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EP-3955901-B1 - TRANSDERMAL THERAPEUTIC SYSTEM

EP3955901B1EP 3955901 B1EP3955901 B1EP 3955901B1EP-3955901-B1

Inventors

  • HAMMES, Florian
  • KLEUDGEN, TOBIAS
  • TOMELERI, ANJA

Dates

Publication Date
20260506
Application Date
20200417

Claims (10)

  1. A transdermal therapeutic system, comprising a backing layer, which is not permeable for the active ingredient, and at least one matrix layer on one side of the backing layer, wherein the matrix layer contains at least one pressure sensitive adhesive, at least one penetration enhancer, and (S)-ketamine or a pharmaceutically acceptable salt or solvate thereof, characterized in that the at least one pressure sensitive adhesive comprises free hydroxyl groups, wherein the at least one pressure sensitive adhesive comprises an acrylic copolymer selected from 2-ethylhexyl acrylic acetate, vinyl acetate, and 2-hydroxyethyl acrylate comprising free hydroxyl groups, and wherein the at least one penetration enhancer is a mixture of levulinic acid and methyl laurate.
  2. The transdermal therapeutic system of claim 1, characterized in that the at least one pressure sensitive adhesive comprises less than 4 wt.%, preferably 1-3 wt.%, more preferably less than 1 % free carboxyl groups.
  3. The transdermal therapeutic system of any of the preceding claims, characterized in that the at least one pressure sensitive adhesive comprises no free carboxyl groups.
  4. The transdermal therapeutic system of any of the preceding claims, characterized in that the matrix layer comprises the at least one penetration enhancer in an amount of 1 to 15 wt.-%, based on the weight of the matrix layer.
  5. The transdermal therapeutic system of any of the preceding claims, characterized in that the matrix layer comprises ketamine in an amount of 1 to 25 wt.-%, based on the weight of the matrix layer.
  6. The transdermal therapeutic system of any of the preceding claims, characterized in that the matrix layer comprises at least one antioxidant, preferably selected from the group consisting of alpha-tocopherol, ascorbyl palmitate and/or dibutylhydroxytoluene.
  7. The transdermal therapeutic system of any of the preceding claims, characterized in that the matrix layer has an area weight of 30 to 400 g/m 2 .
  8. The transdermal therapeutic system of any of the preceding claims, characterized in that the transdermal therapeutic system comprises a detachable protective layer on that side of the matrix layer on which the backing layer is not arranged.
  9. The transdermal therapeutic system of any of the preceding claims for use as a medicament.
  10. The transdermal therapeutic system of any of the preceding claims for use in the treatment of depression and/or pain.

Description

The present invention relates to a transdermal therapeutic system (TTS) comprising (S)-ketamine as active ingredient. The invention further concerns the use of such a system as drug, in particular for the use in the treatment of depression and/or pain. In the past years, transdermal therapeutic systems have become increasingly important as dosage form for treating numerous diseases, because they have advantages over common dosage forms. Those are, for example, a precise and constant drug release, which is necessary for a constant concentration of the active ingredient in the blood plasma. Further, the first pass effect can be avoided and compliance can be increased, because the patient does not need to take tablets regularly. An advantage of transdermal therapeutic systems over other topical application systems such as ointments or creams is that they can be applied area accurate and therefore dosage accurate and that there is no risk of incidental wiping off the ointment with contamination of other regions. Further, ointments or tablets must be administered regularly, because a sustained release of the active ingredient usually cannot be achieved otherwise. A few years ago, it was believed that the implementation of active ingredients in transdermal therapeutic system would be easily achievable, so that this application form would be available for a large number of active ingredients. However, it turned out that this is not correct, because the molecular transport of ingredients via the skin poses a limiting factor. Thus, intense research is always required in order to provide transdermal therapeutic systems for the administration of new active ingredients. The active ingredient ketamine is long known for the treatment of pain. Recently, it has also been discovered that ketamine is suitable for the treatment of psychological disorders, in particular of depression. A transdermal therapeutic system provides an attractive option for the administration of ketamine. Transdermal therapeutic systems for the administration of ketamine are known from the prior art. For example, WO 2017/003935 A1 and WO 2018/195318 A1 disclose a TTS for the administration of ketamine, wherein a pressure sensitive adhesive is employed, which comprises free carboxyl groups as well as crystallization inhibitors. US 2007/196453 A1 discloses adhesive formulations, methods of drug delivery, and solidified layers for dermal delivery of a drug. The formulation can include a drug which is ketamine, a solvent vehicle, and a solidifying agent. However, the TTS for the administration of ketamine known from the prior art require optimization with regard to the flux of the active ingredient and the utilization of the active ingredient contained in the matrix layer. Further it is of advantage to provide formulations in which ketamine is present in a stable form without utilizing crystallization inhibitors. Thus, it was an object of the present invention to provide a TTS for the administration of (S)-ketamine, which has an optimal, i.e. as high flux of active ingredient as possible, especially in the first 2 to 12 hours after application, and in which the ketamine contained in the matrix layer is utilized in an optimal manner. Further, the ketamine contained in the TTS shall be present under conditions, where it is chemically and physically as stable as possible. Further, the TTS shall be simple in design and be economic in its production. This task has surprisingly been solved by a transdermal therapeutic system according to claim 1. Preferred embodiments are given in the dependent claims. In the present disclosure, the expressions "comprising" or "containing" can also mean "consisting of". The present invention concerns a transdermal therapeutic system, comprising a backing layer, which is not permeable for the active ingredient, and at least one matrix layer on one side of the backing layer, wherein the matrix layer contains at least one pressure sensitive adhesive, at least one penetration enhancer, and (S)-ketamine or a pharmaceutically acceptable salt or solvate thereof, characterized in that the at least one pressure sensitive adhesive comprises free hydroxyl groups, wherein the at least one pressure sensitive adhesive comprises an acrylic copolymer selected from 2-ethylhexyl acrylic acetate, vinyl acetate, and 2-hydroxyethyl acrylate comprising free hydroxyl groups, and wherein the at least one penetration enhancer is a mixture of levulinic acid and methyl laurate. Generally, the person skilled in the art knows several types of transdermal therapeutic systems. There are DIR (drug-in-reservoir)-systems, comprising a backing layer, a reservoir layer, an adhesive layer and a detachable protective layer. In these systems, the pharmaceutically active ingredient is only present in the reservoir layer, but not in the adhesive layer, which contains at least one adhesive polymer. Further, DIA (drug-in-adhesive)-systems are known, wherein a reservoir