TRANSDERMAL THERAPEUTIC SYSTEM COMPRISING AN ACTIVE AGENT-CONTAINING LAYER COMPRISING AN ACRYLIC POLYMER AND A SKIN CONTACT LAYER COMPRISING A SILICONE GEL ADHESIVE

Abstract

The present invention relates to a transdermal therapeutic system for the transdermal administration of an active agent comprising an active agent-containing layer structure, said active agent-containing layer structure comprising: A) a backing layer; B) an active agent-containing layer comprising at least one acrylic polymer; C) a skin contact layer; and wherein the skin contact layer is an adhesive layer comprising a silicone gel adhesive.

Claims

1. Transdermal therapeutic system for the transdermal administration of an active agent comprising an active agent-containing layer structure, said active agent-containing layer structure comprising: A) a backing layer; B) an active agent-containing layer comprising at least one acrylic polymer; C) a skin contact layer; and an intermediate layer between the active agent-containing layer and the skin contact layer; wherein the skin contact layer is an adhesive layer comprising a silicone gel adhesive.

2. Transdermal therapeutic system according to claim 1, wherein the intermediate layer is a membrane which is at least semipermeable for the active agent, wherein preferably the membrane is selected from the group consisting of polyethylene membranes, polyurethane coated polyethylene terephthalate/polyethylene membranes, polyurethane membranes, and ethylene vinyl acetate (EVA) membranes.

3. Transdermal therapeutic system according to claim 1, wherein the intermediate layer is a pressure-sensitive adhesive layer comprising a silicone-based polymer, wherein the silicone-based polymer is obtainable by polycondensation of silanol endblocked polydimethylsiloxane with a silicate resin.

4. Transdermal therapeutic system according to any one of claims 1 to 3, wherein the silicone gel adhesive is obtainable by reacting a gel producing composition comprising (i) at least one alkenyl-substituted polydiorganosiloxane, (ii) at least one organosiloxane, which contains silicone-bonded hydrogen atoms, and (iii) at least one catalyst for the reaction of the SiH groups with the Si-alkenyl groups.

5. Transdermal therapeutic system according to any one of claims 1 to 4, wherein the silicone gel adhesive is obtainable by reacting a gel producing composition comprising (i) a copolymer of vinylmethylsiloxane and dimethylsiloxane with (ii) methylhydrogen polysiloxane with trimethylsilyl endgroups in the presence of (iii) a platinum catalyst.

6. Transdermal therapeutic system according to any one of claims 1 to 5, wherein the silicone gel adhesive is a silicate resin-reinforced silicone gel adhesive that contains from about 2 to about 45% by weight, preferably from about 20 to about 30% by weight of at least one hydroxyl substituted silicate resin.

7. Transdermal therapeutic system according to any one of claims 1 to 6, wherein the at least one acrylate polymer is obtainable from one or more monomers selected from acrylic acid, butylacrylate, 2-ethylhexylacrylate, glycidylmethacrylate, 2-hydroxyethylacrylate, methylacrylate, methylmethacrylate, butylmethacrylate t-octylacrylamide, and vinylacetate.

8. Transdermal therapeutic system according to any one of claims 1 to 7, wherein the active agent-containing layer is an active agent-containing matrix layer comprising: the active agent; and at least one acrylic polymer.

9. Transdermal therapeutic system according to any one of claims 1 to 8, wherein the active agent is rivastigmine.

10. Transdermal therapeutic system according to claim 9, wherein the amount of rivastigmine contained in the active agent-containing layer structure ranges from 0.5 to 5 mg/cm.sup.2, preferably from 1 to 3 mg/cm.sup.2.

11. Transdermal therapeutic system according to claim 9 or 10, wherein the active agent is present in the active agent-containing layer in an amount of from 5 to 40% by weight, preferably from 20 to 35% by weight, based on the total weight of the active agent-containing layer.

12. Transdermal therapeutic system according to any one of claims 1 to 11, the active agent-containing layer has an area weight of from 30 to 250 g/m.sup.2, preferably from 40 to 120 g/m.sup.2.

13. Transdermal therapeutic system according to any one of claims 1 to 12, for use in a method of treatment, wherein the transdermal therapeutic system is preferably applied to the skin of the patient for at least 24 hours.

14. A process for manufacturing an active-agent containing layer structure for use in a transdermal therapeutic system according to any one of claims 1 to 13 comprising the steps of: 1.1) coating a coating composition comprising an active agent; and at least one acrylic polymer on a first foil; 1.2) drying the coated coating composition to form the active agent-containing layer; 1.3) laminating the open side of the active agent-containing layer with a backing layer; 1.4) removing the first foil from the active agent-containing layer and laminating the open side with the open side of the intermediate layer; 2.1) coating the gel producing composition comprising (i) at least one alkenyl-substituted polydiorganosiloxane, (ii) at least one organosiloxane, which contains silicone-bonded hydrogen atoms, and (iii) at least one catalyst for the reaction of the SiH groups with the Si-alkenyl groups, on a second foil; 2.2) crosslinking the gel producing composition at a temperature of from 50° C. to 150° C. or by applying UV light to form the skin contact layer; 2.3) laminating the skin contact layer with a release liner; 3.1) removing the foil from the skin contact layer; and 3.2) laminating the open side of the intermediate layer onto the open side of the skin contact layer to obtain an active agent-containing layer structure.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0110] FIG. 1 depicts the rivastigmine cumulative permeated amounts of TTS prepared according to Examples 2A-G as well as Reference Example 1 (Exelon®).

DETAILED DESCRIPTION

TTS Structure

[0111] The present invention relates to a transdermal therapeutic system for the transdermal administration of an active agent comprising an active agent-containing layer structure, said active agent-containing layer structure comprising:

[0112] A) a backing layer;

[0113] B) an active agent-containing layer comprising at least one acrylic polymer;

[0114] C) a skin contact layer; and

an intermediate layer between the active agent-containing layer and the skin contact layer; wherein the skin contact layer is an adhesive layer comprising a silicone gel adhesive.

[0115] Preferably, the aforementioned layers of the TTS according to the invention are directly attached to each other, i.e. the backing layer is directly attached to the active agent-containing layer, which is on the other side directly attached to the intermediate layer. Further, the other side of the intermediate layer is directly attached to the skin contact layer. In other words, the TTS according to the present invention comprises its layers in the following order: (i) backing layer, (ii) active agent-containing layer, (iii) intermediate layer, and (iv) skin contact layer. Further, a release liner may optionally be present on the skin contact layer.

[0116] The TTS according to the present invention may be a matrix-type TTS or a reservoir-type TTS. Thus, the active agent-containing layer may preferably be a matrix layer or a reservoir layer. Preferably, the TTS according to the present invention is a matrix-type TTS, wherein the active agent is homogeneously dissolved and/or dispersed within a polymeric carrier, i.e. the matrix, which forms the together with the active agent and optionally further ingredients a matrix layer. Accordingly, it is preferred that the active agent-containing layer is an active agent-containing matrix layer. Thus, in a preferred embodiment of the TTS according to the present invention, the active agent-containing layer is an active agent-containing matrix layer comprising [0117] the active agent; and [0118] at least one acrylic polymer.

[0119] Thus, in a preferred embodiment, the present invention relates to a transdermal therapeutic system for the transdermal administration of an active agent comprising an active agent-containing layer structure, said active agent-containing layer structure comprising

[0120] A) a backing layer;

[0121] B) an active agent-containing matrix layer comprising [0122] an active agent; and [0123] at least one acrylic polymer;

[0124] C) a skin contact layer; and

an intermediate layer between the active agent-containing layer and the skin contact layer; wherein the skin contact layer is an adhesive layer comprising a silicone gel adhesive.

[0125] The at least one acrylic polymer is a polymer obtainable from one or more monomers selected from acrylic acid, butylacrylate, 2-ethylhexylacrylate, glycidylmethacrylate, 2-hydroxyethylacrylate, methylacrylate, methylmethacrylate, butylmethacrylate, t-octylacrylamide, and vinylacetate. It is preferably a thermoplastic polymer, which is applied by hot-melt or a solvent based process and typically does not undergo further curing to solidify.

[0126] Thus, in a more preferred embodiment, the present invention relates to a transdermal therapeutic system for the transdermal administration of an active agent comprising an active agent-containing layer structure, said active agent-containing layer structure comprising

[0127] A) a backing layer;

[0128] B) an active agent-containing matrix layer comprising [0129] an active agent; and [0130] at least one acrylic polymer obtainable from one or more monomers selected from acrylic acid, butylacrylate, 2-ethylhexylacrylate, glycidylmethacrylate, 2-hydroxyethylacrylate, methylacrylate, methylmethacrylate, butylmethacrylate, t-octylacrylamide, and vinylacetate;

[0131] C) a skin contact layer; and

an intermediate layer between the active agent-containing layer and the skin contact layer; wherein the skin contact layer is an adhesive layer comprising a silicone gel adhesive.

[0132] The intermediate layer of the TTS according to the present invention may be a membrane or a polymer layer, in particular a pressure sensitive adhesive layer comprising a silicone-based polymer obtainable by polycondensation of silanol endblocked polydimethylsiloxane with a silicate resin. The intermediate layer is positioned between the active agent-containing layer and the skin contact layer. Thus, one side of the intermediate layer is preferably directly attached to the active agent-containing layer, while the other side is preferably directly attached to the skin contact layer. The intermediate layer improves the stability of the TTS by holding the active agent-containing layer and the skin contact layer together. Typically, the intermediate layer is manufactured active-free. However, due to the concentration gradient, the active agent may migrate from the active agent-containing layer to the intermediate layer over time, until an equilibrium is reached.

[0133] Thus, in a preferred embodiment, the present invention relates to a transdermal therapeutic system for the transdermal administration of an active agent comprising an active agent-containing layer structure, said active agent-containing layer structure comprising:

[0134] A) a backing layer;

[0135] B) an active agent-containing layer comprising at least one acrylic polymer;

[0136] C) a skin contact layer; and

[0137] In another preferred embodiment, the present invention relates to a transdermal therapeutic system for the transdermal administration of an active agent comprising an active agent-containing layer structure, said active agent-containing layer structure comprising:

[0138] A) a backing layer;

[0139] B) an active agent-containing matrix layer comprising [0140] an active agent; and [0141] at least one acrylic polymer;

[0142] C) a skin contact layer; and

[0143] In a more preferred embodiment, the present invention relates to a transdermal therapeutic system for the transdermal administration of an active agent comprising an active agent-containing layer structure, said active agent-containing layer structure comprising:

[0144] A) a backing layer;

[0145] B) an active agent-containing matrix layer comprising [0146] an active agent; and [0147] at least one acrylic polymer obtainable from one or more monomers selected from acrylic acid, butylacrylate, 2-ethylhexylacrylate, glycidylmethacrylate, 2-hydroxyethylacrylate, methylacrylate, methylmethacrylate, butylmethacrylate, t-octylacrylamide, and vinylacetate;

[0148] C) a skin contact layer; and

[0149] The TTS according to the present invention comprises a skin contact layer. The skin contact layer is an adhesive layer comprising a silicone gel adhesive, which is preferably directly attached to the intermediate layer, which itself is preferably directly attached to the active agent-containing layer. The silicone gel adhesive in the skin contact layer provides for the adhesive properties, while at the same time reducing the problem of skin irritation. Typically, the skin contact layer is manufactured active-free. However, due to the concentration gradient, the active agent may migrate from the active agent-containing layer to the skin contact layer over time, until an equilibrium is reached.

[0150] The silicone gel adhesive is an elastic, jelly-like material formed by lightly crosslinking silicone polymers. It may be prepared from a gel producing composition as described further below upon curing. Thus, while the silicone-containing polymer as used in the active agent-containing layer of the TTS of the present invention is preferably a non-curing polymer, i.e. a polymer, which does not undergo a curing reaction to solidify, the silicone gel adhesive forms upon curing of silicones comprising reactive groups such as Si—H reactive groups and aliphatic unsaturated groups, which react with each other in the presence of a hydrosilylation catalyst. Further details in this regard are provided below.

[0151] Thus, in a preferred embodiment, the present invention relates to a transdermal therapeutic system for the transdermal administration of an active agent comprising an active agent-containing layer structure, said active agent-containing layer structure comprising:

[0152] A) a backing layer;

[0153] B) an active agent-containing layer comprising at least one acrylic polymer;

[0154] C) a skin contact layer; and

an intermediate layer between the active agent-containing layer and the skin contact layer; and wherein the skin contact layer is an adhesive layer comprising a silicone gel adhesive;

[0155] and wherein the silicone gel adhesive is obtained from curable silicones comprising reactive groups, in particular Si—H groups and aliphatic unsaturated groups.

[0156] In another preferred embodiment, the present invention relates to a transdermal therapeutic system for the transdermal administration of an active agent comprising an active agent-containing layer structure, said active agent-containing layer structure comprising:

[0157] A) a backing layer;

[0158] B) an active agent-containing matrix layer comprising [0159] an active agent; and [0160] at least one acrylic polymer;

[0161] C) a skin contact layer; and

an intermediate layer between the active agent-containing layer and the skin contact layer; wherein the intermediate layer is a pressure-sensitive adhesive layer comprising a silicone-based polymer;
and wherein the skin contact layer is an adhesive layer comprising a silicone gel adhesive; and wherein the silicone gel adhesive is obtained from curable silicones comprising reactive groups, in particular Si—H groups and aliphatic unsaturated groups.

[0162] In a more preferred embodiment, the present invention relates to a transdermal therapeutic system for the transdermal administration of an active agent comprising an active agent-containing layer structure, said active agent-containing layer structure comprising:

[0163] A) a backing layer;

[0164] B) an active agent-containing matrix layer comprising [0165] an active agent; and [0166] at least one acrylic polymer obtainable from one or more monomers selected from acrylic acid, butylacrylate, 2-ethylhexylacrylate, glycidylmethacrylate, 2-hydroxyethylacrylate, methylacrylate, methylmethacrylate, butylmethacrylate, t-octylacrylamide, and vinylacetate;

[0167] C) a skin contact layer; and

an intermediate layer between the active agent-containing layer and the skin contact layer; wherein the intermediate layer is a pressure-sensitive adhesive layer comprising a silicone-based polymer obtainable by polycondensation of silanol endblocked polydimethylsiloxane with a silicate resin;
and wherein the skin contact layer is an adhesive layer comprising a silicone gel adhesive; and wherein the silicone gel adhesive is obtainable by reacting a gel producing composition comprising (i) a copolymer of vinylmethylsiloxane and dimethylsiloxane with (ii) methylhydrogen polysiloxane with trimethylsilyl endgroups in the presence of (iii) a platinum catalyst.

[0168] It is to be understood that the TTS according to the invention contains a therapeutically effective amount of the active agent. A preferred active agent is rivastigmine. In a preferred embodiment, the active agent is present in the active agent-containing layer in an amount of from 5 to 40% by weight, preferably 20 to 35% by weight, based on the total weight of the active agent-containing layer.

[0169] In a preferred embodiment, the active agent is rivastigmine. Preferably, the amount of rivastigmine contained in the active agent-containing layer structure ranges from 0.5 to 5 mg/cm.sup.2, preferably from 1 to 3 mg/cm.sup.2.

[0170] The area of release of the TTS according to the invention may be from 1 to 30 cm.sup.2, preferably from 2 to 22 cm.sup.2.

[0171] The layer thicknesses and area weights of the active agent-containing layer, the intermediate layer, and the skin contact layer may vary over a broad range. Surprisingly, it has been found that the skin contact layer does not negatively affect the release properties of the TTS even at greater thicknesses of up to 220 μm. Similarly, the intermediate layer may have a thickness of up to 100 μm.

[0172] Thus, in a preferred embodiment, the active agent-containing layer has a thickness of from 50 to 150 μm and/or an area weight of from 30 to 200 g/m.sup.2, preferably from 40 to 120 g/m.sup.2. In another preferred embodiment, the intermediate layer has a thickness of from 20 to 100 μm, preferably from 25 to 55 μm and/or an area weight of from 20 to 80 g/m.sup.2, preferably from 20 to 60 g/m.sup.2. In another preferred embodiment, the skin contact layer has a thickness of from 30 to 220 μm, preferably from 40 to 160 μm and/or an area weight of 20 to 120 g/m.sup.2, preferably from 30 to 90 g/m.sup.2.

[0173] The backing layer is preferably substantially impermeable for the active agent. In a preferred embodiment, the backing layer is occlusive as outlined above.

[0174] 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 active agent-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 active agent. 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, silicone-based polymers, 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.

[0175] The active agent-containing layer structure according to the invention 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.

Active Agent-Containing Layer

[0176] As outlined in more detail above, the TTS according to the present invention comprises an active agent-containing layer structure comprising inter alia an active agent-containing layer, which comprises at least one silicone-containing polymer.

[0177] In a preferred embodiment, the active agent-containing layer comprises a therapeutically affective amount of the active agent. In a particular preferred embodiment, the active agent is present in the active agent-containing layer in an amount of from 5 to 40% by weight, preferably 20 to 35% by weight based on the total weight of the active agent-containing layer. Preferably, the active agent is rivastigmine

[0178] The active agent is preferably homogeneously distributed within the active agent-containing layer. In a preferred embodiment, the active agent-containing layer is therefore an active agent-containing matrix layer.

[0179] In a preferred embodiment, the active agent-containing layer has a thickness of from 50 to 150 μm. In another preferred embodiment, the active agent-containing layer has an area weight of from 30 to 200 g/m.sup.2, preferably from 40 to 120 g/m.sup.2.

[0180] In a preferred embodiment, the acrylic polymer is present in the active agent-containing layer in an amount of from 30 to 90% by weight, preferably 60 to 80% by weight based on the total weight of the active agent-containing layer. It is to be understood that the afore-mentioned amounts refer to the overall amount of acrylic polymers in the active agent-containing layer. Thus, if two different acrylic polymers are present, the overall amount is from 30 to 90% by weight, preferably 60 to 80% by weight based on the total weight of the active agent-containing layer.

[0181] In a preferred embodiment, the at least one acrylate polymer is obtainable from one or more monomers selected from acrylic acid, butylacrylate, 2-ethylhexylacrylate, glycidylmethacrylate, 2-hydroxyethylacrylate, methylacrylate, methylmethacrylate, butylmethacrylate, t-octylacrylamide, and vinylacetate, preferably from one or more monomers selected from acrylic acid, 2-ethylhexylacrylate, glycidylmethacrylate, and methylacrylate. Preferably, the active agent-containing layer comprises two acrylate polymers, of which the first acrylate polymer is a copolymer based on acrylic acid, 2-ethylhexylacrylate, glycidylmethacrylate and methylacrylate, and the second acrylate polymer is a copolymer based on butylmethacrylate and methylmethacrylate. More preferably, the first acrylate polymer is present in an amount of from 10 to 30% by weight based on the total weight of the active agent-containing layer, and the second acrylate polymer is present in an amount of from 40 to 60% by weight based on the total weight of the active agent-containing layer. Particularly preferably, the first acrylate polymer is present in an amount of from 15 to 25% by weight based on the total weight of the active agent-containing layer, and the second acrylate polymer is present in an amount of from 45 to 55% by weight based on the total weight of the active agent-containing layer.

[0182] In another preferred embodiment, the active agent-containing layer further comprises at least one additive. Preferred additives are described further below. Preferably, the at least one additive is a stabilizer selected from tocopherol and ester derivatives thereof. In a particularly preferred embodiment, the active agent-containing layer comprises at least one stabilizer selected from tocopherol and ester derivatives thereof in an amount of from 0.001 to 2.0% by weight, preferably from 0.01 to 1.0% by weight, even more preferably from 0.05 to 0.2% by weight based on the total weight of the active agent-containing layer.

Intermediate Layer

[0183] As outlined in more detail above, the TTS according to the present invention comprises an active agent-containing layer structure comprising inter alia an intermediate layer between the active agent-containing layer and the skin contact layer. The intermediate layer may be a membrane or a polymer layer, preferably a polymer layer, in particular a silicone-based polymer layer.

[0184] In one preferred embodiment, the intermediate layer is a membrane, which is at least semipermeable for the active agent. In another preferred embodiment, the intermediate layer is a membrane selected from the group consisting of polyethylene membranes, polyurethane coated polyethylene terephthalate/polyethylene membranes, polyurethane membranes, and ethylene vinyl acetate (EVA) membranes.

[0185] In another preferred embodiment, the intermediate layer is a pressure-sensitive adhesive layer comprising a silicone-based polymer. In a more preferred embodiment, the silicone-based polymer is obtainable by polycondensation of silanol endblocked polydimethylsiloxane with a silicate resin. In an even more preferred embodiment, the residual silanol functionality of the silicone-based polymer is capped with trimethylsiloxy groups.

[0186] In a preferred embodiment, the intermediate layer is provided free of active agent. However, due to the concentration gradient, the active agent may migrate from the active agent-containing layer to the skin contact layer over time, until an equilibrium is reached.

[0187] The intermediate layer is decisive for the stability of the TTS as it provides a stable connection between the active agent-containing layer and the skin contact layer. Furthermore, the intermediate layer does not negatively affect the transdermal delivery of the active agent.

[0188] In a preferred embodiment, the intermediate layer has a thickness of from 20 to 100 μm, preferably from 25 to 55 μm. In another preferred embodiment, the intermediate layer has an area weight of from 20 to 80 g/m.sup.2, preferably from 20 to 60 g/m.sup.2.

Skin Contact Layer

[0189] As outlined in more detail above, the TTS according to the present invention comprises an active agent-containing layer structure comprising inter alia a skin contact layer, wherein the skin contact layer is an adhesive layer comprising a silicone gel adhesive. The skin contact layer is preferably directly attached to the intermediate layer, which is itself preferably directly attached to the active agent-containing layer.

[0190] The skin contact layer is typically provided free of active agent. However, due to the concentration gradient, the active agent may migrate from the active agent-containing layer to the skin contact layer over time, until an equilibrium is reached.

[0191] The silicone gel adhesive in the skin contact layer is decisive for the adhesive properties as well as the reduction of skin irritation inter alia due to its resiliency. Furthermore, the silicone gel adhesive does not negatively affect the transdermal delivery of the active agent. In a preferred embodiment the skin contact layer comprises the silicone gel adhesive in an amount of at least 95% by weight, preferably at least 99% by weight. Particularly preferably, the skin contact layer essentially consists of the silicone gel adhesive.

[0192] The silicone gel adhesive is an elastic, jelly-like material formed by lightly crosslinking silicone polymers provided as a so-called gel producing composition. The silicone gel adhesives are generally formed from linear or branched silicones having reactive groups thereon. Such reactive groups undergo a crosslinking reaction during curing. Examples of crosslinking reactions include the hydrosilylation reaction in which a silicone having an Si—H reactive group reacts with a silicone having an aliphatic unsaturated reactive group in the presence of a hydrosilylation catalyst. Typically, the silicone gel adhesive is obtainable by reacting a gel producing composition comprising (i) at least one alkenyl-substituted polydiorganosiloxane, (ii) at least one organosiloxane, which contains silicone-bonded hydrogen atoms, and (iii) at least one catalyst for the reaction of the Si—H groups with the Si-alkenyl groups. Preferably, the silicone gel adhesive is obtainable by reacting a gel producing composition comprising (i) a copolymer of vinylmethylsiloxane and dimethylsiloxane with (ii) methylhydrogen polysiloxane with trimethylsilyl endgroups in the presence of (iii) a platinum catalyst. Further details in this regard are provided below.

[0193] In a preferred embodiment, the skin contact layer has a thickness of from 30 to 220 μm, preferably from 40 to 160 μm. In another preferred embodiment, the skin contact layer has an area weight of from 20 to 120 g/m.sup.2, preferably from 30 to 90 g/m.sup.2.

Acrylic Polymer (Non Hybrid

[0194] As indicated above, the TTS according to the present invention comprises at least one acrylic polymer in the active agent-containing layer.

[0195] As used herein, the terms acrylic polymer and acrylate polymer are synonymously used. Preferably, the acrylic polymers are pressure-sensitive adhesives based on acrylates. Pressure-sensitive adhesives based on acrylates may also be referred to as acrylate-based pressure-sensitive adhesives, or acrylate pressure-sensitive adhesives.

[0196] Pressure-sensitive adhesives based on acrylates may be provided in the form of a solution with a solids content preferably between 30% and 60%.

[0197] 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.

[0198] 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, butylmethacrylate, t-octylacrylamide and vinylacetate, and are provided in ethyl acetate, heptane, n-heptane, hexane, methanol, ethanol, isopropanol, 2,4-pentanedione, toluene or xylene or mixtures thereof.

[0199] Specific acrylate-based pressure-sensitive adhesives are available as: [0200] 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), [0201] 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), [0202] 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), [0203] 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), [0204] Duro-Tak′ 87-4098 (a copolymer based on 2-ethylhexyl-acrylate and vinyl acetate, provided as a solution in ethyl acetate).

[0205] Additional polymers may also be added to enhance cohesion and/or adhesion.

[0206] Certain polymers in particular reduce the cold flow and are thus in particular suitable as additional polymer. A polymeric matrix may show a cold flow, since such polymer compositions often exhibit, despite a very high viscosity, the ability to flow very slowly. Thus, during storage, the matrix may flow to a certain extent over the edges of the backing layer. This is a problem with storage stability and can be prevented by the addition of certain polymers. A basic acrylate polymer (e.g. Eudragit® E100) may e.g. be used to reduce the cold flow. Thus, in certain embodiments, the matrix layer composition comprises additionally a basic polymer, in particular an amine-functional acrylate as e.g. Eudragit® E100. Eudragit® E100 is a cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate with a ratio of 2:1:1. The monomers are randomly distributed along the copolymer chain. Based on SEC method, the weight average molar mass (Mw) of Eudragit® E100 is approximately 47,000 g/mol. Further, polymers such as Plastoid B, acrylic polymers such as Eudragits, Chitosan, celluloses and derivatives thereof, and polystyrene may be useful to increase the dryness of the adhesive (e.g. the matrix layer).

Silicone-Based Polymer (Non Hybrid

[0207] As indicated above, the TTS according to the present invention may comprise at least one silicone-based polymer in the intermediate layer.

[0208] As used herein, the silicone-based polymer is a non-hybrid polymer, i.e. a polymer, which does not include a hybrid species. Silicone-based polymers are based on polysiloxanes. They may therefore also be referred to as polymers based on polysiloxanes. Preferably, the silicone-based polymers are silicone-based pressure sensitive adhesives, i.e. pressure sensitive adhesives based on polysiloxanes.

[0209] As the silicone-based polymer is preferably a non-curing polymer, it is typically supplied and used in solvents, such as n-heptane and ethyl acetate. The solids content is usually between 30% and 80%.

[0210] Suitable silicone-based polymers are commercially available under the brand names BIO-PSAs (pressure sensitive adhesives based on polysiloxanes).

[0211] Pressure-sensitive adhesives based on polysiloxanes provide for suitable tack and for quick bonding to various skin types, including wet skin, suitable adhesive and cohesive qualities, long lasting adhesion to the skin, a high degree of flexibility, a permeability to moisture, and compatibility to many actives and film-substrates. It is possible to provide the pressure-sensitive adhesives based on polysiloxanes with sufficient amine resistance and therefore enhanced stability in the presence of amines. Such pressure-sensitive adhesives are based on a resin-in-polymer concept wherein, by condensation reaction of silanol end blocked polydimethylsiloxane with a silica resin (also referred to as silicate resin), a pressure-sensitive adhesive based on polysiloxane is prepared wherein for amine stability the residual silanol functionality is additionally capped with trimethylsiloxy groups. The silanol end blocked polydimethylsiloxane content contributes to the viscous component of the visco-elastic behavior, and impacts the wetting and the spreadability properties of the adhesive. The resin acts as a tackifying and reinforcing agent, and participates in the elastic component. The correct balance between silanol end blocked polydimethylsiloxane and resin provides for the correct adhesive properties.

[0212] In view of the above, silicone-based polymers, and in particular silicone-based pressure sensitive adhesives, are generally obtainable by polycondensation of silanol endblocked polydimethylsiloxane with a silicate resin. Amine-compatible silicone-based polymers, and in particular amine-compatible silicone-based pressure sensitive adhesives, can be obtained by reacting the silicone-based polymer, in particular the silicone-based pressure sensitive adhesive, with trimethylsilyl (e.g. hexamethyldisilazane) in order to reduce the silanol content of the polymer. As a result, the residual silanol functionality is at least partly, preferably mostly or fully capped with trimethylsiloxy groups.

[0213] As indicated above, the tackiness of the silicone-based polymer may be modified by the resin-to-polymer ratio, i.e. the ratio of the silanol endblocked polydimethylsiloxane to the silicate resin, which is preferably in the range of from 70:30 to 50:50, preferably from 65:35 to 55:45. The tackiness will be increased with increasing amounts of the polydimethylsiloxane relative to the resin. High tack silicone-based polymers preferably have a resin-to-polymer ratio of 55:45, medium tack silicone-based polymers preferably have a resin-to-polymer ratio of 60:40, and low tack silicone-based polymers preferably have a resin-to-polymer ratio of 65:35. High tack silicone-based polymers preferably have a complex viscosity at 0.01 rad/s and 30° C. of about 5×10.sup.6 Poise, medium tack silicone-based polymers preferably have a complex viscosity at 0.01 rad/s and 30° C. of about 5×10.sup.7 Poise, and low tack silicone-based polymers preferably have a complex viscosity at 0.01 rad/s and 30° C. of about 5×10.sup.8 Poise. High tack amine-compatible silicone-based polymers preferably have a complex viscosity at 0.01 rad/s and 30° C. of about 5×10.sup.6 Poise, medium tack amine-compatible silicone-based polymers preferably have a complex viscosity at 0.01 rad/s and 30° C. of about 5×10.sup.8 Poise, and low tack amine-compatible silicone-based polymers preferably have a complex viscosity at 0.01 rad/s and 30° C. of about 5×10.sup.9 Poise.

[0214] Examples of silicone-based PSA compositions which are commercially available include the standard BIO-PSA series (7-4400, 7-4500 and 7-4600 series), the amine compatible (endcapped) BIO-PSA series (7-4100, 7-4200 and 7-4300 series) and the Soft Skin Adhesives series (7-9800) manufactured and typically supplied in n-heptane or ethyl acetate by Dow Corning. For example, BIO-PSA 7-4201 is characterized by a solution viscosity at 25° C. and about 60% solids content in heptane of 450 mPa s and a complex viscosity at 0.01 rad/s at 30° C. of 1×10.sup.8 Poise. BIO-PSA 7-4301 has a solution viscosity at 25° C. and about 60% solids content in heptane of 500 mPa s and a complex viscosity at 0.01 rad/s at 30° C. of 5×10.sup.6 Poise.

[0215] The pressure-sensitive adhesives based on polysiloxanes are supplied and used in solvents like n-heptane, ethyl acetate or other volatile silicone fluids. The solids content of pressure-sensitive adhesives based on polysiloxanes in solvents is usually between 60 and 85%, preferably between 70 and 80% or between 60 and 75%. The skilled person is aware that the solids content may be modified by adding a suitable amount of solvent.

[0216] Pressure-sensitive adhesives based on polysiloxanes, which are, e.g., available from Dow Corning, may be obtained according to the following scheme:

##STR00001##

Such pressure-sensitive adhesives based on polysiloxanes are available from Dow Corning, e.g., under the tradenames BIO-PSA 7-4401, BIO-PSA-7-4501, or BIO-PSA 7-4601, which are provided in the solvent n-heptane (indicated by the code “01”), or under the tradenames BIO-PSA 7-4402, BIO-PSA 7-4502, and BIO 7-4602, which are provided in the solvent ethyl acetate (indicated by the code “02”). Typical solids contents in the solvent are in the range of from 60 to 75%. The code “44” indicates a resin-to-polymer ratio of 65:35 resulting in a low tackiness, the code “45” indicates a resin-to-polymer ratio of 60:40 resulting in medium tackiness, the code “46” indicates a resin-to-polymer ratio of 55:45 resulting in high tackiness.

[0217] Amine-compatible pressure-sensitive adhesives based on polysiloxanes, which are, e.g., available from Dow Corning may be obtained according to the following scheme:

##STR00002##

Such amine-compatible pressure-sensitive adhesives based on polysiloxanes are available from Dow Corning, e.g., under the tradenames BIO-PSA 7-4101, BIO-PSA-7-4201, or BIO-PSA 7-4301, which are provided in the solvent n-heptane (indicated by the code “01”), or under the tradenames BIO-PSA 7-4102, BIO-PSA 7-4202, and BIO 7-4302, which are provided in the solvent ethyl acetate (indicated by the code “02”). Typical solids contents in the solvent are in the range of from 60 to 75%. The code “41” indicates a resin-to-polymer ratio of 65:35 resulting in a low tackiness, the code “42” indicates a resin-to-polymer ratio of 60:40 resulting in medium tackiness, the code “43” indicates a resin-to-polymer ratio of 55:45 resulting in high tackiness.

[0218] The preferred pressure-sensitive adhesives based on polysiloxanes in accordance with the invention are characterized by a solution viscosity at 25° C. and 60% solids content in n-heptane of more than about 150 mPa s, or from about 200 mPa s to about 700 mPa s, preferably as measured using a Brookfield RVT viscometer equipped with a spindle number 5 at 50 rpm. Theses may also be characterized by a complex viscosity at 0.01 rad/s at 30° C. of less than about 1×10.sup.9 Poise or from about 1×10.sup.5 to about 9×10.sup.8 Poise.

Silicone Gel Adhesive

[0219] As indicated above, the TTS according to the present invention comprises a skin contact layer, which is an adhesive layer comprising a silicone gel adhesive. The silicone gel adhesive is an elastic, jelly-like solid material formed by lightly crosslinking silicone polymers. Thus, in contrast to the silicone-based polymers as used herein, the silicone gel adhesive is based on a curable gel producing composition. The silicone gel adhesive provides for the adhesiveness of the TTS to the skin, while at the same time reducing the problem of skin irritation. Furthermore, the drug delivery of the TTS is not negatively affected.

[0220] Silicone gel adhesives are also referred to as silicone gels and, e.g., described in WO 2011/022199 A2.

[0221] The silicone gel adhesive is generally formed from linear or branched silicones having reactive groups thereon. Such reactive groups undergo a crosslinking during curing. Examples of crosslinking reactions include the hydrosilylation reaction in which a silicone having an Si—H group reacts with a silicone having an aliphatic unsaturated reactive group in the presence of a hydrosilylation catalyst. These materials are described, for example in U.S. Pat. Nos. 5,656,279, 5,891,076, EP 0 322 118 and U.S. Pat. No. 4,991,574 which are incorporated herein by reference. An alternative reaction is the condensation cure in which an alkoxy and/or hydroxy containing siloxanes are cured with a catalyst as described in U.S. Pat. No. 4,831,070 which is hereby incorporated by reference.

[0222] Typically, the silicone gel adhesive is obtainable by reacting a gel producing composition comprising (i) at least one alkenyl-substituted polydiorganosiloxane, (ii) at least one organosiloxane, which contains silicone-bonded hydrogen atoms, and (iii) at least one catalyst for the reaction of the SiH groups with the Si-alkenyl groups. These compositions cure at normal ambient temperatures, but curing can be expedited by heating to elevated temperatures, e.g., from 40 to 140° C., or by applying UV light.

[0223] Suitable alkenyl groups contain from 2 carbon to about 6 carbon atoms and are exemplified by, but not limited to, vinyl, allyl, and hexenyl. The alkenyl groups in this component may be located at terminal, pendant (non-terminal), or both terminal and pendant positions. The remaining silicon-bonded organic groups in the alkenyl-substituted polydiorganosiloxane are independently selected from the group consisting of monovalent hydrocarbon and monovalent halogenated hydrocarbon groups free of aliphatic unsaturation. These groups typically contain from 1 carbon to about 20 carbon atoms, alternatively from 1 carbon to 8 carbon atoms and are exemplified by, but not limited to, alkyl such as methyl, ethyl, propyl, and butyl; aryl such as phenyl; and halogenated alkyl such as 3,3,3-trifluoropropyl. Typically, at least 50 percent of the organic groups in the alkenyl-substituted polydiorganosiloxane are methyl. The structure of the alkenyl-substituted polydiorganosiloxane is typically linear, however, it may contain some branching due to the presence of trifunctional siloxane units. The viscosity of the alkenyl-substituted polydiorganosiloxane can be any desired. For example, it can be >0 mm.sup.2/s to 100,000 mm.sup.2/s, alternatively 50 mm.sup.2/s to 80,000 mm.sup.2/s, alternatively 300 mm.sup.2/s-3,000 mm.sup.2/s.

[0224] Methods for preparing the alkenyl-substituted polydiorganosiloxanes (i) of the present invention, such as condensation of the corresponding halosilanes or equilibration of cyclic polydiorganosiloxanes, are well known in the art.

[0225] The alkenyl-substituted polydiorganosiloxanes can be used in the gel producing composition in an amount of 10 wt. %-90 wt. % based on the weight of the composition, alternatively 40 wt. %-90 wt. %, alternatively 50 wt. %-80 wt. %. The amount of alkenyl groups present in the alkenyl-substituted polydiorganosiloxane is typically in the range of 0.05 wt. %-1% wt %, alternatively 0.05 wt. % to 1 wt. % based on the weight of the alkenyl-substituted polydiorganosiloxane.

[0226] The organosiloxane containing silicon-bonded hydrogen atoms (ii) are also known in the art as described, for example in U.S. Pat. No. 3,983,298. The hydrogen atoms in this component may be located at terminal, pendant (non-terminal), or both terminal and pendant positions. The remaining silicon-bonded organic groups in this component are independently selected from the group consisting of monovalent hydrocarbon and monovalent halogenated hydrocarbon groups free of aliphatic unsaturation. These groups typically contain from 1 carbon to about 20 carbon atoms, alternatively from 1 carbon to 8 carbon atoms, and are exemplified by, but not limited to, alkyl such as methyl, ethyl, propyl, and butyl; aryl such as phenyl; and halogenated alkyl such as 3,3,3-trifluoropropyl. In one embodiment of the invention, at least 50 percent of the organic groups in the organosiloxane containing silicon-bonded hydrogen atoms are methyl.

[0227] The structure of the organosiloxane containing silicon-bonded hydrogen atoms is typically linear however; it may contain some branching due to the presence of trifunctional siloxane units. The viscosity of the organosiloxane containing silicon-bonded hydrogen atoms can be any desired. For example, it can be >0 mm.sup.2/s to 100,000 mm.sup.2/s, alternatively, 5 mm.sup.2/s to 500 mm.sup.2/s.

[0228] The organosiloxanes containing silicon-bonded hydrogen atoms can be used in the gel producing composition in an amount of 1 wt. %-30 wt. % based on the weight of the composition, alternatively 5 wt. %-20 wt %, and alternatively 5 wt. %-15 wt. %. In one embodiment, the amount of hydrogen group present in the organosiloxane containing silicon-bonded hydrogen atoms is between 0.05 wt. %-1.44 wt % based on the weight of the organosiloxane containing silicon-bonded hydrogen atoms.

[0229] Methods of preparing the organosiloxane containing silicon-bonded hydrogen atoms of the present invention by co-hydrolysis of the appropriate chlorosilanes are known in the art; U.S. Pat. No. 2,877,255 to Clark; Japanese Laid Open Patent Application (KOKAI) SHO 62(1987)-39660 to Mogi et al.; and U.S. Pat. Nos. 5,446,185 and 5,493,040 to Cobb et al., which are all hereby incorporated by reference.

[0230] In the gel producing compositions (i) and (ii) are present such that the ratio of (H as SiH):(Alkenyl as Si-Alkenyl) is generally in the range of 0.1:1 to 10:1.

[0231] The hydrosilylation catalyst (iii) promotes the addition reaction of the alkenyl-substituted polydiorganosiloxane with the organosiloxane containing silicon-bonded hydrogen. The hydrosilylation catalyst can be any of the well known hydrosilylation catalysts comprising a platinum group metal, a compound containing a platinum group metal, or a microencapsulated platinum group metal or compound containing same. These platinum group metals include platinum, rhodium, ruthenium, palladium, osmium and iridium. Platinum and platinum compounds are preferred catalysts based on their high activity level in hydrosilylation reactions. One class of platinum catalysts is the complexes of chloroplatinic acid with certain vinyl-containing organosiloxane compounds disclosed by Willig in U.S. Pat. No. 3,419,593, which is hereby incorporated by reference. A specific catalyst of this type is the reaction product of chloroplatinic acid and 1,3-diethenyl-1,1,3,3-tetramethyldisiloxane.

[0232] The hydrosilylation catalyst is present in an amount sufficient to cure the composition of the present invention. Typically, the concentration of the catalyst is sufficient to provide from 0.1 ppm to 500 ppm (part per million), alternatively from 1 ppm to 100 ppm, alternatively from 1 ppm to 50 ppm of a platinum group metal, based on the weight of (i) and (ii).

[0233] An optional ingredient is a hydroxy substituted silicone resin as described in US. Patent Application No. 2007-0202245, herein incorporated by reference. The resin is typically comprised of groups having the formula R.sup.3.sub.3 SiO.sub.1/2 (“M” groups) and groups having the formula SiO.sub.4/2 (“Q” groups) where R.sup.3 is a alkyl group having 1 carbon to 6 carbon atoms or alkylene group having 1 carbon to 6 carbon atoms, typically methyl or vinyl.

[0234] If an alkenyl group is present in the resin, typically the mol-% of R groups present as alkenyl groups is <10 mol-%, alternatively 5 mol-%.

[0235] The number ratio of M groups to Q groups is typically in the range of 0.6:1 to 4:1, alternatively 0.6:1 to 1.0:1. The silicone resin typically contains 0.1 wt % to 5 wt %, alternatively 1.0 wt % to 5 wt % silicone-bonded hydroxy groups.

[0236] The resin can be used in the gel producing composition in an amount of 2 wt % to 45 wt %, based on the weight of the gel producing composition and resin; alternatively 5 wt % to 40 wt %, alternatively 10 wt % to 35 wt %.

[0237] The silicone gel adhesive layer can be made by processes known in the art. For example, the gel may be preformed (e.g. as a sheet) by molding, calendaring, extruding, spraying, brushing, applying by hand, casting or coating on a substrate such as a liner. Or the silicone gel layer can be made by applying the gel producing composition to a substrate by spraying, coating, bar coating, etc. Once applied to the substrate the gel producing composition is cured to produce the silicone gel adhesive on the substrate.

[0238] In view of the above, in a preferred embodiment of the invention, the silicone gel adhesive is obtainable by reacting a gel producing composition comprising (i) a copolymer of vinylmethylsiloxane and dimethylsiloxane with (ii) methylhydrogen polysiloxane with trimethylsilyl endgroups in the presence of (iii) a platinum catalyst. Preferably, (i) and (ii) are present such that the ratio of (H as SiH):(Alkenyl as Si-Alkenyl) is generally in the range of 0.1:1 to 10:1.

[0239] Further, in certain preferred embodiments, the silicone gel adhesive is a silicate resin-reinforced silicone gel adhesive that contains from about 2 to about 45% by weight of at least one hydroxyl substituted silicate resin.

Further Additives

[0240] The TTS according to the invention, and in particular the active agent-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 substances for skincare, tackifiers, softeners, and stabilizers. Such additives may be present in the active agent-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 active agent-containing layer.

[0241] 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 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.

[0242] In one embodiment, the active agent-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 active agent-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, e.g., if the active agent is used in the form of a salt.

[0243] In one embodiment, the active agent-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 active agent-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.

[0244] In one embodiment, the active agent-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.

[0245] In one embodiment, the active agent-containing layer further comprises a solubilizer. The solubilizer preferably improves the solubility of the active agent in the active agent-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 monolinoleate, medium chain glycerides and medium chain triglycerides, non-ionic solubilisers 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; 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.

[0246] However, also the permeation enhancers mentioned below can act as solubilizers. Furthermore, also crystallization inhibitors may act as solubilizers.

[0247] In one embodiment, the active agent-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.

[0248] In one embodiment, the active agent-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.

[0249] In one embodiment, the active agent-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 active agent-containing layer.

[0250] If the active agent-containing layer is required to have self-adhesive properties and one or more polymers is/are selected, which does/do not provide sufficient self-adhesive properties, a tackifier is added. Preferred tackifiers include Miglyol, which is a liquid wax ester based on long-chain, unsaturated, even-numbered fatty acids and long-chain, unsaturated, even-numbered fatty alcohols of vegetable origin, and polyethyleneglycols. In particular, the tackifier may be selected from polyvinylpyrrolidone (which, due to its ability to absorb water, is able to maintain the adhesive properties of the matrix layer and thus can be regarded as a tackifier in a broad sense), triglycerides, polyethylene glycols, dipropylene glycol, resins, resin esters, terpenes and derivatives thereof, ethylene vinyl acetate adhesives, dimethylpolysiloxanes and polybutenes, preferably polyvinylpyrrolidone and more preferably soluble polyvinylpyrrolidone. Preferably, the tackifier may be selected from polyvinylpyrrolidone, triglycerides, dipropylene glycol, resins, resin esters, terpenes and derivatives thereof, ethylene vinyl acetate adhesives, dimethylpolysiloxanes and polybutenes, preferably polyvinylpyrrolidone and more preferably soluble polyvinylpyrrolidone. In some embodiments, the tackifier can be present in an amount of from 5 to 15% by weight based on the total weight of the active agent-containing layer.

[0251] 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 Kollidon® 90 F supplied by BASF, or povidone K90F. 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.

[0252] 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”.

[0253] 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.

[0254] In one embodiment, the active agent-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.

[0255] If the active agent-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.

[0256] 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 active agent-containing layer does not comprise a permeation enhancer or solubilizer.

Release Characteristics

[0257] It has been found that the TTS according to the present invention is suitable for the transdermal administration of an active agent, in particular rivastigmine, to the systemic circulation, while at the same time providing good adhesive properties and reduced skin irritation in comparison to other TTS known in the art.

[0258] The TTS according to the present invention is suitable for the transdermal administration of an active agent, in particular rivastigmine, to the systemic circulation for a predefined extended period of time, preferably for at least 24 hours.

[0259] Preferably, the TTS provides therapeutically effective plasma concentrations of the active agent, preferably rivastigmine, within less than 8 hours, preferably less than 6 hours, more preferably less than 4 hours after application of the TTS to the skin.

[0260] Preferably, the TTS provides, after a steady state of the plasma concentration is reached, a therapeutically effective steady state plasma concentration of the active agent, preferably rivastigmine, for at least 12 hours, preferably at least 18 hours, more preferably at least 20 hours, provided that the TTS is administered to the skin for a sufficient time, e.g., for at least 24 hours, so that the steady state can be reached and maintained.

[0261] In one embodiment, the TTS provides by transdermal delivery a mean release rate of from 150 to 3500 μg/cm.sup.2*day, preferably from 200 to 3000 μg/cm.sup.2*day rivastigmine over about 24 hours of administration.

[0262] In another embodiment, the TTS provides a cumulative permeated amount of rivastigmine as measured in a Franz diffusion cell with an EVA membrane of about 600 to 1200 μg/cm.sup.2 over a time period of about 24 hours.

Method of Treatment/Medical Use

[0263] The TTS according to the present invention is suitable for use in a method of treatment. If the active agent is rivastigmine, the TTS is suitable 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. Furthermore, the TTS is suitable for use in a method of treating mild to moderate dementia caused by Alzheimer's or Parkinson's disease.

[0264] In one embodiment, the TTS according to the invention is for use in a method of treatment, wherein the transdermal therapeutic system is preferably applied to the skin of the patient for at least 24 hours. In another embodiment, the present invention relates to a method of treatment comprising applying a transdermal therapeutic system according to the invention to the skin of a patient, preferably for at least 24 hours.

[0265] In one embodiment, the TTS comprises rivastigmine as active agent and is 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. In a preferred embodiment, the TTS is applied to the skin of the patient for a dosing interval of at least 24 hours, preferably about 24 hours. In another embodiment, the present invention relates to 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 comprising applying a transdermal therapeutic system according to the invention comprising rivastigmine to the skin of a patient, preferably for at least 24 hours, in particular about 24 hours.

[0266] 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.

[0267] The preferred application time of a TTS according to the invention is at least 24 hours, preferably about 24 hours (1 day). 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

[0268] The invention further relates to a process of manufacture of an active agent-containing layer structure for use in a transdermal therapeutic system.

[0269] In accordance with the invention, the process for manufacturing the active agent-containing layer for use in a transdermal therapeutic system according to the present invention comprises the steps of [0270] 1.1) coating a coating composition comprising [0271] an active agent; and [0272] at least one acrylic polymer on a first foil; [0273] 1.2) drying the coated coating composition to form the active agent-containing layer; [0274] 1.3) laminating the open side of the active agent-containing layer with a backing layer; [0275] 1.4) removing the first foil from the active agent-containing layer and laminating the open side with the open side of the intermediate layer.

[0276] If the intermediate layer is a silicone-based polymer layer, the intermediate layer may be prepared in advance by coating a composition comprising at least one silicone-based polymer onto an abhesively equipped foil, and drying the composition to form the intermediate layer.

[0277] As explained above, the acrylic polymer as well as the silicone-based polymer as used in the active agent-containing layer and the intermediate layer, respectively, are preferably non-curing polymers and therefore typically applied by a solvent-based process. Accordingly, the acrylic or silicone-based polymer is preferably provided in a solvent, wherein the solids content in the solvent is preferably from 40 to 75% by weight. The solvent is preferably selected from alcoholic solvents, in particular methanol, ethanol, isopropanol and mixtures thereof, and from non-alcoholic solvents, in particular ethyl acetate, hexane, heptane, petroleum ether, toluene, and mixtures thereof, and is more preferably selected from non-alcoholic solvents, and is most preferably ethyl acetate or n-heptane. In case of the coating composition for the active agent-containing layer, the active agent is preferably homogeneously dissolved or dispersed in the coating composition.

[0278] The coated coating composition is preferably solidified by drying. Drying is preferably performed at a temperature of from 20 to 90° C., more preferably from 40 to 70° C.

[0279] The process for manufacturing the skin contact layer for use in a transdermal therapeutic system according to the present invention comprises the steps of [0280] 2.1) coating the gel producing composition comprising [0281] (i) at least one alkenyl-substituted polydiorganosiloxane, [0282] (ii) at least one organosiloxane, which contains silicone-bonded hydrogen atoms, and [0283] (iii) at least one catalyst for the reaction of the SiH groups with the Si-alkenyl groups, on a second foil; [0284] 2.2) crosslinking the gel producing composition at a temperature of from 50° C. to 150° C. or by applying UV light to form the skin contact layer; [0285] 2.3) laminating the skin contact layer with a release liner.

[0286] As explained above, the gel producing composition forms the silicone gel adhesive of the skin contact layer upon curing, i.e. crosslinking of the reactive groups of the silicone polymers.

[0287] Crosslinking is preferably performed at a temperature of from 40° C. to 140° C.

[0288] The active agent-containing layer, the intermediate layer and the skin contact layer are preferably prepared separately as indicated above, and then laminated together by removing the foils and then laminating the open sides of the layers together in the desired order, so as to give an active agent-containing layer structure.

[0289] Accordingly, the process for manufacturing an active agent-containing layer structure for use in a transdermal therapeutic system according to the present invention comprises the steps of: [0290] 1.1) coating a coating composition comprising [0291] an active agent; and [0292] at least one acrylic polymer [0293] on a first foil; [0294] 1.2) drying the coated coating composition to form the active agent-containing layer; [0295] 1.3) laminating the open side of the active agent-containing layer with a backing layer; [0296] 1.4) removing the first foil from the active agent-containing layer and laminating the open side with the open side of the intermediate layer; [0297] 2.1) coating the gel producing composition comprising [0298] (i) at least one alkenyl-substituted polydiorganosiloxane, [0299] (ii) at least one organosiloxane, which contains silicone-bonded hydrogen atoms, and [0300] (iii) at least one catalyst for the reaction of the SiH groups with the Si-alkenyl groups, on a second foil; [0301] 2.2) crosslinking the gel producing composition at a temperature of from 50° C. to 150° C. or by applying UV light to form the skin contact layer; [0302] 2.3) laminating the skin contact layer with a release liner; [0303] 3.1) removing the foil from the skin contact layer; and [0304] 3.2) laminating the open side of the intermediate layer onto the open side of the skin contact layer to obtain an active agent-containing layer structure.
The preparation of the active-agent containing layer may be performed before or after the preparation of the skin contact layer, or the preparation of the two layers may be performed in parallel. Furthermore, if the intermediate layer is a polymer layer, the preparation may preferably be performed before the preparation of active agent-containing layer.

[0305] The present invention also relates to a transdermal therapeutic system obtainable by the above described process.

EXAMPLES

[0306] 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 Examples 1A-F

Active-Containing Coating Composition

[0307] The formulation of the rivastigmine-containing coating compositions of Comparative examples 1A-F (Comp. 1A-F) is summarized in Table 1.1 below. The solids %-values refer to the amounts (Amt) in % by weight.

TABLE-US-00001 TABLE 1.1 Comp. 1A-F Ingredient (Trade Name) Amt [g] Solids [%] Rivastigmine base 54.00 30.0 Copolymer of butylmethacrylate and 36.00 20.0 methylmethacrylate (Plastoid ® B from Evonik) Acrylic adhesive in ethyl acetate 89.82 49.9 Solids content of 37.5% by weight (239.52 with (Durotak ® 387-2353 from Henkel) ethyl acetate) Alpha-tocopherol 0.18 0.1 Total 180.00 100.0 Area Weight [g/m.sup.2] 60

Preparation of the Active-Containing Coating Composition and Coating of the Active-Containing Coating Composition

[0308] The active-containing coating composition was taken from the commercial process for preparing Exelon®, wherein the coating composition was applied to a siliconized release liner as abhesively equipped foil.

[0309] The coating thickness was chosen such that removal of the solution resulted in an area weight of the active-containing layer of about 60.0 g/m.sup.2.

[0310] The resulting active-containing layer was then laminated with a backing layer (FO PET 15 μm, transparent).

Active-Free Coating Composition

[0311] The formulation of the active-free coating composition of Comp. 1A-F is summarized in Table 1.2 below. The solids %-values refer to the amounts (Amt) in % by weight.

TABLE-US-00002 TABLE 1.2 Comp. 1A-F Ingredient (Trade Name) Amt [g] Solids [%] Component A of 2 component Soft Skin 25 50.0 Adhesive from Dow Corning (MG 7-9900 (A)) Component B of 2 component Soft Skin 25 50.0 Adhesive from Dow Corning (MG 7-9900 (B)) Total 50 100.0 Area Weight [g/m.sup.2] 58, 65, 87 Layer thickness [μm] 50, 100, 150

Preparation of the Active-Free Coating Composition

[0312] Both components were weighed separately into a suitable vessel, e.g. a glass vessel. Subsequently, component A was added to the mixing vessel followed by component B. Then the mixture was mixed at approx. 200 rpm for approx. 5 min until a homogeneous mixture of Component A and Component B was obtained.

Coating of the Active-Free Coating Composition

[0313] Within a time frame of approx. 30 min, the resulting active-free coating composition was coated on an abhesively equipped foil (DuPont′ Teflon FEP) using hand over knife lab coating equipment, e.g. an erichson coater.

[0314] The coating thickness was chosen such that removal of the solvents resulted in a layer thickness of the active-free (skin contact) layer of approx. 150 μm.

[0315] The curing conditions according to Table 1.3 were then applied.

TABLE-US-00003 TABLE 1.3 Comparative example Curing conditions 1A 60° C. for 5 minutes 1B 60° C. for 10 minutes 1C 60° C. for 15 minutes 1D 60° C. for 20 minutes 1E 60° C. for 30 minutes 1F 120° C. for 5 minutes

[0316] The resulting active-free (skin contact) layer was laminated with a release liner (FEP, fluorinated ethylene propylene, 100 μm).

Lamination of the Active-Containing Layer and the Active-Free (Skin Contact) Layer

[0317] The active-free (skin contact) layer was then laminated with the active-containing layer. For this purpose, the abhesively equipped foils used for the coating and drying of the layers were removed and the resulting open sides of the active-containing layer and the active-free (skin contact) layer were laminated together resulting in an active-containing self-adhesive layer structure comprising the backing layer, the active-containing layer, and the active-free (skin contact) layer, wherein the active-containing layer is attached to the backing layer, and the active-free (skin contact) layer is attached to the active-containing layer, and wherein the structure is closed by a release liner, which is attached to the active-free (skin contact layer).

Preparation of the TTS

[0318] The individual systems (TTS) were punched out from the active-containing self-adhesive layer structure obtained as described above. Then, the TTS were sealed into pouches of the primary packaging material.

Removal of the Release Liner

[0319] The release liners of the TTS of Comparative examples 1A-F were then peeled off. The results are summarized in table 1.4 below.

TABLE-US-00004 TABLE 1.4 Comparative example Observations when release liner is peeled off from the layer structure 1A-F Adherence of the skin contact layer to the rivastigmine-containing layer was not sufficient; upon removal of the release liner, the skin contact layer was separated from the rivastigmine-containing layer, so that the layer structure was destroyed.

Examples 1A-N

Active-Containing Coating Composition

[0320] The formulation of the rivastigmine-containing coating compositions of Examples 1A-N (Ex. 1A-N) is summarized in Table 2.1 below. The solids %-values refer to the amounts (Amt) in % by weight.

TABLE-US-00005 TABLE 2.1 Ex. 1A-N Ingredient (Trade Name) Amt [g] Solids [%] Rivastigmine base 54.00 30.0 Copolymer of butylmethacrylate and 36.00 20.0 methylmethacrylate (Plastoid ® B from Evonik) Acrylic adhesive in ethyl acetate 89.82 49.9 Solids content of 37.5% by weight (239.52 with (Durotak ® 387-2353 from Henkel) ethyl acetate) Alpha-tocopherol 0.18 0.1 Total 180.00 100.0 Area Weight [g/m.sup.2] 60

Preparation of the Active-Containing Coating Composition and Coating of the Active-Containing Coating Composition

[0321] The active-containing coating composition was taken from the commercial process for preparing Exelon®, wherein the coating composition was applied to a siliconized release liner as abhesively equipped foil.

[0322] The coating thickness was chosen such that removal of the solution resulted in an area weight of the active-containing layer of about 60.0 g/m.sup.2.

[0323] The resulting active-containing layer was then laminated with a backing layer (FO PET 23 μm, transparent).

Active-Free Coating Composition

[0324] The formulation of the active-free coating composition of Ex. 1A-N is summarized in Table 2.2 below. The solids %-values refer to the amounts (Amt) in % by weight.

TABLE-US-00006 TABLE 2.2 Ex. 1A, C, E, G, Ex. 1B, D, F, H, I, K, M J, L, N Amt Solids Amt Solids Ingredient (Trade Name) [g] [%] [g] [%] Component A of 2 component Soft Skin 25 50.0 25 50.0 Adhesive from Dow Corning (MG 7-9900 (A)) Component B of 2 component Soft Skin 25 50.0 25 50.0 Adhesive from Dow Corning (MG 7-9900 (B)) Total 50 100.0 50 100.0 Area Weight [g/m.sup.2] 60 105 Layer thickness [μm] 100 200

Preparation of the Active-Free Coating Composition

[0325] Both components were weighed separately into a suitable vessel, e.g. a glass vessel. Subsequently, component A was added to the mixing vessel followed by component B. Then the mixture was mixed at approx. 200 rpm for approx. 5 min until a homogeneous mixture of Component A and Component B was obtained.

Coating of the Active-Free Coating Composition

[0326] Within a time frame of approx. 30 min, the resulting active-free coating composition was coated on a membrane as indicated in Table 2.3 using a coating block.

[0327] The coating thickness was chosen such that removal of the solvents resulted in a layer thickness of the active-free (skin contact) layer of approx. 100 μm or 200 μm as indicated above in Table 2.2.

[0328] The curing conditions according to Table 2.3 were then applied.

TABLE-US-00007 TABLE 2.3 Curing Example Membrane conditions 1A Ultra high molecular polyethylene membrane, 20 μm, 0.7 μm 120° C. for 5 1B pore size (Solupor ® 3P07A) minutes 1C Ultra high molecular polyethylene membrane, 55 μm, 0.45 μm 1D pore size (Solupor ® 4P4A) 1E Ultra high molecular polyethylene membrane, 40 μm, 1.1 μm 1F pore size (Solupor ® 5P09B) 1G Ultra high molecular polyethylene membrane, 45 μm, 0.7 μm 1H pore size (Solupor ® 7P07C) 1I Polyurethane coating onto a polyethylene 1J terephthalate/polethylene foil (FO PUR (25 g/m.sup.2) on PET/PE) 1K Polyurethane foil, 50 μm, spread and rolled onto a cover paper 1L which is removed after lamination (FO PU 50 μm mat 1300 mm) 1M Controlled ethylene vinyl acetate (EVA) membrane containing 60° C. for 5 1N 19% vinyl acetate (Cotran 9728 (EVA 19%)) minutes

[0329] The resulting active-free (skin contact) layer was laminated with a release liner (Scotchpak 9755, AB1F).

Lamination of the Active-Containing Layer and the Active-Free (Skin Contact) Layer with the Membrane in Between

[0330] The abhesively equipped foil of the rivastigmine-containing layer was removed and cast away. The rivastigmine-containing layer attached to the PET backing layer was then laminated with its adhesive side onto the membrane side of the active-free (skin contact) layer. The result is an active-containing self-adhesive layer structure comprising the backing layer, the rivastigmine-containing layer, the membrane as an intermediate layer, and the active-free (skin contact) layer, wherein the system is closed by the release liner.

Preparation of the TTS

[0331] The individual systems (TTS) were punched out from the active-containing self-adhesive layer structure obtained as described above. Then, the TTS were sealed into pouches of the primary packaging material.

Removal of the Release Liner

[0332] The release liners of the TTS of Examples 1A-N were then peeled off. The results are summarized in table 2.4 below.

TABLE-US-00008 TABLE 2.4 Observations when release liner is peeled off from the Example layer structure 1A-N Adherence of the skin contact layer to the active agent- containing layer via the membrane was sufficient.

Examples 2A-G

Active-Containing Coating Composition

[0333] The formulation of the rivastigmine-containing coating compositions of Examples 2A-G (Ex. 2A-G) is summarized in Table 3.1 below. The solids %-values refer to the amounts (Amt) in % by weight.

TABLE-US-00009 TABLE 3.1 Ex. 2A-G Ingredient (Trade Name) Amt [g] Solids [%] Rivastigmine base 54.00 30.0 Copolymer of butylmethacrylate and 36.00 20.0 methylmethacrylate (Plastoid ® B from Evonik) Acrylic adhesive in ethyl acetate 89.82 49.9 Solids content of 37.5% by weight (239.52 with (Durotak ® 387-2353 from Henkel) ethyl acetate) Alpha-tocopherol 0.18 0.1 Total 180.00 100.0 Area Weight [g/m.sup.2] 60

Preparation of the Active-Containing Coating Composition and Coating of the Active-Containing Coating Composition

[0334] The active-containing coating composition was taken from the commercial process for preparing Exelon®, wherein the coating composition was applied to a siliconized release liner as abhesively equipped foil.

[0335] The coating thickness was chosen such that removal of the solution resulted in an area weight of the active-containing layer of about 60.0 g/m.sup.2.

[0336] The resulting active-containing layer was then laminated with a backing layer (FO PET 23 μm, transparent).

Composition of the Intermediate Layer

[0337] The formulation of composition for the intermediate layer of Ex. 2A-G is summarized in Table 3.2 below. The solids %-values refer to the amounts (Amt) in % by weight.

TABLE-US-00010 TABLE 3.2 Ingredient (Trade Name) Ex. 2A-C Ex. 2D/F Ex. 2E/G Amine-compatible silicone adhesive (silanol + + + endblocked polydimethylsiloxane polycondensed with a silicate resin and reacted with trimethylsilyl) in ethyl acetate Solids content of 62% by weight (DOW CORNING ® BIO-PSA Q7-4202) Area Weight [g/m.sup.2] 30 30 50

Coating of the Composition of the Intermediate Layer

[0338] The composition for the intermediate layer was coated on an abhesively equipped foil (Scotchpak 1022 AB1F) using a coating block.

[0339] The coating thickness was chosen such that removal of the solvent resulted in an area weight as indicated above in Table 3.2.

[0340] The coating was dried at about 50° C. for about 10 min.

Lamination of the Active-Containing Layer and Intermediate Layer

[0341] The abhesively equipped foil of the rivastigmine-containing layer was removed and cast away. The rivastigmine-containing layer was then laminated with its open side onto the open side of the intermediate layer.

Active-Free Coating Composition

[0342] The formulation of the active-free coating composition of Ex. 2A-G is summarized in Table 3.3 below. The solids %-values refer to the amounts (Amt) in % by weight.

TABLE-US-00011 TABLE 3.3 Ex. 2A, D, E Ex. 2B, F, G Ex. 2C Amt Solids Amt Solids Amt Solids Ingredient (Trade Name) [g] [%] [g] [%] [g] [%] Component A of 2 component Soft Skin 25 50.0 25 50.0 25 50 Adhesive from Dow Corning (MG 7-9900 (A)) Component B of 2 component Soft Skin 25 50.0 25 50.0 25 50 Adhesive from Dow Corning (MG 7-9900 (B)) Total 50 100.0 50 100.0 50 100 Area Weight [g/m.sup.2] 40 60 85 Layer thickness [μm] 50 100 150

Preparation of the Active-Free Coating Composition

[0343] Both components were weighed separately into a suitable vessel, e.g. a glass vessel. Subsequently, component A was added to the mixing vessel followed by component B. Then the mixture was mixed at approx. 200 rpm for approx. 5 min until a homogeneous mixture of Component A and Component B was obtained.

Coating of the Active-Free Coating Composition

[0344] Within a time frame of approx. 30 min, the resulting active-free coating composition was coated on an abhesively equipped foil (DuPont′ Teflon FEP) using hand over knife lab coating equipment, e.g. an erichson coater. The coating temperature was set to 120° C. The resulting active-free layer was heated at this temperature for approx. 5 min.

[0345] The coating thickness was chosen such that removal of the solvents resulted in a layer thickness of the active-free (skin contact) as indicated in Table 3.3.

[0346] The resulting active-free (skin contact) layer was laminated with a release liner (FEP, fluorinated ethylene propylene, 100 μm).

Lamination of the Active-Containing Layer and the Active-Free (Skin Contact) Layer with the Intermediate Layer in Between

[0347] The abhesively equipped foil of intermediate layer on top of the rivastigmine-containing layer was removed and cast away. Further, the abhesively equipped foil on top of the active-free (skin contact) layer was removed and cast away. The open side of the intermediate layer being part of the double layer system attached to the PET backing layer was then laminated onto the open side of the active-free (skin contact) layer. The result is an active-containing self-adhesive layer structure comprising the backing layer, the rivastigmine-containing layer, the silicone-based intermediate layer, and the active-free (skin contact) layer, wherein the system is closed by the FEP release liner.

Preparation of the TTS

[0348] The individual systems (TTS) were punched out from the active-containing self-adhesive layer structure obtained as described above. Then, the TTS were sealed into pouches of the primary packaging material.

Removal of the Release Liner

[0349] The release liners of the TTS of Examples 2A-G were then peeled off. The results are summarized in table 3.4 below.

TABLE-US-00012 TABLE 3.4 Observations when release liner is peeled off from the Example layer structure 2A-G Adherence of the skin contact layer to the active agent- containing layer via the intermediate layer was sufficient.

Measurement of the Skin Permeation

[0350] The permeated amounts of the TTS prepared according to Examples 2A-G were determined by experiments in accordance with the EMA Guideline on quality of transdermal patches (adopted Oct. 23, 2014) carried out with a 10.0 ml Franz diffusion cell, wherein an EVA-membrane (9% vinyl acetate; Nitroderm TTS K-Membrane 343 mm from PetroplastVinora AG) having a thickness of 50 μm was used. Diecuts with an area of release of 1.118 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.

[0351] The results are shown in Table 3.5 and in FIG. 1.

TABLE-US-00013 TABLE 3.5 Cumulative permeated amount with SD [μg/cm.sup.2] Elapsed Ex. 2A (n = 3) Ex. 2B (n = 3) Ex. 2C (n = 3) time [h] Amount SD Amount SD Amount SD 3 127 2.52 130 1.53 128 4.36 6 247 2.65 239 2.89 237 6.43 8 322 4.14 316 3.67 313 6.62 24 727 9.61 727 11.0 726 12.4 Elapsed Ex. 2D (n = 3) Ex. 2E (n = 3) Ex. 2F (n = 3) time [h] Amount SD Amount SD Amount SD 3 85.6 28.1 57.9 12.8 82.5 26.4 6 273 71.1 191 36.1 242 52.7 8 423 92.5 311 50.9 362 58.7 24 1062 n.d. 969 n.d. 928 n.d. Elapsed Ex. 2G (n = 3) time [h] Amount SD 3 43.5 11.6 6 165 38 8 281 57.9 24 935 n.d.

Reference Example 1

TTS

[0352] Reference Example 1 (Ref 1) is 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), which is available from Novartis Pharma.

Measurement of the Skin Permeation

[0353] The permeated amount of the commercially available Exelon® TTS (Ref 1) was determined as described for Examples 3A-G

[0354] The results are shown in Table 4 and in FIG. 1.

TABLE-US-00014 TABLE 4 Cumulative permeated amount with SD [μg/cm.sup.2] Elapsed Ref. 1 (n = 3) time [h] Amount SD 3 127 59.6 6 370 141 8 538 172 24 1117 n.d.

[0355] The invention relates in particular to the following further items:

1. Transdermal therapeutic system for the transdermal administration of an active agent comprising an active agent-containing layer structure, said active agent-containing layer structure comprising:

[0356] A) a backing layer;

[0357] B) an active agent-containing layer comprising at least one acrylic polymer;

[0358] C) a skin contact layer; and

an intermediate layer between the active agent-containing layer and the skin contact layer; wherein the skin contact layer is an adhesive layer comprising a silicone gel adhesive.
2. Transdermal therapeutic system according to item 1, wherein the intermediate layer is a membrane, which is at least semipermeable for the active agent.
3. Transdermal therapeutic system according to item 1 or 2, wherein the intermediate layer is a membrane selected from the group consisting of polyethylene membranes, polyurethane coated polyethylene terephthalate/polyethylene membranes, polyurethane membranes, and ethylene vinyl acetate (EVA) membranes.
4. Transdermal therapeutic system according to any one of items 1 to 3, wherein the intermediate layer is a pressure-sensitive adhesive layer comprising a silicone-based polymer.
5. Transdermal therapeutic system according to item 4, wherein the silicone-based polymer is obtainable by polycondensation of silanol endblocked polydimethylsiloxane with a silicate resin.
6. Transdermal therapeutic system according to item 5, wherein the residual silanol functionality of the silicone-based polymer is capped with trimethylsiloxy groups.
7. Transdermal therapeutic system according to any one of items 1 or 4 to 6, wherein the intermediate layer has a thickness of from 20 to 100 μm, preferably from 25 to 55 μm.
8. Transdermal therapeutic system according to any one of items 1 or 4 to 7, wherein the intermediate layer has an area weight of from 20 to 80 g/m.sup.2, preferably from 20 to 60 g/m.sup.2.
9. Transdermal therapeutic system according to any one of items 1 to 8, wherein the silicone gel adhesive is obtainable by reacting a gel producing composition comprising (i) at least one alkenyl-substituted polydiorganosiloxane, (ii) at least one organosiloxane, which contains silicone-bonded hydrogen atoms, and (iii) at least one catalyst for the reaction of the SiH groups with the Si-alkenyl groups.
10. Transdermal therapeutic system according to any one of items 1 to 9, wherein the silicone gel adhesive is obtainable by reacting a gel producing composition comprising (i) a copolymer of vinylmethylsiloxane and dimethylsiloxane with (ii) methylhydrogen polysiloxane with trimethylsilyl endgroups in the presence of (iii) a platinum catalyst.
11. Transdermal therapeutic system according to any one of items 1 to 10, wherein the silicone gel adhesive is a silicate resin-reinforced silicone gel adhesive that contains from about 2 to about 45% by weight, preferably from about 20 to about 30% by weight of at least one hydroxyl substituted silicate resin.
12. Transdermal therapeutic system according to any one of items 1 to 11, wherein the skin contact layer has a thickness of from 30 to 220 μm, preferably from 40 to 160 μm.
13. Transdermal therapeutic system according to any one of items 1 to 12, wherein the skin contact layer has an area weight of from 20 to 120 g/m.sup.2, preferably from 30 to 90 g/m.sup.2.
14. Transdermal therapeutic system according to any one of items 1 to 13, wherein the active agent-containing layer is an active agent-containing matrix layer comprising [0359] the active agent; and [0360] the at least one acrylic polymer.
15. Transdermal therapeutic system according to any one of items 1 to 14, wherein the active agent-containing layer has a thickness of from 50 to 150 μm.
16. Transdermal therapeutic system according to any one of items 1 to 15, wherein the active agent-containing layer has an area weight of from 30 to 200 g/m.sup.2, preferably from 40 to 120 g/m.sup.2.
17. Transdermal therapeutic system according to any one of items 1 to 16, wherein the at least one acrylic polymer is present in the active agent-containing layer in an amount of from 30 to 90% by weight, preferably 60 to 80% by weight based on the total weight of the active agent-containing layer.
18. Transdermal therapeutic system according to any one of items 1 to 17, wherein the at least one acrylate polymer is obtainable from one or more monomers selected from acrylic acid, butylacrylate, 2-ethylhexylacrylate, glycidylmethacrylate, 2-hydroxyethylacrylate, methylacrylate, methylmethacrylate, butylmethacrylate, t-octylacrylamide, and vinylacetate, preferably from one or more monomers selected from acrylic acid, 2-ethylhexylacrylate, glycidylmethacrylate, and methylacrylate.
19. Transdermal therapeutic system according to any one of items 1 to 18, wherein the active agent-containing layer further comprises at least one additive, preferably a stabilizer selected from tocopherol and ester derivatives thereof.
20. Transdermal therapeutic system according to item 19, wherein the active agent-containing layer comprises at least one stabilizer selected from tocopherol and ester derivatives thereof in an amount of from 0.001 to 2.0% by weight, preferably from 0.01 to 1.0% by weight, based on the total weight of the active agent-containing layer.
21. Transdermal therapeutic system according to any one of items 1 to 20, wherein the active agent is present in the active agent-containing layer in an amount of from 5 to 40% by weight, preferably from 20 to 35% by weight, based on the total weight of the active agent-containing layer.
22. Transdermal therapeutic system according to any one of items 1 to 21, wherein the active agent is rivastigmine.
23. Transdermal therapeutic system according to item 22, wherein the amount of rivastigmine contained in the active agent-containing layer structure ranges from 0.5 to 5 mg/cm.sup.2, preferably from 1 to 3 mg/cm.sup.2.
24. Transdermal therapeutic system according to any one of items 1 to 23, wherein the active agent is rivastigmine, and 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 200 to 3000 μg/cm.sup.2*day rivastigmine over about 24 hours of administration.
25. Transdermal therapeutic system according to any one of items 1 to 24, wherein the active agent is rivastigmine, and wherein transdermal therapeutic system provides a cumulative permeated amount of rivastigmine as measured in a Franz diffusion cell with an EVA membrane of about 600 to 1200 μg/cm.sup.2 over a time period of about 24 hours.
26. Transdermal therapeutic system according to any one of items 1 to 25, for use in a method of treatment, wherein the transdermal therapeutic system is preferably applied to the skin of the patient for at least 24 hours.
27. Transdermal therapeutic system according to any one of items 1 to 26, 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.
28. A process for manufacturing an active agent-containing layer structure for use in a transdermal therapeutic system according to any one of items 1 to 27 comprising the steps of: [0361] 1.1) coating a coating composition comprising [0362] an active agent; and [0363] at least one acrylic polymer on a first foil; [0364] 1.2) drying the coated coating composition to form the active agent-containing layer; [0365] 1.3) laminating the open side of the active agent-containing layer with a backing layer; [0366] 1.4) removing the first foil from the active agent-containing layer and laminating the open side with the open side of the intermediate layer; [0367] 2.1) coating the gel producing composition comprising [0368] (i) at least one alkenyl-substituted polydiorganosiloxane, [0369] (ii) at least one organosiloxane, which contains silicone-bonded hydrogen atoms, and [0370] (iii) at least one catalyst for the reaction of the SiH groups with the Si-alkenyl groups, on a second foil; [0371] 2.2) crosslinking the gel producing composition at a temperature of from 50° C. to 150° C. or by applying UV light to form the skin contact layer; [0372] 2.3) laminating the skin contact layer with a release liner; [0373] 3.1) removing the foil from the skin contact layer; and [0374] 3.2) laminating the open side of the intermediate layer onto the open side of the skin contact layer to obtain an active agent-containing layer structure.
29. Transdermal therapeutic system obtainable by a process in accordance with item 28.
30. Transdermal therapeutic system for the transdermal administration of an active agent comprising an active agent-containing layer structure, said active agent-containing layer structure comprising:

[0375] A) a backing layer;

[0376] B) an active agent-containing layer comprising at least one acrylic polymer;

[0377] C) a skin contact layer; and

an intermediate layer between the active agent-containing layer and the skin contact layer; wherein the skin contact layer is an adhesive layer comprising a silicone gel adhesive; and wherein the silicone gel adhesive is obtainable by reacting a gel producing composition comprising (i) a copolymer of vinylmethylsiloxane and dimethylsiloxane with (ii) methylhydrogen polysiloxane with trimethylsilyl endgroups in the presence of (iii) a platinum catalyst.
31. Transdermal therapeutic system according to item 30, wherein the active agent is rivastigmine, and wherein the active agent is present in a therapeutically effective amount.
32. Transdermal therapeutic system according to item 30 or 31, wherein the skin contact layer does not comprise an active agent.
33. Transdermal therapeutic system for the transdermal administration of an active agent comprising an active agent-containing layer structure, said active agent-containing layer structure comprising: [0378] A) a backing layer; [0379] B) an active agent-containing matrix layer comprising an active agent in an amount of from 5 to 40% by weight, and at least one acrylic polymer in an amount of from 30 to 90% by weight in each case based on the total weight of the active agent-containing matrix layer; and [0380] C) a skin contact layer; and
an intermediate layer between the active agent-containing layer and the skin contact layer;
wherein the intermediate layer is a pressure-sensitive adhesive layer comprising a silicone-based polymer;
and wherein the skin contact layer is an adhesive layer comprising a silicone gel adhesive;
and wherein the silicone gel adhesive is obtainable by reacting a gel producing composition comprising (i) a copolymer of vinylmethylsiloxane and dimethylsiloxane with (ii) methylhydrogen polysiloxane with trimethylsilyl endgroups in the presence of (iii) a platinum catalyst.
34. Transdermal therapeutic system according to item 33, wherein the active agent containing matrix layer has an area weight of from 30 to 200 g/m.sup.2, the intermediate layer has an area weight of from 20 to 80 g/m.sup.2, and the skin contact layer has an area weight of from 20 to 120 g/m.sup.2.
35. Transdermal therapeutic system according to item 33 or 34, wherein the active agent containing matrix layer has an area weight of from 40 to 120 g/m.sup.2, the intermediate layer has an area weight of from 20 to 60 g/m.sup.2, and the skin contact layer has an area weight of from 30 to 90 g/m.sup.2.
36. Transdermal therapeutic system according to any one of items 33 to 35, wherein the active agent-containing matrix layer comprises tocopherol in an amount of from 0.01 to 1.0% by weight.
37. Transdermal therapeutic system according to any one of items 33 to 36, wherein the active agent is rivastigmine.
38. Transdermal therapeutic system according to any one of items 33 to 37, wherein the skin contact layer does not comprise an active agent.

TRANSDERMAL THERAPEUTIC SYSTEM COMPRISING AN ACTIVE AGENT-CONTAINING LAYER COMPRISING AN ACRYLIC POLYMER AND A SKIN CONTACT LAYER COMPRISING A SILICONE GEL ADHESIVE

Inventors

Cpc classification

Classification Explorer

A61F13/0253

HUMAN NECESSITIES

Classification Explorer

A61K31/325

HUMAN NECESSITIES

Classification Explorer

A61F13/00991

HUMAN NECESSITIES

Classification Explorer

A61F2013/00646

HUMAN NECESSITIES

Classification Explorer

A61F2013/00604

HUMAN NECESSITIES

Classification Explorer

A61K9/7084

HUMAN NECESSITIES

Classification Explorer

A61K47/32

HUMAN NECESSITIES

International classification

Classification Explorer

A61K9/70

HUMAN NECESSITIES

Classification Explorer

A61F13/00

HUMAN NECESSITIES

Classification Explorer

A61F13/02

HUMAN NECESSITIES

Classification Explorer

A61K31/325

HUMAN NECESSITIES

Classification Explorer

A61K47/32

HUMAN NECESSITIES

Abstract

Claims

Description