TRANSDERMAL THERAPEUTIC SYSTEM CONTAINING ASENAPINE

Abstract

The present invention relates to transdermal therapeutic systems (TTS) for the transdermal administration of asenapine comprising a self-adhesive layer structure containing a therapeutically effective amount of asenapine, such asenapine TTS for use in a method of treatment, processes of manufacture of such TTS as well as asenapine and transdermal therapeutic systems containing asenapine for use in a method of treatment and to a method of treating a human patient by transdermal administration of asenapine.

Claims

1-27. (canceled)

28. A transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure containing asenapine, said self-adhesive layer structure comprising an asenapine-containing matrix layer comprising asenapine and a polymer, wherein the transdermal therapeutic system has an area of release of from 10 to 80 cm.sup.2; the amount of asenapine in the asenapine-containing matrix layer ranges from 2% to 20% by weight; the asenapine-containing matrix layer has an area weight ranging from 90 to 230 g/m.sup.2; and further wherein, the transdermal therapeutic system provides: a mean transdermal asenapine release rate of 0.5 to 20 mg/day; and an asenapine C.sub.max value of from 0.5 to 10 ng/ml following administration of the transdermal system to the skin of a subject in need thereof.

29. The transdermal therapeutic system according to claim 28, wherein the polymer is selected from the group consisting of acrylic polymers, polyisobutylenes, styrene-isoprene-styrene block copolymers, polysiloxanes, and mixtures thereof.

30. The transdermal therapeutic system according to claim 28, wherein the transdermal therapeutic system provides an asenapine C.sub.max value of from 1 to 8 ng/ml or from 1.5 to 5 ng/ml following administration of the transdermal therapeutic system to the skin of the subject in need thereof.

31. The transdermal therapeutic system according to claim 28, wherein the transdermal therapeutic system provides a mean transdermal asenapine release rate of 2.0 to 10 mg/day.

32. The transdermal therapeutic system according to claim 28, wherein the transdermal therapeutic system contains from 0.70 mg/cm.sup.2 to 4.0 mg/cm.sup.2, from 0.80 mg/cm.sup.2 to 3.0 mg/cm.sup.2, from 0.82 mg/cm.sup.2 to 2.0 mg/cm.sup.2, or from 0.83 mg/cm.sup.2 to 1.7 mg/cm.sup.2 asenapine.

33. The transdermal therapeutic system according to claim 28, wherein the polymer comprises an acrylic polymer.

34. The transdermal therapeutic system according to claim 28, wherein the polymer comprises an acrylic polymer selected from the group consisting of acrylic polymers comprising functional groups; acrylic polymers comprising a functional group selected from the group consisting of hydroxyl groups, carboxylic acid groups, neutralized carboxylic acid groups, and mixtures thereof; acrylic polymers comprising hydroxyl groups and no carboxylic acid groups; a copolymer of vinyl acetate, 2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and glycidyl-methacrylate; a copolymer of methyl acrylate, 2-ethylhexyl acrylate and t-octyl acrylamide; a copolymer of 2-ethylhexyl-acrylate and vinyl acetate; a copolymer of vinyl acetate, 2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and glycidyl-methacrylate cross-linked by a cross-linking agent; and mixtures thereof.

35. The transdermal therapeutic system according to claim 28, wherein the polymer is an acrylic polymer, and wherein the acrylic polymer is present in an amount ranging from 60 to 97%, from 70 to 96%, from 75 to 88%, or from 91 to 96% by weight of the asenapine-containing matrix layer.

36. The transdermal therapeutic system according to claim 28, wherein the asenapine-containing matrix layer composition comprises a total amount of polymer content ranging from 75 to 97%, from 80 to 96%, or from 85 to 95% by weight of the asenapine-containing matrix layer.

37. The transdermal therapeutic system according to claim 28, wherein the asenapine-containing matrix layer further comprises a tackifier selected from the group consisting of polyvinylpyrrolidone, soluble polyvinylpyrrolidone, triglycerides, dipropylene glycol, resins, resin esters, terpenes and derivatives thereof, ethylene vinyl acetate adhesives, dimethylpolysiloxanes, and polybutenes.

38. The transdermal therapeutic system according to claim 28, wherein the asenapine-containing matrix layer further comprises a stabilizer selected from the group consisting of sodium metabisulfite, ascorbic acid and ester derivatives thereof, ascorbyl palmitate, butylated hydroxytoluene, tocopherol and ester derivatives thereof, α-tocopherol, and mixtures thereof.

39. The transdermal therapeutic system according to claim 28, wherein the transdermal therapeutic system further provides an asenapine AUC.sub.0-24 ranging from about 20 [(ng/ml)h] to about 78 [(ng/ml)h] following administration of the system to the skin of the subject in need thereof.

40. The transdermal therapeutic system according to claim 28, wherein the transdermal therapeutic system further provides a des-methyl-asenapine AUC.sub.0-24 ranging from about 0.4 [(ng/ml)h] to about 6 [(ng/ml)h] following administration of the system to the skin of the subject in need thereof.

41. The transdermal therapeutic system according to claim 28, wherein the transdermal therapeutic system further provides an AUC.sub.0-24 within 10% to 1000% of the steady state AUC.sub.0-24 obtained upon administration of twice daily 5 mg sublingual asenapine following administration of the system to skin of the subject in need thereof.

42. The transdermal therapeutic system according to claim 28, wherein the transdermal therapeutic system provides one or more pharmacokinetic parameter(s) selected from the group consisting of: an asenapine AUC.sub.0-48 ranging from 20 to 300 [(ng/ml)h]; an asenapine AUC.sub.0-48 ranging from 300 to 450 [(ng/ml)h]; an asenapine AUC.sub.0-72 ranging from 30 to 400 [(ng/ml)h]; an asenapine AUC.sub.0-72 ranging from 400 to 600 [(ng/ml)h]; an asenapine AUC.sub.0-84 ranging from 35 to 450 [(ng/ml)h]; an asenapine AUC.sub.0-84 ranging from 450 to 700 [(ng/ml)h]; a C.sub.max to C.sub.48 ratio of less than 2.0; a C.sub.max to C.sub.72 ratio of less than 3.0; and a C.sub.max to C.sub.84 ratio of less than 3.5 following administration of the transdermal therapeutic system to the skin of the subject in need thereof.

43. The transdermal therapeutic system according to claim 28, wherein the asenapine in the asenapine-containing matrix layer is included in the form of asenapine free base.

44. The transdermal therapeutic system according to claim 28, wherein at least 90 mol %, at least 95 mol %, at least 98 mol %, or at least 99 mol % of the asenapine in the asenapine-containing matrix layer is present in the form of asenapine free base.

45. The transdermal therapeutic system according to claim 28, wherein the asenapine-containing matrix layer comprises from 3 to 15%, or from 4 to 12% asenapine by weight of the asenapine-containing matrix layer.

46. The transdermal therapeutic system according to claim 28, wherein the transdermal therapeutic system contains from about 5 to 100 mg asenapine.

47. The transdermal therapeutic system according to claim 28, 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.2h) to 10 μg/(cm.sup.2h) in the first 8 hours, 2 μg/(cm.sup.2h) to 20 μg/(cm.sup.2h) from hour 8 to hour 24, 3 μg/(cm.sup.2h) to 20 μg/(cm.sup.2h) from hour 24 to hour 32, 3 μg/(cm.sup.2h) to 20 μg/(cm.sup.2h) from hour 32 to hour 48, and 2 μg/(cm.sup.2h) to 15 μg/(cm.sup.2h) from hour 48 to hour 72.

48. A method of treating schizophrenia, the method comprising administering the transdermal therapeutic system according to claim 28 to the skin of a human patient in need thereof.

Description

BRIEF DESCRIPTION OF THE D WINGS

[0151] FIG. 1a depicts the asenapine skin permeation rate of TTS prepared according to Examples 1a, 1b, 1c and 1d for hours 0 to 72.

[0152] FIG. 1b depicts the asenapine skin permeation rate of TTS prepared according to Examples 1a, 1b, 1c and 1d for hours 0 to 168.

[0153] FIG. 1c depicts the utilisation of asenapine of TTS prepared according to Examples 1a, 1b, 1c and 1d after 72 h.

[0154] FIG. 2a depicts the asenapine skin permeation rate of TTS prepared according to Examples 2a, 2b, 2c and 2d for hours 0 to 72.

[0155] FIG. 2b depicts the asenapine skin permeation rate of TTS prepared according to Examples 2a, 2b, 2c and 2d for hours 0 to 168.

[0156] FIG. 2c depicts the utilisation of asenapine of TTS prepared according to Examples 2a, 2b, 2c and 2d after 72 h.

[0157] FIG. 2d depicts the asenapine skin permeation rate of TTS prepared according to Examples 2e to 2j for hours 0 to 72.

[0158] FIG. 2e depicts the utilisation of asenapine of TTS prepared according to Examples 2e to 2j after 72 h.

[0159] FIG. 3a depicts the asenapine skin permeation rate of TTS prepared according to Examples 3a, 3b, 3c, 3d and 3e.

[0160] FIG. 3b depicts the utilisation of asenapine of TTS prepared according to Examples 3a, 3b, 3c, 3d and 3e after 56 h.

[0161] FIG. 4a depicts the asenapine skin permeation rate of TTS prepared according to Examples 4a and 4b for hours 0 to 72.

[0162] FIG. 4b depicts the asenapine skin permeation rate of TTS prepared according to Examples 4a and 4b for hours 0 to 168.

[0163] FIG. 4c depicts the utilisation of asenapine of TTS prepared according to Examples 4a and 4b after 72 h and 168 h.

[0164] FIG. 5a depicts the asenapine skin permeation rate of TTS prepared according to Examples 5a, 5b and 5c for hours 0 to 72.

[0165] FIG. 5b depicts the utilisation of asenapine of TTS prepared according to Examples 5a, 5b and 5c after 72 h.

[0166] FIG. 6a depicts the asenapine skin permeation rate of TTS prepared according to Examples 6a, 6b and 6c for hours 0 to 72.

[0167] FIG. 6b depicts the utilisation of asenapine of TTS prepared according to Examples 6a, 6b and 6c after 72 h.

[0168] FIG. 7a depicts the asenapine skin permeation rate of TTS prepared according to Examples 7a, 7b and 7c for hours 0 to 72.

[0169] FIG. 7b depicts the utilisation of asenapine of TTS prepared according to Examples 7a, 7b and 7c after 72 h.

[0170] FIG. 8a depicts the asenapine skin permeation rate of TTS prepared according to Examples 8a, 8b and 8c for hours 0 to 72.

[0171] FIG. 8b depicts the utilisation of asenapine of TTS prepared according to Examples 8a, 8b and 8c after 72 h.

[0172] FIG. 9a depicts the asenapine skin permeation rate of TTS prepared according to Examples 9a and 9b for hours 0 to 72.

[0173] FIG. 9b depicts the utilisation of asenapine of TTS prepared according to Examples 9a and 9b after 72 h.

[0174] FIG. 10a depicts the asenapine skin permeation rate of TTS prepared according to Example 10 for hours 0 to 72.

[0175] FIG. 10b depicts the utilisation of asenapine of TTS prepared according to Example 10 after 72 h.

[0176] FIG. 11 depicts the asenapine blood plasma concentration of TTS prepared according to Examples 11a, 11b, 11c and 11d.

[0177] FIG. 12a depicts the asenapine skin permeation rate of TTS prepared according to Examples 12a and 12b for hours 0 to 72.

[0178] FIG. 12b depicts the utilisation of asenapine of TTS prepared according to Examples 12a and 12b after 72 h.

[0179] FIG. 13a depicts the asenapine blood plasma concentration (arithmetic mean values with standard deviation as error bars) obtained in an in vivo clinical study of the TTS prepared according to Examples 13a and 13b for hours 0 to 168.

[0180] FIG. 13b depicts the asenapine blood plasma concentration (arithmetic mean values with standard deviation as error bars) obtained in an in vivo clinical study of the TTS prepared according to Examples 13a and 13b for hours 0 to 84.

[0181] FIG. 13c depicts the asenapine-glucuronide blood plasma concentration (geometric mean values with geometric mean multiplied with/divided by the geometric standard deviation as error bars) obtained in an in vivo clinical study of the TTS prepared according to Examples 13a and 13b for hours 0 to 168.

[0182] FIG. 13d depicts the asenapine-glucuronide blood plasma concentration (geometric mean values with geometric mean multiplied with/divided by the geometric standard deviation as error bars) obtained in an in vivo clinical study of the TTS prepared according to Examples 13a and 13b for hours 0 to 96.

[0183] FIG. 13e depicts the N-desmethyl-asenapine blood plasma concentration (geometric mean values with geometric mean multiplied with/divided by the geometric standard deviation as error bars) obtained in an in vivo clinical study of the TTS prepared according to Examples 13a and 13b for hours 0 to 108.

DETAILED DESCRIPTION

TTS STRUCTURE

[0184] The present invention is related to a transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure containing asenapine.

[0185] In particular, the self-adhesive layer structure may comprise therapeutically effective amounts of asenapine.

[0186] Preferably, the self-adhesive layer structure according to the present invention comprises A) a backing layer, and B) an asenapine-containing matrix layer consisting of a matrix layer composition comprising 1. asenapine and 2. a polymer.

[0187] Thus, according to a certain 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: [0188] A) a backing layer; [0189] B) an asenapine-containing matrix layer consisting of a matrix layer composition comprising: [0190] 1. asenapine; and [0191] 2. a polymer selected from acrylic polymers;
wherein the transdermal therapeutic system has an area of release of from 5 to 100 cm.sup.2.

[0192] According to another certain 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: [0193] A) a backing layer; [0194] B) an asenapine-containing matrix layer consisting of a matrix layer composition comprising: [0195] 1. asenapine in the form of the free base; and [0196] 2. a polymer; [0197] wherein the area weight of the matrix layer is at least 90 g/m.sup.2, and [0198] wherein the asenapine-containing matrix layer does not comprise isopropyl palmitate.

[0199] The backing layer is in particular substantially asenapine-impermeable.

[0200] 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.

[0201] In such a matrix-type TTS, the asenapine, and preferably a therapeutically effective amount of asenapine, is included in the asenapine-containing matrix layer. The self-adhesive layer structure in such a matrix-type TTS can include one or more further layers such as a skin contact layer. In such a further layer, the active agent may be included or may not be included. As outlined above, a skin contact layer can, even if manufactured as an active agent-free layer, after equilibration, comprise asenapine and then may also be regarded as a (further) matrix layer. The further 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 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.

[0202] In a reservoir-type TTS according to the present invention, the asenapine is included in a liquid or semi-liquid reservoir. The self-adhesive layer structure in such a reservoir-type TTS can include one or more further layers such as a skin contact layer. In such a further layer, the active agent may be included or may not be included. As outlined above, a skin contact layer can, even if manufactured as an active agent-free layer, after equilibration, comprise asenapine and then may also be regarded as a matrix layer. The reservoir-type TTS further includes a rate controlling membrane separating the reservoir and skin contact layer.

[0203] Thus, in certain embodiments, the self-adhesive layer structure comprises an additional reservoir layer which is located between the backing layer and the matrix layer, and a further rate controlling membrane which is located between the additional reservoir layer and the matrix layer.

[0204] In specific embodiments, 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.

[0205] In such embodiments, the self-adhesive layer structure may or may not comprise a membrane which is located between the matrix layer and the additional skin contact layer, wherein the membrane is preferably a rate controlling membrane.

[0206] 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. an asenapine-containing matrix layer and/or an adhesive layer.

[0207] Thus, according to certain embodiments of the invention, the TTS may further comprise an adhesive overlay or does not comprise an adhesive overlay, and preferably does not 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.

[0208] The self-adhesive layer structure according to the invention is no' many 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 seam-sealed pouch. The packaging may be child resistant and/or senior friendly.

Matrix Layer and Matrix Layer Composition

[0209] As outlined in more detail above, the TTS according to certain embodiments of the present invention comprises a self-adhesive layer structure comprising an asenapine-containing matrix layer consisting of a matrix layer composition.

[0210] In these embodiments, the matrix layer composition comprises:

[0211] 1. asenapine; and

[0212] 2. a polymer;

[0213] In a specific embodiment of the invention, the matrix layer composition comprises asenapine and a polymer selected from acrylic polymers, wherein the transdermal therapeutic system has an area of release of from 5 to 100 cm.sup.2.

[0214] In certain embodiments of the invention, the area of release ranges from 5 to 100 cm.sup.2, preferably from 10 to 80 cm.sup.2, and more preferably from 10 to 25 cm.sup.2 or from 10 to 20 cm.sup.2, from 25 to 55 cm.sup.2 or from 25 to 35 cm.sup.2 or from 55 to 65 cm.sup.2, i.e. the transdermal therapeutic system has an area of release of from 5 to 100 cm.sup.2, preferably from 10 to 80 cm.sup.2, and more preferably from 10 to 25 cm.sup.2 or from 10 to 20 cm.sup.2, from 25 to 55 cm.sup.2 or from 25 to 35 cm.sup.2 or from 55 to 65 cm.sup.2.

[0215] In another specific embodiment of the invention, the matrix layer composition comprises asenapine in the form of the free base and a polymer, wherein the area weight of the matrix layer is at least 90 g/m.sup.2 and wherein the asenapine-containing matrix layer does not comprise isopropyl palmitate.

[0216] In certain embodiments of the invention, the area weight of the matrix layer ranges from 90 to 230 g/m.sup.2, preferably from 110 to 210 g/m.sup.2, and most preferably from 120 to 170 g/m.sup.2.

[0217] Without wishing to be bound by theory, it is believed that the advantageous features of the TTS according to the present invention, such as good in vitro skin permeation are inter alia achieved by the amount of asenapine contained in the TTS, which can be controlled two-way by adjusting concentration and/or the area weight of the asenapine-containing layers such as the matrix layer.

[0218] Thus, in certain embodiments of the invention, the transdermal therapeutic system contains at least 0.70 mg/cm.sup.2, preferably at least 0.80 mg/cm.sup.2, more preferably at least 0.82 mg/cm.sup.2 and most preferably at least 0.83 mg/cm.sup.2 asenapine per area of release. In certain further embodiments of the invention, the transdermal therapeutic system contains at least 0.90 mg/cm.sup.2, at least 1.00 mg/cm.sup.2, at least 1.2 mg/cm.sup.2, at least 1.5 mg/cm.sup.2 or at least 2.0 mg/cm.sup.2 asenapine per area of release.

[0219] In particular, the transdermal therapeutic system contains from 0.70 mg/cm.sup.2 to 4.0 mg/cm.sup.2, preferably from 0.80 mg/cm.sup.2 to 3.0 mg/cm.sup.2, more preferably from 0.82 mg/cm.sup.2 to 2.0 mg/cm.sup.2 and most preferably from 0.83 mg/cm.sup.2 to 1.7 mg/cm.sup.2 asenapine.

[0220] In certain embodiments of the invention, the matrix layer composition is a pressure-sensitive adhesive composition. The matrix layer composition may comprise a second polymer or may comprise two or more further polymers.

[0221] According to certain embodiments of the invention, the total polymer content in the matrix layer composition ranges from 75 to 97%, preferably from 80 to 96% and more preferably from 85 to 95% of the matrix layer composition. In any event does the matrix layer include sufficient amounts of polymer to provide sufficient cohesion.

[0222] According to certain embodiments, the amount of asenapine contained in the TTS, in particular in the matrix layer of the TTS, ranges from 5 to 100 mg, preferably from 10 to 80 mg, and most preferably from 15 to 60 mg.

[0223] In certain embodiments, the transdermal therapeutic system has an area of release of from 5 to 100 cm.sup.2, and the amount of asenapine contained in the TTS ranges from 5 to 100 mg.

[0224] In certain embodiments of the invention, the asenapine-containing matrix layer does not comprise isopropyl palmitate in an amount of 10% of the matrix layer composition, preferably does not comprise isopropyl palmitate in an amount of 5-15% of the matrix layer composition and most preferably does not comprise isopropyl palmitate.

[0225] In certain embodiments of the invention, the asenapine-containing matrix layer does not comprise isopropyl myristate in an amount of 5% of the matrix layer composition, preferably does not comprise isopropyl myristate in an amount of 1-10% of the matrix layer composition and most preferably does not comprise isopropyl myristate.

[0226] In certain embodiments of the invention, the asenapine-containing matrix layer does not comprise ethyl cellulose in an amount of 10-20% of the matrix layer composition and preferably does not comprise ethyl cellulose.

[0227] In certain embodiments of the invention, the asenapine-containing matrix layer does not comprise hydrogen chloride.

[0228] In certain embodiments of the invention, the asenapine-containing matrix 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.

[0229] In certain embodiments of the invention, the matrix layer composition does not comprise any of polysiloxanes and polyisobutylenes in an amount of more than 50% of the matrix layer composition.

[0230] In certain embodiments, the asenapine-containing matrix layer is obtainable by drying a coated coating composition wherein no hydrochloric acid has been included in the coating composition.

[0231] In certain embodiments of the invention, the asenapine-containing matrix layer does not comprise toluene.

[0232] In certain embodiments of the invention, the asenapine-containing matrix layer is obtainable by drying a coated coating composition comprising no toluene.

Asenapine

[0233] In accordance with the invention, the self-adhesive layer structure contains asenapine, in particular in a therapeutically effective amount.

[0234] In certain embodiments, the self-adhesive layer structure comprises an asenapine-containing matrix layer consisting of a matrix layer composition comprising asenapine.

[0235] While in accordance with the present invention, the active agent may be present in the TTS in protonated or in free base form, the free base form is preferred.

[0236] Thus, in certain embodiments, the asenapine in the matrix layer composition is included in the form of the free base.

[0237] In certain embodiments, the matrix layer composition is obtainable by incorporating the asenapine in the form of the free base.

[0238] In particular, at least 90 mol %, preferably at least 95 mol %, more preferably at least 98 mol % and most preferably at least 99 mol % of the asenapine in the matrix layer is present in the form of the free base.

[0239] The asenapine in the matrix layer may be completely dissolved, or the matrix layer composition may contain asenapine particles, preferably constituted of asenapine free base.

[0240] As outlined above, the amount of asenapine in the TTS is believed to be important for a good release of the active, and can be e.g. adjusted by the asenapine concentration. Thus, in certain embodiments, the amount of asenapine in the matrix layer composition ranges from 2 to 20%, preferably from 3 to 15% and more preferably from 4 to 12% of the matrix layer composition.

[0241] 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:

TABLE-US-00001 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:

TABLE-US-00002 Column: Octadecyl phase acc. Ph. Eur. 2.2.29 (USP phase LI) 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:  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

[0242] As outlined above, the TTS according to a specific embodiment of the present invention comprises a self-adhesive layer structure comprising an asenapine-containing matrix layer consisting of a matrix layer composition, wherein the matrix layer composition comprises a polymer.

[0243] This polymer provides for sufficient cohesion of the matrix layer. According to certain embodiments the polymer may also provide for sufficient adhesion. In those embodiments the polymer is selected from pressure sensitive adhesive polymers.

[0244] In a preferred embodiment, the polymer is selected from pressure-sensitive adhesive polymers.

[0245] Polymers which are suitable as the polymer in accordance with the invention are polysiloxanes, polyisobutylenes, styrene-isoprene-styrene block copolymers and acrylic polymers.

[0246] Corresponding commercial products are available e.g. under the brand names Bio-PSAs (polysiloxanes), Oppanol B10/B100 (a polyisobutylene polymer, 85:15), JSR-SIS (a styrene-isoprene-styrene copolymer) or Duro-Tak™ (acrylic polymers, see below for details).

[0247] 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. Typically, the low molecular 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. 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.

[0248] Preferably, the polymer is selected from acrylic polymers, wherein the acrylic polymers comprise or do not comprise functional groups.

[0249] Corresponding commercial products are available e.g. under the brand names Duro-Tak™ 387-2287 (an acrylic copolymer comprising hydroxyl groups), Dura-Tak™ 387-2516 (an acrylic copolymer comprising hydroxyl groups), Dura-Tak™ 387-2051 (an acrylic copolymer comprising carboxylic acid groups), Duro-Tak™ 387-2353 (an acrylic copolymer comprising carboxylic acid groups), Duro-Tak™ 387-4098 (an acrylic copolymer comprising no functional groups) and Duro-Tak™ 387-9301 (an acrylic copolymer comprising no functional groups).

[0250] In certain embodiments, the polymer is selected from acrylic polymers comprising functional groups wherein the functional groups are selected from hydroxyl groups, carboxylic acid groups, neutralized carboxylic acid groups and mixtures thereof. Preferably, the functional groups are limited to hydroxyl groups.

[0251] In certain embodiments, the polymer is selected from acrylic polymers which do not comprise carboxylic acid groups or neutralized carboxylic acid groups or both groups, and preferably the polymer is selected from acrylic polymers which do not comprise acidic groups.

[0252] In further preferred embodiments, the polymer is selected from acrylic polymers comprising hydroxyl groups and no carboxylic acid groups, and more preferably, the polymer is a copolymer based on vinyl acetate, 2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and glycidyl-methacrylate.

[0253] Such a copolymer based on vinyl acetate, 2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and glycidyl-methacrylate is commercially available under the brand names Duro-Tak™ 387-2287 (provided as a solution in ethyl acetate without cross-linking agent) and Duro-Tak™ 387-2516 (provided as a solution in ethyl acetate, ethanol, n-heptane and methanol with a titanium cross-linking agent). Thus, depending on the type of commercially available acrylic polymer used and depending on whether a cross-linking agent is added to the coating composition, the polymer in the finalized matrix layer is cross-linked (and preferably is cross-linked by a titanium cross-linking agent) or is not cross-linked by a cross-linking agent.

[0254] In certain other embodiments, the polymer is selected from acrylic polymers comprising no hydroxyl groups and no carboxylic acid groups, and preferably, the polymer is selected from acrylic polymers comprising no functional groups.

[0255] In further preferred embodiments, the polymer is a copolymer based on methyl acrylate, 2-ethylhexyl acrylate and t-octyl acrylamide, and which is commercially available under the brand name Duro-Tak™ 387-9301 (provided as a solution in ethyl acetate).

[0256] In further preferred embodiments, the polymer is a copolymer based on 2-ethylhexyl-acrylate and vinyl acetate, which is commercially available under the brand name Duro-Tak™ 387-4098 (provided as a solution in ethyl acetate).

[0257] In certain preferred embodiments, the amount of the polymer ranges from 60 to 97%, preferably from 65 to 80% or from 70 to 96% and more preferably from 75 to 88% or from 91 to 96%, and most preferably from 77 to 82% or from 81 to 85% of the matrix layer composition. These amounts are in particular preferred in case the matrix layer composition does not comprise any further, additional polymer(s).

[0258] However, the matrix layer composition may also comprise a second or further, additional polymer(s), and in particular may comprise one of the aforementioned polymers as second or further, additional polymer(s).

[0259] Additional polymers and additives may also be added to enhance cohesion and/or adhesion.

[0260] 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 prohibited by the addition of certain polymers. A basic acrylate polymer (e.g. Eudragit E100 which is a copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate) 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.

[0261] According to certain embodiments, the total polymer content in the matrix layer composition ranges from 60 to 97%, preferably from 70 to 96%, and more preferably from 75 to 95% or from 75 to 90% of the matrix layer composition. In some embodiments, the total polymer content in the matrix layer composition ranges from 75 to 97%, preferably from 80 to 96%, more preferably from 85 to 95% and most preferably from 87 to 92% or from 91 to 95% of the matrix layer composition.

Further Additives

[0262] As outlined above, the TTS according to a specific embodiment of the present invention comprises a self-adhesive layer structure comprising an asenapine-containing matrix layer consisting of a matrix layer composition. In such embodiments, the matrix layer composition of the TTS according to the invention may comprise further excipients or additives selected from the group consisting of cross-linking agents, solubilizers, fillers, tackifiers, plasticizers, stabilizers, softeners, substances for skincare, permeation enhancers, i.e. substances which influence the barrier properties of the stratum corneum in the sense of increasing the active agent permeability, pH regulators, and preservatives. Particularly preferred additives are tackifiers and stabilizers. Such additives may be present in the asenapine-containing layer in an amount of from 0.001% to 15% of the matrix layer composition per additive. In a certain embodiment, the total amount of all additives is from 0.001% to 25% of the matrix layer composition. Hereinafter, where a range for an amount of a specific additive is given, such a range refers to the amount per individual additive.

[0263] 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.

[0264] The cross-linking agent may be selected from the group consisting of aluminium and titanium cross-linking agents such as aluminium acetylacetonate, titanium acetylacetonate or polybutyltitanate, and preferably is a titanium cross-linking agent. The amount of cross-linking agent may range from 0.005 to 1%, and preferably from 0.01 to 0.1% of the matrix layer composition. The matrix layer composition may also comprise a polymer which is self-crosslinking, i.e. comprises a cross-linking functional group such as glycidyl groups, which reacts upon heating. According to a further specific embodiment, the matrix layer composition comprises a cross-linking agent as above and a self-crosslinking polymer.

[0265] In one embodiment, the matrix layer composition further comprises a solubilizer. The solubilizer preferably improves the solubility of the asenapine in the asenapine-containing layer. Preferred solubilizers include, e.g., glycerol-, polyglycerol-, propylene glycol- and polyoxyethylene-esters of medium chain and/or long chain fatty acids, such as glyceryl monolinoleate, medium chain glycerides and medium chain triglycerides, non-ionic solubilizers made by reacting castor oil with ethylene oxide, and any mixtures thereof which may further contain fatty acids or fatty alcohols; cellulose and methylcellulose and derivatives thereof such as hydroxypropylcellulose and hypromellose acetate succinate; various cyclodextrins and derivatives thereof; non-ionic tri-block copolymers having a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene known as poloxamers;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.

[0266] However, also the permeation enhancers mentioned below can act as solubilizers. Furthermore, also crystallization inhibitors may act as solubilizers.

[0267] 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.

[0268] In case the matrix 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. 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. In certain embodiments, the matrix layer composition comprises a tackifier in an amount of from 5 to 15% of the matrix layer composition.

[0269] 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.

[0270] Within the meaning of this invention, the tet in “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”.

[0271] In certain embodiments, the matrix layer composition comprises a stabilizer selected from sodium metabisulfite, ascorbic acid and ester derivatives thereof, butylated hydroxytoluene, tocopherol and ester derivatives thereof such as tocopheryl acetate and tocopheryl linoleate, preferably from tocopherol and ester derivatives thereof and ascorbic acid and ester derivatives thereof, and is more preferably selected from ascorbyl esters of fatty acids and tocopherol, and most preferably is ascorbyl palmitate or α-tocopherol. Also particularly preferred is a combination of tocopherol and ascorbyl palmitate. Where the matrix layer composition comprises a stabilizer, the amount of the stabilizer is from 0.001 to 2% of the matrix layer composition.

[0272] In one embodiment, the matrix layer composition 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.

[0273] In one embodiment, the matrix layer composition further comprises a substance for skincare. Such substances may be used to avoid or reduce skin irritation as determined by assessment of the skin using dermal response scores. 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% of the matrix layer composition.

[0274] In certain embodiments, the matrix layer composition comprises a permeation enhancer selected from diethylene glycol monoethyl ether, diisopropyl adipate, isopropyl myristate, isopropyl palmitate, lauryl lactate, dimethylpropylene urea and a mixture of propylene glycol monoesters and diesters of fatty acids. Such a mixture of propylene glycol monoesters and diesters of fatty acids is commercially available e.g. under the brand name Capryol, which is a propylene glycol monocaprylate (type II), a mixture of propylene glycol monoesters and diesters of fatty acids with a ratio of >90% monoesters and <10% diesters, wherein the fatty acids mainly consist of caprylic acid.

[0275] In certain other embodiments, the matrix layer composition does not comprise a permeation enhancer selected from oleic acids, triglycerides, oleic alcohols, and mixtures thereof, and in particular the matrix layer composition does not comprise a permeation enhancer at all. In another embodiment, the matrix layer composition 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 matrix layer composition does not comprise a maleic acid alkali salt.

[0276] The matrix layer composition according to the invention may comprise a pH regulator. Preferably, the pH regulator is selected from amine derivatives, inorganic alkali derivatives, polymers with basic and acidic functionality, respectively.

Release Characteristics

[0277] The TTS in accordance with the invention are designed for transdermally administering asenapine to the systemic circulation for a predefined extended period of time.

[0278] In one aspect, the TTS according to the invention provide a mean release rate of 0.5 to 20 mg/day, 0.5 to 20 mg/24 h, 500 to 20,000 μg/day, 500 to 20,000 μs/24 h, 0.021 to 0.833 mg/h or 21 to 833 μg/h, preferably of 1.0 to 15 mg/day, 1.0 to 15 mg/24 h, 1,000 to 15,000 μg/day, 1,000 to 15,000 μg/24 h, 0.042 to 0.625 mg/h or 42 to 625 μg/h, and more preferably of 2.0 to 10 mg/day, 2.0 to 10 mg/24 h, 2,000 to 10,000 μg/day, 2,000 to 10,000 μs/24 h, 0.083 to 0.417 mg/h or 83 to 417 μg/h over at least 24 hours of administration, preferably over at least 48 hours of administration, more preferably over at least 72 hours of administration, and most preferably over at least 84 hours of administration.

[0279] According to certain embodiments, the TTS according to the invention provide a cumulative skin permeation rate of asenapine at hour 48 or at hour 72 as measured in a Franz diffusion cell with dermatomed human skin of 1 μg/(cm.sup.2 h) to 20 μg/(cm.sup.2 h), preferably of 2 μg/(cm.sup.2 h) to 15 μg/(cm.sup.2 h) and more preferably of 4 μg/(cm.sup.2 h) to 12 μg/(cm.sup.2 h).

[0280] In specific embodiments of the invention, the TTS according to the invention as described above provides a skin permeation rate of asenapine as measured in a Franz diffusion cell with dermatomed human skin of

[0281] 0 μg/(cm.sup.2 h) to 10 μg/(cm.sup.2 h) in the first 8 hours,

[0282] 2 μg/(cm.sup.2 h) to 20 μg/(cm.sup.2 h) from hour 8 to hour 24,

[0283] 3 μg/(cm.sup.2 h) to 20 μg/(cm.sup.2 h) from hour 24 to hour 32,

[0284] 3 μg/(cm.sup.2 h) to 20 μg/(cm.sup.2 h) from hour 32 to hour 48,

[0285] 2 μg/(cm.sup.2 h) to 15 μg/(cm.sup.2 h) from hour 48 to hour 72.

[0286] In certain embodiments, 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 0.05 mg/cm.sup.2 to 1.0 mg/cm.sup.2, preferably of 0.1 mg/cm.sup.2 to 0.7 mg/cm.sup.2 over a time period of 48 hours.

[0287] In certain embodiments, 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 0.1 mg/cm.sup.2 to 2.0 mg/cm.sup.2, preferably 0.2 mg/cm.sup.2 to 1.0 mg/cm.sup.2 over a time period of 72 hours.

Method of Treatment/Medical Use

[0288] 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.

[0289] In certain embodiments, the TTS according to the invention is preferably for use in a method of treating psychosis, and more preferably 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 particular 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.

[0290] 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. 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.

[0291] The TTS according to the invention is further preferably for use in a method of treating schizophrenia or bipolar disorder in a subject in need thereof, the method comprising transdermally administering a therapeutically effective amount of asenapine to the subject, wherein the asenapine is contained in a transdermal therapeutic system for the transdermal administration of asenapine, and wherein the transdermal therapeutic system is in contact with at least one body surface on the subject for at least 48 hours or 2 days or for at least 72 hours or 3 days, or for about 48 hours or about 2 days, or about 72 hours or about 3 days, or about 84 hours or about 3.5 days.

[0292] Within the meaning of the present invention, the body surface may be located at any part of the body, and is in certain embodiments selected from the upper outer arm, upper chest, upper back or the side of the chest.

[0293] The TTS may be further for use in a method of treatment with a dosing interval of at least 24 hours or 1 day, at least 48 hours or 2 days, or at least 72 hours or 3 days, and/or with a dosing interval of up to 168 hours or 7 days, up to 120 hours or 5 days, or up to 96 hours or 4 days. The dosing interval may in particular be 24 hours or 1 day, 48 hours or 2 days, or 84 hours or 3.5 days.

[0294] Accordingly the invention is also related to TTS for use in a method of treatment, and in particular for use in a method of treating schizophrenia and/or bipolar disorder, and in particular acute manic or mixed episodes of bipolar disorder, in an around-the-clock treatment with a once-a-day TTS exchange mode (dosing interval of 24 hours or 1 day), a twice-a-week TTS exchange mode (dosing interval of 84 hours or 3.5 days) or a once-a-week TTS exchange mode (dosing interval of 168 hours, or 7 days).

[0295] The TTS according to the invention is further preferably for use in a method of treating a patient, wherein the transdermal therapeutic system provides a reduction in at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine.

[0296] Relative to an equivalent dose of sublingual asenapine should be understood as a comparison in the incidence and intensity of side effects in a clinical study when using a dose of transdermal and sublingual asenapine that leads substantially to the same blood plasma exposure of asenapine.

[0297] In another embodiment, the TTS according to the invention may also be for use in a method of reducing, in a patient, at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine.

[0298] In such a method of treating a patient or in such a method of reducing at least one asenapine-related side effect, but also in all the transdermal therapeutic systems for use in a method of treatment, the transdermal therapeutic systems for use in a method of reducing at least one asenapine-related side effect, the methods of treatment and methods of reducing at least one asenapine-related side effect as well as the asenapine for use in a method of treating a human patient as will be described below, the following may generally further apply:

[0299] (i) The at least one asenapine-related side effect is in particular fatigue, somnolence, dizziness, oral hypoaesthesia, or any combination thereof.

[0300] (ii) As these side effects are reduced, in one embodiment, the inventive methods and transdermal therapeutic systems for use in the methods are in particular suitable for a human patient already suffering from such a condition, i.e. suffering from fatigue, somnolence, dizziness, or any combination thereof.

[0301] (iiii) Further, the incidence of the at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine may be reduced by at least about 30%, at least about 40%, at least about 70% or at least about 80%, and/or the intensity of the at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine may be reduced. The intensity of a side effect can be determined e.g. by classifying the side effects on a scale indicating “mild”, “moderate” or “severe” intensity, and a reduction of the intensity can be quantified by comparing the median intensity.

[0302] (iv) In such embodiments, the at least one asenapine-related side effect may be fatigue and the incidence of fatigue relative to an equivalent dose of sublingual asenapine may be reduced by at least about 30% or at least about 40% and/or the intensity of fatigue relative to an equivalent dose of sublingual asenapine may be reduced.

[0303] (v) alternatively, the at least one asenapine-related side effect may be dizziness, and the incidence of dizziness relative to an equivalent dose of sublingual asenapine may be reduced by at least about 30%, at least about 40%, at least about 70% or at least about 80%.

[0304] As concerns the type of side effects, it should be noted that fatigue and somnolence, while designating clinically different conditions, have common and/or similar symptoms and may be therefore difficult to distinguish, in particular if not followed on a long term.

[0305] In accordance with another specific aspect, the present invention is also related to a method of treatment, and in particular a method of treating a human patient.

[0306] The invention is in particular related to a method of treating psychosis, and in particular to 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, and preferably to a method of treating schizophrenia and/or bipolar disorder in a human patient, and in particular acute manic or mixed episodes of bipolar disorder including applying a transdermal therapeutic system according to the invention to the skin of a human patient.

[0307] In certain embodiments, the invention is also related to 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. In certain embodiments, the invention is also related to a method of treating bipolar disorder in a human patient, in particular an adult, as an adjunctive treatment to lithium or valproate. In certain embodiments, the invention is also related to a maintenance monotherapy treatment in a method of treating bipolar disorder in a human patient, in particular an adult.

[0308] The invention is further preferably also related to a method of treating schizophrenia or bipolar disorder in a subject in need thereof, the method comprising transdermally administering a therapeutically effective amount of asenapine to the subject, wherein the asenapine is contained in a transdermal therapeutic system for the transdermal administration of asenapine, and wherein the transdermal therapeutic system is in contact with at least one body surface (as defined above) on the subject for at least 48 hours or 2 days or for at least 72 hours or 3 days, or for about 48 hours or about 2 days, or about 72 hours or about 3 days, or about 84 hours or about 3.5 days.

[0309] The invention is also related to a method of treatment by applying a transdermal therapeutic system according to the invention for at least 24 hours or 1 day, at least 48 hours or 2 days, or at least 72 hours or 3 days, and/or for up to 168 hours or 7 days, up to 120 hours or 5 days, or up to 96 hours or 4 days to the skin of a human patient. The transdermal therapeutic system according to the invention may in particular be applied for 24 hours or 1 day, 48 hours or 2 days, or 84 hours or 3.5 days to the skin of a human patient.

[0310] Accordingly the invention is also related to a method of treatment in an around-the-clock treatment with a once-a-day TTS exchange mode (dosing interval of 24 hours or 1 day), a twice-a-week TTS exchange mode (dosing interval of 84 hours or 3.5 days) or a once-a-week TTS exchange mode (dosing interval of 168 hours, or 7 days).

[0311] In such a method, as previously outlined, the transdermal therapeutic system may provide a reduction in at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine.

[0312] In another embodiment, the present invention is also related to a method of reducing, in a patient, at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine, the method comprising administering a transdermal therapeutic system according to the invention.

[0313] The invention is also related to a method of reducing at least one asenapine-related side effect in a patient being treated with sublingual asenapine therapy, the method comprising [0314] a) discontinuing sublingual asenapine therapy; and [0315] b) administering a transdermal therapeutic system according to the invention to the skin of the patient, wherein the transdermal therapeutic system provides a reduction in at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine.

[0316] In such a method, the transdermal therapeutic system may deliver an amount of asenapenaine equivalent to the amount of asenapine originally provided by the sublingual asenapine therapy.

[0317] The inventors have surprisingly shown that a relatively constant asenapine blood plasma concentration can be maintained for an extended period of time by transdermal delivery of asenapine.

[0318] Thus, in accordance with one specific aspect, the present invention is related to asenapine for use in a method of treating a human patient by transdermal administration of asenapine for a dosing interval of at least 48 hours or 2 days or for a dosing interval of at least 72 hours or 3 days.

[0319] In such embodiments, the dosing interval may be up to 168 hours or 7 days, up to 120 hours or 5 days, or up to 96 hours or 4 days, and in particular may be 48 hours or 2 days, or 72 hours or 3 days, or 84 hours or 3.5 days.

[0320] Further, the asenapine is preferably for use in a method of treating psychosis, 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, or for use in a method of treating schizophrenia and/or bipolar disorder, more preferably bipolar disorder and in particular acute manic or mixed episodes of bipolar disorder. The asenapine is also preferably 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, for use as an adjunctive treatment to lithium or valproate or for use as maintenance monotherapy treatment in a method of treating bipolar disorder in a human patient, in particular an adult.

[0321] The asenapine is further preferably for use in a method of treating schizophrenia or bipolar disorder in a subject in need thereof, the method comprising transdermally administering a therapeutically effective amount of asenapine to the subject, wherein the asenapine is contained in a transdermal therapeutic system for the transdermal administration of asenapine, and wherein the transdermal therapeutic system is in contact with at least one body surface (as defined above) on the subject for at least 48 hours or 2 days or for at least 72 hours or 3 days, or for about 48 hours or about 2 days, or about 72 hours or about 3 days, or about 84 hours or about 3.5 days.

[0322] The relatively constant asenapine blood plasma concentration can be described by several pharmacokinetic parameters as obtained in an in vivo clinical study on human subjects.

[0323] Thus, in certain embodiments, the present invention is related to asenapine for use in a method of treating a human patient by transdermal administration of asenapine as described above, [0324] providing by transdermal delivery a mean release rate of 0.5 to 20 mg/day, 0.5 to 20 mg/24 h, 500 to 20,000 μg/day, 500 to 20,000 μg/24 h, 0.021 to 0.833 mg/h or 21 to 833 μg/h, preferably 1.0 to 15 mg/day, 1.0 to 15 mg/24 h, 1,000 to 15,000 μg/day, 1,000 to 15,000 μg/24 h, 0.042 to 0.625 mg/h or 42 to 625 μg/h, more preferably of 2.0 to 10 mg/day, 2.0 to 10 mg/24 h, 2,000 to 10,000 μg/day, 2,000 to 10,000 μg/24 h, 0.083 to 0.417 mg/h or 83 to 417 μg/h over at least 48 hours or 2 days of administration, or providing by transdermal delivery a mean release rate of 0.5 to 20 mg/day, 0.5 to 20 mg/24 h, 500 to 20,000 μg/day, 500 to 20,000 μg/24 h, 0.021 to 0.833 mg/h or 21 to 833 μg/h, preferably 1.0 to 15 mg/day, 1.0 to 15 mg/24 h, 1,000 to 15,000 μg/day, 1,000 to 15,000 μg/24 h, 0.042 to 0.625 mg/h or 42 to 625 μg/h, more preferably of 2.0 to 10 mg/day, 2.0 to 10 mg/24 h, 2,000 to 10,000 μg/day, 2,000 to 10,000 μg/24 h, 0.083 to 0.417 mg/h or 83 to 417 μg/h over at least 72 hours or 3 days of administration, or providing by transdermal delivery a mean release rate of 0.5 to 20 mg/day, 0.5 to 20 mg/24 h, 500 to 20,000 μg/day, 500 to 20,000 μg/24 h, 0.021 to 0.833 mg/h or 21 to 833 μg/h, preferably 1.0 to 15 mg/day, 1.0 to 15 mg/24 h, 1,000 to 15,000 μg/day, 1,000 to 15,000 μg/24 h, 0.042 to 0.625 mg/h or 42 to 625 μg/h, more preferably of 2.0 to 10 mg/day, 2.0 to 10 mg/24 h, 2,000 to 10,000 μg/day, 2,000 to 10,000 μg/24 h, 0.083 to 0.417 mg/h or 83 to 417 μg/h over at least 84 hours or 3.5 days of administration.

[0325] Further, in certain embodiments, the present invention is related to asenapine for use in a method of treating a human patient by transdermal administration of asenapine as described above, [0326] providing by transdermal delivery an AUC.sub.0-48 from 20 to 300 (ng/ml) h or from more than 300 to 450 (ng/ml) h and preferably from 30 to 200 (ng/ml) h, or providing by transdermal delivery an AUC.sub.0-72 from 30 to 400 (ng/ml) h or from more than 400 to 600 (ng/ml) h and preferably from 50 to 300 (ng/ml) h, or providing by transdermal delivery an AUC.sub.0-84 from 35 to 450 (ng/ml) h or from more than 450 to 700 (ng/ml) h and preferably from 60 to 350 (ng/ml) h.

[0327] Still further, in certain embodiments, the present invention is related to asenapine for use in a method of treating a human patient by transdermal administration of asenapine as described above, [0328] providing by transdermal delivery a C.sub.max to C.sub.48 ratio of less than 2.0, preferably of less than 1.5 and more preferably of less than 1.3, or [0329] providing by transdermal delivery a C.sub.max to C.sub.72 ratio of less than 3.0, preferably of less than 2.5 and more preferably of less than 2.0, or [0330] providing by transdermal delivery a C.sub.max to C.sub.84 ratio of less than 3.5, preferably of less than 3.0, more preferably of less than 2.5 and most preferably of less than 2.0.

[0331] Still further, in certain embodiments, the present invention is related to asenapine for use in a method of treating a human patient by transdermal administration of asenapine as described above, [0332] providing by transdermal delivery a C.sub.max value of from 0.5 to 10 ng/ml and preferably of from 1 to 8 ng/ml.

[0333] In further embodiments, the present invention is further related to asenapine for use in a method of treating a human patient as outlined above, wherein at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced.

[0334] In accordance with another specific aspect, the present invention is related to a transdermal therapeutic system for the transdermal administration of asenapine for use in a method of treating a human patient for a dosing interval of at least 48 hours or 2 days or for a dosing interval of at least 72 hours or 3 days.

[0335] In such embodiments, the dosing interval may be up to 168 hours or 7 days, up to 120 hours or 5 days, or up to 96 hours or 4 days, and in particular may be 48 hours or 2 days, or 72 hours or 3 days, or 84 hours or 3.5 days.

[0336] Such a transdermal therapeutic system for use in a method of treating a human patient as described above preferably comprises a self-adhesive layer structure containing a therapeutically effective amount of asenapine.

[0337] Further, the transdermal therapeutic system is preferably for use in a method of treating psychosis, 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, or for use in a method of treating schizophrenia and/or bipolar disorder, more preferably bipolar disorder and in particular acute manic or mixed episodes of bipolar disorder. The transdermal therapeutic system is also preferably 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, for use as an adjunctive treatment to lithium or valproate or for use as maintenance monotherapy treatment in a method of treating bipolar disorder in a human patient, in particular an adult.

[0338] The transdermal therapeutic system is further preferably for use in a method of treating schizophrenia or bipolar disorder in a subject in need thereof, the method comprising transdermally administering a therapeutically effective amount of asenapine to the subject, wherein the asenapine is contained in a transdermal therapeutic system for the transdermal administration of asenapine, and wherein the transdermal therapeutic system is in contact with at least one body surface (as defined above) on the subject for at least 48 hours or 2 days or for at least 72 hours or 3 days, or for about 48 hours or about 2 days, or about 72 hours or about 3 days, or about 84 hours or about 3.5 days.

[0339] Thus, in certain embodiments, the present invention is related to a transdermal therapeutic system for the transdermal administration of asenapine for use in a method of treating a human patient as described above, [0340] providing by transdermal delivery a mean release rate of 0.5 to 20 mg/day, 0.5 to 20 mg/24 h, 500 to 20,000 μg/day, 500 to 20,000 424 h, 0.021 to 0.833 mg/h or 21 to 833 μg/h, preferably 1.0 to 15 mg/day, 1.0 to 15 mg/24 h, 1,000 to 15,000 μg/day, 1,000 to 15,000 μg/24 h, 0.042 to 0.625 mg/h or 42 to 625 μg/h, more preferably of 2.0 to 10 mg/day, 2.0 to 10 mg/24 h, 2,000 to 10,000 μg/day, 2,000 to 10,000 μg/24 h, 0.083 to 0.417 mg/h or 83 to 417 μg/h over at least 48 hours or 2 days of administration, or providing by transdermal delivery a mean release rate of 0.5 to 20 mg/day, 0.5 to 20 mg/24 h, 500 to 20,000 μg/day, 500 to 20,000 μg/24 h, 0.021 to 0.833 mg/h or 21 to 833 μg/h, preferably 1.0 to 15 mg/day, 1.0 to 15 mg/24 h, 1,000 to 15,000 μg/day, 1,000 to 15,000 μg/24 h, 0.042 to 0.625 mg/h or 42 to 625 μg/h, more preferably of 2.0 to 10 mg/day, 2.0 to 10 mg/24 h, 2,000 to 10,000 μg/day, 2,000 to 10,000 μg/24 h, 0.083 to 0.417 mg/h or 83 to 417 μg/h over at least 72 hours or 3 days of administration, or providing by transdermal delivery a mean release rate of 0.5 to 20 mg/day, 0.5 to 20 mg/24 h, 500 to 20,000 μg/day, 500 to 20,000 μg/24 h, 0.021 to 0.833 mg/h or 21 to 833 μg/h, preferably 1.0 to 15 mg/day, 1.0 to 15 mg/24 h, 1,000 to 15,000 μg/day, 1,000 to 15,000 μg/24 h, 0.042 to 0.625 mg/h or 42 to 625 μg/h, more preferably of 2.0 to 10 mg/day, 2.0 to 10 mg/24 h, 2,000 to 10,000 μg/day, 2,000 to 10,000 μg/24 h, 0.083 to 0.417 mg/h or 83 to 417 μg/h over at least 84 hours or 3.5 days of administration.

[0341] Further, in certain embodiments, the present invention is related to a transdermal therapeutic system for the transdermal administration of asenapine for use in a method of treating a human patient as described above, [0342] providing by transdermal delivery an AUC.sub.0-48 from 20 to 300 (ng/ml) h or from more than 300 to 450 (ng/ml) h and preferably from 30 to 200 (ng/ml) h, or [0343] providing by transdermal delivery an AUC.sub.0-72 from 30 to 400 (ng/ml) h or from more than 400 to 600 (ng/ml) h and preferably from 50 to 300 (ng/ml) h, or [0344] providing by transdermal delivery an AUC.sub.0-84 from 35 to 450 (ng/ml) h or from more than 450 to 700 (ng/ml) h and preferably from 60 to 350 (ng/ml) h.

[0345] Still further, in certain embodiments, the present invention is related to a transdermal therapeutic system for the transdermal administration of asenapine for use in a method of treating a human patient as described above, [0346] providing by transdermal delivery a C.sub.max to C.sub.48 ratio of less than 2.0, preferably of less than 1.5 and more preferably of less than 1.3, or [0347] providing by transdermal delivery a C.sub.max to C.sub.72 ratio of less than 3.0, preferably of less than 2.5 and more preferably of less than 2.0, or [0348] providing by transdermal delivery a C.sub.max to C.sub.84 ratio of less than 3.5, preferably of less than 3.0, more preferably of less than 2.5 and most preferably of less than 2.0.

[0349] Still further, in certain embodiments, the present invention is related to a transdermal therapeutic system for the transdermal administration of asenapine for use in a method of treating a human patient as described above, [0350] providing by transdermal delivery a C.sub.max value of from 0.5 to 10 ng/ml and preferably of from 1 to 8 ng/ml.

[0351] In all such embodiments, as previously described, the TTS may be for use in a method of treating a human patient, wherein the transdermal therapeutic system provides a reduction in at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine.

[0352] In accordance with yet another specific aspect, the present invention is related to a method of treating a human patient by transdermal administration of asenapine for a dosing interval of at least 48 hours or 2 days or for a dosing interval of at least 72 hours or 3 days.

[0353] In such embodiments, the dosing interval may be up to 168 hours or 7 days, up to 120 hours or 5 days, or up to 96 hours or 4 days, and in particular may be 48 hours or 2 days, or 72 hours or 3 days, or 84 hours or 3.5 days.

[0354] Such a method of treating a human patient by transdermal administration of asenapine as described above preferably includes applying a transdermal therapeutic system for the transdermal administration of asenapine for at least 48 hours or 2 days, for at least 72 hours or 3 days, for 48 hours or 2 days, for 72 hours or 3 days, or for 84 hours or 3.5 days to the skin of a patient.

[0355] Such a transdermal therapeutic system for the transdermal administration of asenapine preferably comprises a self-adhesive layer structure containing a therapeutically effective amount of asenapine.

[0356] Further, the method described above is preferably a method of treating psychosis, and in particular 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, or a method of treating schizophrenia and/or bipolar disorder, more preferably bipolar disorder and in particular acute manic or mixed episodes of bipolar disorder. In certain embodiments, the method is also preferably 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, or a method of treating bipolar disorder in a human patient, in particular an adult, as an adjunctive treatment to lithium or valproate or as a maintenance monotherapy treatment.

[0357] In certain embodiments, the method is further preferably a method of treating schizophrenia or bipolar disorder in a subject in need thereof, the method comprising transdermally administering a therapeutically effective amount of asenapine to the subject, wherein the asenapine is contained in a transdermal therapeutic system for the transdermal administration of asenapine, and wherein the transdermal therapeutic system is in contact with at least one body surface (as defined above) on the subject for at least 48 hours or 2 days or for at least 72 hours or 3 days, or for about 48 hours or about 2 days, or about 72 hours or about 3 days, or about 84 hours or about 3.5 days.

[0358] The relatively constant asenapine blood plasma concentration can be described by several pharmacokinetic parameters as obtained in an in vivo clinical study on human subjects.

[0359] Thus, in certain embodiments, the present invention is related to a method of treating a human patient as described above, [0360] providing by transdermal delivery a mean release rate of 0.5 to 20 mg/day, 0.5 to 20 mg/24 h, 500 to 20,000 μg/day, 500 to 20,000 μg/24 h, 0.021 to 0.833 mg/h or 21 to 833 μg/h, preferably 1.0 to 15 mg/day, 1.0 to 15 mg/24 h, 1,000 to 15,000 μg/day, 1,000 to 15,000 μg/24 h, 0.042 to 0.625 mg/h or 42 to 625 μg/h, more preferably of 2.0 to 10 mg/day, 2.0 to 10 mg/24 h, 2,000 to 10,000 μg/day, 2,000 to 10,000 μg/24 h, 0.083 to 0.417 mg/h or 83 to 417 μg/h over at least 48 hours or 2 days of administration, or providing by transdermal delivery a mean release rate of 0.5 to 20 mg/day, 0.5 to 20 mg/24 h, 500 to 20,000 μg/day, 500 to 20,000 μg/24 h, 0.021 to 0.833 mg/h or 21 to 833 μg/h, preferably 1.0 to 15 mg/day, 1.0 to 15 mg/24 h, 1,000 to 15,000 μg/day, 1,000 to 15,000 μg/24 h, 0.042 to 0.625 mg/h or 42 to 625 μg/h, more preferably of 2.0 to 10 mg/day, 2.0 to 10 mg/24 h, 2,000 to 10,000 μg/day, 2,000 to 10,000 μg/24 h, 0.083 to 0.417 mg/h or 83 to 417 μg/h over at least 72 hours or 3 days of administration, or providing by transdermal delivery a mean release rate of 0.5 to 20 mg/day, 0.5 to 20 mg/24 h, 500 to 20,000 μg/day, 500 to 20,000 μg/24 h, 0.021 to 0.833 mg/h or 21 to 833 μg/h, preferably 1.0 to 15 mg/day, 1.0 to 15 mg/24 h, 1,000 to 15,000 μg/day, 1,000 to 15,000 μg/24 h, 0.042 to 0.625 mg/h or 42 to 625 μg/h, more preferably of 2.0 to 10 mg/day, 2.0 to 10 mg/24 h, 2,000 to 10,000 μg/day, 2,000 to 10,000 μg/24 h, 0.083 to 0.417 mg/h or 83 to 417 μg/h over at least 84 hours or 3.5 days of administration.

[0361] Further, in certain embodiments, the present invention is related to a method of treating a human patient as described above, [0362] providing by transdermal delivery an AUC.sub.0-48 from 20 to 300 (ng/ml) h or from more than 300 to 450 (ng/ml) h and preferably from 30 to 200 (ng/ml) h, or [0363] providing by transdermal delivery an AUC.sub.0-72 from 30 to 400 (ng/ml) h or from more than 400 to 600 (ng/ml) h and preferably from 50 to 300 (ng/ml) h, or [0364] providing by transdermal delivery an AUC.sub.0-84 from 35 to 450 (ng/ml) h or from more than 450 to 700 (ng/ml) h and preferably from 60 to 350 (ng/ml) h.

[0365] Still further, in certain embodiments, the present invention is related to a method of treating a human patient as described above, [0366] providing by transdermal delivery a C.sub.max to C.sub.48 ratio of less than 2.0, preferably of less than 1.5 and more preferably of less than 1.3, or [0367] providing by transdermal delivery a C.sub.max to C.sub.72 ratio of less than 3.0, preferably of less than 2.5 and more preferably of less than 2.0, or [0368] providing by transdermal delivery a C.sub.max to C.sub.84 ratio of less than 3.5, preferably of less than 3.0, more preferably of less than 2.5 and most preferably of less than 2.0.

[0369] Still further, in certain embodiments, the present invention is related to a method of treating a human patient as described above, [0370] providing by transdermal delivery a C.sub.max value of from 0.5 to 10 ng/ml and preferably of from 1 to 8 ng/ml.

[0371] In such methods as described above, the transdermal therapeutic system may provide a reduction in at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine.

[0372] In a yet further aspect, the present invention is related to a transdermal therapeutic system for the transdermal administration of asenapine for use in a method of treating a human patient, wherein

[0373] the transdermal therapeutic system provides a reduction in at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine, and wherein

[0374] the human patient is suffering from fatigue, somnolence, dizziness, or any combination thereof, and/or the at least one asenapine-related side effect is fatigue, somnolence, dizziness, oral hypoaesthesia, or any combination thereof.

[0375] In another aspect, the present invention is directed to a method of treating a human patient by transdermal administration of asenapine, wherein at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced, and wherein

[0376] the human patient is suffering from fatigue, somnolence, dizziness, or any combination thereof, and/or the at least one asenapine-related side effect is fatigue, somnolence, dizziness, oral hypoaesthesia, or any combination thereof.

[0377] In yet another aspect, the present invention is directed to a method of reducing, in a human patient, at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine, the method comprising transdermal administration of asenapine, wherein

[0378] the human patient is suffering from fatigue, somnolence, dizziness, or any combination thereof, and/or the at least one asenapine-related side effect is fatigue, somnolence, dizziness, oral hypoaesthesia, or any combination thereof.

[0379] In a yet further aspect, the present invention is directed to a method of reducing at least one asenapine-related side effect in a patient, and in particular a human patient, being treated with sublingual asenapine therapy, the method comprising

[0380] a) discontinuing sublingual asenapine therapy; and

[0381] b) transdermal administration of asenapine,

wherein the patient is suffering from fatigue, somnolence, dizziness, or any combination thereof, and/or the at least one asenapine-related side effect is fatigue, somnolence, dizziness, oral hypoaesthesia, or any combination thereof.

Process of Manufacture

[0382] The invention further relates to a process of manufacture of a matrix layer for use in a transdermal therapeutic system and a corresponding matrix layer structure and a corresponding TTS.

[0383] In accordance with the invention, the process of manufacture of a matrix layer for use in a transdermal therapeutic system comprises the steps of: [0384] 1) combining at least the components asenapine and polymer, in a solvent to obtain a coating composition; [0385] 2) coating the coating composition onto the backing layer or release liner or any intermediate liner; and [0386] 3) drying the coated coating composition to form the matrix layer.

[0387] In this process of manufacture, preferably in step 1) the asenapine is dissolved to obtain a coating composition.

[0388] In the above described process preferably 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, n-heptane, petroleum ether, toluene, and mixtures thereof, and more preferably is selected from ethanol and ethyl acetate.

[0389] In certain embodiments, the polymer in the above process is an acrylic polymer and preferably a copolymer based on vinyl acetate, 2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and glycidyl-methacrylate, which is provided as a solution and preferably as a solution in ethyl acetate, n-heptane, methanol or ethanol with a solids content of from 30 to 60% by weight.

[0390] In step 3), drying is performed preferably at a temperature of from 50 to 90° C., more preferably from 60 to 80° C.

EXAMPLES

[0391] 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.

Examples 1A-D

Coating Composition

[0392] The formulations of the asenapine-containing coating compositions of Examples 1a-d are summarized in Table 1.1 below. The formulations are based on weight percent as also indicated in Table 1.1.

TABLE-US-00003 TABLE 1.1 Ex. 1a Ex. 1b Ex. 1c Ex. 1d Ingredient (Trade Amt Solids Amt Solids Amt Solids Amt Solids Name) [g] [%] [g] [%] [g] [%] [g] [%] Asenapine base 0.34 6.72 0.93 12.34 0.93 12.26 1.97 25.93 Acrylic adhesive in ethyl 9.29 93.28 12.14 81.11 12.16 81.07 11.13 74.07 acetate. Solids content of 50.5% by weight (Duro-Tak ™ 387-2287) Isopropyl myristate — — 0.49 6.55 — — — — Diethylene glycol — — — — 0.51  6.67 — — monoethyl ether (Transcutol) Ethyl acetate 2.06 — 3.81 — 3.83 — 3.79 — Total 11.69 100.00 17.37 100.00 17.43 100.00  16.89 100.00 Area Weight [g/m.sup.2] 200.1 141.5 136.9 149.0 Asenapine content 1.345 1.746 1.678 3.864 [mg/cm.sup.2]

Preparation of the Coating Composition

[0393] For Examples 1a-1c, a beaker was loaded with the asenapine base and with the solvent (ethyl acetate), and the isopropyl myristate (Example 1b) or the diethylene glycol monoethyl ether (Example 1c) was added, if applicable. The acrylic pressure sensitive adhesive Duro-Tak™ 387-2287 was added and the mixture was then stirred at up to 500 rpm until a homogeneous mixture was obtained (stirring time is 60 min. or longer throughout the examples, if not indicated otherwise).

[0394] For Example 1d, a beaker was loaded with approx. 1.41 g of the asenapine base and the solvent (ethyl acetate) was added. The acrylic pressure sensitive adhesive was added and the mixture was stirred at approx. 200 rpm for approx. 30 min. Further approx. 0.56 g of the asenapine base was added in two portions, while stirring continued at approx. 500 rpm for approx. 30 min.

Coating of the Coating Composition, Example 1a

[0395] The resulting asenapine-containing coating composition was coated on a polyethylene terephthalate film (siliconised, 100 μm thickness, which may function as release liner) and dried for approx. 10 min at room temperature and 20 min at 60° C. The coating thickness gave an area weight of the matrix layer of 100.1 g/m.sup.2. A first part of the dried film was laminated with a polyethylene terephthalate backing layer (23 μm thickness) to provide a first asenapine-containing self-adhesive layer structure. A second, unmodified part of the dried film serves as the second asenapine-containing self-adhesive layer structure, comprising a release liner but not a backing layer.

[0396] The polyethylene terephthalate film (siliconised, 100 μm thickness, which may function as a release liner) of the first layer structure was removed and the adhesive site of the first layer structure was laminated on the adhesive site of the second layer structure. This results in an asenapine-containing self-adhesive layer structure with an area weight of the matrix layer of 200.1 g/m.sup.2, with a backing layer and a release liner.

Coating of the Coating Composition, Examples 1b-d

[0397] The resulting asenapine-containing coating composition was coated on a polyethylene terephthalate film (siliconised, 100 μm thickness, which may function as release liner) and dried for approx. 15 min at room temperature and 25 min at 60° C. The coating thickness gave an area weight of the matrix layer of 141.5 g/m.sup.2 (Example 1b), 136.9 g/m.sup.2 (Example 1c), and 149.0 g/m.sup.2 (Example 1d), respectively. The dried film was laminated with a polyethylene terephthalate backing layer (23 μm thickness) to provide an asenapine-containing self-adhesive layer structure.

Preparation of the TTS (Concerning all Examples)

[0398] 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.

Measurement of Skin Permeation Rate

[0399] The permeated amount and the corresponding skin permeation rates of TTS prepared according to Examples 1a-d 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 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 1.156 cm.sup.2 were punched from the TTS. The asenapine permeated amount in the receptor medium of the Franz cell (solution containing 60% phosphate buffer pH 5.5, 30% dipropylene glycol and 10% acetonitrile) 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 FIGS. 1a and 1b.

TABLE-US-00004 TABLE 1.2 Skin permeation rate with SD [μg/(cm.sup.2 h)] Ex. 1a Ex. 1b Ex. 1c Ex. 1d 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 4 0.19 0.27 0.46 0.43 0.22 0.16 0.94 0.32 8 2.04 0.9 3.37 1.4 3.17 0.71 6.11 0.99 12 4.06 1.57 6.65 2.07 5.9 0.74 11.86 1.15 16 5.61 1.94 9.36 2.19 7.89 1.08 15.54 1 20 6.8 2.16 10.95 2.34 9.27 1.03 18.09 0.98 24 7.41 2.17 11.73 2.09 9.59 0.92 18.72 0.78 32 7.04 1.87 10.8 1.71 9.62 1.08 18.51 0.3 40 7.98 1.75 12.36 1.54 10.05 0.51 19.3 1.25 48 7.91 1.6 11.92 1.49 9.89 0.67 18.92 0.69 56 7.64 1.27 11.16 1.17 9.69 0.52 18.19 1.2 64 7.4 1.1 10.74 1.01 9.25 0.52 17.88 0.44 72 6.95 0.97 10.23 0.72 8.69 0.38 17.2 0.14 96 5.29 0.14 / / 5.33 0.34 14.6 0.65 120 4.67 0.24 / / 6.43 0.36 13.69 0.86 144 3.99 0.17 / / 5.49 0.13 11.7 0.51 168 3.22 0.29 / / 4.95 0.18 9.98 0.01

Utilization of Asenapine

[0400] 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 1.3 and in FIG. 1c.

TABLE-US-00005 TABLE 1.3 Utilization of asenapine after 72 h [%] Example 1a Example 1b Example 1c Example 1d (n = 3) (n = 3) (n = 3) (n = 3) 34.43 40.49 35.87 30.18

Examples 2A-D

Coating Composition

[0401] The formulations of the asenapine-containing coating compositions of Examples 2a-d are summarized in Table 2.1 below. The formulations are based on weight percent, as also indicated in Table 2.1.

TABLE-US-00006 TABLE 2.1 Ex. 2a Ex. 2b Ex. 2c Ex. 2d Ingredient (Trade Amt Solids Amt Solids Amt Solids Amt Solids Name) [g] [%] [g] [%] [g] [%] [g] [%] Asenapine base 0.35 6.86 0.34 6.63  1.34 13.33  1.34 13.33 Acrylic adhesive in ethyl 8.53 85.38  — — 14.13 71.14 14.13 71.14 acetate. Solids content of 50.5% by weight (Duro-Tak ™ 387-2287) Polyisobutylene adhesive — — 10.7  86.47  — — — — in petroleum ether, bp 80-110° C. Solids content of 40.9% (Oppanol B10/B100, 85/15) Diethylene glycol 0.39 7.76 — —  1.56 15.53  1.56 15.53 monoethyl ether (Transcutol) Polyvinylpyrrolidone — — 0.35 6.90 — — — — (Kollidon ® 90F) Ethyl acetate 2.54 — — — 3.1 — 3.1 — Petroleum ether, bp 80- — — 5.42 — — — — — 110° C. Total 11.81  100.00  16.81  100.00  20.13 100.00  20.13 100.00  Area Weight [g/m.sup.2] 91.3 85.7 90.15 159.6 Asenapine content 0.627 0.568 1.201 2.127 [mg/cm.sup.2]

Preparation of the Coating Composition

[0402] For Examples 2a, c, and d, the coating compositions were prepared as described in Example 1c except that the diethylene glycol monoethyl ether was added before the solvent ethyl acetate.

[0403] For Example 2b, the beaker was loaded with the solvent (petroleum ether) first and the polyisobutylene adhesive was added. The polyvinylpyrrolidone (Kollidon® 90 F) was added while stirring at approx. 200 rpm. The asenapine base was added while stirring at up to 1500 rpm until a homogeneous mixture was obtained.

Coating of the Coating Composition, Examples 2a-2c

[0404] The resulting asenapine-containing coating composition was coated on a polyethylene terephthalate film (siliconised, 100 μm thickness, which may function as release liner) and dried for approx. 10 min at room temperature and 20 min at 60° C. (Examples 2a and 2c) or at 90° C. (Example 2b). The coating thickness gave an area weight of the matrix layer of 91.3 g/m.sup.2 (Example 2a), 85.7 g/m.sup.2 (Example 2b), and 90.15 g/m.sup.2 (Example 2c), respectively. The dried film was laminated with a polyethylene terephthalate backing layer (23 μm thickness) to provide an asenapine-containing self-adhesive layer structure.

Preparation of the Self-Adhesive Layer Structure, Example 2d

[0405] For Example 2d, a double layer self-adhesive layer structure was prepared as described for Example 1a, starting from two layers as prepared for Example 2c. This results in an asenapine-containing self-adhesive layer structure with an area weight of the matrix layer of 159.6 g/m.sup.2, with a backing layer and a release liner.

Preparation of the TTS

[0406] See Example 1.

Measurement of Skin Permeation Rate

[0407] The permeated amount and the corresponding skin permeation rates of TTS prepared according to Examples 2a-d 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 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 1.145 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 FIGS. 2a and 2b.

TABLE-US-00007 TABLE 2.2 Skin permeation rate with SD [μg/(cm.sup.2 h)] Ex. 2a Ex. 2b Ex. 2c Ex. 2d Elapsed (n = 3) (n = 2) (n = 2) (n = 3) time [h] Rate SD Rate SD Rate SD Rate SD 0 0 0 0 0 0 0 0 0 4 0 0 1.28 1.28 0.39 0.39 0 0 8 0.77 0.55 4.58 2.7 5.14 1.07 2.28 0.69 12 3.2 0.76 9.34 1.12 10.37 0.47 13.55 5.27 16 5.7 1.99 10.06 1.08 12.81 1.04 15.21 2.23 20 11.49 4.18 9.1 1.65 15.16 1.44 26.1 4.67 24 10.62 2.25 9.74 0.27 11.62 0.47 25.37 2.63 32 7.73 1.47 8.07 0.44 13.67 0.82 19.02 0.41 40 7.28 1.44 7.11 0.41 14.06 0.46 21.22 2.11 48 7.25 0.55 5.83 0.19 12.77 0.51 20.42 2.13 56 6.11 0.63 4.48 0.2 11.97 0.66 19.27 1.98 64 / / 3.85 0.44 7.42 0.34 14.54 0.88 72 3.38 0.97 2.97 0.19 9.55 0.19 15.71 0.75 96 / / / / 6.45 0.13 12.98 0.4 120 / / / / 4.25 0.49 11.39 0.47 144 / / / / 2.38 0.44 8.55 0.23 168 / / / / 1.45 0.38 6.49 0.67

Utilization of Asenapine

[0408] 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 2.3 and in FIG. 2c.

TABLE-US-00008 TABLE 2.3 Utilization of asenapine after 72 h [%] Example 2a Example 2b Example 2c Example 2d (n = 3) (n = 2) (n = 2) (n = 3) 60.74 76.4 64.76 56.93

Examples 2E-J

Coating Composition

[0409] The formulations of the asenapine-containing coating compositions of Examples 2e-j are summarized in Table 2.4 below. The formulations are based on weight percent, as also indicated in Table 2.4.

TABLE-US-00009 TABLE 2.4 Ingredient (Trade Examples 2e, 2f and 2g Examples 2h, 2i and 2j Name) Amt [g] Solids [%] Amt [g] Solids [%] Asenapine base 2.40 5.97 4.00 10.01 Polyisobutylene adhesive 82.91 84.06 78.38 79.98 in petroleum ether, bp 80-110° C. Solids content of 40.8% (Oppanol B10/B100 85/15) Polyvinylpyrrolidone 4.01 9.97 4.01 10.01 (Kollidon ® 90F) Ethanol 12.03 — 12.18 — n-heptane 8.15 — 7.47 — Total 109.51 — 106.04 — Ex. 2e Ex. 2f Ex. 2g Ex. 2h Ex. 2i Ex. 2j Area Weight [g/m.sup.2] 52.8 129.6 188.4 51.6 128.2 185.9 Asenapine content 0.32 0.77 1.12 0.52 1.28 1.86 [mg/cm.sup.2]

Preparation of the Coating Composition

[0410] For Example 2b, 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.

Coating of the Coating Composition, Examples 2a-2c

[0411] 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 2e), 129.6 g/m.sup.2 (Example 2f), 188.4 g/m.sup.2 (Example 2g), 51.6 g/m.sup.2 (Example 2h), 128.2 g/m.sup.2 (Example 2i),and 185.9 g/m.sup.2 (Example 2j), respectively. The dried film was laminated with a polyethylene terephthalate backing layer (23 82 m thickness) to provide an asenapine-containing self-adhesive layer structure.

Preparation of the TTS

[0412] See Example 1.

Measurement of Skin Permeation Rate

[0413] The permeated amount and the corresponding skin permeation rates of TTS prepared according to Examples 2e to 2j 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 2.5 and 2.6 and FIG. 2d.

TABLE-US-00010 TABLE 2.5 Skin permeation rate with SD [μg/(cm.sup.2 h)] Ex. 2e Ex. 2f Ex. 2g 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

TABLE-US-00011 TABLE 2.6 Skin permeation rate with SD [μg/(cm.sup.2 h)] Ex. 2h Ex. 2i Ex. 2j 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

[0414] 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 2.7 and in FIG. 2e.

TABLE-US-00012 TABLE 2.7 Utilization of asenapine after 72 h [%] Example Example Example Example Example Example 2e 2f 2g 2h 2i 2j (n = 3) (n = 3) (n = 3) (n = 3) (n = 3) (n = 3) 81.02 60.84 52.40 87.78 62.49 53.46

Examples 3A-E

[0415] Coating composition

[0416] The formulations of the asenapine-containing coating compositions of Examples 3a-e are summarized in Table 3.1 below. The formulations are based on weight percent, as also indicated in Table 3.1.

TABLE-US-00013 TABLE 3.1 Ex. 3a Ex. 3b Ex. 3c Ex. 3d Ex. 3e Ingredient Amt Solids Amt Solids Amt Solids Amt Solids Amt Solids (Trade Name) [g] [%] [g] [%] [g] [%] [g] [%] [g] [%] Asenapine base 4.00 16.33 1.15 16.35 1.15 16.22 1.15 16.39 1.15 16.37 Acrylic adhesive 36.66 75.54 10.26  73.68 11.07  78.84 9.33 67.14 9.36 67.29 in ethyl acetate. Solids content of 50.5% by weight (Duro-Tak ™ 387- 2287) Diethylene glycol 1.99 8.13 — — — — — — — — monoethyl ether (Transcutol) Polyethylene — — 0.70 9.97 — — — — — — glycol 400 Polyvinylpyrrolidone — — — — 0.35 4.94 — — — — (Povidone K90F) Diisopropyl — — — — — — 1.16 16.47 — — adipate Propylene glycol — — — — — — — — 1.15 16.34 monocaprylate, type II (Capryol 90) Ethyl acetate 25.20 — 4.23 — 3.90 — 4.66 — 4.67 — Total 57.03 100 16.34  100 16.47  100 16.30  100    16.32  100    Area Weight [g/m.sup.2] 137.3 144.1 146.05 152.1 147.6 Asenapine content 2.242 2.356 2.368 2.493 2.417 [mg/cm.sup.2]

Preparation of the Coating Composition

[0417] The coating composition of Example 3a was prepared as described in Example 1c.

[0418] For Examples 3b, 3d and 3e, a beaker was loaded with the excipients polyethylene glycol 400, diisopropyl adipate or propylene glycol monocaprylate type II, as applicable, and with the solvent (ethyl acetate). The acrylic pressure sensitive adhesive Duro-Tak™ 387-2287 was added and the mixture was then stirred at up to 500 rpm until a homogeneous mixture was obtained. The asenapine base was added and the mixture again stirred at up to 500 rpm until a homogeneous mixture was obtained.

[0419] For Example 3c, a beaker was loaded with the acrylic pressure sensitive adhesive Duro-Tak™ 387-2287. The solvent (ethyl acetate) was added and the mixture was stirred at up to 500 rpm. The polyvinylpyrrolidone was added and the mixture was then stirred at approx. 500 rpm until a homogeneous mixture was obtained. Finally, the asenapine base was added and the mixture again stirred at up to 500 rpm until a homogeneous mixture was obtained.

Coating of the Coating Composition

[0420] See Examples 1b-d for the coating process. The coating thickness gave an area weight of the matrix layer of 137.3 g/m.sup.2 (Example 3a), 144.1 g/m.sup.2 (Example 3b), 146.05 g/m.sup.2 (Example 3c), 152.1 g/m.sup.2 (Example 3d), and 147.6 g/m.sup.2 (Example 3e) respectively. The dried film was laminated with a polyethylene terephthalate backing layer (23 μm thickness) to provide an asenapine-containing self-adhesive layer structure.

Preparation of the TTS

[0421] See Example 1.

Measurement of Skin Permeation Rate

[0422] The permeated amount and the corresponding skin permeation rates of TTS prepared according to Examples 3a-e 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 Goettingen minipig skin 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 1.156 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 3.2 and FIG. 3a.

TABLE-US-00014 TABLE 3.2 Skin permeation rate with SD [μg/(cm.sup.2 h)] Ex. 3a Ex. 3b Ex. 3c Ex. 3d Ex. 3e Elapsed (n = 3) (n = 3) (n = 3) (n = 3) (n = 3) time [h] Rate SD Rate SD Rate SD Rate SD Rate SD 0 0 0 0 0 0 0 0 0 0 0 4 2.21 0.42 0.91 0.5 0.88 0.16 2.29 1.31 1.21 0.5 8 9.7 2.52 5.95 2.31 6.25 0.93 13.72 5.98 7.75 1.98 12 16.26 4.98 9.95 3.38 11 2.01 22.9 8.39 14.2 2.45 16 15.33 4.69 11.67 3.77 15.49 1.59 27.02 8.07 17.94 2.93 20 15.42 4.82 11.69 3.25 19.09 2.81 28.47 8.1 20.22 1.84 24 22.24 3.41 20.37 3.13 18.11 1.5 28.93 6.73 20.88 1.78 32 20.32 2.04 18.94 2.54 17.8 1.71 23.74 4.95 18.65 1.3 40 20.48 1.83 18.89 1.74 17.76 1.94 22.27 3.42 18.68 1.26 48 21.67 2.97 17.89 1.06 15.98 0.99 20.53 1.76 18.06 1.12 56 18.05 0.73 16.53 0.67 15.52 1.63 18.55 1.15 17.04 0.39

Utilization of Asenapine

[0423] The utilization of asenapine at 56 h was calculated based on the cumulative permeated amount at 72 h and the initial asenapine content. The results are shown in Table 3.3 and in FIG. 3b.

TABLE-US-00015 TABLE 3.3 Utilization of asenapine after 56 h [%] Example 3a Example 3b Example 3c Example 3d Example 3e (n = 3) (n = 3) (n = 3) (n = 3) (n = 3) 43.19 34.80 34.64 47.10 37.60

Examples 4A, 4B

Coating Composition

[0424] The formulations of the asenapine-containing coating compositions of Examples 4a and 4b are summarized in Table 4.1 below. The formulations are based on weight percent, as also indicated in Table 4.1.

TABLE-US-00016 TABLE 4.1 Ex. 4a Ex. 4b Solids Solids Ingredient (Trade Name) Amt [g] [%] Amt [g] [%] Asenapine base 2.72 18.02 1.26 17.81 Acrylic adhesive in ethyl 29.49 81.98 — — acetate, ethanol, n-heptane and methanol. Solids content of 42.0% by weight (Duro-Tak ™ 387-2516) Acrylic adhesive in ethyl — — 10.04 72.12 acetate. Solids content of 50.5% by weight (Duro-Tak ™ 387-2287) Basic butylated — — 0.71 10.07 methacrylate copolymer (Eudragit ® E100) Ethyl acetate 2.91 4.35 Total 35.12 100.00 16.41 100.00 Area Weight [g/m.sup.2] 146.7 126.85 Asenapine content 2.644 2.259 [mg/cm.sup.2]

Preparation of the Coating Composition

[0425] For Example 4a, a beaker was loaded with the acrylic pressure sensitive adhesive Duro-Tak™ 387-2516 and with the asenapine. The solvent ethyl acetate was added and the mixture was then stirred at approx. 500 rpm until a homogeneous mixture was obtained.

[0426] For Example 4b, a beaker was loaded with the asenapine and the solvent ethyl acetate. The acrylic pressure sensitive adhesive Duro-Tak™ 387-2287 was added and the mixture was then stirred at approx. 500 rpm until a homogeneous mixture was obtained. The basic butylated methacrylate copolymer Eudragit E100 was added while stirring at up to 1000 rpm.

Coating of the coating Composition

[0427] See Examples 1b-d for the coating process. The coating thickness gave an area weight of the matrix layer of 146.7 g/m.sup.2 (Example 4a) and 126.85 g/m.sup.2 (Example 4b) respectively. The dried film was laminated with a polyethylene terephthalate backing layer (23 μm thickness) to provide an asenapine-containing self-adhesive layer structure.

Preparation of the TTS

[0428] See Example 1.

Measurement of Skin Permeation Rate

[0429] The permeated amount and the corresponding skin permeation rates of TTS prepared according to Examples 4a and 4b 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 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 1.156 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 4.2 and FIGS. 4a and 4b.

TABLE-US-00017 TABLE 4.2 Skin permeation rate with SD [μg/(cm.sup.2 h)] Elapsed Ex. 4a (n = 3) Ex. 4b (n = 3) time [h] Rate SD Rate SD 0 0 0 0 0 4 0.57 0.04 0.62 0.23 8 3.28 0.32 3.07 0.7 12 6.78 0.59 5.97 1.09 16 9.5 0.47 7.87 1.27 20 10.21 0.22 9.01 1.17 24 11.4 0.71 9.64 1.09 32 10.6 0.21 9.67 1.02 40 12.05 0.26 10.43 0.96 48 12.09 0.36 10.52 0.89 56 12.57 0.78 10.44 0.83 64 11.36 0.52 10.53 0.83 72 10.5 1.48 10.62 0.58 96 7.41 2.26 8.96 0.42 120 7.6 1.91 8.55 0.43 144 7.23 1.67 8.06 0.46 168 6.6 1.02 7.31 0.58

Utilization of Asenapine

[0430] The utilization of asenapine at 72 h and 168 h was calculated based on the cumulative permeated amount at 72 h and the initial asenapine content. The results are shown in Table 4.3 and in FIG. 4c.

TABLE-US-00018 TABLE 4.3 Utilization of asenapine after 72 h and after 168 h [%] Example Example Example Example 4a - 72 h 4a - 168 h 4b - 72 h 4b - 168 h (n = 3) (n = 3) (n = 3) (n = 3) 27.24 53.44 28.46 63.34

Examples 5A-C

Coating Composition

[0431] The formulations of the asenapine-containing coating compositions of Examples 5a-c are summarized in Table 5.1 below. The formulations are based on weight percent, as also indicated in Table 5.1.

TABLE-US-00019 TABLE 5.1 Ex. 5a Ex. 5b Ex. 5c Amt Solids Amt Solids Amt Solids Ingredient (Trade Name) [g] [%] [g] [%] [g] [%] Asenapine base 0.35 6.92 0.36  6.91 0.34  6.60 Acrylic adhesive in ethyl acetate. 12.61 93.08 — — — — Solids content of 36.90% by weight (Duro-Tak ™ 87-9301) Acrylic adhesive in ethyl acetate. — — 5.82 57.10 5.78 56.98 Solids content of 50.5% by weight (Duro-Tak ™ 387-2287) Acrylic adhesive in ethyl acetate. — — 3.73 28.36 — — Solids content of 39.10% by weight (Duro-Tak ™ 87-4098) Polyisobutylene adhesive in — — — — 4.12 28.49 petroleum ether, bp 80-110° C. Solids content of 40.9% — — — — — — (Oppanol B10/B100, 85/15) Diethylene glycol monoethyl — — 0.38  7.63 0.41  7.93 ether (Transcutol) Ethyl acetate 1.36 — 1.96 — 2.17 — Total 14.32 100.00 12.26  100.00  12.81  100.00  Area Weight [g/m.sup.2] 99.6 102.55 98.4 Asenapine content [mg/cm.sup.2] 0.689 0.709 0.650

Preparation of the Coating Composition

[0432] For Example 5a, a beaker was loaded with the asenapine and with the acrylic pressure sensitive adhesive Duro-Tak™ 387-9301. The solvent ethyl acetate was added in two portions and the mixture was then stirred at approx. 200 rpm until a homogeneous mixture was obtained.

[0433] For Example 5b, a beaker was loaded with the acrylic pressure sensitive adhesive Duro-Tak™ 387-2287, the acrylic pressure sensitive adhesive Duro-Tak™ 387-4098, with the asenapine and with the diethylene glycol monoethyl ether. The solvent ethyl acetate was added in two portions and the mixture was then stirred at approx. 200 rpm until a homogeneous mixture was obtained.

[0434] For Example 5c, a beaker was loaded with the polyisobutylene adhesive Oppanol B10/B100 and with the acrylic pressure sensitive adhesive Duro-Tak™ 387-2287. A first portion (1.50 g) of the solvent ethyl acetate was added and the mixture was then stirred at approx. 100 rpm until a homogeneous mixture was obtained. The diethylene glycol monoethyl ether was added and the mixture was then stirred at approx. 200 rpm until a homogeneous mixture was obtained. The asenapine base was added and the mixture was again stirred at approx. 1000 rpm and the remaining portion of the solvent ethyl acetate (0.67 g) was added while stirring.

Coating of the Coating Composition

[0435] The resulting asenapine-containing coating composition was coated on a polyethylene terephthalate film (siliconised, 100 μm thickness, which may function as release liner) and dried for approx. 10 min at room temperature and 20 min at 60° C. (Examples 5a and 5b) or at 90° C. (Example 5c). The coating thickness gave an area weight of the matrix layer of 99.6 g/m.sup.2 (Example 5a), 102.55 g/m.sup.2 (Example 5b), and 98.4 g/m.sup.2 (Example 5c), respectively. The dried film was laminated with a polyethylene terephthalate backing layer (23 μm thickness) to provide an asenapine-containing self-adhesive layer structure.

Preparation of the TTS

[0436] See Example 1.

Measurement of Skin Permeation Rate

[0437] The permeated amount 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 7.0 ml Franz diffusion cell. Split thickness Goettingen minipig skin 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 1.145 cm.sup.2 were punched from the TTS. The asenapine permeated amount in the receptor medium of the Franz cell (solution containing 60% phosphate buffer pH 5.5, 30% dipropylene glycol and 10% acetonitrile) at a temperature of 32±1° C. was measured and the corresponding skin permeation rate calculated. The results are shown in Table 5.2 and FIG. 5a.

TABLE-US-00020 TABLE 5.2 Skin permeation rate with SD [μg/(cm.sup.2 h)] Ex. 5a Ex. 5b Ex. 5c Elapsed (n = 3) (n = 3) (n = 3) time [h] Rate SD Rate SD Rate SD 0 0 0 0 0 0 0 4 1.4 0.33 1.03 0.27 1.37 0.18 8 3.7 0.59 2.45 0.47 3.85 1.06 12 5.72 1.25 4.91 0.87 6.83 1.38 16 7.23 0.97 5.7 1.07 7.88 1.59 20 8.1 0.79 6.81 0.76 8.38 1.59 24 8.58 0.22 7.14 0.38 8.18 1.59 32 7.15 0.26 6.73 0.19 7.79 1.41 40 7.39 0.33 6.91 0.38 6.89 0.84 48 7.12 0.34 6.96 0.37 6.42 0.79 56 6.56 0.6 6.51 0.5 5.65 0.31 64 5.82 0.54 5.96 0.47 5.12 0.01 72 5.32 0.49 5.61 0.46 4.34 0.05

Utilization of Asenapine

[0438] 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 5.3 and in FIG. 5b.

TABLE-US-00021 TABLE 5.3 Utilization of asenapine after 72 h [%] Example 5a Example 5b Example 5c (n = 3) (n = 3) (n = 3) 65.79 59.57 67.04

Examples 6A-C

Coating Composition

[0439] The formulations of the asenapine-containing coating compositions of Examples 6a-c are summarized in Table 6.1 below. The formulations are based on weight percent, as also indicated in Table 6.1.

TABLE-US-00022 TABLE 6.1 Ex. 6a Ex. 6b Ex. 6c Amt Solids Amt Solids Amt Solids Ingredient (Trade Name) [g] [%] [g] [%] [g] [%] Asenapine base 0.33 6.73 0.34 6.73 0.34 6.10 Acrylic adhesive in ethyl acetate. 2.15 22.00 4.69 46.93 7.00 72.65 Solids content of 50.5% by weight (Duro-Tak ™ 387-2287) Polysiloxane adhesive in n-heptane. 4.88 71.26 3.23 46.34 1.62 21.25 Solids content of 72.40% by weight (DOW CORNING ® BIO- PSA Q7-4301) Petroleum ether, bp 80-110° C. 2.53 — — — — — Ethyl acetate — — 2.31 — 4.02 — Total 9.89 100.00 10.57  100.00 12.98  100.00 Area Weight [g/m.sup.2] 93.7 130.2 105.3 Asenapine content [mg/cm.sup.2] 0.631 0.876 0.642

Preparation of the Coating Composition

[0440] A beaker was loaded with the asenapine and with the acrylic pressure sensitive adhesive Duro-Tak™ 387-2287 and with the polysiloxane adhesive Bio-PSA Q7-4301. The solvent (petroleum ether for Example 6a and ethyl acetate for Examples 6b and 6c) was added and the mixture was then stirred at up to 1500 rpm until a homogeneous mixture was obtained.

Coating of the Coating Composition

[0441] The resulting asenapine-containing coating composition was coated on a polyester film (fluoro polymer coated, 75 μm thickness, which may function as release liner) and dried for approx. 10 min at room temperature and 20 min at 90° C. The coating thickness gave an area weight of the matrix layer of 93.7 g/m.sup.2 (Example 6a), 130.2 g/m.sup.2 (Example 6b), and 105.3 g/m.sup.2 (Example 6c), respectively. The dried film was laminated with a polyethylene terephthalate backing layer (23 pm thickness) to provide an asenapine-containing self-adhesive layer structure.

Preparation of the TTS

[0442] See Example 1.

Measurement of Skin Permeation Rate

[0443] The permeated amount 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 7.0 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 1.145 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 6.2 and FIG. 6a.

TABLE-US-00023 TABLE 6.2 Skin permeation rate with SD [μg/(cm.sup.2 h)] 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 0 0 0 0 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

Utilization of Asenapine

[0444] 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 6.3 and in FIG. 6b.

TABLE-US-00024 TABLE 6.3 Utilization of asenapine after 72 h [%] Example 6a Example 6b Example 6c (n = 3) (n = 3) (n = 3) 81.21 53.92 53.57

Examples 7A-C

Coating Composition

[0445] The formulations of the asenapine-containing coating compositions of Examples 7a-c are summarized in Table 7.1 below. The formulations are based on weight percent, as also indicated in Table 7.1.

TABLE-US-00025 TABLE 7.1 Ex. 7c Ex. 7a Ex. 7b Layer 1 Layer 2 Amt Solids Amt Solids Amt Solids Amt Solids Ingredient (Trade Name) [g] [%] [g] [%] [g] [%] [g] [%] Asenapine base 0.67 13.35 0.67 13.41 0.68 13.58 0.67 13.15 Acrylic adhesive in ethyl 10.41 86.69 — — — — — — acetate. Solids content of 42.0% by weight (Duro- Tak ™ 387-2516) Acrylic adhesive in ethyl — — 7.93 79.67 8.55 86.42 — — acetate. Solids content of 50.5% by weight (Duro- Tak ™ 387-2287) Polysiloxane adhesive in n- — — — — — — 6.07 86.85 heptane. Solids content of 72.40% by weight (DOW CORNING ® BIO-PSA Q7-4301) Isopropylmyristate — — 0.35  6.92 — — — — Ethyl acetate 0.61 — 2.72 — 2.37 — 0.58 — Total 11.69 100.00  11.68  100.00  11.60  100.00  7.32 100.00  Area Weight [g/m.sup.2] 94.15 99.85 100.9 90.3 Asenapine content 1.257 1.339 2.515 [mg/cm.sup.2]

Preparation of the Coating Composition

[0446] For Example 7a, a beaker was loaded with the asenapine base, the acrylic pressure sensitive adhesive Duro-Tak™ 387-2516 was added and the mixture was then stirred at approx. 250 rpm until a homogeneous mixture was obtained. The solvent ethyl acetate was added and the mixture again stirred at up to 400 rpm.

[0447] For Example 7b, a beaker was loaded with the asenapine base and with the solvent (ethyl acetate), and the isopropyl myristate was added. The acrylic pressure sensitive adhesive Duro-Tak™ 387-2287 was added and the mixture was then stirred at approx. 400 rpm until a homogeneous mixture was obtained.

[0448] For the first and second layer of Example 7c, a beaker was loaded with the asenapine base and with the solvent (ethyl acetate), and the acrylic pressure sensitive adhesive Duro-Tak™ 387-2287 or the polysiloxane adhesive was added, respectively, and the mixture was then stirred at approx. 400 rpm until a homogeneous mixture was obtained.

Coating of the Coating Composition of Examples 7a and 7b

[0449] The resulting asenapine-containing coating composition was coated on a polyethylene terephthalate film (siliconised, 100 μm thickness, which may function as release liner) and dried for approx. 10 min at room temperature and 20 min at 60° C. (Example 7b) or at 90° C. (Example 7a). The coating thickness gave an area weight of the matrix layer of 94.15 g/m.sup.2 (Example 7a) and 99.85 g/m.sup.2 (Example 7b), respectively. The dried film was laminated with a polyethylene terephthalate backing layer (23 μm thickness) to provide an asenapine-containing self-adhesive layer structure.

Coating of the Coating Composition of Examples 7c

[0450] For Example 7c, the resulting asenapine-containing coating compositions were coated on a polyethylene terephthalate film (siliconised, 100 μm thickness, for Layer 1, or fluoro polymer coated, 75 μm thickness, for Layer 2, which may function as release liner) and dried for approx. 10 min at room temperature and 20 min at 60° C. (Layer 1) or at 90° C. (Layer 2). A double layer self-adhesive layer structure was then prepared as described for Example 1 a, with Layer 1 intended to be the layer contacting the skin (i.e. the dried film of Layer 2 was laminated with a polyethylene terephthalate backing layer (23 μm thickness) and Layer 1 was used unmodified).

Preparation of the TTS

[0451] See Example 1.

Measurement of Skin Permeation Rate

[0452] The permeated amount and the corresponding skin permeation rates of TTS prepared according to Examples 7a-c 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 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 1.156 cm.sup.2 were punched from the TTS. The asenapine permeated amount in the receptor medium of the Franz cell (solution containing 60% phosphate buffer pH 5.5, 30% dipropylene glycol and 10% acetonitrile) at a temperature of 32±1° C. was measured and the corresponding skin permeation rate calculated. The results are shown in Table 7.2 and FIG. 7a.

TABLE-US-00026 TABLE 7.2 Skin permeation rate with SD [μg/(cm.sup.2 h)] Ex. 7a Ex. 7b Ex. 7c Elapsed (n = 3) (n = 3) (n = 3) time [h] Rate SD Rate SD Rate SD 0 0 0 0 0 0 0 4 1.81 0.71 2.54 2.11 3.35 1.69 8 6.92 2.03 8.64 4.36 12.37 4.18 12 9.03 2.27 13.93 5.95 19.68 5.27 16 9.27 2.71 15.86 6.79 21.77 4.63 20 11.12 1.03 15.78 5.32 23.17 4.47 24 12.54 3.32 15.39 4.2 22.85 3.29 32 10.53 1.47 13.52 2.9 20.4 2.79 40 10.78 1.4 13.25 2.11 20.52 1.54 48 9.85 0.89 11.72 1.33 18.38 1.4 56 9.04 0.64 10.37 1.09 17.07 0.3 64 8.48 0.48 9.01 1.09 16.31 1.08 72 7.93 0.19 8.03 1.18 14.52 0.22

Utilization of Asenapine

[0453] 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 7.3 and in FIG. 7b.

TABLE-US-00027 TABLE 7.3 Utilization of asenapine after 72 h [%] Example 7a Example 7b Example 7c (n = 3) (n = 3) (n = 3) 52.15 60.83 50.51

Examples 8A-C

Coating Composition

[0454] The formulations of the asenapine-containing coating compositions of Examples 8a-c are summarized in Table 8.1 below. The formulations are based on weight percent, as also indicated in Table 8.1.

TABLE-US-00028 TABLE 8.1 Ex. 8a Ex. 8b Ex. 8c Amt Solids Amt Solids Amt Solids Ingredient (Trade Name) [g] [%] [g] [%] [g] [%] Asenapine base 0.70 10.00 0.98 7.00 0.49 7.00 Acrylic adhesive in ethyl acetate. 15.17  90.00 31.39 93.00 14.83 87.98 Solids content of 41.5% by weight (Duro-Tak ™ 387-2516) Polyvinylpyrrolidone (Povidone — — — 0.35 5.02 K90F) Ethyl acetate 0.46 — 0.21 — — — Ethanol — — — — 0.56 — Total 16.33  100.00  32.58 100.00 16.23 100.00 Area Weight [g/m.sup.2] 134.8 168.5 134.9 Asenapine content [mg/cm.sup.2] 1.348 1.180 0.944

Preparation of the Coating Composition

[0455] For Examples 8a and 8b, a beaker was loaded with the asenapine base and the solvent ethyl acetate. The acrylic pressure sensitive adhesive Duro-Tak™ 387-2516 was added and the mixture was then stirred at up to 500 rpm (Example 8a) or at approx. 300 rpm (Example 8b), until a homogeneous mixture was obtained.

[0456] For Example 8c, a beaker was loaded with the asenapine base. The acrylic pressure sensitive adhesive Duro-Tak™ 387-2516 was added and the mixture was then stirred at approx. 300 rpm until a homogeneous mixture was obtained. The polyvinylpyrrolidone and the solvent ethanol were consecutively added while stirring at approx. 300 rpm and approx. 500 rpm, respectively.

Coating of the Coating Composition of Examples 8a and 8c

[0457] The resulting asenapine-containing coating composition was coated on a polyethylene terephthalate film (siliconised, 100 μm thickness, which may function as release liner) and dried for approx. 15 min at room temperature and 25 min at 75° C. The coating thickness gave an area weight of the matrix layer of 134.8 g/m.sup.2 (Example 8a) and 134.9 g/m.sup.2 (Example 8c), respectively. The dried film was laminated with a polyethylene terephthalate backing layer (23 μm thickness) to provide an asenapine-containing self-adhesive layer structure.

Coating of the Coating Composition of Example 8b

[0458] The resulting asenapine-containing coating composition was coated on a polyethylene terephthalate film (siliconised, 100 μm thickness, which may function as release liner) and dried for approx. 15 min at room temperature and 25 min at 75° C., and additionally 25 min at 75° C. A double layer self-adhesive layer structure was then prepared as described for Example 1 a. This results in an asenapine-containing self-adhesive layer structure with an area weight of the matrix layer of 168.5 g/m.sup.2, with a backing layer and a release liner.

Preparation of the TTS

[0459] See Example 1.

Measurement of Skin Permeation Rate

[0460] The permeated amount and the corresponding skin permeation rates of TTS prepared according to Examples 8a-c 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 1954) was used. A dermatome was used to prepare skin to a thickness of 800 p.m, with an intact epidermis for all TTS. Diecuts with an area of 1.148 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 8.2 and FIGS. 8a and 8b.

TABLE-US-00029 TABLE 8.2 Skin permeation rate with SD [μg/(cm.sup.2 h)] Ex. 8a Ex. 8b Ex. 8c Elapsed (n = 3) (n = 3) (n = 3) time [h] Rate SD Rate SD Rate SD 0 0 0 0 0 0 0 4 1.19 0.62 0.8 0.12 0.77 0.52 8 4.85 1.07 3.41 0.2 2.2 0.37 12 8.75 1.44 6.38 0.67 4.87 0.64 16 11.06 1.42 8.96 0.61 6.95 0.75 20 12.74 0.89 10.75 0.92 8.38 0.77 24 13.11 0.78 9.35 0.96 8.93 0.69 32 12.7 0.77 9.12 0.29 8.7 0.62 40 12.71 0.79 9.97 0.33 8.92 0.6 48 11.94 0.66 9.24 0.11 8.26 0.34 56 11.31 0.63 8.65 0.24 7.14 0.66 64 9.92 0.44 7.66 0.71 7.22 0.39 72 9.02 0.3 7.79 0.43 6.27 0.05 96 5.92 0.29 4.64 0.2 3.92 0.13 120 4.39 0.33 3.95 0.1 2.77 0.19 144 3.13 0.23 2.83 0.04 2.01 0.16

Utilization of Asenapine

[0461] 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 8.3 and in FIG. 8c.

TABLE-US-00030 TABLE 8.3 Utilization of asenapine after 72 h [%] Example 8a Example 8b Example 8c (n = 3) (n = 3) (n = 3) 55.34 48.92 52.84

Examples 9A, 9B

Coating Composition

[0462] The formulations of the asenapine-containing coating compositions of Examples 9a and 9b are summarized in Table 9.1 below. The formulations are based on weight percent, as also indicated in Table 9.1.

TABLE-US-00031 TABLE 9.1 Ex. 9a Ex. 9b Solids Solids Ingredient (Trade Name) Amt [g] [%] Amt [g] [%] Asenapine base 0.35 7.00 1.06 7.06 Acrylic adhesive in ethyl 11.19 93.00 33.61 92.82 acetate, ethanol, n-heptane and methanol. Solids content of 41.5% by weight (Duro-Tak ™ 387-2516) Ascorbyl palmitate — — 0.02 0.11 Total 11.54 100.00 34.69 100.00 Area Weight [g/m.sup.2] 85.8 149.0 Asenapine content 0.601 1.052 [mg/cm.sup.2]

Preparation of the Coating Composition

[0463] A beaker was loaded with the asenapine base and the ascorbyl palmitate (Example 9b), if applicable, and the acrylic pressure sensitive adhesive Duro-Tak™ 387-2516 was added. The mixture was then stirred at approx. 250 rpm (Example 9a) or up to 1000 rpm (Example 9b), until a homogeneous mixture was obtained.

Coating of the Coating Composition

[0464] For Example 9a, the resulting asenapine-containing coating composition was coated on a polyethylene terephthalate film (siliconised, 100 μm thickness, which may function as release liner) and dried for approx. 10 min at room temperature and 15 min at 70° C. For Example 9b, 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. 15 min at room temperature and 25 min at 70° C. The coating thickness gave an area weight of the matrix layer of 85.8 g/m.sup.2 (Example 9a) and 149.0 g/m.sup.2 (Example 9b) respectively. The dried film was laminated with a polyethylene terephthalate backing layer (23 μm thickness) to provide an asenapine-containing self-adhesive layer structure.

Preparation of the TTS

[0465] See Example 1.

Measurement of Skin Permeation Rate

[0466] The permeated amount 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 April 13, 2004) carried out with a 7.0 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 1.149 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 9.2 and FIG. 9a.

TABLE-US-00032 TABLE 9.2 Skin permeation rate with SD [μg/(cm.sup.2 h)] Elapsed Ex. 9a (n = 3) Ex. 9b (n = 2) time [h] Rate SD Rate SD 0 0 0 0 0 4 0.66 0.07 0.69 0.02 8 4.61 0.16 4.71 0.01 12 8.14 0.61 9.11 0.13 16 10.49 0.17 11.45 0.03 20 11.53 0.25 13.04 0.4 24 10.43 0.51 13.07 0.16 32 8.27 0.49 11.58 0.07 40 7.16 0.36 11.29 0.24 48 6.15 0.07 10.08 0.12 56 4.95 0.34 8.01 0.36 64 3.15 0.72 8.3 0.09 72 2.92 0.25 7.14 0.1

Utilization of Asenapine

[0467] 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 9.3 and in FIG. 9b.

TABLE-US-00033 TABLE 9.3 Utilization of asenapine after 72 h [%] Example 9a Example 9b (n = 3) (n = 2) 73.99 62.67

Example 10

Coating Composition

[0468] The formulation of the asenapine-containing coating composition is summarized in

[0469] Table 10.1 below. The formulation is based on weight percent, as also indicated in Table 10.1.

TABLE-US-00034 TABLE 10.1 Ex. 10 Solids Ingredient (Trade Name) Amt [g] [%] Asenapine base 0.50 4.96 Acrylic adhesive in ethyl 23.01 94.78 acetate, ethanol, n-heptane and methanol. Solids content of 41.5% by weight (Duro-Tak ™ 387-2516) α-Tocopherol 0.03 0.26 Total 23.54 100.00 Area Weight [g/m.sup.2] 148.35 Asenapine content 0.736 [mg/cm.sup.2]

Preparation of the Coating Composition

[0470] A beaker was loaded with the asenapine base and the α-Tocopherol and the acrylic pressure sensitive adhesive Duro-Tak™ 387-2516 was added. The mixture was then stirred at up to 500 rpm until a homogeneous mixture was obtained.

Coating of the Coating Composition

[0471] 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. 15 min at room temperature and 25 min at 70° C. The coating thickness gave an area weight of the matrix layer of 148.35 g/m.sup.2. The dried film was laminated with a polyethylene terephthalate backing layer (23 μm thickness) to provide an asenapine-containing self-adhesive layer structure.

Preparation of the TTS

[0472] See Example 1.

Measurement of Skin Permeation Rate

[0473] The permeated amount and the corresponding skin permeation rates of TTS prepared according to Example 10 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 1.154 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 10.2 and FIG. 10a.

TABLE-US-00035 TABLE 10.2 Skin permeation rate with SD [μg/(cm.sup.2 h)] Elapsed Ex. 10 (n = 3) time [h] Rate SD 0 0 0 4 0.17 0.05 8 1.8 0.65 24 4.86 1.15 32 6.32 1.24 48 5.4 0.82 72 4.32 0.51

Utilization of Asenapine

[0474] The utilization of asenapine at 72 h was calculated based on the cumulative permeated amount at 72 h and the initial asenapine content. The result is shown in Table 10.3 and in FIG. 10b.

TABLE-US-00036 TABLE 10.3 Utilization of asenapine after 72 h [%] Example 10 (n = 3) 44.36

Example 11

Coating Composition

[0475] The formulations of the asenapine-containing coating compositions of Examples 11a-d are summarized in Table 11.1 below. The formulations are based on weight percent, as also indicated in Table 11.1.

TABLE-US-00037 TABLE 11.1 Ex. 11a Ex. 11b Ex. 11c Ex. 11d Amt Solids Amt Solids Amt Solids Amt Solids Ingredient (Trade Name) [g] [%] [g] [%] [g] [%] [g] [%] Asenapine base 4.00 16.38  4.00 16.48  4.00 16.33  4.00 16.48 Acrylic adhesive in ethyl 49.26 83.62 — — — — — — acetate, ethanol, n-heptane and methanol. Solids content of 41.5% by weight (Duro-Tak ™ 387-2516) Acrylic adhesive in ethyl — — 40.16 83.52 36.66 75.54 35.41 73.48 acetate. Solids content of 50.5% by weight (Duro-Tak ™ 387-2287) Diethylene glycol — — — —  1.99  8.13 — — monoethyl ether (Transcutol) Basic butylated — — — — — —  2.45 10.07 methacrylate copolymer (Eudragit ® E100) Ethyl acetate 3.75 — 12.32 — 14.37 — 14.66 — Total 57.02 100.00  56.48 100.00  57.03 100.00  56.52 100.00  Area Weight [g/m.sup.2] 146.0 135.7 137.3 140.3 Asenapine content 2.391 2.237 2.242 2.307 [mg/cm.sup.2]

Preparation of the Coating Composition

[0476] For Examples 11a-11c, a beaker was loaded with the asenapine base and with the solvent (ethyl acetate), and the diethylene glycol monoethyl ether (Example 11c) was added, if applicable. The acrylic pressure sensitive adhesive Duro-Tak™ 387-2516 (Example 11a) or Duro-Tak™ 387-2287 (Examples 11b and 11c) was added and the mixture was then stirred at approx. 500 rpm (Examples 11a and 11b) or approx. 700 rpm (Example 11c) until a homogeneous mixture was obtained.

[0477] For Example 11d, a beaker was loaded with the asenapine base and with the solvent (ethyl acetate). The acrylic pressure sensitive adhesive Duro-Tak™ 387-2516 was added and the mixture was then stirred at approx. 500 rpm until a homogeneous mixture was obtained. The basic butylated methacrylate copolymer Eudragit E100 was then added while stirring at approx. 500 rpm.

Coating of the Coating Composition

[0478] The resulting asenapine-containing coating composition was coated on a polyethylene terephthalate film (siliconised, 100 μm thickness, which may function as release liner) and dried for approx. 15 min at room temperature and 25 min at 60° C. (Examples 11b-11d) or 90° C. (Example 11a). The coating thickness gave an area weight of the matrix layer of 146.0 g/m.sup.2 (Example 11a), 135.7 g/m.sup.2 (Example 11b), 137.3 g/m.sup.2 (Example 11c), and 140.3 g/m.sup.2 (Example 11d) respectively. The dried film was laminated with a polyethylene terephthalate backing layer (23 μm thickness) to provide an asenapine-containing self-adhesive layer structure.

Preparation of the TTS

[0479] See example 1.

In Vivo Study Using Goettingen Minipigs

[0480] The in vivo releases and the corresponding skin permeation rates of TTS prepared according to Examples 11a-11d were determined by in vivo experiments using Goettingen minipigs (female, about 6 months, randomized by simple random sample method). Diecuts with an area of 10 cm.sup.2 were punched from the TTS and one Goettingen minipig was used for one TTS formulation. Three drug containing and one placebo 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.

[0481] 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.

[0482] Following the above single dose application of the 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 x 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 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 TTS. The results are shown in Tables 11.2, 11.3, and FIG. 11.

TABLE-US-00038 TABLE 11.2 Values Ex. 11a Ex. 11b Ex. 11c Ex. 11d Asenapine content of 71.8 66.3 67.5 65.9 preclinical sample [mg] Draize* score (3*verum/ 1/1/1/0 1/1/1/0 1/1/1/0 1/1/1/0 placebo) at 84 and 96 hours Amount of asenapine dermally 38/27.3 35/23.4 40/27.4 44/28.8 delivered after 84 h [%/mg] *Score schemes for the evaluation of skin irritation potential according to Draize: 0 = No erythema, no edema, 1 = Very slight erythema (barely perceptible), very slight edema (barely perceptible), 2 = Well-defined erythema, Slight edema, 3 = Moderate to severe erythema, moderate edema, 4 = Severe erythema, severe edema.

TABLE-US-00039 TABLE 11.3 Asenapine Blood plasma concentration [ng/ml] Time [h] Ex. 11a Ex. 11b Ex. 11c Ex. 11d  0 0 0 0 0  4 0.2885 0.3042 0.7746 0.5393  8 2.1691 1.8003 3.5723 3.7003 12 3.8569 3.3173 5.8001 6.8128 24 3.9563 4.4292 5.6102 6.3384 32 4.4426 4.0957 5.6204 5.8559 48 4.1034 3.6241 4.8330 5.6987 56 2.7035 2.8258 2.7434 4.2988 72 4.0017 3.0152 3.4307 4.0930 84 3.4551 2.5156 3.2065 4.2309 96 0.8566 0.8502 0.5821 1.0256 AUC.sub.(0-24) [(ng/ml) h] 64.4 61.5 97.4 109.5 AUC.sub.(0-48) [(ng/ml) h] 166.4 157.4 226.0 250.7 AUC.sub.(0-72) [(ng/ml) h] 247.3 229.9 305.7 357.8 AUC.sub.(0-84) [(ng/ml) h] 292.0 263.1 345.5 407.8 AUC.sub.(0-96) [(ng/ml) h] 317.9 283.3 368.3 439.3 C.sub.max [ng/ml] 4.4 4.4 5.8 6.8

Examples 12A, 12B

Coating Composition

[0483] The formulations of the asenapine-containing coating compositions of Examples 12a and 12b are summarized in Table 12.1 below. The formulations are based on weight percent, as also indicated in Table 12.1.

TABLE-US-00040 TABLE 12.1 Ex. 12a Ex. 12b Solids Solids Ingredient (Trade Name) Amt [g] [%] Amt [g] [%] Asenapine base 27.0 6.0 45.0 10.0 Acrylic adhesive in ethyl acetate. 903.6 83.5 860.0 79.5 Solids content of about 41.6% by weight (Duro-Tak ™ 387-2516) Polyvinylpyrrolidone (Povidone 45.1 10.0 45.0 10.0 K90F) α-Tocopherol 2.25 0.5 2.25 0.5 Ethanol denat. (1% (v/v) methyl 106.8 — 132.3 — ethyl ketone) Total 1084.8 100.0 1084.6 100.0 Area weight [g/m.sup.2] 148.6 149.6 Asenapine content [mg/cm.sup.2] 0.89 1.50

Preparation of the Coating Composition

[0484] For Examples 12a and 12b, a stainless steel vessel was loaded with the α-tocopherol, the asenapine and the ethanol. The acrylic pressure sensitive adhesive Duro-Tak™ 387-2516 was added and the mixture was then stirred until a clear solution was obtained (about 20 min). The polyvinylpyrrolidone was added slowly while stirring and dissolved under stirring until a clear solution was obtained.

Coating of the Coating Composition of Examples 12a and 12b

[0485] The resulting asenapine-containing coating composition was coated on a polyethylene terephthalate film (one side siliconized, 75 μm thickness, which may function as release liner) and dried for approx. 15 min at 80° C. The coating thickness gave an area weight of 148.6 g/m.sup.2 (Ex. 12a) and 149.6 g/m.sup.2 (Ex. 12b), respectively. The dried film was laminated with a polyethylene terephthalate backing layer (23 μm thickness) to provide an asenapine-containing self-adhesive layer structure.

Preparation of the TTS

[0486] See Example 1.

Measurement of Skin Permeation Rate

[0487] The permeated amount and the corresponding skin permeation rates of TTS prepared according to Examples 12a and 12b 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 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 1.154 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. 12a.

TABLE-US-00041 TABLE 12.2 Skin permeation rate with SD* [μg/(cm.sup.2 h)] Elapsed Ex. 12a (n = 3) Ex. 12b (n = 3) time [h] Rate SD Rate SD 0 0.00 0.00 0.00 0.00 2 0.00 0.00 0.00 0.00 4 0.42 0.01 0.42 0.04 8 1.39 0.08 1.62 0.23 12 3.81 0.17 4.86 0.46 16 6.07 0.12 7.94 0.78 20 7.19 0.42 10.24 0.72 24 7.80 0.24 11.90 1.09 32 6.98 0.36 10.78 0.85 40 7.47 0.43 12.11 0.78 48 7.79** 0.24 11.97 0.65 56 8.20** 0.70 12.25 0.60 64 6.67** 0.18 11.09 0.20 72 6.10** 0.13 9.83 0.21 *Standard deviation in this Example was, as in all other Examples, calculated based on the n-method. **n = 2.

Utilization of Asenapine

[0488] 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 12.3 and in FIG. 12b.

TABLE-US-00042 TABLE 12.3 Utilization of asenapine after 72 h [%] Example 12a Example 12b (n = 2) (n = 3) 51.30 46.20

Examples 13A, 13B

Coating Composition

[0489] The formulations of the asenapine-containing coating compositions of Examples 13a and 13b are summarized in Table 13.1 below. The formulations are based on weight percent, as also indicated in Table 13.1.

TABLE-US-00043 TABLE 13.1 Ex. 13a Ex. 13b Solids Solids Ingredient (Trade Name) Amt [g] [%] Amt [g] [%] Asenapine base 54.0 6.0 135 10.0 Acrylic adhesive in ethyl acetate. 1820 83.5 2580 79.5 Solids content of about 41.5% by weight (Duro-Tak ™ 387-2516) Polyvinylpyrrolidone (Povidone 90.0 10.0 135 10.0 K90F) α-Tocopherol 4.50 0.5 6.75 0.5 Ethanol denat. (1% (v/v) methyl 211.8 — 414.2 — ethyl ketone) Total 2180.3 100.0 3271.0 100.0 Label area weight [g/m.sup.2] 140 140 Asenapine content [mg/cm.sup.2] 0.88 1.47

Preparation of the Coating Composition

[0490] For Examples 13a and 13b, the stainless steel vessel was loaded with α-tocopherol. The acrylic pressure sensitive adhesive Duro-Tak™ 387-2516 was added and the mixture was then stirred until a clear solution was obtained. The polyvinylpyrrolidone was added slowly while stirring and dissolved under stirring until a clear solution was obtained. The asenapine was suspended in the ethanol and transferred to the stainless steel vessel. After addition of the asenapine, the mixture was stirred at until a clear, slightly yellow colored solution was obtained.

Coating of the Coating Composition of Examples 13a and 13b

[0491] The resulting asenapine-containing coating composition was coated on a polyethylene terephthalate film (one side siliconized, 75 μm thickness, which may function as release liner) and dried for approx. 15 min at 80° C. The coating thickness gave an area weight of about 140 g/m.sup.2 in accordance with the label requirements (hereinafter, where reference is made to a label value, it is understood that the actual value is within a tolerance off 7.5% of the label value).

[0492] The dried film was laminated with a polyethylene terephthalate backing layer (23 μm thickness) to provide an asenapine-containing self-adhesive layer structure. Residual solvents amounts fulfilled the requirement the ICH guideline Q3C (R3), i.e. methanol ≤3,000 ppm, ethanol ≤5,000 ppm, ethyl acetate ≤5,000 ppm and n-heptane ≤5,000 ppm.

Preparation of the TTS

[0493] Individual systems (TTS) of 10 cm.sup.2 (Ex. 13a) as well as 15 cm.sup.2 (Ex. 13b) were then punched out from the asenapine-containing self-adhesive layer structure.

Example 14

In Vivo Clinical Study

[0494] An in vivo clinical trial was conducted to investigate the relative bioavailability of asenapine after transdermal application of the inventive TTS (Examples 13a and 13b) compared to sublingual administration. The study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki.

Trial Design

[0495] The trial was conducted in a single center, Phase I, open-label design with 3 treatments, 3 treatment periods, a fixed treatment sequence in 16 healthy male and female subjects, comparing the relative bioavailability of asenapine in plasma after single dose transdermal application of the TTS prepared in Examples 13a and 13b to the currently marketed sublingual tablets (Sycrest®, 5 mg).

[0496] For each subject, the trial consisted of: [0497] An ambulant screening period in which informed consent was obtained and eligibility of the subjects assessed. Depending on the outcome of the screening, subjects were included in the trial. [0498] A treatment and observation period consisting of 3 sequential treatment periods (each several days long). [0499] An ambulant follow-up visit after the end of last treatment.

[0500] Regarding the 3 sequential treatment periods, the subjects received sublingual tablets of 5 mg asenapine b.i.d. (=twice daily) (Reference) on the first day of period 1, a single dose of the TTS prepared in Example 13a (3 TTS of 10 cm.sup.2 each) during period 2 and a single dose of the TTS prepared in Example 13b (1 TTS of 15 cm.sup.2) during period 3.

Selection of Trial Population

[0501] Only subjects meeting all inclusion and none of the exclusion criteria were included into the treatment phase. The criteria were assessed at screening and a re-check was performed on Day-1 of Period 1.

Inclusion Criteria

[0502] Subjects had to fulfill all of the following criteria to be eligible for participation in the treatment period. [0503] 1. Subjects who are able to understand and follow instructions during the study. [0504] 2. Signed informed consent. [0505] 3. White. [0506] 4. Age ≥18 and ≤55 years. [0507] 5. Nonsmoker. [0508] 6. In general good physical health as determined by medical and surgical history, physical examination, 12-lead electrocardiogram (ECG), vital signs, and clinical laboratory tests. [0509] 7. Weight within the normal range according to accepted values for the body mass index (BMI) within 18.0 to 29.4 kg/m.sup.2. [0510] 8. Normal blood pressure (Systolic Blood Pressure (SBP) ≥90 ≤139 mmHg; Diastolic Blood Pressure ≥55 <≤89 mmHg) measured after 5 min rest in supine position. [0511] 9. A pulse rate of ≥50 and ≤99 b/min measured after 5 min rest in supine position. [0512] 10. ECG recording without clinically significant abnormalities. [0513] 11. Having had no febrile or infectious illness for at least 7 days prior to the first administration.
Exclusion Criteria 104351 To ensure that the subjects are healthy and in a comparable status, the following exclusion criteria were applied.

Lifestyle Restrictions

[0514] 1. Demonstrating excess in xanthine consumption (more than 5 cups of coffee or equivalent per day). [0515] 2. More than moderate alcohol consumption (>35 g of ethanol regularly per day or >245 g regularly per week). [0516] 3. Any history of alcohol or drug abuse. [0517] 4. Vegetarian. [0518] 5. Positive drug screen.

[0519] 6. Positive alcohol breath test. [0520] 7. Consumption of xanthine-containing food or beverages as well as grapefruit juice or Seville oranges within 48 hours before first dosing. [0521] 8. Consumption of char-grilled food, broccoli, or Brussel sprouts within 72 h before first dosing.

Prior Medication

[0522] 9. Use of any medication (self-medication or prescription medication) except hormonal contraception within 4 weeks before first dosing (or at least 10 times the respective elimination half-life, whichever is longer).

Medical and Surgical History

[0523] 10. Demonstrating any active physical disease, acute or chronic. [0524] 11. Any history of drug hypersensitivity, asthma, urticaria or other severe allergic diathesis as well as current hay fever. [0525] 12. Any history of hypersensitivity of any component of the investigated dosage Rams. [0526] 13. Any history of chronic gastritis or peptic ulcers. [0527] 14. Any history of chronic or recurrent metabolic, renal, hepatic, pulmonary, gastrointestinal, neurological (esp. history of epileptic seizures), endocrinological (esp. diabetes mellitus), immunological, psychiatric or cardiovascular disease, myopathies, dermal diseases, and bleeding tendency. [0528] 15. Gilbert syndrome. [0529] 16. Any gastrointestinal complaints within 7 days prior to first dosing. [0530] 17. Any scars, moles, tattoos, skin irritation or excessive hair growth at the TTS application site. [0531] 18. Any suicidal ideation of type 2 to 5 on the C-SSRS (Columbia Suicidal Severity Rating Scale) in the past 12 months (i.e., active suicidal thought, active suicidal thought with method, active suicidal thought with intent but without specific plan, or active suicidal thought with plan and intent).

Laboratory Examinations

[0532] 19. Laboratory values outside the reference range that are of clinical relevance (e.g., suggesting an unknown disease and requiring further clinical evaluation assessed by the investigator), especially regarding aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl transpeptidase (GGT). [0533] 20. Positive test for human immunodeficiency virus (HIV) antibodies/p24 antigen. [0534] 21. Positive Hepatitis B-virus surface antigen (HBsAg) test. [0535] 22. Positive Anti-hepatitis C-virus antibodies (Anti-HCV) test.

Other

[0536] 23. Blood donation within 30 days before signing informed consent to this trial. [0537] 24. Participation in the treatment phase of a clinical study 30 days or blocked by the follow-up period of a previous clinical trial before signing informed consent to this trial. [0538] 25. Women of childbearing potential not using a highly effective method of birth control. Highly-effective methods of birth control are defined as those which result in a low failure rate, i.e. less than 1% per year, when used consistently and correctly (e.g., combination of intrauterine device and condom). Female subjects are considered to be of childbearing potential unless surgically sterilized by hysterectomy or bilateral tubal ligation, or postmenopausal for at least 2 years. [0539] 26. Pregnant or breastfeeding women.

Treatments During the Study

[0540] The treatments administered during the study are summarised in Table 14.1 below and their characteristics are detailed below.

TABLE-US-00044 TABLE 14.1 Dose (Active amount based on label composition of Formu- Mode of Treatment the dosage form) lation administration Reference 5 mg per tablet sublingual Two administrations (Period 1) tablet b.i.d. (q12h) TTS of 3*(8.4 mg/10 cm.sup.2) TTS Single administration, Example 13a TTS applied for (Period 2) 3.5 days TTS of 21.0 mg/15 cm.sup.2 TTS Single administration, Example 13b TTS applied for (Period 3) 3.5 days b.i.d. = twice daily; q12h = every 12 h

[0541] The reference formulation administered in period 1 contains the active ingredient asenapine maleate and is marketed under the trade name Sycrest® 5 mg Sublingualtabletten by N. V. Organon, Oss, Netherlands. The pharmacy central number (PZN) is 07728207.

Administration of the Sublingual Tablets (Reference)

[0542] Sublingual tablets were administered in the morning and in the evening of the first day only with 12 h in between the two administrations according to the administration instructions given in the summary of product characteristics. The subjects were instructed to place the tablets under the tongue for at least 10 min to allow dissolving of the sublingual tablet and not to chew or swallow the sublingual tablets.

Application of the TTS

[0543] The TTS were applied to intact skin on the upper chest or upper back. Hairs on the application area were trimmed with scissors (not shaved) before application, if necessary. The subjects were instructed to verify that the skin is free of detergents, oils and fat before TTS application. The TTS was placed on the desired position and pressed for at least 30 sec with fingers or the palm to fixate the TTS on the skin surface. In case of need and to avoid further detachment, the TTS was additionally fixated with an adhesive overlay free of active agent. The optional adhesive overlay was placed above the TTS in such a way that each side was equally covered by the adhesive overlay. Afterwards, to fixate the TTS, it was pressed again for at least 30 sec with fingers or the palm. The TTS were removed after 3.5 days (84 h, Period 2 and Period 3). After removal, the used TTS (including the adhesive overlay, if applicable) were handled and stored under nitrogen in the refrigerator until they were further analyzed.

Timing of Dose for Each Subject

[0544] On the first day of Period 1, no breakfast was served; the subjects fasted overnight before morning administration. A standardized lunch was given 4 h and dinner approximately 10 h after morning administration. Fluid intake was not allowed from 1 h before until 1 h after morning and evening administration. As food does not interact with the TTS, the subjects received standardized meals and beverages during in-house days at customary times during Period 2 and 3. During in-house days, the subjects were only allowed to consume food or beverages provided by the study unit.

Restrictions and Precautions

[0545] During the trial, subjects were instructed to abstain from all activities which may increase body temperature, i.e., physical exertion, sauna, environments with great heat. During the time the TTS were worn, subjects were not allowed to perform any activities which may influence adhesion of the TTS such as any activities which would increase sweating. Further restrictions on food and beverages intakes were placed e.g. in accordance with the exclusion criteria.

Sample Collection and Determination of Blood Plasma Concentrations

[0546] Blood samples for the determination of the concentration of asenapine and its metabolites in blood plasma were collected at specified time points after administration.

[0547] A validated internally standardized liquid chromatography tandem mass spectrometry method was used for the determination of the blood plasma concentration of asenapine, N-desmethyl-asenapine and asenapine-glucuronide, which was carried out by a GLP (Good Laboratory Practice)—certified laboratory. Plasma concentrations of asenapine-glucuronide were only determined for 8 subjects, which had no influence on the validity of the results, or the interpretation of the trial results. The lower limits of quantification (LLOQs) were 0.1 ng/ml for asenapine and N-desmethyl-asenapine in plasma, and 0.25 ng/ml for asenapine-glucuronide.

Adverse Events (AE)

[0548] Adverse events were ascertained by the investigator using non-leading questions, noted as spontaneously reported by the subjects to the medical staff or observed during any measurements on all study days after administration of the dosage form and rated by a study physician.

[0549] Furthermore, suicide risk was monitored. All positive reports during the trial were documented as adverse events. Suicidal ideation of type 1-3 was documented as a non-serious AE. Suicidal ideation of type 4 and 5 and all suicidal behavior during the trial were documented as a serious adverse event (SAE) and reported.

[0550] An AE was referred to the treatment and time point after which it occurred, i.e., any AE occurring before the first dosing was counted as baseline complaint/pre-treatment AE and is not included in the below analysis.

Results and Analysis

[0551] All 16 subjects completed period 1 (reference) of the trial. After period 1 (reference) and before commencing period 2 (Ex. 13a), 1 subject dropped out. Another subject dropped out during period 3 (Ex. 13b), but could be assessed for the adverse events analysis. Safety laboratory parameters, vital signs, and ECG parameters showed no medically relevant changes. The results of the study are shown in Tables 14.2 to 14.9 and FIGS. 13a to 13e.

Arithmetic Mean Blood Plasma Concentration of Asenapine

[0552] Arithmetic mean values of the asenapine blood plasma concentration based on all 16 subjects for period 1 and based on the 15 and 14 subjects that completed periods 2 and 3, respectively, along with the standard deviation values are presented in Table 14.2 as well as FIGS. 13a and 13b. AUC values were calculated from the blood plasma concentration. The t.sub.lag was calculated approximatively as the mean arithmetic value of the first point in time when a measurable (i.e. non-zero) asenapine blood plasma concentration was obtained, and the results also indicated in Table 14.2.

TABLE-US-00045 TABLE 14.2 Asenapine blood plasma concentration [ng/ml] Reference Ex. 13a Ex. 13b (n = 16) (n = 15) (n = 14) Time [h] mean SD mean SD mean SD 0 0.00 0.00 0.00 0.00 0.00 0.00 0.5 2.89 (n = 15) 1.86 — — — — 1 3.58 1.68 — — — — 2 3.07 1.10 0.02 0.07 0.02 0.07 4 2.85 1.09 0.56 0.58 0.47 0.34 6 — — 0.92 0.70 0.86 0.44 8 1.48 0.57 1.63 1.09 1.47 0.63 12 0.73 0.28 2.13 0.98 1.95 0.67 12.5 3.76 1.65 — — — — 13 4.14 1.90 — — — — 14 3.27 1.56 — — — — 16 2.42 1.12 2.49 1.08 2.23 0.95 20 1.62 0.80 — — — — 24 1.27 0.71 2.93 1.14 2.44 0.80 36 0.39 0.18 1.81 (n = 14) 0.61 1.55 0.37 48 0.30 0.15 2.11 0.59 1.81 0.46 60 0.15 0.12 1.45 (n = 14) 0.34 1.31 0.29 72 0.14 0.13 1.67 0.37 1.42 0.36 84 0.06 0.09 1.21 (n = 14) 0.22 1.09 0.26 86 — — 1.19 0.24 1.02 0.23 88 — — 1.04 0.18 0.88 0.20 96 0.06 0.09 0.79 0.16 0.68 0.13 108 — — 0.41 0.09 0.36 0.06 120 0.03 0.06 0.37 0.11 0.30 0.07 132 — — 0.22 0.08 0.19 0.04 144 0.01 0.04 0.20 0.06 0.17 0.04 156 — — 0.11 0.07 0.09 0.07 168 0.01 0.03 0.11 0.07 0.09 0.07 192 — — 0.04 0.06 0.02 0.04 216 — — 0.01 0.03 0.01 0.03 240 — — 0.01 0.03 0.00 0.00 AUC.sub.(0-48) — — 95.06  37.20  82.26  25.65  [(ng/ml) h] AUC.sub.(0-72) — — 135.12  46.05  117.34  33.44  [(ng/ml) h] AUC.sub.(0-84) 178.44*  63.59  152.36  48.81  132.38  36.84  [(ng/ml) h] C.sub.max [ng/ml] 4.71 1.68 2.93 1.14 2.51 0.90 C.sub.48 [ng/ml] — — 2.11 0.59 1.81 0.46 C.sub.72 [ng/ml] — — 1.67 0.37 1.42 0.36 C.sub.84 [ng/ml] — — 1.21 0.22 1.09 0.26 t.sub.lag [h] 0.5  0   4.27 1.00 3.71 0.70 Residual amount** 12.0 (3*10 cm.sup.2) 3.3 (3*10 cm.sup.2) 10.3 (15 cm.sup.2) 2.3 (15 cm.sup.2) [mg/total area of release] Mean release — — 3.8  0.9  3.1  0.6  rate*** [mg/day] *The AUC.sub.(0-84) value is calculated for the reference period by multiplying the AUC.sub.(0-24) value by 3.5. **The residual amount is determined by extraction of the active from a sample of the used TTS with an appropriate solvent followed by determination of the active amount using a validated HPLC method with a UV photometric detector. ***The mean release rate is calculated based on the initial asenapine content in the TTS (according to the label composition) applied and on the residual amount in the TTS after 84 hours referring to the total dose administered (see Table 13.1).

Pharmacokinetic Analysis of Asenapine and Metabolites

[0553] Based on the plasma concentration time data of asenapine and metabolites, plasma pharmacokinetic parameters were calculated using non compartmental procedures and the results are presented in Tables 14.3 to 14.5, wherein C.sub.ab represents the average concentration observed during the relevant dosing interval (12 h for Period 1/Reference and 84 h for Periods 2 and 3/Examples 13a and 13b), and wherein t.sub.lag represents the time of first quantifiable concentration after administration. For C.sub.av and t.sub.lag of the Reference formulation merely the first dosing interval (0-12 h) was considered. Further, the blood plasma concentration profile of the metabolites asenapine glucuronide and N-desmethyl-asenapine was depicted as geometric mean values and indicating the geometric mean multiplied with and divided by the geometric standard deviation as error bars in FIGS. 13c, 13d and 13e.

[0554] The biometrical evaluation was carried out using SAS software, Version 9.3 of the SAS

[0555] System for windows. Pharmacokinetics calculations were carried out using Phoenix WinNonlin version 6.4 The pharmacokinetic calculation was based on all subjects who completed at least 2 treatment periods, i.e., who have evaluable data for the Reference and at least one of Examples 13a or 13b for asenapine and N-desmethyl-asenapine. Thus, the subject number was n=15 for Periods 1 and 2 (Reference and Example 13a) and n=14 for Period 3 (Example 13b). For asenapine-glucuronide, the subject number was n=8 for all Periods. Values below LLOQ were excluded from any calculations for descriptive statistics. Descriptive statistics of concentrations were calculated if at least 1/2 of the individual data points were measured equal or above LLOQ.

[0556] Calculation of the pharmacokinetic characteristics were based on actual blood sampling times [h] (relative to the corresponding administration time—accepted deviations from planned blood sampling times were within 3,5%) rounded to 2 decimal digits and negative pre dose times set to zero.

[0557] At time points in the lag time between time zero and the first quantifiable concentration, concentrations below LLOQ were calculated as zero. Concentrations below LLOQ between 2 quantifiable concentrations were calculated with half the LLOQ. Trailing concentrations below LLOQ were not used in calculations.

[0558] Descriptive statistics of pharmacokinetic parameters were calculated separately for each of the Periods 1, 2 and 3. For t.sub.max, frequency tables were drawn by treatment based on the nominal time of t.sub.max.

[0559] For each of Reference and Examples 13a and 13b, pharmacokinetic parameters of asenapine and metabolites were compared by means of an exploratory analysis of variance

[0560] (ANOVA) model. Arithmetic and geometric means used for the calculation of point estimators such as differences or ratios between treatments were derived from the ANOVA as least square means (LSMEANS) or exponential transformed LSMEANS, respectively. The inclusion of a 90% confidence interval implies a value of α=0.05 for the type-I error. No a-adjustment was performed.

[0561] Based on fundamental pharmacokinetic relationships, the multiplicative model was applied for all concentration related parameters. This implied that these characteristics were rather log normally than normally distributed. The ANOVA, therefore, was performed after logarithmic transformation. Exemplary results are shown in Tables 14.6 and 7.

[0562] The plasma concentration profile of asenapine shows that therapeutic concentrations may be maintained over the entire wearing period of the TTS without major fluctuations. Compared to sublingual administration, maximum concentrations were lower and reached later after transdermal application. The formation of the major metabolites, N-desmethyl-asenapine and asenapine-glucuronide, is markedly reduced compared to sublingual administration.

TABLE-US-00046 TABLE 14.3 Descriptive statistics: geometric means and standard deviation factors of asenapine blood plasma concentration [ng/ml] Reference Ex. 13a Ex. 13b (n = 15) (n = 15) (n = 14) Time [h] Mean SD Mean SD Mean SD 0.5 2.32 2.11 — — — — 1 3.21 1.72 — — — — 2 2.9 1.47 — — — — 4 2.64 1.52 0.451 2.78 0.337 2.41 6 — — 0.65 2.45 0.703 1.81 8 1.37 1.55 1.28 2.08 1.25 1.68 12 0.683 1.57 1.92 1.61 1.76 1.46 12.5 3.21 1.78 — — — — 13 3.52 1.85 — — — — 14 2.88 1.7  — — — — 16 2.18 1.65 2.27 1.55 1.93 1.61 20 1.44 1.68 — — — — 24 1.12 1.76 2.72 1.49 2.32 1.39 36 0.35 1.57 1.71 1.44 1.51 1.28 48 0.273 1.64 2.03 1.33 1.75 1.3  60 0.182 1.59 1.41 1.27 1.28 1.25 72 0.183 1.63 1.62 1.28 1.37 1.31 84 — — 1.18 1.22 1.06 1.28 86 — — 1.17 1.22 1 1.24 88 — — 1.02 1.2  0.862 1.25 96 — — 0.776 1.24 0.665 1.24 108 — — 0.401 1.27 0.352 1.2  120 — — 0.35 1.35 0.291 1.28 132 — — 0.223 1.31 0.188 1.26 144 — — 0.194 1.33 0.163 1.31 156 — — 0.144 1.23 0.129 1.23 168 — — 0.148 1.26 0.132 1.21 Key pharmacokinetic characteristics of Asenapine in plasma Reference Ex. 13a Ex. 13b (n = 15) (n = 15) (n = 14) AUC.sub.(0-24) * 47.4 (1.51) 38.6 (1.61) 35.6 (1.46) [(ng/ml) h] 27.3-89.6 22.3-77.5 19.7-72.8 AUC.sub.(24-48) * 12.6 (1.66) 49.2 (1.41) 42.7 (1.31) [(ng/ml) h 5.61-28.3 27.5-86.8 31.0-67.6 AUC.sub.(48-72) * — 39.0 (1.28) 34.1 (1.27) [(ng/ml) h] 24.5-60.7 22.2-51.7 AUC.sub.(0-48) * 88.2 (1.49) 78.6 (1.36) [(ng/ml) h] 49.7-161  51.8-140  AUC.sub.(0-72) * 128 (1.42) 113 (1.33) [(ng/ml) h] 74.2-222  80.3-192  AUC.sub.(0-84) * — 145 (1.39) 128 (1.32) [(ng/ml) h] 85.5-245  89.4-215  C.sub.max [ng/ml] * 3.47 (1.61) 2.72 (1.49) 2.37 (1.41) 1.43-6.88 1.46-5.08 1.56-4.78 C.sub.48 [ng/ml] — 2.03 (1.33) 1.75 (1.30) 1.27-3.47 1.10-2.65 C.sub.72 [ng/ml] — 1.62 (1.28) 1.37 (1.31) 1.01-2.26 0.822-2.13  C.sub.84 [ng/ml] — 1.18 (1.22) 1.06 (1.28) 0.826-1.61  0.675-1.70  C.sub.av [ng/ml] * 1.92 (1.52) 1.72 (1.39) 1.52 (1.32) 0.796-3.34  1.02-2.92 1.06-2.56 t.sub.max [h] ** 1.03 24.0 24.0 0.5-4.0 24.0-24.0 16.0-24.1 t.sub.lag [h] ** 0.5   4.0  4.0 0.5-1.1 2.0-6.0 2.0-4.0 t.sub.1/2 λz [h] * 16.5 (1.85) 28.0 (1.38) 27.1 (1.41) 8.18-55.5 16.0-42.7 17.5-52.7 * AUC, C.sub.max, C.sub.av and t.sub.1/2 λz given as geometric mean (Standard deviation), Minimum-Maximum; Standard deviation (SD) given is the geometric standard deviation factor for both, the descriptive statistics and key PK characteristics. ** t.sub.max and t.sub.lag as Median (Minimum-Maximum)

TABLE-US-00047 TABLE 14.4 Key pharmacokinetic characteristics of asenapine-glucuronide in plasma Reference Ex. 13a Ex. 13b (n = 8) (n = 8) (n = 8) AUC.sub.(0-24) *  221 (1.41) 44.0 (1.68) 42.6 (1.69) [(ng/ml) h] 147-383 22.8-115  23.0-116  AUC.sub.(24-48) * 84.4 (1.35) 92.7 (1.52) 76.6 (1.49) [(ng/ml) h] 51.8-131  64.0-226  54.4-166  AUC.sub.(0-48) * —  137 (1.56)  120 (1.55) [(ng/ml) h] 87.6-340  77.4-281  AUC.sub.(0-72) * —  220 (1.50)  185 (1.50) [(ng/ml) h] 152-521 134-418 AUC.sub.(0-84) * —  259 (1.48)  214 (1.49) [(ng/ml) h] 183-593 158-478 C.sub.max [ng/ml] * 13.4 (1.56) 4.66 (1.54) 3.84 (1.45) 7.75-28.0 3.05-11.1 2.68-7.71 t.sub.max [h] ** 4.00 36.0 36.0 4.00-4.05 36.0-83.9 36.0-60.0 t.sub.lag [h] ** 1.00  6.01  6.00 1.00-1.03 4.00-8.00 4.00-8.02 t.sub.1/2 λz [h] * 15.9 (1.47) 27.9 (1.38) 21.6 (1.24) 8.12-29.2 17.3-50.0 14.4-27.4 * AUC, C.sub.max and t.sub.1/2 λz given as geometric mean (Standard deviation), Minimum-Maximum; Standard deviation given is the geometric standard deviation factor ** t.sub.max and t.sub.lag as Median (Minimum-Maximum)

TABLE-US-00048 TABLE 14.5 Key pharmacokinetic characteristics of N-desmethyl-asenapine in plasma Reference Ex. 13a Ex. 13b (n = 15) (n = 15) (n = 14) AUC.sub.(0-24) * 11.5 (1.42) 1.67 (2.43) 1.27 (2.16) [(ng/ml) h] 6.34-20.1 0.452-5.79  0.420-3.87  AUC.sub.(0-48) * — 9.10 (1.69) 7.51 (1.54) [(ng/ml) h] 4.27-24.1 3.97-16.2 AUC.sub.(0-72) * — 16.8 (1.62) 14.4 (1.51) [(ng/ml) h] 8.27-42.9 7.79-30.8 AUC.sub.(0-84) * — 20.3 (1.59) 17.5 (1.50) [(ng/ml) h] 10.1-51.5 9.31-38.0 C.sub.max [ng/ml] * 0.514 (1.43)  0.351 (1.58)  0.310 (1.49)  0.259-0.969 0.173-0.846 0.165-0.634 t.sub.max [h] ** 8.00 48.0 60.0 4.00-11.9 36.0-84.1 36.0-72.0 t.sub.lag [h] ** 2.02 16.0 16.0 1.00-4.05 8.00-24.0 12.0-24.1 * AUC and C.sub.max given as geometric mean (Standard deviation), Minimum-Maximum; Standard deviation given is the geometric standard deviation factor ** t.sub.max and t.sub.lag as Median (Minimum-Maximum)

TABLE-US-00049 TABLE 14.6 90% confidence intervals for log transformed pharmacokinetic characteristics of asenapine-glucuronide Point Lower limit Upper limit estimate of 90% CI of 90% CI Comparison (%) (%) (%) AUC.sub.(0-48) Period 2/Reference 44.70 37.04 53.93 Period 3/Reference 39.04 32.35 47.10 Period 2/Period 3 114.49 94.90 138.14 C.sub.max Period 2/Reference 34.87 27.01 45.03 Period 3/Reference 28.74 22.26 37.11 Period 2/Period 3 121.34 93.97 156.70

TABLE-US-00050 TABLE 14.7 90% confidence intervals for log transformed pharmacokinetic characteristics of N-desmethyl-asenapine Point Lower limit Upper limit estimate of 90% CI of 90% CI Comparison (%) (%) (%) AUC.sub.(0-48) Period 2/Reference 41.47 34.95 49.21 Period 3/Reference 33.13 27.80 39.47 Period 2/Period 3 125.18 105.05 149.17 C.sub.max Period 2/Reference 68.34 58.52 79.80 Period 3/Reference 58.77 50.14 68.90 Period 2/Period 3 116.28 99.19 136.31
Adverse events (AE)

[0563] Tables 14.8 and 14.9 reflect the number of adverse events reported in the different categories.

[0564] Although treatment duration for the sublingual tablet (Reference) was only 12 h (i.e., 2 administrations) compared to 3.5 days TTS application (Examples 13a and 13b), common systemic side effects of asenapine treatment, such as fatigue and dizziness, were observed less frequently after TTS application and, in case of fatigue, only with mild intensity. In comparison to the sublingually administered treatment (Reference), the frequency and intensity of fatigue was notably lower after transdermal administration, and dizziness occurred with lower frequency.

[0565] Oral discomfort symptoms, such as hypoaesthesia and dry mouth, as observed following the administration of the reference treatment, were not observed under TTS application (Examples 13a and 13b).

[0566] Local tolerance at the application site was good, only mild reactions were observed occasionally (five AEs) which subsided without intervention.

[0567] The dysmenorrhea reported during period 3, which was moderate in intensity, had no relationship to the TTS of Example 13b administered.

[0568] No SAE was reported and none of the subjects had suicidal ideations.

[0569] Overall, transdermal application of asenapine was safe and well tolerated. The AEs observed after administration of either TTS (Periods 2 and 3) were mostly mild and transient, resolved without intervention, and the frequency of AEs was lower compared to the reference period 1.

TABLE-US-00051 TABLE 14.8 Adverse events (AE) and serious adverse events (SAE) reported during the study Period 1 Period 2 Period 3 (Reference) (Example 13a) (Example 13b) (n = 16) (n = 15) (n = 15) total Mild (AE) 41 26 17 84 Moderate (AE) 13 1 2 16 Severe (AE) 3 0 1 4 Serious (SAE) 0 0 0 0 total 57 27 20 104 Outcome: 57 27 20 104 Number of subjects recovered

TABLE-US-00052 TABLE 14.9 Adverse events (AE) by type of AE Period 1 Period 2 Period 3 (Reference) (Example 13a) (Example 13b) (n = 16) (n = 15) (n = 15) total Fatigue* 21 (8/11/2) 12 (11/1/0) 11 (10/1/0) 44 Dizziness 11 2 2 15 Hypoaesthesia 12 0 0 12 oral Gastrointestinal 5 1 0 6 disorders (Abdominal pain upper, constipation, diarrhoea, dry mouth) Other general 1 6 2 9 disorders and administration site conditions Musculoskeletal 1 0 0 1 and connective tissue disorders (pain in extremity) Other nervous 6 6 4 16 system disorders (akathisia, head discomfort, headache, paraesthesia, presyncope) Dysmenorrhoea 0 0 1 1 total 57 27 20 104 *Numbers in parentheses indicate incidences by intensity (milk/moderate/severe)

The Invention Relates in Particular to the Following Further Items:

[0570] 1. Transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure containing a therapeutically effective amount of asenapine, said self-adhesive layer structure comprising: [0571] A) a backing layer; [0572] B) an asenapine-containing matrix layer consisting of a matrix layer composition comprising: [0573] 1. asenapine; and [0574] 2. a polymer selected from acrylic polymers; [0575] wherein the transdermal therapeutic system has an area of release of from 5 to 100 cm.sup.2. [0576] 2. Transdermal therapeutic system according to item 1, [0577] wherein the transdermal therapeutic system contains at least 0.70 mg/cm.sup.2, preferably at least 0.80 mg/cm.sup.2, more preferably at least 0.82 mg/cm.sup.2 and most preferably at least 0.83 mg/cm.sup.2 asenapine. [0578] 3. Transdermal therapeutic system according to item 1 or 2, [0579] wherein the transdermal therapeutic system contains from 0.70 mg/cm.sup.2 to 4.0 mg/cm.sup.2, preferably from 0.80 mg/cm.sup.2 to 3.0 mg/cm.sup.2, more preferably from 0.82 mg/cm.sup.2 to 2.0 mg/cm.sup.2 and most preferably from 0.83 mg/cm.sup.2 to 1.7 mg/cm.sup.2 asenapine. [0580] 4. Transdermal therapeutic system according to any one of items 1 to 3, [0581] wherein the area weight of the matrix layer ranges from 90 to 230 g/m.sup.2, preferably from 110 to 210 g/m.sup.2, and most preferably from 120 to 170 g/m.sup.2. [0582] 5. Transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure containing asenapine, [0583] wherein the transdermal therapeutic system provides by transdermal delivery a mean release rate of 0.5 to 20 mg/day over at least 48 hours of administration. [0584] 6. Transdermal therapeutic system according to item 5, [0585] wherein the transdermal therapeutic system provides by transdermal delivery a mean release rate of 0.5 to 20 mg/day over at least 72 hours, preferably over 84 hours of administration. [0586] 7. Transdermal therapeutic system according to item 5 or 6, [0587] wherein the transdermal therapeutic system provides by transdermal delivery a mean release rate of 1.0 to 15 mg/day, preferably of 2.0 to 10 mg/day over at least 48 hours of administration, or [0588] wherein the transdermal therapeutic system provides by transdermal delivery a mean release rate of 1.0 to 15 mg/day, preferably of 2.0 to 10 mg/day over at least 72 hours of administration, or [0589] wherein the transdermal therapeutic system provides by transdermal delivery a mean release rate of 1.0 to 15 mg/day, preferably of 2.0 to 10 mg/day over 84 hours of administration. [0590] 8. Transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure containing asenapine, [0591] wherein the transdermal therapeutic system provides by transdermal delivery an AUC.sub.0-48 from 20 to 300 (ng/ml) h or from more than 300 to 450 (ng/ml) h. [0592] 9. Transdermal therapeutic system according to item 8, [0593] wherein the transdermal therapeutic system provides by transdermal delivery an AUC.sub.0-48 from 30 to 200 (ng/ml) h. [0594] 10. Transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure containing asenapine, [0595] wherein the transdermal therapeutic system provides by transdermal delivery an AUC.sub.0.72 from 30 to 400 (ng/ml) h or from more than 400 to 600 (ng/ml) h. [0596] 11. Transdermal therapeutic system according to item 10, [0597] wherein the transdermal therapeutic system provides by transdermal delivery an AUC.sub.0-72 from 50 to 300 (ng/ml) h. [0598] 12. Transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure containing asenapine, [0599] wherein the transdermal therapeutic system provides by transdermal delivery an AUC.sub.0-84 from 35 to 450 (ng/ml) h or from more than 450 to 700 (ng/ml) h. [0600] 13. Transdermal therapeutic system according to item 12, [0601] wherein the transdermal therapeutic system provides by transdermal delivery an AUC.sub.0-84 from 60 to 350 (ng/ml) h. [0602] 14. Transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure containing asenapine, [0603] wherein the transdermal therapeutic system provides by transdermal delivery a C.sub.max to C.sub.48 ratio of less than 2.0. [0604] 15. Transdermal therapeutic system according to item 14, [0605] wherein the transdermal therapeutic system provides by transdermal delivery a C.sub.max to C.sub.48 ratio of less than 1.5 and preferably of less than 1.3. [0606] 16. Transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure containing asenapine, [0607] wherein the transdermal therapeutic system provides by transdermal delivery a C.sub.max to C.sub.72 ratio of less than 3.0. [0608] 17. Transdermal therapeutic system according to item 16, [0609] wherein the transdermal therapeutic system provides by transdermal delivery a C.sub.max to C.sub.72 ratio of less than 2.5 and preferably of less than 2.0. [0610] 18. Transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure containing asenapine, [0611] wherein the transdermal therapeutic system provides by transdermal delivery a C.sub.max to C.sub.84 ratio of less than 3.5. [0612] 19. Transdermal therapeutic system according to item 18, [0613] wherein the transdermal therapeutic system provides by transdermal delivery a C.sub.max to C.sub.84 ratio of less than 3.0, preferably of less than 2.5 and more preferably of less than 2.0. [0614] 20. Transdermal therapeutic system according to any one of items 5 to 19, comprising a self-adhesive layer structure containing a therapeutically effective amount of asenapine, said self-adhesive layer structure comprising: [0615] A) a backing layer; [0616] B) an asenapine-containing matrix layer consisting of a matrix layer composition comprising: [0617] 1. asenapine; and [0618] 2. a polymer. [0619] 21. Transdermal therapeutic system according to any one of items 1 to 4 and 20, [0620] wherein the asenapine-containing matrix layer does not comprise isopropyl palmitate in an amount of 10% of the matrix layer composition, preferably does not comprise isopropyl palmitate in an amount of 5-15% of the matrix layer composition and most preferably does not comprise isopropyl palmitate. [0621] 22. Transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure containing a therapeutically effective amount of asenapine, said self-adhesive layer structure comprising: [0622] A) a backing layer; [0623] B) an asenapine-containing matrix layer consisting of a matrix layer composition comprising: [0624] 1. asenapine in the form of the free base; and [0625] 2. a polymer; [0626] wherein the area weight of the matrix layer is at least 90 g/m.sup.2, and [0627] wherein the asenapine-containing matrix layer does not comprise isopropyl palmitate. [0628] 23. Transdermal therapeutic system according to any one of items 5 to 22, [0629] wherein the transdermal therapeutic system contains at least 0.70 mg/cm.sup.2, preferably at least 0.80 mg/cm.sup.2, more preferably at least 0.82 mg/cm.sup.2 and most preferably at least 0.83 mg/cm.sup.2 asenapine. [0630] 24. Transdermal therapeutic system according to any one of items 5 to 23, wherein the transdermal therapeutic system contains from 0.70 mg/cm.sup.2 to 4.0 mg/cm.sup.2, preferably from 0.80 mg/cm.sup.2 to 3.0 mg/cm.sup.2, more preferably from 0.82 mg/cm.sup.2 to 2.0 mg/cm.sup.2 and most preferably from 0.83 mg/cm.sup.2 to 1.7 mg/cm.sup.2 asenapine. [0631] 25. Transdermal therapeutic system according to any one of items 5 to 24, wherein the area weight of the matrix layer ranges from 90 to 230 g/m.sup.2, preferably from 110 to 210 g/m.sup.2, and most preferably from 120 to 170 g/m.sup.2. [0632] 26. Transdermal therapeutic system according to any one of items 1 to 4 and 20 to 25, wherein the matrix layer composition does not comprise any of polysiloxanes and polyisobutylenes in an amount of more than 50% of the matrix layer composition. [0633] 27. Transdermal therapeutic system according to any one of items 20 to 26, wherein the polymer is selected from polysiloxanes, polyisobutylenes, styrene-isoprene-styrene block copolymers and acrylic polymers. [0634] 28. Transdermal therapeutic system according to any one of items 20 to 26, wherein the polymer is selected from acrylic polymers. [0635] 29. Transdermal therapeutic system according to any one of items 5 to 28, wherein the transdermal therapeutic system has an area of release of from 5 to 100 cm.sup.2. [0636] 30. Transdermal therapeutic system according to any one of items 1 to 4 and 20 to 29, wherein the asenapine-containing matrix layer does not comprise isopropyl myristate in an amount of 5% of the matrix layer composition, preferably does not comprise isopropyl myristate in an amount of 1-10% of the matrix layer composition and most preferably does not comprise isopropyl myristate. [0637] 31. Transdermal therapeutic system according to any one of items 1 to 4 and 20 to 30, wherein the asenapine-containing matrix layer does not comprise ethyl cellulose in an amount of 10-20% of the matrix layer composition and preferably does not comprise ethyl cellulose. [0638] 32. Transdermal therapeutic system according to any one of items 1 to 4 and 20 to 31, wherein the asenapine-containing matrix layer does not comprise hydrogen chloride. [0639] 33. Transdermal therapeutic system according to any one of items 1 to 4 and 20 to 32, wherein the asenapine-containing matrix layer does not comprise toluene. [0640] 34. Transdermal therapeutic system according to any one of items 1 to 4 and 20 to 33, wherein the asenapine-containing matrix layer is obtainable by drying a coated coating composition wherein no hydrochloric acid has been included in the coating composition. [0641] 35. Transdermal therapeutic system according to any one of items 1 to 4 and 20 to 34, wherein the asenapine-containing matrix layer is obtainable by drying a coated coating composition comprising no toluene. [0642] 36. Transdermal therapeutic system according to any one of items 1 to 4 and 20 to 35, wherein the asenapine in the matrix layer composition is included in the form of the free base. [0643] 37. Transdermal therapeutic system according to any one of items 1 to 4 and 20 to 36, wherein the matrix layer composition is obtainable by incorporating the asenapine in the form of the free base. [0644] 38. Transdermal therapeutic system according to any one of items 1 to 4 and 20 to 37, wherein at least 90 mol %, preferably at least 95 mol %, more preferably at least 98 mol % and most preferably at least 99 mol % of the asenapine in the matrix layer is present in the form of the free base. [0645] 39. Transdermal therapeutic system according to any one of items 1 to 4 and 20 to 38, wherein the asenapine in the matrix layer is completely dissolved. [0646] 40. Transdermal therapeutic system according to any one of items 1 to 4 and 20 to 39, wherein the matrix layer composition contains asenapine particles, preferably constituted of asenapine free base. [0647] 41. Transdermal therapeutic system according to any one of items 1 to 4 and 20 to 40, wherein the amount of asenapine in the matrix layer composition ranges from 2 to 20%, preferably from 3 to 15% and more preferably from 4 to 12% of the matrix layer composition. [0648] 42. Transdermal therapeutic system according to any one of items 1 to 41, wherein 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. [0649] 43. Transdermal therapeutic system according to any one of items 1 to 4 and 20 to 42, wherein the matrix layer composition is a pressure-sensitive adhesive composition. [0650] 44. Transdermal therapeutic system according to any one of items 1 to 4 and 20 to 43, wherein the polymer is selected from pressure-sensitive adhesive polymers. [0651] 45. Transdermal therapeutic system according to any one of items 1 to 4 and 20 to 44, wherein the polymer is selected from acrylic polymers comprising functional groups. [0652] 46. Transdermal therapeutic system according to item 45, wherein the functional groups are selected from hydroxyl groups, carboxylic acid groups, neutralized carboxylic acid groups and mixtures thereof. [0653] 47. Transdermal therapeutic system according to item 46, wherein the functional groups are limited to hydroxyl groups. [0654] 48. Transdermal therapeutic system according to any one of items 1 to 4 and 20 to 47, wherein the polymer is selected from acrylic polymers which do not comprise carboxylic acid groups or neutralized carboxylic acid groups or both groups. [0655] 49. Transdermal therapeutic system according to any one of items 1 to 4 and 20 to 48, wherein the polymer is selected from acrylic polymers which do not comprise acidic groups. [0656] 50. Transdermal therapeutic system according to any one of items 1 to 4 and 20 to 49, wherein the polymer is selected from acrylic polymers comprising hydroxyl groups and no carboxylic acid groups. [0657] 51. Transdermal therapeutic system according to item 50, wherein the polymer is a copolymer based on vinyl acetate, 2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and glycidyl-methacrylate. [0658] 52. Transdermal therapeutic system according to item 51, wherein the polymer is cross-linked by a cross-linking agent and preferably is cross-linked by a titanium cross-linking agent. [0659] 53. Transdermal therapeutic system according to item 51, wherein the polymer is not cross-linked by a cross-linking agent. [0660] 54. Transdermal therapeutic system according to any one of items 1 to 4 and 20 to 44, wherein the polymer is selected from acrylic polymers comprising no hydroxyl groups and no carboxylic acid groups. [0661] 55. Transdermal therapeutic system according to item 54, wherein the polymer is selected from acrylic polymers comprising no functional groups. [0662] 56. Transdermal therapeutic system according to item 55, wherein the polymer is a copolymer based on methyl acrylate, 2-ethylhexyl acrylate and t-octyl acrylamide, or a copolymer based on 2-ethylhexyl-acrylate and vinyl acetate. [0663] 57. Transdermal therapeutic system according to any one of items 1 to 4 and 20 to 56, wherein the amount of the polymer ranges from 60 to 97%, preferably from 70 to 96% and more preferably from 75 to 88% or from 91 to 96% of the matrix layer composition. [0664] 58. Transdermal therapeutic system according to any one of items 1 to 4 and 20 to 57, wherein the total polymer content in the matrix layer composition ranges from 75 to 97%, preferably from 80 to 96% and more preferably from 85 to 95% of the matrix layer composition. [0665] 59. Transdermal therapeutic system according to any one of items 1 to 58, wherein the transdermal therapeutic system has an area of release of from 5 to 100 cm.sup.2, preferably from 10 to 80 cm.sup.2, and more preferably from 10 to 20 cm.sup.2, from 25 to 35 cm.sup.2 and 55 to 65 cm.sup.2. [0666] 60. Transdermal therapeutic system according to any one of items 1 to 59, wherein the amount of asenapine contained in the transdermal therapeutic system ranges from 5 to 100 mg, preferably from 10 to 80 mg, and most preferably from 15 to 60 mg. [0667] 61. Transdermal therapeutic system according to any one of items 1 to 60, wherein the transdermal therapeutic system has an area of release of from 5 to 100 cm.sup.2, and the amount of asenapine contained in the transdermal therapeutic system ranges from 5 to 100 mg. [0668] 62. Transdermal therapeutic system according to any one of items 1 to 4 and 20 to 61, wherein the matrix layer composition comprises further excipients or additives selected from the group consisting of cross-linking agents, solubilizers, fillers, tackifiers, plasticizers, stabilizers, softeners, substances for skincare, permeation enhancers, pH regulators, and preservatives. [0669] 63. Transdermal therapeutic system according to item 62, wherein the tackifier is 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. [0670] 64. Transdermal therapeutic system according to item 62, wherein the stabilizer is selected from sodium metabisulfite, ascorbic acid and ester derivatives thereof, butylated hydroxytoluene, tocopherol and ester derivatives thereof such as tocopheryl acetate and tocopheryl linoleate, as well as a combination of tocopherol and ascorbyl palmitate, preferably from tocopherol and ester derivatives thereof and ascorbic acid and ester derivatives thereof, and is more preferably selected from ascorbyl esters of fatty acids and tocopherol, and most preferably is ascorbyl palmitate or α-tocopherol or a combination thereof. [0671] 65. Transdermal therapeutic system according to item 62, wherein the permeation enhancer is selected from diethylene glycol monoethyl ether, diisopropyl adipate, isopropyl myristate, isopropyl palmitate, lauryl lactate, dimethylpropylene urea and a mixture of propylene glycol monoesters and diesters of fatty acids. [0672] 66. Transdermal therapeutic system according to any one of items 1 to 4 and 20 to 65, wherein the matrix layer composition does not comprise a permeation enhancer selected from oleic acids, triglycerides, oleic alcohols, and mixtures thereof. [0673] 67. Transdermal therapeutic system according to any one of items 1 to 4 and 20 to 66, wherein the matrix layer composition does not comprise a permeation enhancer. [0674] 68. Transdermal therapeutic system according to any one of items 1 to 4 and 20 to 67, wherein the matrix layer composition further comprises a copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate. [0675] 69. Transdermal therapeutic system according to any one of items 1 to 68, wherein the transdermal therapeutic system provides a mean release rate of 0.5 to 20 mg/day, preferably of 1.0 to 15 mg/day, and more preferably of 2.0 to 10 mg/day over at least 24 hours of administration, preferably over at least 48 hours of administration, more preferably over at least 72 hours of administration. [0676] 70. Transdermal therapeutic system according to any one of items 1 to 69, providing a cumulative skin permeation rate of asenapine at hour 48 or at hour 72 as measured in a Franz diffusion cell with dermatomed human skin of 1 μg/(cm.sup.2 h) to 20 μg/(cm.sup.2 h), preferably of 2 μg/(cm.sup.2 h) to 15 μg/(cm.sup.2 h) and more preferably of 4 μg/(cm.sup.2 h) to 12 μg/(cm.sup.2 h). [0677] 71. Transdermal therapeutic system according to any one of items 1 to 70, providing a skin permeation rate of asenapine as measured in a Franz diffusion cell with dermatomed human skin of

[0678] 0 μg/(cm.sup.2 h) to 10 μg/(cm.sup.2 h) in the first 8 hours,

[0679] 2 μg/(cm.sup.2 h) to 20 μg/(cm.sup.2 h) from hour 8 to hour 24,

[0680] 3 μg/(cm.sup.2 h) to 20 μg/(cm.sup.2 h) from hour 24 to hour 32,

[0681] 3 μg/(cm.sup.2 h) to 20 μg/(cm.sup.2 h) from hour 32 to hour 48,

[0682] 2 μg/(cm.sup.2 h) to 15 μg/(cm.sup.2 h) from hour 48 to hour 72. [0683] 72. Transdermal therapeutic system according to any one of items 1 to 71, providing a cumulative permeated amount of asenapine as measured in a Franz diffusion cell with dermatomed human skin of 0.05 mg/cm.sup.2 to 1.0 mg/cm.sup.2, preferably of 0.1 mg/cm.sup.2 to 0.7 mg/cm.sup.2 over a time period of 48 hours. [0684] 73. Transdermal therapeutic system according to any one of items 1 to 72, providing a cumulative permeated amount of asenapine as measured in a Franz diffusion cell with dermatomed human skin of 0.1 mg/cm.sup.2 to 2.0 mg/cm.sup.2, preferably 0.2 mg/cm.sup.2 to 1.0 mg/cm.sup.2 over a time period of 72 hours. [0685] 74. Transdermal therapeutic system according to any one of items 1 to 73, further comprising a release liner. [0686] 75. Transdermal therapeutic system according to any one of items 1 to 74, further comprising an adhesive overlay or comprising no adhesive overlay, and preferably comprising no adhesive overlay. [0687] 76. Transdermal therapeutic system according to any one of items 1 to 75, wherein the backing layer is substantially asenapine-impermeable. [0688] 77. Transdermal therapeutic system according to any one of items 1 to 76, wherein the self-adhesive layer structure does not comprise an additional skin contact layer. [0689] 78. Transdermal therapeutic system according to any one of items 1 to 76, wherein the self-adhesive layer structure comprises an additional skin contact layer. [0690] 79. Transdermal therapeutic system according to item 78, wherein the self-adhesive layer structure comprises a membrane which is located between the matrix layer and the additional skin contact layer, wherein the membrane is preferably a rate controlling membrane. [0691] 80. Transdermal therapeutic system according to any one of items 1 to 79, wherein the self-adhesive layer structure comprises an additional reservoir layer which is located between the backing layer and the matrix layer, and a further rate controlling membrane which is located between the additional reservoir layer and the matrix layer. [0692] 81. Transdermal therapeutic system according to any one of items 1 to 80, wherein the transdermal therapeutic system is a matrix-type TTS. [0693] 82. Transdermal therapeutic system according to any one of items 1 to 81 for use in a method of treatment, preferably for use in a method of treating psychosis and more preferably 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. [0694] 83. Transdermal therapeutic system according to item 82 for use in a method of treating schizophrenia and/or bipolar disorder. [0695] 84. Transdermal therapeutic system according to item 82 for use in a method of treating bipolar disorder, in particular acute manic or mixed episodes of bipolar disorder. [0696] 85. Transdermal therapeutic system according to any one of items 82 to 84 for use in a method of treatment with a dosing interval of at least 24 hours or 1 day, at least 48 hours or 2 days, or at least 72 hours or 3 days. [0697] 86. Transdermal therapeutic system according to any one of items 82 to 85 for use in a method of treatment with a dosing interval of up to 168 hours or 7 days, up to 120 hours or 5 days, or up to 96 hours or 4 days. [0698] 87. Transdermal therapeutic system according to item 85 for use in a method of treatment with a dosing interval of 24 hours or 1 day. [0699] 88. Transdermal therapeutic system according to item 85 for use in a method of treatment with a dosing interval of 48 hours or 2 days. [0700] 89. Transdermal therapeutic system according to item 85 for use in a method of treatment with a dosing interval of 84 hours or 3.5 days. [0701] 90. Transdermal therapeutic system according to any one of items 82 to 89 for use in a method of treating a patient,

[0702] wherein the transdermal therapeutic system provides a reduction in at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine. [0703] 91. Transdermal therapeutic system according to item 90 for use in a method of treating a patient, wherein

[0704] the patient is a human patient suffering from fatigue, somnolence, dizziness, or any combination thereof, or

[0705] the at least one asenapine-related side effect is fatigue, somnolence, dizziness, oral hypoaesthesia, or any combination thereof, or

[0706] the incidence of the at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced by at least about 30%, at least about 40%, at least about 70% or at least about 80%, and/or the intensity of the at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced, or

[0707] the at least one asenapine-related side effect is fatigue and the incidence of fatigue relative to an equivalent dose of sublingual asenapine is reduced by at least about 30% or at least about 40% and/or the intensity of fatigue relative to an equivalent dose of sublingual asenapine is reduced, or

[0708] the at least one asenapine-related side effect is dizziness, and the incidence of dizziness relative to an equivalent dose of sublingual asenapine is reduced by at least about 30%, at least about 40%, at least about 70% or at least about 80%. [0709] 92. Transdermal therapeutic system according to any one of items 1 to 81 for use in a method of reducing, in a patient, at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine. [0710] 93. Transdermal therapeutic system according to item 92 for use in a method of reducing, in a patient, at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine, wherein

[0711] the patient is a human patient suffering from fatigue, somnolence, dizziness, or any combination thereof, or

[0712] the at least one asenapine-related side effect is fatigue, somnolence, dizziness, oral hypoaesthesia, or any combination thereof, or

[0713] the incidence of the at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced by at least about 30%, at least about 40%, at least about 70% or at least about 80%, and/or the intensity of the at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced, or

[0714] the at least one asenapine-related side effect is fatigue and the incidence of fatigue relative to an equivalent dose of sublingual asenapine is reduced by at least about 30% or at least about 40% and/or the intensity of fatigue relative to an equivalent dose of sublingual asenapine is reduced, or

[0715] the at least one asenapine-related side effect is dizziness and the incidence of dizziness relative to an equivalent dose of sublingual asenapine is reduced by at least about 30%, at least about 40%, at least about 70% or at least about 80%. [0716] 94. A method of treatment, and in particular a method of treating psychosis and more preferably 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 including applying a transdermal therapeutic system according to any one of items 1 to 81 to the skin of a patient. [0717] 95. A method of treating schizophrenia and/or bipolar disorder including applying a transdermal therapeutic system according to any one of items 1 to 81 to the skin of a patient. [0718] 96. A method of treating bipolar disorder and in particular acute manic or mixed episodes of bipolar disorder including applying a transdermal therapeutic system according to any one of items 1 to 81 to the skin of a patient. [0719] 97. A method of treatment according to any one of items 94 to 96 including applying a transdermal therapeutic system according to any one of items 1 to 81 for at least 24 hours or 1 day, at least 48 hours or 2 days, or at least 72 hours or 3 days to the skin of a patient. [0720] 98. A method of treatment according to any one of items 94 to 96 including applying a transdermal therapeutic system according to any one of items 1 to 81 for up to 168 hours or 7 days, up to 120 hours or 5 days, or up to 96 hours or 4 days to the skin of a patient. [0721] 99. A method of treatment according to any one of items 94 to 96 including applying a transdermal therapeutic system according to any one of items 1 to 81 for 24 hours or 1 day to the skin of a patient. [0722] 100. A method of treatment according to any one of items 94 to 96 including applying a transdermal therapeutic system according to any one of items 1 to 81 for 48 hours or 2 days to the skin of a patient. [0723] 101. A method of treatment according to any one of items 94 to 96 including applying a transdermal therapeutic system according to any one of items 1 to 81 for 84 hours or 3.5 days to the skin of a patient. [0724] 102. The method of treatment according to any one of items 94 to 101 wherein the transdermal therapeutic system provides a reduction in at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine. [0725] 103. The method of treatment according to item 102, wherein the patient is a human patient suffering from fatigue, somnolence, dizziness, or any combination thereof. [0726] 104. The method of treatment according to item 102 or 103, wherein the at least one asenapine-related side effect is fatigue, somnolence, dizziness, oral hypoaesthesia, or any combination thereof. [0727] 105. The method of treatment according to any one of items 102 to 104 wherein the incidence of the at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced by at least about 30%, at least about 40%, at least about 70% or at least about 80%, and/or wherein the intensity of the at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced.

[0728] 106. The method of treatment according to item 105, wherein

[0729] the at least one asenapine-related side effect is fatigue and the incidence of fatigue relative to an equivalent dose of sublingual asenapine is reduced by at least about 30% or at least about 40% and/or the intensity of fatigue relative to an equivalent dose of sublingual asenapine is reduced, or

[0730] the at least one asenapine-related side effect is dizziness and the incidence of dizziness relative to an equivalent dose of sublingual asenapine is reduced by at least about 30%, at least about 40%, at least about 70% or at least about 80%. [0731] 107. A method of reducing, in a patient, at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine, the method comprising administering a transdermal therapeutic system according to any one of items 1 to 81. [0732] 108. The method according to item 107, [0733] wherein the patient is a human patient suffering from fatigue, somnolence, dizziness, or any combination thereof. [0734] 109. The method according to item 107 or 108, [0735] wherein the at least one asenapine-related side effect is fatigue, somnolence, dizziness, oral hypoaesthesia, or any combination thereof. [0736] 110. The method according to any one of items 107 to 109 [0737] wherein the incidence of the at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced by at least about 30%, at least about 40%, at least about 70% or at least about 80%, and/or wherein the intensity of the at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced. [0738] 111. The method according to item 110, wherein

[0739] the at least one asenapine-related side effect is fatigue and the incidence of fatigue relative to an equivalent dose of sublingual asenapine is reduced by at least about 30% or at least about 40% and/or the intensity of fatigue relative to an equivalent dose of sublingual asenapine is reduced, or

[0740] the at least one asenapine-related side effect is dizziness and the incidence of dizziness relative to an equivalent dose of sublingual asenapine is reduced by at least about 30%, at least about 40%, at least about 70% or at least about 80%. [0741] 112. A method of reducing at least one asenapine-related side effect in a patient being treated with sublingual asenapine therapy, the method comprising: [0742] a) discontinuing sublingual asenapine therapy; and [0743] b) administering a transdermal therapeutic system according to any of items 1 to 81 to the skin of the patient, wherein the transdermal therapeutic system provides a reduction in at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine. [0744] 113. The method of item 112, wherein the transdermal therapeutic system delivers an amount of asenapenaine equivalent to the amount of asenapine originally provided by the sublingual asenapine therapy. [0745] 114. Asenapine for use in a method of treating a human patient by transdermal administration of asenapine for a dosing interval of at least 48 hours or 2 days. [0746] 115. Asenapine for use in a method of treating a human patient by transdermal administration of asenapine for a dosing interval of at least 72 hours or 3 days. [0747] 116. Asenapine for use in a method of treating a human patient according to item 114 or 115 wherein the dosing interval is up to 168 hours or 7 days, up to 120 hours or 5 days, or up to 96 hours or 4 days. [0748] 117. Asenapine for use in a method of treating a human patient according to item 114 or 115, wherein the dosing interval is 48 hours or 2 days, or 72 hours or 3 days, or 84 hours or 3.5 days. [0749] 118. Asenapine for use in a method of treating a human patient according to any one of items 114 to 117, [0750] for use in a method of treating psychosis, and in particular for use in a method of treating one or more conditions selected from schizophrenia, bipolar disorder, posttraumatic stress disorder, [0751] major depressive disorder, dementia related psychosis, agitation and manic disorder, or for use in a method of treating schizophrenia and/or bipolar disorder, preferably bipolar disorder and in particular acute manic or mixed episodes of bipolar disorder. [0752] 119. Asenapine for use in a method of treating a human patient according to any one of items 114 to 118 [0753] providing by transdermal delivery a mean release rate of 0.5 to 20 mg/day, preferably 1.0 to 15 mg/day, more preferably of 2.0 to 10 mg/day over at least 48 hours or 2 days of administration, or [0754] providing by transdermal delivery a mean release rate of 0.5 to 20 mg/day, preferably 1.0 to 15 mg/day, more preferably of 2.0 to 10 mg/day over at least 72 hours or 3 days of administration, or [0755] providing by transdermal delivery a mean release rate of 0.5 to 20 mg/day, preferably 1.0 to 15 mg/day, more preferably of 2.0 to 10 mg/day over at least 84 hours or 3.5 days of administration. [0756] 120. Asenapine for use in a method of treating a human patient according to any one of items 114 to 119 [0757] providing by transdermal delivery an AUC.sub.0-48 from 20 to 300 (ng/ml) h or from more than 300 to 450 (ng/ml) h and preferably from 30 to 200 (ng/ml) h, or [0758] providing by transdermal delivery an AUC.sub.0-72 from 30 to 400 (ng/ml) h or from more than 400 to 600 (ng/ml) h and preferably from 50 to 300 (ng/ml) h, or [0759] providing by transdermal delivery an AUC.sub.0-84 from 35 to 450 (ng/ml) h or from more than 450 to 700 (ng/ml) h and preferably from 60 to 350 (ng/ml) h. [0760] 121. Asenapine for use in a method of treating a human patient according to any one of items 114 to 120 [0761] providing by transdermal delivery a C.sub.max to C.sub.48 ratio of less than 2.0, preferably of less than 1.5 and more preferably of less than 1.3, or [0762] providing by transdermal delivery a C.sub.max to C.sub.72 ratio of less than 3.0, preferably of less than 2.5 and more preferably of less than 2.0, or [0763] providing by transdermal delivery a C.sub.max to C.sub.84 ratio of less than 3.5, preferably of less than 3.0, more preferably of less than 2.5 and most preferably of less than 2.0. [0764] 122. Asenapine for use in a method of treating a human patient according to any one of items 114 to 121 [0765] wherein at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced. [0766] 123. Asenapine for use in a method of treating a human patient according to item 122, wherein

[0767] the human patient is suffering from fatigue, somnolence, dizziness, or any combination thereof, or

[0768] the at least one asenapine-related side effect is fatigue, somnolence, dizziness, oral hypoaesthesia, or any combination thereof, or

[0769] the incidence of the at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced by at least about 30%, at least about 40%, at least about 70% or at least about 80%, and/or the intensity of the at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced, or

[0770] the at least one asenapine-related side effect is fatigue and the incidence of fatigue relative to an equivalent dose of sublingual asenapine is reduced by at least about 30% or at least about 40% and/or the intensity of fatigue relative to an equivalent dose of sublingual asenapine is reduced, or

[0771] the at least one asenapine-related side effect is dizziness and the incidence of dizziness relative to an equivalent dose of sublingual asenapine is reduced by at least about 30%, at least about 40%, at least about 70% or at least about 80%. [0772] 124. Transdermal therapeutic system for the transdermal administration of asenapine for use in a method of treating a human patient for a dosing interval of at least 48 hours or 2 days. [0773] 125. Transdermal therapeutic system for the transdermal administration of asenapine for use in a method of treating a human patient for a dosing interval of at least 72 hours or 3 days. [0774] 126. Transdermal therapeutic system for use in a method of treating a human patient according to item 124 or 125 [0775] wherein the dosing interval is up to 168 hours or 7 days, up to 120 hours or 5 days, or up to 96 hours or 4 days. [0776] 127. Transdermal therapeutic system for use in a method of treating a human patient according to item 124 or 125 [0777] wherein the dosing interval is 48 hours or 2 days, or 72 hours or 3 days, or 84 hours or 3.5 days. [0778] 128. Transdermal therapeutic system for use in a method of treating a human patient according to any one of items 124 to 127, [0779] comprising a self-adhesive layer structure containing a therapeutically effective amount of asenapine. [0780] 129. Transdermal therapeutic system for use in a method of treating a human patient according to any one of items 124 to 128 [0781] for use in a method of treating psychosis, and in particular for use in a method of treating one or more conditions selected from schizophrenia, bipolar disorder, posttraumatic stress disorder, [0782] major depressive disorder, dementia related psychosis, agitation and manic disorder, or for use in a method of treating schizophrenia and/or bipolar disorder, preferably bipolar disorder and in particular acute manic or mixed episodes of bipolar disorder. [0783] 130. Transdermal therapeutic system for use in a method of treating a human patient according to any one of items 124 to 129 [0784] providing by transdermal delivery a mean release rate of 0.5 to 20 mg/day, preferably 1.0 to 15 mg/day, more preferably of 2.0 to 10 mg/day over at least 48 hours of administration, or [0785] providing by transdermal delivery a mean release rate of 0.5 to 20 mg/day, preferably 1.0 to 15 mg/day, more preferably of 2.0 to 10 mg/day over at least 72 hours of administration, or [0786] providing by transdermal delivery a mean release rate of 0.5 to 20 mg/day, preferably 1.0 to 15 mg/day, more preferably of 2.0 to 10 mg/day over at least 84 hours of administration. [0787] 131. Transdermal therapeutic system for use in a method of treating a human patient according to any one of items 124 to 130 [0788] providing by transdermal delivery an AUC.sub.0-48 from 20 to 300 (ng/ml) h or from more than 300 to 450 (ng/ml) h and preferably from 30 to 200 (ng/ml) h, or [0789] providing by transdermal delivery an AUC.sub.0-72 from 30 to 400 (ng/ml) h or from more than 400 to 600 (ng/ml) h and preferably from 50 to 300 (ng/ml) h, or [0790] providing by transdermal delivery an AUC.sub.0-84 from 35 to 450 (ng/ml) h or from more than 450 to 700 (ng/ml) h and preferably from 60 to 350 (ng/ml) h. [0791] 132. Transdermal therapeutic system for use in a method of treating a human patient according to any one of items 124 to 131 [0792] providing by transdermal delivery a C.sub.max to C.sub.48 ratio of less than 2.0, preferably of less than 1.5 and more preferably of less than 1.3, or [0793] providing by transdermal delivery a C.sub.max to C.sub.72 ratio of less than 3.0, preferably of less than 2.5 and more preferably of less than 2.0, or [0794] providing by transdermal delivery a C.sub.max to C.sub.84 ratio of less than 3.5, preferably of less than 3.0, more preferably of less than 2.5 and most preferably of less than 2.0. [0795] 133. Transdermal therapeutic system according to any one of items 124 to 132 for use in a method of treating a patient,

[0796] wherein the transdermal therapeutic system provides a reduction in at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine. [0797] 134. Transdermal therapeutic system according to item 133 for use in a method of treating a patient, wherein

[0798] the patient is a human patient suffering from fatigue, somnolence, dizziness, or any combination thereof, or

[0799] the at least one asenapine-related side effect is fatigue, somnolence, dizziness, oral hypoaesthesia, or any combination thereof, or

[0800] the incidence of the at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced by at least about 30%, at least about 40%, at least about 70% or at least about 80%, and/or the intensity of the at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced, or

[0801] the at least one asenapine-related side effect is fatigue and the incidence of fatigue relative to an equivalent dose of sublingual asenapine is reduced by at least about 30% or at least about 40% and/or the intensity of fatigue relative to an equivalent dose of sublingual asenapine is reduced, or

[0802] the at least one asenapine-related side effect is dizziness and the incidence of dizziness relative to an equivalent dose of sublingual asenapine is reduced by at least about 30%, at least about 40%, at least about 70% or at least about 80%. [0803] 135. A method of treating a human patient by transdermal administration of asenapine for a dosing interval of at least 48 hours or 2 days. [0804] 136. A method of treating a human patient by transdermal administration of asenapine for a dosing interval of at least 72 hours or 3 days. [0805] 137. The method of treating a human patient by transdermal administration of asenapine according to item 135 or 136, wherein the dosing interval is up to 168 hours or 7 days, up to 120 hours or 5 days, or up to 96 hours or 4 days. [0806] 138. The method of treating a human patient by transdermal administration of asenapine according to item 135 or 136, [0807] wherein the dosing interval is 48 hours or 2 days, or 72 hours or 3 days, or 84 hours or 3.5 days. [0808] 139. The method of treating a human patient by transdermal administration of asenapine according to any one of items 135 to 138, [0809] including applying a transdermal therapeutic system for the transdermal administration of asenapine for at least 48 hours or 2 days, for at least 72 hours or 3 days, for 48 hours or 2 days, for 72 hours or 3 days, or for 84 hours or 3.5 days to the skin of a patient. [0810] 140. The method of treating a human patient by transdermal administration of asenapine according to any one of items 135 to 139, [0811] wherein the transdermal therapeutic system for the transdermal administration of asenapine comprises a self-adhesive layer structure containing a therapeutically effective amount of asenapine. [0812] 141. The method of treating psychosis, and in particular the 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, or the method of treating schizophrenia and/or bipolar disorder according to any one of items 135 to 140. [0813] 142. The method of treating schizophrenia and/or bipolar disorder, preferably bipolar disorder and in particular acute manic or mixed episodes of bipolar disorder according to any one of items 135 to 141. [0814] 143. The method of treating a human patient according to any one of items 135 to 142 [0815] providing by transdermal delivery a mean release rate of 0.5 to 20 mg/day, preferably 1.0 to 15 mg/day, more preferably of 2.0 to 10 mg/day over at least 48 hours of administration, or [0816] providing by transdermal delivery a mean release rate of 0.5 to 20 mg/day, preferably 1.0 to 15 mg/day, more preferably of 2.0 to 10 mg/day over at least 72 hours of administration, or [0817] providing by transdermal delivery a mean release rate of 0.5 to 20 mg/day, preferably 1.0 to 15 mg/day, more preferably of 2.0 to 10 mg/day over at least 84 hours of administration. [0818] 144. The method of treating a human patient according to any one of items 135 to 143 [0819] providing by transdermal delivery an AUC.sub.0-.sub.48 from 20 to 300 (ng/ml) h or from more than 300 to 450 (ng/ml) h and preferably from 30 to 200 (ng/ml) h, or [0820] providing by transdermal delivery an AUC.sub.0-72 from 30 to 400 (ng/ml) h or from more than 400 to 600 (ng/ml) h and preferably from 50 to 300 (ng/ml) h, or [0821] providing by transdermal delivery an AUC.sub.0-84 from 35 to 450 (ng/ml) h or from more than 450 to 700 (ng/ml) h and preferably from 60 to 350 (ng/ml) h. [0822] 145. The method of treating a human patient according to any one of items 135 to 144 providing by transdermal delivery a C.sub.max to C.sub.48 ratio of less than 2.0, preferably of less than 1.5 and more preferably of less than 1.3, or [0823] providing by transdermal delivery a C.sub.max to C.sub.72 ratio of less than 3.0, preferably of less than 2.5 and more preferably of less than 2.0, or [0824] providing by transdermal delivery a C.sub.max to C.sub.84 ratio of less than 3.5, preferably of less than 3.0, more preferably of less than 2.5 and most preferably of less than 2.0. [0825] 146. The method of treating a human patient according to any one of items 135 to 145 wherein the transdermal therapeutic system provides a reduction in at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine. [0826] 147. The method of treating a human patient according to item 146, wherein the human patient is suffering from fatigue, somnolence, dizziness, or any combination thereof. [0827] 148. The method of treating a human patient according to item 146 or 147, wherein the at least one asenapine-related side effect is fatigue, somnolence, dizziness, oral hypoaesthesia, or any combination thereof. [0828] 149. The method of treating a human patient according to any one of items 146 to 148 wherein the incidence of the at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced by at least about 30%, at least about 40%, at least about 70% or at least about 80%, and/or wherein the intensity of the at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced. [0829] 150. The method of treating a human patient according to item 149, wherein

[0830] the at least one asenapine-related side effect is fatigue and the incidence of fatigue relative to an equivalent dose of sublingual asenapine is reduced by at least about 30% or at least about 40% and/or the intensity of fatigue relative to an equivalent dose of sublingual asenapine is reduced, or [0831] the at least one asenapine-related side effect is dizziness and the incidence of dizziness relative to an equivalent dose of sublingual asenapine is reduced by at least about 30%, at least about 40%, at least about 70% or at least about 80%. [0832] 151. Transdermal therapeutic system for the transdermal administration of asenapine for use in a method of treating a human patient, wherein

[0833] the transdermal therapeutic system provides a reduction in at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine, and wherein

[0834] the human patient is suffering from fatigue, somnolence, dizziness, or any combination thereof, and/or the at least one asenapine-related side effect is fatigue, somnolence, dizziness, oral hypoaesthesia, or any combination thereof. [0835] 152. Transdermal therapeutic system according to item 151 for use in a method of treating a human patient, wherein

[0836] the incidence of the at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced by at least about 30%, at least about 40%, at least about 70% or at least about 80%, and/or the intensity of the at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced, or

[0837] the at least one asenapine-related side effect is fatigue and the incidence of fatigue relative to an equivalent dose of sublingual asenapine is reduced by at least about 30% or at least about 40% and/or the intensity of fatigue relative to an equivalent dose of sublingual asenapine is reduced, or

[0838] the at least one asenapine-related side effect is dizziness and the incidence of dizziness relative to an equivalent dose of sublingual asenapine is reduced by at least about 30%, at least about 40%, at least about 70% or at least about 80%. [0839] 153. A method of treating a human patient by transdermal administration of asenapine wherein at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced, and wherein

[0840] the human patient is suffering from fatigue, somnolence, dizziness, or any combination thereof, and/or the at least one asenapine-related side effect is fatigue, somnolence, dizziness, oral hypoaesthesia, or any combination thereof. [0841] 154. The method of treating a human patient according to item 153, wherein

[0842] the incidence of the at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced by at least about 30%, at least about 40%, at least about 70% or at least about 80%, and/or the intensity of the at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced, or

[0843] the at least one asenapine-related side effect is fatigue and the incidence of fatigue relative to an equivalent dose of sublingual asenapine is reduced by at least about 30% or at least about 40% and/or the intensity of fatigue relative to an equivalent dose of sublingual asenapine is reduced, or

[0844] the at least one asenapine-related side effect is dizziness and the incidence of dizziness relative to an equivalent dose of sublingual asenapine is reduced by at least about 30%, at least about 40%, at least about 70% or at least about 80%. [0845] 155. A method of reducing, in a human patient, at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine, the method comprising transdermal administration of asenapine, wherein

[0846] the human patient is suffering from fatigue, somnolence, dizziness, or any combination thereof, and/or the at least one asenapine-related side effect is fatigue, somnolence, dizziness, oral hypoaesthesia, or any combination thereof. [0847] 156. The method of treating a human patient according to item 155, wherein

[0848] the incidence of the at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced by at least about 30%, at least about 40%, at least about 70% or at least about 80%, and/or the intensity of the at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced, or

[0849] the at least one asenapine-related side effect is fatigue and the incidence of fatigue relative to an equivalent dose of sublingual asenapine is reduced by at least about 30% or at least about 40% and/or the intensity of fatigue relative to an equivalent dose of sublingual asenapine is reduced, or

[0850] the at least one asenapine-related side effect is dizziness and the incidence of dizziness relative to an equivalent dose of sublingual asenapine is reduced by at least about 30%, at least about 40%, at least about 70% or at least about 80%. [0851] 157. A method of reducing at least one asenapine-related side effect in a patient being treated with sublingual asenapine therapy, the method comprising:

[0852] a) discontinuing sublingual asenapine therapy; and

[0853] b) transdermal administration of asenapine, [0854] wherein the patient is suffering from fatigue, somnolence, dizziness, or any combination thereof, and/or the at least one asenapine-related side effect is fatigue, somnolence, dizziness, oral hypoaesthesia, or any combination thereof. [0855] 158. The method of item 157, wherein the transdermal therapeutic system delivers an amount of asenapenaine equivalent to the amount of asenapine originally provided by the sublingual asenapine therapy. [0856] 159. Process of manufacture of a matrix layer for use in a transdermal therapeutic system according to any one of items 1 to 4 and 20 to 89 and 124 to 134 comprising the steps of: [0857] 1) combining at least the components asenapine and polymer, in a solvent to obtain a coating composition; [0858] 2) coating the coating composition onto the backing layer or release liner or any intermediate liner; and [0859] 3) drying the coated coating composition to form the matrix layer. [0860] 160. Process of manufacture of a matrix layer according to item 159, wherein in step 1 the asenapine is dissolved to obtain a coating composition. [0861] 161. The process according to item 159 or 160, [0862] wherein preferably 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, n-heptane, petroleum ether, toluene, and mixtures thereof, and more preferably is selected from ethanol and ethyl acetate. [0863] 162. The process according to any one of items 159 to 161, wherein the polymer is an acrylic polymer and preferably a copolymer based on vinyl acetate, 2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and glycidyl-methacrylate, which is provided as a solution and preferably as a solution in ethyl acetate, n-heptane, methanol, ethanol, or any mixtures thereof, with a solids content of from 30 to 60% by weight. [0864] 163. The process according to any one of items 159 to 162, wherein drying is performed at a temperature of from 50 to 90° C., more preferably from 60 to 80° C. [0865] 164. Transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure comprising: [0866] A) a backing layer; [0867] B) an asenapine-containing matrix layer consisting of a matrix layer composition comprising: [0868] 1. asenapine included in the form of the free base; [0869] 2. a copolymer based on vinyl acetate, 2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and glycidyl-methacrylate; and [0870] 3. a stabilizer. [0871] 165. Transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure comprising: [0872] A) a backing layer; [0873] B) an asenapine-containing matrix layer consisting of a matrix layer composition comprising: [0874] 1. asenapine included in the form of the free base in an amount of 3% to 9% of the matrix layer composition; [0875] 2. a copolymer based on vinyl acetate, 2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and glycidyl-methacrylate in an amount of from 90 to 96.5% of the matrix layer composition; and [0876] 3. a stabilizer in an amount of from 0.1% to 2% of the matrix layer composition; [0877] wherein the area weight of the matrix layer ranges from 120 to 170 g/m.sup.2. [0878] 166. Transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure comprising: [0879] A) a backing layer; [0880] B) an asenapine-containing matrix layer consisting of a matrix layer composition comprising: [0881] 1. asenapine included in the form of the free base; [0882] 2. a copolymer based on vinyl acetate, 2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and glycidyl-methacrylate; [0883] 3. a stabilizer; and [0884] 4. a polyvinyl pyrrolidone. [0885] 167. Transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure comprising: [0886] A) a backing layer; [0887] B) an asenapine-containing matrix layer consisting of a matrix layer composition comprising: [0888] 1. asenapine included in the form of the free base in an amount of 3% to 9% of the matrix layer composition; [0889] 2. a copolymer based on vinyl acetate, 2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and glycidyl-methacrylate in an amount of from 80 to 90% of the matrix layer composition; [0890] 3. a stabilizer in an amount of from 0.1% to 2% of the matrix layer composition; and [0891] 4. a polyvinyl pyrrolidone in an amount of from 5 to 15% of the matrix layer composition. [0892] wherein the area weight of the matrix layer ranges from 120 to 170 g/m.sup.2. [0893] 168. Transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure comprising: [0894] A) a backing layer; [0895] B) an asenapine-containing matrix layer consisting of a matrix layer composition comprising: [0896] 1. asenapine included in the form of the free base in an amount of 7% to 13% of the matrix layer composition; [0897] 2. a copolymer based on vinyl acetate, 2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and glycidyl-methacrylate in an amount of from 75 to 85% of the matrix layer composition; [0898] 3. a stabilizer in an amount of from 0.1% to 2% of the matrix layer composition; and [0899] 4. a polyvinyl pyrrolidone in an amount of from 5 to 15% of the matrix layer composition. [0900] wherein the area weight of the matrix layer ranges from 120 to 170 g/m.sup.2. [0901] 169. Transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure comprising: [0902] A) a backing layer; [0903] B) an asenapine-containing matrix layer consisting of a matrix layer composition comprising: [0904] 1. asenapine included in the form of the free base in an amount of from more than 13% to 20% of the matrix layer composition; [0905] 2. a copolymer based on vinyl acetate, 2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and glycidyl-methacrylate in an amount of from 65 to 82% of the matrix layer composition; [0906] 3. a stabilizer in an amount of from 0.001% to 2% of the matrix layer composition; and [0907] 4. a polyvinyl pyrrolidone in an amount of from 5 to 15% of the matrix layer composition. [0908] wherein the area weight of the matrix layer ranges from 120 to 230 g/m.sup.2. [0909] 170. Transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure comprising: [0910] A) a backing layer; [0911] B) an asenapine-containing matrix layer consisting of a matrix layer composition comprising: [0912] 1. asenapine included in the form of the free base in an amount of 7% to 20% of the matrix layer composition; [0913] 2. a copolymer based on vinyl acetate, 2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and glycidyl-methacrylate in an amount of from 75 to 85% of the matrix layer composition; [0914] 3. a stabilizer in an amount of from 0.001% to 2% of the matrix layer composition; and [0915] 4. a polyvinyl pyrrolidone in an amount of from 5 to 15% of the matrix layer composition. [0916] wherein the area weight of the matrix layer ranges from more than 170 to 230 g/m.sup.2.

The Invention Relates in Particular to the Following Further Embodiments:

[0917] 1. Transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure containing a therapeutically effective amount of asenapine, said self-adhesive layer structure comprising: [0918] a) a backing layer; [0919] b) an asenapine-containing matrix layer consisting of a matrix layer composition comprising: [0920] i) asenapine; and [0921] ii) at least one acrylic polymer; [0922] wherein the transdermal therapeutic system has an area of release of from 5 to 100 cm.sup.2. [0923] 2. Transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure containing asenapine, [0924] wherein the transdermal therapeutic system provides by transdermal delivery a mean release rate of 0.5 to 20 mg/day over at least 48 hours of administration. [0925] 3. Transdermal therapeutic system according to embodiment 2, [0926] wherein the transdermal therapeutic system provides by transdermal delivery a mean release rate of 0.5 to 20 mg/day over at least 72 hours, or over 84 hours of administration, and/or [0927] wherein the transdermal therapeutic system provides by transdermal delivery a mean release rate of 1.0 to 15 mg/day, or of 2.0 to 10 mg/day over at least 48 hours of administration. [0928] 4. Transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure containing asenapine, [0929] wherein the transdermal therapeutic system provides by transdermal delivery one or more pharmacokinetic parameter(s) selected from the group consisting of [0930] an asenapine AUC.sub.0-48 from 20 to 300 (ng/ml) h or from more than 300 to 450 (ng/ml) h, [0931] an asenapine AUC.sub.0-72 from 30 to 400 (ng/ml) h or from more than 400 to 600 (ng/ml) h, [0932] an asenapine AUC.sub.0-84 from 35 to 450 (ng/ml) h or from more than 450 to 700 (ng/ml) h, [0933] an asenapine C.sub.max to C.sub.48 ratio of less than 2.0, [0934] an asenapine C.sub.max to C.sub.72 ratio of less than 3.0, [0935] an asenapine C.sub.max to C.sub.84 ratio of less than 3.5, and [0936] an asenapine C.sub.max value of from 0.5 to 10 ng/ml. [0937] 5. Transdermal therapeutic system according to any one of embodiments 2 to 4, comprising a self-adhesive layer structure containing a therapeutically effective amount of asenapine, said self-adhesive layer structure comprising: [0938] a) a backing layer; [0939] b) an asenapine-containing matrix layer consisting of a matrix layer composition comprising: [0940] i) asenapine; and [0941] ii) a polymer. [0942] 6. Transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure containing a therapeutically effective amount of asenapine, said self-adhesive layer structure comprising: [0943] a) a backing layer; [0944] b) an asenapine-containing matrix layer consisting of a matrix layer composition comprising: [0945] i) asenapine free base; and [0946] ii) a polymer; [0947] wherein the asenapine-containing matrix layer has an area weight that is at least 90 g/m.sup.2, and [0948] wherein the asenapine-containing matrix layer does not comprise isopropyl palmitate. [0949] 7. Transdermal therapeutic system according to any one of embodiments 1 to 6, [0950] wherein the transdermal therapeutic system contains at least 0.70 mg/cm.sup.2, at least 0.80 mg/cm.sup.2, at least 0.82 mg/cm.sup.2 or at least 0.83 mg/cm.sup.2 asenapine, and/or [0951] wherein the transdermal therapeutic system contains from 0.70 mg/cm.sup.2 to 4.0 mg/cm.sup.2, from 0.80 mg/cm.sup.2 to 3.0 mg/cm.sup.2, from 0.82 mg/cm.sup.2 to 2.0 mg/cm.sup.2 or from 0.83 mg/cm.sup.2 to 1.7 mg/cm.sup.2 asenapine, and/or [0952] wherein the asenapine-containing matrix layer has an area weight that ranges from 90 to 230 g/m.sup.2, from 110 to 210 g/m.sup.2, or from 120 to 170 g/m.sup.2. [0953] 8. Transdermal therapeutic system according to any one of embodiments 1 and 5 to 7, [0954] wherein the asenapine-containing matrix layer composition does not comprise any of polysiloxanes and polyisobutylenes in an amount of more than 50% of the asenapine-containing matrix layer composition. [0955] 9. Transdermal therapeutic system according to any one of embodiments 1 and 5 to 8, [0956] wherein the asenapine-containing matrix layer does not comprise isopropyl myristate in an amount of 5% of the asenapine-containing matrix layer composition, does not comprise isopropyl myristate in an amount of 1-10% of the asenapine-containing matrix layer composition or does not comprise isopropyl myristate, and/or [0957] wherein the asenapine-containing matrix layer does not comprise ethyl cellulose in an amount of 10-20% of the asenapine-containing matrix layer composition or does not comprise ethyl cellulose, or [0958] wherein the asenapine-containing matrix layer does not comprise hydrogen chloride. [0959] 10. Transdermal therapeutic system according to any one of embodiments 1 and 5 to 9, [0960] wherein the asenapine in the asenapine-containing matrix layer composition is included in the form of the free base, or [0961] wherein the asenapine-containing matrix layer composition is obtainable by incorporating asenapine free base, and/or [0962] wherein at least 90 mol %, preferably at least 95 mol %, more preferably at least 98 mol % and most preferably at least 99 mol % of the asenapine in the asenapine-containing matrix layer is present in the form of the free base, and/or [0963] wherein the amount of asenapine in the asenapine-containing matrix layer composition ranges from 2 to 20%, from 3 to 15% or from 4 to 12% of the asenapine-containing matrix layer composition.

[0964] 11. Transdermal therapeutic system according to any one of embodiments 1 to 3, [0965] wherein the acrylic polymer is selected from a copolymer based on vinyl acetate, 2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and glycidyl-methacrylate, a copolymer based on methyl acrylate, 2-ethylhexyl acrylate and t-octyl acrylamide, or a copolymer based on 2-ethylhexyl-acrylate and vinyl acetate. [0966] 12. Transdermal therapeutic system according to any one of embodiments 5 to 10, [0967] wherein the polymer is selected from acrylic polymers, or from a copolymer based on vinyl acetate, 2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and glycidyl-methacrylate, a copolymer based on methyl acrylate, 2-ethylhexyl acrylate and t-octyl acrylamide, or a copolymer based on 2-ethylhexyl-acrylate and vinyl acetate. [0968] 13. Transdermal therapeutic system according to any one of embodiments 1 and 5 to 12, wherein the amount of polymer ranges from 60 to 97%, from 70 to 96% from 75 to 88% or from 91 to 96% of the asenapine-containing matrix layer composition, or [0969] wherein the total polymer content in the asenapine-containing matrix layer composition ranges from 75 to 97%, from 80 to 96% or from 85 to 95% of the asenapine-containing matrix layer composition. [0970] 14. Transdermal therapeutic system according to any one of embodiments 1 and 5 to 13, [0971] wherein the asenapine-containing matrix layer composition comprises further excipients or additives selected from the group consisting of cross-linking agents, solubilizers, fillers, tackifiers, plasticizers, stabilizers, softeners, substances for skincare, permeation enhancers, pH regulators, and preservatives. [0972] 15. Transdermal therapeutic system according to embodiment 14, [0973] wherein the tackifier is 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, [0974] wherein the stabilizer is selected from sodium metabisulfite, ascorbic acid and ester derivatives thereof, butylated hydroxytoluene, tocopherol and ester derivatives thereof such as tocopheryl acetate and tocopheryl linoleate, as well as a combination of tocopherol and ascorbyl palmitate, preferably from tocopherol and ester derivatives thereof and ascorbic acid and ester derivatives thereof, and is more preferably selected from ascorbyl esters of fatty acids and tocopherol, and most preferably is ascorbyl palmitate or α-tocopherol or a combination thereof, or [0975] wherein the permeation enhancer is selected from diethylene glycol monoethyl ether, diisopropyl adipate, isopropyl myristate, isopropyl palmitate, lauryl lactate, dimethylpropylene urea and a mixture of propylene glycol monoesters and diesters of fatty acids.

[0976] 16. Transdermal therapeutic system according to any one of embodiments 1 to 15, providing a skin permeation rate of asenapine as measured in a Franz diffusion cell with dermatomed human skin of

[0977] 0 μg/(cm.sup.2 h) to 10 μg/(cm.sup.2 h) in the first 8 hours,

[0978] 2 μg/(cm.sup.2 h) to 20 μg/(cm.sup.2 h) from hour 8 to hour 24,

[0979] 3 μg/(cm.sup.2 h) to 20 μg/(cm.sup.2 h) from hour 24 to hour 32,

[0980] 3 μg/(cm.sup.2 h) to 20 μg/(cm.sup.2 h) from hour 32 to hour 48,

[0981] 2 μg/(cm.sup.2 h) to 15 ∥g/(cm.sup.2 h) from hour 48 to hour 72, or [0982] providing a cumulative permeated amount of asenapine as measured in a Franz diffusion cell with dermatomed human skin of 0.05 mg/cm.sup.2 to 1.0 mg/cm.sup.2, or of 0.1 mg/cm.sup.2 to 0.7 mg/cm.sup.2 over a time period of 48 hours, or [0983] providing a cumulative permeated amount of asenapine as measured in a Franz diffusion cell with dermatomed human skin of 0.1 mg/cm.sup.2 to 2.0 mg/cm.sup.2, or of 0.2 mg/cm.sup.2 to 1.0 mg/cm.sup.2 over a time period of 72 hours. [0984] 17. Transdermal therapeutic system according to any one of embodiments 1 to 16 for use in a method of treatment, for use in a method of treating psychosis, 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, for use in a method of treating schizophrenia and/or bipolar disorder or for use in a method of treating bipolar disorder, in particular acute manic or mixed episodes of bipolar disorder. [0985] 18. Transdermal therapeutic system according to embodiment 17 for use in a method of treating a patient,

[0986] wherein the transdermal therapeutic system provides a reduction in at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine. [0987] 19. Transdermal therapeutic system according to embodiment 18 for use in a method of treating a patient, wherein

[0988] the patient is a human patient suffering from fatigue, somnolence, dizziness, or any combination thereof, or

[0989] the at least one asenapine-related side effect is fatigue, somnolence, dizziness, oral hypoaesthesia, or any combination thereof, or

[0990] the incidence of the at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced by at least about 30%, at least about 40%, at least about 70% or at least about 80%, and/or the intensity of the at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced, or

[0991] the at least one asenapine-related side effect is fatigue and the incidence of fatigue relative to an equivalent dose of sublingual asenapine is reduced by at least about 30% or at least about 40% and/or the intensity of fatigue relative to an equivalent dose of sublingual asenapine is reduced, or

[0992] the at least one asenapine-related side effect is dizziness, and the incidence of dizziness relative to an equivalent dose of sublingual asenapine is reduced by at least about 30%, at least about 40%, at least about 70% or at least about 80%. [0993] 20. Transdermal therapeutic system according to embodiment 17 [0994] for use in a method of reducing, in a patient, at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine. [0995] 21. Transdermal therapeutic system according to embodiment 20 for use in a method of reducing, in a patient, at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine, wherein

[0996] the patient is a human patient suffering from fatigue, somnolence, dizziness, or any combination thereof, or

[0997] the at least one asenapine-related side effect is fatigue, somnolence, dizziness, oral hypoaesthesia, or any combination thereof, or

[0998] the incidence of the at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced by at least about 30%, at least about 40%, at least about 70% or at least about 80%, and/or the intensity of the at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced, or

[0999] the at least one asenapine-related side effect is fatigue and the incidence of fatigue relative to an equivalent dose of sublingual asenapine is reduced by at least about 30% or at least about 40% and/or the intensity of fatigue relative to an equivalent dose of sublingual asenapine is reduced, or

[1000] the at least one asenapine-related side effect is dizziness and the incidence of dizziness relative to an equivalent dose of sublingual asenapine is reduced by at least about 30%, at least about 40%, at least about 70% or at least about 80%. [1001] 22. A method of treatment, a method of treating psychosis, 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, a method of treating schizophrenia and/or bipolar disorder, or a method of treating bipolar disorder and in particular acute manic or mixed episodes of bipolar disorder, including applying a transdermal therapeutic system according to any one of embodiments 1 to 16 to the skin of a patient. [1002] 23. The method of treatment according to embodiment 22 [1003] wherein the transdermal therapeutic system provides a reduction in at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine. [1004] 24. The method of treatment according to embodiment 23, [1005] wherein the patient is a human patient suffering from fatigue, somnolence, dizziness, or any combination thereof. [1006] 25. The method of treatment according to embodiment 23, [1007] wherein the at least one asenapine-related side effect is fatigue, somnolence, dizziness, oral hypoaesthesia, or any combination thereof. [1008] 26. The method of treatment according to embodiment 23 [1009] wherein the incidence of the at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced by at least about 30%, at least about 40%, at least about 70% or at least about 80%, and/or wherein the intensity of the at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced. [1010] 27. The method of treatment according to embodiment 26, wherein

[1011] the at least one asenapine-related side effect is fatigue and the incidence of fatigue relative to an equivalent dose of sublingual asenapine is reduced by at least about 30% or at least about 40% and/or the intensity of fatigue relative to an equivalent dose of sublingual asenapine is reduced, or

[1012] the at least one asenapine-related side effect is dizziness and the incidence of dizziness relative to an equivalent dose of sublingual asenapine is reduced by at least about 30%, at least about 40%, at least about 70% or at least about 80%. [1013] 28. A method of reducing, in a patient, at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine, the method comprising administering a transdermal therapeutic system according to any one of embodiments 1 to 16. [1014] 29. The method according to embodiment 28, [1015] wherein the patient is a human patient suffering from fatigue, somnolence, dizziness, or any combination thereof. [1016] 30. The method according to embodiment 28 or 29, [1017] wherein the at least one asenapine-related side effect is fatigue, somnolence, dizziness, oral hypoaesthesia, or any combination thereof. [1018] 31. The method according to any one of embodiments 28 to 30 [1019] wherein the incidence of the at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced by at least about 30%, at least about 40%, at least about 70% or at least about 80%, and/or wherein the intensity of the at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced. [1020] 32. The method according to embodiment 31, wherein

[1021] the at least one asenapine-related side effect is fatigue and the incidence of fatigue relative to an equivalent dose of sublingual asenapine is reduced by at least about 30% or at least about 40% and/or the intensity of fatigue relative to an equivalent dose of sublingual asenapine is reduced, or

[1022] the at least one asenapine-related side effect is dizziness and the incidence of dizziness relative to an equivalent dose of sublingual asenapine is reduced by at least about 30%, at least about 40%, at least about 70% or at least about 80%. [1023] 33. A method of reducing at least one asenapine-related side effect in a patient being treated with sublingual asenapine therapy, the method comprising: [1024] a) discontinuing sublingual asenapine therapy; and [1025] b) administering a transdermal therapeutic system according to any of embodiments 1 to 16 to the skin of the patient, wherein the transdermal therapeutic system provides a reduction in at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine. [1026] 34. The method of embodiment 33, wherein the transdermal therapeutic system delivers an amount of asenapenaine equivalent to the amount of asenapine originally provided by the sublingual asenapine therapy. [1027] 35. Asenapine for use in a method of treating a human patient by transdermal administration of asenapine for a dosing interval of at least 48 hours or 2 days. [1028] 36. Asenapine for use in a method of treating a human patient according to embodiment 35, wherein the dosing interval is at least 72 hours or 3 days, up to 168 hours or 7 days, up to 120 hours or 5 days, or up to 96 hours or 4 days, or [1029] wherein the dosing interval is 48 hours or 2 days, or 72 hours or 3 days, or 84 hours or 3.5 days, and/or [1030] providing by transdermal delivery a mean release rate of 0.5 to 20 mg/day, 1.0 to 15 mg/day, or of 2.0 to 10 mg/day over at least 48 hours or 2 days of administration, or [1031] providing by transdermal delivery a mean release rate of 0.5 to 20 mg/day, 1.0 to 15 mg/day, or of 2.0 to 10 mg/day over at least 72 hours or 3 days of administration, or [1032] providing by transdermal delivery a mean release rate of 0.5 to 20 mg/day, 1.0 to 15 mg/day, or of 2.0 to 10 mg/day over at least 84 hours or 3.5 days of administration, or [1033] providing by transdermal delivery an AUC.sub.0-48 from 20 to 300 (ng/ml) h, from more than 300 to 450 (ng/ml) h or from 30 to 200 (ng/ml) h, or [1034] providing by transdermal delivery an AUC.sub.0-72 from 30 to 400 (ng/ml) h, from more than 400 to 600 (ng/ml) h or from 50 to 300 (ng/ml) h, or [1035] providing by transdermal delivery an AUC.sub.0-84 from 35 to 450 (ng/ml) h, from more than 450 to 700 (ng/ml) h or from 60 to 350 (ng/ml) h, or [1036] providing by transdermal delivery a C.sub.max to C.sub.48 ratio of less than 2.0, less than 1.5 or less than 1.3, or [1037] providing by transdermal delivery a C.sub.max to C.sub.72 ratio of less than 3.0, less than 2.5 or less than 2.0, or [1038] providing by transdermal delivery a C.sub.max to C.sub.84 ratio of less than 3.5, less than 3.0, less than 2.5 or less than 2.0, or [1039] providing by transdermal delivery a C.sub.max value of from 0.5 to 10 ng/ml or from 1 to 8 ng/ml. [1040] 37. Asenapine for use in a method of treating a human patient according to embodiment 35 or 36 [1041] wherein at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced. [1042] 38. Asenapine for use in a method of treating a human patient according to embodiment 37, wherein

[1043] the human patient is suffering from fatigue, somnolence, dizziness, or any combination thereof, or

[1044] the at least one asenapine-related side effect is fatigue, somnolence, dizziness, oral hypoaesthesia, or any combination thereof, or

[1045] the incidence of the at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced by at least about 30%, at least about 40%, at least about 70% or at least about 80%, and/or the intensity of the at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced, or

[1046] the at least one asenapine-related side effect is fatigue and the incidence of fatigue relative to an equivalent dose of sublingual asenapine is reduced by at least about 30% or at least about 40% and/or the intensity of fatigue relative to an equivalent dose of sublingual asenapine is reduced, or

[1047] the at least one asenapine-related side effect is dizziness and the incidence of dizziness relative to an equivalent dose of sublingual asenapine is reduced by at least about 30%, at least about 40%, at least about 70% or at least about 80%. [1048] 39. Transdermal therapeutic system for the transdermal administration of asenapine for use in a method of treating a human patient for a dosing interval of at least 48 hours or 2 days. [1049] 40. Transdermal therapeutic system for use in a method of treating a human patient according to embodiment 39, [1050] for a dosing interval of at least 72 hours or 3 days, up to 168 hours or 7 days, up to 120 hours or 5 days, or up to 96 hours or 4 days, or [1051] wherein the dosing interval is 48 hours or 2 days, or 72 hours or 3 days, or 84 hours or 3.5 days, and/or [1052] providing by transdermal delivery a mean release rate of 0.5 to 20 mg/day, 1.0 to 15 mg/day, or of 2.0 to 10 mg/day over at least 48 hours of administration, or [1053] providing by transdermal delivery a mean release rate of 0.5 to 20 mg/day, 1.0 to 15 mg/day, or of 2.0 to 10 mg/day over at least 72 hours of administration, or [1054] providing by transdermal delivery a mean release rate of 0.5 to 20 mg/day, 1.0 to 15 mg/day, or of 2.0 to 10 mg/day over at least 84 hours of administration, or [1055] providing by transdermal delivery an AUC.sub.0-48 from 20 to 300 (ng/ml) h, from more than 300 to 450 (ng/ml) h or from 30 to 200 (ng/ml) h, or [1056] providing by transdermal delivery an AUC.sub.0-72 from 30 to 400 (ng/ml) h, from more than 400 to 600 (ng/ml) h or from 50 to 300 (ng/ml) h, or [1057] providing by transdermal delivery an AUC.sub.0-84 from 35 to 450 (ng/ml) h, from more than 450 to 700 (ng/ml) h or from 60 to 350 (ng/ml) h, or [1058] providing by transdermal delivery a C.sub.max to C.sub.48 ratio of less than 2.0, less than 1.5 or less than 1.3, or [1059] providing by transdermal delivery a C.sub.max to C.sub.72 ratio of less than 3.0, less than 2.5 or less than 2.0, or [1060] providing by transdermal delivery a C.sub.max to C.sub.84 ratio of less than 3.5, less than 3.0, less than 2.5 or less than 2.0, or [1061] providing by transdermal delivery a C.sub.max value of from 0.5 to 10 ng/ml or from 1 to 8 ng/ml. [1062] 41. Transdermal therapeutic system according to embodiment 39 or 40 for use in a method of treating a patient,

[1063] wherein the transdermal therapeutic system provides a reduction in at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine. [1064] 42. Transdermal therapeutic system according to embodiment 41 for use in a method of treating a patient, wherein

[1065] the patient is a human patient suffering from fatigue, somnolence, dizziness, or any combination thereof, or

[1066] the at least one asenapine-related side effect is fatigue, somnolence, dizziness, oral hypoaesthesia, or any combination thereof, or

[1067] the incidence of the at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced by at least about 30%, at least about 40%, at least about 70% or at least about 80%, and/or the intensity of the at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced, or

[1068] the at least one asenapine-related side effect is fatigue and the incidence of fatigue relative to an equivalent dose of sublingual asenapine is reduced by at least about 30% or at least about 40% and/or the intensity of fatigue relative to an equivalent dose of sublingual asenapine is reduced, or

[1069] the at least one asenapine-related side effect is dizziness and the incidence of dizziness relative to an equivalent dose of sublingual asenapine is reduced by at least about 30%, at least about 40%, at least about 70% or at least about 80%. [1070] 43. A method of treating a human patient by transdermal administration of asenapine for a dosing interval of at least 48 hours or 2 days. [1071] 44. The method of treating a human patient by transdermal administration of asenapine according to embodiment 43, for a dosing interval of at least 72 hours or 3 days, up to 168 hours or 7 days, up to 120 hours or 5 days, or up to 96 hours or 4 days, or [1072] wherein the dosing interval is 48 hours or 2 days, or 72 hours or 3 days, or 84 hours or 3.5 days, and/or [1073] providing by transdermal delivery a mean release rate of 0.5 to 20 mg/day, 1.0 to 15 mg/day, or of 2.0 to 10 mg/day over at least 48 hours of administration, or [1074] providing by transdermal delivery a mean release rate of 0.5 to 20 mg/day, 1.0 to 15 mg/day, or of 2.0 to 10 mg/day over at least 72 hours of administration, or [1075] providing by transdermal delivery a mean release rate of 0.5 to 20 mg/day, 1.0 to 15 mg/day, or of 2.0 to 10 mg/day over at least 84 hours of administration, or [1076] providing by transdermal delivery an AUC.sub.0-48 from 20 to 300 (ng/ml) h, from more than 300 to 450 (ng/ml) h or from 30 to 200 (ng/ml) h, or [1077] providing by transdermal delivery an AUC.sub.0-72 from 30 to 400 (ng/ml) h, from more than 400 to 600 (ng/ml) h or from 50 to 300 (ng/ml) h, or [1078] providing by transdermal delivery an AUC.sub.0-84 from 35 to 450 (ng/ml) h, from more than 450 to 700 (ng/ml) h or from 60 to 350 (ng/ml) h, or [1079] providing by transdermal delivery a C.sub.max to C.sub.48 ratio of less than 2.0, less than 1.5 or less than 1.3, or [1080] providing by transdermal delivery a C.sub.max to C.sub.72 ratio of less than 3.0, less than 2.5 or less than 2.0, or [1081] providing by transdermal delivery a C.sub.max to C.sub.84 ratio of less than 3.5, less than 3.0, less than 2.5 or less than 2.0, or [1082] providing by transdermal delivery a C.sub.max value of from 0.5 to 10 ng/ml or from 1 to 8 ng/ml. [1083] 45. The method of treating a human patient according to embodiment 43 or 44 [1084] wherein the transdermal administration of asenapine provides a reduction in at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine. [1085] 46. The method of treating a human patient according to embodiment 45, [1086] wherein the human patient is suffering from fatigue, somnolence, dizziness, or any combination thereof. [1087] 47. The method of treating a human patient according to embodiment 45 or 46, [1088] wherein the at least one asenapine-related side effect is fatigue, somnolence, dizziness, oral hypoaesthesia, or any combination thereof. [1089] 48. The method of treating a human patient according to any one of embodiments 45 to 47 [1090] wherein the incidence of the at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced by at least about 30%, at least about 40%, at least about 70% or at least about 80%, and/or wherein the intensity of the at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced. [1091] 49. The method of treating a human patient according to embodiment 48, wherein

[1092] the at least one asenapine-related side effect is fatigue and the incidence of fatigue relative to an equivalent dose of sublingual asenapine is reduced by at least about 30% or at least about 40% and/or the intensity of fatigue relative to an equivalent dose of sublingual asenapine is reduced, or

[1093] the at least one asenapine-related side effect is dizziness and the incidence of dizziness relative to an equivalent dose of sublingual asenapine is reduced by at least about 30%, at least about 40%, at least about 70% or at least about 80%. [1094] 50. Transdermal therapeutic system for the transdermal administration of asenapine for use in a method of treating a human patient, wherein

[1095] the transdermal therapeutic system provides a reduction in at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine, and wherein

[1096] the human patient is suffering from fatigue, somnolence, dizziness, or any combination thereof, and/or the at least one asenapine-related side effect is fatigue, somnolence, dizziness, oral hypoaesthesia, or any combination thereof. [1097] 51. Transdermal therapeutic system according to embodiment 50 for use in a method of treating a human patient, wherein

[1098] the incidence of the at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced by at least about 30%, at least about 40%, at least about 70% or at least about 80%, and/or the intensity of the at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced, or

[1099] the at least one asenapine-related side effect is fatigue and the incidence of fatigue relative to an equivalent dose of sublingual asenapine is reduced by at least about 30% or at least about 40% and/or the intensity of fatigue relative to an equivalent dose of sublingual asenapine is reduced, or

[1100] the at least one asenapine-related side effect is dizziness and the incidence of dizziness relative to an equivalent dose of sublingual asenapine is reduced by at least about 30%, at least about 40%, at least about 70% or at least about 80%. [1101] 52. A method of treating a human patient by transdermal administration of asenapine wherein at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced, and wherein

[1102] the human patient is suffering from fatigue, somnolence, dizziness, or any combination thereof, and/or the at least one asenapine-related side effect is fatigue, somnolence, dizziness, oral hypoaesthesia, or any combination thereof. [1103] 53. The method of treating a human patient according to embodiment 52, wherein

[1104] the incidence of the at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced by at least about 30%, at least about 40%, at least about 70% or at least about 80%, and/or the intensity of the at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced, or

[1105] the at least one asenapine-related side effect is fatigue and the incidence of fatigue relative to an equivalent dose of sublingual asenapine is reduced by at least about 30% or at least about 40% and/or the intensity of fatigue relative to an equivalent dose of sublingual asenapine is reduced, or

[1106] the at least one asenapine-related side effect is dizziness and the incidence of dizziness relative to an equivalent dose of sublingual asenapine is reduced by at least about 30%, at least about 40%, at least about 70% or at least about 80%. [1107] 54. A method of reducing, in a human patient, at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine, the method comprising transdermal administration of asenapine, wherein

[1108] the human patient is suffering from fatigue, somnolence, dizziness, or any combination thereof, and/or the at least one asenapine-related side effect is fatigue, somnolence, dizziness, oral hypoaesthesia, or any combination thereof. [1109] 55. The method of treating a human patient according to embodiment 54, wherein

[1110] the incidence of the at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced by at least about 30%, at least about 40%, at least about 70% or at least about 80%, and/or the intensity of the at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced, or

[1111] the at least one asenapine-related side effect is fatigue and the incidence of fatigue relative to an equivalent dose of sublingual asenapine is reduced by at least about 30% or at least about 40% and/or the intensity of fatigue relative to an equivalent dose of sublingual asenapine is reduced, or

[1112] the at least one asenapine-related side effect is dizziness and the incidence of dizziness relative to an equivalent dose of sublingual asenapine is reduced by at least about 30%, at least about 40%, at least about 70% or at least about 80%. [1113] 56. A method of reducing at least one asenapine-related side effect in a patient being treated with sublingual asenapine therapy, the method comprising:

[1114] a) discontinuing sublingual asenapine therapy; and

[1115] b) transdermal administration of asenapine, [1116] wherein the patient is suffering from fatigue, somnolence, dizziness, or any combination thereof, and/or the at least one asenapine-related side effect is fatigue, somnolence, dizziness, oral hypoaesthesia, or any combination thereof. [1117] 57. Process of manufacture of a matrix layer for use in a transdermal therapeutic system according to any one of embodiments 1 and 5 to 16 comprising the steps of: [1118] 1) combining at least the components asenapine and polymer, in a solvent to obtain a coating composition; [1119] 2) coating the coating composition onto the backing layer or release liner or any intermediate liner; and [1120] 3) drying the coated coating composition to form the matrix layer. [1121] 58. Transdermal therapeutic system according to any one of embodiments 1, 5-17, and 22 wherein the matrix layer composition comprises: [1122] i) 3 to 9% by weight of asenapine free base; [1123] ii) 80 to 90% by weight of a copolymer based on vinyl acetate, 2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate, and glycidyl-methacrylate; [1124] iii) 0.1 to 2% by weight of tocopherol; and [1125] iv) 5 to 15% by weight of polyvinylpyrrolidone. [1126] 59. Transdermal therapeutic system according to any one of embodiments 1, 5-17, 22, and 58, wherein the matrix layer composition comprises: [1127] i) about 6% by weight of asenapine free base; [1128] ii) about 83.5% by weight of an acrylic polymer; [1129] iii) about 0.5% by weight of tocopherol; and [1130] iv) about 10% by weight of polyvinylpyrrolidone. [1131] 60. Transdermal therapeutic system according to any one of embodiments 1, 5-17, and 22 wherein the matrix layer composition comprises: [1132] i) 7 to 13% by weight of asenapine free base; [1133] ii) 75 to 85% by weight of a copolymer based on vinyl acetate, 2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate, and glycidyl-methacrylate; [1134] iii) 0.1 to 2% by weight of tocopherol; and [1135] iv) 5 to 15% by weight of polyvinylpyrrolidone. [1136] 61. Transdermal therapeutic system according to any one of embodiments 1, 5-17, 22, and 60, wherein the matrix layer composition comprises: [1137] i) about 10% by weight of asenapine free base; [1138] ii) 77 to 82% by weight of an acrylic polymer; [1139] iii) about 0.5% by weight of tocopherol; and [1140] iv) about 10% by weight of polyvinylpyrrolidone. [1141] 62. A method of treating schizophrenia in a patient in need thereof, the method comprising administering to the patient a transdermal therapeutic system comprising a self-adhesive layer structure, the self-adhesive layer structure comprising: [1142] a) a backing layer; [1143] b) an asenapine-containing matrix layer consisting of a matrix layer composition comprising: [1144] i) a therapeutically effective amount of asenapine; and [1145] ii) an acrylic polymer. [1146] 63. The method according to embodiment 62, wherein the transdermal therapeutic system provides by transdermal delivery a mean release rate of 0.5 to 20 mg/day over at least 48 hours of administration. [1147] 64. The method according to any of embodiments 62 or 63, wherein the transdermal therapeutic system provides by transdermal delivery a mean release rate of 0.5 to 20 mg/day over at least 84 hours of administration. [1148] 65. The method according to any of embodiments 62-64, wherein the transdermal therapeutic system provides by transdermal delivery a mean release rate of 1.0 to 15 mg/day over at least 48 hours of administration. [1149] 66. The method according to any of embodiments 62-65, wherein the transdermal therapeutic system provides by transdermal delivery a mean release rate of 2.0 to 10 mg/day over at least 48 hours of administration. [1150] 67. The method according to any one of embodiments 62-66, wherein the transdermal therapeutic system provides by transdermal delivery one or more pharmacokinetic parameter(s) selected from the group consisting of [1151] an asenapine AUC.sub.0-48 from 20 to 300 (ng/ml) h, or from more than 300 to 450 (ng/ml) h, [1152] an asenapine AUC.sub.0-72 from 30 to 400 (ng/ml) h or from more than 400 to 600 (ng/ml) h, [1153] an asenapine AUC.sub.0-84 from 35 to 450 (ng/ml) h or from more than 450 to 700 (ng/ml) h, [1154] an asenapine C.sub.max to C.sub.48 ratio of less than 2.0, [1155] an asenapine C.sub.max to C72 ratio of less than 3.0, [1156] an asenapine C.sub.max to C.sub.84 ratio of less than 3.5, and [1157] an asenapine C.sub.max value of from 0.5 to 10 ng/ml. [1158] 68. The method according to any one of embodiments 62-67, wherein the asenapine-containing matrix layer has an area weight that is at least 90 g/m.sup.2. [1159] 69. The method according to any one of embodiments 62-68, wherein the transdermal therapeutic system contains at least 0.70 mg/cm.sup.2 of asenapine. [1160] 70. The method according to any one of embodiments 62-69, wherein the asenapine-containing matrix layer has an area weight that ranges from 90 to 230 g/m.sup.2. [1161] 71. The method according any one of embodiments 62-70, wherein the asenapine in the asenapine-containing matrix layer composition is asenapine free base. [1162] 72. The method according any one of embodiment 62-71, wherein at least 90 mol % of the asenapine in the asenapine-containing matrix layer is asenapine free base. [1163] 73. The method according to any one of embodiments 62-72, wherein the matrix layer composition comprises further excipients or additives selected from the group consisting of cross-linking agents, solubilizers, fillers, tackifiers, plasticizers, stabilizers, softeners, substances for skincare, permeation enhancers, pH regulators, and preservatives, wherein

[1164] the tackifier is selected from polyvinylpyrrolidone, triglycerides, dipropylene glycol, resins, resin esters, terpenes and derivatives thereof, ethylene vinyl acetate adhesives, dimethylpolysiloxanes and polybutenes;

[1165] the stabilizer is selected from tocopherol and ester derivatives thereof and ascorbic acid and ester derivatives thereof; and

[1166] the permeation enhancer is selected from diethylene glycol monoethyl ether, diisopropyl adipate, isopropyl myristate, isopropyl palmitate, lauryl lactate, dimethylpropylene urea and a mixture of propylene glycol monoesters and diesters of fatty acids. [1167] 74. The method according to any one of embodiments 62-73, wherein the transdermal therapeutic system provides a skin permeation rate of asenapine as measured in a Franz diffusion cell with dermatomed human skin of

[1168] 0 μg/(cm.sup.2 h) to 10 μg/(cm.sup.2 h) in the first 8 hours,

[1169] 2 μg/(cm.sup.2 h) to 20 μg/(cm.sup.2 h) from hour 8 to hour 24,

[1170] 3 μg/(cm.sup.2 h) to 20 μg/(cm.sup.2 h) from hour 24 to hour 32,

[1171] 3 μg/(cm.sup.2 h) to 20 μg/(cm.sup.2 h) from hour 32 to hour 48, or

[1172] 2 μg/(cm.sup.2 h) to 15 μg/(cm.sup.2 h) from hour 48 to hour 72. [1173] 75. The method according to any one of embodiments 62-74, wherein the transdermal therapeutic system is administered at a dosing interval of at least 48 hours or 2 days. [1174] 76. The method according to any one of embodiments 62-75, wherein the transdermal therapeutic system provides by transdermal delivery a mean release rate of 0.5 to 20 mg/day over at least 48 hours or 2 days of administration. [1175] 77. The method according to any one of embodiments 62-76, wherein the transdermal therapeutic system provides by transdermal delivery an AUC.sub.0-48 from 20 to 300 (ng/ml) h or from more than 300 to 450 (ng/ml) h. [1176] 78. The method according to any one of embodiments 62-77, wherein the transdermal therapeutic system provides by transdermal delivery a C.sub.max to C.sub.48 ratio of less than 2.0. [1177] 79. The method according to any one of embodiments 62-78, wherein the matrix layer composition comprises:

[1178] i) 4 to 12% by weight of asenapine free base;

[1179] ii) 75 to 88% by weight of an acrylic polymer;

[1180] iii) 0.01 to 1.0% by weight of tocopherol; and

[1181] iv) 7 to 13% by weight of polyvinylpyrrolidone. [1182] 80. The method according to any one of embodiments 62-79, wherein the matrix layer composition comprises:

[1183] i) about 6% by weight of asenapine free base;

[1184] ii) 81 to 85% by weight of an acrylic polymer;

[1185] iii) about 0.5% by weight of tocopherol; and

[1186] iv) about 10% by weight of polyvinylpyrrolidone. [1187] 81. The method according to any one of embodiments 62-80, wherein the matrix layer composition comprises:

[1188] i) about 10% by weight of asenapine;

[1189] ii) 77 to 82% by weight of an acrylic polymer;

[1190] iii) about 0.5% by weight of tocopherol; and

[1191] iv) about 10% by weight of polyvinylpyrrolidone. [1192] 82. A method of treating bipolar disorder in a patient in need thereof, the method comprising administering to the patient a transdermal therapeutic system comprising a self-adhesive layer structure, said self-adhesive layer structure comprising:

[1193] a) a backing layer; and

[1194] b) an asenapine-containing matrix layer consisting of a matrix layer composition comprising: [1195] i) a therapeutically effective amount of asenapine; and [1196] ii) an acrylic polymer. [1197] 83. The method according to embodiment 82, wherein the bipolar disorder is acute manic bipolar disorder. [1198] 84. The method according to embodiment 82, wherein the bipolar disorder is mixed episodes of bipolar disorder. [1199] 85. The method according to any of embodiments 82-84, wherein the transdermal therapeutic system provides by transdermal delivery a mean release rate of 0.5 to 20 mg/day over at least 48 hours of administration. [1200] 86. The method according to any of embodiments 82-85, wherein the transdermal therapeutic system provides by transdermal delivery a mean release rate of 0.5 to 20 mg/day over at least 84 hours of administration. [1201] 87. The method according to any of embodiments 82-86, wherein the transdermal therapeutic system provides by transdermal delivery a mean release rate of 1.0 to 15 mg/day over at least 48 hours of administration. [1202] 88. The method according to any of embodiments 82-87, wherein the transdermal therapeutic system provides by transdermal delivery a mean release rate of 2.0 to 10 mg/day over at least 48 hours of administration. [1203] 89. The method according to any one of embodiments 82-88, wherein the transdermal therapeutic system provides by transdermal delivery one or more pharmacokinetic parameter(s) selected from the group consisting of [1204] an asenapine AUC.sub.0-48 from 20 to 300 (ng/ml) h, or from more than 300 to 450 (ng/ml) h, [1205] an asenapine AUC.sub.0-72 from 30 to 400 (ng/ml) h, or from more than 400 to 600 (ng/ml) h, [1206] an asenapine AUC.sub.0-84 from 35 to 450 (ng/ml) h, or from more than 450 to 700 (ng/ml) h, [1207] an asenapine C.sub.max to C.sub.48 ratio of less than 2.0, [1208] an asenapine C.sub.max to C.sub.72 ratio of less than 3.0, [1209] an asenapine C.sub.max to C.sub.84 ratio of less than 3.5, and [1210] an asenapine Cm.sub.ax value of from 0.5 to 10 ng/ml. [1211] 90. The method according to any one of embodiments 82-89, wherein the asenapine-containing matrix layer has an area weight that is at least 90 g/m.sup.2. [1212] 91. The method according to any one of embodiments 82-90, wherein the transdermal therapeutic system contains at least 0.70 mg/cm.sup.2 of asenapine. [1213] 92. The method according to any one of embodiments 82-91, wherein the asepnapine-containing matrix layer has an area weight that ranges from 90 to 230 g/m.sup.2. [1214] 93. The method according any one of embodiments 82-92, wherein the asenapine in the asenapine-containing matrix layer composition is asenapine free base. [1215] 94. The method according any one of embodiment 82-93, wherein at least 90 mol % of the asenapine in the asenapine-containing matrix layer is asenapine free base. [1216] 95. The method according to any one of embodiments 82-94, wherein the matrix layer composition comprises further excipients or additives selected from the group consisting of cross-linking agents, solubilizers, fillers, tackifiers, plasticizers, stabilizers, softeners, substances for skincare, permeation enhancers, pH regulators, and preservatives, wherein

[1217] the tackifier is selected from polyvinylpyrrolidone, triglycerides, dipropylene glycol, resins, resin esters, terpenes and derivatives thereof, ethylene vinyl acetate adhesives, dimethylpolysiloxanes and polybutenes;

[1218] the stabilizer is selected from tocopherol and ester derivatives thereof and ascorbic acid and ester derivatives thereof; and

[1219] the permeation enhancer is selected from diethylene glycol monoethyl ether, diisopropyl adipate, isopropyl myristate, isopropyl palmitate, lauryl lactate, dimethylpropylene urea, and a mixture of propylene glycol monoesters and diesters of fatty acids. [1220] 96. The method according to any one of embodiments 82-95, wherein the transdermal therapeutic system provides a skin permeation rate of asenapine as measured in a Franz diffusion cell with dermatomed human skin of [1221] 0 μg/(cm.sup.2 h) to 10 μg/(cm.sup.2 h) in the first 8 hours, [1222] 2 μg/(cm.sup.2 h) to 20 μg/(cm.sup.2 h) from hour 8 to hour 24, [1223] 3 μg/(cm.sup.2 h) to 20 μg/(cm.sup.2 h) from hour 24 to hour 32, [1224] 3 μg/(cm.sup.2 h) to 20 μg/(cm.sup.2h) from hour 32 to hour 48, or [1225] 2 μg/(cm.sup.2 h) to 15 μg/(cm.sup.2 h) from hour 48 to hour 72. [1226] 97. The method according to any one of embodiments 82-96, wherein the transdermal therapeutic system provides by transdermal delivery a mean release rate of 0.5 to 20 mg/day over at least 48 hours of administration. [1227] 98. The method according to any one of embodiments 82-97, wherein the transdermal therapeutic system provides by transdermal delivery a mean release rate of 0.5 to 20 mg/day over at least 84 hours of administration. [1228] 99. The method according to any one of embodiments 82-98, wherein the transdermal therapeutic system provides by transdermal delivery a mean release rate of 1.0 to 15 mg/day over at least 48 hours of administration. [1229] 100. The method according to any one of embodiments 82-99, wherein the transdermal therapeutic system provides by transdermal delivery a mean release rate of 2.0 to 10 mg/day over at least 48 hours of administration. [1230] 101. The method according to any one of embodiments 82-100, wherein the matrix layer composition comprises:

[1231] i) 4 to 12% by weight of asenapine free base;

[1232] ii) 75 to 88% by weight of an acrylic polymer;

[1233] iii) 0.01 to 1.0% by weight of tocopherol; and

[1234] iv) 7 to 13% by weight of polyvinylpyrrolidone. [1235] 102. The method according to any one of embodiments 82-101, wherein the matrix layer composition comprises:

[1236] i) about 6% by weight of asenapine free base;

[1237] ii) 81 to 85% by weight of an acrylic polymer;

[1238] iii) about 0.5% by weight of tocopherol; and

[1239] iv) about 10% by weight of polyvinylpyrrolidone. [1240] 103. The method according to any one of embodiments 82-102, wherein the matrix layer composition comprises:

[1241] i) about 10% by weight of asenapine free base;

[1242] ii) 77 to 82% by weight of an acrylic polymer;

[1243] iii) about 0.5% by weight of tocopherol; and

[1244] iv) about 10% by weight of polyvinylpyrrolidone. [1245] 104. A method of treating schizophrenia or bipolar disorder in a subject in need thereof, the method comprising transdermally administering a therapeutically effective amount of asenapine to the subject, wherein the asenapine is contained in a transdermal therapeutic system for the transdermal administration of asenapine, and wherein the transdermal therapeutic system is in contact with at least one body surface on the subject for about 84 hours. [1246] 105. The method according to embodiment 104, wherein the transdermal therapeutic system provides by transdermal delivery one or more pharmacokinetic parameter(s) selected from the group consisting of [1247] an asenapine AUC.sub.0-48 from 20 to 300 (ng/ml) h, or from more than 300 to 450 (ng/ml) h, [1248] an asenapine AUC.sub.0-72 from 30 to 400 (ng/ml) h, or from more than 400 to 600 (ng/ml) h, [1249] an asenapine AUC.sub.0-84 from 35 to 450 (ng/ml) h, or from more than 450 to 700 (ng/ml) h, [1250] an asenapine C.sub.max to C.sub.48 ratio of less than 2.0, [1251] an asenapine C.sub.max to C.sub.72 ratio of less than 3.0, [1252] an asenapine C.sub.max to C.sub.84 ratio of less than 3.5, and [1253] an asenapine C.sub.max value of from 0.5 to 10 ng/ml. [1254] 106. The method according to any of embodiments 104 or 105, wherein the transdermal therapeutic system provides by transdermal delivery a mean release rate of 0.5 to 20 mg/day. [1255] 107. The method according to any of embodiments 104-106, wherein the transdermal therapeutic system comprises a self-adhesive layer structure, said self-adhesive layer structure comprising: [1256] a) a backing layer; and [1257] b) an asenapine-containing matrix layer consisting of a matrix layer composition comprising: [1258] i) a therapeutically effective amount of asenapine; and [1259] ii) an acrylic polymer. [1260] 108. The method of embodiment 107, wherein the asenapine in the asenapine-containing matrix layer is asenapine free base. [1261] 109. The method according to embodiment 107 or 108, wherein at least 90 mol % of the asenapine in the asenapine-containing matrix layer is asenapine free base. [1262] 110. The method according to any one of embodiments 107-109, wherein the matrix layer composition comprises further excipients or additives selected from the group consisting of cross-linking agents, solubilizers, fillers, tackifiers, plasticizers, stabilizers, softeners, substances for skincare, permeation enhancers, pH regulators, and preservatives. [1263] 111. The method according to any one of embodiments 107-110, wherein the transdermal therapeutic system provides a skin permeation rate of asenapine as measured in a Franz diffusion cell with dermatomed human skin of

[1264] 0 μg/(cm.sup.2 h) to 10 μg/(cm.sup.2 h) in the first 8 hours,

[1265] 2 μg/(cm.sup.2 h) to 20 μg/(cm.sup.2 h) from hour 8 to hour 24, [1266] 3 μg/(cm.sup.2 h) to 20 μg/(cm.sup.2 h) from hour 24 to hour 32, [1267] 3 μg/(cm.sup.2 h) to 20 μg/(cm.sup.2 h) from hour 32 to hour 48, or [1268] 2 μg/(cm.sup.2 h) to 15 μg/(cm.sup.2 h) from hour 48 to hour 72. [1269] 112. The method according to any one of embodiments 107-111, wherein the matrix layer composition comprises:

[1270] i) 4 to 12% by weight of asenapine free base;

[1271] ii) 75 to 88% by weight of an acrylic polymer;

[1272] iii) 0.01 to 1.0% by weight of tocopherol; and

[1273] iv) 7 to 13% by weight of polyvinylpyrrolidone. [1274] 113. The method according to any one of embodiments 107-112, wherein the matrix layer composition comprises:

[1275] i) about 6% by weight of asenapine free base;

[1276] ii) 81 to 85% by weight of an acrylic polymer;

[1277] iii) about 0.5% by weight of tocopherol; and

[1278] iv) about 10% by weight of polyvinylpyrrolidone. [1279] 114. The method according to any one of embodiments 107-113, wherein the matrix layer composition comprises:

[1280] i) about 10% by weight of asenapine free base;

[1281] ii) 77 to 82% by weight of an acrylic polymer;

[1282] iii) about 0.5% by weight of tocopherol; and

[1283] iv) about 10% by weight of polyvinylpyrrolidone.