Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene

Abstract

The present invention relates to a transdermal therapeutic system (TTS) for the transdermal administration of asenapine comprising a self-adhesive layer structure comprising a therapeutically effective amount of asenapine, said self-adhesive layer structure comprising: A) a backing layer; B) an asenapine-containing layer comprising: 1. asenapine in the form of the free base; and 2. a polymer selected from the group consisting of polysiloxanes and polyisobutylenes in an amount of more than 50% by weight based on the total weight of the asenapine-containing layer; and C) optionally an additional skin contact layer.

Claims

1. A transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure comprising a therapeutically effective amount of asenapine, said self-adhesive layer structure comprising: A) a backing layer; B) an asenapine-containing layer comprising: a) asenapine free base; and b) a polymer selected from the group consisting of polysiloxanes and polyisobutylenes in an amount of more than 50% by weight based on the total weight of the asenapine-containing layer; and C) optionally an additional skin contact layer; wherein the asenapine-containing layer comprises a crystallization inhibitor in an amount of 0.5 to 10% by weight based on the total weight of the asenapine-containing layer.

2. The transdermal therapeutic system according to claim 1, wherein the asenapine-containing layer is an asenapine-containing matrix layer; and/or wherein the area weight of the asenapine-containing layer ranges from 50 to 120 g/m.sup.2, or from 70 to 100 g/m.sup.2.

3. The transdermal therapeutic system according to claim 1, wherein the amount of asenapine in the asenapine-containing layer ranges from 1 to 10%, or from 2 to 7% by weight based on the total weight of the asenapine-containing layer, and/or wherein the amount of asenapine contained in the transdermal therapeutic system ranges from 3 to 21 mg, or from 3.5 to 14 mg.

4. The transdermal therapeutic system according to claim 1, wherein the amount of the polymer ranges from 55 to 98%, from 70 to 98%, from 80 to 98% or from 92 to 98% by weight based on the total weight of the asenapine-containing layer.

5. The transdermal therapeutic system according to claim 1, wherein the polymer is a polysiloxane.

6. The transdermal therapeutic system according to claim 1, wherein the asenapine-containing layer comprises a stabilizer in an amount of 0.01 to 1.0% by weight based on the total weight of the asenapine-containing layer.

7. The transdermal therapeutic system according to claim 1, wherein the asenapine-containing layer is an asenapine-containing matrix layer comprising: a) asenapine free base in an amount of 2 to 7% by weight based on the total weight of the asenapine-containing matrix layer; b) polysiloxane in an amount of from 92 to 98% by weight based on the total weight of the asenapine-containing layer; c) a stabilizer in an amount of from 0.01 to 1.0% by weight based on the total weight of the asenapine-containing layer; and/or d) a crystallization inhibitor in an amount of from 0.5 to 10% by weight based on the total weight of the asenapine-containing layer.

8. The transdermal therapeutic system according to claim 1, wherein the asenapine-containing layer is an asenapine-containing matrix layer comprising: a) asenapine free base in an amount of 2 to 7% by weight based on the total weight of the asenapine-containing matrix layer; b) a polysiloxane in an amount of 92 to 98% by weight based on the total weight of the asenapine-containing matrix layer; c) tocopherol in an amount of 0.01 to 1.0% by weight based on the total weight of the asenapine-containing matrix layer; and/or d) polyvinylpyrrolidone in an amount of 0.5 to 10% by weight based on the total weight of the asenapine-containing matrix layer; wherein the matrix layer has an area weight ranging from 70 to 100 g/m.sup.2.

9. A transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure comprising a therapeutically effective amount of asenapine, said self-adhesive layer structure comprising: A) a backing layer; B) an asenapine-containing layer comprising: a) asenapine in an amount of from 2 to 7% by weight based on the total weight of the asenapine-containing layer; b) at least one silicone polymer in an amount of from 85 to 98% by weight based on the total weight of the asenapine-containing layer; c) a stabilizer in an amount of from 0.01 to 1.0% by weight based on the total weight of the asenapine-containing layer; and d) a crystallization inhibitor in an amount of from 0.5 to 10% by weight based on the total weight of the asenapine-containing layer; and C) optionally an additional skin contact layer.

10. The transdermal therapeutic system according to claim 9, wherein the stabilizer is tocopherol and the crystallization inhibitor is polyvinylpyrrolidone.

11. The transdermal therapeutic system according to claim 9, wherein the asenapine-containing layer has an area weight ranging from 50 to 120 g/m.sup.2, or from 70 to 100 g/m.sup.2.

12. The transdermal therapeutic system according to claim 9, wherein the silicone polymer is obtainable by polycondensation of silanol endblocked polydimethylsiloxane with a silicate resin, wherein the ratio of the silanol endblocked polydimethylsiloxane to the silicate resin is in the range of from 70:30 to 50:50, and wherein a residual functionality of the at least one silicone polymer is capped with trimethylsiloxy groups.

13. A transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure comprising a therapeutically effective amount of asenapine, said self-adhesive layer structure comprising: A) a backing layer; B) an asenapine-containing layer comprising: a) asenapine in an amount of from 2 to 15% by weight based on the total weight of the asenapine-containing layer; b) at least one polyisobutylene in an amount of from 70 to 98% by weight based on the total weight of the asenapine-containing layer; and c) a hydrophilic polymer in an amount of from 1 to 20% by weight based on the total weight of the asenapine-containing layer; and C) optionally an additional skin contact layer.

14. The transdermal therapeutic system according to claim 13, wherein the self-adhesive layer structure comprises A) a backing layer; B) an asenapine-containing layer, which is an asenapine-containing matrix layer, comprising: a) asenapine in an amount of from 4 to 12% by weight based on the total weight of the asenapine-containing layer; b) at least one polyisobutylene in an amount of from 70 to 90% by weight based on the total weight of the asenapine-containing layer; and c) polyvinylpyrrolidone in an amount of from 1 to 20% by weight based on the total weight of the asenapine-containing layer; and C) optionally an additional skin contact layer.

15. The transdermal therapeutic system according to claim 13, wherein the asenapine-containing layer has an area weight ranging from 40 to 250 g/m.sup.2, or from 40 to 125 g/m.sup.2.

16. The transdermal therapeutic system according to claim 13, wherein the at least one polyisobutylene is a combination of a low molecular weight polyisobutylene and a high molecular weight polyisobutylene in a ratio of from 99:1 to 50:50, and wherein the low molecular weight polyisobutylene has a viscosity average molecular weight of from 38,000 to 42,000 g/mol and/or a weight average molecular weight of from 34,000 to 40,000 g/mol, and wherein the high molecular weight polyisobutylene has a viscosity average molecular weight of from 1,100,000 to 1,120,000 g/mol and/or a weight average molecular weight of from 1,540,000 to 1,560,000 g/mol.

17. A method of treating bipolar disorder and/or schizophrenia in a patient in need thereof, comprising administering to the patient the transdermal therapeutic system according to claim 1.

18. The method according to claim 17, wherein the transdermal therapeutic system is applied to the skin of the patient for a dosing interval of from 20 to 30 hours.

19. A process for manufacturing an asenapine-containing layer for use in a transdermal therapeutic system according to claim 1 comprising: A) combining a) asenapine; b) a polymer selected from the group consisting of polysiloxanes and polyisobutylenes in an amount of more than 50% by weight based on the total weight of the asenapine-containing layer; and c) a crystallization inhibitor in an amount of 0.5 to 10% by weight based on the total weight of the asenapine-containing layer; to obtain a coating composition; B) coating the coating composition onto the backing layer, a release liner, or any intermediate liner; and C) drying the coated coating composition to form the asenapine-containing layer.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 depicts the asenapine skin permeation rate of TTS prepared according to Example 1.

(2) FIG. 2 depicts the asenapine skin permeation rate of TTS prepared according to Example 2.

(3) FIG. 3a depicts the asenapine skin permeation rate of TTS prepared according to Examples 3aa and 3ba; FIG. 3b depicts the asenapine skin permeation rate of TTS prepared according to Examples 3ab and 3bb.

(4) FIG. 4 depicts the asenapine skin permeation rate of TTS prepared according to Examples 4a, 4b and 4c.

(5) FIG. 5 depicts the asenapine skin permeation rate of TTS prepared according to Examples 5a, 5b and 5c.

(6) FIG. 6 depicts the asenapine skin permeation rate of TTS prepared according to Examples 6a, 6b and 6c.

(7) FIG. 7 depicts the asenapine skin permeation rate of TTS prepared according to Examples 7a and 7b.

(8) FIG. 8 depicts the asenapine skin permeation rate of TTS prepared according to Examples 8a and 8b.

(9) FIG. 9 depicts the asenapine skin permeation rate of TTS prepared according to Examples 9a and 9b.

(10) FIG. 10 depicts the ascnapinc blood plasma concentrations provided by a reservoir system comprising silicone oil prepared according to Example 10 in minipigs.

(11) FIG. 11 depicts the asenapine skin permeation rate of TTS prepared according to Examples 11a and 11b.

(12) FIG. 12 depicts the asenapine skin permeation rate of TTS prepared according to Examples 12a and 12b.

(13) FIG. 13a and FIG. 13b depict the asenapine skin permeation rate and the substance utilization of TTS prepared according to Examples 13a-f

DETAILED DESCRIPTION

TTS Structure

(14) The present invention relates to a transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure comprising a therapeutically effective amount of asenapine. Several aspects of the invention in this regard have been described above.

(15) Preferably, the self-adhesive layer structure according to the present invention comprises A) a backing layer, and B) an asenapine-containing layer comprising 1. asenapine in the form of the free base and 2. a polymer selected from the group consisting of polysiloxanes and polyisobutylenes in an amount of more than 50% by weight based on the total weight of the asenapine-containing layer; and C) optionally an additional skin contact layer.

(16) Thus, according to one embodiment of the invention, the transdermal therapeutic system for the transdermal administration of asenapine comprises a self-adhesive layer structure containing a therapeutically effective amount of asenapine, said self-adhesive layer structure comprising: A) a backing layer; B) an asenapine-containing layer comprising: 1. asenapine in the form of the free base; and 2. a polymer selected from the group consisting of polysiloxanes and polyisobutylenes in an amount of more than 50% by weight based on the total weight of the asenapine-containing layer; and C) optionally an additional skin contact layer.

(17) In one embodiment, the backing layer is substantially asenapine-impermeable. Such a backing layer may also be referred to as occlusive backing layer.

(18) The TTS according to the present invention may be a matrix-type TTS or a reservoir-type TTS, and preferably is a matrix-type TTS.

(19) In a matrix-type TTS according to the invention, the asenapine is included in an asenapine-containing matrix layer. Thus, the asenapine-containing layer is preferably an asenapine-containing matrix layer as defined in detail above. The self-adhesive layer structure in such a matrix-type TTS can include one or more further layers such as an additional skin contact layer. Preferably, the skin contact layer is active agent-free. The skin contact layer and the asenapine-containing matrix layer may comprise the same polymer or different polymers. Any of the asenapine-containing matrix layer and the further layer(s) may be directly contacting each other or separated by a membrane such as a rate controlling membrane. If an asenapine-containing matrix layer is prepared by laminating two asenapine-containing matrix layers, which are of substantially the same composition, the resulting double layer is to be regarded as one matrix layer.

(20) In a reservoir-type TTS according to the present invention, the asenapine is included in a liquid or semi-liquid reservoir. Thus, the asenapine-containing layer may also be an asenapine-containing reservoir layer comprising a reservoir comprising the asenapine and a polymer layer, wherein the reservoir and the polymer layer may optionally be separated from each other by a rate-controlling membrane. The self-adhesive layer structure in such a reservoir-type TTS can include one or more further layers such as an additional skin contact layer. Preferably, the skin contact layer is active agent-free. Any of the asenapine-containing reservoir layer and the further layer(s) may be directly contacting each other or separated by a membrane such as a rate controlling membrane.

(21) In one specific embodiment, the self-adhesive layer structure according to the invention comprises an additional skin contact layer. The additional skin contact layer is self-adhesive and provides for adhesion between the self-adhesive layer structure and the skin of the patient during administration.

(22) In another embodiment, the self-adhesive layer structure according to the invention does not comprise an additional skin contact layer. Sufficient adhesion between the self-adhesive layer structure and the skin of the patient during administration is then provided for by other means, e.g. by the asenapine-containing layer, preferably the asenapine-containing matrix layer. Alternatively, or additionally, an adhesive overlay may be used.

(23) Thus, according to certain embodiments of the invention, the TTS may further comprise an adhesive overlay. This adhesive overlay is in particular larger than the asenapine-containing self-adhesive layer structure and is attached thereto for enhancing the adhesive properties of the overall transdermal therapeutic system. Said adhesive overlay comprises also a backing layer. The area of said adhesive overlay adds to the overall size of the TTS but does not add to the area of release. The adhesive overlay comprises a self-adhesive polymer or a self-adhesive polymer mixture selected from the group of acrylic polymers, polyisobutylenes, styrene-isoprene-styrene copolymers, polysiloxanes, and mixtures thereof, which may be identical to or different from any polymer or polymer mixture included in the active agent-containing self-adhesive layer structure.

(24) The self-adhesive 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.

Asenapine-Containing Layer

(25) As outlined in more detail above, the TTS according to the present invention comprises a self-adhesive layer structure comprising an asenapine-containing layer.

(26) In one embodiment, the asenapine-containing layer comprises: 1. asenapine in the form of the free base; and 2. a polymer selected from the group consisting of polysiloxanes and polyisobutylenes in an amount of more than 50% by weight based on the total weight of the asenapine-containing layer.

(27) In one embodiment of the invention, the asenapine-containing layer is a matrix layer. In another embodiment, the asenapine-containing layer is a reservoir layer. It is preferred that the asenapine-containing layer is an asenapine-containing matrix layer.

(28) In one embodiment of the invention, the asenapine-containing layer is obtainable by incorporating the asenapine in the form of the free base. As a result, the asenapine-containing layer of the TTS according to the invention typically comprises asenapine in the form of the free base. In addition, the asenapine may partly be present in protonated form. However, it is preferred that at least 50 mol %, preferably at least 75 mol % of the asenapine in the asenapine-containing layer are present in the form of the free base. In a particular preferred embodiment, at least 90 mol %, preferably at least 95 mol %, more preferably at least 99 mol % of the asenapine in the asenapine-containing layer are present in the form of the free base. Preferably, the asenapine-containing layer does not comprise asenapine maleate. In certain embodiments, the asenapine-containing layer is free of asenapine salts.

(29) In one embodiment of the invention, the amount of asenapine in the asenapine-containing layer ranges from 1 to 10% by weight, preferably from 2 to 7% by weight based on the total weight of the asenapine-containing layer.

(30) In one embodiment of the invention, the amount of asenapine in the asenapine-containing layer ranges from 3 to 21 mg, preferably from 3.5 to 14 mg.

(31) In one embodiment, the polymer in the asenapine-containing layer is selected from the group consisting of polysiloxanes and polyisobutylenes. Preferably, the polymer in the asenapine-containing layer is a polysiloxane. In certain embodiments of the invention, the polymer is a pressure-sensitive adhesive polymer. In this case, the asenapine-containing layer is preferably a matrix layer, which has adhesive properties, so that no additional skin contact layer is required. The matrix layer composition may comprise a second polymer or may comprise two or more further polymers.

(32) In one embodiment of the invention, the amount of the polymer, which is selected from the group consisting of polysiloxanes and polyisobutylene, is from 55 to 98%, preferably from 70 to 98% or from 80 to 98% by weight based on the total weight of the asenapine-containing layer. In a preferred embodiment of the invention, the asenapine-containing layer comprises the polymer, which is selected from the group consisting of polysiloxanes and polyisobutylenes, in an amount of from 80 to 96% by weight, preferably from 90 to 96% by weight. It is to be understood that also mixtures of polymers may be present in the asenapine-containing layer. Thus, in addition to a polymer selected from the group consisting of polysiloxanes and polyisobutylenes in an amount of more than 50% by weight based on the total weight of the asenapine-containing layer, a further polymer, e.g., an additional polysiloxane or polyisobutylene, an acrylic polymer or a styrene-isoprene-styrene copolymer, or a mixture thereof may be present. It is preferred that the asenapine-containing layer comprises at least 55%, preferably at least 70% by weight of a polysiloxane or polyisobutylene and optionally at least one additional polymer, which may be selected from other polymers including polysiloxanes, polyisobutylenes, acrylic polymers and styrene-isoprene-styrene copolymers. Particularly preferred is an asenapine-containing layer comprising a polysiloxane in an amount from 55 to 98%, preferably from 70 to 98% or from 80 to 98% by weight based on the total weight of the asenapine-containing layer. In an especially preferred embodiment of the invention, the asenapine-containing layer comprises a polysiloxane in an amount of from 80 to 96% by weight, preferably from 90 to 96% by weight.

(33) Without wishing to be bound by theory, it is believed that the advantageous properties of the TTS according to the present invention, such as the good in vitro skin permeation, suitability for 24 hours dosing intervals as well as high active ingredient utilization are inter alia achieved by the fact that asenapine is present in the form of the free base and by the selection of the polymer in the asenapine-containing layer, which is selected from the group consisting of polysiloxanes and polyisobutylenes and is present in an amount of more than 50% by weight based on the total weight of the asenapine-containing layer. In particular, it has been found that it is advantageous if at least 90 mol % of the total amount of asenapine in the asenapine-containing layer is present in the form of the free base, and the asenapine-containing layer further comprises a polymer selected from the group consisting of polysiloxanes and polyisobutylenes in an amount of more than 50%, preferably at least 55%, more preferably at least 70% by weight based on the total weight of the asenapine-containing layer. Polysiloxanes are particularly advantageous for providing TTS suitable for 24 hours dosing intervals.

(34) It has been found that it is not necessarily required that a peilneation enhancer is present in the asenapine-containing layer, but that nevertheless good in vitro skin permeation can be achieved. In one embodiment, the asenapine-containing therefore does not comprise a permeation enhancer. In one preferred embodiment, the asenapine-containing layer does not comprise isopropyl palmitate. In one preferred embodiment, the asenapine-containing layer does not comprise a permeation enhancer selected from oleic acids, oleic alcohols, and triglycerides. In another embodiment, the asenapine-containing layer does not comprise sodium acetate or sodium diacetate. In yet another embodiment, the asenapine-containing layer does not comprise a dicarboxylic acid alkali salt. In yet another embodiment, the asenapine-containing layer does not comprise a maleic acid alkali salt.

(35) In certain embodiments of the invention, the area of release ranges from 5 to 60 cm.sup.2, preferably from 10 to 40 cm.sup.2. In certain preferred embodiments, the area of release is from 10 to 50 cm.sup.2, e.g., from 10 to 25 cm.sup.2 or from 25 to 50 cm.sup.2. In certain particularly preferred embodiments, the area of release ranges is from 20 to 40 cm.sup.2.

(36) In certain embodiments of the invention, the area weight of the asenapine-containing layer ranges from 50 to 120 g/m.sup.2, preferably from 70 to 100 g/m.sup.2. In certain preferred embodiments, the area weight ranges from 75 to 85 g/m.sup.2.

(37) In another embodiment, the asenapine-containing layer comprises: 1. asenapine in an amount of from 2 to 7% by weight based on the total weight of the asenapine-containing layer; and 2. at least one silicone polymer in an amount of from 85 to 98% by weight based on the total weight of the asenapine-containing layer.
Preferably, the asenapine-containing layer is an asenapine-containing matrix-layer, which comprises 1. ascnapinc in an amount of 2 to 7% by weight based on the total weight of the asenapine-containing layer; 2. at least one silicone polymer in an amount of from 85 to 98% by weight based on the total weight of the asenapine-containing layer; and 3. a stabilizer in an amount of from 0.01 to 1.0% by weight based on the total weight of the asenapine-containing layer; and 4. a crystallization inhibitor in an amount of from 0.5 to 10% by weight based on the total weight of the asenapine-containing layer.
The area-weight of the asenapine-containing layer preferably ranges from 70 to 100 g/m.sup.2. Preferably, the stabilizer is tocopherol, ascorbyl palmitate, or a combination thereof, and the crystallization inhibitor is polyvinylpyrrolidone. Furthermore, it is preferred that the asenapine is in the form of the free base. Moreover, the silicone polymer is preferably obtainable by polycondensation of silanol endblocked polydimethylsiloxane with a silicate resin. More preferably, the ratio of the silanol endblocked polydimethylsiloxane to the silicate resin is in the range of from 70:30 to 50:50, preferably from 56:44 to 54:46, e.g. about 55:45. Particularly preferably, the residual functionality of the at least one silicone polymer is capped with trimethylsiloxy groups. This provides amine compatibility of the silicone polymer.

(38) In yet another embodiment, the asenapine-containing layer comprises 1. asenapine in an amount of from 2 to 15% by weight based on the total weight of the asenapine-containing layer; and 2. at least one polyisobutylene in an amount of from 70 to 98% by weight based on the total weight of the asenapine-containing layer;
Preferably, the asenapine-containing layer is an asenapine-containing matrix-layer, which comprises 1. asenapine in an amount of from 2 to 15% by weight based on the total weight of the asenapine-containing layer; and 2. at least one polyisobutylene in an amount of from 70 to 98% by weight based on the total weight of the asenapine-containing layer; and 3. a hydrophilic polymer in an amount of from 1 to 20% by weight based on the total weight of the asenapine-containing layer.
As indicated above, the amount of the at least one polyisobutylene is the total amount of polyisobutylene(s) contained in the asenapine-containing layer. The area weight of the asenapine-containing layer preferably ranges from 40 to 250 g/m.sup.2, and is particularly preferably from 40 to 125 g/m.sup.2 is a dosing interval of from 20 to 30 hours, preferably 24 hours is intended. Preferably, the hydrophilic polymer is polyvinylpyrrolidone. Furthermore, it is preferred that the asenapine is in the form of the free base. The amount of asenapine is preferably in the range of from 4 to 12% by weight, preferably from 6 to 10% by weight based on the total weight of the asenapine-containing layer. Moreover, it is preferred that the at least one polyisobutylene is a combination of a low molecular weight polyisobutylene and a high molecular weight polyisobutylene in a ratio of from 99:1 to 50:50, preferably from 90:10 to 60:40, more preferably from 85:15 to 70:30. Particularly preferably, the low molecular weight polyisobutylene has a viscosity average molecular weight of from 38,000 to 42,000 g/mol and/or a weight average molecular weight of from 34,000 to 40,000 g/mol, and the high molecular weight polyisobutylene has a viscosity average molecular weight of from 1,100,000 to 1,120,000 g/mol and/or a weight average molecular weight of from 1,540,000 to 1,560,000 g/mol. The amount of the at least one polyisobutylene, in particular the above combination of low and high molecular weight polyisobutylenes, is preferably from 70 to 90% by weight, based on the total weight of the asenapine-containing layer.

Asenapine

(39) In accordance with the invention, the self-adhesive layer structure comprises asenapine, in particular in a therapeutically effective amount. Preferably, the therapeutically effective amount of asenapine is provided in the asenapine-containing layer of the self-adhesive layer structure, and is present in the form of the free base.

(40) In one embodiment of the invention, the asenapine-containing layer is obtainable by incorporating the asenapine in the form of the free base.

(41) In one embodiment of the invention, at least 50 mol %, preferably at least 75 mol % of the asenapine in the asenapine-containing layer are present in the form of the free base. In a particular preferred embodiment, at least 90 mol %, preferably at least 95 mol %, more preferably at least 99 mol % of the asenapine in the asenapine-containing layer are present in the form of the free base.

(42) In one embodiment of the invention, at least 50 mol %, preferably at least 75 mol % of the total amount of asenapine in the TTS are present in the form of the free base. In a particular preferred embodiment, at least 90 mol %, preferably at least 95 mol %, more preferably at least 99 mol % of the total amount of asenapine in the TTS are present in the form of the free base.

(43) In one embodiment, the asenapine-containing layer does not comprise asenapine maleate. In certain embodiments, the asenapine-containing layer is free of asenapine salts.

(44) In one embodiment, the TTS of the invention does not comprise asenapine maleate.

(45) The asenapine in the asenapine-containing layer may be present in the form of asenapine particles, preferably constituted of asenapine free base. The particles are preferably homogeneously distributed within the asenapine-containing layer.

(46) As outlined above, the TTS of the invention provides for a high active ingredient utilization. Typically, a therapeutically effective amount of asenapine is released from the TTS over a dosing interval of 24 hours. Due to the high active ingredient utilization, a rather low amount of asenapine in the asenapine-containing layer is sufficient.

(47) In certain embodiments, the amount of asenapine in the asenapine-containing layer ranges from 1 to 10%, preferably from 2 to 7% by weight based on the total weight of the asenapine-containing layer.

(48) In certain embodiments, the amount of asenapine contained in the transdermal therapeutic system ranges from 3 to 21 mg, preferably from 3.5 to 14 mg.

(49) In certain embodiments, the asenapine has a purity of at least 95%, preferably of at least 98% and more preferably of at least 99% as determined by quantitative HPLC. Quantitative HPLC may be performed with Reversed-Phase-HPLC with UV detection. In particular, the following conditions can be used if HPLC is performed isocratically: Column: Octadecyl phase acc. Ph. Eur. 2.2.29 (USP phase L1) Kromasil C18 125 mm×4.0 mm; 5 μm or equivalent Mobile phase: KH.sub.2PO.sub.4/Methanol/TEA (45:55:0.1; v:v:v); pH 2.5±0.05 (TEA=triethylamine) Gradient: isocratic Flux: 1.0 mL Injection volume: 30 μL Column temperature: 40° C. Wavelength: 225 nm, 270 nm and 3-D-field; Evaluation is performed at 270 nm Run time: 10 min Furthermore, the following conditions can be used if HPLC is performed with a gradient: Column: Octadecyl phase acc. Ph. Eur. 2.2.29 (USP phase L1) Kinetex C18 EVO 100 mm×4.6 mm; 2.1 μm or equivalent Mobile phase: A: 0.02 mol KH.sub.2PO.sub.4 Buffer/Methanol/TEA (70:30:0.1; v:v:v) adj. to pH 2.5 B: 0.02 mol KH.sub.2PO.sub.4 Buffer/Methanol/TEA (30:70:0.1; v:v:v); adj. to pH 2.5 (TEA=triethylamine) Flux: 1.0 mL Injection volume: 30 μL Column temperature: 40° C. Wavelength: 225 nm, 270 nm and 3-D-field; Evaluation is performed at 225 nm Run time: 32 min Gradient profile:

(50) TABLE-US-00001  0.00 min: A: 100% B: 0% 12.00 min: A: 40% B: 60% 18.00 min: A: 0% B: 100% 27.00 min: A: 0% B: 100% 27.01 min: A: 100% B: 0% 32.00 min: A: 100% B: 0%

Polymer

(51) As outlined above, the TTS according to a specific embodiment of the present invention comprises a self-adhesive layer structure comprising an asenapine-containing layer comprising a polymer selected from the group consisting of polysiloxanes and polyisobutylenes in an amount of more than 50% by weight based on the total weight of the asenapine-containing layer. It has been found that the use of a polysiloxane or a polyisobutylene in the asenapine-containing layer is advantageous in terms of the active ingredient utilization and the permeation properties of the TTS. The resulting TTS according to the invention are particularly suitable for dosing intervals of 24 hours.

(52) In certain embodiments, the polymer, i.e. the polysiloxane or the polyisobutylene, is a pressure-sensitive adhesive polymer, so that good adhesive properties are also obtained. This is particularly relevant, if the asenapine-containing layer is an asenapine-containing matrix layer, which is preferred according to the invention. Preferably, an additional skin contact layer is not required, if the asenapine-containing matrix layer comprises a polysiloxane or a polyisobutylene in an amount of more than 50% by weight, wherein said polysiloxane or polyisobutylene is a pressure-sensitive adhesive polymer. In this case, the TTS is preferably based on a monolayer structure with the asenapine-containing matrix layer as the only layer being present on the backing layer. The pressure-sensitive adhesive polymer provides for sufficient cohesion and adhesion of the matrix layer.

(53) In certain embodiments of the invention, the polymer, which is selected from polysiloxanes and polyisobutylenes, is present in the asenapine-containing layer in an amount of at least 55%, preferably at least 70%, more preferably at least 80% by weight based on the total weight of the asenapine-containing layer. Preferably, the amount ranges from 55 to 98%, preferably from 70 to 98% or from 80 to 98% by weight based on the total weight of the asenapine-containing layer. In a preferred embodiment of the invention, the asenapine-containing layer comprises the polymer, which is selected from the group consisting of polysiloxanes and polyisobutylenes, in an amount of from 80 to 98% by weight, preferably from 90 to 98% by weight, more preferably from 92 to 98% by weight. If the polymer, which is present in the asenapine-containing layer in an amount as defined above, is selected from polysiloxanes, it is to be understood that also combinations of polysiloxanes are covered. Preferably, only one type of polysiloxane is present in the asenapine-containing layer. If the polymer, which is present in the asenapine-containing layer in an amount as defined above, is selected from polyisobutylenes, it is to be understood that also combinations of polyisobutylenes are covered. In one embodiment, only one type of polyisobutylene is present in the asenapine-containing layer. In another embodiment, a combination of two different types of polyisobutylenes is present in the asenapine-containing layer.

(54) In addition, at least one further polymer may be present in the asenapine-containing layer. The at least one further polymer may be selected from polysiloxanes, polyisobutylenes, styrene-isoprene-styrene block copolymers and acrylic polymers. For example, the additional polymer may be an acrylic polymer.

(55) In one embodiment, the polymer, which is present in the asenapine-containing layer in an amount of more than 50% by weight, is a polysiloxane or a combination of polysiloxanes. In a preferred embodiment, the polysiloxane or the combination of polysiloxanes is present in an amount of at least 55%, more preferably at least 70%, most preferably at least 80% by weight. In another preferred embodiment, the polysiloxane or the combination of polysiloxanes is present in an amount ranging from 55 to 98%, preferably from 70 to 98% or from 80 to 98% by weight based on the total weight of the asenapine-containing layer. Preferably, the asenapine-containing layer comprises only one polysiloxane in an amount of more than 50% by weight. In a preferred embodiment, the polysiloxane is present in an amount of at least 55%, more preferably at least 70%, most preferably at least 80% by weight. In another preferred embodiment, the polysiloxane is present in an amount ranging from 55 to 98%, preferably from 70 to 98% or from 80 to 98% by weight based on the total weight of the asenapine-containing layer. In an especially preferred embodiment of the invention, the asenapine-containing layer comprises the polysiloxane in an amount of from 80 to 98% by weight, preferably from 90 to 98% by weight, more preferably from 92 to 98% by weight. In certain embodiments, it is preferred that no additional polymer apart from the polysiloxane is present. In other embodiments, especially if the amount of the polysiloxane is in the range of, e.g., from 55 to 80% by weight based on the total weight of the asenapine-containing layer, an additional polymer selected from polyisobutylenes, styrene-isoprene-styrene block copolymers and acrylic polymers may be present in the asenapine-containing layer. It is then preferred that the total amount of all polymers in the asenapine-containing layer is from 80 to 98% by weight based on the total weight of the asenapine-containing layer.

(56) In another embodiment, the polymer, which is present in the asenapine-containing layer in an amount of more than 50% by weight, is a polyisobutylene or a combination of polyisobutylenes. In a preferred embodiment, the polyisobutylene or the combination of polyisobutylenes is present in an amount of at least 55%, more preferably at least 70%, most preferably at least 80% by weight. In another preferred embodiment, the polyisobutylene or the combination of polyisobutylenes is present in an amount ranging from 55 to 98%, preferably from 70 to 98%, especially preferably from 70 to 90% by weight, based on the total weight of the asenapine-containing layer. In certain embodiments, it is preferred that no additional polymer apart from the polyisobutylene is present. In other embodiments, especially if the amount of the polyisobutylene or the combination of polyisobutylenes is in the range of, e.g., from 55 to 80% by weight based on the total weight of the asenapine-containing layer, an additional polymer selected from polysiloxanes, styrene-isoprene-styrene block copolymers and acrylic polymers may be present. It is then preferred that the total amount of all polymers in the asenapine-containing layer is from 80 to 98% by weight based on the total weight of the asenapine-containing layer.

(57) Suitable polymers according to the invention are commercially available e.g. under the brand names BIO-PSAs (polysiloxanes), Oppanol™ (polyisobutylenes), JSR-SIS (a styrene-isoprene-styrene copolymer) or Duro-Tak™ (acrylic polymers).

(58) The term “polysiloxane” as used herein refers to a polymer, which is based on a polysiloxane, and may also be referred to as silicone-based polymer, silicone polymer, or silicone. Pressure-sensitive polysiloxanes, i.e. pressure-sensitive adhesives based on polysiloxanes may also be referred to as silicone-based pressure-sensitive adhesives, or silicone pressure-sensitive adhesives. For the present invention, pressure-sensitive adhesive polysiloxanes are preferred. These pressure-sensitive adhesives 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 them 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 silicate resin, a 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 dimethiconol and resin provides for the correct adhesive properties.

(59) In view of the above, the silicone polymers of the invention (herein also referred to as “polysiloxanes”) are generally obtainable by polycondensation of silanol endblocked polydimethylsiloxane with a silicate resin. Amine-compatible silicone polymers can be obtained by reacting the silicone polymer 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.

(60) As indicated above, the tackiness of the silicone 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 polymer relative to the resin. High tack silicone polymers preferably have a resin-to-polymer ratio of 55:45, medium tack silicone polymers preferably have a resin-to-polymer ratio of 60:40, and low tack silicone polymers preferably have a resin-to-polymer ratio of 65:35. High tack silicone polymers preferably have a complex viscosity at 0.01 rad/s and 30° C. of 5×10.sup.6 Poise, medium tack silicone polymers preferably have a complex viscosity at 0.01 rad/s and 30° C. of 5×10.sup.7 Poise, and low tack silicone polymers preferably have a complex viscosity at 0.01 rad/s and 30° C. of 5×10.sup.8 Poise. High tack amine-compatible silicone polymers preferably have a complex viscosity at 0.01 rad/s and 30° C. of 5×10.sup.6 Poise, medium tack amine-compatible silicone polymers preferably have a complex viscosity at 0.01 rad/s and 30° C. of 5×10.sup.8 Poise, and low tack amine-compatible silicone polymers preferably have a complex viscosity at 0.01 rad/s and 30° C. of 5×10.sup.9 Poise.

(61) Examples of useful pressure-sensitive adhesives based on polysiloxane 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 by Dow Coming. Preferred pressure-sensitive adhesives based on polysiloxane are heptane-solvated pressure-sensitive adhesives including BIO-PSA 7-4201, BIO-PSA 7-4301, BIO-PSA 7-4501. For example, BIO-PSA 7-4201 is characterized by a solution viscosity at 25° C. and about 70% 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 70% 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.

(62) The silicone polymers are supplied and used in solvents like n-heptane, ethyl acetate or other volatile silicone fluids. For the present invention n-heptane is preferred. The solids content of the silicone polymers in the solvents is usually between 60 and 80%, preferably between 70 and 80% or between 60 and 70%. The skilled person is aware that the solids content may be modified by adding a suitable amount of solvent.

(63) Silicone polymers, which are, e.g., available from Dow Corning, may be obtained according to the following scheme:

(64) ##STR00001##
Such silicone polymers are also referred to as standard silicone adhesive and 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.

(65) Amine-compatible silicone polymers, which are, e.g., available from Dow Corning may be obtained according to the following scheme:

(66) ##STR00002##
Such amine-compatible silicone polymers 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.

(67) 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.

(68) The adhesive strength of the polysiloxanes may be sufficient for the desired skin contact. In certain embodiments of the invention a plasticizer or a tackifying agent is incorporated into the formulation to improve the adhesive characteristics of the pressure-sensitive adhesive. It may be advantageous in an individual case to improve the tack by adding small amounts of tackifiers such as polyterpenes, rosin derivatives, or silicone oils. In preferred embodiments, the tackifying agent is a silicone oil (e.g., 360 Medical Fluid, available from Dow Coming Corporation, Midland, Mich.).

(69) The pressure-sensitive adhesives are supplied and used in solvents like n-heptane, ethyl acetate or other volatile silicone fluids. For the present invention n-heptane is preferred. The solids content of polysiloxanes in solvents is usually between 60 and 85%, preferably between 70 and 80%. The solids content of polyisobutylenes in solvents is usually between 30 and 50%, preferably between 35 and 40%. The skilled person is aware that the solids content may be modified by adding a suitable amount of solvent.

(70) 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. 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.

(71) Suitable pressure-sensitive adhesives based on polysiloxanes may be obtained from Dow Corning® BIO-PSA Standard Silicone Adhesives. Preferred is the BIO-PSA 7 4301.

(72) Suitable polyisobutylenes according to the invention are available under the tradename Oppanol®. Combinations of high-molecular weight polyisobutylenes (B100/B80) and low-molecular weight polyisobutylenes (B10, B11, B12, B13) may be used. Suitable ratios of low-molecular weight polyisobutylene to high-molecular weight polyisobutylene are in the range of from 100:1 to 1:100, preferably from 95:5 to 40:60, more preferably from 90:10 to 80:20. In particular, it is preferred that the at least one polyisobutylene is a combination of a low molecular weight polyisobutylene and a high molecular weight polyisobutylene in a ratio of from 99:1 to 50:50, preferably from 90:10 to 60:40. Typically, the low molecular weight polyisobutylene has a viscosity average molecular weight of from 10,000 to 70,000 g/mol and/or a weight average molecular weight of from 10,000 to 70,000 g/mol, and the high molecular weight polyisobutylene has a viscosity average molecular weight of from 1,000,000 to 1,200,000 g/mol and/or a weight average molecular weight of from 1,400,000 to 1,600,000 g/mol. Particularly preferably, the low molecular weight polyisobutylene has a viscosity average molecular weight of from 38,000 to 42,000 g/mol and/or a weight average molecular weight of from 34,000 to 40,000 g/mol, and the high molecular weight polyisobutylene has a viscosity average molecular weight of from 1,100,000 to 1,120,000 g/mol and/or a weight average molecular weight of from 1,540,000 to 1,560,000 g/mol. A preferred example for a polyisobutylene combination is B10/B100 in a ratio of 85/15 or 90/10. Oppanol® B100 has a viscosity average molecular weight M.sub.v of 1,110,000, and a weight average molecular weight M.sub.w of 1,550,000. Oppanol® B10 has a viscosity average molecular weight M.sub.v of 40,000, and a weight average molecular weight M.sub.w of 36,000. In certain embodiments, polybutene may be added to the polyisobutylenes.

(73) Additional polymers and additives may also be added to enhance cohesion and/or adhesion.

(74) 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 Additives

(75) The TTS according to the invention, and in particular the asenapine-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, hydrophilic polymers, 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. Furthermore, 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. Such additives may be present in the asenapine-containing layer in an amount of from 0.001% to 20% by weight or 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 asenapine-containing layer per additive. In certain embodiments, the total amount of all additives is from 0.001% to 25% of the asenapine-containing layer. Hereinafter, where a range for an amount of a specific additive is given, such a range refers to the amount per individual additive.

(76) Particularly preferred additives are selected from crystallization inhibitors and stabilizers. In a preferred embodiment of the invention, the TTS comprises a stabilizer in an amount of from 0.01 to 1.0% by weight and/or a crystallization inhibitor in an amount of from 0.5 to 10% by weight based on the total weight of the asenapine-containing layer. These additives are particularly preferred in connection with a TTS comprising a silicone polymer in the asenapine-containing layer.

(77) In connection with a TTS comprising a polyisobutylene in the asenapine-containing layer, it is preferred that the TTS comprises a hydrophilic polymer in an amount of from 1 to 20% by weight, preferably 5 to 15% by weight. The hydrophilic polymer allow that the TTS takes up water, which may improve the release properties.

(78) 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.

(79) In one embodiment, the asenapine-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 asenapine-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.

(80) In one embodiment, the asenapine-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. If the asenapine-containing layer comprises a stabilizer, the stabilizer is present 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 asenapine-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.

(81) In one embodiment, the asenapine-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.

(82) In one embodiment, the asenapine-containing layer further comprises a solubilizer. 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; 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; as well as any of the below mentioned soluble polyvinylpyrrolidones, but also insoluble/cross-linked polyvinylpyrrolidones also known as crospovidones such as Kollidon® CL, Kollidon® CL-M and Kollidon® CL-SF, and polyvinylpyrrolidone-polyvinyl acetate copolymers, also known as copovidones, such as Kollidon® VA64.

(83) However, also the permeation enhancers mentioned below can act as solubilizers. Furthermore, also crystallization inhibitors may act as solubilizers.

(84) In one embodiment, the asenapine-containing layer further comprises a hydrophilic polymer, which preferably allows that the TTS takes up water. Some of the above-mentioned solubilizers may also be useful as hydrophilic polymers. Preferred hydrophilic polymers include glycerol-, polyglycerol-, propylene glycol- and polyoxyethylene-esters, cellulose and methylcellulose and derivatives thereof such as hydroxypropylcellulose and hypromellose acetate succinate; non-ionic tri-block copolymers having a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene known as poloxamers; 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 polyoxyethylene sorbitan monooleate (such as polysorbate 80) or of propylene glycols; diethylene glycol monoethyl ether; as well as any of the below mentioned soluble polyvinylpyrrolidones, but also insoluble/cross-linked polyvinylpyrrolidones also known as crospovidones such as Kollidon® CL, Kollidon® CL-M and Kollidon® CL-SF, and polyvinylpyrrolidone-polyvinyl acetate copolymers, also known as crospovidones, such as Kollidon® VA64. A particularly preferred hydrophilic polymer is polyvinylpyrrolidone.

(85) In one embodiment, the asenapine-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.

(86) In one embodiment, the asenapine-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.

(87) In one embodiment, the asenapine-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 asenapine-containing layer.

(88) If the asenapine-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 asenapine-containing layer.

(89) 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.

(90) 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”.

(91) In one embodiment, the asenapine-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.

(92) If the asenapine-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.

(93) In one embodiment, the asenapine-containing layer does not comprise isopropyl palmitate as permeation enhancer.

(94) In one embodiment, the asenapine-containing layer does not comprise a permeation enhancer selected from oleic acids, oleic alcohols, and triglycerides.

(95) In one embodiment, the asenapine-containing layer does not comprise sodium acetate or sodium diacetate. In yet another embodiment, the asenapine-containing layer does not comprise a dicarboxylic acid alkali salt. In yet another embodiment, the asenapine-containing layer does not comprise a maleic acid alkali salt.

(96) 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 asenapine-containing layer does not comprise a permeation enhancer.

(97) 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.

Release Characteristics

(98) The TTS in accordance with the invention are designed for transdermally administering asenapine to the systemic circulation for a predefined extended period of time.

(99) In one embodiment, the TTS according to the invention provides a mean release rate of from 0.5 to 20 mg/day, preferably from 3 to 10 mg/day, more preferably of from 3 to 8 mg/day asenapine over at least 24 hours of administration.

(100) In one embodiment, the TTS according to the invention provides a skin permeation rate of asenapine as measured in a Franz diffusion cell with dermatomed human skin of 0 μg/(cm.sup.2*h) to 12 μg/(cm.sup.2*h) in the first 4 hours, 1 μg/(cm.sup.2*h) to 22 μg/(cm.sup.2*h) from hour 4 to hour 8, 6 μg/(cm.sup.2*h) to 25 μg/(cm.sup.2*h) from hour 8 to hour 12, 5 μg/(cm.sup.2*h) to 20 μg/(cm.sup.2*h) from hour 12 to hour 16, 4 μg/(cm.sup.2*h) to 18 μg/(cm.sup.2*h) from hour 16 to hour 20, 2 μg/(cm.sup.2*h) to 12 μg/(cm.sup.2*h) from hour 20 to hour 24.

(101) In one embodiment, the transdermal therapeutic system according to the invention provides a cumulative permeated amount of asenapine as measured in a Franz diffusion cell with dermatomed human skin of 120 μg/cm.sup.2 to 380 μg/cm.sup.2 over a time period of 24 hours.

(102) In one embodiment, the transdermal therapeutic system according to the invention provides a permeated amount of asenapine as measured in a Franz diffusion cell with dermatomed human skin of 0 μg/cm.sup.2 to 50 μg/cm.sup.2 in the first 4 hours, 20 μg/cm.sup.2 to 120 μg/cm.sup.2 from hour 4 to hour 8, 40 μg/cm.sup.2 to 220 μg/cm.sup.2 from hour 8 to hour 12, 60 μg/cm.sup.2 to 290 μg/cm.sup.2 from hour 12 to hour 16, 80 μg/cm.sup.2 to 340 μg/cm.sup.2 from hour 16 to hour 20, 100 μg/cm.sup.2 to 380 μg/cm.sup.2 from hour 20 to hour 24.

Method of Treatment/Medical Use

(103) In accordance with a specific aspect of the present invention, the TTS according to the invention is for use in a method of treatment, and in particular in a method of treating a human patient.

(104) In certain embodiments, the TTS according to the invention is for use in a method of treating psychosis in general, and in particular for use in a method of treating one or more conditions selected from schizophrenia, bipolar disorder, posttraumatic stress disorder, major depressive disorder, dementia related psychosis, agitation and manic disorder in a human patient.

(105) In certain embodiments, the TTS according to the invention is for use in a method of treating schizophrenia and/or bipolar disorder in a human patient, and in particular for use in a method of treating acute manic or mixed episodes of bipolar disorder in a human patient. In certain embodiments, the TTS according to the invention is for use in a method of treating acute manic or mixed episodes of bipolar disorder in an adult or a pediatric patient 10 to 17 years of age.

(106) In certain embodiments, the TTS according to the invention is for use as an adjunctive treatment to lithium or valproate in a method of treating bipolar disorder in a human patient, in particular an adult. In certain embodiments, the TTS according to the invention is for use as a maintenance monotherapy treatment in a method of treating bipolar disorder in a human patient, in particular an adult.

(107) In certain embodiments, the TTS according to the invention is for use in a method of treatment, preferably in a method of treating psychosis in general, and in particular for use in a method of treating one or more conditions selected from schizophrenia, bipolar disorder, posttraumatic stress disorder, major depressive disorder, dementia related psychosis, agitation and manic disorder in a human patient, and especially preferably in a method of treating schizophrenia and/or bipolar disorder, wherein the TTS is applied to the skin of the patient for a dosing interval of at least 20 hours. In one embodiment, the TTS according to the invention is for use in a method of treatment, wherein the TTS is applied to the skin of the patient for a dosing interval of from 20 to 30 hours, preferably about 24 hours. Accordingly, the TTS is preferably for use in a method of treatment, preferably in a method of treating schizophrenia and/or bipolar disorder, wherein an around-the-clock treatment is performed with a once-a-day TTS exchange mode (dosing interval of 24 hours). In connection with the afore-mentioned embodiments, the term “dosing interval” is to be understood as the time period between the time of administering a first TTS of the invention and replacing the TTS by a second TTS of the invention. Thus, the administration time of the TTS preferably corresponds to the time of the dosing interval and is preferably from 20 to 30 hours, particularly preferably about 24 hours. 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 hack or the side of the chest for the defined dosing intervals.

(108) It has been found that the TTS of the invention provides blood plasma concentrations of asenapine over 24 hours, which are comparable to the blood plasma concentrations obtained with sublingual asenapine tablets, when administered in dosage strengths of 5 mg or 10 mg twice daily (BID).

(109) Thus, in one embodiment, the TTS according to the invention provides by passive transdermal delivery an AUC.sub.0-24 of from 5 to 100 (ng/ml)*h. In a preferred embodiment, the TTS provides by passive transdermal delivery an AUC.sub.0-24 of from 10 to 90 (ng/mL)*h.

Process of Manufacture

(110) The invention further relates to a process of manufacture of an asenapine-containing layer, preferably an asenapine-containing matrix layer, for use in a transdermal therapeutic system.

(111) In accordance with the invention, the process for manufacturing an asenapine-containing layer for use in a transdermal therapeutic system according to the invention comprises the steps of: 1) combining at least the components 1. asenapine in the form of asenapine base; 2. a polymer selected from the group consisting of polysiloxanes and polyisobutylenes in an amount of more than 50% by weight based on the total weight of the asenapine-containing layer; and 3. optionally at least one additive; to obtain a coating composition; 2) coating the coating composition onto the backing layer or release liner or any intermediate liner; and 3) drying the coated coating composition to form the matrix layer.

(112) In this process of manufacture, preferably in step 1) the asenapine is preferably dissolved to obtain a coating composition.

(113) In the above described process, 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.

(114) In certain embodiments, the polymer in the above process is polysiloxane, which is provided as a solution and preferably as a solution in n-heptane or ethyl acetate with a solids content of from 60 to 80% by weight.

(115) In step 3), drying is performed preferably at a temperature of from 50 to 90° C., more preferably from 60 to 90° C.

(116) It is to be understood that the process above may be modified in line with the aspects and embodiments of the invention outlined above, in particular with regard to the preferences provided in connection with the asenapine, the polymer and the additives.

EXAMPLES

(117) 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.

Example 1

(118) Coating Composition

(119) The formulation of the asenapine-containing coating composition of Example 1 is summarized in Table 1.1 below.

(120) TABLE-US-00002 TABLE 1.1 Ex. 1 Solid Solid Liquid Liquid Ingredient (Trade Name) [g] [%] [g] [%] Asenapine Base 0.4899 7.001 0.4899 4.805 Silicone adhesive in n-heptane. 6.508 92.999 8.9890 88.161 Solids content of 72.40% by weight (DOW CORNING ® BIO-PSA Q7-4301) Ethyl acetate 0.7172 7.034 Total 6.9979 100.00 10.1961 100.00 Area Weight [g/m.sup.2] 77.8 Loading API [μg/cm.sup.2] 544.7
Preparation of the Coating Composition

(121) A beaker was loaded with the asenapine base. The solvent (ethyl acetate) was added, followed by the addition of the silicone pressure sensitive adhesive (DOW CORNING® BIO-PSA Q7-4301). The mixture was stirred at approx. 300 rpm until a homogenous mixture was obtained (at least 60 min).

(122) Coating of the Coating Composition of Example

(123) The resulting asenapine-containing coating composition was coated on a polyethylene terephthalate film (one side fluoropolymer coated, 75 μm thickness, which may function as release liner) and dried for approx. 15 min at approx. room temperature and approx. 25 min at approx. 60° C. The coating thickness gave an area weight of the matrix layer of 77.8 g/m.sup.2. The dried film was laminated with a polyethylene terephthalate backing layer (beige lacquered, 23 μm thickness) to provide an asenapine-containing self-adhesive layer structure.

(124) Preparation of the TTS (Concerning all Examples)

(125) The individual systems (TTS) were then punched out from the asenapine-containing self-adhesive layer structure. In specific embodiments a TTS as described above can be provided with a further self-adhesive layer of larger surface area, preferably with rounded corners, comprising a pressure-sensitive adhesive matrix layer which is free of active agent. This is of advantage when the TTS, on the basis of its physical properties alone, does not adhere sufficiently to the skin and/or when the asenapine-containing matrix layer, for the purpose of avoiding waste, has pronounced corners (square or rectangular shapes). The TTS are then punched out and sealed into pouches of the primary packaging material.

(126) Measurement of Skin Permeation Rate

(127) The permeated amount and the corresponding skin permeation rates of TTS prepared according to Example 1 was determined by in vitro experiments in accordance with the OECD Guideline (adopted Apr. 13, 2004) carried out with a 10.0 ml Franz diffusion cell. Split thickness human skin from cosmetic surgeries (e.g., female abdomen, date of birth 1954) was used. A dermatome was used to prepare skin to a thickness of 800 μm, with an intact epidermis for all TTS. Diecuts with an area of 1.15 cm.sup.2 were punched from the TTS. The asenapine permeated amount in the receptor medium of the Franz cell (phosphate buffer solution pH 5.5 with 0.1% saline azide as antibacteriological agent) at a temperature of 32±1° C. was measured and the corresponding skin permeation rate calculated. The results are shown in Table 1.2 and FIG. 1.

(128) TABLE-US-00003 TABLE 1.2 Skin permeation rate with SD [μg/cm.sup.2h] Elapsed Ex. 1 (n = 3) time [h] Rate SD 0 0 0 4 2.65 2.29 8 20.02 0.22 12 23.35 0.16 16 18.71 0.52 20 13.26 0.03 24 8.52 0.4 32 8.4 0.59 40 3.07 0.08 48 1.99 0.12

Example 2

(129) Coating Composition

(130) The formulation of the asenapine-containing coating composition of Example 2 is summarized in Table 2.1 below.

(131) TABLE-US-00004 TABLE 2.1 Ex. 2 Solid Solid Liquid Liquid Ingredient (Trade Name) [g] [%] [g] [%] Asenapine Base 0.2484 3.543 0.2484 2.436 Silicone adhesive in n-heptane. 6.7444 96.195 9.3155 91.343 Solids content of 72.40% by weight (DOW CORNING ® BIO-PSA Q7-4301) α-Tocopherol 0.0184 0.262 0.0184 0.180 Ethyl acetate 0.6161 6.041 Total 7.0112 100.00 10.1984 100.00 Area Weight [g/m.sup.2] 75.1 Loading API [μg/cm.sup.2] 275.6
Preparation of the Coating Composition

(132) The coating composition was prepared as described in Example 1, wherein α-tocopherol was added before the addition of the solvent. The mixture was however stirred from approx. 250 rpm to approx. 1000 rpm until a homogenous mixture was obtained (at least 60 min).

(133) Coating of the Coating Composition

(134) See Example 1 for the coating process. The coating was however dried for approx. 10 min at approx. room temperature and approx. 15 min at approx. 60° C. The coating thickness gave an area weight of the matrix layer of 75.1 g/m.sup.2. The dried film was laminated with a polyethylene terephthalate backing layer (beige lacquered, 23 μm thickness) to provide an asenapine-containing self-adhesive layer structure.

(135) Preparation of the TTS

(136) See Example 1.

(137) Measurement of Skin Permeation Rate

(138) The permeated amount and the corresponding skin permeation rates of TTS prepared according to Example 2 was determined by in vitro experiments in accordance with the OECD Guideline (adopted Apr. 13, 2004) carried out with a 10.0 ml Franz diffusion cell. Split thickness human skin from cosmetic surgeries (female abdomen, date of birth 1981) was used. A dermatome was used to prepare skin to a thickness of 800 μm, with an intact epidermis for all TTS. Diecuts with an area of 1.15 cm.sup.2 were punched from the TTS. The asenapine permeated amount in the receptor medium of the Franz cell (phosphate buffer solution pH 5.5 with 0.1% saline azide as antibacteriological agent) at a temperature of 32±1° C. was measured and the corresponding skin permeation rate calculated. The results are shown in Table 2.2 and FIG. 2.

(139) TABLE-US-00005 TABLE 2.2 Skin permeation rate with SD [μg/cm.sup.2h] Elapsed Ex. 2 (n = 3) time [h] Rate SD 0 0 0 4 3.11 0.49 8 10.87 0.87 12 11.62 0.79 16 8.43 0.4 20 6.2 0.19 24 4.58 0.22

Examples 3AA-BB

(140) Coating Composition

(141) The formulations of the asenapine-containing coating compositions of Examples 3aa-bb are summarized in Tables 3.1a and 3.1b.

(142) TABLE-US-00006 TABLE 3.1a Ex. 3aa/3ab Solid Solid Liquid Liquid Ingredient (Trade Name) [g] [%] [g] [%] Asenapine Base 0.2484 3.543 0.2484 2.436 Silicone adhesive in n-heptane. 6.7444 96.195 9.3155 91.343 Solids content of 72.40% by weight (DOW CORNING ® BIO-PSA Q7-4301) α-Tocopherol 0.0184 0.262 0.0184 0.180 Ethyl acetate 0.6161 6.041 Total 7.0112 100.00 10.1984 100.00 Area Weight [g/m.sup.2] 75.1 Loading API [μg/cm.sup.2] 275.6

(143) TABLE-US-00007 TABLE 3.1b Ex. 3ba/3bb Solid Solid Liquid Liquid Ingredient (Trade Name) [g] [%] [g] [%] Asenapine Base 0.2997 2.992 0.2997 2.054 Silicone adhesive in n-heptane. 9.6881 96.714 13.3814 91.702 Solids content of 72.40% by weight (DOW CORNING ® BIO-PSA Q7-4301) α-Tocopherol 0.0295 0.294 0.0295 0.202 Ethyl acetate 0.8817 6.042 Total 10.0173 100.00 14.5923 100.00 Area Weight [g/m.sup.2] 110.45 Loading API [μg/cm.sup.2] 330.5
Preparation of the Coating Composition

(144) The coating compositions for Examples 3aa and 3ab were prepared as described in Example 2. The coating compositions for Examples 3ba and 3bb were prepared as described in Example 2. The mixture was however stirred from approx. 400 rpm to approx. 1000 rpm until a homogenous mixture was obtained (at least 60 min).

(145) Coating of the Coating Composition

(146) For Examples 3aa and 3ab see Example 2 for the coating process. For Examples 3ba and 3bb see Example 1 for the coating process. The coating was however dried for approx. 10 min at approx. room temperature and approx. 20 min at approx. 60° C. The coating thickness gave an area weight of the matrix layer of 75.1 (3aa and 3ab) and 110.45 (3ba and 3bb) g/m.sup.2 respectively. The dried film was laminated with a polyethylene terephthalate backing layer (beige lacquered, 23 μm thickness) to provide an asenapine-containing self-adhesive layer structure.

(147) Preparation of the TTS

(148) See Example 1.

(149) Measurement of Skin Permeation Rate for Examples 3aa and 3ba

(150) The permeated amounts and the corresponding skin permeation rates of TTS prepared according to Examples 3aa and 3ba were determined by in vitro experiments in accordance with the OECD Guideline (adopted Apr. 13, 2004) carried out with a 10.0 ml Franz diffusion cell. Split thickness human skin from cosmetic surgeries (male abdomen, date of birth 1955) was used. A dermatome was used to prepare skin to a thickness of 800 μm, with an intact epidermis for all TTS. Diecuts with an area of 1.15 cm.sup.2 were punched from the TTS. The asenapine permeated amounts in the receptor medium of the Franz cell (phosphate buffer solution pH 5.5 with 0.1% saline azide as antibacteriological agent) at a temperature of 32±1° C. were measured. The results are shown in Table 3.2 and FIG. 3a.

(151) Measurement of Skin Permeation Rate for Examples 3ab and 3bb

(152) The permeated amounts and the corresponding skin permeation rates of TTS prepared according to Examples 3ab and 3bb were determined by in vitro experiments in accordance with the OECD Guideline (adopted Apr. 13, 2004) carried out with a 10.0 ml Franz diffusion cell. Split thickness human skin from cosmetic surgeries (female abdomen, date of birth 1978) was used. A dermatome was used to prepare skin to a thickness of 800 μm, with an intact epidermis for all TTS. Diecuts with an area of 1.15 cm.sup.2 were punched from the TTS. The asenapine permeated amounts in the receptor medium of the Franz cell (phosphate buffer solution pH 5.5 with 0.1% saline azide as antibacteriological agent) at a temperature of 32±1° C. were measured and the corresponding skin permeation rates calculated. The results are shown in Table 3.2 and FIG. 3b.

(153) TABLE-US-00008 TABLE 3.2 Skin permeation rate with SD [μg/cm.sup.2h] Ex. 3aa Ex. 3ba Ex. 3ab Ex. 3bb Elapsed (n = 3) (n = 3) (n = 3) (n = 3) time [h] Rate SD Rate SD Rate SD Rate SD 0 0 0 0 0 0 0 0 0 2 / / / / 2.58 0.06 1.45 0.61 4 1.89 0.23 2.98 1.06 11.54 0.95 8.62 2.37 8 8.01 0.31 12.66 2.12 12.47 0.72 10.99 1.85 24 5.69 0.48 8.25 1.17 4.59 0.38 6.26 0.71 32 3.56 0.34 4.59 0.47 / / / /

Examples 4A-C

(154) Coating Composition

(155) The formulations of the ascnapinc-containing coating compositions of Examples 4a-c are summarized in Tables 4.1a, 4.1b, and 4.1c below.

(156) TABLE-US-00009 TABLE 4.1a Ex. 4a Solid Solid Liquid Liquid Ingredient (Trade Name) [g] [%] [g] [%] Asenapine Base 0.334 6.644 0.334 4.235 Silicone adhesive in n-heptane. 4.29 85.34 5.93 75.19 Solids content of 72.40% by weight (DOW CORNING ® BIO-PSA Q7-4301) Transcutol (diethylene glycol 0.403 8.017 0.403 5.110 monoethyl ether) Petroleum ether, bp 80-110° C. 1.22 15.47 Total 5.027 100.00 7.887 100.01 Area Weight [g/m.sup.2] 96.2 Loading API [μg/cm.sup.2] 639.2

(157) TABLE-US-00010 TABLE 4.1b Ex. 4b Solid Solid Liquid Liquid Ingredient (Trade Name) [g] [%] [g] [%] Asenapine Base 0.330 6.565 0.330 4.163 Silicone adhesive in n-heptane. 4.29 85.34 5.92 74.68 Solids content of 72.40% by weight (DOW CORNING ® BIO-PSA Q7-4301) Diisopropyladipate 0.407 8.096 0.407 5.134 Petroleum ether, bp 80-110° C. 1.27 16.02 Total 5.027 100.00 7.977 100.00 Area Weight [g/m.sup.2] 98.8 Loading API [μg/cm.sup.2] 648.1

(158) TABLE-US-00011 TABLE 4.1c Ex. 4c Solid Solid Liquid Liquid Ingredient (Trade Name) [g] [%] [g] [%] Asenapine Base 0.333 6.627 0.333 4.261 Silicone adhesive in n-heptane. 4.30 85.57 5.90 75.50 Solids content of 72.40% by weight (DOW CORNING ® BIO-PSA Q7-4301) Dimethylpropylene urea 0.392 7.801 0.392 5.016 Petroleum ether, bp 80-110° C. 1.19 15.23 Total 5.025 100.00 7.815 100.01 Area Weight [g/m.sup.2] 99.4 Loading API [μg/cm.sup.2] 658.7
Preparation of the Coating Composition

(159) For the coating compositions of Examples 4a-c, a beaker was loaded with the asenapine base. Dimethylpropylene urea (diisopropyladipate respectively) and the silicone pressure sensitive adhesive (DOW CORNING® BIO-PSA Q7-4301) were added. The mixture was stirred from approx. 200 rpm to approx. 500 rpm for approx. 30 min. Then, for Examples 4a and 4b, the solvent petroleum ether, bp 80-110° C. was added and the mixture was stirred at approx. 500 rpm until a homogenous mixture was obtained for approx. 60 min. For Examples 4c, the solvent petroleum ether, bp 80-110° C. was added while stirring from approx. 500 rpm to approx. 1500 rpm until a homogenous mixture was obtained for approx. 60 min.

(160) Coating of the Coating Composition

(161) For Examples 4a-c see Example 1 for the coating process. The coatings were however dried for approx. 10 min at approx. room temperature and approx. 15 min at approx. 90° C. The coating thickness gave an area weight of the matrix layer of 96.2 (4a), 98.8 (4b), and 99.4 (4c) g/m.sup.2 respectively. The dried film was laminated with a polyethylene terephthalate backing layer (beige lacquered, 23 μm thickness) to provide an asenapine-containing self-adhesive layer structure.

(162) Preparation of the TTS

(163) See Example 1.

(164) Measurement of Skin Permeation Rate

(165) The permeated amount and the corresponding skin permeation rates of TTS prepared according to Examples 4a-c was determined by in vitro experiments in accordance with the OECD Guideline (adopted Apr. 13, 2004) carried out with a 10.0 ml Franz diffusion cell. Split thickness Goettingen minipig skin (female) was used. A dermatome was used to prepare skin to a thickness of 800 μm, with an intact epidermis for all TTS. Diecuts with an area of 1.15 cm.sup.2 were punched from the TTS. The asenapine permeated amounts in the receptor medium of the Franz cell (phosphate buffer solution pH 5.5 with 0.1% saline azide as antibacteriological agent) at a temperature of 32±1° C. were measured and the corresponding skin permeation rates calculated. The results are shown in Table 4.2 and FIG. 4.

(166) TABLE-US-00012 TABLE 4.2 Skin permeation rate with SD [μg/cm.sup.2h] Ex. 4a Ex. 4b Ex. 4c Elapsed (n = 3) (n = 3) (n = 3) time [h] Rate SD Rate SD Rate SD 0 0 0 0 0 0 0 8 5.69 0.5 5.06 0.9 4.85 0.75 24 16.48 0.74 16.19 0.44 16.65 0.91 32 12.47 0.14 12.63 0.35 13.17 0.33 48 5.58 0.39 6.34 0.49 6.81 0.62

Examples 5A-C

(167) Coating Composition

(168) The formulations of the asenapine-containing coating compositions of Examples 5a-c are summarized in Tables 5.1a, 5.1b, and 5.1c below.

(169) TABLE-US-00013 TABLE 5.1a Ex. 5a Solid Solid Liquid Liquid Ingredient (Trade Name) [g] [%] [g] [%] Asenapine Base 0.3342 6.717 0.3342 3.74 Silicone adhesive in n-heptane. 4.29 86.23 5.92 66.25 Solids content of 72.40% by weight (DOW CORNING ® BIO-PSA Q7-4301) Kollidon ® 90 F 0.3511 7.057 0.3511 3.929 (polyvinylpyrrolidone) Ethanol 2.33 26.08 Total 4.9753 100.00 8.9353 100.00 Area Weight [g/m.sup.2] 110.5 Loading API [μg/cm.sup.2] 742.23

(170) TABLE-US-00014 TABLE 5.1b Ex. 5b Solid Solid Liquid Liquid Ingredient (Trade Name) [g] [%] [g] [%] Asenapine Base 0.3374 6.631 0.3374 2.007 Isobutylene adhesive in 4.40 86.47 10.70 63.66 petroleum ether, bp 80-110° C. Solids content of 40.85% by weight (Oppanol ® B10/B100 (85:15)) Kollidon ® 90 F 0.3509 6.896 0.3509 2.088 (polyvinylpyrrolidone) Petroleum ether, bp 80-110° C. 5.42 32.25 Total 5.0883 100.00 16.8083 100.00 Area Weight [g/m.sup.2] 85.7 Loading API [μg/cm.sup.2] 568.28

(171) TABLE-US-00015 TABLE 5.1c Ex. 5c Solid Solid Liquid Liquid Ingredient (Trade Name) [g] [%] [g] [%] Asenapine Base 0.3373 6.63 0.3373 4.315 Silicone adhesive in n-heptane. 4.75 93.37 6.56 83.92 Solids content of 72.40% by weight (DOW CORNING ® BIO-PSA Q7-4301) Petroleum ether, bp 80-110° C. 0.92 11.77 Total 5.0873 100.00 7.8173 100.01 Area Weight [g/m.sup.2] 113.5 Loading API [μg/cm.sup.2] 749.52
Preparation of the Coating Composition

(172) The coating compositions of Examples 5a and 5c were prepared as described in Example 1. Kollidon 90 F (polyvinylpyrrolidone), if any, was added before the addition of the silicone pressure sensitive adhesive, while stirring the mixture from approx. 200 to approx. 500 rpm over approx. 20 min. After addition of the silicone pressure sensitive adhesive, the mixture was then stirred from approx. 200 rpm to approx. 1000 rpm until a homogenous mixture was obtained for further approx. 60 min (for Example 5c, from approx. 1000 rpm to approx. 1500 rpm for further approx. 180 min). For Example 5b, a beaker was loaded with the solvent petroleum ether, bp 80-110° C. The isobutylene pressure sensitive adhesive was added while stirring at approx. 200 rpm, followed by the addition of Kollidon 90 F (polyvinylpyrrolidone) and the asenapine base. The mixture was then stirred from approx. 200 rpm to approx. 1500 rpm until a homogenous mixture was obtained for approx. 160 min.

(173) Coating of the Coating Composition

(174) See Example 4 for the coating process. The coatings of Examples 5b and 5c were however dried for approx. 10 min at approx. room temperature and approx. 20 min at approx. 90° C. The coating thickness gave an area weight of the matrix layer of 110.5 (5a), 85.7 (5b), and 113.5 (5c) g/m.sup.2 respectively. The dried film was laminated with a polyethylene terephthalate backing layer (beige lacquered, 23 μm thickness) to provide an asenapine-containing self-adhesive layer structure. For Example 5b, a siliconized polyethylene terephthalate release liner having 100 μm thickness is used.

(175) Preparation of the TTS

(176) See Example 1.

(177) Measurement of Skin Permeation Rate

(178) The permeated amounts and the corresponding skin permeation rates of TTS prepared according to Examples 5a-c were determined by in vitro experiments in accordance with the OECD Guideline (adopted Apr. 13, 2004) carried out with a 10.0 ml Franz diffusion cell. Split thickness Goettingen minipig skin (female) was used. A dermatome was used to prepare skin to a thickness of 800 μm, with an intact epidermis for all TTS. Diecuts with an area of 1.15 cm.sup.2 were punched from the TTS. The asenapine permeated amounts in the receptor medium of the Franz cell (phosphate buffer solution pH 5.5 with 0.1% saline azide as antibacteriological agent) at a temperature of 32±1° C. were measured and the corresponding skin permeation rates calculated. The results are shown in Table 5.2 and FIG. 5.

(179) TABLE-US-00016 TABLE 5.2 Skin permeation rate with SD [μg/cm.sup.2h] Ex. 5a Ex. 5b Ex. 5c Elapsed (n = 3) (n = 2) (n = 3) time [h] Rate SD Rate SD Rate SD 0 0 0 0 0 0 0 4 1.08 0.91 1.28 1.28 / / 8 7.02 4.01 4.58 2.7 3.31 1.73 12 15.24 3.11 9.34 1.12 10.26 4.34 16 20.29 5.26 10.06 1.08 19.7 9.55 20 21.15 1.21 9.1 1.65 22.67 5.01 24 20.03 0.45 9.74 0.27 16.38 2.31 32 13.76 1.71 8.07 0.44 12.61 1.55 40 10.25 1.76 7.11 0.41 9.47 1.22 48 7.23 0.9 5.83 0.19 7.42 1.28

Examples 6A-C

(180) Coating Composition

(181) The formulations of the asenapine-containing coating compositions of Examples 6a-c are summarized in Tables 6.1a, 6.1b, and 6.1c below.

(182) TABLE-US-00017 TABLE 6.1a Ex. 6a Solid Solid Liquid Liquid Ingredient (Trade Name) [g] [%] [g] [%] Asenapine Base 0.3335 6.733 0.3335 3.371 Silicone adhesive in n-heptane. 3.53 71.26 4.88 49.33 Solids content of 72.40% by weight (DOW CORNING ® BIO-PSA Q7-4301) Acrylate adhesive in ethyl 1.09 22.00 2.15 21.73 acetate. Solids content of 50.50% by weight (DURO- TAK ® 387-2287) Petroleum ether, bp 80-110° C. 2.53 25.57 Total 4.9535 99.99 9.8935 100.00 Area Weight [g/m.sup.2] 93.7 Loading API [μg/cm.sup.2] 630.66

(183) TABLE-US-00018 TABLE 6.1b Reference Ex. 6b Solid Solid Liquid Liquid Ingredient (Trade Name) [g] [%] [g] [%] Asenapine Base 0.3399 6.731 0.3399 3.216 Silicone adhesive in n-heptane. 2.34 46.34 3.23 30.56 Solids content of 72.40% by weight (DOW CORNING ® BIO-PSA Q7-4301) Acrylate adhesive in ethyl 2.37 46.93 4.69 44.37 acetate. Solids content of 50.50% by weight (DURO- TAK ® 387-2287) Ethyl acetate 2.31 21.85 Total 5.0499 100.00 10.5699 100.00 Area Weight [g/m.sup.2] 130.2 Loading API [μg/cm.sup.2] 876.38

(184) TABLE-US-00019 TABLE 6.1c Reference Ex. 6c Solid Solid Liquid Liquid Ingredient (Trade Name) [g] [%] [g] [%] Asenapine Base 0.3357 6.097 0.3357 2.587 Silicone adhesive in n-heptane. 1.17 21.25 1.62 12.48 Solids content of 72.40% by weight (DOW CORNING ® BIO-PSA Q7-4301) Acrylate adhesive in ethyl 4.0 72.65 7.00 53.95 acetate. Solids content of 50.50% by weight (DURO- TAK ® 387-2287) Ethyl acetate 4.02 30.98 Total 5.5057 100.00 12.9757 100.00 Area Weight [g/m.sup.2] 105.3 Loading API [μg/cm.sup.2] 641.81
Preparation of the Coating Composition

(185) A beaker was loaded with the asenapine base. The acrylic pressure sensitive adhesive was added, followed by the silicone pressure sensitive adhesive. Then the solvent was added while stirring from approx. 200 rpm to approx. 500 rpm (for Example 6b, to approx. 1000 rpm). The mixture was then stirred at approx. 1500 rpm until a homogenous mixture was obtained for approx. 150 min. For Example 6c, the solvent was added while stirring from approx. 200 rpm to approx. 1500 rpm. The mixture was then stirred at approx. 1500 rpm until a homogenous mixture was obtained for approx. 120 min.

(186) Coating of the Coating Composition

(187) See Example 5c for the coating process. The coating thickness gave an area weight of the matrix layer of 93.7 (6a), 130.2 (6b), and 105.3 (6c) g/m.sup.2 respectively. The dried film was laminated with a polyethylene terephthalate backing layer (beige lacquered, 23 μm thickness) to provide an asenapine-containing self-adhesive layer structure.

(188) Preparation of the TTS

(189) See Example 1.

(190) Measurement of Skin Permeation Rate

(191) The permeated amounts and the corresponding skin permeation rates of TTS prepared according to Examples 6a-c were determined by in vitro experiments in accordance with the OECD Guideline (adopted Apr. 13, 2004) carried out with a 10.0 ml Franz diffusion cell. Split thickness Goettingen minipig skin (female) was used. A dermatome was used to prepare skin to a thickness of 800 μm, with an intact epidermis for all TTS. Diecuts with an area of 1.15 cm.sup.2 were punched from the TTS. The asenapine permeated amounts in the receptor medium of the Franz cell (phosphate buffer solution pH 5.5 with 0.1% saline azide as antibacteriological agent) at a temperature of 32±1° C. were measured and the corresponding skin peimeation rates calculated. The results are shown in Table 6.2 and FIG. 6.

(192) TABLE-US-00020 TABLE 6.2 Skin permeation rate with SD [μg/cm.sup.2h] Ex. 6a Ex. 6b Ex. 6c Elapsed (n = 3) (n = 3) (n = 3) time [h] Rate SD Rate SD Rate SD 0 0 0 0 0 0 0 4 2.26 0.19 / / / / 8 7.43 0.04 1.61 0.2 0.37 0.52 12 12.12 0.84 4.33 1.16 2.7 0.45 16 12.38 0.57 9.63 1.1 5.16 1.81 20 13.05 0.48 12.02 4.49 7.86 1.18 24 12.12 0.39 14.12 0.95 8.26 1.36 32 10.13 0.42 9.71 0.92 6.96 1.01 40 8.05 0.4 9.4 1.17 6.67 0.69 48 6.04 0.48 9.07 0.58 6.96 0.47 56 4.52 0.46 7.16 0.2 6.17 0.43 64 3.3 0.39 / / / / 72 2.39 0.44 2.94 0.26 4.03 0.7

Examples 7A, 7B

(193) Coating Composition

(194) The formulations of the asenapine-containing coating compositions of Examples 7a and 7b are summarized in Tables 7.1a and 7.1b below.

(195) TABLE-US-00021 TABLE 7.1a Ex. 7a Solid Solid Liquid Liquid Ingredient (Trade Name) [g] [%] [g] [%] Asenapine Base 0.3683 7.268 0.3683 4.822 Silicone adhesive in n-heptane. 4.12 81.31 5.69 74.50 Solids content of 72.40% by weight (DOW CORNING ® BIO-PSA Q7-4301) Transcutol (diethylene glycol 0.4039 7.971 0.4039 5.289 monoethyl ether) Kollidon 90 F 0.1750 3.454 0.1750 2.291 (polyvinylpyrrolidone) Ethanol 1.00 13.09 Total 5.0672 100.00 7.6372 99.99 Area Weight [g/m.sup.2] 105.5 Loading API [μg/cm.sup.2] 766.8

(196) TABLE-US-00022 TABLE 7.1b Ex. 7b Solid Solid Liquid Liquid Ingredient (Trade Name) [g] [%] [g] [%] Asenapine Base 0.3384 6.604 0.3384 4.822 Silicone adhesive in n-heptane. 2.92 56.98 5.78 74.50 Solids content of 72.40% by weight (DOW CORNING ® BIO-PSA Q7-4301) Isobutylene adhesive in 1.46 28.49 4.12 5.289 petroleum ether, bp 80-110° C. Solids content of 40.85% by weight (Oppanol ® B10/B100 (85:15) Transcutol (diethylene glycol 0.4061 7.925 0.4061 2.291 mono ethyl ether) Ethyl acetate 1.50 13.09 Total 5.1245 100.00 12.1445 99.99 Area Weight [g/m.sup.2] 98.4 Loading API [μg/cm.sup.2] 649.8
Preparation of the Coating Composition

(197) For Example 7a, the coating compositions were prepared as described in Example 1. Transcutol (diethylene glycol monoethyl ether) was added before addition of the solvent. Kollidon 90 K (polyvinylpyrrolidone), was added before the addition of the silicone pressure sensitive adhesive. The mixture was stirred at approx. 200 rpm for approx. 180 min and then at approx. 1000 rpm until a homogenous mixture was obtained for approx. 50 min. For Example 7b, a beaker was loaded with the isobutylene pressure sensitive adhesive, followed by addition of the acrylic pressure sensitive adhesive. Transcutol was added while stirring at approx. 200 rpm, followed by the addition of the solvent while stirring at approx. 100 rpm. Then the asenapine base was added and the mixture was stirred at approx. 1000 rpm until a homogenous mixture was obtained for approx. 40 min.

(198) Coating of the Coating Composition

(199) For Example 7a, see Example 4 for the coating process. For Example 7b, see Example 5b for the coating process. The coating thickness gave an area weight of the matrix layer of 105.5 (7a) and 98.4 (7b) g/m.sup.2 respectively. The dried film was laminated with a polyethylene terephthalate backing layer (beige lacquered, 23 μm thickness) to provide an asenapine-containing self-adhesive layer structure.

(200) Preparation of the TTS

(201) See Example 1.

(202) Measurement of Skin Permeation Rate

(203) The permeated amounts and the corresponding skin permeation rates of TTS prepared according to Examples 7a and 7b were determined by in vitro experiments in accordance with the OECD Guideline (adopted Apr. 13, 2004) carried out with a 10.0 ml Franz diffusion cell. Split thickness Goettingen minipig skin (female) was used. A dermatome was used to prepare skin to a thickness of 800 μm, with an intact epidermis for all TTS. Diecuts with an area of 1.16 cm.sup.2 were punched from the TTS. The asenapine permeated amounts in the receptor medium of the Franz cell (phosphate buffer solution pH 5.5 with 0.1% saline azide as antibacteriological agent) at a temperature of 32±1° C. were measured and the corresponding skin permeation rates calculated. The results are shown in Table 7.2 and FIG. 7.

(204) TABLE-US-00023 TABLE 7.2 Skin permeation rate with SD [μg/cm.sup.2h] Elapsed Ex. 7a (n = 3) Ex. 7b (n = 3) time [h] Rate SD Rate SD 0 0 0 0 0 4 2.97 0.56 1.37 0.18 8 9.8 1.92 3.85 1.06 12 15.34 1.53 6.83 1.38 16 15.06 3.6 7.88 1.59 20 15.98 0.87 8.38 1.59 24 14.59 0.7 8.18 1.59 32 10.89 0.85 7.79 1.41 40 8.6 0.84 6.89 0.84 48 6.9 0.11 6.42 0.79

Examples 8A, 8B

(205) Coating Composition

(206) The formulations of the asenapine-containing coating compositions of Examples 8a and 8b are summarized in Table 8.1a and 8.1b below.

(207) TABLE-US-00024 TABLE 8.1a Ex. 8a Solid Solid Liquid Liquid Ingredient (Trade Name) [g] [%] [g] [%] Asenapine Base 0.6711 6.72 0.6711 4.613 Silicone adhesive in n-heptane. 9.3149 93.28 12.8659 88.444 Solids content of 72.40% by weight (DOW CORNING ® BIO-PSA Q7-4301) Ethyl acetate 1.01 6.94 Total 9.986 100.00 14.547 100.00 Area Weight [g/m.sup.2] 134.25 (95.2 + 39.05) Loading API [μg/cm.sup.2] 902.16

(208) TABLE-US-00025 TABLE 8.1b Ex. 8b Solid Solid Liquid Liquid Ingredient (Trade Name) [g] [%] [g] [%] Asenapine Base 0.6711 6.72 0.6711 4.613 Silicone adhesive in n-heptane. 9.3149 93.28 12.8659 88.444 Solids content of 72.40% by weight (DOW CORNING ® BIO-PSA Q7-4301) Ethyl acetate 1.01 6.94 Total 9.986 100.00 14.547 100.00 Area Weight [g/m.sup.2] 134.25 (95.2 + 39.05) Loading API [μg/cm.sup.2] 902.16
Preparation of the Coating Composition

(209) The coating compositions were prepared as described in Example 1. The mixture was however stirred at approx. 500 rpm until a homogenous mixture was obtained for approx. 90 min.

(210) Coating of the Coating Composition

(211) See Example 5c for the coating process. Two asenapine-containing matrix layer having different area weights were prepared. The thickness gave an area weight of the first matrix layer of 95.2 g/m.sup.2 and an area weight of the second matrix layer of 39.05 g/m.sup.2. A first and a second asenapine-containing self-adhesive layer structure were prepared.

(212) The first layer structure was laminated with a polyethylene terephthalate backing layer (beige lacquered, 23 μm thickness) to provide an asenapine-containing self-adhesive layer structure. The second layer structure was laminated with the EVA (19%, VA) membrane 9712 (for Example 8b, EVA (9%, VA) membrane 9702 respectively). The release liner of the first layer structure was removed and this adhesive side was laminated on the EVA side of the second layer structure. This results in an asenapine-containing self-adhesive layer structure with an area weight of the matrix layer of 134.25 g/m.sup.2, with a backing layer and a release liner.

(213) Preparation of the TTS

(214) See Example 1.

(215) Measurement of Skin Permeation Rate

(216) The permeated amounts and the corresponding skin permeation rates of TTS prepared according to Examples 8a and 8b were determined by in vitro experiments in accordance with the OECD Guideline (adopted Apr. 13, 2004) carried out with a 10.0 ml Franz diffusion cell. Split thickness Goettingen minipig skin (female) was used. A dermatome was used to prepare skin to a thickness of 800 μm, with an intact epidermis for all TTS. Diecuts with an area of 1.15 cm.sup.2 were punched from the TTS. The asenapine permeated amount in the receptor medium of the Franz cell (phosphate buffer solution pH 5.5 with 0.1% saline azide as antibacteriological agent) at a temperature of 32±1° C. were measured and the corresponding skin permeation rates calculated. The results are shown in Table 8.2 and FIG. 8.

(217) TABLE-US-00026 TABLE 8.2 Skin permeation rate with SD [μg/cm.sup.2h] Elapsed Ex. 8a (n = 3) Ex. 8b (n = 2) time [h] Rate SD Rate SD 0 0 0 0 0 4 2.98 0.64 2.7 0.04 8 13.32 1.6 12.33 0.21 12 18.23 1.33 19.69 1.72 16 21.01 1.55 22.41 1.04 20 20.87 2.11 21.33 0.64 24 19.42 3.09 20.82 1.25 32 13.63 0.62 14.42 0.43 40 9.67 0.11 10.17 0.03 48 7.12 0.26 6.65 0.1

Examples 9A, 9B

(218) Coating Composition

(219) The formulations of the asenapine-containing coating compositions of Examples 9a and 9b are summarized in Table 9.1a and 9.1b below.

(220) TABLE-US-00027 TABLE 9.1a Ex. 9b Solid Solid Liquid Liquid Ingredient (Trade Name) [g] [%] [g] [%] Asenapine Base 0.6693 6.692 0.6693 4.591 Silicone adhesive in n-heptane. 9.3328 93.308 12.8906 88.414 Solids content of 72.40% by weight (DOW CORNING ® BIO-PSA Q7-4301) Ethyl acetate 1.02 7.00 Total 10.0021 100.00 14.5799 100.01 Asenapine Base 0.6693 6.692 0.6693 4.591 Silicone adhesive in n-heptane. 9.3328 93.308 12.8906 88.414 Solids content of 72.40% by weight (DOW CORNING ® BIO-PSA Q7-4301) Ethyl acetate 1.02 7.00 Total 10.0021 100.00 14.5799 100.01 Area Weight [g/m.sup.2] 132.05 (94.15 + 37.9) Loading API [μg/cm.sup.2] 883.7

(221) TABLE-US-00028 TABLE 9.1b Ex. 9b Solid Solid Liquid Liquid Ingredient (Trade Name) [g] [%] [g] [%] Asenapine Base 0.6657 13.154 0.6657 9.099 Silicone adhesive in n-heptane. 4.3953 86.846 6.0708 82.974 Solids content of 72.40% by weight (DOW CORNING ® BIO-PSA Q7-4301) Ethyl acetate 0.58 7.93 Total 5.061 100.00 7.3165 100.00 Asenapine Base 0.6787 13.577 0.6787 5.849 Acrylate adhesive in 4.3202 86.423 8.5548 73.726 ethyl acetate. Solids content of 50.50% by weight (DURO-TAK ® 387-2287) Ethyl acetate 2.37 20.42 Total 4.9989 100.00 11.6035 100.00 Area Weight [g/m.sup.2] 191.2 (100.9 + 90.3) Loading API [μg/cm.sup.2] 2557.72
Preparation of the Coating Composition

(222) The coating compositions were prepared as described in Example 1. The mixture was however stirred at approx. 400 rpm until a homogenous mixture was obtained for approx. 240 min.

(223) Coating of the Coating Composition of Example 9a

(224) See Example 8 for the coating composition. The second matrix layer was however dried for approx. 10 min at approx. room temperature and approx. 10 min at approx. 90° C. The thickness gave an area weight of the first matrix layer of 94.15 g/m.sup.2 and an area weight of the second matrix layer of 37.9 g/m.sup.2. The ethylene vinyl acetate (EVA) (2% VA) membrane Co Trans 9726 was used. This results in an asenapine-containing self-adhesive layer structure with an area weight of the matrix layer of 132.05 g/m.sup.2, with a backing layer and a release liner.

(225) Coating of the Coating Composition of Example 9b

(226) See Example 9a for the coating process, wherein the first asenapine-containing self-adhesive layer structure comprises DOW CORNING® BIO-PSA Q7-4301 (one side fluoropolymer coated, 75 μm thickness as release liner) and the second asenapine-containing self-adhesive layer structure comprises Duro-Tak™ 387-2287 (PET siliconized, 100 thickness as release liner). The coating thickness of the acrylate layer gave an area weight of the matrix layer of 100.9 g/m.sup.2 and is the skin contact layer, wherein no EVA membrane is used. The coating thickness of the silicone layer gave an area weight of the matrix layer of 90.3 g/m.sup.2. This results in an asenapine-containing self-adhesive layer structure with an area weight of the matrix layer of 191.2 g/m.sup.2, with a backing layer and a release liner.

(227) Preparation of the TTS

(228) See Example 1.

(229) Measurement of Skin Permeation Rate

(230) The permeated amounts and the corresponding skin permeation rates of TTS prepared according to Examples 9a and 9b were determined by in vitro experiments in accordance with the OECD Guideline (adopted Apr. 13, 2004) carried out with a 10.0 ml Franz diffusion cell. Split thickness Goettingen minipig skin (female) was used. A dermatome was used to prepare skin to a thickness of 800 μm, with an intact epidermis for all TTS. Diecuts with an area of 1.16 cm.sup.2 were punched from the TTS. The asenapine permeated amount in the receptor medium of the Franz cell (phosphate buffer solution pH 5.5 with 0.1% saline azide as antibacteriological agent) at a temperature of 32±1° C. were measured. The results are shown in Table 9.2 and FIG. 9.

(231) TABLE-US-00029 TABLE 9.2 Skin permeation rate with SD [μg/cm.sup.2h] Elapsed Ex. 9a (n = 3) Ex. 9b (n = 3) time [h] Rate SD Rate SD 0 0 0 0 0 4 3.87 0.93 3.35 1.69 8 13.04 1.98 12.37 4.18 12 17.83 2.56 19.68 5.27 16 18.76 2.19 21.77 4.63 20 18.43 1.39 23.17 4.47 24 16.71 1.17 22.85 3.29 32 12.82 0.85 20.4 2.79 40 10.63 0.82 20.52 1.54 48 7.34 0.45 18.38 1.4

Example 10

(232) Reservoir Composition

(233) The formulation of the asenapine-containing reservoir composition of Examples 10 is summarized in Table 10.1 below.

(234) TABLE-US-00030 TABLE 10.1 Ex. 10 Solid Solid Liquid Liquid Ingredient (Trade Name) [g] [%] [g] [%] Asenapine Base 0.7224 3.612 0.7224 3.612 Silicone Oil Q7-9120 16.4009 82.008 16.4009 82.008 350 CST Transcutol (diethylene 2.8758 14.38 2.8758 14.38 glycol monoethyl ether) Total 19.9991 100.00 19.9991 100.00
Preparation of the Reservoir Composition

(235) A beaker was loaded with the asenapine base. Transcutol (diethylene glycol monoethyl ether) was added, followed by the addition of the silicone oil Q7-9120 350 CST. The mixture was first stirred at approx. room temperature at approx. 400 rpm for approx. 10 min. Then the mixture was stirred at approx. 80° C. at approx. 400 rpm until a homogenous mixture was obtained for approx. 10 min.

(236) Preparation of the Reservoir-Type TTS

(237) A reservoir-type TTS is formed comprising a backing layer, a strip of paper, a foam with an adhesive layer, a membrane with an adhesive layer, and a release liner. The foam is chemically inert and forms the reservoir room for the active agent. The membrane is made of PP and/or PE (Celgard 24000) with a pore size of 0.028 to 0.5%. The membrane is not a rate-controlling membrane. Thus, the liquid reservoir composition is directly applied without using a rate-controlling membrane.

(238) In Vivo Study Using Goettingen Minipigs

(239) The in vivo releases and the corresponding skin permeation rates of the reservoir-type TTS prepared according to Example 10 were determined by in vivo experiments using Goettingen minipigs (female, about 6 months, randomized by simple random sample method). Reservoir-type TTS with an area of 10 cm.sup.2 were used, and one Goettingen minipig was used for one TTS formulation. Three drug containing and one placebo reservoir-type TTS (each 10 cm.sup.2) were used per minipig. The total wear time of all 4 patches per minipig (3 active and 1 placebo) patches was 84 h.

(240) During the study, the minipigs were kept at 22±3° C., at a relative humidity of 40±15%, lighted from 6 am to 6 pm with calorie reduced breeding food, ssniff, twice daily of about 140-200 g per animal, and with water ad libitum.

(241) Following the above single dose application of the reservoir-type TTS (3*verum and 1 placebo, each 10 cm.sup.2), 3 ml blood samples were taken at 0 h, 4 h, 8 h, 12 h, 24 h, 32 h, 48 h, 56 h, 72 h, 84 h and 96 h, and the blood samples were centrifuged 10 minutes at 2000×g in order to obtain blood plasma. The asenapine blood plasma concentration was determined by an LC method with MS/MS detection. AUC values were calculated from the blood plasma concentration. After removal of the TTS, the skin condition was macroscopically determined and a Draize score obtained based on the score scheme below. Histopathological examination of the epidermis and the dermis revealed no morphological or pathological transformation indicating an irritation of the deeper tissue layers. Histological results also show no lesion or removal of stratum corneum. The residual amount of asenapine was determined in the removed reservoir-type TTS by quantitative HPLC (see above) and the dermally delivered amount of asenapine calculated as the difference to the initial amount of asenapine included in the reservoir-type TTS. The results are shown in Table 10.2 and FIG. 10.

(242) TABLE-US-00031 TABLE 10.2 Values Ex. 10 AUC(.sub.0-24 h) [ng/ml*h] 78.2 AUC(.sub.0-96 h) [ng/ml*h] 262.4 c.sub.max [ng/ml] 5.0 Histopathological assessment no important finding Draize Score 1/1/1/0 (3*verum/1*placebo) Content of API in minipig skin 0.5 [mg] API content of preclinical 73.9 sample [mg] API dermal delivered 69/50.7* [%/amount in mg] after 84 h *One of the three 10 cm.sup.2 patches was leaking after 8 h

Example 11A-B

(243) Coating Composition

(244) The formulations of the asenapine-containing coating compositions of Examples 11a and Example 11b is summarized in Tables 11.1a and 11.1b below.

(245) TABLE-US-00032 TABLE 11.1a Ex. 11a Ingredient Solid Solid Liquid Liquid (Trade Name) [g] [%] [g] [%] Asenapine Base 2.1001 2.995 2.1001 2.056 Silicone adhesive 67.99 96.95 93.91 91.96 in n-heptane. Solids content of 72.40% by weight (DOW CORNING ® BIO-PSA Q7-4301) α-Tocopherol 0.0414 0.059 0.0414 0.041 n-Heptane 6.0721 5.946 Total 70.1315 100.00 102.1236 100.00 Area Weight 91.1 [g/m.sup.2] Loading API 272.94 [μg/cm.sup.2]

(246) TABLE-US-00033 TABLE 11.1b Ex. 11b Ingredient Solid Solid Liquid Liquid (Trade Name) [g] [%] [g] [%] Asenapine Base 22.499 3.000 22.499 2.060 Silicone adhesive 727.21 96.95 998.92 91.46 in n-heptane. Solids content of 72.40% by weight (DOW CORNING ® BIO-PSA Q7-4301) α-Tocopherol 0.3739 0.050 0.3739 0.034 n-Heptane 70.40 6.45 Total 750.0829 100.00 1092.193 100.00 Area Weight 82.0 [g/m.sup.2] Loading API 245.9 [μg/cm.sup.2]
Preparation of the Coating Composition

(247) The coating composition was prepared in a beaker as described in Example 1, wherein, in Example 11a, the α-tocopherol was added to the asenapine before the addition of the solvent and the silicone adhesive, while in Example 11b, the asenapine is added to the α-tocopherol followed by the addition of the solvent, and then the silicone adhesive is added. The mixture was in each case stirred from approx. 250 rpm to approx. 1,000 rpm until a homogenous mixture was obtained (at least 60 min).

(248) Coating of the Coating Composition

(249) See Example 1 for the coating process. The coating was however dried for approx. 10 min at approx. room temperature and approx. 15 min at approx. 60° C. in case of Example 11a, and for approx. 10 min at approx. 60° C. in case of Example 11b. The coating thickness gave an area weight of the matrix layer of 91.1 g/m.sup.2 in case of Example 11a and 82.0 g/m.sup.2 in case of Example 11b. The dried film was in each case laminated with a polyethylene terephthalate backing layer (beige lacquered, 23 μm thickness) to provide an asenapine-containing self-adhesive layer structure.

(250) Preparation of the TTS

(251) See Example 1.

(252) Measurement of Skin Permeation Rate

(253) The permeated amount and the corresponding skin permeation rates of TTS prepared according to Example 11a and 11b were determined by in vitro experiments in accordance with the OECD Guideline (adopted Apr. 13, 2004) carried out with a 10.0 ml Franz diffusion cell. Split thickness human skin from cosmetic surgeries (female abdomen, date of birth 1986) was used. A dermatome was used to prepare skin to a thickness of 800 μm, with an intact epidermis for all TTS. Diecuts with an area of 1.15 cm.sup.2 were punched from the TTS. The asenapine permeated amount in the receptor medium of the Franz cell (phosphate buffer solution pH 5.5 with 0.1% saline azide as antibacteriological agent) at a temperature of 32±1° C. was measured and the corresponding skin permeation rate calculated. The results are shown in Table 11.2 and FIG. 11.

(254) TABLE-US-00034 TABLE 11.2 Skin permeation rate with SD [μg/cm.sup.2h] Elapsed Ex. 11a (n = 3) Ex. 11b (n = 3) time [h] Rate SD Rate SD 2 0.44 0.06 0.34 0.09 4 3.81 0.52 3.00 0.61 8 7.37 0.58 7.09 0.49 12 10.00 0.58 10.02 0.40 16 8.54 0.58 9.17 0.12 20 6.04 0.31 6.72 0.05 24 4.79 0.46 4.90 0.11 32 2.59 0.00 2.62 0.80 40 2.22 0.08 2.08 0.02 48 1.49 0.20 1.34 0.04 56 1.15 0.13 1.11 0.13 64 0.75 0.05 0.69 0.09 72 0.65 0.06 0.62 0.04

Example 12A-B

(255) Coating Composition

(256) The formulations of the asenapine-containing coating compositions of Examples 12a and Example 12b is summarized in Tables 12.1a and 12.1b below.

(257) TABLE-US-00035 TABLE 12.1a Ex. 12a Ingredient Solid Solid Liquid Liquid (Trade Name) [g] [%] [g] [%] Asenapine Base 12.0069 3.001 12.0069 2.040 Silicone adhesive 375.86 93.95 516.29 87.73 in n-heptane. Solids content of 72.40% by weight (DOW CORNING ® BIO-PSA Q7-4301) α-Tocopherol 0.1988 0.05 0.1988 0.034 Polyvinyl- 12.01 3.00 12.01 2.04 pyrrolidone (Povidone K90 F) Ethanol 47.9894 8.155 Total 400.0757 100.00 588.4951 100.00 Area Weight 81.0 [g/m.sup.2] Loading API 243.08 [μg/cm.sup.2]

(258) TABLE-US-00036 TABLE 12.1b Ex. 12b Ingredient Solid Solid Liquid Liquid (Trade Name) [g] [%] [g] [%] Asenapine Base 12.0005 2.999 12.0005 2.041 Silicone adhesive 375.87 93.95 517.02 87.92 in n-heptane. Solids content of 72.40% by weight (DOW CORNING ® BIO-PSA Q7-4301) α-Tocopherol 0.2154 0.054 0.2154 0.037 Polyvinyl- 12.0 3.00 12.00 2.04 pyrrolidone (Povidone K90 F) Ethanol 46.8241 7.962 Total 400.0855 100.00 588.06 100.00 Area Weight 78.9 [g/m.sup.2] Loading API 236.52 [μg/cm.sup.2]
Preparation of the Coating Composition

(259) The coating composition was prepared in a beaker. In Example 12a, the asenapine is added to the α-tocopherol followed by the addition of the solvent, and then first the polyvinylpyrrolidone, and then the silicone adhesive is added, while in Example 12b, the silicone adhesive is added to the α-tocopherol followed by the addition of the polyvinylpyrrolidone, and then the first the asenapine, and then the solvent was added. The mixture was in each case stirred from approx. 200 rpm to approx. 2000 rpm until a homogenous mixture was obtained (at least 60 min).

(260) Coating of the Coating Composition

(261) See Example 1 for the coating process. The coating was however dried for approx. 10 min at approx. 80° C. in case of Example 12a, and for approx. 10 min at room temperature and for approx. 10 min at approx. 80° C. in case of Example 12b. The coating thickness gave an area weight of the matrix layer of 81.0 g/m.sup.2 in case of Example 12a and 78.9 g/m.sup.2 in case of Example 12b. The dried film was in each case laminated with a polyethylene terephthalate backing layer (beige lacquered, 23 μm thickness) to provide an asenapine-containing self-adhesive layer structure.

(262) Preparation of the TTS

(263) See Example 1.

(264) Measurement of Skin Permeation Rate

(265) The permeated amount and the corresponding skin permeation rates of TTS prepared according to Examples 12 a and 12 b were deteiinined by in vitro experiments in accordance with the OECD Guideline (adopted Apr. 13, 2004) carried out with a 10.0 ml Franz diffusion cell. Split thickness human skin from cosmetic surgeries (female leg, date of birth 1965) was used. A dermatome was used to prepare skin to a thickness of 800 μm, with an intact epidermis for all TTS. Diecuts with an area of 1.15 cm.sup.2 were punched from the TTS. The asenapine permeated amount in the receptor medium of the Franz cell (phosphate buffer solution pH 5.5 with 0.1% saline azide as antibacteriological agent) at a temperature of 32±1° C. was measured and the corresponding skin permeation rate calculated. The results are shown in Table 12.2 and FIG. 12.

(266) TABLE-US-00037 TABLE 12.2 Skin permeation rate with SD [μg/cm.sup.2h] Elapsed Ex. 12a (n = 3) Ex. 12b (n = 3) time [h] Rate SD Rate SD 2 1.53 0.16 2.79 0.46 4 8.67 0.46 12.62 0.18 8 11.46 0.26 13.61 0.22 12 10.38 0.52 10.64 0.22 16 7.11 0.09 6.57 0.15 20 4.85 0.29 4.34 0.10 24 3.66 0.12 2.94 0.08

Examples 13A-F

(267) Coating Composition

(268) The formulations of the asenapine-containing coating compositions of Examples 13a-f are summarized in Table 13.1 below. The formulations are based on weight percent, as also indicated in Table 13.1.

(269) TABLE-US-00038 TABLE 13.1 Examples 13a, Examples 13d, 13b and 13c 13e and 13f Ingredient Amounts Solids Amounts Solids (Trade Name) [g] [%] [g] [%] Asenapine Base 2.40 5.97 4.00 10.01 Polyisobutylene 82.91 84.06 78.38 79.98 adhesive in petroleum ether, bp 80-110° C. Solids content by 40.8% (Oppanol B10/B100 = 85/15) Polyvinyl- 4.01 9.97 4.01 10.01 pyrrolidone (Killidon ® 90F) Ethanol 12.03 — 12.18 — n-heptane 8.15 — 7.47 — Total 109.51 — 106.04 — Ex. 13a Ex. 13b Ex. 13c Ex. 13d Ex 13e Ex. 13f Area Weight 52.8 129.6 188.4 51.6 128.2 185.9 [g/m.sup.2] Asenapine content 0.32 0.77 1.12 0.52 1.28 1.86 [mg/cm.sup.2]
Preparation of the Coating Composition

(270) For Examples 13a-f, the beaker was loaded with the polyvinylpyrrolidone (Kollidon® 90 F) first and ethanol was added while stirring at approx. 100-200 rpm. The polyisobutylene adhesive was then added while stirring at approx. 400 rpm. Further, the asenapine base was added while stirring at approx. 400 rpm and finally, n-heptane was added while stirring at approx. 400-500 rpm until a homogeneous mixture was obtained.

(271) Coating of the Coating Composition, Examples 13a-f

(272) The resulting asenapine-containing coating composition was coated on a polyethylene terephthalate film (siliconised, 75 μm thickness, which may function as release liner) and dried for approx. 10 min-20 min at room temperature and 20 min-25 min at 80° C. The coating thickness gave an area weight of the matrix layer of 52.8 g/m.sup.2 (Example 13a), 129.6 g/m.sup.2 (Example 13b), 188.4 g/m.sup.2 (Example 13c), 51.6 g/m.sup.2 (Example 13d), 128.2 g/m.sup.2 (Example 13e), and 185.9 g/m.sup.2 (Example 13f), respectively. The dried film was laminated with a polyethylene terephthalate backing layer (23 μm thickness) to provide an asenapine-containing self-adhesive layer structure.

(273) Preparation of the TTS

(274) See Example 1.

(275) Measurement of Skin Permeation Rate

(276) The permeated amount and the corresponding skin permeation rates of TTS prepared according to Examples 13a to 13f were determined by in vitro experiments in accordance with the OECD Guideline (adopted Apr. 13, 2004) carried out with a 7.0 ml Franz diffusion cell. Split thickness human skin from cosmetic surgeries (female abdomen, date of birth 1969) was used. A dermatome was used to prepare skin to a thickness of 800 μm, with an intact epidermis for all TTS. Diecuts with an area of 1.151 cm.sup.2 were punched from the TTS. The asenapine permeated amount in the receptor medium of the Franz cell (phosphate buffer solution pH 5.5 with 0.1% saline azide as antibacteriological agent) at a temperature of 32±1° C. was measured and the corresponding skin permeation rate calculated. The results are shown in Tables 13.2 and 13.3 and FIG. 13a.

(277) TABLE-US-00039 TABLE 13.2 Skin permeation rate with SD [μg/(cm.sup.2h)] Ex. 13a Ex. 13b Ex. 13c Elapsed (n = 3) (n = 3) (n = 3) time [h] Rate SD Rate SD Rate SD 0 1.04 0.11 1.28 0.16 2.25 1.50 4 5.44 0.18 6.27 0.31 8.82 3.99 8 8.15 0.09 9.93 0.19 12.31 3.68 12 8.49 0.21 10.97 0.07 13.27 2.44 16 7.62 0.18 10.68 0.12 12.15 2.30 20 6.64 0.06 10.19 0.14 12.09 1.31 24 4.59 0.15 8.10 0.24 9.59 0.87 32 3.22 0.18 7.36 0.05 8.90 0.21 40 2.14 0.13 6.14 0.11 7.53 0.19 48 1.47 0.12 5.05 0.04 6.44 0.33 56 1.01 0.06 4.11 0.07 5.65 0.55 64 0.81 0.02 3.42 0.08 5.11 0.63 72 1.04 0.11 1.28 0.16 2.25 1.50

(278) TABLE-US-00040 TABLE 13.3 Skin permeation rate with SD [μg/(cm.sup.2h)] Ex. 13d Ex. 13e Ex. 13f Elapsed (n = 3) (n = 3) (n = 3) time [h] Rate SD Rate SD Rate SD 0 1.51 0.28 2.47 0.27 1.68 0.12 4 8.42 0.44 10.69 0.31 10.35 0.45 8 13.86 0.77 16.43 0.48 17.79 0.68 12 15.01 0.69 17.51 0.66 20.25 0.73 16 13.69 0.50 16.90 0.51 20.42 0.56 20 12.12 0.28 16.25 0.42 19.73 0.51 24 7.81 0.17 12.65 0.25 16.11 0.14 32 6.23 0.54 12.31 0.49 15.86 0.15 40 4.23 0.67 11.20 0.26 14.03 0.16 48 2.82 0.57 9.50 0.14 12.56 0.12 56 1.91 0.45 7.45 0.77 10.90 0.28 64 1.35 0.29 7.00 0.37 9.77 0.13 72 1.51 0.28 2.47 0.27 1.68 0.12
Utilization of Asenapine

(279) The utilization of asenapine at 72 h was calculated based on the cumulative permeated amount at 72 h and the initial asenapine content. The results are shown in Table 13.4 and in FIG. 13b.

(280) TABLE-US-00041 TABLE 13.4 Utilization of asenapine after 72 h [%] Example Example Example Example Example Example 13a 13b 13c 13d 13e 13f (n = 3) (n = 3) (n = 3) (n = 3) (n = 3) (n = 3) 81.02 60.84 52.40 87.78 62.49 53.46

The Invention Relates in Particular to the Following Further Items

(281) 1. Transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure comprising a therapeutically effective amount of asenapine, said self-adhesive layer structure comprising:

(282) A) a backing layer; B) an asenapine-containing layer comprising: 1. asenapine in the form of the free base; and 2. a polymer selected from the group consisting of polysiloxanes and polyisobutylenes in an amount of more than 50% by weight based on the total weight of the asenapine-containing layer;
and C) optionally an additional skin contact layer.
2. Transdermal therapeutic system according to item 1, wherein the asenapine-containing layer is an asenapine-containing matrix layer.
3. Transdermal therapeutic system according to item 1, wherein the asenapine-containing layer is an asenapine-containing reservoir layer.
4. Transdermal therapeutic system according to any one of items 1 to 3, wherein the asenapine-containing layer is obtainable by incorporating the asenapine in the form of the free base.
5. Transdermal therapeutic system according to any one of items 1 to 4, wherein at least 90 mol %, preferably at least 95 mol %, more preferably at least 99 mol % of the asenapine in the asenapine-containing layer are present in the form of the free base.
6. Transdermal therapeutic system according to any one of items 1 to 5, wherein the amount of asenapine in the asenapine-containing layer ranges from 1 to 10%, preferably from 2 to 7% by weight based on the total weight of the asenapine-containing layer.
7. Transdermal therapeutic system according to any one of items 1 to 6, wherein the amount of asenapine contained in the transdermal therapeutic system ranges from 3 to 21 mg, preferably from 3.5 to 14 mg.
8. Transdermal therapeutic system according to any one of items 1 to 7, wherein the asenapine has a purity of at least 95%, preferably at least 98% and more preferably at least 99% as determined by quantitative HPLC.
9. Transdermal therapeutic system according to any one of items 1 to 8, wherein the amount of the polymer ranges from 55 to 98%, preferably from 70 to 98% or from 80 to 98% by weight based on the total weight of the asenapine-containing layer.
10. Transdermal therapeutic system according to any one of items 1 to 9, wherein the polymer is a pressure-sensitive adhesive polymer.
11. Transdermal therapeutic system according to any one of items 1 to 10, wherein the polymer is a polysiloxane.
12. Transdermal therapeutic system according to any one of items 1 to 10, wherein the polymer is a polyisobutylene.
13. Transdermal therapeutic system according to any one of items 1 to 12, wherein the asenapine-containing layer further comprises at least one additive or excipient selected from 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.
14. Transdermal therapeutic system according to any one of items 1 to 13, wherein the asenapine-containing layer further comprises a crystallization inhibitor, wherein the crystallization inhibitor is preferably polyvinylpyrrolidone, more preferably soluble polyvinylpyrrolidone.
15. Transdermal therapeutic system according to any one of items 1 to 14, wherein the asenapine-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.
16. Transdermal therapeutic system according to any one of items 1 to 15, wherein the asenapine-containing layer further comprises a permeation enhancer, wherein the permeation enhancer is preferably selected from diethylene glycol monoethyl ether (transcutol), diisopropyl adipate, isopropyl myristate, isopropyl palmitate, lauryl lactate, and dimethylpropylene urea.
17. Transdermal therapeutic system according to any one of items 1 to 16, wherein the asenapine-containing layer does not comprise isopropyl palmitate.
18. Transdermal therapeutic system according to any one of items 1 to 17, wherein the asenapine-containing layer does not comprise a permeation enhancer selected from oleic acids, oleic alcohols, and triglycerides.
19. Transdermal therapeutic system according to any one of items 1 to 18, wherein the asenapine-containing layer does not comprise a permeation enhancer.
20. Transdermal therapeutic system according to any one of items 1 to 19, wherein the asenapine-containing layer further comprises a copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate.
21. Transdermal therapeutic system according to any one of items 1 to 20, wherein the area of release ranges from 5 to 60 cm.sup.2, preferably from 10 to 40 cm.sup.2.
22. Transdermal therapeutic system according to any one of items 1 to 21, wherein the area weight of the asenapine-containing layer ranges from 50 to 120 g/m.sup.2, preferably from 70 to 100 g/m.sup.2.
23. Transdermal therapeutic system according to any one of items 1 to 22, wherein the transdermal therapeutic system provides a skin permeation rate of asenapine as measured in a Franz diffusion cell with dermatomed human skin of 0 μg/(cm.sup.2*h) to 12 μg/(cm.sup.2*h) in the first 4 hours, 1 μg/(cm.sup.2*h) to 22 μg/(cm.sup.2*h) from hour 4 to hour 8, 6 μg/(cm.sup.2*h) to 25 μg/(cm.sup.2*h) from hour 8 to hour 12, 5 μg/(cm.sup.2*h) to 20 μg/(cm.sup.2*h) from hour 12 to hour 16, 4 μg/(cm.sup.2*h) to 18 μg/(cm.sup.2*h) from hour 16 to hour 20, 2 μg/(cm.sup.2*h) to 12 μg/(cm.sup.2*h) from hour 20 to hour 24.
24. Transdermal therapeutic system according to any one of items 1 to 23, wherein the transdermal therapeutic system provides a cumulative permeated amount of asenapine as measured in a Franz diffusion cell with dermatomed human skin of 120 μg/cm.sup.2 to 380 μg/cm.sup.2 over a time period of 24 hours.
25. Transdermal therapeutic system according to any one of items 1 to 24, wherein the transdermal therapeutic system provides a permeated amount of asenapine as measured in a Franz diffusion cell with dermatomed human skin of 0 μg/cm.sup.2 to 50 μg/cm.sup.2 in the first 4 hours, 20 μg/cm.sup.2 to 120 μg/cm.sup.2 from hour 4 to hour 8, 40 μg/cm.sup.2 to 220 μg/cm.sup.2 from hour 8 to hour 12, 60 μg/cm.sup.2 to 290 μg/cm.sup.2 from hour 12 to hour 16, 80 μg/cm.sup.2 to 340 μg/cm.sup.2 from hour 16 to hour 20, 100 μg/cm.sup.2 to 380 μg/cm.sup.2 from hour 20 to hour 24.
26. Transdermal therapeutic system according to any one of items 1 to 25, wherein the transdermal therapeutic system provides a mean release rate of from 0.5 to 20 mg/day, preferably from 3 to 10 mg/day, more preferably of from 3 to 8 mg/day asenapine over at least 24 hours of administration.
27. Transdermal therapeutic system according to any one of items 1 to 26, wherein the transdermal therapeutic system provides by passive transdermal delivery an AUC.sub.0 24 from 5 to 100 (ng/mL)*h.
28. Transdermal therapeutic system according to any one of items 1 to 27, wherein the transdermal therapeutic system provides by passive transdermal delivery an AUC.sub.0-24 from 10 to 90 (ng/mL)*h.
29. Transdermal therapeutic system according to any one of items 1 to 28, wherein the transdermal therapeutic system further comprises a release liner.
30. Transdermal therapeutic system according to any one of items 1 to 29, wherein the transdermal therapeutic system further comprises an adhesive overlay.
31. Transdermal therapeutic system according to any one of items 1 to 30, wherein the backing layer is substantially asenapine-impermeable.
32. Transdermal therapeutic system according to any one of items 1 to 31, wherein the transdermal therapeutic system comprises an additional skin contact layer.
33. Transdermal therapeutic system according to any one of items 1 to 32, wherein the transdermal therapeutic system does not comprise an additional skin contact layer.
34. Transdermal therapeutic system according to any one of items 1 to 33 for use in a method of treating a human patient.
35. Transdermal therapeutic system according to any one of items 1 to 34 lbr use in a method of treating bipolar disorder and/or schizophrenia, preferably bipolar disorder and in particular acute manic or mixed episodes of bipolar disorder.
36. Transdermal therapeutic system for use according to item 34 or 35, wherein the transdermal therapeutic system is applied to the skin of the patient for a dosing interval of from 20 to 30 hours, preferably of about 24 hours.
37. Method of treating a human patient by applying a transdermal therapeutic system as defined in any one of items 1 to 33 to the skin of the patient.
38. Method of treating bipolar disorder and/or schizophrenia, preferably bipolar disorder and in particular acute manic or mixed episodes of bipolar disorder by applying a transdermal therapeutic system as defined in any one of items 1 to 33 to the skin of the patient.
39. Method of treatment according to item 37 or 38, wherein the transdermal therapeutic system is applied to the skin of the patient for a dosing interval of from 20 to 30 hours, preferably of about 24 hours.
40. A process for manufacturing an asenapine-containing layer for use in a transdermal therapeutic system according to any one of items 1 to 33 comprising the steps of: 1) combining at least the components 1. asenapine in the form of asenapine base; 2. a polymer selected from the group consisting of polysiloxanes and polyisobutylenes in an amount of more than 50% by weight based on the total weight of the asenapine-containing layer; and 3. optionally at least one additive;  to obtain a coating composition; 2) coating the coating composition onto the backing layer or release liner or any intermediate liner; and 3) drying the coated coating composition to form the asenapine-containing layer.
41. Process for manufacturing an asenapine-containing layer according to item 40, wherein the polymer is provided as a solution, wherein the solvent is 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 more preferably is selected from non-alcoholic solvents and most preferably is ethyl acetate or n-heptane.
42. Process for manufacturing an asenapine-containing layer according to item 40 or 41, wherein the polymer is polysiloxane, which is provided as a solution preferably as a solution in n-heptane or ethyl acetate with a solids content of from 60 to 80% by weight.
43. Transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure comprising a therapeutically effective amount of asenapine, said self-adhesive layer structure comprising: A) a backing layer; B) an asenapine-containing matrix layer comprising: 1. asenapine in the form of the free base; 2. a polysiloxane in an amount of at least 50% by weight based on the total weight of the asenapine-containing layer; and 3. a stabilizer; and 4. a crystallization inhibitor;
and C) optionally an additional skin contact layer.
44. Transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure comprising a therapeutically effective amount of asenapine, said self-adhesive layer structure comprising: A) a backing layer; B) an asenapine-containing matrix layer comprising: 1. asenapine in the form of the free base in an amount of 2 to 7% by weight based on the total weight of the asenapine-containing layer; 2. a polysiloxane in an amount of from 85 to 98% by weight based on the total weight of the asenapine-containing layer; and 3. a stabilizer in an amount of from 0.01 to 1.0% by weight based on the total weight of the asenapine-containing layer; and 4. crystallization inhibitor in an amount of from 0.5 to 10% by weight based on the total weight of the asenapine-containing layer;
and C) optionally an additional skin contact layer;
wherein the area weight of the matrix layer ranges from 70 to 100 g/m.sup.2.
45. Transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure comprising a therapeutically effective amount of asenapine, said self-adhesive layer structure comprising: A) a backing layer; B) an asenapine-containing matrix layer comprising: 1. asenapine in the form of the free base in an amount of 2 to 7% by weight based on the total weight of the asenapine-containing layer; 2. a polysiloxane in an amount of from 85 to 98% by weight based on the total weight of the asenapine-containing layer; and 3. tocopherol in an amount of from 0.01 to 1.0% by weight based on the total weight of the asenapine-containing layer; and 4. polyvinylpyrrolidone in an amount of from 0.5 to 10% by weight based on the total weight of the asenapine-containing layer;
and C) optionally an additional skin contact layer;
wherein the area weight of the matrix layer ranges from 70 to 100 g/m.sup.2.
46. Transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure comprising a therapeutically effective amount of asenapine, said self-adhesive layer structure comprising: A) a backing layer; B) an asenapine-containing layer comprising: 1. asenapine in an amount of from 2 to 7% by weight based on the total weight of the asenapine-containing layer; and 2. at least one silicone polymer in an amount of from 85 to 98% by weight based on the total weight of the asenapine-containing layer;
and C) optionally an additional skin contact layer.
47. The transdermal therapeutic system according to item 46, wherein the self-adhesive layer structure comprises A) a backing layer; B) an asenapine-containing layer, which is an asenapine-containing matrix layer, comprising: 1. asenapine in an amount of 2 to 7% by weight based on the total weight of the asenapine-containing layer; 2. at least one silicone polymer in an amount of from 85 to 98% by weight based on the total weight of the asenapine-containing layer; and 3. a stabilizer in an amount of from 0.01 to 1.0% by weight based on the total weight of the asenapine-containing layer; and 4. a crystallization inhibitor in an amount of from 0.5 to 10% by weight based on the total weight of the asenapine-containing layer;
and C) optionally an additional skin contact layer.
48. The transdermal therapeutic system according to item 47, wherein the area weight of the asenapine-containing layer ranges from 50 to 120 g/m.sup.2, preferably from 70 to 100 g/m.sup.2.
49. The transdermal therapeutic system according to item 48, wherein the stabilizer is tocopherol, ascorbyl palmitate or a combination thereof, and/or the crystallization inhibitor is polyvinylpyrrolidone.
50. The transdermal therapeutic system according to any one of items 46 to 49, wherein the asenapine is in the form of the free base.
51. The transdermal therapeutic system according to any one of items 46 to 50, wherein the silicone polymer is obtainable by polycondensation of silanol endblocked polydimethylsiloxane with a silicate resin.
52. The transdermal therapeutic system according to item 51, wherein the ratio of the silanol endblocked polydimethylsiloxane to the silicate resin is in the range of from 70:30 to 50:50, preferably from 56:44 to 54:46, e.g. about 55:45.
53. The transdermal therapeutic system according to item 51 or 52, wherein the residual functionality of the at least one silicone polymer is capped with trimethylsiloxy groups.
54. The transdermal therapeutic system according to any one of items 46 to 53, which is for use in a method of treating a human patient.
55. The transdermal therapeutic system according to any one of items 46 to 53, which is for use in a method of treating bipolar disorder and/or schizophrenia, preferably bipolar disorder and in particular acute manic disorder or mixed episodes of bipolar disorder.
56. The transdermal therapeutic system for use according to item 54 or 55, wherein the transdermal therapeutic system is applied to the skin of the patient for a dosing interval of from 20 to 30 hours, preferably of about 24 hours.
57. A process for manufacturing an asenapine-containing layer for use in a transdermal therapeutic system according to any one of items 46 to 53 comprising the steps of: 1) combining at least the components 1. asenapine in an amount of from 2 to 7% by weight based on the total weight of the asenapine-containing layer; 2. at least one silicone polymer in an amount of from 85 to 98% by weight based on the total weight of the asenapine-containing layer; and 3. optionally a stabilizer; and 4. optionally a crystallization inhibitor; to obtain a coating composition; 2) coating the coating composition onto the backing layer or release liner or any intermediate liner; and 3) drying the coated coating composition to form the asenapine-containing layer.
58. Transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure comprising a therapeutically effective amount of asenapine, said self-adhesive layer structure comprising: A) a backing layer; B) an asenapine-containing layer comprising: 1. asenapine in an amount of from 2 to 15% by weight based on the total weight of the asenapine-containing layer; and 2. at least one polyisobutylene in an amount of from 70 to 98% by weight based on the total weight of the asenapine-containing layer;
and C) optionally an additional skin contact layer.
59. The transdermal therapeutic system according to item 58, wherein the self-adhesive layer structure comprises A) a backing layer; B) an asenapine-containing layer, which is an asenapine-containing matrix layer, comprising: 1. asenapine in an amount of from 2 to 15% by weight based on the total weight of the asenapine-containing layer; and 2. at least one polyisobutylene in an amount of from 70 to 98% by weight based on the total weight of the asenapine-containing layer; and 3. a hydrophilic polymer in an amount of from 1 to 20% by weight based on the total weight of the asenapine-containing layer;
and C) optionally an additional skin contact layer.
60. The transdermal therapeutic system according to item 58 or 59, wherein the self-adhesive layer structure comprises A) a backing layer; B) an asenapine-containing layer, which is an asenapine-containing matrix layer, comprising: 1. asenapine in an amount of from 4 to 12% by weight based on the total weight of the asenapine-containing layer; and 2. at least one polyisobutylene in an amount of from 70 to 90% by weight based on the total weight of the asenapine-containing layer; and 3. a hydrophilic polymer in an amount of from 5 to 15% by weight based on the total weight of the asenapine-containing layer;
and C) optionally an additional skin contact layer.
61. The transdermal therapeutic system according to any one of items 58 to 60, wherein the area weight of the asenapine-containing layer ranges from 40 to 250 g/m.sup.2.
62. The transdermal therapeutic system according to any one of items 59 to 61, wherein the hydrophilic polymer is polyvinylpyrrolidone.
63. The transdermal therapeutic system according to any one of items 58 to 62, wherein the asenapine is in the form of the free base.
64. The transdermal therapeutic system according to any one of items 58 to 63, wherein the at least one polyisobutylene is a combination of a low molecular weight polyisobutylene and a high molecular weight polyisobutylene in a ratio of from 99:1 to 50:50, preferably from 90:10 to 60:40.
65. The transdermal therapeutic system according to item 64, wherein the low molecular weight polyisobutylene has a viscosity average molecular weight of from 38,000 to 42,000 g/mol and/or a weight average molecular weight of from 34,000 to 40,000 g/mol, and wherein the high molecular weight polyisobutylene has a viscosity average molecular weight of from 1,100,000 to 1,120,000 g/mol and/or a weight average molecular weight of from 1,540,000 to 1,560,000 g/mol.
66. The transdermal therapeutic system according to any one of items 58 to 65, which is for use in a method of treating a human patient.
67. The transdermal therapeutic system according to any one of items 58 to 65, which is for use in a method of treating bipolar disorder and/or schizophrenia, preferably bipolar disorder and in particular acute manic disorder or mixed episodes of bipolar disorder.
68. The transdermal therapeutic system for use according to item 66 or 67, wherein the transdermal therapeutic system has an area weight of from 40 to 125 g/m.sup.2, preferably from 60 to 100 g/m.sup.2, and is applied to the skin of the patient for a dosing interval of from 20 to 30 hours, preferably of about 24 hours.
69. The transdermal therapeutic system for use according to item 66 or 67, wherein the transdermal therapeutic system has an area weight of from more than 125 to 250 g/m.sup.2, preferably from 150 to 250 g/m.sup.2 and is applied to the skin of the patient for a dosing interval of at least 72 hours, preferably of about 84 hours.
70. A process for manufacturing an asenapine-containing layer for use in a transdermal therapeutic system according to any one of items 58 to 65 comprising the steps of: 1) combining at least the components 1. asenapine in an amount of from 2 to 15% by weight based on the total weight of the asenapine-containing layer; 2. at least one polyisobutylene in an amount of from 70 to 98% by weight based on the total weight of the asenapine-containing layer; and 3. optionally a hydrophilic polymer; to obtain a coating composition; 2) coating the coating composition onto the backing layer or release liner or any intermediate liner; and 3) drying the coated coating composition to form the asenapine-containing layer.

The Invention Further Relates in Particular to the Following Embodiments

(283) 1. Transdeiiiial therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure comprising a therapeutically effective amount of asenapine, said self-adhesive layer structure comprising:

(284) a) a backing layer; b) an asenapine-containing layer comprising: (i) asenapine in the form of the free base; and (ii) more than 50% by weight of a polymer selected from the group consisting of polysiloxanes and polyisobutylenes;
and c) optionally an additional skin contact layer.
2. Transdermal therapeutic system according to embodiment 1, wherein the asenapine-containing layer is an asenapine-containing matrix layer.
3. Transdermal therapeutic system according to embodiment 1, wherein the asenapine-containing layer is an asenapine-containing reservoir layer.
4. Transdermal therapeutic system according to any one of embodiments 1 to 3, wherein the asenapine-containing layer is obtainable by incorporating the asenapine in the foiiu of the free base.
5. Transdermal therapeutic system according to any one of embodiments 1 to 4, wherein at least 90 mol %, preferably at least 95 mol %, more preferably at least 99 mol % of the asenapine in the asenapine-containing layer are present in the form of the free base.
6. Transdermal therapeutic system according to any one of embodiments 1 to 5, wherein the amount of asenapine in the asenapine-containing layer ranges from 1 to 10%, preferably from 2 to 7% by weight based on the total weight of the asenapine-containing layer.
7. Transdeiinal therapeutic system according to any one of embodiments 1 to 6, wherein the amount of asenapine contained in the transdermal therapeutic system ranges from 3 to 21 mg, preferably from 3.5 to 14 mg.
8. Transdermal therapeutic system according to any one of embodiments 1 to 7, wherein the amount of the polymer ranges from 55 to 98%, preferably from 70 to 98% or from 80 to 98% by weight based on the total weight of the asenapine-containing layer.
9. Transdermal therapeutic system according to any one of embodiments 1 to 8, wherein the polymer is a pressure-sensitive adhesive polymer.
10. Transdermal therapeutic system according to any one of embodiments 1 to 9, wherein the polymer is a polysiloxane.
11. Transdermal therapeutic system according to any one of embodiments 1 to 9, wherein the polymer is a polyisobutylene.
12. Transdermal therapeutic system according to any one of embodiments 1 to 11 for use in a method of treating a human patient.
13. Transdermal therapeutic system according to any one of embodiments 1 to 12 for use in a method of treating bipolar disorder and/or schizophrenia, preferably bipolar disorder and in particular acute manic or mixed episodes of bipolar disorder.
14. Transdermal therapeutic system for use according to embodiment 12 or 13, wherein the transdermal therapeutic system is applied to the skin of the patient for a dosing interval of from 20 to 30 hours, preferably of about 24 hours.
15. A process for manufacturing an asenapine-containing layer for use in a transdermal therapeutic system according to any one of embodiments 1 to 11 comprising the steps of: 1) combining at least the components (i) asenapine in the form of asenapine base; (ii) a polymer selected from the group consisting of polysiloxanes and polyisobutylenes in an amount of more than 50% by weight based on the total weight of the asenapine-containing layer; and (iii) optionally at least one additive; to obtain a coating composition; 2) coating the coating composition onto the backing layer or release liner or any intermediate liner; and 3) drying the coated coating composition to form the asenapine-containing layer.
16. Transdermal therapeutic system according to any one of embodiments 1-14, wherein the asenapine-containing layer further comprises at least one excipient selected from the group consisting of crystallization inhibitors, solubilizers, fillers, substances for skincare, pH regulators, preservatives, tackifiers, softeners, stabilizers, and permeation enhancers.
17. Transdermal therapeutic system according to embodiment 16, wherein the asenapine-containing layer comprises a stabilizer in an amount of 0.01 to 1.0% by weight based on the total weight of the asenapine-containing layer, and a crystallization inhibitor in an amount of 0.5 to 10% by weight based on the total weight of the asenapine-containing layer.
18. Transdermal therapeutic system according to embodiment 2, wherein the asenapine-containing matrix layer comprises: (ii) asenapine in the form of the free base; (iii) a polysiloxane in an amount of at least 50% by weight based on the total weight of the asenapine-containing layer; (iv) tocopherol; and (v) polyvinylpyrrolidone.
19. Transdermal therapeutic system according to embodiment 18, wherein the asenapine-containing matrix layer comprises: (ii) asenapine in the form of the free base in an amount of 2 to 7% by weight based on the total weight of the asenapine-containing matrix layer; (iii) a polysiloxane in an amount of 85 to 98% by weight based on the total weight of the asenapine-containing matrix layer; (iv) tocopherol in an amount of 0.01 to 1.0% by weight based on the total weight of the asenapine-containing matrix layer; and (v) polyvinylpyrrolidone in an amount of 0.5 to 10% by weight based on the total weight of the asenapine-containing matrix layer;
wherein the area weight of the matrix layer ranges from 70 to 100 g/m.sup.2.
20. A method of treating schizophrenia in a patient in need thereof, the method comprising administering to the patient a transdermal therapeutic system comprising an asenapine-containing self-adhesive layer structure, said self-adhesive layer structure comprising: a) a backing layer; and b) an asenapine-containing matrix layer comprising: (i) a therapeutically effective amount of asenapine free base; and (ii) at least 50% by weight of a polymer selected from the group consisting of polysiloxanes and polyisobutylenes.
21. The method according to embodiment 20, wherein the asenapine-containing matrix layer further comprises at least one excipient selected from the group consisting of crystallization inhibitors, solubilizers, fillers, substances for skincare, pH regulators, preservatives, tackifiers, softeners, stabilizers, and permeation enhancers.
22. The method according to any of embodiments 20 or 21, wherein the asenapine-containing matrix layer comprises: (i) asenapine in the form of the free base in an amount of 2 to 7% by weight based on the total weight of the asenapine-containing matrix layer; (ii) a polysiloxane in an amount of 85 to 98% by weight based on the total weight of the asenapine-containing matrix layer; (iii) tocopherol in an amount of 0.01 to 1.0% by weight based on the total weight of the asenapine-containing matrix layer; and (iv) polyvinylpyrrolidone in an amount of 0.5 to 10% by weight based on the total weight of the asenapine-containing matrix layer.
23. The method according to any of embodiments 20-22, wherein the transdermal therapeutic system is administered once a day.
24. The method according to any of embodiments 20-23, wherein the transdermal therapeutic system provides an asenapine AUC.sub.0-24 of from about 5 to about 100 (ng/ml)*h.
25. The method according to embodiment 24, wherein the transdermal therapeutic system provides an asenapine AUC.sub.0-24 of from about 10 to about 90 (ng/ml)*h.
26. A method of treating bipolar disorder in a patient in need thereof, the method comprising administering to the patient a transdermal therapeutic system comprising an asenapine-containing self-adhesive layer structure, said self-adhesive layer structure comprising: a) a backing layer; and b) an asenapine-containing matrix layer comprising: (i) a therapeutically effective amount of asenapine free base; and (ii) at least 50% by weight of a polymer selected from the group consisting of polysiloxanes and polyisobutylenes.
27. The method according to embodiment 26, wherein the bipolar disorder is acute manic bipolar disorder.
28. The method according to embodiment 26, wherein the bipolar disorder is mixed episodes of bipolar disorder.
29. The method according to any of embodiments 26-28, wherein the asenapine-containing matrix layer further comprises at least one excipient selected from the group consisting of crystallization inhibitors, solubilizers, fillers, substances for skincare, pH regulators, preservatives, tackifiers, softeners, stabilizers, and permeation enhancers.
30. The method according to any of embodiments 26-28, wherein the asenapine-containing matrix layer comprises: (i) 2 to 7% by weight of asenapine in the form of the free base; (ii) 85 to 98% by weight of a polysiloxane; (iii) 0.01 to 1.0% by weight of tocopherol; and (iv) 0.5 to 10% by weight of polyvinylpyrrolidone.
31. The method according to any of embodiments 26-29, wherein the transdermal therapeutic system is administered once a day.
32. The method according to any of embodiments 26-30, wherein the transdermal therapeutic system provides an asenapine AUC.sub.0-24 of from about 5 to about 100 (ng/ml)*h.
33. The method according to any of embodiment 32, wherein the transdermal therapeutic system provides an asenapine AUC.sub.0-24 of from about 10 to about 90 (ng/ml)*h.