RU2578971C2 - Transdermal administration of memantine - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine. Described are transdermal therapeutic systems (TTSs), which contain memantine, an NMDA-receptor antagonist or its physiologically compatible salt as a biologically active substance.

EFFECT: transdermal therapeutic systems can be produced and used for treating central nervous system diseases and can administer memantine for a longer period of time, eg at least for 24 h, and pharmacologically effective plasma memantine concentrations can be maintained over this period of time.

15 cl, 4 tbl, 3 dwg, 3 ex

Description

The invention relates to transdermal therapeutic systems (TTC), which, as a biologically active substance, contain an antagonist of NMDA receptors (N-methyl-D-aspartate receptors) memantine or a physiologically compatible salt thereof. These transdermal therapeutic systems can be prepared and used to treat diseases of the central nervous system.

According to the state of the art, diseases of the central nervous system, especially diseases associated with dementia, such as Alzheimer's disease in its forms from mild to moderate, are treated with acetylcholinesterase inhibitors (e.g. donepezil). To treat Alzheimer's disease in moderate to severe forms, NMDA receptor antagonists are used.

The onset of Alzheimer's disease is based on neurodegenerative processes with the drying of cells in the cerebral cortex or, respectively, parts of the brain. In this case, cholinergic nerve fibers, including their projection areas, are affected to a greater extent. At an early stage of the disease, the glutamatergic system is damaged. Due to the excess intake of calcium in neurons, it can reach neurodegeneration over time. Moreover, the NMDA complex plays a central role as the most important glutamatergic synapse. Its suppression using a selective antagonist can protect the neuronal region from nerve damage.

Symptoms of Alzheimer's disease are strongly dilated ventricles, microscopically distinguishable atherosclerotic plaques, and neurofibrillar nodules. The clinical picture for the most part is expressed by loss of memory, as well as the gradual degradation of personality and intelligence. In this regard, the goal of treating Alzheimer's is to alleviate personal suffering and thus prevent social exclusion. Medical therapy is currently unavailable. While it is desirable to delay the development of dementia, which in most cases proceeds progressively. At the same time, facilitating therapy has the following goals: improving cognitive capacity, minimizing conspicuous neurological behaviors, delaying the progress of the disease and preventing attacks.

According to the prior art, it is known that NMDA receptor antagonists are suitable as neuroprotectors, by preventing the harmful effects of glutamate on NMDA receptors. A group of NMDA receptor antagonists include, for example, substances such as MK 801, dextromethorphan, ketamine, memantine, amantadine, dextrofan, felbamate, acamprosate, MRZ 2/579, phencyclidine, aptiganel, and these substances are also considered as individual substances, and as mixtures or, accordingly, their physiologically compatible salts, for example, hydrochlorides, citrates, maleates, etc.

It is known that the use of antagonists of NMDA receptors, especially due to psychomimetic side effects, is limited, in this regard, their widespread use is still not carried out. In this case, of particular importance in the treatment of patients with Alzheimer's disease is given to the NMDA receptor antagonist memantine (3,5-dimethyl-9-aminoadamantane) or, accordingly, its hydrochloride. Memantine is prescribed for the treatment of Alzheimer's disease in moderate to severe forms. This medicine is available in Germany under the name Axura ^® . This medicine is available in oral form as drops for administration or in the form of coated tablets. This medication can be taken only under the supervision of caring personnel, and the dosage of the biologically active substance should be gradually increased over a period of several weeks in order to minimize the side effects described especially in the treatment of Alzheimer's disease in moderate to severe forms, such as hallucinations, confusion, dizziness, headaches, and fatigue, among others. After the initial phase, this drug should also be taken respectively strictly once in the morning and once after lunch (drops) or, respectively, when using coated tablets daily at the same time.

Due to this strict treatment regimen and the associated supervision obligation, an unfavorable situation arises with very high costs or a correspondingly high cost of treatment when caring for these patients.

Based on these indicated disadvantages, a need arises for new therapeutic systems that overcome these disadvantages, especially those systems in which case care costs may be reduced.

It is known from the prior art that NMDA receptor antagonists, if necessary in combination with analgesics, can be used to treat topical pains in external dosage forms (international applications WO 00/03716; WO 03/015 699; US patents US 2002/0016319, US 6,194,000). Also in US patents US 2004/0102525, US 2003/0139698 and international application WO 04/009062 proposed the introduction of antagonists of NMDA receptors. International application WO 04/106275 provides specific salts of NMDA receptor antagonists.

However, the dosage forms of the prior art are not suitable or only conditionally suitable in order to, after external use, create systemic plasma concentrations of NMDA receptor antagonists that cause a sufficient pharmacological effect for a period of a sufficient duration. With respect to percutaneous permeability, no experimental data are proposed in the art.

However, in the prophylaxis and treatment of diseases of the central nervous system, it is particularly desirable dosage forms that can maintain pharmacologically effective plasma concentrations for a relatively long period of time (for example, 12 hours, 24 hours or longer), not least, since In such cases, the cost of patient care for nurses could be reduced.

Therefore, the invention is based on the task of providing a dosage form for the treatment or prevention of diseases of the central nervous system, especially diseases associated with dementia, preferably Alzheimer's disease (Morbus Alzheimer), which has advantages over dosage forms from the prior art.

Advantages may be shown with regard to applicability, dosage and / or tolerance. If possible, this single dosage form should provide a pharmacologically effective concentration of the biologically active substance in the plasma over a longer period of time, for example, at least 12 hours, preferably at least 24 hours or even several days so that reuse, and thus re-monitoring by maintenance personnel is required less frequently (for example, only once a day).

This problem is solved using the subject matter of this patent application.

It has been unexpectedly discovered that a transdermal therapeutic system can be obtained which is suitable for administering memantine transdermally, the use being for a period of, for example, at least 12 hours, or, for example, for a longer period of time, for example, for at least 24 hours, and during this period of time, pharmacologically effective plasma concentrations of memantine can be maintained.

The invention relates to a transdermal therapeutic system (TTC) for administering the biologically active substance memantine in the form of a free base or a physiologically compatible salt or prodrug, moreover, this TTC has

- carrier layer impervious to the biologically active substance;

- at least one layer containing a biologically active substance, which contains a retaining material in which this biologically active substance is placed;

- if necessary, a protective film;

- tmax for at least 24 hours;

and moreover, when following one after another or time-shifted, preferably repeated applications of, respectively, one or more transdermal therapeutic systems for the intervals between applications, respectively independently comprising at least 12 hours, preferably over the entire period of at least 300 h, in the individual in need of treatment in his blood plasma, respectively, from the beginning of the first application, the following concentrations of biologically active substances:

after 24 hours at least 14 ng / ml, preferably at least 16.2 ng / ml,

after 48 hours at least 27 ng / ml, preferably at least 29.2 ng / ml,

after 60 hours, at least 32 ng / ml, preferably at least 34.5 ng / ml,

after 72 hours at least 37 ng / ml, preferably at least 39.1 ng / ml,

after 96 hours at least 44 ng / ml, preferably at least 46.6 ng / ml,

after 144 hours at least 54 ng / ml, preferably at least 56.5 ng / ml,

after 192 hours at least 60 ng / ml, preferably at least 62.3 ng / ml,

after 240 hours, at least 63 ng / ml, preferably at least 65.5 ng / ml, and

after 300 hours at least 65 ng / ml, preferably at least 67.8 ng / ml.

Preferably, the maximum release rate of the biologically active substance is not more than 100 μg / cm ³ .

TTS according to the invention contains the biologically active substance memantine (3,5-dimethyladamantan-1-amine) in the form of a free base or a physiologically compatible salt or prodrug. For the purposes of the description, the term “biologically active substance” includes memantine and its physiologically compatible solvates. Moreover, memantine may be present in the form of a free base, in the form of a physiologically compatible salt and / or in the form of a solvate, especially a hydrate or, optionally, in the form of any mixtures of the above compounds.

In one preferred embodiment, the TTC according to the invention comprises memantine in the form of a free base. The principle preparation of the free base from hydrochloride is known to the skilled person. This can be done, for example, using ion exchange resins. Another method is extraction from an alkaline aqueous medium using organic solvents that are usually not miscible or slightly miscible with water. Removal of the organic solvent gives the free base (3,5-dimethyladamantane-1-amine).

In another preferred embodiment, the TTC according to the invention comprises memantine in the form of a physiologically compatible salt. Preferred physiologically compatible salts of memantine are, for example, its hydrochloride, hydrobromide, sulfate, hydrosulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, propionate, lactate, citrate, ascorbate, formate, fumarate, maleate, sebacinate, mesylate and bezylate. Memantine hydrochloride is particularly preferred.

TTS according to the invention may contain a prodrug of memantine. In this regard, an inactive or slightly active pharmacological substance is designated as a prodrug, which is only converted through metabolism in the body into an active biologically active substance (metabolite). Examples of prodrugs of memantine or its pharmacologically compatible salts are derivatives obtained by the amine functional group, for example, amidated with physiologically compatible carboxylic acids. In this case, these amides are cleaved under physiological conditions, if necessary by enzymatic catalysis. Another example of a prodrug of memantine is its N-oxide.

TTS according to the invention as a biologically active substance, in addition to memantine or its physiologically compatible salts or prodrugs, may contain other pharmacologically active substances. However, preferably, in addition to memantine or its physiologically compatible salts, no other biologically active substances are contained.

Preferably, the TTC according to the invention is a patch containing a biologically active substance.

Typically, such a TTC includes at least

a) a carrier layer impervious to the biologically active substance (backing layer), a carrier layer which is impervious to liquid water and / or water vapor is preferred;

b) at least one layer containing a biologically active substance, which at least partially covers the carrier layer and preferably itself has the ability to stick. If necessary, an additional adhesive layer can be applied to ensure sufficient adhesion to the skin;

c) if necessary, a protective film that covers the layer containing the biologically active substance, and can be removed from it (removable substrate, release liner). Preferred is a protective film that is impervious to liquid water and / or water vapor.

Typically, prior to use of the TTC, the protective film, if necessary, is removed to expose the adhesive layer. This protective film may consist, for example, of polyethylene, polyester, polyethylene terephthalate, polypropylene, polysiloxane, polyvinyl chloride or polyurethane, and, if necessary, of processed paper fibers, such as, for example, cellophane, and, if necessary, have a silicone, fluorosilicon or fluorocarbon coating.

The TTC according to the invention has a carrier layer impermeable to the biologically active substance and one layer containing the biologically active substance, or several layers containing the biologically active substance, and, of course, not all layers other than the carrier layer must contain a biologically active substance.

In one preferred embodiment, the TTC according to the invention has a total of no more than 3, 4, 5, 6, 7, 8, or 9 different layers. In another preferred embodiment, the TTC according to the invention has a total of at least 3, 4, 5, 6, 7, 8, or 9 different layers.

The carrier layer impermeable to the biologically active substance (back or outer layer) of the TTC according to the invention is preferably for substances contained in the layer containing the biologically active substance and in the adhesive layer, especially for the biologically active substance contained if necessary, is impermeable and inert and can be formed from polymers such as polyesters, for example polyethylene terephthalate, polyolefins such as polyethylene, polypropylene or polybutylene, polycarbonates , polyethylene oxides, polyterephthalates, such as polyethylene terephthalates, polyurethanes, polystyrenes, polyamides, polyimides, polyvinyl acetates, polyvinyl chlorides and / or polyvinylidene chlorides, copolymers such as acrylonitrile / butadiene / styrene copolymers containing paper fibers, textile blends, and if necessary, can be metallized or pigmented. The carrier layer can also be formed from a combination of a metal film and a polymer layer. These polymers can be used in the form of a film, fabric, felted material or foam.

The layer impermeable to the biologically active substance preferably has a layer thickness in the range of 15 to 2000 microns.

TTS according to the invention has a layer containing a biologically active substance, which contains a retaining material in which the biologically active substance is placed. This layer containing the biologically active substance can simultaneously be an adhesive layer in which the biologically active substance is present in dissolved form and / or dispersed in the matrix together with the adhesive substance (drug in adhesive). However, in the case of a TTS according to the invention, the layer containing the biologically active substance and the adhesive layer may also be present separately from each other.

The layer containing the biologically active substance preferably has a layer thickness in the range from 10 to 9000 μm.

The TTC according to the invention can be designed, for example, as a membrane-controlled system (TTC of the reservoir type), or as a diffusion-controlled system (TTC of the matrix type) (compare with K.N. Bauer et al. Pharmazeutische Technologie; RH Müller, et al., Pharmazeutische Technologie: ModerneArzneiformen).

Tank-type TTS usually includes a flat pack that self-adheres to the skin, which contains the biologically active substance in dissolved form. From the side facing the skin, the package is equipped with a membrane permeable to the biologically active substance, which regulates the release of the biologically active substance. The adhesive layer and the layer containing the biologically active substance (reservoir) are usually sub-components that are separated from each other in space.

In the case of a TTC matrix type, the biologically active substance is embedded in the matrix, and it may be present in a dispersed liquid, semi-solid or solid state or in dissolved form. If the matrix simultaneously has adhesive properties, then the adhesive layer at the same time is also a layer containing a biologically active substance (drug in adhesive). But it is also possible that the adhesive layer and the layer containing the biologically active substance, as in the case of the TTC of the reservoir type, are separated from each other. In this case, the adhesive layer can be applied to the layer containing the biologically active substance, or, respectively, the membrane of the reservoir over the entire surface, partially or in the form of a ring.

By composition and structuring of the matrix and / or membrane, the release of the biologically active substance can be controlled. For further details, reference may be made, for example, to T.K. Gosh, Transdermal and Topical Drug Delivery Systems Es Into Practice, CRC Press, 1997; R.O. Potts et al., Mechanisms of Transdermal Drug Delivery (Drugs and the Pharmaceutical Sciences), Marcel Dekker, 1997; and R. Gurny et al., Dermal and Transdermal Drug Delivery. New Insights and Perspectives, Wissenschaftliche VG., Stuttgart, 1998.

As adhesives for the manufacture of the TTS adhesive layer according to the invention, pressure sensitive adhesives (self-adhesive materials, pressure-sensitive adhesives, PSA) can be used. An adhesive layer may be formed, for example, as an adhesive region or an adhesive surface that delimits a layer containing a biologically active substance on the sides. For the manufacture of the adhesive layer, for example, polymers such as polyacrylates, polyvinyl ethers, polyisobutylenes (PIB), styrene / isoprene or butadiene / styrene copolymers or polyisoprene rubbers are suitable. In addition, silicone adhesives are suitable, such as, for example, if necessary, polymer crosslinked polydimethylsiloxanes. In addition, resins such as, for example, glycine, glycerol or pentaerythritol esters, or hydrocarbon resins, such as polyterpenes, are suitable. Acrylate-based adhesives are obtained by the polymerization of acrylates, methacrylates, alkyl acrylates and / or alkyl methacrylates, optionally with other unsaturated monomers, such as acrylamide, dimethyl acrylamide, dimethylaminoethyl acrylate, hydroxyethyl acrylate, methacrylate acrylate, methyryl acrylate acrylate, methyryl acrylate acrylate, methyryl acrylate, acrylate, acrylate, acrylate, acrylate, acrylate, acrylate, acrylate, acrylate, acrylate, acrylate, acrylate, acrylate, acrylate, acrylate, acrylate. Examples of suitable polymers are commercially available under the name Durotak ^®, e.g., products 2516, 2287, 900A, or 9301. Other suitable polymers are commercially available, polyisobutylenes, polyacrylates, such as, e.g., GMS 3083, Plastoid B and Eudragit ^® E 100.

The adhesive layer may additionally contain auxiliary substances, such as plasticizers, for example phthalates, such as dibutyl phthalate, mineral oils, citric acid esters or glycerol esters, skin permeability enhancers, for example, dimethyl sulfoxide, an adhesion promoter (tackifier, tackifier), fillers (such as zinc oxide or silica), a crosslinking agent, a preservative and / or a solvent. Excipients of this type are known to those skilled in the art. In relation to them, reference may be made, for example, to publications by R. Niedner et al., Dermatika: therapeutischer Einsatz, Pharmakologie und Pharmazie, Wiss. Verl.-Ges. 1992; H.P. Fiedler, Lexikon der Hilfsstoffe für Pharmazie, Kosmetik und angrenzende Gebiete, Editio Cantor Aulendorff, 2002.

The biologically active substance in the layer containing this biologically active substance is present in dissolved or solid form. Preferably, the biologically active substance is present in fully dissolved form, that is, it is preferably practically impossible to detect a crystalline portion of the biologically active substance. In one preferred embodiment, the concentration of the biologically active substance in the layer containing the biologically active substance according to the invention is at least 25%, more preferably at least 50%, even more preferably at least 66%, most preferably at least 75% , but in particular at least 80% of its saturation concentration. Determination of saturation concentration is known to those skilled in the art. For example, a saturation concentration has not yet been achieved if a crystal of a pure biologically active substance is brought into contact with a layer containing this biologically active substance and is absorbed by this layer within 5 minutes, that is, it dissolves. If the biologically active substance is present at least partially in solid form, then it is preferably microdispersion.

A layer containing a biologically active substance, TTC according to the invention contains a retaining material in which this biologically active substance is placed.

In one preferred embodiment, this retaining material is positioned between the carrier layer impermeable to the active substance and the membrane layer of the membrane active material, so that the TTC according to the invention is preferably a tank type TTC.

In another preferred embodiment, the retaining material serves as a matrix, so that the TTC according to the invention is preferably a matrix type TTC.

Suitable retention materials are natural or (semi) synthetic polymers that form the matrix. As the matrix-forming polymers, for example, polyethylenes, chlorinated polyethylenes, polypropylenes, polyurethanes, polycarbonates, polyacrylic acid esters, polyacrylates, polymethacrylates, polyvinyl alcohols, polyvinyl chlorides, polyvinylidene chlorides, polyvinylpyrrolidonylethylene, polyethylene, polyethylene, polyethylene , ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, ethylene / vinyl alcohol copolymers, ethylene / vinyloxyethanol copolymers, vinyl chloride copolymers / vinyl acetate, vinylpyrrolidone / ethylene / vinyl acetate copolymers, rubbers, rubber-like synthetic homo-, co- or block copolymers, silicones, silicone derivatives, such as polysiloxane / polymethacrylate copolymers, cellulose derivatives, such as cellulose ethers, especially methyl cellulose, ethyl cellulose, , hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose and / or mixtures thereof. Particularly preferred are polyacrylates or polysilicones.

The retention material may include the above polymers, which are suitable for the manufacture of an adhesive layer (drug in adhesive).

The content of the retaining material is preferably from 10 to 99.9% of the mass. in terms of the total weight of the layer containing the biologically active substance, more preferably from 50 to 95% of the mass.

As for the quantitative ratios of the retention material / content of the biologically active substance, the ratios of 99: 1 to 50:50 (weight of the retention material: mass of the biologically active substance) are preferably selected, preferably 95: 5 to 60:40. In preferred embodiments, 99.5: 0.5 to 80:20 (matrix weight: biologically active substance mass) is selected, preferably 99: 1 to 85:15. The relatively high proportion of biologically active substances is justified by the proportionately high need for a substance for the treatment of Alzheimer's disease in forms from moderate to severe.

Preferably, the retaining material includes:

- a liquid or gel composition in which the biologically active substance is partially or completely dissolved; and / or

- a matrix based on a polymer material in which the biologically active substance is present in dissolved form or distributed as microdispersion; and / or

- polymer material based on polyacrylate or polysilicon; and / or

- lipogel, which preferably contains from 10 to 50% of the mass. biologically active substance.

In one preferred embodiment, the active compound layer comprises a hydrogel or lipogel. In the framework of this description, hydrogels are gels that contain water and / or other hydrophilic or completely or partially miscible with water substances that give this gel hydrophilic properties. As part of this description, lipogels are gels that mainly contain water immiscible substances that impart lipophilic properties to this gel.

In one preferred embodiment, the biologically active substance in the layer containing the biologically active substance is present in the form of a physiologically compatible salt, especially as memantine hydrochloride. Preferably, the layer containing the biologically active substance further comprises at least one basic material, the basicity of which is sufficient to react with the physiologically compatible salt of the biologically active substance with the release of the free base of the biologically active substance. Suitable base materials are known to those skilled in the art, and their suitability can be evaluated based on the pK _a value of memantine base. Preferably, the base material is selected from the group consisting of polymers with basic side groups, organic bases, and inorganic bases. In one preferred embodiment, the base material is selected from the group consisting of acrylate-based polymers that have aminoalkyl side groups; inorganic oxides or hydroxides, especially oxides of alkali or alkaline earth metals; organic amines or their salts; alkali metal or alkaline earth metal alcoholates or carboxylates.

Preferred examples of suitable basic materials include calcium oxide (CaO), sodium ethoxide and basic methacrylate copolymers, such as, for example, Eudragit ^® E100.

In one preferred embodiment, the layer containing the biologically active substance contains from 20 to 90% of the mass. retaining material, from 10 to 50% of the mass. biologically active substances, and also, if necessary, from 5 to 40% of the mass. basic material, calculated on the total weight of the layer containing the biologically active substance.

A layer containing a biologically active substance, TTS according to the invention, in addition to the biologically active substance and optionally present adhesive, may also contain a tackifier, a plasticizer, substances, penetration enhancers, viscosity enhancers, solubility enhancers, crosslinking agents, preservatives, emulsifiers , thickeners and / or other conventional excipients. Additives of this type are known to those skilled in the art.

Examples of solubility enhancers and / or amplifiers penetrating power are acetyl acetone, acetyl tributyl citrate, acetyl triethyl citrate, benzyl alcohol, butyl stearate, cetyl lactate, cetyl palmitate, cetyl stearate, cetyl stearyl alcohol / cetyl alcohol, chlorobutanol, cineole, decylmethylsulfoxide, decyl oleate, dibutyl phthalate, diethylene glycol monoethyl ether, diethyl phthalate, diethyl sebacinate, diisopropyl adipate, dimethyl phthalate, dioctyl adipate, dipropylene glycol, glyceryl monooleate, glyceryl monostearate, stearyl alcohol, peanuts Own oil, ethyl lactate, ethyl linoleate, ethyl (9,12,15) -linoleate, eugenol, farnesol, glycerol, glyceryl ester, glyceryl stearate, glycol distearate, glyoxal, hexadecanol, isoleutyl stealtol, hexobenzyl iso-steral, , isopropyl stearate, isostearyl neopentanoate, lauric acid diethanolamide, limonene, linolenic acid, linolenic acid diethanolamide, menthol, myristyl lactate, myristyl myristate, myristyl stearate, m-tolyl acetate, octyl dodecanol, oct ilpalmitate, octyl stearate, oleic acid diethanolamide, oleyl alcohol, oleyl oleate, phenylethyl alcohol, propylene glycol, propylene carbonate, isostearic acid, octanoic acid, hydrogenated castor oil, 1,3-butylene glycol, safflower trichlorocetate, glaucetric acid, trifluoroacetate, gallic acid chloride acid, (+) - fenhon, simple ammonium lauryl ether sulfate, cholesterol, lecithin, glycerol hydroxide stearate, fatty acid mono- and diglycerides, sodium caprylate, sodium simple lauryl ether sulfate, sodium / potassium fatty acid oli, sodium lauryl sulfate, PEG- (2) -searate, sodium sulfosuccinate, polyglyceryl fatty acid esters, polyoxyethylene alkyl ethers, cetomacrogol, sorbitol and polyoxyethylene fatty acid esters, propylene glycol stearate, sorbitan fatty acid esters, fatty acid esters medium chain triglycerides (preferably 12-14 carbon atoms) (according to the European Pharmacopoeia, Ph. Eur.).

Dissolution aids include N-methyl-2-pyrrolidone, lauryl pyrrolidone, triethanolamine, triacetin, diethylene glycol monoethyl ether, derivatives of fatty acids or fatty alcohols and / or low molecular weight polyols, such as, for example, propylene glycol or glycerol.

In the case of substances that increase the viscosity, this description preferably refers to a gelling agent, that is, a substance that, on the one hand, increases the viscosity of the composition and, on the other hand, promotes the formation of a gel. Examples of such viscosity enhancers are gelatins (e.g. Gelatin), locust bean gum (e.g. Cesagum ^® LA-200, Cesagum ^® LID / 150, Cesagum ^® LN-1), pectins such as citrus pectin (e.g. Cesapectin ^® HM Medium Rapid Set), Apple Pectin, Lemon Peel Pectin, Waxy Corn Starch (C ^* Gel ^® 04201), Sodium Alginate (e.g. Frimulsion ^® ALG (E401)), Guar Gum (e.g. Frimulsion ^® BM, Polygum ^® 26 / 1-75), iota-carrageenan (for example, Frimulsion ^® D021), karaya gum, gellan gum ^{(e.g., Kelcogel ® F, Kelcogel ® LT100} ), galactomannan (e.g., Meyprogat ^® 150), tara gum (nap Emer, Polygum ^® 43/1), propylene glycol ^{(e.g., Protanal ® -Ester SD-LB)} , sodium hyaluronate, tragacanth, tara gum (e.g., Vidogum ^® SP 200), fermented polysaccharide welan gum (e.g., K1A96), xanthan gum (e.g., Xantural ^® 180).

If the TTC according to the invention is formed by a system with a reservoir, the reservoir membrane may consist of inert polymers such as, for example, polyethylene, polypropylene, polyvinyl acetate, polyamide, ethylene / vinyl acetate copolymers and / or silicones. Using a reservoir membrane, a controlled release of the biologically active substance from the reservoir can be achieved.

The matrix containing the biologically active substance, or respectively the reservoir containing the biologically active substance, may also contain a solvent, such as, for example, water, ethanol, 1-propanol, isopropanol, a low molecular weight polyhydric alcohol, for example, propylene glycol or glycerol, or an ester, such as isopropyl myristate, or mixtures thereof. However, in a preferred embodiment, the matrix containing the biologically active substance, or, accordingly, the reservoir containing the biologically active substance, mainly do not contain ethanol and / or isopropanol.

As preservatives for the layer containing the biologically active substance, antioxidants such as Vitamin E, butylhydroxytoluene, butylhydroxyanisole, parabens, ascorbic acid, ascorbyl palmitate, and / or chelating agents such as disodium salt of ethylene diamine citrate, can be used . In addition, polyhydroxybutyrate esters (PHB) are suitable as preservatives, such as PHB methyl ester and PHB propyl ester, benzalkonium chloride, chlorhexidine, sorbic acid, benzoic acid, propionic acid, salicylic acid and its salts, formaldehyde and paraformaldehyde, hexachlorophene, o-phenylphenol, zincpyrithione, inorganic sulfites, sodium iodate, chlorobutol, dehydroacetic acid, formic acid, dibromhexamide, merthiolate, phenylmercury salts (phenylmercury compounds), undecylenic acid , hexetidine, bronidox, bronopol, 2,4-dichlorobenzyl alcohol, triclocarbane, parachloromethacresol, triclosan, parachloromethaxylene, imidazolidinyl urea derivatives, polyhexamethylene biguanide hydrochloride, phenoxyethanol, methenamine, 1-dimethyl-3-d-idyl dimethylbutan-2-one, dimethylhydantoin, benzyl alcohol, 1-hydroxy-4-methyl-6- (2,4,4-trimethylpentyl) -2-pyridone, 1,2-dibromo-2,4-dicyanobutane, 3.3 '-dibromo-5,5'-dichloro-2,2-dihydroxydiphenylmethane, isopropylmethacresol and a caton.

The TTC according to the invention may also contain at least one plasticizer in one layer or in several layers selected from the group consisting of long chain alcohols such as dodecanol, undecanol, octanol, carboxylic esters with polyethoxylated alcohols, aliphatic dicarboxylic acid esters, such like adipic acid, and medium chain length caprylic acid and / or capric acid triglycerides, coconut oil, polyhydric alcohols such as 1,2-propanediol, polyhydric esters such as glycerin, with levulinic acid or caprylic acid and polyhydric alcohols converted into ethers.

The preparation of TTC according to the invention can be carried out according to known methods of preparation, especially for patches containing active substances, using process steps such as lamination, punching, delamination, rolling, cutting, rewinding, assembly or dosing (compare with Verpackungs-Rundschau 4 / 2002, 83-84).

The release of the biologically active substance from the TTC according to the invention is preferably controlled. Moreover, the TTC according to the invention preferably has a maximum release rate of the biologically active substance of not more than 100 μg / cm ² h, preferably not more than 95 μg / cm ² h, not more than 90 μg / cm ² h or not more than 85 μg / cm ² h; more preferably not more than 80 μg / cm ² h, not more than 75 μg / cm ² h or not more than 70 μg / cm ² h; even more preferably not more than 65 μg / cm ² h, not more than 60 μg / cm ² h or not more than 55 μg / cm ² h; most preferably not more than 50 μg / cm ² h, not more than 45 μg / cm ² h or not more than 40 μg / cm ² h; and in particular not more than 35 μg / cm ² h or not more than 32 μg / cm ² h

In one preferred embodiment, the maximum release rate of the active substance is in the range of 20 ± 15 μg / cm ² h, more preferably 20 ± 12.5 μg / cm ² h, even more preferably 20 ± 10 μg / cm ² h, most preferably 20 ± 7.5 μg / cm ² h and in particular 20 ± 5 μg / cm ² h. In another preferred embodiment, the maximum release rate of the active substance is in the range of 25 ± 10 μg / cm ² h, even more preferably 25 ± 7.5 micrograms / cm ² h, most preferably 25 ± 5 mg / cm ² h and in particular STI 25 ± 2.5 ug / cm ² hr. In another preferred embodiment, the maximum rate of release of the biologically active substance is in the range of 30 ± 5 mg / cm ² h, still more preferably 30 ± 2.5 ug / cm ² hr.

Typically, the rate of release varies during the interval between TTC applications. So, on the one hand, the amount of biologically active substance in the TTC due to the release is continuously decreasing, on the other hand, the skin can exhibit a certain accumulating ability. Both effects can affect the rate of release.

The maximum release rate of TTC and its determination are known to the skilled person. The maximum release rate can be denoted as the maximum penetration for human skin and in vitro determined in vitro, for example, using a Franz diffusion cell. Preferably, this determination is carried out under the conditions given in the experimental part.

The TTC according to the invention has a t _max of at least 24 hours, more preferably at least 26 hours, even more preferably at least 28 hours, most preferably at least 30 hours and in particular at least 32 hours. In one preferred embodiment TTC according to the invention t _max lies in the range 36 ± 12 hours, more preferably 36 ± 10 hours, even more preferably 36 ± 8 hours, most preferably 36 ± 6 hours, and in particular 36 ± 4 hours. In another preferred embodiment, TTC according to The invention t _max lies in the range 32 ± 8 h, more pr preferably 32 ± 7 hours, even more preferably 32 ± 6 hours, most preferably 32 ± 5 hours, and in particular 32 ± 4 hours. In another preferred embodiment of the TTC according to the invention, t _max lies in the range 28 ± 4 hours, more preferably 28 ± 3 hours, most preferably 28 ± 2 hours

In this case, t _{max is} preferably determined as the time after which, in the course of a single and first use of TTC according to the invention, the maximum concentration of biologically active substance in the blood plasma (C _max ) is reached, measured from the moment of application of this TTC on the skin. Suitable methods for determining t _max and C _{max are} known to those skilled in the art.

The TTC according to the invention preferably has a C _max von mindestens of 4 ng / ml, at least 4.5 ng / ml, at least 5 ng / ml, or at least 5.5 ng / ml, more preferably at least 6 ng / ml, even more preferably at least 8 ng / ml, most preferably at least 10 ng / ml and in particular at least 12 ng / ml.

The TTC according to the invention preferably has a pharmacokinetic delay time t _{lag of} not more than 6 hours, more preferably 1.33 ± 1.00 hours, even more preferably 1.33 ± 0.66 hours and in particular 1.33 ± 0.33 hours. most pharmacokinetic delay time t _lag TTC according to the invention is unexpectedly short, which entails advantages. So, effective concentrations of biologically active substances in blood plasma are achieved in a relatively short time after applying TTC to the skin.

The TTC according to the invention preferably has a bioanalytical detectability duration t _last of at least 200 hours, more preferably at least 220 hours and particularly preferably at least 240 hours

The TTC according to the invention preferably has a pharmacokinetic half-life of the biologically active substance t _{1/2, z} in the range of 60-100 hours, more preferably in the range of 52 ± 25 hours, more preferably 52 ± 15 hours, most preferably 52 ± 10 hours and in particular 52 ± 5 hours

Suitable methods for determining these pharmacokinetic parameters are known to those skilled in the art. The determination of the concentration of biologically active substances in blood plasma is also known to the specialist. It is preferably carried out using liquid chromatography (LC), for example, high performance liquid chromatography (HPLC), preferably in combination with mass spectrometry (MS) (LC-MS or HPLC-MS, respectively).

The TTC according to the invention preferably has a slight interindividual variability, preferably not more than 25%, more preferably not more than 20%. Low interindividual variability of this type has the advantage that the level achieved in vivo in the blood can be well predicted, which, among other things, is also accompanied by increased therapeutic reliability.

At the maximum value of the interindividual variability of the pharmacokinetic parameters of 25% TTC according to the invention differs from other TTC, which are provided for the introduction of other active substances. For example, TTC has been reported for administering the biologically active substance rivastigmine, in which the variability of the parameters is> 32% (compare with G. Lefevre et al., Clinical Pharmacology & Therapeutics, 83 (1), 2008, 106-114).

In one preferred embodiment, the TTC according to the invention, after its intended use, has a relatively low residual active substance content. Preferably, this residual content after 24 hours of use is not more than 75% by mass, more preferably not more than 70% by mass, even more preferably not more than 65% by mass. and in particular not more than 60% of the mass. of the amount originally contained in the TTC. This is an advantage for economic and security reasons.

The TTC according to the invention is designed in such a way that when following one after another or time-shifted, preferably repeated, applications of one or more TTC according to the invention for intervals between applications, respectively independently for at least 12 hours, over the entire period of time of at least 300 hours, in the individual in need of treatment in his blood plasma, respectively, from the beginning of the first use, the following biological concentrations are achieved and active substance:

after 24 hours at least 14 ng / ml, preferably at least 16.2 ng / ml,

after 48 hours at least 27 ng / ml, preferably at least 29.2 ng / ml,

after 60 hours, at least 32 ng / ml, preferably at least 34.5 ng / ml,

after 72 hours at least 37 ng / ml, preferably at least 39.1 ng / ml,

after 96 hours at least 44 ng / ml, preferably at least 46.6 ng / ml,

after 144 hours at least 54 ng / ml, preferably at least 56.5 ng / ml,

after 192 hours at least 60 ng / ml, preferably at least 62.3 ng / ml,

after 240 hours, at least 63 ng / ml, preferably at least 65.5 ng / ml, and

after 300 hours at least 65 ng / ml, preferably at least 67.8 ng / ml.

In this case, repeated applications are preferably carried out directly one after another, that is, when one or more TTC according to the invention is removed at the end of the interval between applications, one or more TTC according to the invention is immediately applied to the next interval between applications. Moreover, the time period over which, if necessary, no TTS according to the invention is applied to the body, is preferably not more than 10 minutes, more preferably not more than 5 minutes.

In one preferred embodiment, the use of all TTC according to the invention over the entire period of time is carried out on the same area of the skin of the individual, that is, on this part of the skin of the individual is reapplied or glued TTC according to the invention.

In another preferred embodiment, the use of all TTS according to the invention over the entire period of time is carried out respectively on other parts of the skin of the individual, that is, on this part of the skin of the individual TTS according to the invention is not reapplied or, accordingly, is not glued.

In this case, the TTC according to the invention are used for successive intervals between applications, respectively independently at least 12 hours, preferably during the entire period of at least 300 hours. If each interval between applications lasts, for example, 12 hours, then at least 25 consecutive intervals between applications are required to cover a total period of at least 300 hours. For example, if each interval between applications lasts 18 hours, then t ebuyutsya respectively at least 17 consecutive intervals between applications to cover the total period of time of at least 300 hours.

Separate intervals between applications may have the same exact or different duration. Preferably, all intervals between applications have the same duration, preferably 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 26 hours, 28 hours, 30 hours, 32 hours, 34 hours, 36 hours, 38 hours, 40 hours, 42 hours, 44 hours, 46 hours, 48 hours, 50 hours, 52 hours, 54 hours, 56 hours, 58 hours, 60 hours, 62 hours, 64 hours, 66 hours, 68 hours, 70 or 72 hours. In one preferred embodiment, each interval between applications, independently of the others, is not more than 168 hours or not more than 144 hours, more preferably not more than 120 hours or not more than 96 hours, even more preferably not more than 72 hours or not more than 48 hours most preferably not more than 36 hours or not more than 24 hours and in particular singularity is not more than 12 hours.

The intervals between applications are explained in more detail in Figures 1 and 2. Both Figures schematically show the process of changing the minimum concentration of a biologically active substance in blood plasma over time. In Figure 1, each bar in the diagram is equal to the interval between applications of 12 hours, in Figure 2, the interval between applications of 24 hours. The height of these columns respectively equals the minimum achieved plasma concentration.

During each interval between applications, one TTC according to the invention can be used, or several TTC according to the invention can be respectively applied simultaneously. The amount of TTC used can vary from one interval between applications to another interval between applications. Preferably, the number of TTC used in each interval between applications is the same.

In one preferred embodiment, the indicated concentrations of the biologically active substance are achieved by using during one interval between applications, respectively, one or two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen or sixteen TTC according to the invention.

In one preferred embodiment, for each interval between applications, the duration in hours divided by the number of simultaneously used TTCs, independently of each other, ranges from 4 to 24, more preferably from 5 to 20, even more preferably from 6 to 18. B in one preferred embodiment, for each interval between applications, the duration in hours divided by the number of simultaneously used TTCs, independently of each other, is in the range ONET from 3 to 8, more preferably 4 to 7 and especially about 6.

Preferred embodiments of the TTC according to the invention which achieve the above active substance concentrations are listed below: 12 ² , 12 ³ , 12 ⁴ , 18 ² , 18 ³ , 18 ⁴ , 18 ⁵ , 24 ³ , 24 ⁴ , 24 ⁵ , 24 ⁶ , 24 ⁷ , 36 ⁵ , 36 ⁶ , 36 ⁷ , 36 ⁸ , 36 ⁹ , 36 ¹⁰ , 36 ¹¹ , 48 ⁷ , 48 ⁸ , 48 ⁹ , 48 ¹⁰ , 48 ¹¹ , 48 ¹² , 48 ¹³ , 48 ¹⁴ , 48 ¹⁵ , 48 ¹⁶ , 60 ⁹ , 60 ¹⁰ , 60 ¹¹ , 60 ¹² , 60 ¹³ , 60 ¹⁴ , 60 ¹⁵ , 60 ¹⁶ , 60 ¹⁷ , 60 ¹⁸ , 60 ¹⁹ , 72 ¹² , 72 ¹³ , 72 ¹⁴ , 72 ¹⁵ , 72 ¹⁶ , 72 ¹⁷ , 72 ¹⁸ , 72 ¹⁹ , 72 ²⁰ , 72 ²¹ , 72 ²² , 84 ¹⁴ , 84 ¹⁵ , 84 ¹⁶ , 84 ¹⁷ , 84 ¹⁸ , 84 ¹⁹ , 84 ²⁰ , 84 ²¹ , 84 ²² , 84 ²³ , 84 ²⁴ , 96 ¹⁹ , 96 ²⁰ , 96 ²¹ , 96 ²² , 96 ²³ , 96 ²⁴ . In this case, the duration of each interval between applications in hours (for example, “12”) is first indicated, and then, in the form of an upper index, the number, respectively, if necessary, of simultaneously used TTS according to the invention (for example, “ ³ ”). In accordance with this, for example, "24 ² " means, respectively, the simultaneous use of two TTC according to the invention during successive intervals between applications, respectively 24 hours.

Preferably, the TTC according to the invention is prepared to be used in accordance with the above-mentioned intervals between applications. Another aspect of the invention relates to a method for the treatment or prophylaxis of diseases of the central nervous system, comprising the subsequent use of several TTC according to the invention in compliance with the above-defined intervals between applications.

The specialist understands that a certain ratio of the duration of application and the number of TTC, which, if necessary, should be applied simultaneously, while reducing this number of TTC, which, if necessary, should be applied simultaneously, can similarly be achieved by a corresponding increase in TTC, and vice versa. Thus, the pharmacological efficacy of a TTC with a surface releasing a biologically active substance of, for example, 5 cm ² is approximately twice higher than the pharmacological efficacy of an otherwise identical TTC with a surface releasing a biologically active substance of 2.5 cm ² .

The surface of the TTC according to the invention, releasing a biologically active substance (contact surface containing a biologically active substance), preferably lies in the range from 0.1 to 400 cm ² . In one preferred embodiment, the surface of the TTC according to the invention releasing a biologically active substance lies in the range of 10 ± 9 cm ² , more preferably 10 ± 7.5 cm ² , even more preferably 10 ± 5 cm ² , most preferably 10 ± 2.5 cm ² and in particular 10 ± 1 cm ² . In another preferred embodiment, the surface of the TTC according to the invention releasing a biologically active substance lies in the range of 20 ± 9 cm ² , more preferably 20 ± 7.5 cm ² , even more preferably 20 ± 5 cm ² , most preferably 20 ± 2.5 cm ² and in particular 20 ± 1 cm ² . In another preferred embodiment, the surface of the TTC according to the invention releasing a biologically active substance lies in the range of 25 ± 20 cm ² , more preferably 25 ± 15 cm ² , even more preferably 25 ± 10 cm ² , most preferably 25 ± 5 cm ² features 25 ± 2.5 cm ² . In another preferred embodiment, the surface of the TTC according to the invention releasing a biologically active substance lies in the range of 30 ± 9 cm ² , more preferably 30 ± 7.5 cm ² , even more preferably 30 ± 5 cm ² , most preferably 30 ± 2.5 cm ² and in particular 30 ± 1 cm ² . In another preferred embodiment, the surface of the TTC according to the invention releasing a biologically active substance lies in the range of 100 ± 90 cm ² , more preferably 100 ± 75 cm ² , even more preferably 100 ± 50 cm ² , most preferably 100 ± 25 cm ² and Features 100 ± 10 cm ² . In another preferred embodiment, the surface of the TTC according to the invention releasing a biologically active substance lies in the range of 200 ± 90 cm ² , more preferably 200 ± 75 cm ² , even more preferably 200 ± 50 cm ² , most preferably 200 ± 25 cm ² and features 200 ± 10 cm ² .

If the surface releasing the biologically active substance is large enough, for example, greater than, for example, 10 cm ² , then as a result of closing a part of the surface containing the biologically active substance with a protective layer impermeable to the biologically active substance, the actual surface releasing a biologically active substance, may decrease. For example, if the TTC according to the invention has a 6 × 6 cm square surface containing the biologically active substance, then 26 cm ^{2 of} this surface can be coated with a layer impermeable to the biologically active substance to provide a surface area releasing the biologically active substance with an area of 10 cm ² . The specialist is aware that, if necessary, the diffusion in the transverse direction should be taken into account, especially in the case of substances that penetrate well into the adhesive-containing layer, so that the size of the protective layer must be selected if necessary.

In one preferred embodiment, the TTC according to the invention from the start of the first use, respectively, the following concentrations of active substance are achieved:

after 24 hours, a maximum of 50 ng / ml,

after 48 hours, maximum 90 ng / ml,

after 60 hours, maximum 110 ng / ml,

after 72 h, maximum 130 ng / ml,

after 96 h, maximum 150 ng / ml,

after 144 h, maximum 180 ng / ml,

after 192 h, maximum 195 ng / ml,

after 240 hours, a maximum of 200 ng / ml, and

after 300 h, a maximum of 210 ng / ml.

Preferred concentration ranges of the active substance B ₁ to B _{4 are} summarized in the following Table 1:

Table 1 later IN 1 IN 2 IN 3 AT 4 24 h 24.3 ng / ml ± 30% 22.7 ng / ml ± 25% 21.1 ng / ml ± 20% 20.3 ng / ml ± 15% 48 h 43.8 ng / ml ± 30% 40.9 ng / ml ± 25% 38.0 ng / ml ± 20% 36.5 ng / ml ± 15% 60 h 51.8 ng / ml ± 30% 48.3 ng / ml ± 25% 44.9 ng / ml ± 20% 43.1 ng / ml ± 15% 72 h 58.7 ng / ml ± 30% 54.7 ng / ml ± 25% 50.8 ng / ml ± 20% 48.9 ng / ml ± 15% 96 h 69.9 ng / ml ± 30% 65.2 ng / ml ± 25% 60.6 ng / ml ± 20% 58.3 ng / ml ± 15% 144 h 84.9 ng / ml ± 30% 79.2 ng / ml ± 25% 73.6 ng / ml ± 20% 70.8 ng / ml ± 15% 192 h 93.5 ng / ml ± 30% 87.2 ng / ml ± 25% 81.0 ng / ml ± 20% 77.9 ng / ml ± 15% 240 h 98.3 ng / ml ± 30% 91.7 ng / ml ± 25% 85.2 ng / ml ± 20% 81.9 ng / ml ± 15% 300 h 101.7 ng / ml ± 30% 94.9 ng / ml ± 25% 88.1 ng / ml ± 20% 84.8 ng / ml ± 15%

In one preferred embodiment, with continuous use in accordance with the purpose of the TTC according to the invention, stationary (Steady-State) levels of pharmacological concentrations of the biologically active substance in the blood plasma are achieved in the range from 70 to 150 ng / ml.

In one preferred embodiment of the TTC according to the invention, its rate of release of the active substance averaged over the entire interval between applications is in the range from 0.2 to 2.0 mg / h. In one preferred embodiment, this averaged release rate is in the range of 0.7 ± 0.5 mg / h, more preferably 0.7 ± 0.4 mg / h, even more preferably 0.7 ± 0.3 mg / h. In another preferred embodiment, this average release rate is in the range of 1.0 ± 0.5 mg / h, more preferably 1.0 ± 0.4 mg / h, even more preferably 1.0 ± 0.3 mg / h. In another preferred embodiment, this averaged release rate is in the range 1.3 ± 0.5 mg / h, more preferably 1.3 ± 0.4 mg / h, even more preferably 1.3 ± 0.3 mg / h. In another preferred embodiment, this average release rate is in the range of 1.5 ± 0.5 mg / h, more preferably 1.5 ± 0.4 mg / h, even more preferably 1.5 ± 0.3 mg / h.

Preferably contained in the TTC according to the invention, the transdermally released amount of the active substance corresponds to at least half the daily dose, preferably at least the whole daily dose, which is necessary for the treatment or prevention of a corresponding disease of the central nervous system. The magnitude of the required daily dose is known to the specialist.

In one preferred embodiment, the TTC according to the invention contains an appropriate dose of at least

- 1 day (transdermally released dose = single daily dose)

- 2 days (transdermally released dose = twice daily dose),

- 3 days (transdermally released dose = three times daily dose),

- 4 days (transdermally released dose = four times daily dose),

- 5 days (transdermally released dose = five times daily dose)

- 6 days (transdermally released dose = six times daily dose) or

- 7 days (transdermally released dose = seven times daily dose).

If in the case of central nervous system disease we are talking about Alzheimer's disease in moderate to severe forms, then the preferred daily, transdermally administered dose is about 20 mg (equivalent amount, calculated on memantine hydrochloride). However, in the first weeks of treatment, it may be recommended to start with a lower daily dose administered transdermally and increase this dose over time until the value reaches about 20 mg. It is preferable, for example, that the daily transdermal dose administered in the first week is about 5.0 mg, in the second week about 10 mg, in the third week about 15 mg, and then about 20 mg constantly (equivalent amount, respectively calculated on memantine hydrochloride) .

Preferably, the surface concentration of memantine or a physiologically compatible salt thereof is at least 1.0 mg / cm ² , more preferably at least 5.0, 10 or 15 mg / cm ² , even more preferably at least 20, 25 or 30 mg / cm ² , most preferably at least 35, 40 or 50 mg / cm ² and in particular at least 60 or 70 mg / cm ² .

In a preferred embodiment, the TTS according to the invention has a total layer thickness ranging from 50 to 4000 μm, more preferably from 100 to 2500 μm, even more preferably from 200 to 2000 μm, most preferably from 250 to 1500 μm and in particular from 300 to 1200 microns.

TTC according to the invention are suitable in order to combat, in addition to dementia, other diseases of the central nervous system. These include acute neurodegenerative processes, for example, with injuries and strokes, chronic processes (in addition to the Alzheimer's disease described above, these diseases are, for example, Parkinson's disease and Huntington's disease [Chorea Huntington]), as well as symptomatic diseases of various types associated with with epilepsy, drug addiction, depression and anxiety.

Another aspect of the invention relates to a unit of packaging comprising at least two different types of the above-described TTC according to the invention, which preferably differ in the dose they contain per day (memantine or its physiologically compatible salt). Preferably there are at least 2, more preferably at least 3, and in particular at least 4 different types of TTC with different doses released per day, and the types of TTC with the same dose released per day can be presented repeatedly (several types of the same same kind).

In a preferred embodiment, the packaging unit according to the invention includes as many TTCs as required so that, based on the initial dose released per day, by gradual increase (titration), the maximum dose released per day is reached. Preferably, this maximum dose is achieved in 2, 3 or 4 stages, and each stage may include the same or different time intervals, one or more intervals of use. In this regard, the interval of application is the time period during which, when used according to the purpose of the corresponding TTC, the declared daily dose can actually be released, which should be administered transdermally. For example, if the application interval covers 48 hours, then the TTC should ensure that during this period the appropriate daily dose, which should be administered transdermally, can really be released from this TTC.

In a preferred embodiment, the intervals of use correspond to the intervals between applications described above in the section relating to the concentration of the active substance.

Another subject of the invention relates to a kit for treating or accordingly preventing diseases of the central nervous system, including

- at least one dosage form for the initial, non-transdermal, preferably oral or parenteral administration of memantine or a physiologically compatible salt thereof

- and at least one TTC according to the invention.

Another aspect of the invention relates to the use of memantine or a physiologically compatible salt or prodrug for the manufacture of the TTC described above for the treatment or prevention of diseases of the central nervous system. Preferably, the central nervous system disease is selected among dementia, especially Alzheimer's disease, trauma, stroke, Parkinson's disease, Huntington's disease, epilepsy, drug dependence, depression and anxiety.

The following examples serve to provide a more detailed explanation of the invention, but should not be construed as limiting:

Example 1:

Received TTS in the form of a patch containing a biologically active substance of the following composition:

Memantine base 6.36% of the mass. Medium chain triglyceride (e.g. Miglyol 812) 25.42% of the mass. Acrylate copolymer with vinyl acetate (e.g. Durotak2516) 68.22% of the mass. Biologically active substance surface 10 cm ² The content of biologically active substances (recalculated to the base) 11.0 mg

For this, a dosage solution was prepared from memantine (free base) and Miglyol 812 with the following ratio in the mixture.

Memantine base 20.00% of the mass. Medium chain triglyceride (e.g. Miglyol 812) 80.00% of the mass.

The corresponding acrylate, for example, Durotak 2516, is coated onto a suitable protective film (for example, polyethylene terephthalate film, PET), dried and coated with a suitable covering layer of the carrier (1st layer). A second layer is then made, for example, of Durotak 2516, as described above, but is not covered by a suitable covering layer of the carrier. Instead, a suitable fabric is applied to the dried acrylate layer, for example, of paper made from long LF26 fibers, of a certain size (for example, 10 cm ² ), and an appropriate amount of the dosage solution is metered onto this suitable fabric. The 1st layer is superimposed on the 2nd layer containing the fabric after removing the protective film. After the TTS has been stamped (in the form so that the fabric is in the middle), these TTS are packaged in a suitable material, preferably PET.

Example 2:

The sample of Example 1 received eight different TTS in the form of patches containing a biologically active substance (drug in adhesive}, the following composition:

% of the mass. 2-1 2-2 2-3 2-4 2-5 2-6 2-7 2-8 Memantine base 6.00 6.00 - - - - - - Memantine HCl - - 40.00 10.00 30.00 30.00 30.00 30.00 Cao - ^- - - 7.50 7.50 7.50 7.50 Caprylate-Na - - 10.00 - - - - - Ethylate-Na - - - 7.00 - - - - Basic methacrylate copolymer (e.g. Eudragit ^® E 100) - - 20.00 - - - - - Poly (butyl methacrylate, 2.00 2.00 - - - - - -

methyl methacrylate) (e.g. Plastoid® B) Acrylate and B and Nile Acetate Copolymer (e.g. Durotak® 2516) 92.00 83.00 Acrylate and B and Nile Acetate Copolymer (e.g. Durotak® 2287) - 92.00 30.00 - - - - - Polyisobutylene - - - - 62.50 - - - Neutral polyacrylate (e.g. Durotak® 900A) - - - - - 62.50 - - Neutral polyacrylate (e.g. Durotak® 9301) - - - - - - 62.50 - Neutral polyacrylate (e.g. GMS 3083) - - - - - - - 62.50 Biologically active substance surface 30 cm ² 30 cm ² 30 cm ² 30 cm ² 10 cm ² 10 cm ² 10 cm ² 10 cm ² The content of biologically active substances (in terms of base) 39.8 mg 48.9 mg 98.2 mg 27.5 mg 24.7 mg 23.4 mg 25.6 mg 24.8 mg

An appropriate amount of memantine hydrochloride or its base is taken and suspended or, in the case of a base, dissolved in an amount of about 1/3 of the amount of the biologically active substance, an organic solvent (for example, ethyl acetate). After adding the appropriate amount of a suitable acrylate, mix to ensure a homogeneous distribution of the active substance in the polymer.

Then, other appropriate starting materials are added to this mass with stirring (Plastoid ^® B for 2-1 and 2-2 or sodium caprylate and Eudragit ^® E100 for 2-3, respectively, or sodium ethylate for 2-4, or CaO for systems from 2-5 to 2-8) and mix further until a homogeneous mass is formed. After being applied to a suitable protective film (for example, polyethylene terephthalate film, PET), this laminated article is dried and coated with a suitable covering layer of the carrier. At the same time, in order to achieve the required thickness or content of the biologically active substance, for example 2-1, three layers are applied together (respectively with a suitable fabric (for example, non-woven material from PET) for reinforcement between acrylate layers) or, respectively, for 2-2 and 2- 3 three layers without fabric, or for 2-4 two layers, or for examples 2-5 to 2-8 one layer. After cutting the TTS with a stamp, they are packed in a suitable material, preferably PET.

TTC according to the invention, corresponding to examples 2-1, 2-2, 2-3 and 2-4 were investigated in vivo (in rabbits). The concentration of memantine in blood plasma after three days of use (removal of TTC after 72 hours) are presented in Figure 3.

Example 3:

TTCs corresponding to Example 2-7 were investigated in clinical trials in humans. The test group (group 1) received 3 plasters containing a biologically active substance, with a content of biologically active substance, respectively 24.0 mg of memantine in terms of base. After 24 hours, one of the patches was removed. After another 24 hours, another patch was removed. After the next 24 hours, the last patch was removed. Another group of subjects (group 2) received for 48 hours 2 patches containing a biologically active substance, with the content of this biologically active substance, respectively, 24.0 mg of memantine in terms of base.

Pharmacokinetic parameters were determined from the measured plasma concentrations and are summarized in the following tables 2 and 3:

C _max [ng / ml] t _max [h] t _lag [h] t _last [h] AUC _0-t [h · g / ml] AUC _0-8 [h · ng / ml] t _{1/2, z} [h] table 2 N 3 3 3 3 3 3 3 Average 17.1 32,0 1.33 240 1711 1749 49.8 Average value 17.6 36.0 0.00 240 1758 1839 48.1 Standard deviation S.D. 2.64 6.93 2,31 0.00 260 262 3.65 Coefficient of variation C.V. [%] 15,5 21.7 173 0.00 15,2 14.6 7.34

Table 3 N 3 3 3 3 3 3 3 Average 11.5 36.0 1.33 240 1156 1236 56.9 Average value 12,2 36.0 0.00 240 1230 1306 57.0 S.D. 1,59 0.00 2,31 0.00 166 173 1.80 C.V. [%] 13.8 0.00 173 0.00 14,4 14.0 3.17 Group 1 / Group 2 Ratio 1.49 0.89 1.00 1.00 1.48 1.45 0.88

The residual content of the biologically active substance in the TTC after use was also determined and summarized for all 6 subjects in the following table 4:

Table 4 Residual Memantine Content Test subject TTS 10 cm ² TTC [mg / 10 cm ² ] one one 16,569 2 15,152 3 14,257 average value 15,326 Standard deviation 1,1656 2 one 17,058 2 15,112 3 13,500 average value 15,223 Standard deviation 1.7816 3 one 17,412 2 16,865 3 16,404

average value 16,894 Standard deviation 0.5046 four one 16,193 2 15,858 average value 16,026 Standard deviation 0.2369 5 one 15,330 2 15,356 average value 15,343 Standard deviation 0.0184 6 one 14,810 2 15,159 average value 14,985 Standard deviation 0.2468

Claims (15)

1. The use of a transdermal therapeutic system containing the biologically active substance memantine in the form of a free base or physiologically compatible salt for the treatment or prevention of diseases of the central nervous system, where the specified system includes
- carrier layer impervious to the biologically active substance;
- at least one layer containing a biologically active substance, which contains a retaining material in which this biologically active substance is placed;
- if necessary, a protective film; and
with the introduction of the biologically active substance memantine in the form of a free base or physiologically compatible salt has
- t _max at least 24 hours,
and moreover, with subsequent successive or time-shifted applications of one or more transdermal therapeutic systems, respectively, for intervals between applications, respectively independently of at least 12 hours, for the individual in need of treatment in his blood plasma, respectively, from the start of the first application the following concentrations of biologically active substance are achieved:
after 24 hours at least 14 ng / ml,
after 48 hours at least 27 ng / ml,
after 60 hours at least 32 ng / ml,
after 72 hours at least 37 ng / ml,
after 96 hours at least 44 ng / ml,
after 144 hours at least 54 ng / ml,
after 192 hours at least 60 ng / ml,
after 240 hours at least 63 ng / ml, and
after 300 hours at least 65 ng / ml. 2. The use of a transdermal therapeutic system according to claim 1, wherein for each interval between applications, the duration in hours divided by the number of simultaneously used transdermal therapeutic systems, independently of each other, is a value in the range from 3 to 8. 3. The use of a transdermal therapeutic system according to claim 1, wherein the concentrations of the biologically active substance when using one or several transdermal therapeutic systems, respectively, are achieved within one interval between applications. 4. The use of the transdermal therapeutic system according to claim 1, wherein, respectively, from the beginning of the first application, the following concentrations of biologically active substance are achieved, respectively:
after 24 hours, a maximum of 50 ng / ml,
after 48 hours, maximum 90 ng / ml,
after 60 hours, maximum 110 ng / ml,
after 72 h, maximum 130 ng / ml,
after 96 h, maximum 150 ng / ml,
after 144 h, maximum 180 ng / ml,
after 192 h, maximum 195 ng / ml,
after 240 hours, a maximum of 200 ng / ml, and
after 300 h, a maximum of 210 ng / ml. 5. The use of the transdermal therapeutic system according to claim 1, wherein the concentrations of the biologically active substance are achieved when each interval between applications is independently maximally 72 hours 6. The use of a transdermal therapeutic system according to claim 1, wherein
- its averaged over the interval between applications, the release rate of the biologically active substance is in the range from 0.2 to 2.0 mg / h; and / or
- its pharmacokinetic delay time t _lag is a maximum of 6 hours 7. The use of a transdermal therapeutic system according to claim 1, wherein the layer of retaining material is located between the carrier layer impermeable to the biologically active substance and the membrane material permeable to the biologically active substance. 8. The use of a transdermal therapeutic system according to claim 1, wherein the retaining material:
- includes a liquid or gel composition in which the biologically active substance is partially or completely dissolved; or
- includes a matrix based on a polymer material in which the biologically active substance is present in dissolved form or distributed as microdispersion; or
- includes a polymeric material based on polyacrylate or polysilicon; or
- is a lipogel that contains from 10 to 50 wt. %, biologically active substance. 9. The use of the transdermal therapeutic system according to one of paragraphs. 1 to 8, and the biologically active substance is present in the form of a physiologically compatible salt. 10. The use of the transdermal therapeutic system according to claim 9, wherein the layer containing the biologically active substance additionally contains at least one basic material, the basicity of which is sufficient to react with the physiologically compatible salt of the biologically active substance with the release of the free base of the biologically active substance . 11. The use of the transdermal therapeutic system according to claim 10, wherein this base material is selected from the group consisting of polymers with basic side groups, organic bases and inorganic bases. 12. The use of the transdermal therapeutic system according to claim 11, wherein this base material is selected from the group consisting of acrylate-based polymers that have aminoalkyl side groups; inorganic oxides or hydroxides, organic amines or their salts; alkali metal or alkaline earth metal alcoholates or carboxylates. 13. The use of the transdermal therapeutic system according to one of paragraphs. 10-12, and the layer containing the biologically active substance contains from 20 to 90 wt.% Retaining material, from 10 to 50 wt.% Of the biologically active substance, and also, if necessary, from 5 to 40 wt.% Of the base material, in terms of the total weight of the layer containing the biologically active substance. 14. The use of memantine or a physiologically compatible salt to obtain the transdermal therapeutic system used
for the treatment or prevention of diseases of the central nervous system, where the specified system includes
- carrier layer impervious to the biologically active substance;
- at least one layer containing a biologically active substance, which contains a retaining material in which this biologically active substance is placed;
- if necessary, a protective film; and
with the introduction of the biologically active substance memantine in the form of a free base or physiologically compatible salt has
- t _max at least 24 hours, and with subsequent or consecutive applications of respectively one or more transdermal therapeutic systems for the intervals between applications, respectively independently comprising at least 12 hours, from the individual in need of treatment in its blood plasma, respectively, from the beginning of the first application, the following concentrations of biologically active substance are achieved:
after 24 hours at least 14 ng / ml,
after 48 hours at least 27 ng / ml,
after 60 hours at least 32 ng / ml,
after 72 hours at least 37 ng / ml,
after 96 hours at least 44 ng / ml,
after 144 hours at least 54 ng / ml,
after 192 hours at least 60 ng / ml,
after 240 hours at least 63 ng / ml, and
after 300 hours at least 65 ng / ml. 15. The application of claim 14, wherein the central nervous system disease is selected among dementia, trauma, stroke, Parkinson's disease, Huntington's disease, epilepsy, drug dependence, depression and anxiety.

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