TRANSDERMAL THERAPEUTIC SYSTEM CONTAINING RIVASTIGMINE

Abstract

The present invention relates to a transdermal therapeutic system for the transdermal administration of rivastigmine comprising a rivastigmine-containing layer structure, said rivastigmine-containing layer structure comprising: A) a backing layer; B) a rivastigmine-containing layer comprising at least one acrylic polymer; and C) a skin contact layer comprising at least one styrene-isoprene-styrene block copolymer and at least one tackifier.

Claims

1. Transdermal therapeutic system for the transdermal administration of rivastigmine comprising a rivastigmine-containing layer structure, said rivastigmine-containing layer structure comprising: A) a backing layer; B) a rivastigmine-containing layer comprising at least one acrylic polymer; and C) a skin contact layer comprising at least one styrene-isoprene-styrene block copolymer and at least one tackifier.

2. Transdermal therapeutic system according to claim 1, wherein the at least one styrene-isoprene-styrene block copolymer comprises styrene blocks and isoprene blocks in a ratio of from 10:90 (%) to 30:70 (%) based on the total weight of the skin contact layer, preferably in a ratio of 15:85 (%) or 22:78 (%) based on the total weight of the skin contact layer.

3. Transdermal therapeutic system according to claim 1 or 2, wherein the at least one tackifier is an alicyclic saturated hydrocarbon resin, or a hydrogenated rosin glycerol ester, or paraffinum liquidum, or a mixture thereof.

4. Transdermal therapeutic system according to any one of claims 1 to 3, wherein the ratio of the amount of styrene-isoprene-styrene block copolymer(s) to the amount of tackifier(s) is between 60:40 (w/w) to 40:60 (w/w), preferably wherein the ratio of the amount of styrene-isoprene-styrene block copolymer(s) to the amount of tackifier(s) is 50:50 (w/w).

5. Transdermal therapeutic system according to any one of claims 1 to 4, wherein the at least one styrene-isoprene-styrene block copolymer and the at least one tackifier are present in the skin contact layer in an overall amount of at least 90% by weight, preferably in an overall amount of at least 99% by weight based on the total weight of the skin contact layer.

6. Transdermal therapeutic system according to any one of claims 1 to 5, wherein the amount of rivastigmine contained in the rivastigmine-containing layer structure ranges from 0.5 to 5 mg/cm.sup.2, preferably from 1 to 3 mg/cm.sup.2.

7. Transdermal therapeutic system according to any one of claims 1 to 6, wherein the rivastigmine-containing layer structure comprises rivastigmine in an amount of from 20 to 40%, preferably from 25 to 35%, most preferably in an amount of 30% by weight based on the total area weight of the rivastigmine-containing layer.

8. Transdermal therapeutic system according to any one of claims 1 to 7, wherein the acrylic polymer is a COOH-functionalized acrylic polymer.

9. Transdermal therapeutic system according to any one of claims 1 to 8, wherein the acrylic polymer is obtainable from one or more monomers selected from acrylic acid, 2-ethylhexylacrylate, glycidylmethacrylate and methylacrylate.

10. Transdermal therapeutic system according to any one of claims 1 to 9, wherein the area weight of the rivastigmine-containing layer ranges from 40 to 250 g/m.sup.2, preferably from 50 to 200 g/m.sup.2, and/or wherein the area of release ranges from 1 to 30 cm.sup.2, preferably from 2 to 22 cm.sup.2.

11. Transdermal therapeutic system according to any one of claims 1 to 10, wherein the transdermal therapeutic system provides by transdermal delivery a mean release rate of from 150 to 3500 μg/cm.sup.2, preferably from 400 to 2000 μg/cm.sup.2 rivastigmine over about 24 hours of administration.

12. Transdermal therapeutic system according to any one of claims 1 to 11 for use in a method of treating a human patient, preferably for use in a method of preventing, treating, or delaying of progression of Alzheimer's disease, dementia associated with Parkinson's disease, and/or symptoms of traumatic brain injury, or for use in a method of treating mild to moderate dementia caused by Alzheimer's or Parkinson's disease.

13. A process for manufacturing a transdermal therapeutic system according to any one of claims 1 to 12 comprising the steps of: 1) providing a rivastigmine-containing coating composition by combining at least the components i) rivastigmine; and ii) at least one acrylic polymer; 2) coating the rivastigmine-containing coating composition onto a film in an amount to provide the desired area weight, 3) drying the coated rivastigmine-containing coating composition to provide the rivastigmine-containing layer, 4) providing an additional coating composition for an additional skin contact layer by combining at least the components a) at least one styrene-isoprene-styrene block copolymer; and b) at least one tackifier; 5) coating and drying the additional coating composition according to steps 2 and 3, wherein the film is a release liner, 6) laminating the adhesive side of the skin contact layer onto the adhesive side of the rivastigmine-containing layer to provide a rivastigmine-containing layer structure with the desired area of release, 7) punching the individual systems from the rivastigmine-containing layer structure, 8) optionally adhering to the individual systems a rivastigmine-free self-adhesive layer structure comprising also a backing layer and a rivastigmine-free pressure-sensitive adhesive layer and which is larger than the individual systems of rivastigmine-containing self-adhesive layer structure.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0072] FIG. 1 depicts the cumulative rivastigmine in vitro permeation over 24 hours from Comparative Example 1 and Examples 1 and 3 to 5 after production (“initial”).

[0073] FIG. 2 depicts the adhesion force of Comparative Example 1 and Examples 2 to 5 after production (“initial”).

[0074] FIG. 3 depicts the peel force of Comparative Example 1 and Examples 1 to 5 after production (“initial”).

[0075] FIG. 4 depicts the rivastigmine in vitro release rate over 24 hours from Comparative

[0076] Example 1 and Examples 1 to 5 after production (“initial”).

DETAILED DESCRIPTION

TTS Structure

[0077] The present invention relates to a transdermal therapeutic system for the transdermal administration of rivastigmine comprising a rivastigmine-containing layer structure, said rivastigmine-containing layer structure comprising: [0078] A) a backing layer; [0079] B) a rivastigmine-containing layer comprising at least one acrylic polymer; and [0080] C) a skin contact layer comprising at least one styrene-isoprene-styrene block copolymer and at least one tackifier.

[0081] The TTS according to the present invention may be a matrix-type TTS or a reservoir-type TTS, and preferably is a matrix-type TTS.

[0082] In a matrix-type TTS according to the invention, the rivastigmine is homogeneously dissolved and/or dispersed within a polymeric carrier, i.e. the matrix, which forms with the rivastigmine and optionally remaining ingredients a matrix layer. Accordingly, the rivastigmine-containing layer may in one embodiment of the invention be a rivastigmine-containing matrix layer, wherein the rivastigmine is homogeneously distributed within a polymer matrix. If a rivastigmine-containing matrix layer is prepared by laminating together two rivastigmine-containing matrix layers, which are of substantially the same composition, the resulting double layer is to be regarded as one rivastigmine-containing matrix layer.

[0083] In a reservoir-type TTS according to the present invention, the rivastigmine-containing layer is a rivastigmine-containing reservoir layer, which preferably comprises a liquid reservoir comprising the rivastigmine. The reservoir-type TTS additionally comprises a skin contact layer, wherein the reservoir layer and the skin contact layer are preferably separated by the rate-controlling membrane. Preferably, the skin contact layer is manufactured such that it is rivastigmine-free.

[0084] The rivastigmine-containing layer structure is preferably a rivastigmine-containing self-adhesive layer structure. It is preferred that the rivastigmine-containing layer, which is preferably a rivastigmine-containing matrix layer, is self-adhesive. Thus, in a preferred embodiment, the rivastigmine-containing layer structure is a rivastigmine-containing self-adhesive layer structure. Alternatively or additionally, it is preferred that the rivastigmine-containing layer is directly attached to the backing layer, so that there is no additional layer between the backing layer and the rivastigmine-containing layer. Consequently, a layer structure of low complexity is obtained, which is advantageous, e.g., in terms of the costs for the manufacture.

[0085] In particular, it is preferred that the rivastigmine-containing layer structure comprises not more than three layers. Sufficient adhesion between the rivastigmine-containing self-adhesive layer structure and the skin of the patient during administration is provided by the skin contact layer.

[0086] It is to be understood that the TTS according to the invention contains a therapeutically effective amount of rivastigmine. Thus, in a preferred embodiment of the invention, the rivastigmine-containing layer structure contains a therapeutically effective amount of rivastigmine. The rivastigmine in the rivastigmine-containing layer structure is preferably present in the form of the free base. Preferred embodiments regarding the rivastigmine in the TTS according to the invention are provided further below.

[0087] It is preferred according to the invention that the area of release of the TTS is rather small. According to one specific embodiment of the invention, the area of release ranges from 1 to 30 cm.sup.2, preferably from 2 to 22 cm.sup.2.

[0088] In a preferred embodiment of the invention, the backing layer is substantially rivastigmine impermeable. Furthermore, it is preferred that the backing layer is occlusive.

[0089] According to certain embodiments of the invention, the TTS may further comprise an adhesive overlay. This adhesive overlay is in particular larger in area than the rivastigmine-containing structure and is attached thereto for enhancing the adhesive properties of the overall transdermal therapeutic system. Said adhesive overlay comprises a backing layer and an adhesive layer. The adhesive overlay provides additional area adhering to the skin but does not add to the area of release of the rivastigmine. The adhesive overlay comprises a self-adhesive polymer or a self-adhesive polymer mixture selected from the group consisting of silicone acrylic hybrid polymers, acrylic polymers, polysiloxanes, polyisobutylenes, styrene-isoprene-styrene copolymers, and mixtures thereof, which may be identical to or different from any polymer or polymer mixture included in the rivastigmine-containing layer structure.

[0090] The rivastigmine-containing layer structure according to the invention, such as a rivastigmine-containing self-adhesive layer structure, is normally located on a detachable protective layer (release liner), from which it is removed immediately before application to the surface of the patient's skin. Thus, the TTS may further comprise a release liner. A TTS protected this way is usually stored in a blister pack or a seam-sealed pouch. The packaging may be child resistant and/or senior friendly.

Rivastigmine-Containing Layer

[0091] As outlined in more detail above, the TTS according to the present invention comprises a rivastigmine-containing layer structure comprising a rivastigmine-containing layer. Preferably, the rivastigmine-containing layer structure is a rivastigmine-containing self-adhesive layer structure. Accordingly, it is also preferred that the rivastigmine-containing layer is a self-adhesive rivastigmine-containing layer, more preferably a self-adhesive rivastigmine-containing matrix layer. In a preferred embodiment, the rivastigmine-containing layer comprises a therapeutically affective amount of the rivastigmine.

[0092] In one embodiment of the invention, the rivastigmine-containing layer is a rivastigmine-containing matrix layer. In another embodiment, the rivastigmine-containing layer is a rivastigmine-containing reservoir layer. It is preferred that the rivastigmine-containing layer is a rivastigmine-containing matrix layer.

[0093] The rivastigmine-containing layer comprises: [0094] 1. rivastigmine, preferably in the form of the free base; and [0095] 2. at least one acrylic polymer.

[0096] In a preferred embodiment, the rivastigmine-containing layer is a rivastigmine-containing matrix layer comprising [0097] 1. rivastigmine, preferably in the form of the free base; and [0098] 2. at least one acrylic polymer.

[0099] In a preferred embodiment, the invention relates to a rivastigmine-containing layer structure, wherein the at least one acrylic polymer is an acrylic pressure-sensitive adhesive.

[0100] In one embodiment of the invention, the rivastigmine-containing layer is obtainable by dissolving, dispersing, or partly dissolving and partly dispersing the rivastigmine, preferably in the form of the free base. As a result, the rivastigmine-containing layer of the TTS according to the invention typically comprises rivastigmine in the form of the free base. In addition, the rivastigmine may, in certain embodiments of the invention, partly be present in protonated form. However, it is preferred that at least 50 mol %, preferably at least 75 mol % of the rivastigmine in the rivastigmine-containing layer are present in the form of the free base. In a particular preferred embodiment, at least 90 mol %, preferably at least 95 mol %, more preferably at least 99 mol % of the rivastigmine in the rivastigmine-containing layer are present in the form of the free base.

[0101] In one embodiment of the invention, the amount of rivastigmine contained in the rivastigmine-containing layer structure ranges from 0.5 to 5 mg/cm.sup.2, preferably from 1 to 3 mg/cm.sup.2.

[0102] In one embodiment of the invention, the rivastigmine-containing layer comprises rivastigmine in an amount of from 20 to 40% by weight, preferably from 25 to 35% by weight, most preferably in an amount of 30% by weight, based on the total weight of the rivastigmine-containing layer.

[0103] In one embodiment, the rivastigmine-containing matrix layer composition may comprise a second polymer or may comprise two or more further polymers.

[0104] It is to be understood that the TTS according to the present invention may also comprise one or more polymers in addition to the at least one acrylic polymer. Exemplarily, polymers based on polysiloxanes, acrylates, polyisobutylenes, or styrene-isoprene-styrene block copolymers may be used. In one embodiment of the invention, the additional polymer is a pressure-sensitive adhesive based on polysiloxanes, acrylates, or polyisobutylene. Additional polymers may also be added to enhance cohesion and/or adhesion. In yet another preferred embodiment, the invention relates to a transdermal therapeutic system, wherein the rivastigmine-containing layer does not comprise a permeation enhancer or solubilizer.

[0105] In certain embodiments of the invention, the acrylic polymer is contained in the rivastigmine-containing layer in an amount of from 5 to 40%, preferably from 8 to 35% by weight based on the total weight of the rivastigmine-containing layer.

[0106] In a preferred embodiment of the invention, the acrylic polymer in the rivastigmine-containing layer does not comprise OH-groups as functional groups. Instead, it is preferred that the acrylic polymer in the rivastigmine-containing layer is a COOH-functionalized acrylic polymer, preferably a COOH-functionalized acrylic polymer obtainable from one or more monomers selected from acrylic acid, 2-ethylhexylacrylate, glycidylmethacrylate and methylacrylate. Particularly preferably, the acrylic polymer in the rivastigmine-containing layer is the acrylate-based pressure-sensitive adhesive Duro-Tak™ 384-2353, a copolymer based on acrylic acid, 2-ethylhexylacrylate, glycidylmethacrylate and methylacrylate, provided as a solution in ethyl acetate and hexane.

[0107] In one embodiment of the invention, the area weight of the rivastigmine-containing layer ranges from 40 to 250 g/m.sup.2, preferably from 50 to 200 g/m.sup.2. In certain preferred embodiments, the area weight ranges from 60 to 180 g/m.sup.2.

Skin Contact Layer

[0108] As outlined in more detail above, the agent-containing layer structure of the TTS according to the present invention comprises a backing layer, a rivastigmine-containing layer, and a skin contact layer. The skin contact layer is preferably in contact with the rivastigmine-containing layer.

[0109] The skin contact layer comprises at least one styrene-isoprene-styrene block copolymer. In particular, the at least one styrene-isoprene-styrene block copolymer is a pressure-sensitive adhesive based on styrene-isoprene-styrene block copolymers. Further details regarding the polymers according to the invention are provided further below.

[0110] In certain preferred embodiments, the at least one styrene-isoprene-styrene block copolymer is comprised in the skin contact layer in an amount of from about 20% to about 90%, preferably of from about 30% to about 80%, or of from about 40% to about 60% by weight based on the total weight of the skin contact layer.

[0111] The skin contact layer comprises at least one tackifier. In a preferred embodiment, the at least one tackifier is an alicyclic saturated hydrocarbon resin, or a hydrogenated rosin glycerol ester, or paraffinum liquidum, or a mixture thereof. Further details regarding the tackifiers according to the invention are provided further below.

[0112] In certain preferred embodiments, the at least one tackifier is comprised in the skin contact layer in an amount of from about 20 to about 80%, preferably from about 35 to about 65%.

[0113] In a preferred embodiment, the at least one styrene-isoprene-styrene block copolymer and the at least one tackifier are comprised in the skin contact layer in a ratio of from about 60:40 (w/w) to about 40:60 (w/w), preferably in a ratio of about 50:50 (w/w) based on the total weight of the skin contact layer.

[0114] In a particularly preferred embodiment, the at least one styrene-isoprene-styrene block copolymer and the at least one tackifier are comprised in the skin contact layer in a ratio of from about 60:40 (w/w) to about 40:60 (w/w).

[0115] In another preferred embodiment, the at least one styrene-isoprene-styrene block copolymer and the at least one tackifier are present in the skin contact layer in an overall amount of at least 90% by weight, preferably in an overall amount of at least 99% by weight based on the total weight of the skin contact layer. Preferably, the skin contact layer does not comprise an acrylic polymer.

[0116] The skin contact layer may comprise an active agent. In a preferred embodiment, the skin contact layer is free of active agent, that is, is prepared without the addition of an active agent.

[0117] The skin contact layer may have an area weight of from 5 to 120 g/m.sup.2. It is preferred, that the skin contact layer has an area weight of from 5 to 60 g/m.sup.2, preferably of from 10 to 50 g/m.sup.2, more preferably of from 20 to 40 g/m.sup.2.

Rivastigmine

[0118] The TTS according to the invention comprises a rivastigmine-containing layer structure, said rivastigmine containing layer structure comprising A) a backing layer; and B) a rivastigmine-containing layer comprising at least one acrylic polymer; and C) a skin contact layer comprising at least one styrene-isoprene-styrene block copolymer and at least one tackifier.

[0119] In one embodiment of the invention, the amount of rivastigmine contained in the rivastigmine-containing layer structure ranges from 0.5 to 5 mg/cm.sup.2, preferably from 1 to 3 mg/cm.sup.2.

[0120] In one embodiment of the invention, the rivastigmine-containing layer structure preferably contains a therapeutically effective amount of rivastigmine. More preferably, the therapeutically effective amount of rivastigmine is present in the rivastigmine-containing layer of the rivastigmine-containing layer structure. Preferably, the rivastigmine in the rivastigmine-containing layer structure is present in the form of the free base.

[0121] In one embodiment of the invention, at least 50 mol %, preferably at least 75 mol % of the total amount of rivastigmine in the TTS are present in the form of the free base. In a particular preferred embodiment, at least 90 mol %, preferably at least 95 mol %, more preferably at least 99 mol % of the total amount of rivastigmine in the TTS are present in the form of the free base. Thus, it is preferred that at least 50 mol %, preferably at least 75 mol % of the rivastigmine in the rivastigmine-containing layer are present in the form of the free base. In a particular preferred embodiment, at least 90 mol %, preferably at least 95 mol %, more preferably at least 99 mol % of the rivastigmine in the rivastigmine-containing layer are present in the form of the free base. In certain embodiments, the rivastigmine-containing layer is free of rivastigmine salts.

[0122] In certain embodiments, the amount of rivastigmine in the rivastigmine-containing layer ranges from 20 to 40% by weight, preferably from 25 to 35% by weight, most preferably rivastigmine is present in the rivastigmine-containing layer in an amount of 30% by weight, based on the total weight of the rivastigmine-containing layer.

[0123] In certain embodiments, the amount of rivastigmine contained in the rivastigmine-containing layer ranges from 1 to 72 mg, preferably from 2 to 36 mg, depending on the patch size. In a patch of the size of e.g. 5 cm.sup.2, the amount of rivastigmine contained in the rivastigmine-containing layer ranges from 3 to 15 mg, preferably from 6 to 12 mg.

[0124] In one embodiment of the invention, the rivastigmine-containing layer is obtainable by dissolving or dispersing the rivastigmine in the form of the free base. If the rivastigmine-containing layer is a rivastigmine-containing matrix layer, said layer is preferably obtainable by dissolving or dispersing the rivastigmine in the form of the free base in the polymeric carrier, which particularly preferably comprises the at least one acrylic polymer.

[0125] In one embodiment, the rivastigmine-containing layer comprises a pharmaceutically acceptable salt of rivastigmine, such as rivastigmine hydrochloride or rivastigmine tartrate.

[0126] However, it is preferred according to the invention that the rivastigmine in the rivastigmine-containing layer is present in the form of the free base.

[0127] In certain embodiments, the rivastigmine has a purity of at least 95%, preferably of at least 98%, and more preferably of at least 99% as determined by quantitative titration according to Ph.Eur. 2.2.20 Assay in the Hyoscine Monography.

Acrylic Polymers

[0128] According to the invention, the TTS comprises at least one acrylic polymer in the rivastigmine-containing layer.

[0129] In certain embodiments, the acrylic polymer is an acrylic pressure-sensitive adhesive.

[0130] Acrylic pressure-sensitive adhesives are usually supplied and used in solvents like n-heptane and ethyl acetate. The solids content of the pressure-sensitive adhesives is usually between 20% and 80%.

[0131] Acrylic pressure-sensitive adhesives may also be referred to as acrylate-based pressure-sensitive adhesives, or pressure-sensitive adhesives based on acrylates. Pressure-sensitive adhesives based on acrylates may have a solids content preferably between 20% and 60%. Such acrylate-based pressure-sensitive adhesives may or may not comprise functional groups such as hydroxy groups, carboxylic acid groups, neutralized carboxylic acid groups and mixtures thereof. Thus, the term “functional groups” in particular refers to hydroxy- and carboxylic acid groups, and deprotonated carboxylic acid groups.

[0132] Corresponding commercial products are available e.g. from Henkel under the tradename Duro Tak®. Such acrylate-based pressure-sensitive adhesives are based on monomers selected from one or more of acrylic acid, butylacrylate, 2-ethylhexylacrylate, glycidylmethacrylate, 2-hydroxyethylacrylate, methylacrylate, methylmethacrylate, t-octylacrylamide and vinylacetate, and are provided in ethyl acetate, heptanes, n-heptane, hexane, methanol, ethanol, isopropanol, 2,4-pentanedione, toluene or xylene or mixtures thereof.

[0133] Specific acrylate-based pressure-sensitive adhesives are available as: [0134] Duro-Tak™ 387-2287 or Duro-Tak™ 87-2287 (a copolymer based on vinyl acetate, 2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and glycidyl-methacrylate provided as a solution in ethyl acetate without cross-linking agent), [0135] Duro-Tak™ 387-2516 or Duro-Tak™ 87-2516 (a copolymer based on vinyl acetate, 2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and glycidyl-methacrylate provided as a solution in ethyl acetate, ethanol, n-heptane and methanol with a titanium cross-linking agent), [0136] Duro-Tak™ 387-2051 or Duro-Tak™ 87-2051 (a copolymer based on acrylic acid, butylacrylate, 2-ethylhexylacrylate and vinyl acetate, provided as a solution in ethyl acetate and heptane), [0137] Duro-Tak™ 387-2353 or Duro-Tak™ 87-2353 (a copolymer based on acrylic acid, 2-ethylhexylacrylate, glycidylmethacrylate and methylacrylate, provided as a solution in ethyl acetate and hexane), [0138] Duro-Tak™ 87-4098 (a copolymer based on 2-ethylhexyl-acrylate and vinyl acetate, provided as a solution in ethyl acetate).

[0139] In a preferred embodiment of the invention, the acrylic polymer in the rivastigmine-containing layer is the acrylate-based pressure-sensitive adhesive Duro-Tak.sup.TM384-2353, a copolymer based on acrylic acid, 2-ethylhexylacrylate, glycidylmethacrylate and methylacrylate, provided as a solution in ethyl acetate and hexane.

[0140] Additional polymers may also be added to enhance cohesion and/or adhesion.

Styrene-Isoprene-Styrene Block Copolymers

[0141] According to the invention, the TTS comprises at least one styrene-isoprene-styrene block copolymer in the skin contact layer. In particular, the at least one styrene-isoprene-styrene block copolymer is a pressure-sensitive adhesives based on styrene-isoprene-styrene block copolymers.

[0142] Suitable styrene-isoprene-styrene copolymers according to the invention are commercially available e.g. under the brand names JSR-SIS.

[0143] In certain embodiments of the invention, the at least one styrene-isoprene-styrene block copolymer comprises styrene blocks and isoprene blocks in a ratio of from about 10:90 (w/w) to about 30:70 (w/w), preferably in a ratio of about 15:85 (w/w) or about 22:78 (w/w).

[0144] In certain embodiments of the invention, the at least one styrene-isoprene-styrene block copolymer is obtainable by polymerisation of three blocks of polystyrene, polyisoprene and polystyrene and has an average molecular weight of from about 100,000 to 200,000.

[0145] Specific styrene-isoprene-styrene block copolymer-based pressure-sensitive adhesives are available under the tradenames JSR-SIS5229 and JSR-SIS5002.

[0146] Additional polymers may also be added to enhance cohesion and/or adhesion.

Tackifiers

[0147] According to the invention, the TTS comprises at least one tackifier in the skin contact layer. In certain embodiments of the invention, the at least one tackifier is an alicyclic saturated hydrocarbon resin, a hydrogenated rosin glycerol ester, paraffinum liquidum, or a mixture thereof. For example, the at least one tackifier may be a mixture comprising an alicyclic saturated hydrocarbon resin and paraffinum liquidum, or a mixture comprising a hydrogenated rosin glycerol ester and paraffinum liquidum.

[0148] Alicyclic saturated hydrocarbon resins are described in detail in the respective monograph in the Japanese pharmacopeia. In certain embodiments of the invention, the alicyclic saturated hydrocarbon resin is obtainable from polymerisation of an unsaturated hydrocarbon obtainable prepared by the decomposition of petroleum naphtha at elevated temperatures.

[0149] A specific alicyclic saturated hydrocarbon resin is available from Arakawa Europe under the tradename Arkon P-100 and has the chemical structure as detailed below.

##STR00002##

[0150] Hydrogenated rosin glycerol esters are described in detail in the respective monograph in the Japanese pharmacopeia. In certain embodiments of the invention, the hydrogenated rosin glycerol ester is a solid resin obtainable from the hydrogenation of rosin, followed by esterification with glycerin.

[0151] A specific hydrogenated rosin glycerol ester is available from Arakawa Europe under the tradename Pinecrystal KE-100 and has the chemical structure as detailed below.

##STR00003##

[0152] Paraffinum liquidum is a refined mixture of liquid, saturated hydrocarbons as defined in the European Pharmacopeia (Ph.Eur.).

[0153] According to certain embodiments of the invention, the at least one tackifier is contained in the skin contact layer in an amount from about 20 to about 80%, preferably from about 35 to about 65%.

Further Additives

[0154] The TTS according to the invention, and in particular the rivastigmine-containing layer may further comprise at least one additive or excipient. Said additives or excipients are preferably selected from the group consisting of crystallization inhibitors, solubilizers, fillers, substances for skincare, pH regulators, preservatives, tackifiers, softeners, stabilizers, and permeation enhancers, in particular from crystallization inhibitors, substances for skincare, tackifiers, softeners, stabilizers, and permeation enhancers. More preferably, said additives are selected from the group consisting of crystallization inhibitors, solubilizers, fillers, substances for skincare, pH regulators, preservatives, tackifiers, softeners, stabilizers, and permeation enhancers, in particular from crystallization inhibitors, substances for skincare, tackifiers, softeners, and stabilizers. Such additives may be present in the rivastigmine-containing layer in an amount of from 0.001 to 15% by weight, e.g. from 1 to 10% by weight or from 0.01 to 5% by weight, based on the total weight of the rivastigmine-containing layer.

[0155] In certain preferred embodiments, the rivastigmine-containing layer does not comprise further additives, in particular the rivastigmine-containing layer does not comprise a permeation enhancer or solubilizer.

[0156] It should be noted that in pharmaceutical formulations, the formulation components are categorized according to their physicochemical and physiological properties, and in accordance with their function. This means in particular that a substance or a compound falling into one category is not excluded from falling into another category of formulation component. E.g. a certain polymer can be a crystallization inhibitor but also a tackifier. Some substances may e.g. be a typical softener but at the same time act as a permeation enhancer. The skilled person is able to determine based on his or her general knowledge in which category or categories of formulation component a certain substance or compound belongs to. In the following, details on the excipients and additives are provided which are, however, not to be understood as being exclusive. Other substances not explicitly listed in the present description may be as well used in accordance with the present invention, and substances and/or compounds explicitly listed for one category of formulation component are not excluded from being used as another formulation component in the sense of the present invention.

[0157] In one embodiment, the rivastigmine-containing layer further comprises a crystallization inhibitor. In some embodiments, the crystallization inhibitor can be present in an amount of from 0.5 to 10% by weight based on the total weight of the rivastigmine-containing layer. Suitable examples of crystallization inhibitors include polyvinylpyrrolidone, vinyl acetate/vinylpyrrolidone copolymer and cellulose derivatives. The crystallization inhibitor is preferably polyvinylpyrrolidone, more preferably soluble polyvinylpyrrolidone. The crystallization inhibitor may increase the solubility of the active agent or inhibit the crystallization of the active agent.

[0158] In one embodiment, the rivastigmine-containing layer further comprises a stabilizer, wherein the stabilizer is preferably selected from tocopherol and ester derivatives thereof and ascorbic acid and ester derivatives thereof. In some embodiments, the stabilizer can be present in an amount of from 0.001 to 2.0%, preferably from 0.01 to 1.0% by weight based on the total weight of the rivastigmine-containing layer. In some embodiments, preferred stabilizers include sodium metabisulfite, ascorbyl esters of fatty acids such as ascorbyl palmitate, ascorbic acid, butylated hydroxytoluene, tocopherol, tocopheryl acetate and tocopheryl linoleate. Preferred stabilizers include ascorbyl esters of fatty acids, ascorbic acid, tocopherol, tocopheryl acetate and tocopheryl linoleate. Particularly preferred is tocopherol. Also particularly preferred is a combination of tocopherol and ascorbyl palmitate.

[0159] In one embodiment, the rivastigmine-containing layer further comprises a softener/plasticizer. Exemplary softeners/plasticizers include linear or branched, saturated or unsaturated alcohols having 6 to 20 carbon atoms, triglycerides and polyethylene glycols.

[0160] In one embodiment, the rivastigmine-containing layer further comprises a solubilizer. The solubilizer preferably improves the solubility of the rivastigmine in the rivastigmine-containing layer. Preferred solubilizers include, e.g., glycerol-, polyglycerol-, propylene glycol- and polyoxyethylene-esters of medium chain and/or long chain fatty acids, such as glyceryl mono lino leate, medium chain glycerides and medium chain triglycerides, non-ionic solubilizers made by reacting castor oil with ethylene oxide, and any mixtures thereof which may further contain fatty acids or fatty alcohols; cellulose and methylcellulose and derivatives thereof such as hydroxypropylcellulose and hypromellose acetate succinate; various cyclodextrins and derivatives thereof; non-ionic tri-block copolymers having a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene known as poloxamers;

[0161] water-soluble derivatives of vitamin E; pharmaceutical graded or agglomerated spherical isomalt; a polyethylene glycol, polyvinyl acetate and polyvinylcaprolactame-based graft copolymer, also abbreviated as PVAc-PVCap- PEG and known as Soluplus®; purified grades of naturally derived castor oil, of polyethylene glycol 400, of polyoxyethylene sorbitan monooleate (such as polysorbate 80) or of propylene glycols; diethylene glycol monoethyl ether; glucono-delta-lactone; maize and potato starch; as well as any of the below mentioned soluble polyvinylpyrrolidones, but also insoluble/cross-linked polyvinylpyrrolidones such as crospovidones.

[0162] However, also the permeation enhancers mentioned below can act as solubilizers.

[0163] In one embodiment, the rivastigmine-containing layer further comprises a pH regulator. Suitable pH regulators include mild acids and bases including amine derivatives, inorganic alkali derivatives, and polymers with basic or acidic functionality.

[0164] In one embodiment, the rivastigmine-containing layer further comprises a preservative. Suitable preservatives include parabens, formaldehyde releasers, isothiazolinones, phenoxyethanol, and organic acids such as benzoic acid, sorbic acid, levulinic acid and anisic acid.

[0165] In one embodiment, the rivastigmine-containing layer further comprises a substance for skincare. Such substances may be used to avoid or reduce skin irritation as detectable by the dermal response score. Suitable substances for skincare include sterol compounds such as cholesterol, dexpanthenol, alpha-bisabolol, and antihistamines. Substances for skincare are preferably used in amounts of from 1 to 10% by weight based on the total weight of the rivastigmine-containing layer.

[0166] The term “soluble polyvinylpyrrolidone” refers to polyvinylpyrrolidone, also known as povidone, which is soluble with more than 10% in at least ethanol, preferably also in water, diethylene glycol, methanol, n-propanol, 2 propanol, n-butanol, chloroform, methylene chloride, 2-pyrrolidone, macrogol 400, 1,2 propylene glycol, 1,4 butanediol, glycerol, triethanolamine, propionic acid and acetic acid. Examples of polyvinylpyrrolidones which are commercially available include Kollidon® 12 PF, Kollidon® 17 PF, Kollidon® 25, Kollidon® 30 and Kollidon0 90 F supplied by BASF, or povidone K9OF. The different grades of Kollidon® are defined in terms of the K-Value reflecting the average molecular weight of the polyvinylpyrrolidone grades. Kollidon® 12 PF is characterized by a K-Value range of 10.2 to 13.8, corresponding to a nominal K-Value of 12. Kollidon® 17 PF is characterized by a K-Value range of 15.3 to 18.4, corresponding to a nominal K-Value of 17. Kollidon® 25 is characterized by a K-Value range of 22.5 to 27.0, corresponding to a nominal K-Value of 25, Kollidon® 30 is characterized by a K-Value range of 27.0 to 32.4, corresponding to a nominal K-Value of 30. Kollidon® 90 F is characterized by a K-Value range of 81.0 to 97.2, corresponding to a nominal K-Value of 90. Preferred Kollidon® grades are Kollidon® 12 PF, Kollidon® 30 and Kollidon® 90 F.

[0167] Within the meaning of this invention, the term “K-Value” refers to a value calculated from the relative viscosity of polyvinylpyrrolidone in water according to the European Pharmacopoeia (Ph.Eur.) and USP monographs for “Povidone”.

[0168] Fillers such as silica gels, titanium dioxide and zinc oxide may be used in conjunction with the polymer in order to influence certain physical parameters, such as cohesion and bond strength, in the desired way.

[0169] In one embodiment, the rivastigmine-containing layer further comprises a permeation enhancer. Permeation enhancers are substances, which influence the barrier properties of the stratum corneum in the sense of increasing the active agent permeability. Some examples of permeation enhancers are polyhydric alcohols such as dipropylene glycol, propylene glycol, and polyethylene glycol; oils such as olive oil, squalene, and lanolin; fatty ethers such as cetyl ether and oleyl ether; fatty acid esters such as isopropyl myristate; urea and urea derivatives such as allantoin; polar solvents such as dimethyldecylphosphoxide, methylcetylsulfoxide, dimethylaurylamine, dodecyl pyrrolidone, isosorbitol, dimethylacetonide, dimethylsulfoxide, decylmethylsulfoxide, and dimethylformamide; salicylic acid; amino acids; benzyl nicotinate; and higher molecular weight aliphatic surfactants such as lauryl sulfate salts. Other agents include oleic and linoleic acids, ascorbic acid, panthenol, butylated hydroxytoluene, tocopherol, tocopheryl acetate, tocopheryl linoleate, propyl oleate, and isopropyl palmitate.

[0170] If the rivastigmine-containing layer further comprises a permeation enhancer, the permeation enhancer is preferably selected from diethylene glycol monoethyl ether (transcutol), diisopropyl adipate, isopropyl myristate, isopropyl palmitate, lauryl lactate, and dimethylpropylene urea.

[0171] It has been found that the TTS provides sufficient permeability of the active agent even if no permeation enhancer is present. Therefore, in certain embodiments of the invention, the rivastigmine-containing layer does not comprise a permeation enhancer or solubilizer.

Release Characteristics

[0172] The TTS in accordance with the invention are designed for transdermally administering rivastigmine to the systemic circulation for a predefined extended period of time, preferably for 24 hours.

[0173] In one embodiment, the TTS according to the invention provides by transdermal delivery a mean release rate of from 150 to 3500 μg/cm.sup.2*day, preferably from 400 to 2000 μg/cm.sup.2*day rivastigmine over about 24 hours of administration.

[0174] In one embodiment, the TTS according to the invention provides by transdermal delivery from 2 to 20 mg of rivastigmine at an approximately constant rate, during an administration period of the TTS to the skin of the patient for about 24 hours.

[0175] In one embodiment, the transdermal therapeutic system according to the invention provides a cumulative permeated amount of rivastigmine as measured in a Franz diffusion cell with an EVA membrane of about 300 μg/cm.sup.2 to 1200 μg/cm.sup.2 over a time period of 24 hours.

[0176] In one embodiment, the transdermal therapeutic system according to the invention provides a permeated amount of rivastigmine as measured in a Franz diffusion cell with EVA-membrane (9% vinyl acetate Cotran 9702 von 3M) of 0μg/cm.sup.2 to 240 μg/cm.sup.2 in the first 3 hours, 80 μg/cm.sup.2 to 350 μg/cm.sup.2 from hour 3 to hour 8, 210 μg/cm.sup.2 to 560 μg/cm.sup.2 from hour 8 to hour 24.

Method of Treatment/Medical Use

[0177] In accordance with a specific aspect of the present invention, the TTS according to the invention is for use in a method of treating a human patient, preferably for use in a method of preventing, treating, or delaying of progression of Alzheimer's disease, dementia associated with Parkinson's disease, and/or symptoms of traumatic brain injury. According to another specific aspect of the present invention, the TTS is for use in a method of treating a human patient, preferably for use in a method of treating mild to moderate dementia caused by Alzheimer's or Parkinson's disease.

[0178] In one embodiment, the TTS according to the invention is for use in a method of treating a human patient, preferably for use in a method of treating a human patient, preferably for use in a method of preventing, treating, or delaying of progression of Alzheimer's disease, dementia associated with Parkinson's disease, and/or symptoms of traumatic brain injury, or for use in a method of treating a human patient, preferably for use in a method of treating mild to moderate dementia caused by Alzheimer's or Parkinson's disease, wherein the transdermal therapeutic system is applied to the skin of the patient for a dosing interval of at least 24 hours, preferably about 24 hours.

[0179] In one embodiment, the TTS according to the invention is for use in a method of treating a human patient, preferably for use in a method of treating a human patient, preferably for use in a method of preventing, treating, or delaying of progression of Alzheimer's disease, dementia associated with Parkinson's disease, and/or symptoms of traumatic brain injury, or for use in a method of treating a human patient, preferably for use in a method of treating mild to moderate dementia caused by Alzheimer's or Parkinson's disease, wherein the transdermal therapeutic system is applied to the skin of the patient for a dosing interval of at least 72 hours, preferably about 84 hours.

[0180] In certain embodiments, the present invention relates to a method of treating a human patient, in particular preventing, treating, or delaying of progression of Alzheimer's disease, dementia associated with Parkinson's disease, and/or symptoms of traumatic brain injury, by applying a transdermal therapeutic system as defined within the invention to the skin of the patient. In another certain embodiment, the present invention relates to a method of treating a human patient, in particular treating a mild to moderate dementia caused by Alzheimer's and Parkinson's disease, by applying a transdermal therapeutic system as defined within the invention to the skin of the patient.

[0181] In one embodiment, the present invention relates to a method of treating a human patient, in particular preventing, treating, or delaying of progression of Alzheimer's disease, dementia associated with Parkinson's disease, and/or symptoms of traumatic brain injury, or a method of treating a human patient, in particular treating a mild to moderate dementia caused by Alzheimer's and Parkinson's disease, wherein the transdermal therapeutic system is applied to the skin of the patient for a dosing interval of at least 24 hours, preferably about 24 hours.

[0182] In one embodiment, the present invention relates to a method of treating a human patient, in particular preventing, treating, or delaying of progression of Alzheimer's disease, dementia associated with Parkinson's disease, and/or symptoms of traumatic brain injury, or a method of treating a human patient, in particular treating a mild to moderate dementia caused by Alzheimer's and Parkinson's disease, wherein the transdermal therapeutic system is applied to the skin of the patient for a dosing interval of at least 72 hours, preferably about 84 hours.

[0183] In connection with the above uses and methods of treatment, the TTS according to the invention is preferably applied to at least one body surface on the subject selected from the upper outer art, upper chest, upper back or the side of the chest for the defined dosing intervals.

[0184] The preferred application time of a TTS according to the invention is at least 24 hours, preferably about 24 hours (1 day) or about 84 hours (3.5 days), particularly preferably about 24 hours. After this time, the TTS may be removed, and optionally a new TTS may be applied, so as to allow an around-the-clock treatment.

Process of Manufacture

[0185] The invention further relates to a process of manufacture of a rivastigmine-containing layer, preferably a rivastigmine-containing matrix layer, for use in a transdermal therapeutic system.

[0186] In accordance with the invention, the process for manufacturing a transdermal therapeutic system according to the invention comprises the steps of: [0187] 1) providing a rivastigmine-containing coating composition by combining at least the components [0188] i) rivastigmine; and [0189] ii) at least one acrylic polymer; [0190] 2) coating the rivastigmine-containing coating composition onto a film in an amount to provide the desired area weight, [0191] 3) drying the coated rivastigmine-containing coating composition to provide the rivastigmine-containing layer, [0192] 4) providing an additional coating composition for an additional skin contact layer by combining at least the components [0193] a) at least one styrene-isoprene-styrene block copolymer; and [0194] b) at least one tackifier; [0195] 5) coating and drying the additional coating composition according to steps 2 and 3, wherein the film is a release liner, [0196] 6) laminating the adhesive side of the skin contact layer onto the adhesive side of the rivastigmine-containing layer to provide a rivastigmine-containing layer structure with the desired area of release, [0197] 7) punching the individual systems from the rivastigmine-containing layer structure, [0198] 8) optionally adhering to the individual systems a rivastigmine-free self-adhesive layer structure comprising also a backing layer and a rivastigmine-free pressure-sensitive adhesive layer and which is larger than the individual systems of rivastigmine-containing self-adhesive layer structure.

[0199] In step 1) of the above process of manufacture, the rivastigmine is preferably dispersed to obtain a homogenous coating composition.

[0200] In certain embodiments of the present invention, the acrylic polymer is provided as a solution, wherein the solvent is ethyl acetate or n-heptane. Preferably ethyl acetate is used. Preferably, the acrylic polymer has a solids content of from 20 to 70% by weight.

[0201] In step 3) of the above process of manufacture, drying is performed preferably at a temperature of from 20 to 90° C., more preferably from 40 to 70° C.

[0202] In certain embodiments of the present invention, the film in step 2) is a release liner, the rivastigmine-containing layer is laminated after step 3) to a backing layer, and the release liner of step 2) is removed before step 6).

EXAMPLES

[0203] The present invention will now be more fully described with reference to the accompanying examples. It should be understood, however, that the following description is illustrative only and should not be taken in any way as a restriction of the invention. Numerical values provided in the examples regarding the amount of ingredients in the composition or the area weight may vary slightly due to manufacturing variability.

Comparative Example 1

[0204] Comparative Example 1 (Comp. 1) is equivalent to the commercially available rivastigmine-containing TTS product Exelon®, having a rivastigmine-containing acrylic based layer (60 g/m.sup.2) and a rivastigmine-free silicone based skin contact layer (30 g/m.sup.2), but includes a transparent backing layer instead of the beige backing layer of the commercial product by Novartis.

[0205] The permeated amount of the commercially available Exelon® TTS as well as the stability in terms of the rivastigmine content, the adhesion force, the peel force and the in vitro release were determined in accordance with Examples 6 and 7, respectively.

[0206] The results are shown in Tables 6 to 7.18 and in FIGS. 1 to 4.

Example 1

Coating Composition

[0207] The formulation of the rivastigmine-containing coating composition of Example 1 is summarized in Table 1.1. The %-values refer to the amounts in % by weight.

TABLE-US-00001 TABLE 1.1 Ingredient (Trade Name) Amt [kg] Solids [%] Rivastigmine base 54.00 30.00 Polybutylmethacrylate, methylmethacrylate 36.00 20.00 Acrylic adhesive in ethyl 89.82 49.90 acetate, solids content (239.52 with of 37.5% (e.g. Durotak ® 387-2353) ethyl acetate) Alpha-tocopherol 0.18 0.10 Total 180.00 100.0 Area Weight [g/m.sup.2] 60

Preparation of the Coating Composition

[0208] A beaker was loaded with the acrylic pressure-sensitive adhesive Durotak 387-2353. The rivastigmine base was added under stirring. The mixture was stirred at about 800 rpm until a homogenous mixture was obtained (at least 20 min).

Coating of the Coating Composition

[0209] The resulting rivastigmine-containing coating composition was coated within less than 24 h after the rivastigmine-containing mixture was finished on an abhesively equipped foil (Scotchpak 9755 AB1F) using hand over knife lab coating equipment, using an erichson coater. The solvent was removed by drying in a first step at about room temperature (23 ±2° C.) for about 10 min, followed by a second drying step at about 60° C. for about 20 min.

[0210] The coating thickness was chosen such that removal of the solvent results in an area weight of the rivastigmine-containing layer of about 60.0 g/m.sup.2. The dried film was then laminated with a backing layer (FO PET 23 gm transparent).

Skin Contact Layer

[0211] The formulation of the skin contact layer of Example 1 is summarized in Table 1.2. The %-values refer to the amounts in % by weight.

TABLE-US-00002 TABLE 1.2 Ingredient (Trade Name) Amt [g] Solids [%] Styrene isoprene block copolymer in benzene 64.94 49.95 (JSR SIS 5229) Alicyclic saturated hydrocarbon resin (Arkon 64.94 49.95 P-100) Alpha-tocopherol 0.13 0.10 Total 130.01 100.0 Area Weight [g/m.sup.2] 30

Preparation of the Skin Contact Layer

[0212] A beaker was loaded with the styrene isoprene block copolymer and the alicyclic saturated hydrocarbon resin. The mixture was stirred at about 800 rpm until a homogenous mixture was obtained (at least 20 min).

[0213] The resulting composition was coated within less than 24 h after the mixture was finished on an abhesively equipped foil (Scotchpak 9755 AB1F) using hand over knife lab coating equipment, using an erichson coater. The solvent was removed by drying in a first step at about room temperature (23±2° C.) for about 10 min, followed by a second drying step at about 60° C. for about 20 min.

[0214] The coating thickness was chosen such that removal of the solvent results in an area weight of the skin contact layer of about 30.0 g/m.sup.2. The abhesively equipped foil of the rivastigmine-containing layer was removed and the dried skin contact layer was then laminated on top of it to form a rivastigmine-containing self-adhesive layer structure.

Preparation of the TTS

[0215] The individual systems (TTS) were then punched out from the rivastigmine-containing self-adhesive layer structure and sealed into pouches of the primary packaging material.

Example 2

Rivastigmine-Containing Layer

[0216] The formulation of the rivastigmine-containing layer of Example 2 corresponds to the rivastigmine-containing layer of Example 1 as summarized in Table 1.1.

Skin Contact Layer

[0217] The formulation of the skin contact layer of Example 2 is summarized in Table 2. The %-values refer to the amounts in % by weight.

TABLE-US-00003 TABLE 2 Ingredient (Trade Name) Amt [g] Solids [%] Styrene isoprene block copolymer in benzene 54.15 41.7 (JSR SIS 5229) Alicyclic saturated hydrocarbon resin (Arkon 66.11 50.9 P-100) Paraffinum liquidum 9.62 7.4 Alpha-tocopherol 0.13 0.10 Total 130.01 100.0 Area Weight [g/m.sup.2] 30

Preparation of the Skin Contact Layer

[0218] A beaker was loaded with the styrene isoprene block copolymer, the alicyclic saturated hydrocarbon resin and paraffinum liquidum. The mixture was stirred at about 800 rpm until a homogenous mixture was obtained (at least 20 min).

[0219] The resulting composition was coated within less than 24 h after the mixture was finished on an abhesively equipped foil (Scotchpak 9755 AB1F) using hand over knife lab coating equipment, using an erichson coater. The solvent was removed by drying in a first step at about room temperature (23±2° C.) for about 10 min, followed by a second drying step at about 60° C. for about 20 min.

[0220] The coating thickness was chosen such that removal of the solution results in an area weight of the skin contact layer of about 30.0 g/m.sup.2. The abhesively equipped foil of the rivastigmine-containing layer was removed and the dried skin contact layer was then laminated on top of it to form a rivastigmine-containing self-adhesive layer structure.

Preparation of the TTS

[0221] The individual systems (TTS) were then punched out from the rivastigmine-containing self-adhesive layer structure and sealed into pouches of the primary packaging material.

Example 3

Rivastigmine-Containing Layer

[0222] The formulation of the rivastigmine-containing layer of Example 3 corresponds to the rivastigmine-containing layer of Example 1 as summarized in Table 1.1.

Skin Contact Layer

[0223] The formulation of the skin contact layer of Example 3 is summarized in Table 3. The %-values refer to the amounts in % by weight.

TABLE-US-00004 TABLE 3 Ingredient (Trade Name) Amt [g] Solids [%] Styrene isoprene block copolymer in benzene 64.94 49.95 (JSR SIS 5229) Hydrogenated rosin glycerol ester (Pinecrystal 64.94 49.95 KE-311) Alpha-tocopherol 0.13 0.10 Total 130.01 100.0 Area Weight [g/m.sup.2] 30

Preparation of the Skin Contact Layer

[0224] A beaker was loaded with the styrene isoprene block copolymer, the hydrogenated rosin glycerol ester and alpha-tocopherol. The mixture was stirred at about 800 rpm until a homogenous mixture was obtained (at least 20 min).

[0225] The resulting composition was coated within less than 24 h after the mixture was finished on an abhesively equipped foil (Scotchpak 9755 AB1F) using hand over knife lab coating equipment, using an erichson coater. The solvent was removed by drying in a first step at about room temperature (23 ±2° C.) for about 10 min, followed by a second drying step at about 60° C. for about 20 min.

[0226] The coating thickness was chosen such that removal of the solution results in an area weight of the skin contact layer of about 30.0 g/m.sup.2. The abhesively equipped foil of the rivastigmine-containing layer was removed and the dried skin contact layer was then laminated on top of it to form a rivastigmine-containing self-adhesive layer structure.

Preparation of the TTS

[0227] The individual systems (TTS) were then punched out from the rivastigmine-containing self-adhesive layer structure and sealed into pouches of the primary packaging material.

Example 4

Rivastigmine-Containing Layer

[0228] The formulation of the rivastigmine-containing layer of Example 4 corresponds to the rivastigmine-containing layer of Example 1 as summarized in Table 1.1.

Skin Contact Layer

[0229] The formulation of the skin contact layer of Example 4 is summarized in Table 4. The %-values refer to the amounts in % by weight.

TABLE-US-00005 TABLE 4 Ingredient (Trade Name) Amt [g] Solids [%] Styrene isoprene block copolymer in benzene 64.87 49.90 (JSR SIS 5229) Alicyclic saturated hydrocarbon resin (Arkon 32.50 25.00 P-100) Hydrogenated rosin glycerol ester (Pinecrystal 32.50 25.00 KE-311) Alpha-tocopherol 0.13 0.10 Total 130.00 100.0 Area Weight [g/m.sup.2] 30

Preparation of the Skin Contact Layer

[0230] A beaker was loaded with the styrene isoprene block copolymer, the alicyclic saturated hydrocarbon resin, the hydrogenated rosin glycerol ester and alpha-tocopherol. The mixture was stirred at about 800 rpm until a homogenous mixture was obtained (at least 20 min).

[0231] The resulting composition was coated within less than 24 h after the mixture was finished on an abhesively equipped foil (Scotchpak 9755 AB1F) using hand over knife lab coating equipment, using an erichson coater. The solvent was removed by drying in a first step at about room temperature (23 ±2° C.) for about 10 min, followed by a second drying step at about 60° C. for about 20 min.

[0232] The coating thickness was chosen such that removal of the solution results in an area weight of the skin contact layer of about 30.0 g/m.sup.2. The abhesively equipped foil of the rivastigmine-containing layer was removed and the dried skin contact layer was then laminated on top of it to form a rivastigmine-containing self-adhesive layer structure.

Preparation of the TTS

[0233] The individual systems (TTS) were then punched out from the rivastigmine-containing self-adhesive layer structure and sealed into pouches of the primary packaging material.

Example 5

Rivastigmine-Containing Layer

[0234] The formulation of the rivastigmine-containing layer of Example 5 corresponds to the rivastigmine-containing layer of Example 1 as summarized in Table 1.1.

Skin Contact Layer

[0235] The formulation of the skin contact layer of Example 5 is summarized in Table 5. The %-values refer to the amounts in % by weight.

TABLE-US-00006 TABLE 5 Ingredient (Trade Name) Amt [g] Solids [%] Styrene isoprene block copolymer in benzene 54.15 41.65 (JSR SIS 5229) Hydrogenated rosin glycerol ester (Pinecrystal 66.11 50.85 KE-311) Paraffinum liquidum 9.62 7.40 Alpha-tocopherol 0.13 0.10 Total 130.01 100.0 Area Weight [g/m.sup.2] 30

Preparation of the Skin Contact Layer

[0236] A beaker was loaded with the styrene isoprene block copolymer, the hydrogenated rosin glycerol ester, the paraffinum liquidum and alpha-tocopherol. The mixture was stirred at about 800 rpm until a homogenous mixture was obtained (at least 20 min).

[0237] The resulting composition was coated within less than 24 h after the mixture was finished on an abhesively equipped foil (Scotchpak 9755 AB1F) using hand over knife lab coating equipment, using an erichson coater. The solvent was removed by drying in a first step at about room temperature (23 ±2° C.) for about 10 min, followed by a second drying step at about 60° C. for about 20 min.

[0238] The coating thickness was chosen such that removal of the solution results in an area weight of the skin contact layer of about 30.0 g/m.sup.2. The abhesively equipped foil of the rivastigmine-containing layer was removed and the dried skin contact layer was then laminated on top of it to form a rivastigmine-containing self-adhesive layer structure.

Preparation of the TTS

[0239] The individual systems (TTS) were then punched out from the rivastigmine-containing self-adhesive layer structure and sealed into pouches of the primary packaging material.

Example 6

Measurement of Permeated Amount

[0240] The permeated amount of the TTS prepared according to Comparative Example 1 and Examples 1 and 3 to 5 was determined by experiments in accordance with the EMA Guideline on quality of transdermal patches (adopted October 23, 2014) carried out with a 10.0 ml Franz diffusion cell, wherein an EVA-membrane (9% vinyl acetate; Scotchpak Cotran 9702 from 3M) having a thickness of 50 gm was used. Diecuts with an area of release of 1.156 cm.sup.2 were punched from the TTS. The permeated amount of rivastigmine in the receptor medium of the Franz diffusion cell (phosphate buffer solution pH 5.5 with 0.1% sodium azide as antibacteriological agent) at a temperature of 32±1° C. was measured.

[0241] The results are shown in Table 6 and FIG. 1.

TABLE-US-00007 TABLE 6 Cumulative amount permeated with SD [μg/cm.sup.2] Elapsed Ex. 1 (n = 3) Ex. 2 (n = 3) Ex. 3 (n = 3) time [h] Amount SD Amount SD Amount SD 3 66 4 n.d. n.d. 110 11 6 205 13 n.d. n.d. 333 29 8 324 21 n.d. n.d. 482 38 24 991 39 n.d. n.d. 1158 44 Cumulative amount permeated with SD [μg/cm.sup.2] Elapsed Ex. 4 (n = 3) Ex. 5 (n = 3) Comp. Ex. 1 (n = 3) time [h] Amount SD Amount SD Amount SD 3 80 11 69 1 81 37 6 259 21 245 9 278 127 8 386 25 379 13 418 175 24 1034 12 1098 65 1098 178

Example 7

Stability

[0242] The stability of the TTS prepared according to Comparative Example 1 and Examples 1 to 5 was determined with regard to different parameters, namely the adhesion force, the peel force, the rivastigmine content and the in vitro release.

[0243] The respective measurements were performed after preparation of the TTS (initial).

[0244] Subsequently, the TTS were stored at different storage conditions and the respective measurements were repeated after 3 months and after 12 months.

[0245] The storage conditions were either 25° C. and 60% relative humidity (25° C./60% RH), or 30° C. and 75% relative humidity (30° C./75% RH), or 40° C. and 75% relative humidity (40° C./75% RH).

[0246] Measurements were repeated after 3 months (25° C./60% RH and 40° C./75% RH) and after 12 months (25° C./60% RH, 30° C./75% RH and 40° C./75% RH). For Examples 1 and 3, no measurements after 12 months were performed.

Example 7A

Measurement of the Adhesion Force and the Peel Force

[0247] The adhesion force and the peel force of the TTS prepared according to Comparative Example 1 and Examples 1 to 5 were determined.

[0248] Adhesion force tests were performed with the TTS using a tensile strength testing machine. Prior testing the samples were equilibrated 24 hours under controlled conditions at approx. room temperature (23±2° C.) and approx. 50% rh (relative humidity). The first millimeters of the abhesively equipped foil was pulled off and a splicing tape is applied to the opened adhesive side. Then, the abhesively foil was totally removed and the TTS was placed with the adhesive surface in longitudinal direction onto the center of the cleaned testing plate (aluminum or stainless steel). The testing plate was fixed to the lower clamp of the tensile strength machine. The machine was adjusted to zero, the splicing tape was gripped into the upper clamp of the machine. The pull angle was set to 90° . After measurement of the adhesion force of three samples, the mean value of the adhesion force was calculated. The measurement value is based on units “N/TTS” [N/TTS].

[0249] Peel force test were performed with the TTS using a tensile strength testing machine. Prior testing the samples were equilibrated 24 hours under controlled conditions at approx. room temperature (23±2° C.) and approx. 50% rh (relative humidity). Further, the samples were cut into pieces with a fixed width of 25 mm and a suitable length. The first millimeters of the abhesively equipped foil was pulled off and a splicing tape is applied to the opened adhesive side. Then, the abhesively foil was totally removed and the sample was placed with the adhesive surface in longitudinal direction onto the center of the cleaned testing plate (aluminum or stainless steel). The testing plate was fixed to the lower clamp of the tensile strength machine. The machine was adjusted to zero, the splicing tape was gripped into the upper clamp of the machine. The pull angle was set to 90° and the peel off velocity was 150 mm/min. After measurement of the peel force of three samples, the mean value of the peel force was calculated. The measurement value is based on units “cN/TTS” [cN/TTS].

[0250] The TTS were stored at different storage conditions as detailed above and measurements were repeated after 3 months and after 12 months.

[0251] The results are shown in Tables 7.1 to 7.6. The intial adhesion force and the initial peel force after production, respectively, of Comparative Example 1 and Examples 1 to 5 are shown in FIGS. 2 and 3.

TABLE-US-00008 TABLE 7.1 30° C./ 25° C./60% RH 75% RH 40° C./75% RH 3 12 12 3 12 Ex. 1 initial months months months months months Adhesion Test Test n.d. n.d. Test n.d. force method method method [N/TTS] not not not suitable suitable suitable Peel 46 48 n.d. n.d. 47 n.d. force [cN/TTS]

TABLE-US-00009 TABLE 7.2 25° C./60% RH 30° C./75% RH 40° C./75% RH 3 12 12 3 12 Ex. 2 initial months months months months months Adhesion 24 21.9 24 25.5 Partial Partial force adhesive adhesive [N/TTS] failure failure Peel 24 30 35 32 29 29 force [cN/TTS]

TABLE-US-00010 TABLE 7.3 25° C./60% RH 30° C./75% RH 40° C./75% RH 3 12 12 3 12 Ex. 3 initial months months months months months Adhesion 12.7 13.2 n.d. n.d. 17.2 n.d. force [N/TTS] Peel 27 30 n.d. n.d. 26 n.d. force [cN/TTS]

TABLE-US-00011 TABLE 7.4 25° C./60% RH 30° C./ 40° C./75% RH 3 12 75% RH 3 12 Ex. 4 initial months months 12 months months months Adhesion 16.4 18.3 17.3 Partial Partial Partial force adhesive adhesive adhesive [N/TTS] failure failure failure Peel 28 30 34 34 33 31 force [cN/TTS]

TABLE-US-00012 TABLE 7.5 25° C./60% RH 30° C./ 3 12 75% RH 40° C./75% RH Ex. 5 initial months months 12 months 3 months 12 months Adhesion 8.9 9 9.2 9.1 8.9 10.6 force [N/TTS] Peel 19 23 29 28 23 24 force [cN/TTS]

TABLE-US-00013 TABLE 7.6 30° C./ 40° C./75% RH Comp. 25° C./60% RH 75% RH 3 12 Ex. 1 initial 3 months 12 months 12 months months months Adhesion 21.1 16.8 14.8 11.7 16.5 9.2 force [N/TTS] Peel force 46 98 139 212 157 435 [cN/TTS]

Example 7B

Measurement of the Rivastigmine Content

[0252] The rivastigmine content of the TTS prepared according to Comparative Example 1 and

[0253] Examples 1 to 5 was determined by using a validated HPLC method (column: stainless steel column 150 mm×4.6 mm internal diameter, 5 μm particle size, C8 phase, e.g. YMC basic (Fa. YMC); column temperature: 30° C.; mobile phase: Acetonitrile/0.1 M KH.sub.2PO.sub.4/TEA 18:82:0.1 (v/v/v); flow rate: 1.2 ml/min; injection volume: 10 μL; Detection: UV at 264 nm, stop time: 8 min).

[0254] The results are shown in Tables 7.7 to 7.12.

TABLE-US-00014 TABLE 7.7 25° C./60% RH 30° C./ 40° C./75% RH 3 12 75% RH 3 12 Ex. 1 initial months months 12 months months months Rivastigmine 66.7 ± 97.2 ± 1.5 n.d. n.d. 94.1 ± n.d. content [% 1.5 5.9 of label claim]

TABLE-US-00015 TABLE 7.8 25° C./60% RH 30° C./ 40° C./75% RH 3 12 75% RH 3 12 Ex. 2 initial months months 12 months months months Rivastigmine 98.8 ± 97.3 ± 98.2 ± 100.3 ± 1.7 92.9 ± 100.4 ± 1.2 content [% 0.6 1.8 5.6 6.9 of label claim]

TABLE-US-00016 TABLE 7.9 25° C./60% RH 30° C./ 40° C./75% RH 3 12 75% RH 3 12 Ex. 3 initial months months 12 months months months Rivastigmine 99.8 ± 97.1 ± n.d. n.d. 96.0 ± n.d. content [% 1.2 3.0 1.8 of label claim]

TABLE-US-00017 TABLE 7.10 25° C./60% RH 30° C./ 40° C./75% RH 3 12 75% RH 3 12 Ex. 4 initial months months 12 months months months Rivastigmine 98.5 ± 94.2 ± 101.3 ± 98.1 ± 1.6 95.9 ± 96.2 ± 1.6 content [% 1.1 4.3 3.3 1.0 of label claim]

TABLE-US-00018 TABLE 7.11 25° C./60% RH 30° C./ 40° C./75% RH 3 12 75% RH 3 12 Ex. 5 initial months months 12 months months months Rivastigmine 98.9 ± 95.0 ± 98.5 ± 98.9 ± 0.5 96.2 ± 97.8 ± content [% 1.1 2.1 2.4 1.6 1.3 of label claim]

TABLE-US-00019 TABLE 7.12 25° C./60% RH 30° C./ 40° C./75% RH 3 12 75% RH 3 12 Comp. Ex. 1 initial months months 12 months months months Rivastigmine 100.2 ± 95.8 ± 99.2 ± 95.7 ± 2.5 91.5 ± 94.0 ± content [% 2.4 2.6 2.2 2.6 1.3 of label claim]

Example 7C

[0255] Measurement of the Rivastigmine in vitro Release Rate

[0256] The rivastigmine in vitro release rate from the TTS prepared according to Comparative Example 1 and Examples 1 to 5 was determined by experiments using the rotating cylinder apparatus of the Ph Eur/USP. The back of the TTS is affixed to the cylinder element using double sided adhesive tape. Following removal of the release liner, the cylinder is lowered into the dissolution medium (500 ml, degassed 0.9% sodium chloride solution at 32° C.) and rotated at 50 rpm. At 0.5, 2, 4, 7 and 24 hours, 4 ml samples are removed and analyzed using a validated HPLC method (column: Stainless steel column, 150mm×3.9mm I.D. packed with C18-Phase (e.g. Novapak C18, 4μm particle size, Waters) or equivalent column, column temperature: 20-25° C.; mobile phase: Acetonitrile/Water 20:80 (v/v) +0.35mL TEA per 100mL, pH 3.5; adjust the pH with phosphoric acid (85%), if necessary; flow rate: 1.0 ml/min; pressure: approx. 100 bar; injection volume: 20 μL; Detection: UV, 210 nm, stop time: 6 min).

[0257] The results are shown in Tables 7.13 to 7.18. The initial (after production) rivastigmine in vitro release rate over 24 hours from Comparative Example 1 and Examples 1 to 5 is shown in FIG. 4.

TABLE-US-00020 TABLE 7.13 Rivastigmine in vitro release rate with SD [% of label claim]-initial Elapsed Ex. 1 (n = 3) Ex. 2 (n = 3) Ex. 3 (n = 3) time [h] Amount SD Amount SD Amount SD 0.5 8.0 0.0 8.0 0.0 17.0 0.0 2 17.3 0.6 18.7 0.6 35.3 0.6 4 28.0 2.0 29.0 1.0 50.0 1.0 7 38.7 1.5 41.7 0.6 63.0 1.0 24 68.7 1.5 70.7 1.5 83.0 1.0 Elapsed Ex. 4 (n = 3) Ex. 5 (n = 3) Comp. Ex. 1 (n = 3) time [h] Amount SD Amount SD Amount SD 0.5 12.0 0.0 20.0 0.0 33.3 0.6 2 27.0 1.0 39.3 0.6 65.0 0.0 4 41.3 1.5 55.0 1.0 76.7 0.6 7 55.0 1.0 68.0 1.0 84.0 1.0 24 78.7 1.5 85.3 1.5 93.0 1.0

TABLE-US-00021 TABLE 7.14 Rivastigmine in vitro release rate with SD [% of label claim]- after storage for 3 months at 25° C./60% RH Elapsed Ex. 1 (n = 3) Ex. 2 (n = 3) Ex. 3 (n = 3) time [h] Amount SD Amount SD Amount SD 0.5 7.7 0.6 8.0 0.0 18.7 0.6 2 17.0 1.0 18.3 0.6 36.0 0.0 4 26.7 1.5 28.3 0.6 49.7 0.6 7 37.3 2.1 39.7 1.5 61.7 0.6 24 55.3 15.9 67.7 1.5 78.7 0.6 Elapsed Ex. 4 (n = 3) Ex. 5 (n = 3) Comp. Ex. 1 (n = 3) time [h] Amount SD Amount SD Amount SD 0.5 12.0 0.0 19.7 0.6 31.3 2.1 2 27.3 0.6 38.7 0.6 58.7 4.2 4 41.0 1.0 53.0 1.0 70.3 3.1 7 54.3 0.6 64.7 1.5 77.7 2.5 24 76.3 0.6 80.7 1.5 87.7 1.5

TABLE-US-00022 TABLE 7.15 Rivastigmine in vitro release rate with SD [% of label claim]- after storage for 12 months at 25° C./60% RH Elapsed Ex. 1 (n = 3) Ex. 2 (n = 3) Ex. 3 (n = 3) time [h] Amount SD Amount SD Amount SD 0.5 n.d. n.d. 8.0 0.0 n.d. n.d. 2 n.d. n.d. 17.7 0.6 n.d. n.d. 4 n.d. n.d. 27.7 0.6 n.d. n.d. 7 n.d. n.d. 38.7 0.6 n.d. n.d. 24 n.d. n.d. 65.7 0.6 n.d. n.d. Elapsed Ex. 4 (n = 3) Ex. 5 (n = 3) Comp. Ex. 1 (n = 3) time [h] Amount SD Amount SD Amount SD 0.5 11.3 0.6 17.3 0.6 29.0 3.6 2 25.3 0.6 33.0 1.0 53.7 6.1 4 38.0 1.0 46.3 1.5 64.0 5.6 7 50.3 1.5 57.7 1.5 72.0 4.6 24 73.0 1.0 75.7 1.2 82.3 3.5

TABLE-US-00023 TABLE 7.16 Rivastigmine in vitro release rate with SD [% of label claim]- after storage for 12 months at 30° C./75% RH Elapsed Ex. 1 (n = 3) Ex. 2 (n = 3) Ex. 3 (n = 3) time [h] Amount SD Amount SD Amount SD 0.5 n.d. n.d. 8.3 0.6 n.d. n.d. 2 n.d. n.d. 17.7 0.0 n.d. n.d. 4 n.d. n.d. 27.0 1.0 n.d. n.d. 7 n.d. n.d. 38.0 1.0 n.d. n.d. 24 n.d. n.d. 64.0 1.0 n.d. n.d. Elapsed Ex. 4 (n = 3) Ex. 5 (n = 3) Comp. Ex. 1 (n = 3) time [h] Amount SD Amount SD Amount SD 0.5 11.0 0.0 14.7 0.6 27.3 2.1 2 24.3 0.6 24.0 3.0 50.7 4.2 4 36.0 0.0 33.3 5.0 61.7 3.5 7 47.7 0.6 43.0 6.6 68.7 2.5 24 70.0 0.0 64.3 5.7 80.0 1.0

TABLE-US-00024 TABLE 7.17 Rivastigmine in vitro release rate with SD [% of label claim]- after storage for 3 months at 40° C./75% RH Elapsed Ex. 1 (n = 3) Ex. 2 (n = 3) Ex. 3 (n = 3) time [h] Amount SD Amount SD Amount SD 0.5 8.0 0.0 8.3 0.6 15.3 0.6 2 17.0 0.0 18.0 0.0 25.0 1.0 4 25.3 0.6 27.3 0.6 34.0 2.0 7 35.0 1.0 38.3 0.6 43.7 2.1 24 61.7 1.5 65.0 1.0 66.0 2.0 Elapsed Ex. 4 (n = 3) Ex. 5 (n = 3) Comp. Ex. 1 (n = 3) time [h] Amount SD Amount SD Amount SD 0.5 11.7 0.6 14.3 0.6 30.3 0.6 2 22.3 2.5 21.3 1.5 56.3 0.6 4 31.0 5.0 28.0 2.0 67.0 1.0 7 40.7 7.0 36.0 3.0 73.0 1.0 24 63.3 7.5 58.0 4.0 82.7 1.5

TABLE-US-00025 TABLE 7.18 Rivastigmine in vitro release rate with SD [% of label claim]- after storage for 12 months at 40° C./75% RH Elapsed Ex. 1 (n = 3) Ex. 2 (n = 3) Ex. 3 (n = 3) time [h] Amount SD Amount SD Amount SD 0.5 n.d. n.d. 8.7 0.6 n.d. n.d. 2 n.d. n.d. 17.7 0.6 n.d. n.d. 4 n.d. n.d. 26.0 1.0 n.d. n.d. 7 n.d. n.d. 35.3 1.2 n.d. n.d. 24 n.d. n.d. 59.7 1.5 n.d. n.d. Elapsed Ex. 4 (n = 3) Ex. 5 (n = 3) Comp. Ex. 1 (n = 3) time [h] Amount SD Amount SD Amount SD 0.5 11.3 0.6 13.3 0.6 23.7 0.6 2 20.0 2.0 19.0 1.0 45.0 1.0 4 26.0 3.0 23.7 1.5 56.0 1.0 7 33.0 5.0 29.7 2.5 63.0 1.0 24 52.0 7.5 47.3 5.0 75.7 0.6

The Invention Relates in Particular to the Following Further Items:

[0258] 1. Transdermal therapeutic system for the transdermal administration of rivastigmine comprising a rivastigmine-containing layer structure, said rivastigmine-containing layer structure comprising:

[0259] A) a backing layer;

[0260] B) a rivastigmine-containing layer comprising at least one acrylic polymer; and

[0261] C) a skin contact layer comprising at least one styrene-isoprene-styrene block copolymer and at least one tackifier. [0262] 2. Transdermal therapeutic system according to item 1, wherein the rivastigmine-containing layer is a rivastigmine-containing matrix layer comprising:

[0263] i) rivastigmine; and

[0264] ii) the acrylic polymer. [0265] 3. Transdermal therapeutic system according to item 1 or 2, wherein the rivastigmine-containing layer structure contains a therapeutically effective amount of rivastigmine. [0266] 4. Transdermal therapeutic system according to any one of items 1 to 3, wherein the rivastigmine in the rivastigmine-containing layer structure is present in the form of the free base. [0267] 5. Transdermal therapeutic system according to any one of items 1 to 4, wherein the amount of rivastigmine contained in the rivastigmine-containing layer structure ranges from 0.5 to 5 mg/cm.sup.2, preferably from 1 to 3 mg/cm.sup.2. [0268] 6. Transdermal therapeutic system according to any one of items 1 to 5, wherein the rivastigmine-containing layer comprises rivastigmine in an amount of from 20 to 40%, preferably from 25 to 35%, most preferably in an amount of 30% by weight based on the total weight of the rivastigmine-containing layer. [0269] 7. Transdermal therapeutic system according to any one of items 1 to 6, wherein the acrylic polymer is an acrylic pressure-sensitive adhesive. [0270] 8. Transdermal therapeutic system according to any one of items 1 to 7, wherein the amount of the acrylic polymer ranges from 5 to 40%, preferably from 8 to 35% by weight based on the total weight of the rivastigmine-containing layer. [0271] 9. Transdermal therapeutic system according to any one of items 1 to 8, wherein the acrylic polymer is obtainable from one or more monomers selected from acrylic acid, butylacrylate, 2-ethylhexylacrylate, glycidylmethacrylate, 2-hydroxyethylacrylate, methylacrylate, methylmethacrylate, t-octylacrylamide, and vinylacetate, preferably from one or more monomers selected from ethylhexylacrylate, glycidylmethacrylate, 2-hydroxyethylacrylate, and vinylacetate. [0272] 10. Transdermal therapeutic system according to any one of items 1 to 9, wherein the acrylic polymer is a COOH-functionalized acrylic polymer, preferably a COOH-functionalized acrylic polymer obtainable from one or more monomers selected from acrylic acid, 2-ethylhexylacrylate, glycidylmethacrylate and methylacrylate, which may be provided as a solution in ethyl acetate and hexane. [0273] 11. Transdermal therapeutic system according to any one of items 1 to 10, wherein the rivastigmine-containing layer does not comprise a permeation enhancer or solubilizer. [0274] 12. Transdermal therapeutic system according to any one of items 1 to 11, wherein the at least one styrene-isoprene-styrene block copolymer comprises styrene blocks and isoprene blocks in a ratio of from 10:90 (%) to 30:70 (%), preferably in a ratio of 15:85 (%) or 22:78 (%). [0275] 13. Transdermal therapeutic system according to any one of items 1 to 12, wherein the at least one styrene-isoprene-styrene block copolymer is obtainable by polymerisation of three blocks of polystyrene, polyisoprene and polystyrene. [0276] 14. Transdermal therapeutic system according to any one of items 1 to 13, wherein the at least one tackifier is an alicyclic saturated hydrocarbon resin, or a hydrogenated rosin glycerol ester, or paraffinum liquidum, or a mixture thereof. [0277] 15. Transdermal therapeutic system according to any one of items 1 to 14, wherein the at least one tackifier is a mixture comprising an alicyclic saturated hydrocarbon resin and paraffinum liquidum. [0278] 16. Transdermal therapeutic system according to any one of items 1 to 15, wherein the at least one tackifier is a mixture comprising a hydrogenated rosin glycerol ester and paraffinum liquidum. [0279] 17. Transdermal therapeutic system according to item 14 or 15, wherein the alicyclic saturated hydrocarbon resin is obtainable from polymerisation of an unsaturated hydrocarbon obtainable prepared by the decomposition of petroleum naphtha at elevated temperatures. [0280] 18. Transdermal therapeutic system according to item 14 or 16, wherein the hydrogenated rosin glycerol ester is a solid resin obtainable from the hydrogenation of rosin, followed by esterification with glycerin. [0281] 19. Transdermal therapeutic system according to any one of items 1 to 18, wherein the amount of tackifier contained in the skin contact layer ranges from 20 to 80%, preferably from 35 to 65%. [0282] 20. Transdermal therapeutic system according any one of items 1 to 19, wherein the ratio of the amount of styrene-isoprene-styrene block copolymer(s) to the amount of tackifier(s) is between 60:40 (w/w) to 40:60 (w/w) based on the total weight of the skin contact layer, preferably wherein the ratio of the amount of styrene-isoprene-styrene block copolymer(s) to the amount of tackifier(s) is 50:50 (w/w) based on the total weight of the skin contact layer. [0283] 21. Transdermal therapeutic system according to any one of items 1 to 20, wherein the at least one styrene-isoprene-styrene block copolymer and the at least one tackifier are present in the skin contact layer in an overall amount of at least 90% by weight, preferably in an overall amount of at least 99% by weight based on the total weight of the skin contact layer. [0284] 22. Transdermal therapeutic system according to any one of items 1 to 21, wherein the area weight of the skin contact layer ranges from 5 to 60 g/m.sup.2, preferably from 20 to 40 g/m.sup.2. [0285] 23. Transdermal therapeutic system according to any one of items 1 to 22, wherein the area weight of the rivastigmine-containing layer ranges from 40 to 250 g/m.sup.2, preferably from 50 to 200 g/m.sup.2. [0286] 24. Transdermal therapeutic system according to any one of items 1 to 23, wherein the area of release ranges from 1 to 30 cm.sup.2, preferably from 2 to 22 cm.sup.2. [0287] 25. Transdermal therapeutic system according to any one of items 1 to 24, wherein the transdermal therapeutic system provides by transdermal delivery a mean release rate of from 150 to 3500 μg/cm.sup.2*day, preferably from 400 to 2000 μg/cm.sup.2*day rivastigmine over about 24 hours of administration. [0288] 26. Transdermal therapeutic system according to any one of items 1 to 25, providing a cumulative permeated amount of rivastigmine as measured in a Franz diffusion cell with an EVA membrane of about 300 to 1200 μg/cm.sup.2 over a time period of about 24 hours. [0289] 27. Transdermal therapeutic system according to any one of items 1 to 26 for use in a method of treating a human patient, preferably for use in a method of preventing, treating, or delaying of progression of Alzheimer's disease, dementia associated with Parkinson's disease, and/or symptoms of traumatic brain injury. [0290] 28. Transdermal therapeutic system according to any one of items 1 to 27 for use in a method of treating a human patient, preferably for use in a method of treating mild to moderate dementia caused by Alzheimer's or Parkinson's disease. [0291] 29. Transdermal therapeutic system for use according to item 27 or 28, wherein the transdermal therapeutic system is applied to the skin of the patient for a dosing interval of at least 24 hours, preferably about 24 hours. [0292] 30. Method of treating a human patient, in particular preventing, treating, or delaying of progression of Alzheimer's disease, dementia associated with Parkinson's disease, and/or symptoms of traumatic brain injury, by applying a transdermal therapeutic system as defined in any one of items 1 to 27 to the skin of the patient. [0293] 31. Method of treating a human patient, in particular treating a mild to moderate dementia caused by Alzheimer's and Parkinson's disease, by applying a transdermal therapeutic system as defined in any one of items 1 to 28 to the skin of the patient. [0294] 32. Method of treating a human patient according to item 30 or 31, wherein the transdermal therapeutic system is applied to the skin of the patient for a dosing interval of at least 24 hours, preferably about 24 hours. [0295] 33. A process for manufacturing a transdermal therapeutic system according to any one of items 1 to 29 comprising the steps of: [0296] 1) providing a rivastigmine-containing coating composition by combining at least the components [0297] i) rivastigmine; and [0298] ii) at least one acrylic polymer; [0299] 2) coating the rivastigmine-containing coating composition onto a film in an amount to provide the desired area weight, [0300] 3) drying the coated rivastigmine-containing coating composition to provide the rivastigmine-containing layer, [0301] 4) providing an additional coating composition for an additional skin contact layer by combining at least the components [0302] a) at least one styrene-isoprene-styrene block copolymer; and [0303] b) at least one tackifier; [0304] 5) coating and drying the additional coating composition according to steps 2 and 3, wherein the film is a release liner, [0305] 6) laminating the adhesive side of the skin contact layer onto the adhesive side of the rivastigmine-containing layer to provide a rivastigmine-containing layer structure with the desired area of release, [0306] 7) punching the individual systems from the rivastigmine-containing layer structure, [0307] 8) optionally adhering to the individual systems a rivastigmine-free self-adhesive layer structure comprising also a backing layer and a rivastigmine-free pressure-sensitive adhesive layer and which is larger than the individual systems of rivastigmine-containing self-adhesive layer structure. [0308] 34. The method of manufacture according to item 33, wherein the film in step 2) is a release liner, wherein the rivastigmine-containing layer is laminated after step 3) to a backing layer, and wherein the release liner of step 2) is removed before step 6). [0309] 35. Process for manufacturing a rivastigmine-containing layer according to items 33 or 34, wherein the acrylic polymer is provided as a solution, wherein the solvent is ethyl acetate or n-heptane. [0310] 36. Transdermal therapeutic system obtainable by a process in accordance with any one of items 33 to 35.