EP2262490A1

EP2262490A1 - Transdermal therapeutic system having stabilized membrane

Info

Publication number: EP2262490A1
Application number: EP09719465A
Authority: EP
Inventors: Michael Horstmann; Mohammad Sameti; Patrick Mohr
Original assignee: LTS Lohmann Therapie Systeme AG
Current assignee: LTS Lohmann Therapie Systeme AG
Priority date: 2008-03-11
Filing date: 2009-02-28
Publication date: 2010-12-22
Also published as: CA2717191C; CN101969937A; DE102008013701A1; KR101640950B1; JP5608565B2; AU2009225053B2; KR20100135233A; ZA201005663B; WO2009112167A1; BRPI0909653A2; JP2011513447A; MX2010009969A; US8882729B2; CA2717191A1; AU2009225053A1; US20120245537A1

Abstract

The invention relates to a transdermal therapeutic system made of the following layers: a carrier layer (T), an active substance layer (R), a membrane layer (M) and optionally an adhesive layer (K), wherein the carrier layer (T) is impenetrable to the active substance and to water, the active substance layer (R) comprises as an active substance component the salt of an alkali reactive active substance, such as a CNS-active amine in combination with at least one alkali reactive further component, and a polymer component (Pl), wherein the active substance is released from the active substance layer (R) only by the moisture entering from the exterior through the membrane layer (M), and the membrane layer (M) is made of a polymer component (P2), allowing a uniform delivery of basic active substances to the skin.

Description

Transdermal therapeutic system with stabilized membrane

The present invention relates to transdermal therapeutic systems and their preparation. Transdermal therapeutic systems (TTS) are pharmaceutical dosage forms that can be applied to the skin of a mammal and are designed to make a drug systemically available after transdermal ingestion. Transdermal therapeutic systems can increase the therapeutic value of administering a drug by ensuring a constant delivery of the drug over a longer period of time into the blood compartment. The benefits of this continuous drug delivery are primarily the extended application intervals leading to improved "patient compliance" and the pharmacokinetically improved plasma concentration time profile, which provides longer duration of action with fewer side effects.Other benefits found in the transdermal route of administration a transdermal therapeutic system are based, are lower dosage, improved gastrointestinal tolerability and increased bioavailability by circumventing the so-called "first-pass effect".

Because of these advantages, transdermal therapeutic systems have enjoyed increasing popularity in the therapy of various diseases for a number of years. Such transdermal systems are, for example, for the active ingredients estradiol, nicotine, norethisterone acetate, fentanyl, tulobuterol, ethinyl estradiol, buprenorphine and nitroglycerin introduced into the therapy. The structure of a transdermal therapeutic system is usually thin and layered, so that with the help of the directly skin-facing layer results in an at least temporary sticky connection to the skin through which the drug is delivered. TTS usually consist of a drug-impermeable carrier layer (T), the so-called "backing layer", an active substance-containing layer (R), for example an active substance layer or matrix layer, and an adhesive layer (K) for attachment to the skin.

This adhesive layer (K) may also be identical to the drug-containing or active substance-containing layer (eg, drug layer or matrix layer). The TTS mostly includes further a drug-impermeable protective layer to be removed before the application, the so-called "release liner." To improve the release of active ingredient, it is also possible to provide a membrane layer (M) which controls the delivery to the skin.

To improve the permeation of the respective active substance from the TTS through the skin, various solid polymers (eg polyacrylates, silicones, polyisobutylenes), resins and other pharmaceutical excipients are also used, which are liquid at room temperature and partly allow an adjustment of the bond strength and the diffusion improvement within the transdermal therapeutic system or to improve the permeation of the skin through the skin.

Both the active ingredients used and the often-used liquid auxiliaries can impair the properties which interfere with the production of TTS, such as e.g. Have volatility and / or thermolability under the process conditions. This can result in significant losses in the process of producing the transdermal systems, which often consists of mixing the starting materials in a suitable organic solvent, then coating them in a thin layer on a base film and subsequently, usually continuous, drying at elevated temperature ,

These losses, especially of expensive active ingredients, inter alia at the last stage of manufacture of the TTS, during drying, can lead to dosing distortions and / or performance losses of the TTS produced. These technical problems may obstruct or limit proper manufacture and adequate therapeutic use, particularly in humans.

Transdermal Therapeutic Systems have been used in different designs (eg reservoir with and without membrane) for many years for different drugs and therapies. Numerous transdermal systems are spatially characterized by a suitable compartmentalization, for example in an active substance layer (R), a membrane layer (M) and an adhesive layer (K) for reasons of better supply control of the active substance. Also, transdermal systems are known, which initially contain the active ingredient in the form of a salt for reasons of stability of the drug and it only after reaction with z. B. alkaline substances available. However, these systems have the technical disadvantage that their release often runs uncontrolled and / or technically difficult to implement addition of liquid alkaline reagents is required.

The transdermal therapeutic systems of the prior art in the field of alkaline agents have a number of other disadvantages. Thus, membrane / reservoir systems which already contain the alkaline active ingredient often have the disadvantage that the initially contained dissolved active substance via the connection with the membrane due to diffusion accumulates the adhesive layer (K) to high concentrations of active ingredient. This high concentration in the adhesive layer (K) is reduced only after several hours of wearing to a level that results from the theoretical metering of the permeation rate due to the membrane permeation.

On the one hand, the undesirable, initially high absorption of active ingredients via the skin can lead to increased skin reactions. Furthermore, when higher blood level peaks occur

Active substance at the beginning of wearing the TTS with corresponding side effects. Another disadvantage of these known systems is the often poor stability of alkaline agents in a membrane preparation. Numerous oxidation,

Ester cleavage and hydrolysis reactions may alter the drug in long-term storage. In contrast, most alkaline agents in salt form are extremely stable.

An object of the present invention is to provide a transdermal therapeutic system (TTS) suitable for a stability-sensitive, volatile and / or skin-irritating active ingredient (W), said active ingredient (W) being brought into a form containing a supply of active substance membrane-controlled allows. Furthermore, the TTS should have a shelf life of at least two years without significant formation of degradation products of the drug. Also, the TTS on the human or animal skin should have a good or at least satisfactory tolerability.

These technical objects are achieved by a transdermal therapeutic system (TTS) containing, or preferably consisting essentially of the following layers:

a) a carrier layer (T) b) an active substance layer (R), c) a membrane layer (M) and optionally d) an adhesive layer (K),

wherein the carrier layer (T) for the active ingredient and preferably also for water impermeable, the active ingredient layer (R) as the active component (WK) the salt of an alkaline reacting active ingredient (W) in combination with at least one alkaline reacting further ingredient (B) and a contains polymeric component (Pl), wherein the active ingredient (W) from the drug layer (R) only by the from the outside through the

Membrane layer (M) immigrating moisture (for example, from the skin of the

Patient) is released from the active component (WK), and the membrane layer (M) consists of a polymeric component (P2).

There are many choices for the different polymeric components of the different layers of the TTS.

In a preferred embodiment of the transdermal therapeutic systems according to the invention, the active ingredient layer is constructed as a so-called matrix system.

This is a system in which the pressure-sensitive or non-pressure-sensitive adhesive polymer matrix generally contains the active ingredient component in dissolved and / or suspended form. The polymer matrix often consists of pressure-sensitive adhesives based on polyacrylates. The polyacrylates used are prepared from monomers (acrylic acid and methacrylic acid and in each case their esters, if appropriate also with vinyl acetate), which may contain functional groups. These functional groups can survive the polymerization of the monomers used unchanged and can influence the properties of the resulting polyacrylate, in particular the tackiness and adhesion.

From EP-A 0 614 356 examples of such polyacrylate-based adhesive formulations are known. The person skilled in the art distinguishes polyacrylates with -OH groups (hydroxyl groups) and those with -COOH groups (carboxyl groups) as functional groups. The hydroxyl-containing polyacrylates include, for example, the commercial product DuroTak 87-2287. The carboxyl-containing polyacrylates include, for example, the product DuroTak 87-2051. Both polyacrylates are provided by the manufacturer National Starch (Bridgewater, USA).

These polyacrylates have proven to be stable and well-tolerated pressure-sensitive adhesive polymers for the preparation of matrices for the transdermal therapeutic systems. A disadvantage of the transdermal therapeutic systems containing polyacrylates, which contain the said functional groups (hydroxyl group, carboxyl group), is the low drug utilization. This is particularly noticeable in hormone-containing transdermal therapeutic systems. It is to be understood by a low drug utilization that after the expiry of the intended application time of the transdermal therapeutic system remains a relatively large amount of the active ingredient unused in the transdermal therapeutic system compared to that before the start of administration of this transdermal therapeutic system contained therein total amount of the active ingredient.

Since sometimes expensive active ingredients are used in the transdermal therapeutic systems of the invention, the low drug utilization is undesirable from an economic and environmental point of view. Finally, in the case of active pharmaceutical ingredients which have a toxic effect in higher concentrations, a high residual content may also represent a risk potential for an abusive intake of a higher dose.

According to the invention, this disadvantage is solved by a transdermal therapeutic system in which the active substance layer (R) stabilizes the active ingredient in such a way that it does not migrate to a greater extent into the membrane layer during unused TTS. When

Active ingredient component (WK) can be used for this purpose the salt (for example a hydrochloride) of an alkaline-reacting pharmaceutical or other active ingredient (W) in combination with an alkaline reacting further ingredient (B), for example disodium hydrogen phosphate, calcium oxide, sodium phosphate or sodium caprylate. Also

Silicates have proven to be a possible component.

This ensures that the transdermal therapeutic system is activated only after the removal of the protective layer (S) and after the adhesion to the skin by the moisture (sweat) of the skin migrating into the TTS. The moisture migrating through the membrane layer (M) into the active substance layer (R) releases the base of the active substance (W) in the active substance layer (R), so that via the membrane layer (M) a continuous release of the active substance (W) to the skin For example, the patient can be done.

In addition to the diffusibility of the membrane layer (M) for moisture and active ingredient (W) is compared to systems without membrane layer achieved a significant stability. In order to It is also possible to use polymer components (P3) for the adhesive layer (K), which without this layer show a clear tendency to cohesive failure.

The invention further relates to a transdermal therapeutic system in which the active ingredient layer (R) is an inorganic salt of an alkaline reacting agent (W) and an inorganic, alkaline reacting ingredient (B) and as a polymeric component (Pl) a polyacrylate, polysilicone, polyisobutylene (PIB) or a styrene (block) copolymer, (for example, SBS, SIS, SBR).

The invention also relates to a transdermal therapeutic system, wherein the membrane layer (M) consists of a moisture-permeable polymeric component (P2).

The invention further relates to a transdermal therapeutic system in which the active ingredient layer (R) in addition to 1 to 50% (m / m) of at least one salt of a pharmaceutically active substance also 1 to 20% (m / m) of at least one alkaline reacting further ingredient ( B) and 30 to 90% (m / m) of at least one polymeric component (P1).

The invention also relates to a transdermal therapeutic system, wherein the active substance layer (R) is a polymer matrix which, in addition to 5 to 40% (m / m) of at least one salt of a pharmaceutically active substance, also contains 5 to 20% (m / m). at least one alkaline reacting further component (B) and 40 to 80% (m / m) of at least one polymeric component (Pl).

The invention furthermore relates to a transdermal therapeutic system in which the active ingredient layer (R) is a polymer matrix based on a polyacrylate or a silicone polymer which contains 5 to 40% (m / m) of at least one salt of an active substance having at least one amino function , also contains 5 to 20% (m / m) of an alkaline-reacting inorganic constituent (B).

The invention also relates to a transdermal therapeutic system, wherein the active substance layer (R) is a polymer matrix based on a polyacrylate or a silicone polymer containing as active ingredient component (WP) an inorganic salt of an active substance for the treatment of disorders of the central nervous system (CNS) in combination containing an alkaline-reacting inorganic constituent (B), wherein the weight ratio between the salt of the active ingredient and the component (B) is from 1:10 to 10: 1, preferably 1: 7 to 7: 1.

The invention also relates to a transdermal therapeutic system, wherein the active ingredient layer (R) is a polymer matrix based on a polyacrylate, which is substantially free of functional groups.

The invention also relates to a transdermal therapeutic system wherein, in addition to a polymeric membrane layer (M), it has an additional adhesive layer (K) consisting of a polymeric component (P3), for example a polyacrylate or a silicone polymer.

The invention also relates to a process for the preparation of a transdermal therapeutic system, wherein a carrier layer (T), for example of a polymer or aluminum foil, at least one active substance layer (R) containing as active ingredient component (WK) the salt of an alkaline reacting active substance (W). in combination with at least one alkaline reacting further constituent (B) and a polymeric component (P1), applying, then applying a membrane layer (M) of a polymeric component (P2), for example of polyvinyl acetate, and optionally an adhesive layer (K) from a polymeric component (P3), e.g. B of a self-adhesive polyacrylate and optionally further layers (for example, a protective layer) added.

Also, the use of a salt of an alkaline reacting active ingredient (W) in combination with at least one alkaline reacting further ingredient (B) and a polymer for the preparation of a pharmaceutical formulation, in particular a TTS, for the treatment of diseases in humans and animals is the subject of this invention.

In use, one may also use an inorganic salt of an alkaline reacting agent (W) in combination with at least one alkaline reacting further ingredient (B) and a polyacrylate for the preparation of a transdermal therapeutic system for the treatment of CNS diseases in humans.

As a polymeric component (Pl) for the drug layer (R) can, for. As a polyacrylate (but also a silicone polymer) are used, for. As a polyacrylate containing a reduced proportion of hydroxyl groups and / or carboxyl groups. As polymeric Component (P1) may also be a polyacrylate which is substantially free of functional groups.

As usable in the drug layer polyacrylates, which may be substantially free of functional groups, come z. B. homopolymers, copolymers and

Block copolymers based on acrylic esters and / or methacrylates in

Question. As monomers for the preparation of the polyacrylate are in particular in

Question n-butyl acrylate, n-butyl methacrylate, ethyl acrylate, 2-ethylhexyl acrylate, ethyl methacrylate, methyl acrylate, methyl methacrylate, tert. Butyl acrylate, sec-butyl acrylate, tert-butyl methacrylate, cyclohexyl methacrylate, 2-ethylhexyl methacrylate, isobornyl methacrylate, isobutyl methacrylate, isopropyl acrylate, isopropyl methacrylate and mixtures of these monomers.

The monomers are often esters of acrylic or methacrylic acid, which carry linear, branched or cyclic aliphatic C] -Ci ₂ substituents without other functional groups. It is also possible to use vinyl acetate as a co-monomer together with at least one of these monomers for the preparation of the polyacrylate.

Among the esters of acrylic acid or methacrylic acid which are suitable for the preparation of the active substance layer and which carry functional groups and in which the monomer mixture used for the preparation of the polyacrylate may be contained, are primarily hydroxyl-containing esters, ie 2-hydroxyethyl acrylate, 2-hydroxyethyl- methacrylate, 3-hydroxypropyl acrylate and 3-hydroxypropyl methacrylate. Substances such as acrylonitrile, methacrylonitrile, acrylamide, dimethylaminoethyl acrylate can also be regarded as esters of acrylic acid or methacrylic acid with functional groups in the sense of this description. The proportion of the sum of acrylic acid, methacrylic acid, 2-hydroxyethyl hydroxyacrylate, 2-hydroxyethyl methacrylate, 3-hydroxypropyl acrylate and / or 3-hydroxypropyl methacrylate in the monomer mixture used to prepare the polyacrylate should not be too large.

For the purposes of the present specification, "substantially free of functional groups" is to be understood as meaning that the total proportion of acrylic acid, methacrylic acid and esters of acrylic acid or methacrylic acid which carry functional groups in the polyacrylate is less than 2% by weight.

The monomer mixtures for the preparation of the active substance layer can be polymerized in various ways, for. B. ionic, radical, light-induced, wherein optionally crosslinkers are used such. As aluminum acetylacetonate, allyl glycidyl ether and / or glycidyl methacrylate. Optionally, the preparation is also carried out using excipients such as antioxidants, stabilizers and / or alkyl mercaptans. It is also possible to use emulsifiers or organic solvents as the reaction medium.

Preferred polymer components (P1) are z. Example, the acrylic acid polymer GMS 3083 manufacturer Cytec or the silicone polymers BioPSA Dow Corning.

For the preparation of the membrane layer (M) preferred polymer components (P2) are z. For example, polymers of the polyolefins type (e.g., polyvinyl acetate (PUA) or polypropylene (PP)), polyurethanes and silicones.

For the preparation of the applied on the membrane layer (M) adhesive layer (K) preferred polymer components (P3) are z. As the following polymers: polyacrylates such. DuroTak 87-2287; Silicone polymers (such as PSA 7-4202) or polyisubutylenes.

As alkaline reacting ingredient (B), which is used together with the salt of the active ingredient in the drug layer (R), the following substances are particularly suitable: CaO, Na ₂ HPO ₄ , silicates, Na ₃ PO ₄ , Na-caprylate.

In a particularly simple embodiment, the active substance layer (in particular the polymer matrix) consists exclusively of the active substance salt, an alkaline component (B) and the polymer (P1), preferably a polyacrylate. Embodiments are also possible in which a mixture of a polyacrylate having no functional groups with a polyacrylate having functional groups is used.

In addition to the preferred active ingredients for the therapy of central nervous system disorders (such as memantine and ropinirole) can be used alone or in combination as active ingredient components of various pharmaceutical active ingredients.

For this purpose, for example, the following active ingredients in question, wherein in particular the basic active substances or their salts are of interest:

alpha adrenoreceptor agonists such. B. xylometazoline, adrenolone, clonidine, ephedrine, tiamenidine, ß-adrenoceptor agonists such. As formoterol, terbuterol, ritodrine, alpha-adrenoreceptor blockers such. Dapiperazole, doxazosin, prazosin, yohimbine,

Trimazosin, ß-Adrenoceptor B loose such. As acebutolol, atenolol, bisoprolol, bopindolol, bupranolol, propranolol, metoprolol, nadolol, pindolol, timolol, anabolic steroids such. As androstenediol, Bolandiol, Clostebol, 4-hydroxy-19-nortestosterone, methenolone, narcotics such. Alfentanil, buprenorphine, codeine, dimenoxadol, fentanyl, isomethadone, lofentanil, methadone, morphine, morphine derivatives, normethadone, normorphin, propiram, sufentanil, tilidine, analgesics (non-narcotics) such as. Aminopyrine, antipyrine, aspirin, benoxaprofen, bucetin, clometacin, keterolac,

Androgens such as B. boldenone, fluoxymesterone, mestanolone, mesterolone, methandrostenolone, 17-methyltestosterone, 17a-methyl-testosterone-3-cyclopentylenol ether, norethandrolone, standard ethanone, oxandrolone, oxymetholone, prasterone, stanolone, stanozolol, testosterone, testosterone-17-chloral hemiacetal , Testosterone 17β-cypionate, testosterone enanthate, testosterone nicotinate, testosterone phenylacetate, testosterone propionate, tiomesterone,

Anesthetics such. B. amucaine, amylocaine, biphenamine, cocaine, diperodone, ecgonidine, euprocin, fenalcomin, fomocaine, hexylcain, hydroxydione, hydroxyprocaine, hydroxytetracaine, ketamine, leucinocaine mesylate, levoxadrol, lidocaine, mepivacaine, meprylcain, metabutoxycaine, methohexital, midazolam, Naepain, octacaine, Orthocaine, oxethazain, parethoxycain, phenacaine, piperocaine, polidocanol, pramoxin, prilocaine, procaine, propanocaine, propofol, risocaine, tetracaine, thialbarbital, thiamylal, thiobutabarbital, thiopental, tolycaine, trimecaine, zolamin,

Antiallergic agents such. Amlexanox, astemizole, azelastine, cromolyn, fenpipran, histamine,

Repirinast, Tiaramid, Tranilast, Traxanox, Urushiol, Ketotifen, Nedocromil, Oxatomide,

Pentigetide,

Antiandrogens such. B. bifuranol, cyoctol, cyproterone, oxendrolone, antianginosa such. As amlodipine, amyl nitrite, Cinepazetmaleat, imolamine, isosorbide dinitrate, limaprost, molsidomine, nitroxyalkylamide derivatives, antiarrhythmics such. Acecainide, adenosine, ajmaline, alprenolol, amoproxan, aprindine, bretylium tosylate, bubumolol, bunaftine, butidrine, butobendin, meobentin, mexiletine, moriccine, pirmenol, pronethalol, propafenone, pyrinoline,

Penicillins such. Amdinocillin, pivoxil, amoxicillin, ampicillin, apalcillin, aspoxicillin, azidocillin, azlocillin, bacampicillin, benzylpenicillin, carbenicillin, Carfillillin, carindacillin, clometocillin, cloxacillin, cyclacillin, dicloxacillin, diphenicillin, epicillin, fenbenicillin, floxicillin, hetacillin, lenampicillin, metampicillin, methicillin, mezlocillin, nafcillin, oxacillin, penetillin, penethillate hydride, penicillin G benethamine, penicillin G benzathine, penicillin G Benzhydrylamine, Penicillin G Calcium, Penicillin G Hydrabamine, Penicillin N, Penicillin 0, Penicillin V, Penicillin V Benzathine, Penicillin V Hydrabamine, Penimepicycline, Phenethicillin, Piperacillin, Pivapicillin, Propicillin, Quinacillin, Sulbenicillin, Talampicillin, Temocillin, Tiacarcillin,

Antidiabetics such. B. sulfonylurea derivatives, acetohexamide, carbutamide, chlorpropamide, glibornuride, gliclazide, glimepiride, glipizides, gliquidone, glisoxepid, glyburide, glybuthiazole, glybuzole, glyhexamide, glymidine, glypinamide, phenbutamide, tolazamide, tolbutamide, tolcyclamide, acarbose, benzylthiazolidine-2, 4- dion, calcium mesoxalate, miglitol, antihistamines such. Acrivastine, bamipin, brompheniramine, chlorpheniramine, dimethindene, metron S, pheniramine, pyrrobutamine, thenaldine, tolpropamine, triprolidine, bietanautin, bromodiphenhydramine, carbinoxamine, clemastine, diphenylpyraline, doxylamine, embramine, medrylamine, mephenohydrine, p-methyldiphenhydramine, ophphenadrin, phenyltoloxamine , Pipinhydrinate, setastin, alloclamide, chloropyramine, chlorothen, histapyrrodine, methafurylene, methaphenilene, methapyrilene, phenbenzamine, pyrilamine, talastine, thenyldiamine, thonzylamine, tripelennamine, zolamin, cetirizine, chlorcyclizine, clocinizine, hydroxyzine, tricyclic, antimigraine, hydrogenated ergot alkaloids, beta Adrenoreceptor blockers, Ca antagonists, serotonin antagonists, platelet aggregation inhibitors,

Antidepressants such. B. Alpiropride, Dihydroergotamine, ergocornine, ergocorninine, ergocryptine, ergot, ergotamine, flumedroxone acetate, fonazine, methysergide, oxetoron, pizotylin, sumatriptan, anagrelide, argatroban, cilostazol, daltroban, defibrotide, enoxaparin, fraxiparin, indobufen, lamoparan, ozagrel, picotamide, Plafibrid, Tedelparin, Ticlopidine, Triflusal,

Bronchodilators such as ephedrine derivatives such. Albuterol, bambuterol, bitolterol, carbuterol, clenbuterol, chlorprenaline, dioxethedrin, eprozinol, etafedrine, ethylnorepinephrine, fenoterol, hexoprenaline, isoetharine, isoproterenol, mabuterol, metaproterenol, N-methylephedrine, pirbuterol, procaterol, protokylol, reproterol, rimiterol, soterenol, Terbutaline, tulobuterol,

Estrogens such. B. Benzestrol, Broparoestrol, Chlorotrianisen, Dienestrol, Diethylstilbestrol, Diethylstilbestroldipropionate, Dimestrol, Fosfestrol, Hexestrol, Methaleestrile, Methestrol, Colpormon, Equilenin, Equilin, Conjugated Estrogenic Hormones, Estrogen Esters, Estropipate, 17ß-Estradiol, Estradiol, Estradiolbenzoate, Estradiol-17ß-cypionate, Estriol, Estrone, Ethinylestradiol, Mestranol, Moxestrol, Mytatrienediol, Polyestradiolphosphate, Quinestradiol, Quinestrol, Progestins such. Allylestrenol, anagestone, chlormadinone acetate, delmadinone acetate, demegestone, desogestrel, dimethisterone, dydrogesterone, ethinylestrenol, ethisterone, ethynodiol, ethynodiol diacetate, flurogestone acetate, gestodene, gestonoron caproate, haloprogesterones, 17-hydroxy-16-methylene progesterone, 17a-hydroxyprogesterone, 17a-hydroxygesterone caproate, Levonorgestrel, Lynestrenol, Medrogestone, Medroxy-progesterone, Megestrol Acetate, Melengestrol, Norethindrone, Norethindrone Acetate, Norethynodrel, Norgesterone, Norgestimate, Norgestrel, Norgestrienone, 19-norprogesterone, Norvinisterone, Pentagestron, Progesterone, Promegestone, Quingestron, Trengestone,

Vasodilators such. B. bencyclan, ciclonicat, cinnarizine, citicoline, diisopropylamine dichloroacetate, eburnamonine, fenoxedil, ibudilast, ivfenprodil, nafronyl, nicametate, nicergoline, ninodipine, papaverine, pentifylline, tinofedrine, vincamine, vinpocetine, amotriphene, bendazole, benfurodil hemisuccinate, benziodarone, chloracycine, Chromonar, clobenfurol, clonitrate, dilazep, dipyridamole, dropenilamine, efloxate, erythritol, erythrityl tetranitrate, etafenone, floredil, ganglefen, hexestrol bis (.beta.-diethylaminoethyl ether), hexobendine, isosorbide dinitrate, ittramintosylate, khellin, lidoflazine, mannitol hexanitrate, medibazine, nicorandil, nitroglycerin , Pentaerythritol tetranitrate, pentrinitrole, pimefylline, prenylamine, propatylnitrate, pyridofylline, trapidil, tricromyl, trimetazidine, trolnitrate phosphate, visnadine, bamethane, betahistine, bradykinin, brovincamine, bufoniod, buflomedil, butalamine, cetiedil, ciclonicat, cinepazide, cyclandelate, eledoisine , Hepronicat, Inositolniacinat, Isoxsuprin, Kallidin, Kallikrein, Moxisylyt, Nicofu ranose, nylidrin, piribedil, suloctidil, xanthinal and niacinate as well as nicotine.

Preference is given to using basic CNS active substances, in particular amines.

The following salts of the active compounds with the following anions are preferably also used: Cl ^" , PO ₄ ^3" , HPO ₄ ^{2 "} , H ₂ PO ₄ ^" , acetate, maleate, Br ^" , I ^" , oxalate, nitrate, carbonate, HCO ₃ ^" and stearates.

The invention is also illustrated by the following examples. example 1

For the production of a transdermal therapeutic system with an anti-dementia active ingredient, use is made of the components listed in the table below (data in% M / M), the active substance used being a salt of memantine.

Example 2

For the preparation of a transdermal therapeutic system with an anti-dementia active substance, use is made of the components listed in the table below (data in% M / M), using as active ingredient a salt of memantine (for example hydrochloride).

In Example 2, the membrane layer (M) simultaneously acts as an adhesive layer (K). In addition, depending on the active ingredient (W) and constituent (B), a further membrane layer (M) can be used, for example, with polyvinyl acetate (PVA) or polypropylene (PP) as the polymer component (P2). An adhesive layer (K) based on polyacrylate is used to bond the skin to the skin.

As the protective layer (S), in both Examples 1 and 2, a polyethylene terephthalate film can be used. The active substance amounts, from the respective active substance layers can be delivered to the skin via the membrane layer can be measured in a Franz 'cell known to those skilled in the art.

Claims

claims

1. Transdermal therapeutic system (TTS) containing the following layers

wherein the carrier layer (T) is impermeable to the active substance, the active substance layer (R) as active component (WK) the salt of an alkaline reacting active substance (W) in combination with at least one alkaline reacting further component (B) and a polymeric component (P1) contains, wherein the active ingredient (W) from the drug layer (R) is released from the active ingredient component (WK) only by the moisture migrating from the outside through the membrane layer (M), and the membrane layer (M) consists of a polymeric component (P2) ,

2. Transdermal therapeutic system according to claim 1, characterized in that the active substance layer (R) contains an inorganic salt of an alkaline reacting active ingredient (W) and an inorganic, alkaline reacting ingredient (B) and as a polymeric component (Pl) a polyacrylate or polysilicone ,

3. Transdermal therapeutic system according to one of claims 1 or 2, characterized in that the membrane layer (M) consists of a moisture-permeable polymeric component (P2).

4. Transdermal therapeutic system according to one of claims 1 to 3, characterized in that the active substance layer (R) in addition to 1 to 50% (m / m) of at least one salt of a pharmaceutically active substance also 1 to 20% (m / m) of at least one alkaline reacting further ingredient (B) and 30 to 90% (m / m) of at least one polymeric component (Pl).

5. Transdermal therapeutic system according to one of claims 1 to 4, characterized in that the active substance layer (R) in addition to 5 to 40% (m / m) at least a salt of a pharmaceutically active substance also 5 to 20% (m / m) of at least one alkaline reacting further ingredient (B) and 40 to 80% (m / m) of at least one polymeric component (Pl).

6. Transdermal therapeutic system according to one of claims 1 to 5, characterized in that it is the active ingredient layer (R) is a polymer matrix based on a polyacrylate or a silicone polymer, in addition to 5 to 40% (m / m) at least one salt of an active ingredient having at least one amino function, also 5 to 20% (m / m) of an alkaline inorganic component (B).

7. Transdermal therapeutic system according to one of claims 1 to 6, characterized in that it is the active ingredient layer (R) is a polymer matrix based on a polyacrylate or a silicone polymer containing as active ingredient component (WK) an inorganic salt of a CNS Active ingredient in combination with an alkaline-reacting inorganic ingredient (B), wherein the weight ratio between the salt of the active ingredient and the ingredient (B) is from 1:10 to 10: 1.

8. Transdermal therapeutic system according to one of claims 1 to 7, characterized in that it is the active ingredient layer (R) is a polymer matrix based on a polyacrylate, which is substantially free of functional groups.

9. Transdermal therapeutic system according to one of claims 1 to 8, characterized in that it comprises an additional adhesive layer (K), which consists of a polymeric component (P3).

10. A method for producing a transdermal therapeutic system according to any one of claims 1 to 9, characterized in that on a carrier layer (T) at least one active substance layer (R), the active ingredient component (WK), the salt of an alkaline reacting agent (W) in combination with at least one alkaline reacting further constituent (B) and a polymeric component (P1), applying, then applying a membrane layer (M) of a polymeric component (P2) and optionally an adhesive layer (K) of a polymeric component ( P3).

11. Use of a salt of an alkaline reacting active ingredient (W) in combination with at least one alkaline reacting further ingredient (B) and a polymer for the preparation of a transdermal therapeutic system for the treatment of diseases in humans and animals.

12. Use according to claim 11, characterized in that one comprises an inorganic salt of an alkaline reacting active ingredient (W) in combination with at least one alkaline reacting further ingredient (B) and a polyacrylate for the preparation of a transdermal therapeutic system for the treatment of CNS diseases in humans ,