US008882729B2

(12) United States Patent (10) Patent No.: US 8,882,729 B2 Horstmann et al. (45) Date of Patent: Nov. 11, 2014

(54) TRANSDERMAL THERAPEUTIC SYSTEM (56) References Cited HAVING STABILIZED MEMBRANE U.S. PATENT DOCUMENTS (75) Inventors: Michael Horstmann, Neuwied (DE); 4,781,924 A 11/1988 Lee et al. Patrick Mohr, Breisig (DE); 5,215,751 A 6/1993 Muller et al. Mohammad Sameti, Bonn (DE) 6,221,383 B1 * 4/2001 Miranda et al...... 424/449 6,620,429 B1 9, 2003 Muller et al. 6,884,434 B1 4/2005 Muller et al. (73) Assignee: LTS Lohmann Therapie Systeme AG, 7, 175,853 B1 2, 2007 Bracht Andernach (DE) 2004/O253.299 A1 12/2004 Beier et al. 2005/O169977 A1* 8/2005 Kanios et al...... 424/449 (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 FOREIGN PATENT DOCUMENTS U.S.C. 154(b) by 779 days. DE 39 05 050 8, 1990 DE 39 05 051 8, 1990 (21) Appl. No.: 12/921,988 DE 19814 083 10, 1999 DE 19814 084 10, 1999 DE 19814 087 10, 1999 (22) PCT Filed: Feb. 28, 2009 EP O 316 065 5, 1989 WO WO 93/10772 6, 1993 (86). PCT No.: PCT/EP2O09/OO1446 WO WO, 96/39 136 12/1996 WO WO 97.11696 4f1997 S371 (c)(1), WO WOO3,O11291 2, 2003 (2), (4) Date: Dec. 15, 2011 OTHER PUBLICATIONS (87) PCT Pub. No.: WO2009/112167 International Search Repot dated Jun. 17, 2009, 4pgs. PCT Pub. Date: Sep. 17, 2009 * cited by examiner Primary Examiner — Melanie Hand (65) Prior Publication Data (74) Attorney, Agent, or Firm — Frommer Lawrence & US 2012/O245537 A1 Sep. 27, 2012 Haug LLP (57) ABSTRACT (30) Foreign Application Priority Data The invention relates to a transdermal therapeutic system made of the following layers: a carrier layer (T), an active Mar. 11, 2008 (DE) ...... 10 2008 O13 701 ingredient layer (R), a membrane layer (M) and optionally an adhesive layer (K), wherein the carrier layer (T) is impen (51) Int. Cl. etrable to the active substance and to water, the active sub A6M 35/00 (2006.01) stance layer (R) comprises as an active Substance component A6 IK9/00 (2006.01) the salt of an alkali reactive active substance, such as a CNS A 6LX 9/70 (2006.01) active amine in combination with at least one alkali reactive (52) U.S. Cl. further component, and a polymer component (P1), wherein CPC ...... A61 K9/7084 (2013.01); A61 K9/0014 the active substance is released from the active substance (2013.01) layer (R) only by the moisture entering from the exterior USPC ...... 604/289: 424/449; 602/48: 602/54 through the membrane layer (M), and the membrane layer (58) Field of Classification Search (M) is made of a polymer component (P2), allowing a uni USPC ...... 604/289, 290; 424/443, 449 form delivery of basic active substances to the skin. See application file for complete search history. 17 Claims, No Drawings US 8,882,729 B2 1. 2 TRANSIDERMAL THERAPEUTC SYSTEM reductions in the TTS produced. These technical problems HAVING STABILIZED MEMBRANE may limit, or rule out the possibility of proper production and an appropriate therapeutic application, particularly in The present invention relates to transdermal therapeutic humans. systems and their production. Transdermal therapeutic sys Transdermal therapeutic systems in different embodiments tems (TTS) are forms of pharmaceutical administration (e.g., reservoir with and without membrane) have been in use which can be applied to the skin of a mammal and are for many years for different active ingredients and therapies. designed to make a drug, following transdermal uptake, avail For reasons of improved control of the Supply of active ingre able systemically. Transdermal therapeutic systems can dient, many transdermal systems are characterized spatially increase the therapeutic value of the administration of a drug 10 by a Suitable compartmentalization, into—for example—an by ensuring a constant delivery of the active ingredient into active ingredient layer (R), a membrane layer (M), and an the blood compartment over a prolonged time period. The adhesive layer (K). Also known are transdermal systems advantages of this continuous delivery of active ingredient are which, for reasons of the stability of the active ingredient, primarily the extended intervals of application, which result comprise the active ingredient initially in the form of a salt, in improved patient compliance, and the pharmacokinetically 15 and make it available only after reaction with, for example, improved time profile of the plasma concentration, which alkaline Substances. ensures a longer time of action with fewer side effects. Other A technical drawback effecting these systems, however, is advantages arising from the transdermal administration route that their release is frequently uncontrolled and/or they neces by means of a transdermal therapeutic system are reduced sitate an addition of liquid alkaline reagents that is technically dosage, improved gastrointestinal compatibility, and difficult to implement. increased bioavailability as a result of circumvention of what The transdermal therapeutic systems of the prior art in the is called the first pass effect. field of alkaline active ingredients have a range of further On the basis of these advantages, transdermal therapeutic drawbacks. For instance, a frequent drawback of membrane/ systems have for Some few years been enjoying increasing reservoir systems which contain the alkaline active ingredient popularity in the therapy of diverse diseases. Transdermal 25 already in Solution is that the dissolved active ingredient systems of this kind have been introduced into therapy for— initially present, via the connection of the membrane, and for example—the active ingredients estradiol, nicotine, nore owing to the diffusion, enriches the adhesive layer (K) with thisterone acetate, fentanyl, tulobuterol, ethynylestradiol, high concentrations of active ingredient. This high concen buprenorphine, and nitroglycerine. The structure of a trans tration in the adhesive layer (K) is reduced only after several dermal therapeutic system is generally thin and laminar, and 30 hours of wear to a level which is given by the theoretical So, with the aid of the layer directly facing the skin, an at least apportionment of the permeation rate on the basis of the temporarily adhesive bond to the skin is produced, via which membrane permeation. the active ingredient is delivered. TTS consists typically of a The unwanted, initially high uptake of active ingredient via backing layer (T) which is impervious to the drug, an active the skin may, first, lead to increased skin reactions. Further ingredient-containing layer (R), such as an active ingredient 35 more, the incidence of relatively high blood level peaks of layer or matrix layer, for example, and an adhesive layer (K) active ingredient at the beginning of the wear of the TTS is for attachment to the skin. likely to have corresponding side effects. Another drawback This adhesive layer (K) may also be identical with the drug of these known systems is the frequently poor stability of or active ingredient layer (e.g., active ingredient layer or alkaline active ingredients in a membrane preparation. matrix layer). The TTS further usually comprises a protective 40 Numerous oxidation, ester cleavage, and hydrolysis reactions layer which is drug-impervious and is intended for removal may alter the active ingredient in the course of long-term prior to application, called the release liner. To enhance deliv storage. In contrast, the majority of alkaline active ingredients ery of active ingredient there may also be a membrane layer in salt form are extraordinarily stable. (M) provided, which controls delivery to the skin. It is an object of the present invention to provide a trans Permeation of the particular active ingredient from the TTS 45 dermal therapeutic system (TTS) which is suitable for a sta through the skin is improved using not only various solid bility-sensitive, Volatile and/or skin-irritating active ingredi polymers (e.g., polyacrylates, silicones, polyisobutylenes), ent (W), this active ingredient (W) being brought into a form resins, and other pharmaceutical excipients, but also various which allows membrane-controlled Supply of active ingredi system components which are liquid at room temperature, ent. Furthermore, the TTS is to have a shelflife of at least two and which in some cases allow adjustment of the bond 50 years without significant formation of degradation products strength and of the improvement in diffusion within the trans of the active ingredient. The TTS is also to exhibit good or at dermal therapeutic system, or else serve to improve the per least satisfactory compatibility on human or animal skin. meation of active ingredient through the skin. These technical objects are achieved by means of a trans Not only the active ingredients used but also the excipients dermal therapeutic system (TTS) comprising, and preferably used, which are often liquid, may have properties which are 55 consisting Substantially of the following layers: disruptive to the production of TTS, such as volatility and/or a) a backing layer (T), thermal instability under the operating conditions, for b) an active ingredient layer (R), example. This may have the consequence that, in the course of c) a membrane layer (M), and optionally the process of producing the transdermal systems, which d) an adhesive layer (K), frequently consists of the mixing of the starting materials in a 60 the backing layer (T) being impervious to the active ingredi Suitable organic solvent, their Subsequent coating in a thin ent and preferably to water as well, the active ingredient layer layer on a base sheet, and drying, usually continuous drying, (R) comprising as active component (WK) the salt of an at an elevated temperature thereafter, considerable losses alkaline active ingredient (W) in combination with at least OCCU. one alkaline further constituent (B) and also a polymeric These losses, particularly of expensive active ingredients, 65 component (P1), the active ingredient (W) being released not least during the final production stage of the TTS, the from the active ingredient layer (R) only as a result of the drying, may result in missed dosages and/or performance moisture from the active component (WK), which migrates in US 8,882,729 B2 3 4 from the outside through the membrane layer (M) (for layer (S) and after having being adhered to the skin, by means example, from the skin of the patient), and the membrane of the moisture (perspiration) of the skin that migrates into the layer (M) being composed of a polymeric component (P2). TTS. The moisture that migrates into the active ingredient As far as the various polymeric components of the different layer (R) through the membrane layer (M) releases the base of layers of the TTS are concerned, there are numerous possi- 5 the active ingredient (W) in the active ingredient layer (R), bilities for selection. and so, via the membrane layer (M), the active ingredient (W) In one preferred embodiment of the transdermal therapeu can be delivered continuously to the skin of for example— tic systems of the invention, the active ingredient layer is the patient. constructed as a matrix system. In addition to the diffusiveness of the membrane layer (M) This is a system in which the adhesive or nonadhesive 10 for moisture and active ingredient (W), a significant stability polymer matrix comprises the active component, generally in is achieved relative to systems without a membrane layer. As dissolved and/or suspended form. Often in this case the poly a result it is possible, for the adhesive layer (K), to use even mer matrix is composed of pressure-sensitive adhesives polymeric components (P3) which without this layer display based on polyacrylates. The polyacrylates used in that case a significant tendency toward cohesive fracture. are prepared from monomers (acrylic acid and methacrylic 15 The invention further provides a transdermal therapeutic acid and also their respective esters, optionally also with vinyl system in which the active ingredient layer (R) comprises an acetate), which may contain functional groups. These func inorganic salt of an alkaline active ingredient (W) and an tional groups are able to withstand the polymerization of the inorganic, alkaline constituent (B) and also as polymeric monomers employed, while remaining unchanged, and are component (P1) a polyacrylate, polysilicone, polyisobuty able to influence the properties of the resultant polyacrylate, 20 lene (PIB) or a styrene (block) copolymer (SBS, SIS, SBR), particularly the tack and the adhesiveness. for example. The invention also relates to a transdermal thera EP-A 0 614356 discloses examples of polyacrylate-based peutic system where the membrane layer (M) is composed of adhesive formulations of this kind. The skilled person distin a moisture-permeable polymeric component (P2). guishes between polyacrylates with —OH groups (hydroxyl The invention further provides a transdermal therapeutic groups) and those with —COOH groups (carboxyl groups) as 25 system wherein the active ingredient layer (R) in addition to functional groups. The hydroxyl-containing polyacrylates 1% to 50% (m/m) of at least one salt of an active pharmaceu include, for example, the commercial product DuroTak tical ingredient also comprises 1% to 20% (m/m) of at least 87-2287. The carboxyl-containing polyacrylates include, for one alkaline further constituent (B) and also 30% to 90% example, the product DuroTak 87-2051. Both polyacrylates (m/m) of at least one polymeric component (P1). are provided by the manufacturer, National Starch (Bridge- 30 The invention also relates to a transdermal therapeutic water, USA). system where the active ingredient layer (R) is a polymer These polyacrylates have proven to be stable and highly matrix which in addition to 5% to 40% (m/m) of at least one compatible adhesive polymers for the production of matrices salt of an active pharmaceutical ingredient also comprises 5% for the transdermal therapeutic systems. to 20% (m/m) of at least one alkaline further constituent (B) A disadvantage effecting the transdermal therapeutic sys- 35 and also 40% to 80% (m/m) of at least one polymeric com tems comprising polyacrylates which contain the stated func ponent (P1). tional groups (hydroxyl group, carboxyl group) is the poor The invention further provides a transdermal therapeutic active ingredient utilization rate. This is observed particularly system wherein the active ingredient layer (R) is a polymer with hormonal transdermal therapeutic systems. A poor matrix based on a polyacrylate or on a silicone polymer and active ingredient utilization rate in this context means that, 40 comprising not only 5% to 40% (m/m) of at least one salt of after the expiry of the envisioned application time of the an active ingredient having at least one amino function but transdermal therapeutic system, a relatively large amount of also 5% to 20% (m/m) of an alkaline inorganic constituent the active ingredient, in comparison to the total amount of (B). active ingredient present in this transdermal therapeutic sys The invention also relates to a transdermal therapeutic tem prior to commencement of administration, remains 45 system where the active ingredient layer (R) is a polymer unutilized in the transdermal therapeutic system. matrix based on a polyacrylate or on a silicone polymer which Since active ingredients that are in some cases expensive as active component (WP) comprises an inorganic salt of an are used in the transdermal therapeutic systems of the inven active ingredient for the treatment of disorders of the central tion, the poor active ingredient utilization rate is undesirable nervous system (CNS), in combination with an alkaline inor from both economic and environmental standpoints. Finally, 50 ganic constituent (B), the weight ratio between the salt of the in the case of active pharmaceutical ingredients which are active ingredient and the constituent (B) being from 1:10 to toxic at relatively high concentration, a high residual content 10:1, preferably 1:7 to 7:1. may also constitute a potential hazard for improper intake of The invention also provides a transdermal therapeutic sys a higher dose. tem where the active ingredient layer (R) is a polymer matrix In accordance with the invention, this disadvantage is 55 based on a polyacrylate which is substantially free of func resolved by means of a transdermal therapeutic system in tional groups. which the active ingredient layer (R) stabilizes the active The invention also relates to a transdermal therapeutic ingredient such that, in the unused TTS, it does not cross to system which as well as a polymeric membrane layer (M) has any Substantial extent into the membrane layer. As active an additional adhesive layer (K) which is composed of a component (WK) for this purpose it is possible to use the salt 60 polymeric component (P3), Such as a polyacrylate or a sili (e.g., a hydrochloride) of an alkaline active pharmaceutical or cone polymer, for example. other ingredient (W) in combination with an alkaline further The invention also relates to a method of producing a constituent (B), Such as disodium hydrogen phosphate, cal transdermal therapeutic system, where applied to a backing cium oxide, Sodium phosphate or Sodium caprylate, for layer (T), comprising, for example, a polymer or aluminum example. Silicates too have proven a possible component. 65 foil, at least one active ingredient layer (R) which comprises In this way it is ensured that the transdermal therapeutic as active component (WK) the salt of an alkaline active ingre system is activated only after the removal of the protective dient (W) in combination with at least one alkaline further US 8,882,729 B2 5 6 constituent (B) and also a polymeric component (P1), Subse etonate, allylglycidyl ether and/or glycidyl methacrylate, for quently a membrane layer (M) comprising a polymeric com example. If desired, preparation also takes place with use of ponent (P2), made of polyvinyl acetate, for example, is auxiliaries such as antioxidants, stabilizers, and/or alkyl mer applied, and optionally an adhesive layer (K) comprising a captains. Emulsifiers or organic solvents may also be used as polymeric component (P3), comprising, for example, a self a reaction medium. adhesive polyacrylate, and also, optionally, further layers Preferred polymeric components (P1) are, for example, the (e.g., a protective layer) are added. acrylic acid polymer GMS 3083 from the manufacturer Additionally, the use of a salt of an alkaline active ingre Cytec, or the silicone polymers BioPSA from the manufac dient (W) in combination with at least one alkaline further turer Dow Corning. constituent (B) and a polymer for producing a pharmaceutical 10 Polymeric components (P2) preferred for producing the formulation, more particularly a TTS, for treating diseases in membrane layer (M) are, for example, polymers of the poly humans and animals is provided by this invention. olefin type (e.g., polyvinyl acetate (PUA) or polypropylene In the context of the use, it is also possible to employ an (PP)), polyurethanes, and silicones. inorganic salt of an alkaline active ingredient (W) in combi Polymeric components (P3) that are preferred for produc nation with at least one alkaline further constituent (B) and a 15 ing the adhesive layer (K) for application to the membrane polyacrylate for producing a transdermal therapeutic system layer (M) are, for example, the following polymers: polyacry for treating CNS diseases in humans. lates such as, for example, DuroTak 87-2287; silicone poly As polymeric component (P1) for the active ingredient mers (such as, for example, PSA 7-4202) or polyisobuty layer (R) it is possible, for example, to use a polyacrylate (or lenes. else a silicone polymer), e.g., a polyacrylate containing a Particularly suitable as an alkaline constituent (B) which is reduced fraction of hydroxyl groups and/or carboxyl groups. used together with the salt of the active ingredient in the active As polymeric component (P1) it is also possible to use a ingredient layer (R) are the following substances: CaO. polyacrylate which is Substantially free of functional groups. NaHPO, silicates, NaPO Na caprylate. Polyacrylates contemplated for possible use in the active In one particularly simple embodiment the active ingredi ingredient layer, which may be substantially free of func 25 ent layer (more particularly the polymer matrix) is composed tional groups, include, for example, homopolymers, copoly exclusively of the active ingredient salt, an alkaline constitu mers, and block copolymers based on acrylic esters and/or ent (B), and the polymer (P1), preferably a polyacrylate. Also methacrylic esters. Contemplated particularly in this context possible are embodiments in which a mixture of a polyacry as monomers for preparing the polyacrylate are n-butyl acry late without functional groups with a polyacrylate with func late, n-butyl methacrylate, ethyl acrylate, 2-ethylhexyl acry 30 tional groups is used. late, ethyl methacrylate, methyl acrylate, methyl methacry As well as the preferred active ingredients for the therapy late, tert-butyl acrylate, sec-butyl acrylate, tert-butyl of central nervous system diseases (such as memantine and methacrylate, cyclohexyl methacrylate, 2-ethylhexyl meth ropinirole), a very wide variety of active pharmaceutical acrylate, isobornyl methacrylate, isobutyl methacrylate, iso ingredients, alone or in combination, may be used as active propyl acrylate, isopropyl methacrylate, and mixtures of 35 components. these monomers. Contemplated for this purpose, for example, are the fol The monomers are frequently esters of acrylic and/or lowing active ingredients, with the basic active ingredients methacrylic acid which carry linear, branched or cyclic ali and/or salts thereof being of more particular interest: phatic C-C substituents without other functional groups. It alpha-adrenoceptoragonists such as, for example, Xylometa is also possible to use vinyl acetate as a comonomer together 40 Zoline, adrenolone, clonidine, ephedrine, tiamenidine, with at least one of these monomers for preparing the poly B-adrenoceptor agonists such as, for example, formoterol, acrylate. terbuterol, ritodrine, By the esters of acrylic acid and/or methacrylic acid which alpha-adrenoceptor blockers such as, for example, dapipera carry functional groups and are suitable for producing the Zole, doxazosin, praZosin, yohimbine, trimaZosin active ingredient layer, and which may be present in the 45 B-adrenoceptor blockers such as, for example, acebutolol. monomer mixture used for preparing the polyacrylate, are atenolol, bisoprolol, bopindolol, bupranolol, propanolol. meant, primarily, esters containing hydroxyl groups, i.e., metoprolol, nadolol, pindolol, timolol, anabolics such as, for 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate, 3-hy example, androstenediol, bolandiol, clostebol, 4-hydroxy droxypropyl acrylate, and 3-hydroxypropyl methacrylate. 19-nortestosterone, methenolone, narcotics such as, for Compounds Such as acrylonitrile, methacrylonitrile, acryla 50 example, alfentanil, buprenorphine, codeine, dimenoxadol, mide, dimethylaminoethyl acrylate may also be regarded in fentanyl, isomethadone, lofentanil, methadone, morphine, the context of this description as esters of acrylic and/or morphine derivatives, normethadone, normorphine, propi methacrylic acid with functional groups. The fraction of the ram, Sufentanil, tilidine, Sum of acrylic acid, methacrylic acid, 2-hydroxyethyl acry analgesics (non-narcotics) such as, for example, aminopy late, 2-hydroxyethyl methacrylate, 3-hydroxypropyl acrylate 55 rine, antipyrine, aspirin, benoxaprofen, bucetin, clometacin, and/or 3-hydroxypropyl methacrylate in the monomer mix keterolac, ture used for preparing the polyacrylate should not be too androgens Such as, for example, boldenone, fluoxymester large. one, mestanolone, mesterolone, methandrostenolone, 17-me By “substantially free of functional groups' is meant, in the thyltestosterone, 17C.-methyl-testosterone-3-cyclopentyl sense of the present description, that the total fraction of 60 enol ether, norethandrolone, normethandrone, Oxandrolone, acrylic acid, methacrylic acid, and esters of acrylic acid and oxymetholone, prasterone, stanolone, stanozolol, testoster methacrylic acid that carry functional groups is below 2% by one, testosterone 17-chloral hemiacetal, testosterone 17 B weight in the polyacrylate. cypionate, testosterone enanthate, testosterone nicotinate, The monomer mixtures for producing the active ingredient testosterone phenylacetate, testosterone propionate, tiomes layer may be polymerized in a variety of ways, as for example 65 terone, ionically, free-radically, under light induction, in which case, anesthetics Such as, for example, amucaine, amylocalne, if desired, crosslinkers are used. Such as aluminum acetylac biphenamine, cocaine, diperodon, ecgonidine, euprocin, US 8,882,729 B2 7 8 fenalcomine, fomocaine, hexylcaine, hydroxydione, hydrox buterol, chlorprenaline, dioxethedrine, eprozinol, etafedrine, yprocaine, hydroxytetracaine, ketamine, leucinocaine mesy ethylnorepinephrine, fenoterol, hexoprenaline, isoetharine, late, levoxadrol, lidocaine, mepivacaine, meprylcaine, isoproterenol, mabuterol, metaproterenol, N-methylephe metabutoxycaine, methohexital, midazolam, naepaine, drine, pirbuterol, procaterol, protokylol, reproterol, rimiterol, octacaine, orthocaine, oxethazaine, parethoxycaine, phen soterenol, terbutaline, tulobuterol, acaine, piperocaine, polidocanol, pramoxine, prilocalne, procaine, propanocaine, propofol, risocaine, tetracaine, thi estrogens such as, for example, benzestrol, broparoestrol, albarbital, thiamylal, thiobutabarbital, thiopental, tolycaine, chlorotrianisene, dienestrol, diethylstilbestrol, diethylstil trimecaine, Zolamine, bestrol dipropionate, dimestrol, fosfestrol, hexestrol, methal antiallergics such as, for example, amlexanoX, astemizole, 10 lenestril, methestrol, colpormon, equilenin, equilin, conju aZelastine, cromolyn, fenpiprane, histamine, repirinast, tiara gated estrogenic hormones, estrogen esters, estropipate, 17 B mide, tranilast, traXanox, urushiol, ketotifen, nedocromil. estradiol, estradiol, estradiol benzoate, estradiol 17 B oXatomide, pentigetide antiandrogens such as, for example, cypionate, estriol, estrone, ethinylestradiol, mestranol, bifluranol, cyoctol, cyproterone, Oxendrolone, moxestrol, my tatrienediol, polyestradiol phosphate, antianginals such as, for example, amlodipine, amyl nitrite, 15 quinestradiol, quinestrol, cinepazet maleate, imolamine, isosorbide dinitrate, gestagens such as, for example, allylestrenol, anagestone, limaprost, molsidomine, nitroxyalkylamide derivatives, chlormadinone acetate, delmadinone acetate, demegestone, antiarrhythmics such as, for example, acecamide, adenosine, desogestrel, dimethisterone, dydrogesterone, ethinylestrenol, ajmaline, alprenolol, amoproxan, aprindine, bretylium tosy ethisterone, ethynodiol, ethynodiol diacetate, fluorogestone late, bubumolol, bunaftine, butidrine, butobendine, meoben tine, mexiletine, moricizine, pirmenol, pronethalol, pro acetate, gestodene, gestonorone caproate, haloprogesterone, pafenone, pyrinoline, 17-hydroxy-16-methyleneprogesterone, 17O-hydrox penicillins such as, for example, amdinocillin, pivoxil, amox yprogesterone, 17O-hydroxygesterone caproate, levonorg icillin, amplicillin, apalcillin, aspoxicillin, azidocillin, aZlocil estrel, lynestrenol, medrogestone, medroxyprogesterone, lin, bacampicillin, benzylpenicillin, carbenicillin, carfecillin, 25 megestrol acetate, melengestrol, norethindrone, norethin carindacillin, clometocillin, cloxacillin, cyclacillin, diclox drone acetate, norethynodrel, norgesterone, norgestimate, acillin, diphenicillin, epicillin, fenbenicillin, floxicillin, het norgestrel, norgestrienone, 19-norprogesterone, norvinister acillin, lenampicillin, metampicillin, methicillin, meZlocil One, pentagestrone, progesterone, promegestone, lin, nafcillin, oxacillin, penamecillin, penethamate quingestrone, trengestone, hydriodide, penicillin G benethamine, penicillin G benza 30 vasodilators such as, for example, bencyclane, ciclonicate, thine, penicillin G benzyhydrylamine, penicillin G calcium, penicillin Ghydrabamine, penicillin N, penicillin O, penicil cinnarizine, citicoline, diisopropylamine dichloroacetate, lin V, penicillin V benzathine, penicillinV hydrabamine, pen eburnamonine, fenoxedil, ibudilast, ifenprodil, nafronyl, imepicyclin, phenethicillin, piperacillin, pivapicillin, propi nicametate, nicergoline, ninodipine, papaverine, pentifylline, cillin, quinacillin, Sulbenicillin, talampicillin, temocillin, 35 tinofedrine, Vincamine, Vinpocetine, amotriphene, bendaZol. tiacarcillin, benfurodil hemisuccinate, benZiodarone, chloracyZine, antidiabetics Such as, for example, Sulfonylurea derivatives, chromonar, clobenfurol, clonitrate, dilaZep, dipyridamole, acetohexamide, carbutamide, chlorpropamide, glibornuride, dropenilamine, efloxate, erythritol, erythrity1 tetranitrate, gliclazide, glimepiride, glipizide, gliquidone, glisoxepide, etafenone, floredil, ganglefene, hexestrol bis(B-diethylami glyburide, glybuthiazole, glybuzole, glyhexamide, glymi 40 noethyl ether), hexobendine, isosorbide dinitrate, itramin dine, glypinamide, phenbutamide, tolaZamide, tolbutamide, tosylate, khellin, lidoflazine, mannitol hexanitrate, mediba tolcyclamide, acarbose, benzylthiazolidine-2,4-dione, cal Zine, nicorandil, nitroglycerine, pentaerythritol tetranitrate, cium mesoxalate, miglitol, antihistaminics such as, for example, acrivastine, bamipine, pentrinitrol, pimethylline, prenylamine, propatyl nitrate, brompheniramine, chlorpheniramine, dimethindene, metron 45 pyridofylline, trapidil, tricromyl, trimetazidine, trolnitrate S. pheniramine, pyrrobutamine, thenaldine, tolpropamine, phosphate, visnadine, bamethan, betahistine, bradykinin, triprolidine, bietanautine, bromodiphenhydramine, carbi brovincamine, bufeniode, buflomedil, butalamine, cetiedil, noxamine, clemastine, diphenylpraline, doxylamine, ciclonicate, cinepazide, cyclandelate, eledoisin, hepronicate, embramine, medrylamine, mephenhydramine, p-methyl inositol niacinate, isoxSuprine, kallidin, kallikrein, moxisy diphenhydramine, orphenadrine, phenyltoloxamine, piprin 50 lyte, nicofuranose, nylidrin, piribedil, Suloctidil, Xanthinal hydrinate, setastine, alloclamide, chloropyramine, chlo and niacinate, and nicotine. rothen, histapyrrodine, methafurylene, methaphenilene, methapyrilene, phenbenzamine, pyrilamine, talastine, the It is preferred to use basic active CNS ingredients, more nyldiamine, thonzylamine, tripelennamine, Zolamine, ceti particularly amines. rizine, chlorcyclizine, clocinizine, hydroxy Zine, tricyclics, 55 Preference is additionally given to using the following salts antimigraine agents, hydrogenated ergot alkaloids, B-adreno of the active ingredients with the following anions: Cl, receptor blockers, antagonists, serotonin antagonists, platelet PO, HPO, HPO, acetate, maleate, Br, I, oxalate, aggregation inhibitors, nitrate, carbonate, HCO, and Stearates. antidepressants such as, for example, alpiropride, dihydroer The invention is also illustrated by the examples below. gotamine, ergocornine, ercocorninine, ergocryptine, ergot, 60 ergotamine, flumedroXone acetate, fonazine, methysergide, oxetorone, pizotyline, Sumatriptan, anagrelide, argatroban, EXAMPLE 1. cilostazol, daltroban, defibrotide, enoxaparin, Fraxiparin, indobufen, lamoparan, oZagrel, picotamide, plafibride, tedel A transdermal therapeutic system containing an active parin, ticlopidine, triflusal, 65 antidementia ingredient is produced using the components bronchodilators such as ephedrine derivatives such as, for identified in the table below (figures in % M/M), the active example, albuterol, bambuterol, bitolterol, carbuterol, clen ingredient used being a salt of memantine. US 8,882,729 B2 10 wherein the polymeric component (P1) is a polyacrylate or Components Amount % polysilicone. Active ingredient salt: Memantine HCl 3O.O 3. The transdermal therapeutic system of claim 1: Constituent (B): CaO 7.5 wherein the polymeric component (P2) of the membrane Polymer (P1): acrylate polymer GMS 3083 62.5 layer (M) is moisture-permeable. 4. The transdermal therapeutic system of claim 1: wherein the active ingredient layer (R) comprises: EXAMPLE 2 1% to 50% (m/m) of the active component (WK); 1% to 20% (m/m) of the at least one alkaline further A transdermal therapeutic system containing an active 10 constituent (B); and antidementia ingredient is produced using the components 30% to 90% (m/m) of the polymeric component (P1). identified in the table below (figures in % M/M), the active 5. The transdermal therapeutic system of claim 1: ingredient used being a salt of memantine (e.g., hydrochlo wherein, the active ingredient layer (R) comprises: ride). 5% to 40% (m/m) of the active component (WK); 15 5% to 20% (m/m) of the at least one alkaline further constituent (B); and Components Amount % 40% to 80% (m/m) the polymeric component (P1). 6. The transdermal therapeutic system of claim 1: Active ingredient salt: Memantine HCl 40.O Polymer (P1): basic “butylated methacrylate 2O.O wherein the active ingredient layer (R) is a polymer matrix copolymer based on a polyacrylate or on a silicone polymer, and Excipient: Na caprylate 1O.O comprises: Membrane layer (M): acrylate polymer 30 55 to 40% (m/m) of the active component (WK), which Durotak 2287 has at least one amino function; and 5 to 20% (m/m) of the at least one alkaline further In example 2, the membrane layer (M) functions simulta 25 constituent (B), which is an alkaline responsive inor neously as adhesive layer (K). In addition, however, depend ganic constituent. ing on the active ingredient (W) and constituent (B), it is 7. The transdermal therapeutic system of claim 1: possible to use a further membrane layer (M), with, for wherein the active ingredient layer (R) is a polymer matrix example, polyvinyl acetate (PVA) or polypropylene (PP) as based on a polyacrylate or on a silicone polymer; polymeric component (P2). Bonding on the skin side is 30 wherein active component (WK) is an inorganic salt of an accomplished via a polyacrylate-based adhesive layer (K). active CNS ingredient As a protective layer (S) in both of examples 1 and 2 it is wherein the at least one alkaline further constituent (B) is possible to use a polyethylene terephthalate film. The an alkaline inorganic further constituent; and amounts of active ingredient delivered to the skin from each wherein the weight ratio between the active component of the active ingredient layers, via the membrane layer, can be 35 (WK) and the further constituent (B) is from 1:10 to measured in a Franz's cell, which is known to the skilled 10:1. person. 8. The transdermal therapeutic system of claim 1: wherein the active ingredient layer (R) is a polymer matrix The invention claimed is: based on a polyacrylate concerns which is substantially 1. A transdermal therapeutic system (TTS) comprising the 40 free of functional groups. following layers: 9. The transdermal therapeutic system of claim 1, further a backing layer (T); comprising: an active ingredient layer (R): an additional adhesive layer (K) which is composed of a a membrane layer (M); and polymeric component (P3). optionally an adhesive layer (K); 45 10. A method of producing the transdermal therapeutic wherein the backing layer (T) is impervious to an alkaline system of claim 1, comprising: active ingredient (W); applying the active ingredient layer (R) to the backing layer wherein the active ingredient layer (R) comprises: (T): an active component (WK) which is a salt of the alkaline Subsequently applying the membrane layer (M); and active ingredient (W); 50 optionally adding an adhesive layer (K) comprising a poly at least one alkaline further constituent (B); and meric component (P3). a polymeric component (P1); 11. A method of treating a disease in a patient in need wherein the membrane layer (M) comprises a polymeric thereof, comprising: component (P2); administering a therapeutically effective amount of the wherein the alkaline active ingredient (W) is released from 55 alkaline active ingredient (W) via application of the the active ingredient layer (R) only after moisture transdermal therapeutic system of claim 1. migrates in from the outside of the TTS through the 12. The method of claim 11: membrane layer (M) So as to contact the active compo wherein the disease is a CNS disease. nent (WK); and 13. The method of claim 12: wherein the active ingredient layer (R) is arranged in 60 wherein the disease is Alzheimer's disease and the active between the backing layer (T) and the membrane layer ingredient is memantine. (M). 14. The transdermal therapeutic system of claim 2: 2. The transdermal therapeutic system of claim 1: wherein the active ingredient layer (R) comprises: wherein the active component (WK) is an inorganic salt of 5% to 40% (m/m) of the active component (WK); the alkaline active ingredient (W); 65 5% to 20% (m/m) of the at least one alkaline further wherein the at least one alkaline further constituent (B) is constituent (B); and an inorganic alkaline further constituent; and 40% to 80% (m/m) the polymeric component (P1); US 8,882,729 B2 11 12 wherein the active ingredient layer (R) is a polymer matrix based on a polyacrylate or on a silicone polymer; wherein the active component (WK) is an inorganic salt of an active CNS ingredient; and wherein the weight ratio between the active component 5 (WKS) and the further constituent (B) is from 1:10 to 10:1. 15. The transdermal therapeutic system of claim 14: wherein the active ingredient layer (R) is a polymer matrix based on a polyacrylate concerns which is substantially 10 free of functional groups. 16. The transdermal therapeutic system of claim 14: wherein the active ingredient (W) is memantine. 17. The transdermal therapeutic system of claim 15: wherein the active ingredient (W) is memantine. 15 k k k k k