeutic system on the basis of adhesive plasticizer-polymer matrices

Abstract

The present application relates to a transdermal therapeutic system comprising a backing layer impermeable to active substances and a polymer matrix on one side of the backing layer impermeable to active substances, wherein the polymer matrix comprises at least one pharmaceutically active substance, at least one inherently non-self-adhesive polymer and at least one plasticizer, said polymer matrix being free of adhesive polymers. The invention further relates to a method of producing the transdermal therapeutic system and to the use thereof as a drug.

Claims

1. A transdermal therapeutic system, comprising a backing layer impermeable to active substances and a polymer matrix layer on one side of the backing layer impermeable to active substances, wherein the polymer matrix comprises at least one pharmaceutically active substance, at least one inherently non-adhesive polymer, wherein the inherently non-adhesive polymer comprises a polyvinyl caprolactam/polyvinyl acetate/polyethylene glycol copolymer, shellac, a vinylpyrrolidone/vinyl acetate copolymer, hyroxypropyl cellulose, hydroxypropyl methyl cellulose and/or polyvinylpyrrolidone, and the amount of the at least one inherently non-adhesive polymer in the matrix layer is approximately 50 to 90 wt. %, and at least one plasticiser, wherein the at least one plasticizer comprises glycerol and/or polyethylene glycol, the amount of the at least one plasticizer in the matrix layer is approximately 5 to 50 wt. % in relation to the total weight of the matrix layer, characterised in that the polymer matrix is free of inherently adhesive polymers.

2. The transdermal therapeutic system according to claim 1, characterised in that the transdermal therapeutic system does not comprise an additional adhesive layer on the side of the polymer matrix on which the backing layer impermeable to active substance is not situated.

3. The transdermal therapeutic system according to claim 1, characterised in that the inherently adhesive polymer comprises a water-soluble polymer.

4. The transdermal therapeutic system according to claim 1, characterised in that the at least one plasticiser comprises polyethylene glycol 200.

5. The transdermal therapeutic system according to claim 1, characterised in that the at least one pharmaceutically active substance is selected from the group consisting of idebenone, oxybutynin, riociguat, rotigotine, apixaban, ketamine, alendronate and/or fentanyl.

6. The transdermal therapeutic system according to claim 1, characterised in that the amount of the at least one pharmaceutically active substance is from approximately 1 to 20 wt. % in relation to the total weight of the matrix layer.

7. The transdermal therapeutic system according to claim 1, characterised in that the transdermal therapeutic system comprises at least one auxiliary selected from the group comprising dyes, emulsifiers, penetration enhancers, pH regulators, humectants, preservatives and/or antioxidants.

8. A medicinal product comprised of the transdermal therapeutic system according to claim 1.

9. The transdermal therapeutic system according to claim 7, characterised in that the at least one auxiliary is present in an amount of from 0.01 to 20 wt. % in relation to the total weight of the matrix layer.

10. The transdermal therapeutic system of claim 1, wherein the polymer matrix is applied directly to the backing layer comprised of polyethylene terephthalate.

11. The transdermal therapeutic system of claim 1, consisting of the backing layer, the polymer matrix and a removable barrier.

12. The transdermal therapeutic system of claim 1 being adapted for application to a skin of a patient.

13. The transdermal therapeutic system of claim 1 including no (meth)acrylate, poly(meth) acrylate, polyisobutyhene or silicone inclusive polymers.

14. The transdermal therapeutic system according to claim 1, wherein the amount of the at least one inherently non-adhesive polymer in the matrix layer is approximately 60 to 80 wt. % in relation to the total weight of the matrix layer, the at least one plasticiser in the matrix layer is approximately 10 to 30 wt. % in relation to the total weight of the matrix layer, and the weight ratio in parts by weight of the at least one polymer to the at least one plasticiser is approximately 80 to 60 to approximately 20 to 40.

15. The transdermal therapeutic system according to claim 1 including a penetration enhancer selected from pentanoic acid, hexanoic acid, octanoic acid, nonanoic acid, decanoic acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, isovaleric acid, neoheptanoic acid, neonanonic acid, isostearic acid, oleic acid, palmitoleic acid, linolenic acid, vaccenic acid, petroselinic acid, elaidic acid, oleic acid, arachidonic acid, gadoleic acid, erucic acid, ethyl acetate, methyl propylate, butyl acetate, methyl valerate, diethyl sebacate, methyl laurate, ethyl oleate, isopropyl decanoate, isopropyl myristate (myristic acid isopropyl ester), isopropyl palmitate, and isopropyl oleinate (oleic acid isopropyl ester) and/or esters thereof.

16. The transdermal therapeutic system of claim 15, wherein the penetration enhancer comprises oleic acid and/or acid esters thereof.

Description

DESCRIPTION OF THE DRAWINGS

(1) FIG. 1:

(2) A transdermal therapeutic system according to the invention for administering idebenone according to the formulations in Table 1. The left-hand graph shows the cumulative active substance permeation, and the right-hand graph shows the active substance flux.

(3) FIG. 2:

(4) A transdermal therapeutic system comprising an adhesive on the basis of acrylate/silicone according to the prior art. The left graph shows the cumulative active substance permeation, and the right-hand graph shows the active substance flux.

(5) FIG. 3:

(6) A transdermal therapeutic system according to the invention for administering oxybutynin according to the formulations in Table 1. The left-hand graph shows the cumulative active substance permeation, and the right-hand GRAPH shows the active substance flux.

(7) The invention will be explained hereinafter on the basis of non-limiting examples.

EXAMPLE 1

(8) The following formulations were created and applied to a polyethylene terephthalate film. All formulations had adhesive properties.

(9) TABLE-US-00001 TABLE 1 Formulations according to the invention Formulation code Polymer Plasticiser Active substance 124Idb0029 80% Soluplus 10% PEG 200 10% Idebenone 13XIdb0011 80% Soluplus 10% Glycerol 10% Idebenone 13XIdb0012 70% Soluplus 20% Glycerol 10% Idebenone 13XIdb0009 70% Kollidon 20% Glycerol 10% Idebenone VA 64 13XIdb0010 60% Kollidon 30% Glycerol 10% Idebenone VA 64 13XObu0001 70% Soluplus 20% Glycerol 10% Oxybutynin 13XObu0002 70% Soluplus 20% PEG 200 10% Oxybutynin 13XObu0003 65% Soluplus 25% PEG 200 10% Oxybutynin 13XObu0004 60% Soluplus 30% PEG 200 10% Oxybutynin 13XObu0005 65% Kollidon 25% PEG 200 10% Oxybutynin VA 64 13XObu0006 65% Kollidon 25% Glycerol 10% Oxybutynin VA 64 13XObu0007 65% Kollidon 25% PEG 200 10% Oxybutynin VA 64 13XRio0004 60% Soluplus 30% PEG 200 10% Riociguat 13XRio0005 60% Kollidon 30% Glycerol 10% Riociguat VA 64 13XRio0006 60% Kollidon 30% PEG 200 10% Riociguat VA 64 13XRio0007 60% Soluplus 30% PEG 200 10% Riociguat 13XRio0009 60% Soluplus 30% Glycerol 10% Riociguat 13XRot0001 70% Soluplus 20% Glycerol 10% Rotigotine 13XRot0002 70% Kollidon 20% Glycerol 10% Rotigotine VA 64 13XRot0003 75% Kollidon 15% Glycerol 10% Rotigotine VA 64

(10) TABLE-US-00002 TABLE 2 Comparison formulations in conventional adhesives Formulation code Polymer Active substance 13XIdb0001 90% DuroTak 4098 10% Idebenone 13XIdb0002 90% DuroTak 2516 10% Idebenone 13XIdb0003 80% DuroTak 4098 10% Idebenone 13XIdb0004 90% DuroTak 2353 (80% 10% Idebenone neutralised) 13XIdb0005 90% DuroTak 2353 10% Idebenone 13XIdb0006 90% Bio-PSA 4207 10% Idebenone 13XIdb0007 1.sup.st coat 90% Bio-PSA 4107 10% Idebenone 2.sup.nd coat 10% Enhancer mix (in the 1.sup.st (35% miglyol, 25% coat) dimethyl isosorbide, 25% eucalyptol, 15% n- dodecanol) Bio-PSA 4602 13XIdb0008 92.5% Bio-PSA 4602 7.5% Idebenone DuroTak: adhesives on the basis of acrylate copolymers (Henkel) Bio-PSA: adhesives on the basis of silicone (Dow Corning) Miglyol: Medium-chain triglycerides

(11) The in vitro human skin permeation of some of the systems specified in Example 1 was measured using a Franz cell. The substance or formulation (for example gels, salves, solutions, patches) was situated in the donor compartment. The acceptor compartment was filled with buffer or other solutions. The permeation of a substance through the skin could be tracked over the selected time period by taking samples regularly from the acceptor compartment. The use of the Franz cell as diffusion model is suitable especially for predicting the transport of drugs through human skin (=permeation), which corresponds to the systemic availability. It is important to note here that there is no in-vitro in-vivo correlation. In this case, the Franz cell was loaded with human abdominal skin obtained from surgery. 500 μm of dermatomed skin with a diffusion area of 1.165 cm.sup.2 was incubated with the transdermal therapeutic system. An aqueous, isotonic phosphate buffer pH=7.4 plus 0.1% sodium azide with a filling volume of 10 mL was used as acceptor medium. The permeation measurement was performed at a temperature of 32° C., with measurements being taken after 3, 6, 8 and 24 hours (n=3). The results of the measurements can be seen in FIGS. 1 to 3.

(12) It can be seen from the drawings that the formulations according to the invention, which forego conventional adhesives, can achieve comparable results to known formulations in respect of active substance permeation and active substance flux.