Esketamine Suspension TTS

Abstract

The present invention relates to a transdermal therapeutic system comprising a backing layer that is impermeable to an 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 and ketamine or a pharmaceutically acceptable salt or solvate thereof, and wherein the at least one pressure-sensitive adhesive comprises a silicone pressure-sensitive adhesive, and further to its use as a medicament, particularly for the treatment of depression and pain.

Description

[Technical field]

[0001] The present invention relates to a transdermal therapeutic system (TTS) comprising ketamine as an active ingredient. The present invention further relates to the use of said system as a drug, in particular for use in the treatment of depression and / or pain. [Background technology]

[0002] In the past few years, transdermal therapeutic systems have become increasingly important as a dosage form for treating many diseases, as they have advantages over common dosage forms. For example, these advantages are the accurate and constant drug release required for a constant concentration of active ingredient in plasma. In addition, the patient does not need to take tablets regularly, so the first-pass effect can be avoided and compliance can be increased. The advantage of transdermal therapeutic systems over other topical application systems, such as ointments or creams, is that the area and therefore the dosage can be applied accurately, and there is no risk of accidentally contaminating other areas when wiping off the ointment. In addition, the sustained release of active ingredients usually cannot be achieved in other ways, so ointments or tablets must be administered regularly.

[0003] A few years ago, it was thought that the implementation of active ingredients in transdermal therapeutic systems was easily achievable and that this form of application would be available for a large number of active ingredients. However, this turned out to be incorrect, since the molecular transport of ingredients through the skin creates limiting factors. Therefore, intensive research is always required to provide transdermal therapeutic systems for the administration of new active ingredients.

[0004] The active ingredient ketamine has been known for many years for the treatment of pain. In recent years, it has also been found that ketamine is suitable for the treatment of psychological disorders, in particular depression.

[0005] Transdermal therapeutic systems offer an attractive option for the administration of ketamine.

[0006] Transdermal therapeutic systems for the administration of ketamine are known from the prior art.

[0007] For example, US Pat. Nos. 5,993,333 and 5,993,623 disclose a TTS for the administration of ketamine, in which a pressure-sensitive adhesive is used that contains a crystallization inhibitor in addition to free carboxyl groups.

[0008] In known formulations utilizing (meth)acrylate-based pressure-sensitive adhesives, ketamine is dissolved in the (meth)acrylate-based pressure-sensitive adhesive. This can be problematic because the saturation concentration of ketamine in the (meth)acrylate-based pressure-sensitive adhesive is rather low. If ketamine is present at a higher concentration in the (meth)acrylate-based pressure-sensitive adhesive, ketamine tends to recrystallize in the (meth)acrylate-based pressure-sensitive adhesive. Thus, higher concentrations of ketamine in the (meth)acrylate-based pressure-sensitive adhesive can usually only be achieved by further using crystallization inhibitors and solubility enhancers. In all cases, ketamine tends to recrystallize in the (meth)acrylate-based pressure-sensitive adhesive, adversely affecting the stability of such formulations.

[0009] Furthermore, the TTS for administration of ketamine known from the prior art require optimization with regard to the skin permeation flux of the active ingredient and the utilization of the active ingredient contained in the matrix layer.Furthermore, it would be advantageous to provide a formulation in which ketamine is present in a stable form without utilizing crystallization inhibitors and / or solubility enhancers. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] WO 2017 / 003935 A1 [Patent Document 2] WO 2018 / 195318 A1 Summary of the Invention [Problem to be solved by the invention]

[0011] It was therefore an object of the present invention to provide a TTS for the administration of ketamine, which has an optimal, i.e., as high as possible, skin permeation rate of the active ingredient, especially during the first 2 to 12 hours after application, and in which the ketamine contained in the matrix layer is utilized in an optimal manner. Furthermore, the ketamine contained in the TTS should be present under conditions that are as chemically and physically stable as possible. Furthermore, the TTS should be uncomplicated in design and economical in its manufacture. In particular, the ketamine should be present in the TTS in a non-dissolved state so that recrystallization can be prevented. Furthermore, the TTS should not contain crystallization inhibitors. However, the TTS according to the present invention should have a skin permeation rate of ketamine that is comparable to known formulations based on (meth)acrylate-based pressure-sensitive adhesives. [Means for solving the problem]

[0012] This problem has surprisingly been solved by the transdermal therapeutic system according to claim 1.

[0013] Preferred embodiments are set forth in the dependent claims. [Brief description of the drawings]

[0014] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] In the present disclosure, the expressions "comprising" or "containing" can also mean "consisting of."

[0016] The present invention relates to a transdermal therapeutic system comprising a backing layer that is not permeable to an 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 and ketamine or a pharma- ceutically acceptable salt or solvate thereof, and wherein the transdermal therapeutic system is characterized in that the at least one pressure sensitive adhesive comprises a silicone pressure sensitive adhesive.

[0017] In general, several types of transdermal therapeutic systems are known to those skilled in the art. There are DIR (drug-in-reservoir) systems, which include a backing layer, a reservoir layer, an adhesive layer and optionally a removable protective layer. In these systems, the pharma- ceutically active ingredient is present only in the reservoir layer and not in the adhesive layer, which contains at least one adhesive polymer.

[0018] Furthermore, DIA (drug-in-adhesive) systems are known, in which the reservoir layer is omitted and the pharma- ceutically active ingredient is present directly in the adhesive layer (also called the matrix layer), which contains at least one adhesive polymer.

[0019] The advantages of the DIA system over the DIR system are, among others, the less complicated manufacturing process and the lower risk of abuse, which is particularly relevant for the active ingredient ketamine.

[0020] Thus, the transdermal therapeutic system according to the invention is preferably a DIA system, i.e. the active ingredient ketamine or a pharma- ceutically acceptable salt or solvate thereof is present together with at least one pressure-sensitive adhesive, preferably in one and the same layer.

[0021] Such a TTS is characterized by its relatively simple design and therefore economically advantageous manufacture. Moreover, such a TTS has a higher skin permeation rate of the active ingredient compared to known TTS.

[0022] Importantly, ketamine is only soluble at sufficiently low concentrations, below 1% by weight, in the silicone pressure sensitive adhesive that at such low solubility, ketamine exists in an undissolved state and therefore has no tendency to recrystallize, without the need for any additional crystallization inhibitors and / or solubility enhancers.

[0023] Thus, the TTS according to the invention is preferably a suspension TTS, meaning that ketamine is present in the silicone pressure sensitive adhesive in an undissolved state, preferably in an amount of 99% or more, and is only 1% or less dissolved in the silicone pressure sensitive adhesive.

[0024] The concentration of ketamine in a silicone pressure sensitive adhesive, particularly the saturation concentration, can be determined by the following method.

[0025] A polymer film containing partially the active ingredient as a crystalline suspension (donor layer) is in contact with the drug-free patch matrix (acceptor layer) via a diffusion membrane.

[0026] This "sandwich" is stored and the concentration of the active ingredient in the patch matrix is ​​determined after a specific time interval after removal from the membrane: if it remains constant, a saturation concentration has been reached.

[0027] In this case, the donor is a silicone pressure sensitive adhesive. The membrane is a suitable membrane and should be smaller than the donor. The acceptor is of the same material as the acceptor. The smaller area mass of the acceptor speeds up the attainment of saturation concentration.

[0028] In order to measure the active substance content and concentration, the acceptor layer must be removable from the membrane.

[0029] Another method for determining the concentration of ketamine in a silicone pressure sensitive adhesive, particularly the saturation concentration, is as follows: The smallest possible seed crystals are contacted with the drug-loaded polymer film and their growth and dissolution behavior is evaluated microscopically at specific intervals.

[0030] Thus, films with various concentrations of active ingredient are produced and their spontaneous recrystallization behavior is examined by microscopy. These films can be prepared directly on microscope slides.

[0031] Additionally, another method for determining the concentration, particularly the saturation concentration, of ketamine in a silicone pressure sensitive adhesive is as follows: Masses with various concentrations of the active ingredient are prepared in vials and examined macroscopically for their spontaneous recrystallization behavior. The vials are not closed so that the solvent can evaporate under room temperature conditions.

[0032] Although all three of the above methods yield essentially the same results, the "sandwich" method is preferred.

[0033] Furthermore, the ketamine contained in the matrix layer can be utilized in an optimal manner.

[0034] Furthermore, the TTS according to the invention has high skin tolerance.

[0035] The term "optimally utilized" indicates that the ketamine contained in the matrix layer diffuses to the greatest extent possible from the matrix layer to the patient's skin during application of the TTS on the patient's skin, such that as little as possible of the "unutilized" active ingredient remains in the matrix layer after application.

[0036] The term "backing layer that is not permeable to the active ingredient" indicates that the backing layer is essentially, preferably completely, impermeable to the active ingredient ketamine.

[0037] Suitable materials for the backing layer include, for example, materials such as polyesters, such as polyethylene terephthalate, polybutylene terephthalate, polyethylene naphthalate, polyethylene or polypropylene, polyolefins, such as ethylene-vinyl acetate, polyvinyl chloride, polyamides (nylons) and / or polyurethanes. The backing layer may be composed of a composite material, and preferably includes an aluminum-coated film and one of the above materials.

[0038] The pressure-sensitive adhesive comprises or preferably is a polymer that acts as a pressure-sensitive adhesive as defined in DIN EN 923:2016-03.

[0039] The TTS according to the present invention contains ketamine as a pharma- ceutical active ingredient.

[0040] Ketamine is (S)-(+)-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one ((S)-ketamine), (R)-(-)-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one ((R)-ketamine), as well as racemic (RS)-(±)-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one. Pharmaceutically acceptable salts and solvates of these compounds are also included. Mixtures of these compounds are also included.

[0041] In the transdermal therapeutic system according to the present invention, ketamine is preferably present as (S)-ketamine and / or a pharma- ceutically acceptable salt thereof, such as (S)-ketamine.HCl.

[0042] Most preferably, the pharma- ceutical active ingredient in the transdermal therapeutic system according to the present invention comprises (S)-ketamine, which is present in the form of ketamine free base.

[0043] In certain embodiments, the TTS may contain any additional pharma- ceutically active ingredient apart from ketamine, such as, for example, nonsteroidal anti-inflammatory drugs (NSAIDs, e.g., ibuprofen, ketoprofen, meloxicam, piroxicam, indomethacin), COX-2 inhibitors (e.g., celecoxib, etoricoxib), opioids (e.g., fentanyl, buprenorphine, morphine, codeine, oxycodone, hydrocodone, dihydromorphine, pethidine), MAOIs (irreversible and nonselective, e.g., phenelzine, tranylcypromine, isocarboxazid), MAOIs (reversible inhibitors of MAO-A, e.g., moclobemide), MAOIs (preferential inhibitors of MAO-B, e.g., deprenyl), tricyclic (and tetracyclic) antidepressants (e.g., clomipramine, imi ... The therapeutic agent may be one or more of the following groups: selective serotonin reuptake inhibitors (e.g., fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, escitalopram), selective noradrenaline reuptake inhibitors (e.g., reboxetine, atomoxetine), noradrenaline and dopamine reuptake inhibitors / releasing drugs (e.g., bupropion), serotonin and noradrenaline reuptake inhibitors (e.g., venlafaxine, milnacipran, duloxetine), serotonin antagonists / reuptake inhibitors (e.g., nefazodone, trazodone), alpha2-adrenergic receptor antagonists (e.g., mirtazapine).

[0044] Preferably, silicone pressure sensitive adhesive is obtained after condensation reaction between silanol endblocked polydimethylsiloxane (PDMS) and silicate, preferably silicate resin.To reduce the silanol content of adhesive polymer, silicone pressure sensitive adhesive is further reacted, preferably with trimethylsilyl.Then, silicone pressure sensitive adhesive is preferably diluted with a suitable solvent, for example n-heptane, to obtain solvent-based silicone pressure sensitive adhesive.

[0045] In principle, the solvent is not limited. However, it is preferable to use a solvent in which ketamine is insoluble or only poorly soluble. Preferably, ketamine should be dissolved in the solvent in an amount of less than 3% by weight, preferably less than 2% by weight, and most preferably less than 1% by weight.

[0046] Most preferably, the solvent comprises or is n-heptane.

[0047] Preferably, silicone pressure-sensitive adhesives which can be used according to the invention are pressure-sensitive adhesives made on the basis of silicone polymers, such as dimethiconol / trimethylsilyloxysilicate crosspolymers and / or trimethylsilyl-treated dimethiconol / trimethylsilyloxysilicate crosspolymers, which preferably contain at least 30% by weight, in particular 35-95% by weight, particularly preferably 40-90% by weight or 40-60% by weight or 45-55% by weight of silicone polymer with respect to silicate.

[0048] In one embodiment, the silicone pressure sensitive adhesive that can be used according to the present invention is a pressure sensitive adhesive made based on silicone polymer, such as dimethiconol / trimethylsiloxysilicate crosspolymer and / or trimethylsilyl-treated dimethiconol / trimethylsiloxysilicate crosspolymer, which preferably contains 40% by weight of silicone polymer and 60% by weight of silicate.Such adhesives can be called "medium tack adhesives".

[0049] In another embodiment, the silicone pressure-sensitive adhesive that can be used according to the present invention is a pressure-sensitive adhesive made based on silicone polymer, such as dimethiconol / trimethylsiloxysilicate crosspolymer and / or trimethylsilyl-treated dimethiconol / trimethylsiloxysilicate crosspolymer, which preferably contains 45% by weight of silicone polymer and 55% by weight of silicate.This adhesive can be called "high tack adhesive".

[0050] Preferably, a TTS according to the invention comprises a 1:1 (by weight) ratio of a "weak tack adhesive" and a "strong tack adhesive" as described above.

[0051] The advantage of such a mixture is that it makes it possible to minimize the so-called "cold flow", which is understood as the leakage of adhesive from the edges of the TTS, especially during storage.

[0052] All of the aforementioned silicone pressure sensitive adhesives preferably contain n-heptane as a solvent.

[0053] The aforementioned silicone pressure sensitive adhesives are preferably present in the respective solvent, preferably n-heptane, in an amount of 50-80% by weight, preferably at a solids content of about 60-75% by weight.

[0054] Preferably, the silicone pressure sensitive adhesive has a peel adhesion of about 700 g / cm for a strong tack adhesive and / or 900 g / cm for a weak tack adhesive as defined above.

[0055] Preferably, the silicone pressure sensitive adhesive has a viscosity of about 14 kg / 6.3 cm for a strong adhesive as defined above. 3 , and weak adhesive: approx. 17kg / 6.3cm 3 has a shear value of

[0056] Preferably, the silicone pressure sensitive adhesive has a viscosity of about 5×10 at 0.01 rad / s and 30° C. (P) for a strong tack adhesive as defined above. 6 P and weak adhesive: approx. 1x10 8 It has a viscosity of P.

[0057] The use of the above silicone pressure sensitive adhesives, preferably when based on n-heptane, is that ketamine is not soluble in these materials.

[0058] According to a preferred embodiment, the transdermal therapeutic system according to the invention comprises as pressure sensitive adhesive at least one of the silicone pressure sensitive adhesives described above, which further comprises a silicone polymer preferably formed from polydimethyldiphenylsiloxane.

[0059] Silicone pressure sensitive adhesives for use in the present invention may further contain silicone oils and / or other softeners (plasticizers).

[0060] In addition, mixtures or condensates of silicone resins and polyorganosiloxanes are also contemplated. Amine-resistant silicone pressure sensitive adhesives are further preferred, which are characterized in that they contain no or only low amounts of free silanol functional groups since the Si-OH groups are alkylated.

[0061] In accordance with a preferred embodiment, a silicone pressure sensitive adhesive is used that softens when heated, thereby achieving a suitable viscosity for the incorporation of one, two or more solid drugs, and, for applications using slot extrusion or coating, that again exists in a non-flowable state after cooling.

[0062] Suitable silicone pressure sensitive adhesives have softening temperatures in the range between 50°C and 200°C, preferably between 75°C and 170°C, and particularly preferably between 100°C and 150°C.

[0063] Suitable silicone pressure sensitive adhesives for use in the present invention are, for example, Dow Corning's hot melt pressure sensitive adhesives BIO-PSA Q7-4201 and / or BIO-PSA 4301. Thereby, BIO-PSA Q7-4201 is a "weak tack adhesive" and BIO-PSA Q7-4301 is a "strong tack adhesive" as defined above. Silicone pressure sensitive adhesives, and particularly silicone hot melt pressure sensitive adhesives, suitable for use in the present invention and as described above are known to those skilled in the art and are commercially available.

[0064] Furthermore, the transdermal therapeutic system according to the invention is preferably characterized in that the at least one silicone pressure sensitive adhesive is present in the matrix layer in an amount of 70 to 95% by weight, preferably 75 to 95% by weight, more preferably 78 to 92% by weight, based on the total weight of the matrix layer.

[0065] Furthermore, the transdermal therapeutic system according to the invention is preferably characterized in that the matrix layer does not contain any pressure-sensitive adhesive containing (meth)acrylate groups, which has the advantage that ketamine is present in an undissolved state in the TTS, thereby preventing recrystallization.

[0066] In particular, the matrix layer should not include any pressure sensitive adhesives that contain free hydroxyl groups, including acrylic copolymers selected from 2-ethylhexyl acrylic acetate, vinyl acetate, and 2-hydroxyethyl acrylate.

[0067] Pressure-sensitive adhesives to be avoided in the matrix layer are known under the trade name DURO-TAK from Henkel, Germany, in particular DURO-TAK 87-4287, DURO-TAK 87-2516, DURO-TAK 2287 or DURO-TAK 2510.

[0068] Furthermore, the transdermal therapeutic system according to the invention is preferably characterized in that the matrix layer comprises at least one penetration enhancer.

[0069] The at least one penetration enhancer is a compound that stabilizes the active ingredient and thus provides a relatively high and stable absorption of the active ingredient through the skin over a long period of time.

[0070] The penetration enhancer is preferably selected from carboxylic acids, fatty acids and / or fatty acid esters, such as levulinic acid, valeric acid, hexanoic acid, caprylic acid, nonanoic acid, decanoic acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, 3-methylbutanoic acid, neoheptanoic acid, neonanonic acid, isostearic acid, oleic acid, palmitoleic acid, linoleic acid, vaccenic acid, petroselinic acid, elaidic acid, oleic acid, arachidonic acid, gadoleic acid, erucic acid, methyl propionate, methyl valerate, diethyl sebacate, methyl laurate, ethyl laurate, ethyl oleate, isopropyl decanoate, isopropyl myristate, isopropyl palmitate and / or isopropyl oleate.

[0071] In another embodiment, the TTS according to the invention does not contain levulinic acid.

[0072] Furthermore, compounds such as diethyltoluamide (DEET), propylene glycol monocaprylate, propylene glycol, polyethylene glycol, diisopropyl adipate, eugenol, transcutol, lauryl lactate and / or oleyl alcohol are suitable as penetration enhancers.

[0073] Since methyl laurate has the advantage that ketamine exhibits a fast onset of transdermal flux, the transdermal therapeutic system according to the invention is more preferably characterized in that the at least one penetration enhancer comprises methyl laurate.

[0074] The transdermal therapeutic system according to the invention is more preferably characterized in that only one penetration enhancer, preferably only methyl laurate, is present in at least one matrix layer.

[0075] Furthermore, the transdermal therapeutic system according to the invention is preferably characterized in that the at least one penetration enhancer is present in the matrix layer in an amount of 1 to 15% by weight, preferably 2 to 12% by weight, most preferably about 10% by weight, based on the weight of the matrix layer.

[0076] The transdermal therapeutic system according to the present invention preferably contains ketamine in the matrix layer in an amount of 1 to 25% by mass, preferably 5 to 15% by mass, based on the mass of the matrix layer.

[0077] The transdermal therapeutic system according to the invention is further preferably characterized in that the matrix layer comprises at least one antioxidant.

[0078] The at least one antioxidant is a chemical compound that prevents or reduces the oxidation of other substances, especially active ingredients, and thus acts against the aging of the therapeutic system. In particular, antioxidants are characterized by their effect as radical scavengers and that they prevent the oxidative degradation caused by atmospheric oxygen of sensitive molecules, especially active ingredients. The at least one antioxidant is preferably selected from the group consisting of alpha-tocopherol, ascorbyl palmitate and / or dibutylhydroxytoluene.

[0079] Preferably, the transdermal therapeutic system according to the invention contains at least one antioxidant in the matrix layer in an amount of 0.001 to 5% by weight, preferably 0.01 to 2% by weight, based on the total weight of the matrix layer.

[0080] Apart from the above-mentioned components, the matrix layer may further contain common additives. According to their function, these can be classified as softeners / plasticizers, tackifiers, carriers and / or extenders. The relevant physiologically non-critical substances are known to those skilled in the art.

[0081] Carriers and / or extenders such as silica gel, titanium dioxide, and zinc oxide may be used in conjunction with the polymer to affect certain physical parameters such as cohesiveness and bond strength in desired ways.

[0082] Additionally, abuse deterrent agents may be added to the transdermal therapeutic system to prevent or at least reduce its potential for abuse. Examples of substances that may be used as abuse deterrent agents are bittering agents, gel forming agents, stimulants, substances that produce acute gastrointestinal, cardiac or respiratory effects, substances that produce severe nausea or vomiting, substances that produce unpleasant odors, sleep inducing substances, substances that result in the inactivation or degradation of the active ingredient upon attempted extraction.

[0083] Additionally, the transdermal therapeutic system may also include abuse-deterrent features that render the active agent and / or the system ineffective when used in any manner other than its intended use, i.e., transdermal application.

[0084] Preferably, the transdermal therapeutic system according to the present invention has a matrix layer of 30 to 400 g / m 2 , preferably 50 to 250 g / m 2 , and most preferably 70 to 150 g / m 2 The present invention is further characterized in that it has an areal mass of

[0085] Preferably, the transdermal therapeutic system according to the invention is further characterized in that it comprises a removable protective layer on the side of the matrix layer on which the backing layer is not disposed.

[0086] Removable protective layers, which are in contact with the matrix and are removed before application, comprise, for example, the same materials as those used for the manufacture of the backing layer, except that they have been made removable, for example by siliconization. Other removable protective layers are polytetrafluoroethylene, treated paper, cellophane, polyvinyl chloride, etc.

[0087] Furthermore, the present invention relates to the above-mentioned transdermal therapeutic system as a medicament.

[0088] The present invention also relates to the above-mentioned transdermal therapeutic system for use in the treatment of major depressive disorder (MDD), also known simply as depression. In particular, the described transdermal therapeutic system may be used for reducing the risk of suicide and / or for the treatment of treatment-resistant depression (TRD).

[0089] Major depressive disorder (MDD) is a mental disorder characterized by a pervasive and persistent low mood accompanied by low self-esteem and loss of interest or pleasure in normally enjoyable activities. Major depressive disorder is a disabling condition that adversely affects a person's family, work or school life, sleep and eating habits, and overall health.

[0090] Treatment-resistant depression (TRD) describes a condition suffered by people with major depressive disorder (MDD) who do not respond adequately to a course of appropriate antidepressant medication within a specific period of time.

[0091] Further subtypes recognized by The American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM-5) are melancholic depression, atypical depression, catatonic depression, anxiety-related depression, perinatal-onset depression, and seasonal affective disorder.

[0092] The present invention also relates to the above transdermal therapeutic system for use in the treatment of pain.

[0093] Pain is a sensation of distress caused by an often intense or injurious stimulus. Pain that persists for a long period of time is called chronic or persistent, and pain that dissipates quickly is called acute.

[0094] Nociceptive pain is caused by stimulation of sensory nerve fibers (nociceptors) that respond to stimuli approaching or exceeding noxious intensity, and can be classified according to the modality of the noxious stimulus. The most well-known categories are thermal, mechanical, and chemical. Some nociceptors respond to more than one of these sensory modalities and are therefore designated multimodal.

[0095] Nociceptive pain can also be divided into "visceral" pain, "deep somatic" pain and "superficial somatic" pain.

[0096] Neuropathic pain is caused by injury or disease that affects any part of the nervous system involved in body sensation (somatosensory system). Neuropathic pain can be divided into peripheral, central, or mixed (peripheral and central) neuropathic pain. Peripheral neuropathic pain is often described as "burning," "throbbing," "electrical," "stabbing," or "numb and tingling."

[0097] Additionally, the transdermal therapeutic systems of the present invention may be used in a variety of administration schemes, such as continuous, repeated or staggered administration.

[0098] In continuous administration, the transdermal system is applied at intervals lasting at least 12 hours to achieve a concentration of the active ingredient in the plasma of the individual.

[0099] The repeated administration is preferably carried out consecutively without delay, i.e. when one or more TTS according to the invention are removed at the end of an application interval, one or more TTS according to the invention for the subsequent application interval are immediately applied. Preferably, the time interval during which no TTS according to the invention may be applied to the body at all is equal to or less than 10 minutes, more preferably equal to or less than 5 minutes.

[0100] In staggered administration, the transdermal system is applied at intervals lasting at least 4 hours to achieve a concentration of the active ingredient in the plasma of the individual.

[0101] Staggered administration is preferably performed daily, twice weekly or once weekly, i.e. when one or more TTS according to the invention are removed at the end of an application interval, one or more TTS according to the invention for the subsequent application interval are applied taking into account a drug-free interval of at least 18 hours.

[0102] The application period contemplated for the transdermal therapeutic system according to the invention is preferably at least 6 hours, more preferably at least 12 hours, and even more preferably at least 24 hours. The amount of active ingredient is preferably adapted to the desired application time.

[0103] In a preferred embodiment, all TTS according to the invention are administered to the same skin area of ​​the individual throughout the period, ie a given skin area of ​​the individual is covered or has applied thereto a TTS according to the invention.

[0104] In another preferred embodiment, all TTS according to the invention are administered onto different skin areas of the individual each time throughout the entire period, i.e. a given skin area of ​​the individual is not repeatedly covered with TTS according to the invention or repeatedly applied with TTS according to the invention.

[0105] The invention is further described below using non-limiting examples. EXAMPLES

[0106] In the examples below, the following ingredients were used:

[0107] BIO-PSA Q7-4201 and BIO-PSA 4301: Trimethylsilyl-treated dimethiconol / trimethylsiloxysilicate crosspolymer. DURO-TAK 387-4287: Pressure-sensitive adhesive based on an acrylate-vinyl acetate copolymer containing free hydroxyl groups, obtained without the use of crosslinkers. DURO-TAK 387-2054: Pressure-sensitive adhesive based on an acrylate-vinyl acetate copolymer containing free carboxyl groups, obtained using a crosslinker. Plastoid B: Copolymer of butyl methacrylate and methyl methacrylate (crystallization inhibitor) Transcutol: Diethylene glycol monoethyl ether (accelerant). Eutanol HD: 9-Octadecan-1-ol (accelerator) HPC / isopropanol: Hydroxypropyl cellulose (gelling agent; solids content 2% by weight) dissolved in isopropanol. HPC / 1,2-propanediol: Hydroxypropyl cellulose (gelling agent; solids content 2% by weight) dissolved in 1,2-propanediol Crospovidone: Cross-linked polyvinylpolypyrrolidone (structuring agent)

[0108] Example 1: The formulation of the S-ketamine-containing coating composition of this example is summarized in Table 1 below.

[0109] [Table 1]

[0110] For Example 1a, S-ketamine base was placed in a beaker along with the solvent (ethyl acetate), levulinic acid, and methyl laurate. The acrylic pressure sensitive adhesive polymer DURO-TAK 387-4287 was added, and the mixture was then stirred at up to 300 rpm until a homogenous mixture was obtained (stirring time was approximately 90 minutes).

[0111] For Example 1b, S-ketamine base was placed in a beaker along with a solvent (n-heptane) and methyl laurate. The mixture was stirred at 300 rpm for about 30 minutes, and then silicone pressure sensitive adhesives DOW CORNING BIO-PSA Q7-4201 and DOW CORNING BIO-PSA Q7-4301 were added. The mixture was then stirred at up to 900 rpm until a homogenous mixture was obtained (stirring time was about 90 minutes).

[0112] For Example 1c, a beaker was charged with HPC / isopropanol solution, methyl laurate, and S-ketamine base. The mixture was stirred at 300 rpm for about 30 minutes, and then silicone pressure sensitive adhesives DOW CORNING BIO-PSA Q7-4201 and DOW CORNING BIO-PSA Q7-4301 were added. The mixture was then stirred at up to 900 rpm until a homogenous mixture was obtained (stirring time was about 90 minutes).

[0113] For Example 1d, a beaker was charged with the HPC / 1,2-propanediol solution, methyl laurate, and S-ketamine base. The mixture was stirred at 300 rpm for about 30 minutes, and then silicone pressure sensitive adhesives DOW CORNING BIO-PSA Q7-4201 and DOW CORNING BIO-PSA Q7-4301 were added. The mixture was stirred at up to 900 rpm until a homogenous mixture was obtained (stirring time was about 90 minutes).

[0114] For Example 1e, S-ketamine base was placed in a beaker along with solvent (ethyl acetate), levulinic acid, Eutanol HD, and Transcutol. Acrylic pressure sensitive adhesive polymer DURO-TAK 387-2054 was added, and the mixture was then stirred at up to 300 rpm for approximately 30 minutes. Plastoid B was added, and the mixture was then stirred at up to 350 rpm until a homogenous mixture was obtained (stirring time was approximately 120 minutes).

[0115] For Example 1f, a beaker was charged with the HPC / 1,2-propanediol solution and S-ketamine base. The mixture was stirred at 300 rpm for about 30 minutes, and then silicone pressure sensitive adhesives DOW CORNING BIO-PSA Q7-4201 and DOW CORNING BIO-PSA Q7-4301 were added. The mixture was then stirred at up to 900 rpm until a homogenous mixture was obtained (stirring time was 90 minutes).

[0116] For Examples 1a and 1e, the resulting S-ketamine-containing coating composition was coated onto a polyethylene terephthalate film (silicone-treated, 75 μm thick, which can serve as a release liner) and dried for about 15 minutes at room temperature and 15 minutes at 60° C. The coating thickness was 78.9 g / m, respectively. 2 (Example 1a) and 81.5 g / m 2 The areal mass of the matrix layer of (Example 1e) was obtained. The dried film was laminated with a polyethylene terephthalate backing layer (thickness 23 μm) to obtain an S-ketamine-containing adhesive layer structure.

[0117] For Examples 1b, 1c, 1d and 1f, the resulting S-ketamine-containing coating composition was coated onto a polyethylene terephthalate film (fluoropolymerized, 75 μm thick, which can serve as a release liner) and dried for about 15 minutes at room temperature and 15 minutes at 60° C. The coating thickness was 71.0 g / m, respectively. 2 (Example 1b), 81.9 g / m 2 (Example 1c), 78.5 g / m 2 (Example 1d) and 79.6 g / m 2 The areal mass of the matrix layer of (Example 1f) was obtained. The dried film was laminated with a polyethylene terephthalate backing layer (thickness 19 μm) to obtain an S-ketamine-containing adhesive layer structure.

[0118] Then, individual systems are punched out from the S-ketamine-containing adhesive layer structure. In certain embodiments, the TTS may be provided with an additional adhesive layer, preferably with rounded corners and a larger surface area, including a pressure-sensitive adhesive matrix layer that does not contain an active agent. This is advantageous when the TTS does not adhere well to the skin based on its physical properties alone and / or when the S-ketamine-containing matrix layer has prominent corners (square or rectangular) for the purpose of avoiding waste. The systems are then punched out and sealed in a bag of primary packaging material.

[0119] Skin permeation rate measurement The permeation amount and the corresponding skin permeation rate of the TTS prepared according to Examples 1a-1f were determined by in vitro experiments carried out using 7.0 ml Franz diffusion cells according to the OECD guidelines (adopted on April 13, 2004) and the EMA guidelines on the quality of transdermal patches (EMA / CHMP / QWP / 608924 / 2014, adopted on October 23, 2014). Split-thickness human abdominal skin (female) was used. A dermatome was used to prepare the skin to a thickness of 500 μm for all TTS, leaving the epidermis intact. Area 1.152 cm 2 Die cuts of 100 μg / cm were punched out of the TTS. The amount of S-ketamine permeation in the receptor medium (phosphate buffer pH 5.5 containing 0.1% saline azide as an antibacterial agent) of Franz-type cells at a temperature of 32±1°C was measured after 72 hours, and the corresponding skin permeation rate [μg / cm 2 The results are shown in Table 2 and Figure 1.

[0120] [Table 2]

[0121] Use of S-Ketamine The availability of S-ketamine at 72 hours was calculated based on the amount of S-ketamine permeated through the receptor and the initial S-ketamine content in the TTS. The results are shown in Table 3 and Figure 2.

[0122] [Table 3]

[0123] The results summarized in Figures 1-2 show improved utilization of the active ingredient and improved skin permeation rate of the active ingredient compared to formulations using acrylic adhesives.

[0124] Example 2: The formulations of the S-ketamine-containing coating compositions of Examples 2a-d were prepared similarly to those described in Example 1 and are summarized in Table 4 below.

[0125] [Table 4]

[0126] The skin permeation rates were determined as in Example 1 and are summarized in FIG.

[0127] Use of S-Ketamine The availability of S-ketamine at 72 hours was calculated based on the amount of S-ketamine permeated into the receptor and the initial S-ketamine content in the TTS. The results are shown in Table 5 and FIG.

[0128] [Table 5]

[0129] The results summarized in Figures 3-4 show improved utilization of the active ingredient by reducing the coating mass, and faster and higher onset of skin permeation by using higher concentrations of enhancers. Crospovidone is an equivalent alternative compared to HPC.

[0130] Example 3: The formulations of the S-ketamine-containing coating compositions of Examples 3a-h were prepared similarly to those described in Example 1 and are summarized in Table 6 below.

[0131] [Table 6]

[0132] The skin permeation rate and (S)-ketamine utilization were analyzed as in Example 1.

[0133] The respective results are shown in Figures 5 and 6.

Claims

1. 1. A transdermal therapeutic system comprising a backing layer that is not permeable to an 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 and ketamine or a pharma- ceutically acceptable salt or solvate thereof, wherein the at least one pressure sensitive adhesive comprises a silicone pressure sensitive adhesive, and the matrix layer comprises at least one penetration enhancer, wherein the penetration enhancer is methyl laurate.

2. The transdermal therapeutic system according to claim 1, wherein the ketamine is (S)-ketamine or a pharma- ceutically acceptable salt or solvate thereof.

3. 3. The transdermal therapeutic system of claim 1, wherein the ketamine is present in the form of ketamine free base.

4. A transdermal therapeutic system described in any one of claims 1 to 3, wherein the ketamine present in the form of ketamine free base is (S)-ketamine present in the form of ketamine free base.

5. The transdermal therapeutic system of any one of claims 1 to 4, wherein the silicone pressure sensitive adhesive comprises a dimethiconol / trimethylsiloxysilicate crosspolymer and / or a trimethylsilyl-treated dimethiconol / trimethylsiloxysilicate crosspolymer.

6. The transdermal therapeutic system of any one of claims 1 to 5, wherein the silicone pressure sensitive adhesive is present in the matrix layer in an amount of 70 to 95% by weight, based on the total weight of the matrix layer.

7. The transdermal therapeutic system of any one of claims 1 to 6, wherein the matrix layer comprises at least one penetration enhancer in an amount of 1 to 15% by weight, based on the total weight of the matrix layer.

8. The transdermal therapeutic system according to any one of claims 1 to 7, wherein the matrix layer does not comprise any pressure-sensitive adhesive containing (meth)acrylate groups.

9. The transdermal therapeutic system according to any one of claims 1 to 8, wherein the matrix layer contains ketamine in an amount of 1 to 25% by weight based on the weight of the matrix layer.

10. The transdermal therapeutic system according to any one of claims 1 to 9, wherein the matrix layer comprises at least one antioxidant.

11. The transdermal therapeutic system described in claim 10, wherein at least one antioxidant is selected from the group consisting of alpha-tocopherol, ascorbyl palmitate and / or dibutylhydroxytoluene.

12. The matrix layer has an area mass of 30 to 400 g / m 2 The transdermal therapeutic system according to any one of claims 1 to 11, comprising:

13. The transdermal therapeutic system according to any one of claims 1 to 12, further comprising a removable protective layer on the side of the matrix layer on which the backing layer is not disposed.

14. A transdermal therapeutic system according to any one of claims 1 to 13 for use as a medicament.

15. A transdermal therapeutic system according to any one of claims 1 to 14 for use in the treatment of depression and / or pain.

Images