HK1170945B - Transdermal therapeutic system for administering rivastigmine or derivatives thereof - Google Patents

Description

The present application concerns a system for the transdermal administration of rivastigmine, its physiologically compatible salt, hydrate or solvent for therapeutic purposes.

Rivastigmine is the phenylcarbamate (S) N-ethyl-3-[(1-dimethylamino) ethyl]-N-methylphenylcarbamate of formula I. Other It is a cholinesterase inhibitor that acts in the central nervous system and is therefore an active substance in the treatment of Alzheimer' s disease and Parkinson' s dementia.

Err1:Expecting ',' delimiter: line 1 column 267 (char 266)

A transdermal patch is typically a small self-adhesive bandage containing the active substance to be administered. These bandages can come in various shapes and sizes. The simplest type is an adhesive monolith, which includes a drug reservoir on a carrier (cover layer). The reservoir is typically formed from the active substance in a pharmaceutically acceptable, pressure-sensitive adhesive and is in contact with the skin surface, which is released by transdermal diffusion into the patient's body.

More complex patches are multi-laminate or active substance-based patches, which may have an additional adhesive layer between the reservoir and the skin.

A form of administration via a transdermal patch of rivastigmine has already been described in the basic patent for rivastigmine GB 2203040. The transdermal patch disclosed in this patent consists of a cover layer and a reservoir layer.

Following the publication of GB 2203040, further transdermal therapeutic systems (TTS) containing, inter alia, rivastigmine as an active substance were developed and described.

In DE 199 18 106 the reservoir contains an adhesive polymer containing acrylic acid or methacrylic acid units with a defined content of carboxyl groups, which is intended to increase the water absorption and moisture tolerance of acidic polyacrylic adhesive adhesives.

Accordingly, all formulations in the examples contain the antioxidant vitamin E. The Durotak® 387-2353 used there is a polyacrylate containing carboxyl groups. The reservoir layer is also intended to contain various substances such as glycerin, F-matrix polymer, etc. (see paragraph 7.4.) These contain mostly carboxyl groups or sub-groups of carboxyl, which are not particularly resistant to the effects of the polyacrylate, so that they are not easily removed from the resin.

US 2008/0044461 A1 reveals TTS formulations with donepezil (see examples). Rivastigmine is also mentioned (claim 7). US 2008/0044461 A1 does not reveal a polymer matrixed active substance layer. Rather, release is controlled via a membrane (so-called membrane patch) rather than a polymer matrixed patch (so-called matrix patch). In addition, an essential feature of US 2008/0044461 A1 is that the reservoir layer contains a gel forming agent and a permeation enhancer (see claim 1).

US 2007/0259028 A1 discloses TTS formulations with donepezil (see examples). Rivastigmine is also mentioned (claim 3). It is an essential feature of US 2007/0259028 A1 that the reservoir layer contains a multi-value alcohol, e.g. glycerin. According to US 2007/0259028 A1, therefore, free hydroxyl groups are inevitably present in the polymer matrix of the reservoir layer.

Err1:Expecting ',' delimiter: line 1 column 233 (char 232)

US 6.689.379 B1 reveals TTS formulations with a special adhesive layer. Rivastigmine is also mentioned as a possible active substance. The active substance layer should preferably contain a compound with hydroxyl groups, see claim 10, US 6.689.379 B1 does not teach to select specific polymers for the polymer matrix of the reservoir layer to prevent degradation of rivastigmine.

However, patent EP 1 047 409 reports a general problem with the administration of rivastigmine by a TTS. It was found that the active substance is particularly susceptible to decomposition in the presence of oxygen. In the transdermal composition disclosed in GB 2203040, as disclosed in EP 1 047 409, rivastigmine decomposes despite the formation of a closed polymer matrix around the active substance and an airtight packaging of the composition.

The present invention is therefore intended to identify therapeutic compounds containing rivastigmine for transdermal administration which are sufficiently stable even without the addition of antioxidants.

Surprisingly, it was found that rivastigmine is sufficiently stable in transdermal patches when the polymer matrix of the reservoir has neither hydroxyl nor carboxyl groups.

The present invention therefore provides a sufficiently stable TTS containing rivastigmine and a method for its production, and the invention also provides for the use of polymers or copolymers that do not contain hydroxyl or carboxyl groups in a TTS containing rivastigmine and a TTS for the treatment of Alzheimer's and Parkinson's dementia.

A first aspect of the invention is therefore a TTS for the administration of rivastigmine, comprising the following components: (c) an adhesive layer on the reservoir, including as adhesive a first polyisobutylene polymer of an average molecular weight between 30,000 g/mol and 100,000 g/mol and a second polyisobutylene polymer of an average molecular weight between 300,000 g/mol and 500,000 g/mol; and (d) a release layer on the adhesive layer, characterised by the pool polymer matrix having neither hydroxyl nor carboxyl groups and the pool not containing tocopherol, butyl hydroxyddianol or butyl hydroxytoluol.

A second aspect of the invention is a TTS for the administration of rivastigmine, which includes the following components: (a) a top layer; (b) a reservoir on the top layer containing a polymer matrix in which the active substance is embedded; (c) an adhesive layer on the reservoir containing an adhesive; and (d) a release layer on the adhesive layer; where the active substance is rivastigmine or a physiologically compatible salt, hydrate or solvate thereof, and where the polymer matrix of the reservoir has neither hydroxyl nor carboxyl groups and the reservoir does not contain tocopherol, butyl hydroxydisol or butyl hydroxytoluol.

Err1:Expecting ',' delimiter: line 1 column 48 (char 47)

Err1:Expecting ',' delimiter: line 1 column 122 (char 121)

Err1:Expecting ',' delimiter: line 1 column 922 (char 921)

The duration of use of a TTS according to the invention is preferably about 24 hours; a longer duration of use is possible.

Preferably, no antioxidant is added to any component of the TTS. However, it is quite possible that the TTS of the present invention may contain antioxidants, provided that they do not adversely affect the mode of action of the TTS. It is noted that no antioxidants are required to stabilize rivastigmine according to the present invention. However, antioxidants could also be used for other purposes in the TTS of the invention. It is therefore possible, although not preferred, that the TTS of the invention contains antioxidants.

Err1:Expecting ',' delimiter: line 1 column 47 (char 46)

In a further embodiment, the reservoir, preferably the whole TTS, contains no tocopherol, preferably no tocopherol, preferably no tocopherol, preferably no tocopherol, preferably no tocopherol, preferably no tocopherol, preferably all TTS, preferably no tocopherol, preferably no tocopherol, preferably no tocopherol, preferably no tocopherol, preferably no tocopherol, preferably no tocopherol, preferably no tocopherol, preferably all TTS, preferably no tocopherol, preferably no tocopherol, preferably no tocopherol, preferably no tocopherol, preferably no tocopherol, preferably no tocopherol, preferably no tocopherol, preferably no tocopherol, preferably no tocopherol, preferably no tocopherol, preferably no tocopherol, preferably no tocopherol, preferably no tocopherol, preferably all TTS, preferably all TTS contains no tocopherol, preferably all tocopherol, preferably all TTS preferably all TTS, preferably all TTS contains no tocopherol, preferably all tocopherol, preferably all tocopherol, preferably all tocopherol, preferably all tocopherol, preferably all TTS contains no tocopherol, preferably no tocopherol, preferably all but no tocopherol, preferably all but no tocopherol, preferably all but preferably all but not tocopherol, preferably all but preferably all but preferably all but not preferably all but preferably all but not preferably all but not preferably all but not preferably all but not preferably all but preferably all but preferably preferably preferably preferably preferably preferably preferably preferably preferably preferably preferably preferably preferably

The amount of antioxidants in the TTS of the present invention is usually less than 1% by weight or less than 0.1% by weight, preferably less than 0.05% by weight, preferably less than 0.01% by weight, each by weight of the total formulation (excluding the cover and the pull-off layer).

The structure of the TTS according to the invention consists of several layers: on the end of the TTS facing the skin when applied, the cover layer; on the side of the cover layer facing the human skin when used, the reservoir; on the side of the reservoir facing the human skin when used, the adhesive layer; on the side of the adhesive layer facing the human skin when used, the withdrawal layer, which is removed immediately before the TTS is applied.

The area of the TTS according to the invention is not particularly limited; it is usually about 5 to 30 cm2, but can be much larger or smaller.

The surface area of the cover layer of the TTS according to the invention in one embodiment is at least equal to the surface area of the reservoir or adhesive layer, but may be larger than the surface area of the reservoir, so that it not only completely covers the reservoir but also extends beyond the edge of the reservoir. However, in such an embodiment, either the surface area of the adhesive layer should be equal to the surface area of the cover layer or the skin-facing side of the cover layer should have an additional adhesive layer to ensure that the entire skin-facing surface of the TTS adheres to the skin when applied. In another embodiment, the cover layer should be slightly smaller than the surface area of the reservoir.

Reservoir

The reservoir of the TTS according to the invention contains the active substance rivastigmine embedded in a polymer matrix. The polymer matrix consists, according to this aspect of the invention, exclusively of polymers or copolymers that do not have hydroxyl groups or carboxyl groups. Preferred polymers or copolymers without functional groups that form the polymer matrix are certain polyacrylates, acrylate vinylac acetate copolymers, polyisobutylene and styrene butadiene copolymers, which may be present individually or in combination.

Polymers (homopolymers, copolymers and block copolymers) based on acrylic acid esters and/or methacrylic acid esters may be used as suitable polyacrylates, in particular n-butylacrylate, n-butylmetha alicrylate, ethylcrylate, 2-ethylhexylacrylate, ethylmethacrylate, methylcrylate, methylmethacrylate, butyl-butyl-butyl, sec-butyl, tert-butyl, cyclohexyl, 2-ethyl, butyl, miscrycrylate, isobornyl, isobornyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopyl, isopyl, isop

The polymer matrix is preferably composed of one or more polyacrylates which do not contain substantially any free functional groups. Preferably the polymer matrix consists of polyacrylates produced by polymerisation of acrylic acid esters and/or methacrylic acid esters. In a special embodiment, the polymer matrix consists of polyacrylates produced by polymerisation of acrylic acid esters and/or methacrylic acid esters, of which the acrylic acid ester and/or methacrylic acid ester are selected. The group consists of n-Butyl Methylax, n-Butyl Methylax, n-Butyl Methylax, n-Butyl Ethylax, 2-Ethylax, 2-Ethylax, Ethylax, Polymethylax, Ethylax, Cycloalkyl Methylax, Cycloalkyl Methylax, Cycloalkyl Methylax, Cycloalkyl Methylax, Cycloalkyl Methylax, Cycloalkyl Methylax, Cycloalkyl Methylax, Cycloalkyl Methylax, Cycloalkyl Methylax, Cycloalkyl Methylax, Cycyl Methylax, Cycloalkyl Methylax, Cycyl Methylax, Cycloalkyl, Cycyl, Cycyl, Cycyl, Cycloalkyl, Cycyl, Cycyl, Cycyl, Cycyl, Cycloal, Cyc, Cycloal, Cyc, Cyc, Cyc, Cyc, Cyc, Cyc, Cyc, Cyc, Cyc, Cyc, Cyc, Cyc, Cyc, Cyc, Cyc, Cyc, Cyc, Cyc, Cyc, Cyc, Cyc, Cyc, Cyc, Cyc, Cyc, Cyc, Cyc, Cyc, Cyc, Cyc, Cyc, Cyc, Cyc, Cyc, Cyc, Cyc, Cyc, Cyc, Cyc, Cyc, Cyc, Cyc, Cyc, Cyc, Cyc, Cyc, Cyc, Cyc, Cyc

The most preferred are the acrylate vinyl acetate copolymer Duro-Tak® 87-4098, which is made of approximately 50% of the starting monomers 2-ethylhexylacrylate and vinyl acetate, and the acrylate Duro-Tak® 87-9088 (also an acrylate polymer without functional groups) from Henkel.

The total proportion of monomers containing free hydroxyl groups or free carboxyl groups (e.g. acrylic acid, methacrylic acid and esters of acrylic acid or methacrylic acid bearing functional groups, especially esters containing hydroxyl groups) is less than 1% by weight, preferably less than 0,5% by weight, preferably less than 0,2% by weight, in relation to the monomer mixture from which the polymer matrix is produced. In a particular embodiment, the total proportion of these monomers is less than 0,1%.

A TTS containing polyacrylates free of hydroxyl groups and carboxyl groups as active polymer matrix has been described in WO 03/017988 A1 but not in conjunction with the active substance rivastigmine. The task described in WO 03/017988 was to address the disadvantage of low active substance utilization of a TTS. According to this disclosure, this task was addressed by polymer matrix ideally free of hydroxyl groups or carboxyl groups. The active substance rivastigmine is not mentioned in this publication, let alone a stability enhancing effect of rivastigmine.

The reservoir in one embodiment of the invention essentially contains no polymers or copolymers containing free hydroxyl groups or free carboxyl groups. Preferably, the reservoir essentially contains no free hydroxyl groups and no free carboxyl groups. Preferentially, the reservoir essentially contains no free amines, no free hydroxyl groups and no free carboxyl groups. In a special embodiment, the adhesive layer also essentially contains no polymers or copolymers containing free hydroxyl groups or free carboxyl groups. Preferably, the adhesive layer essentially contains no free hydroxyl groups and no free carboxyl groups. The preferred layer contains no essential amines, no free hydroxyl groups and no free carboxyl groups.

The reservoir preferably contains 20-40% by weight of rivastigmine and 60-80% by weight of polymer matrix, depending on the total weight of the reservoir. In a particularly preferred embodiment of the TTS of the invention, the reservoir contains 25-25%, by weight of rivastigmine and 75-75% by weight of polymer matrix. Preferably, the reservoir does not contain any other ingredients in addition to the active substance and the polymer matrix. However, it is possible that the reservoir may contain additional additives known to the art. For example, plasticizers or gel-forming agents may be added to the reservoir.

The absolute amount of rivastigmine depends on various factors, in particular the size of the TTS to be used, the surface weight and the concentration of active substance in the reservoir. The surface weights of the dried reservoir matrix are preferably in the range of 20 to 100 g/m2, preferably in the range of 25 to 80 g/m2 and even more preferably in the range of 30 to 70 g/m2. The reservoir may have a thickness (dry thickness) in the range of 20 to 400 μm, or 30 to 200 μm or 40 to 100 μm. Other thicknesses than those mentioned above are also possible.

Other, of circular cross-section

Err1:Expecting ',' delimiter: line 1 column 511 (char 510)

The Staudinger index Jo required to determine the viscosity agent MV is determined from the measured specific viscosity ηSP and the concentration of solution according to the Schulz-Blaschke relation.

The specific viscosity ηSP = t/t0 - 1, where t and t0 are the flow time of the solution or solvent (each with Hagenbach-Couette correction) and c is the concentration of the solution in g/cm3.

For example, suitable mean molecular weights of MV of polyisobutyls are in the range of about 40,000 g/mol to about 4,000,000 g/mol. A preferred mixture is that of (1) polyisobutyls with a mean molecular weight MV of about 40,000 g/mol (e.g. Oppanol® B10 available from BASF) and (2) polyisobutyls with a mean molecular weight MV of over about 1,000,000 g/mol (e.g. Oppanol® B100 available from BASF, with a mean molecular weight MV of about 1,110,000 g/mol).

The polyisobutylene in the adhesive layer may have a molecular weight distribution with a first relative maximum between 30,000 g/mol and 100,000 g/mol and a second relative maximum between 300,000 g/mol and 500,000 g/mol. The first relative maximum is preferred between 35,000 g/mol and 50,000 g/mol and, regardless of whether the second relative maximum is between 350,000 g/mol and 450,000 g/mol. The first relative maximum is preferred at about 40,000 g/mol and, regardless of whether the second relative maximum is preferred at about 400,000 g/mol.

The polyisobutylene mixture of the adhesive can be obtained by mixing a first polyisobutylene polymer with a mean molecular weight MV between 30,000 g/mol and 100,000 g/mol with a second polyisobutylene polymer with a mean molecular weight MV between 300,000 g/mol and 500,000 g/mol. The first polyisobutylene polymer preferably has a mean molecular weight MV between 35,000 g/mol and 50,000 g/mol, preferably about 40,000 g/mol. The second polyisobutylene polymer preferably has a mean molecular weight MV between 350,000 g/mol and 450,000 g/mol, preferably about 400,000 g/mol.

The most preferred mixture is that of (1) polyisobutyls with a mean molecular weight MV of about 40,000 g/mol (e.g. Oppanol® B10 SFN, available from BASF) and (2) polyisobutyls with a mean molecular weight MV of about 400,000 g/mol (e.g. Oppanol® B50 SF, available from BASF).

The proportions of the two polyisobutylene polymers in the mixture may vary. The weight ratio of the first polyisobutylene polymer to the second polyisobutylene polymer in the mixture may be 10:1 to 1:10, preferably 2:1 to 1:2, the most preferred ratio being about 4:6. In a particularly preferred embodiment, the polyisobutylene polymer of the adhesive consists of 4 parts by weight of Oppanol® B10 (e.g. Oppanol® B10 SFN) and 6 parts by weight of Oppanol® B50SF.

The adhesive is present in the adhesive layer according to the invention in a quantity in the range of 40-100% by weight, preferably 50-90%, preferably 55-80%, and even more preferably 60-69.9% by weight, based on the total weight of the adhesive layer.

The thickness of the adhesive layer (dry thickness) is not particularly limited. It can be in the range of about 10 - 300 μm, or in the range of 70 - 140 μm. The absolute amount of the adhesive layer can be about 10 - 50 g/m2, or 20 - 40 g/m2, without being limited to that.

The adhesive layer preferably contains additional plasticizers and gels. Suitable plasticizers are known at the state of the art, preferably mineral oil, neutral oil, paraffin, polybutene, linseed oil, octyl palmitate, squalene, squalene, silicone oil, isobutylmyristat, isosteary alcohol and/or oleyl alcohol, especially preferably mineral oil, neutral oil, polybutene and/or paraffin. Mineral oils are colorless, clear hydrocarbons. They are obtained from the distillation fractions of the petroleum oil above about 300°C and are fractionated by coal-freezing of solid hydrocarbons.

The softener is preferably present in the adhesive layer in a quantity in the range of 0 to 60% by weight, preferably 10 to 50% by weight, and preferably 25 to 39.9% by weight, e.g. 35% by weight by weight of the total adhesive layer.

The gel forming material is preferably a gel forming material with a particle structure, which has a high concentration of polar groups on its surface. These cause correspondingly high surface tension towards the oils, which is partially compensated by the aggregation of the particles into gel forming structures. Consequently, the gel grids are increasingly solid the greater the polarity difference between the oils and the surface of the gel forming material. According to the invention, high concentration of silicon dioxide or pyrogenic silica groups is preferably used as a gel forming material. The particle size is also preferably in the nanometer range and is, for example, in the range of 400 - 1500 nm by weight, in particular, in the range of 500 - 0,1% by weight. For example, a gel forming medium known as a pyrogenic bentonite-O-benzene gel is used in the forming medium, for example, 0.0 - 0.0%, and a mineral forming agent known as a pyrogenic bentonite-O-benzene gel is also preferable.

In a particularly preferred embodiment of the TTS according to the invention, the adhesive layer contains 60-69.9% by weight of adhesive glue or polyisobutylene, which may consist of mixtures of polyisobutylene with different molecular weights as described above, 0.1-2.0% by weight of gel forming agent or highly dispersed silicon dioxide or pyrogenic silica, and 25-39.9% by weight of plasticizer or mineral oil, respectively, by weight of the adhesive layer.

The coating layer of the TTS according to the invention is preferably occlusive, i.e. terminating. Such coatings can be in preferred embodiments of polyolefins, in particular polyethylene, or of polyester and polyurethanes. Coatings containing several different polymers stacked on top of each other are also advantageously applicable. Suitable materials include polyolefins, cellophane, cellulose acids, ethylcellulose, polyvinyl chloride copolymers, polyvinyl acetate, polyethylene polyethylene copolymers, polyethylene polyethylene, polypropylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polypropylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polypropylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polypropylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene, poly, polyethylene, poly, polyethylene, polyethylene, polyethylene, poly, polyethylene, poly, polyethylene, poly, poly, poly, poly,

Err1:Expecting ',' delimiter: line 1 column 123 (char 122)

A particularly preferred embodiment of the TTS of the invention is a TTS for the application of an active substance through the skin, comprising: (a) a top layer; (b) a tank on the top layer containing 20 to 30% by weight of the active substance and 70 to 80% by weight of the polymer matrix, based on the total weight of the tank, the polymer matrix being essentially an acrylate-vinyl acetate copolymer without hydroxyl groups and without carboxyl groups, and the active substance being rivastigmine or a physiologically compatible salt, hydrate or solvent thereof; (c) a small layer on the tank containing 0,1 to 1% by weight of silicon dioxide, 25 to 39.9% by weight of light mineral (paraffinum perliquidum) and 60 to 79.9% by weight of polymer woven fabric with a mean molecular weight of about 400 g/mol and a mean molecular weight of about 400 g/mol; and where the total antioxidant content in the non-coated formulation is less than 0,1%, preferably less than 0,01% by weight, and the reservoir does not contain tocopherol, butyl hydroxydisol and butyl hydroxytoluol.

In a particular embodiment, the TTS of the invention does not contain an antioxidant selected from the group consisting of vitamin E and its esters, butyhydroxytoluol and butylhydroxyanisol.

Another aspect of the present invention is to provide a process for the manufacture of the TTS according to the invention. (i) the manufacture of a component containing the reservoir, comprising the top layer and the reservoir, which is on the side of the top layer which is designated as the side facing the skin; (ii) the manufacture of a component containing the adhesive layer, comprising the suction layer and the adhesive layer on the suction layer; (iii) the lamination of the components referred to in (i) and (ii) so that the top and the suction layer are the outermost, opposite layers in the cross-section of the finished TTS.

A preferred implementation of this procedure includes: (i) the application and, where appropriate, subsequent drying of a film of a reservoir composition, where appropriate in the form of a solution or dispersion in a suitable medium, on the side of the cover layer designated as the side facing the skin and, where appropriate, the covering with a siliconised film (liner); or the application and subsequent drying of a film of a reservoir composition, where appropriate in the form of a solution or dispersion in a suitable medium, on a siliconised film (liner) and the covering with a cover layer;

The preparation of a preferred TTS may be carried out by first dispersing or dissolving the components for the reservoir, i.e. rivastigmine and the matrix-forming polymer or copolymer or a mixture thereof, in an organic solvent such as heptane or ethyl acetate (unless the polymer is already dissolved). The matrix-forming polymer or copolymer or the mixture thereof is usually already present in a solvent. The polymer and/or copolymer used according to the invention is defined above as in the context of the TTS of the invention, i.e. a polymer and/or copolymer without hydroxyl groups and without carboxyl groups. The above-mentioned embodiments of the polymer matrix are considered as preferred according to the invention.Err1:Expecting ',' delimiter: line 1 column 379 (char 378)

In a separate step, the adhesive layer is produced by dissolving the adhesive polymer mixture (dissolved in organic solvent), preferably polyisobutyls of different average molecular weights, together with the gelling agent and the plasticizer in an organic solvent such as heptane, but preferably dissolving the gelling agent and the plasticizer in the organic solvent and then dissolving the gelling agent in this solution. This mixture is then applied to the removal oil and allowed to dry.

The components obtained in the two steps are then laminated together, with the adhesive layer applied directly to the reservoir, and the finished laminated film can then be stripped and packed into pieces of the desired size.

In each step, the organic solvents necessary to dissolve or disperse the components are removed by subjecting the products to increasing temperatures, including, where appropriate, the application of pressure.

Another aspect of the present invention is the use of a polymer or copolymer that does not contain hydroxyl or carboxyl groups in a TTS containing rivastigmine, preferably using polyacrylates, acrylate vinyl acetate copolymers, polyisobutylene and styrene butadiene copolymers, which according to the invention constitute the polymer matrix of the reservoir in which the active substance rivastigmine is embedded.

In the application of the invention, hydroxyl- and carboxyl-free polyacrylates and polyacrylate copolymers, such as acrylate vinyl acetate copolymers, are preferred.

In a particularly preferred embodiment of the use of the invention we use the acrylate vinyl acetate copolymer Duro-Tak® 87-4098.

Another aspect of the present invention is the provision of the TTS according to the invention for the treatment of Alzheimer's disease and Parkinson's dementia, where the TTS according to the invention is preferably designed for an application period of approximately 24 hours.

The following describes preferred embodiments of the TTS of the invention using experimental examples and determines their stability characteristics.

Examples Example 1 Manufacture of various formulations

Four different batches A to D of TTS formulations containing rivastigmine base were produced. Acrylate vinyl acetate copolymer was used as a matrix-forming polymer for the reservoir. An overview of the components of the different batches is given in Table 1. Tabelle 1: Zusammensetzung der Chargen A bis D

	Zusammensetzung
A	30% Rivastigmin Base
	70% Duro-Tak® 87-4098
B	Reservoir:	30% Rivastigmin Base
		70% Duro-Tak® 87-4098
	Klebeschicht:	30% Klearol®
		1% Cab-O-Sil®
		69% Oppanol® B10/B100 (7/3)
C	Reservoir:	20% Rivastigmin Base
		80% Duro-Tak® 87-4098
	Klebeschicht:	30% Klearol®
		0,5% Cab-O-Sil®
		69,5% Oppanol® B10/B100 (7/3)
D	Reservoir:	25% Rivastigmin Base
		75% Duro-Tak® 87-4098
	Klebeschicht:	30% Klearol®
		1% Cab-O-Sil®
		69% Oppanol® B10/B100 (7/3)

The components used in the batches can be described in more detail as follows: Tabelle 2: Übersicht der Komponenten der Formulierungsbeispiele A bis D

Duro-Tak® 87-4098	Acrylat/Vinylacetat Copolymer	Matrixpolymer
Cab-O-Sil®	Pyrogenes Siliziumdioxid	Gelbildner
Klearol®	Leichtes Mineralöl	Weichmacher
Oppanol® B10	Haftkleber
Oppanol® B100	Haftkleber

Manufacture from materials of any heading 1. manufacture of the reservoir layer

The acrylate vinyl acetate glue is presented and rivastigmine and ethyl acetate are weighed with it, and the components are then mixed in sufficient quantity of ethyl acetate by means of a stirrer to produce a smooth, homogeneous coating mass.

Err1:Expecting ',' delimiter: line 1 column 113 (char 112)

Manufacture of adhesive layer and total laminate

The polyisobutylene adhesives are weighed together and mixed, then heptane, Klearol® and Cab-O-Sil® are added and stirred until the mass is homogeneous.

Err1:Expecting ',' delimiter: line 1 column 82 (char 81)

The resulting laminate is then stripped to make suitable size patches.

Stability tests

Batches A and B were subjected to stability tests, whereby the TTS extracted were sealed in aluminium foil bags and stored for one month at 25°C and 60% RH and 40°C and 75% RH respectively, and the levels of possible impurities resulting from the degradation of rivastigmine by HPLC and UV absorption were determined. Other Tabelle 3

	RT = 46 min: 0,18%	---	Initial
	Total: 0,18%
	RT = 46 min: 0,22%	RT = 46 min: 0,29%	1 Monat
	RT = 46 min: 0,34%	RT = 46 min: 0,35%	2 Wochen
	RT = 46 min: 0,36%	RT = 46 min: 0,38%	1 Monat

Other The impurity detected is indicated with its respective retention time (RT). The percentage of the impurity is the percentage by weight of the total formulations concerned. The lower limit of the reported measured values RL (Reporting Limit) is 0,1 %, since values below this are within the range of measurement accuracy.

The results of this study clearly show that the TTS formulations of the invention are sufficiently stable, with RT=46 min of impurity at 40°C and 75 per cent relative humidity at less than 0.4 per cent after one month in all the formulations.

Example 2 Manufacture of various formulations

Two different batches of TTS formulations containing rivastigmine base were manufactured using acrylate vinyl acetate copolymer as matrix-forming polymer for the reservoir. Other Tabelle 4: Zusammensetzung der Chargen 179/181 und 179/182:

		Zusammensetzung
179/181	Reservoir:	25 % Rivastigmin Base
		75 % Duro-Tak® 87-4098
	Klebeschicht:	30 % Pionier® 7028P (Hansen & Rosenthal)
		0,5 % Cab-O-Sil®
		69,5 % Oppanol® B10 SFN / B50 SF (4/6)
179/182	Reservoir:	25 % Rivastigmin Base
		75 % Duro-Tak® 87-4098
	Klebeschicht:	35 % Paraffin, dünnfl. (Merck)
		0,5 % Cab-O-Sil®
		64,5 % Oppanol® B10 SFN / B50 SF (4/6)

The components used in the batches can be described in more detail as follows: Tabelle 5: Übersicht der Komponenten der Formulierungsbeispiele

Duro-Tak® 87-4098	Acrylat/Vinylacetat Copolymer	Matrixpolymer
Cab-O-Sil®	Pyrogenes Siliziumdioxid	Gelbildner
Pionier® 7028P	Leichtes Mineralöl (Paraffinum perliquidum)	Weichmacher
Oppanol® B10 SFN		Haftkleber
Oppanol® B50 SF		Haftkleber

Manufacture from materials of any heading 1. manufacture of the reservoir layer

The acrylate vinyl acetate glue is presented and rivastigmine and ethyl acetate are weighed with it, and the components are then mixed in sufficient quantity of ethyl acetate by means of a stirrer to produce a smooth, homogeneous coating mass.

Err1:Expecting ',' delimiter: line 1 column 113 (char 112)

Manufacture of adhesive layer and total laminate

The polyisobutylene adhesives are weighed together and mixed, then heptane, Pionier® 7028P/ paraffin, thinfl. and Cab-O-Sil® are added under stirring and stirred until the mass is homogeneous.

Err1:Expecting ',' delimiter: line 1 column 82 (char 81)

The resulting laminate is then stripped to make suitable size patches.

Stability tests

The two batches were subjected to stability tests, whereby the exuded TTS were sealed in aluminium composite film bags and stored for one month at 25°C and 60% RH and 40°C and 75% RH respectively, and the possible contamination levels resulting from the degradation of rivastigmine were determined by HPLC and UV absorption, the results of which are summarised in Tables 6 and 7.

Imp 1: < RL	Imp 1: < RL	Imp 1: < RL	Imp 1: < RL	Imp 1: < RL	Imp 1: < RL	Imp 1: < RL	Imp 1: < RL
Imp 4: < RL	Imp 4: < RL	Imp 4: 0,13%	Imp 4: 0,12%	Imp 4: 0,12%	Imp 4: 0,25%	Imp 4: 0,14%	Imp 4: 0,30%
Imp 5: < RL	Imp 5: 0,11%	Imp 5: 0,14%	Imp 5: 0,17%	Imp 5: 0,17%	Imp 5: 0,26%	Imp 5: 0,18%	Imp 5: 0,36%

Imp 1: < RL	Imp 1: < RL	Imp 1: < RL	Imp 1: < RL	Imp 1: < RL	Imp 1: < RL	Imp 1: < RL	Imp 1: < RL
Imp 4: < RL	Imp 4: < RL	Imp 4: 0,16%	Imp 4: < RL	Imp 4: 0,13%	Imp 4: 0,25%	Imp 4: 0,14%	Imp 4: 0,36%
Imp 5: < RL	Imp 5: 0,11%	Imp 5: 0,17%	Imp 5: 0,13%	Imp 5: 0,15%	Imp 5: 0,28%	Imp 5: 0,18%	Imp 5: 0,41%

Err1:Expecting ',' delimiter: line 1 column 450 (char 449)

The results of this study clearly show that the TTS formulations of the invention are sufficiently stable.

The present invention relates, inter alia, to the following articles (1) to (19): (1) Transdermal therapeutic system for the administration of an active substance through the skin comprising: (c) an adhesive layer on the reservoir, consisting of a first polybutylene polymer of an average molecular weight of between 30,000 g/mol and 100,000 g/mol and a second polyisobutylene polymer of an average molecular weight of MV between 300,000 g/mol and 500,000 g/mol; and characterised by the polymer matrix of the reservoir having neither hydroxyl nor carboxyl groups and the reservoir having no tocopherol,does not contain butylhydroxydyanol and does not contain butylhydroxytoluol. (2) Transdermal therapeutic system by subject (1) characterised by the absence of any antioxidant selected from the group consisting of tocopherols and their esters, sesamol, coniferous benzoate of benzoic resin, nordihydroxyguayacaric resin and guayaric acid, gallate, butylhydroxydyanol, ascorbic acid and its salts, ascorbylmitate, erythorbic acid and its salts, monoglycerol, sodium transformaldehyde, sodium methabisulfite, sodium sulfite, potassium gel, potassium sulfite, butylhydroxyanide, butylhydroxyanide, which contains up to 80% by weight of ascorbic acid and its salts, ascorbic acid and its salts, ascorbic acid and its salts, ascorbic acid and its salts, ascorbic acid, butylhydroxyanide, butylhydroxyanide, butylhydroxyanide, butylhydroxyanide, butylhydroxyanide, butylhydroxyanide, butylhydroxyanide, butylhydroxyanide, butylhydroxyanide, butylhydroxyanide, butylhydrate and its salts, containing up to 80% by weight of ascorbic acid and its salts, ascorbic acid and its salts, ascorbic acid and its salts, ascorbic acid and its salts, ascorbic acid and its salts, ascorbic acid and its salts, ascorbic acid and its salts, ascorbic acid and its salts, ascorbic acid and its salts, ascorbic acid and ascorbic acid and ascorbic acid and ascorbic acid, and ascorbic acid and ascorbic acid, and ascorbic acid and ascorbic acid, and ascorbic acid and ascorbic acid, and ascorbic acid, and ascorbic acid and ascorbic acid, and ascorbic acid and ascorbic acid, ascorbic acid and ascorbic acid, ascorbic acid and asContains a transdermal therapeutic system by substance (4), the adhesive layer containing 60,0-74,9% by weight of adhesive, 0,1-2,0% by weight of gel-forming agents and 25-39,9% by weight of plasticisers, based on the total weight of the adhesive layer.(7) Transdermal therapeutic system by one of the items (1) to (6), characterised by the adhesive being polyisobutylene.(8) Transdermal therapeutic system by one of the items (1) to (7), characterised by the polyisobutylene being a mixture of two polyisobutylene polymers with different molecular weights.(9) Transdermal therapeutic system by item (8), characterised by the first polyisobutylene polymer having an average molecular weight of 40 000 g/mol and the second polyisobutylene polymer having an average molecular weight of 400 000 g/mol.10) Transdermal therapeutic system by one of the items (8) (9), characterised by the ratio of the polyisobutylene polymer's mass to the second polyisobutylene polymer's mass (1011) to 4:6 (4).characterised by the softener being paraffin, neutral oil, mineral oil, or polybutene or a mixture thereof.(12) Transdermal therapeutic system by one of the items (1) to (11), with the surface of the adhesive layer corresponding to the surface of the reservoir.(13) Transdermal therapeutic system by item (1), comprising: (a) a top layer; (b) a reservoir on the top layer containing 20 to 30% by weight of the active substance and 70 to 80% by weight of the polymer matrix, based on the total weight of the reservoir, the polymer matrix being essentially an acrylate-vinyl acetate copolymer without hydroxyl groups and without carboxyl groups;(d) a release layer on the adhesive layer. (l) Method for the manufacture of a transdermal therapeutic system based on one of the items (1) to (13), including: (i) the manufacture of a component containing the reservoir, comprising the top layer and the reservoir, which is located on the side of the top layer which is designated as the side facing the skin;so that the deck and the draw-off layer are the opposite outermost layers in the cross-section of the finished TTS. (ii) the application and subsequent drying, on the withdrawal layer, of a film of a reservoir composition, where appropriate in the form of a solution or dispersion in a suitable medium, on the side of the cover layer designated as the side facing the skin;The following table shows the main features of the new approach: (i) application and, where appropriate, subsequent drying of a film of a reservoir composition, where appropriate in the form of a solution or dispersion in a suitable medium, on a siliconised film liner and covering with a covering; (ii) application and, where appropriate, subsequent drying of a film of a glue composition, where appropriate in the form of a solution or dispersion in a suitable medium, on the covering; (iii) laminating the components (i) and (ii) together after removal of the liner so that the covering and the covering are the outermost, opposite layers in the cross-section of the TTS.containing neither hydroxyl nor carboxyl groups, where these polymers or copolymers constitute the polymer matrix of the reservoir in which the active substance rivastygmin is embedded, to stabilise the active substance rivastygmin in a transdermal therapeutic system and/or to reduce the degradation of the active substance rivastygmin in a transdermal therapeutic system.(18) Use of a polymer or copolymer by subject (17), characterised by the polymer or copolymer not containing the hydroxyl or carboxyl groups, selected from the group consisting of polyacrylates, acetyl-vinylate copolymers, polybutylbutyrene and styrene butyrate copolymers.(19) After a procedure for the treatment of Alzheimer's disease and a treatment of the disease (1)Other The articles (1) to (19) may be combined with other embodiments described in this application.

Claims (17)

1. A transdermal therapeutic system for administering an active substance through the skin comprising:

   a) a cover layer,

   b) a reservoir present on the cover layer, comprising a polymer matrix containing the active substance,

   c) an adhesive layer present on the reservoir comprising a contact adhesive, and

   d) a removable layer present on the adhesive layer,

   wherein the active substance is rivastigmine or a physiologically tolerable salt, hydrate or solvate thereof, characterized in that the polymer matrix of the reservoir includes neither hydroxyl groups nor carboxyl groups, and the reservoir does not contain tocopherol, butylhydroxdyanisol and butylhydroxytoluol.
2. The transdermal therapeutic system of claim 1, characterized in that it does not contain any antioxidants selected from the group consisting of tocopherols and their esters, sesamol, the coniferyl benzoate of benzoin, nordihydroguaiaretic resin and -guaiaretic acid, gallates, butylhydroxdyanisole, ascorbic acid and salts thereof, ascorbylpalmitate, erythorbic acid and salts thereof, monothioglycerol, sodium formaldehyde sulfoxylate, sodium metabisulphite, sodium bisulphite, sodium sulphite, potassium metabisulphite, butylated hydroxyanisole, butylated hydroxytoluene and propionic acid.
3. The transdermal therapeutic system of claim 1 or 2, wherein the reservoir contains 20-30 wt% active substance and 70-80 wt% polymer matrix in relation to the total weight of the reservoir.
4. The transdermal therapeutic system of any one of claims 1 to 3, wherein the adhesive layer additionally contains a gelling agent selected from the group consisting of highly dispersed silicon dioxide and pyrogenic silica, and an emollient selected from the group consisting of mineral oil, neutral oil, paraffin, polybutene, linseed oid, octyl palmitate, squalene, squalane, silicone oil, isobutyl myristate, isostearyl alcohol and oleyl alcohol.
5. The transdermal therapeutic system of claim 4, wherein the adhesive layer contains 60.0 to 74.9 wt% contact adhesive, 0.1 to 2.0 wt% gelling agent and 25 to 39.9 wt% emollient in relation to the total weight of the adhesive layer.
6. The transdermal therapeutic system of any one of claims 1 to 5, wherein the polymer matrix comprises at least one polymer and/or copolymer selected from the group consisting of polyacrylates, acrylate-vinyl acetate copolymers, polyisobutylene, styrene-butadiene copolymers and mixtures thereof.
7. The transdermal therapeutic system of any one of claims 1 to 6, characterized in that the contact adhesive is polyisobutylene.
8. The transdermal therapeutic system of any one of claims 1 to 7, characterized in that the polyisobutylene is a mixture of two polyisobutylene polymers of different molecular weights.
9. The transdermal therapeutic system of claim 8, characterized in that the first polyisobutylene polymer has a mean molecular weight Mv of 40,000 g/mol, and the second polyisobutylene polymer has a mean molecular weight M_V of 400,000 g/mol.
10. The transdermal therapeutic system of claim 8 or 9, characterized in that the weight ratio of the first polyisobutylene polymer in relation to the second polyisobutylene polymer is 4:6.
11. The transdermal therapeutic system of any one of claims 4 to 10, characterized in that the emollient is paraffin, neutral oil, mineral oil or a mixture thereof.
12. The transdermal therapeutic system of claim 1 comprising

    a) a cover layer,

    b) a reservoir present on the cover layer containing 20-30 wt% active substance and 70-80 wt% polymer matrix in relation to the total weight of the reservoir, wherein the polymer matrix essentially consists of an acrylate-vinyl acetate copolymer without hydroxyl groups and without carboxyl groups;

    c) an adhesive layer present on the reservoir comprising 0.1-1 wt% silicon dioxide, 25-39.9 wt% paraffinum perliquidum (Ph. Eur.) and 60-79.9 wt% of a mixture of polyisobutylene having a mean molecular weight M_V of 40,000 g/mol, and polyisobutylene having a mean molecular weight Mv of 400,000 g/mol; and

    d) a removable layer present on the adhesive layer.
13. A method for preparing the transdermal therapeutic system of anyone of claims 1 to 12 comprising

    i) preparing a component containing the reservoir, comprising the cover layer and the reservoir, which is located on the side of the cover layer that is intended as the side to be directed toward the skin,

    ii) preparing a compound containing the adhesive layer made up of the removable layer and the adhesive layer located on the removable layer and

    iii) laminating to combine the components from i) and ii) so that in the end, in the cross-section of the completed TTS, the cover and removable layers constitute the outermost, opposite layers.
14. The method of claim 13 comprising

    i) applying, and optionally subsequently drying, a film of a composition forming the reservoir, optionally in form of a solution or dispersion in a suitable medium, onto the side of the cover layer that is to be directed toward the skin,

    ii) applying, and optionally subsequently drying, a film of a composition forming the adhesive layer, optionally in the form of a solution or dispersion in a suitable medium, to the removable layer, and

    iii) laminating together the components from i) and ii) in order for the cover layer and the removable layer to constitute in the cross-section of the completed TTS the outermost, opposite layers.
15. Use of a polymer or copolymer having neither hydroxyl groups nor carboxyl groups, wherein these polymers or copolymers constitute the polymer matrix of the reservoir, in which the active substance rivastigmine is embedded, for stabilizing the active substance rivastigmine and/or reducing the degradation of the active substance rivastigmine in the transdermal therapeutic system of claim 1.
16. The use of claim 15, characterized in that the polymer or copolymer containing no hydroxyl groups and no carboxyl groups is selected from the group consisting of polyacrylates, acrylate-vinyl acetate copolymers, polyisobutylene and styrene-butadiene copolymers.
17. The transdermal therapeutic system of anyone of claims 1 to 12 for use in a method for the treatment of Alzheimer's disease and Parkinson's dementia.