BR112019010466B1 - TRANSDERMAL THERAPEUTIC SYSTEMS CONTAINING ASENAPINE, THEIR USES AND PROCESSES FOR MANUFACTURING A MATRIX LAYER FOR USE IN SAID SYSTEMS - Google Patents

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 as asenapine TTS for use in a method of treatment, processes for manufacturing such TTS, as well as asenapine and transdermal therapeutic systems containing asenapine for use in a method of treatment, and to a method for treating a human patient by transdermal administration of asenapine.

Description

Technical field of the invention

[0001] The present invention relates to a transdermal therapeutic system (TTS) for the transdermal administration of asenapine to the systemic circulation, and manufacturing processes, treatment methods and uses thereof.

Background of the invention

[0002] The active agent asenapine (3aRS,12bRS)-rel-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole) is an atypical antipsychotic belonging to the pyrrole family of dibenzo-oxepino, the tetracyclic structure of which is unrelated to those of other antipsychotics such as olanzapine, quetiapine or clozapine (tricyclic structure), risperidone, ziprasidone or aripiprazole (bicyclic structure). Asenapine is an antagonist at dopamine D2 and serotonin 5-HT2A receptors with high affinity for the latter and was developed by Schering-Plough/Organon for the treatment of acute mania schizophrenia associated with bipolar disorder.

[0003] Asenapine is currently commercially available as a sublingual tablet, which is administered in dosage strengths of 2.5 mg, 5 mg, or 10 mg twice daily (BID) under the brand names Sycrest (Swissmedic) and Saphris (Schering-Plough).

[0004] Routine sublingual administration avoids first-pass metabolism and oral administration in order to increase bioavailability, which is 35% when taken sublingually and <2% if swallowed. However, sublingual administration is associated with a bitter or unpleasant taste, as well as numbness of the tongue/oral mucosa induced by a local anesthetic effect, nausea and headaches. Furthermore, eating, drinking and smoking are not permitted immediately after sublingual dosing for 10 minutes. These inconveniences may lead to reduced patient compliance and inappropriate administration, such as dose reduction, dose skipping, irregular drug intake or complete abstinence from the intended intake of asenapine. Sublingual administration is also difficult to monitor in institutionalized psychiatric patients and may not be suitable for children, the elderly and other patients with difficulty swallowing, or for those unable to take medication on their own.

[0005] Asenapine shows side effects that are not uncommon for a neuroleptic drug. Somnolence and anxiety are very common (seen in > 10% of patients). Other common adverse effects (> 1% to < 10% of patients) include weight gain and increased appetite; nervous system disorders such as dystonia, akathisia, dyskinesia, parkinsonism, sedation, dizziness, dysgeusia; gastrointestinal disturbances such as hypoesthesia, nausea, increased salivation; increases in alanine aminotransferase (ALT), muscle rigidity, and fatigue (tiredness).

[0006] Asenapine is hepatically metabolized mainly via CYP1A2 and UGT1A4 (glucuronidation). The clinical relevance of the main human metabolites N-desmethyl-asenapine and asenapine N+ glucuronide remains controversial. At least it seems that the metabolites would not substantially participate in the therapeutic effect. Therefore, a decrease in the amount of these metabolites seems generally desirable.

[0007] Following sublingual administration, asenapine is rapidly absorbed with peak blood plasma concentrations occurring within 0.5 to 1.5 hours and (at therapeutic doses) exhibits 2-compartment pharmacokinetics with a rapid initial distribution phase with a half-life of several hours, followed by a longer terminal disposition half-life of approximately 1 day or longer. The blood plasma concentration thus exhibits a certain degree of fluctuation with peaks approximately 1 hour post-dose, followed by a decrease in concentration, resulting in a trough just prior to the next dose, even at steady state. The relatively rapid decrease in concentration also inevitably leads to multiple daily dosing (currently twice daily), which is associated with poor patient compliance, particularly in chronic conditions.

[0008] Such fluctuation can be avoided, or at least reduced, by transdermal administration of asenapine, which prevents the decrease in plasma concentration between two doses to some extent by providing a prolonged release of the active agent. Transdermal delivery of asenapine has been investigated, but it appears that passive transdermal delivery of asenapine, and in particular a sustained release over a prolonged period of time, is challenging. Passive transport of active agents from a transdermal therapeutic system (TTS) through the skin makes use of the driving force based on the concentration gradient between the concentration of active agent in the transdermal system and on the outer skin surface and the concentration in the bloodstream. Such passive transport is advantageous in view of the complexity of the TTS and the convenience of administration compared to TTS making use of active transport, such as iontophoresis or microporation. To date, no commercial asenapine TTS is available.

[0009] There is therefore a need in the art for a transdermal therapeutic system for the transdermal administration of asenapine.

[0010] There is also a need for an appropriate administration of asenapine that leads to fewer, or less severe, side effects. Objects and Summary of the Invention

[0011] It is an object of the present invention to provide a TTS that overcomes the above-mentioned disadvantages of current asenapine administration.

[0012] Accordingly, it is an object of the present invention to provide a TTS, and in particular a matrix type TTS, for the transdermal administration of asenapine providing a permeation rate that is sufficient to obtain a therapeutically effective dose.

[0013] It is another object of the present invention to provide a TTS, and in particular a matrix type TTS, for the transdermal administration of asenapine in a continuous administration, providing therapeutically effective amount of asenapine for up to 7 days, during a period of administration to the patient's skin of up to 7 days (e.g. 3.5 days).

[0014] It is also an object of the present invention to provide a TTS, and in particular a matrix type TTS, for the transdermal administration of asenapine, wherein the fluctuation in blood plasma concentration of asenapine is reduced when compared to sublingual administration, in particular at steady state.

[0015] It is another object of the present invention to provide a TTS, and in particular a matrix type TTS, for the transdermal administration of asenapine that meets the needs of a convenient application in view of size and thickness and/or that is easy and inexpensive to manufacture.

[0016] It is an object of certain embodiments of the present invention to provide a TTS, and in particular a matrix-type TTS, for the transdermal delivery of asenapine with an improved bioavailability of asenapine.

[0017] It is an object of certain embodiments of the present invention to provide a TTS, and in particular a matrix-type TTS, for the transdermal administration of asenapine, wherein therapeutically effective amounts of asenapine are delivered for 1 day by said transdermal therapeutic system during a 1-day administration period to the patient's skin, allowing for once-daily TTS exchange in a timed treatment.

[0018] It is an object of certain embodiments of the present invention to provide a TTS, and in particular a matrix-type TTS, for the transdermal administration of asenapine, wherein therapeutically effective amounts of asenapine are delivered for 3.5 days by said transdermal therapeutic system during a 3.5-day administration period to the patient's skin, allowing for twice-weekly TTS changes in a timed treatment regimen.

[0019] These and other objects are accomplished by the present invention, which, according to one aspect, relates to a 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: A) a reinforcing layer; B) a matrix layer containing asenapine consisting of a matrix layer composition comprising: 1. asenapine; and 2. a polymer selected from acrylic polymers; wherein the transdermal therapeutic system has a release area of from 5 to 100 cm2.

[0020] According to a second aspect, the present invention relates to a transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure containing asenapine, in which the transdermal therapeutic system provides by transdermal release, an average release rate of 0.5 to 20 mg/day during at least 48 hours of administration.

[0021] According to a third aspect, the present invention relates to a transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure containing asenapine, wherein the transdermal therapeutic system provides by transdermal release, an AUC0-48 of 20 to 300 (ng/mL) h or of more than 300 to 450 (ng/mL) h, preferably of 30 to 200 (ng/mL) h.

[0022] According to a fourth aspect, the present invention relates to a transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure containing asenapine, wherein the transdermal therapeutic system provides by transdermal release, an AUC0-72 of 30 to 400 (ng/mL) h or of more than 400 to 600 (ng/mL) h, preferably of 50 to 300 (ng/mL) h.

[0023] According to a fifth aspect, the present invention relates to a transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure containing asenapine, wherein the transdermal therapeutic system provides by transdermal release, an AUC0-84 of 35 to 450 (ng/mL) h or of more than 450 to 700 (ng/mL) h, preferably of 60 to 350 (ng/mL) h.

[0024] According to a sixth aspect, the present invention relates to a transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure containing asenapine, wherein the transdermal therapeutic system provides upon transdermal release a Cmax to C48 ratio of less than 2.0, preferably less than 1.5 and more preferably less than 1.3.

[0025] According to a seventh aspect, the present invention relates to a transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure containing asenapine, wherein the transdermal therapeutic system provides upon transdermal release a Cmax to C72 ratio of less than 3.0, preferably less than 2.5 and more preferably less than 2.0.

[0026] According to an eighth aspect, the present invention relates to a transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure containing asenapine, wherein the transdermal therapeutic system provides upon transdermal release a Cmax to C84 ratio of less than 3.5, preferably less than 3.0, more preferably less than 2.5, and most preferably less than 2.0.

[0027] According to a ninth aspect, the present invention relates to a 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: A) a reinforcing layer; B) a matrix layer containing asenapine consisting of a matrix layer composition comprising: 1. asenapine in the form of the free base; and 2. a polymer; wherein the areal weight of the matrix layer is at least 90 g/m2, and wherein the matrix layer containing asenapine does not comprise isopropyl palmitate.

[0028] According to certain embodiments of the invention, the transdermal therapeutic system according to the invention is for use in a method of treatment, in particular for use in a method for the treatment of schizophrenia and/or bipolar disorder, in particular during administration over a prolonged period of time.

[0029] Thus, according to certain embodiments of the invention, the transdermal therapeutic system according to the invention is for use in a method for the treatment of schizophrenia and/or bipolar disorder over an administration period of from about 24 hours to about 168 hours, or 1 to 7 days, and in particular for use in a method for the treatment of schizophrenia and/or bipolar disorder over an administration period of from about 24 hours, or 1 day, from about 48 hours, or 2 days, or from about 84 hours, or 3.5 days.

[0030] According to certain other embodiments of the invention, the transdermal therapeutic system according to the invention is for use in a method for the treatment of psychosis in general, and in particular for use in a method for the treatment of one or more conditions selected from schizophrenia, bipolar disorder, post-traumatic stress disorder, major depressive disorder, dementia-related psychosis, agitation or manic disorder, in particular during administration over an extended period of time, for example over an administration period of from about 24 hours to about 168 hours, or 1 to 7 days, and in particular over an administration period of from about 24 hours, or 1 day, from about 48 hours, or 2 days, or from about 84 hours, or 3.5 days.

[0031] According to other embodiments, the present invention relates to a method of treatment, in particular to a method for the treatment of schizophrenia and/or bipolar disorder, including applying a transdermal therapeutic system according to the invention to the skin of a patient for an extended period of time.

[0032] Thus, according to certain other embodiments, the invention relates to a method for treating schizophrenia and/or bipolar disorder including applying a transdermal therapeutic system according to the invention for about 24 hours to about 168 hours, or for 1 to 7 days, or for about 24 hours, 48 hours, or 84 hours, or for 1 day, 2 days, or 3.5 days to the skin of a patient.

[0033] Such modes of administration require once daily, once every other day, twice weekly or once weekly switching of the TTS in a timed treatment.

[0034] According to certain other embodiments of the invention, the present invention relates to a method for the treatment of psychosis in general, and in particular to a method for the treatment of one or more conditions selected from schizophrenia, bipolar disorder, post-traumatic stress disorder, major depressive disorder, dementia-related psychosis, agitation or manic disorder, in particular during administration over an extended period of time, for example, over an administration period of from about 24 hours to about 168 hours, or 1 to 7 days, and in particular over an administration period of from about 24 hours, or 1 day, from about 48 hours, or 2 days, or from about 84 hours, or 3.5 days.

[0035] According to a specific aspect, the present invention relates to asenapine for use in a method for treating a human patient by transdermal administration of asenapine for a dosing interval of at least about 48 hours or 2 days, or at least about 72 hours or 3 days.

[0036] According to another specific aspect, the present invention relates to a transdermal therapeutic system for the transdermal administration of asenapine for use in a method for treating a human patient for a dosing interval of at least about 48 hours or 2 days, or at least about 72 hours or 3 days.

[0037] According to another specific aspect, the present invention relates to a method for treating a human patient by transdermal administration of asenapine for a dosing interval of at least about 48 hours or 2 days, or at least about 72 hours or 3 days.

[0038] According to yet another specific aspect, the invention relates to a process for manufacturing a matrix layer for use in a transdermal therapeutic system comprising the steps of: 1) combining at least the asenapine and polymer components, in a solvent to obtain a coating composition; 2) coating the coating composition over the reinforcement layer or release coating or any intermediate coating; and 3) drying the coated coating composition to form the matrix layer.

[0039] According to certain embodiments the invention also relates to a transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure comprising: A) a reinforcing layer; B) a matrix layer containing asenapine consisting of a matrix layer composition comprising: 1. asenapine included in the form of the free base; 2. a copolymer based on vinyl acetate, 2-ethylhexyl acrylate, 2-hydroxyethyl acrylate and glycidyl methacrylate; and 3. a stabilizer.

[0040] According to certain embodiments the invention also relates to a transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure comprising: A) a reinforcing layer; B) a matrix layer containing asenapine consisting of a matrix layer composition comprising: 1. asenapine included in the form of the free base in an amount of 3% to 9% of the matrix layer composition; 2. a copolymer based on vinyl acetate, 2-ethylhexyl acrylate, 2-hydroxyethyl acrylate and glycidyl methacrylate in an amount of 90 to 96.5% of the matrix layer composition; and 3. a stabilizer in an amount of 0.1% to 2% of the matrix layer composition; 4. wherein the areal weight of the matrix layer ranges from 120 to 170 g/m2.

[0041] According to certain embodiments the invention also relates to a transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure comprising: A) a reinforcing layer; B) a matrix layer containing asenapine consisting of a matrix layer composition comprising: 1. asenapine included in the form of the free base; 2. a copolymer based on vinyl acetate, 2-ethylhexyl acrylate, 2-hydroxyethyl acrylate and glycidyl methacrylate; 3. a stabilizer; and 4. a polyvinyl pyrrolidone.

[0042] According to certain embodiments the invention also relates to a transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure comprising: A) a reinforcing layer; B) a matrix layer containing asenapine consisting of a matrix layer composition comprising: 1. asenapine included in the form of the free base in an amount of 3% to 9% of the matrix layer composition; 2. a copolymer based on vinyl acetate, 2-ethylhexyl acrylate, 2-hydroxyethyl acrylate and glycidyl methacrylate in an amount of 80 to 90% of the matrix layer composition; 3. a stabilizer in an amount of 0.1% to 2% of the matrix layer composition; and 4. a polyvinyl pyrrolidone in an amount of 5 to 15% of the matrix layer composition. where the area weight of the matrix layer varies from 120 to 170 g/m2.

[0043] According to certain embodiments the invention also relates to a transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure comprising: A) a reinforcing layer; B) a matrix layer containing asenapine consisting of a matrix layer composition comprising: 1. asenapine included in the form of the free base in an amount of 7% to 13% of the matrix layer composition; 2. a copolymer based on vinyl acetate, 2-ethylhexyl acrylate, 2-hydroxyethyl acrylate and glycidyl methacrylate in an amount of 75% to 85% of the matrix layer composition; 3. a stabilizer in an amount of 0.1% to 2% of the matrix layer composition; and 4. a polyvinyl pyrrolidone in an amount of 5 to 15% of the matrix layer composition. where the area weight of the matrix layer varies from 120 to 170 g/m2.

[0044] According to certain embodiments the invention also relates to a transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure comprising: A) a reinforcing layer; B) a matrix layer containing asenapine consisting of a matrix layer composition comprising: 1. asenapine included in the form of the free base in an amount greater than 13% to 20% of the matrix layer composition; 2. a copolymer based on vinyl acetate, 2-ethylhexyl acrylate, 2-hydroxyethyl acrylate and glycidyl methacrylate in an amount of 65% to 82% of the matrix layer composition; 3. a stabilizer in an amount of 0.001% to 2% of the matrix layer composition; and 4. a polyvinyl pyrrolidone in an amount of 5 to 15% of the matrix layer composition. where the area weight of the matrix layer varies from 120 to 230 g/m2.

[0045] According to certain embodiments the invention also relates to a transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure comprising: A) a reinforcing layer; B) a matrix layer containing asenapine consisting of a matrix layer composition comprising: 1. asenapine included in the form of the free base in an amount of 7% to 20% of the matrix layer composition; 2. a copolymer based on vinyl acetate, 2-ethylhexyl acrylate, 2-hydroxyethyl acrylate and glycidyl methacrylate in an amount of 75% to 85% of the matrix layer composition; 3. a stabilizer in an amount of 0.001% to 2% of the matrix layer composition; and 4. a polyvinyl pyrrolidone in an amount of 5 to 15% of the matrix layer composition. where the areal weight of the matrix layer ranges from more than 170 to 230 g/m2.

[0046] Within the meaning of this invention, the term "transdermal therapeutic system" (TTS) refers to a system by which the active agent (asenapine) is administered to the systemic circulation by means of transdermal delivery and refers to the entire individual dosage unit that is applied to the skin of a patient, and that comprises a therapeutically effective amount of asenapine in a self-adhesive layer structure and optionally an additional adhesive overlayer on top of a self-adhesive layer structure containing asenapine. The self-adhesive layer structure may be located over a release liner (a peelable protective layer), thus the TTS may also comprise a release liner. Within the meaning of this invention, the term "TTS" in particular refers to a system that provides passive transdermal delivery excluding active transport as in methods including iontophoresis or microporation.

[0047] Within the meaning of this invention, the term "asenapine-containing self-adhesive layer structure containing asenapine" or "self-adhesive layer structure containing a therapeutically effective amount of asenapine" refers to the active agent-containing structure that provides the release area of asenapine during administration. The adhesive overlayer adds to the overall size of the TTS, but does not add to the release area. An asenapine-containing self-adhesive layer structure comprises a reinforcing layer and at least one asenapine-containing layer.

[0048] Within the meaning of this invention, the term "therapeutically effective amount" refers to an amount of active agent in the TTS sufficient to provide, if administered by the TTS to a patient, blood levels of asenapine of a similar range (e.g., from about 10% to about 1000% when measured as an AUC) when compared to blood levels obtained by twice-daily steady-state administration of 5 mg sublingual asenapine for a predefined extended period of time (e.g., 1, 3.5, and 7 days). A TTS generally contains more active agent in the system than is actually delivered to the skin and systemic circulation. This excess amount of active agent is generally necessary to provide sufficient conduction force for passive transport of the TTS into the systemic circulation.

[0049] Within the meaning of this invention, the terms "active", "active agent", and the like, as well as the term "asenapine" refer to asenapine in any pharmaceutically acceptable chemical and morphological form and physical state. Such forms include without limitation asenapine in its free base form, protonated or partially protonated asenapine, salts of asenapine and, in particular, acid addition salts formed by addition of an inorganic or organic acid, such as asenapine hydrochloride or asenapine maleate, hydrates, complexes and so on, as well as asenapine in the form of particles which may be micronized, crystalline and/or amorphous, and any mixtures of the aforementioned forms. Asenapine, when contained in a medium, such as a solvent, may be dissolved or dispersed or partly dissolved and partly dispersed.

[0050] When asenapine is mentioned to be used in a particular form in the manufacture of TTS, this does not exclude interactions between this form of asenapine and other ingredients of a self-adhesive layer structure containing asenapine, for example salt formation or complexation, in the final TTS. This means that, even if asenapine is included in its free base form, it may be present in the final TTS in protonated or partially protonated form or in the form of an acid addition salt, or, if it is included in the form of a salt, parts of it may be present as free base in the final TTS. Unless otherwise indicated in particular, the amount of asenapine in the self-adhesive layer structure refers to the amount of asenapine included in the TTS during the manufacture of the TTS and is calculated based on asenapine in the free base form. For example, when a) 0.1 mmol (equal to 28.6 mg) asenapine base or b) 0.1 mmol (equal to 40.2 mg) asenapine maleate is included in the TTS during manufacture, the amount of asenapine in the self-adhesive layer structure is, within the meaning of the invention, in both cases 0.1 mmol or 28.6 mg.

[0051] The asenapine starting material included in the TTS during the manufacture of the TTS may be in particulate form. Asenapine may, for example, be present in the self-adhesive layer structure in particulate and/or dissolved form.

[0052] Within the meaning of this invention, the term "particles" refers to a solid, particulate material comprising individual particles, the dimensions of which are insignificant in comparison to the material. In particular, the particles are solids, including plastic/deformable solids, including amorphous and crystalline materials.

[0053] Within the meaning of this invention, the term "disperse" refers to a step or a combination of steps, in which a starting material (e.g. asenapine) is not completely dissolved. Dispersing within the meaning of the invention comprises the dissolution of a part of the starting material (e.g. asenapine particles), depending on the solubility of the starting material (e.g. the solubility of asenapine in the coating composition).

[0054] There are two main types of TTS using passive active agent release, namely, matrix-type TTS and reservoir-type TTS. In matrix-type TTS, the active agent is enclosed in a matrix, whereas in a reservoir-type TTS, the active agent is enclosed in a liquid or semi-liquid reservoir. The release of the active agent in a matrix-type TTS is primarily controlled by the matrix, including the active agent itself. In contrast, a reservoir-type TTS requires a rate-controlling membrane to control the release of the active agent. Matrix-type TTS is advantageous in that, compared to reservoir-type TTS, generally no rate-determining membrane is required and no dose discharge can occur due to membrane rupture. In summary, matrix-type transdermal therapeutic systems (TTS) are less complex to manufacture and easy and convenient for patients to use.

[0055] Within the meaning of this invention, "matrix-type TTS" refers to a system or structure in which the active is homogeneously dissolved and/or dispersed within a polymeric carrier, i.e., the matrix, which forms with the active agent and optionally the remaining ingredients, a matrix layer. In such a system, the matrix layer controls the release of the active agent from the TTS. A matrix-type TTS may also include a rate-controlling membrane.

[0056] TTS with a rate-controlling membrane and a reservoir containing liquid or semi-liquid active agent, wherein the release of the active agent from the TTS is controlled by the rate-controlling membrane, are referred to by the term "reservoir-type TTS". Reservoir-type TTS should not be understood as being of matrix type within the meaning of the invention. In particular, within the meaning of this invention, microreservoir systems (biphasic systems having an internal active-containing phase in an external matrix phase), considered in the art to be a mixture between a matrix-type TTS and a reservoir-type TTS, are considered to be of matrix type within the meaning of the invention. Matrix-type TTS may in particular be in the form of a "drug-in-adhesive" type TTS referring to a system in which the active is homogeneously dissolved and/or dispersed within a pressure-sensitive adhesive matrix.

[0057] Within the meaning of this invention, the term "matrix layer" refers to any layer containing the active homogeneously dissolved and/or dispersed within a polymeric vehicle. Typically, the matrix layer is present in a matrix-type TTS as the layer containing the active agent. A reservoir-type TTS may comprise, in addition to a reservoir layer and a rate-controlling membrane, an additional adhesive layer that serves as the skin contact layer. In such a reservoir-type TTS, the additional adhesive layer is often manufactured as an active agent-free layer. However, due to the concentration gradient, the active agent will migrate from the reservoir to the additional adhesive layer over time, until an equilibrium is reached. Therefore, in such a reservoir-type TTS, after some equilibration time, the additional adhesive layer contains the active agent and should be considered as a matrix layer within the meaning of the present invention.

[0058] The matrix layer is the final solidified layer, e.g., obtained after coating and drying of the solvent-containing coating composition. The matrix layer may also be manufactured by laminating two or more such solidified layers (e.g., dry layers) of the same composition to provide the desired area weight. The matrix layer may be self-adhesive (in the form of a pressure-sensitive adhesive matrix) or the TTS may comprise an additional skin contact layer of a pressure-sensitive adhesive to provide sufficient adhesion. In particular, the matrix layer is a pressure-sensitive adhesive matrix.

[0059] Within the meaning of this invention, the term "pressure sensitive adhesive" refers to a material which, in particular, adheres with finger pressure, is permanently tacky, exerts a strong holding force and should be removable from smooth surfaces without leaving a residue. A pressure sensitive adhesive layer, when in contact with the skin, is "self-adhesive", i.e. provides adhesion to the skin so that typically no other attachment aid on the skin is required. A "self-adhesive" layer structure includes a pressure sensitive adhesive layer for contact therewith which may be provided in the form of a pressure sensitive adhesive matrix or in the form of an additional layer, i.e. a pressure sensitive adhesive skin contact layer. An adhesive overlayer may further be employed to promote adhesion.

[0060] Within the meaning of this invention, the term "skin contact layer" refers to a layer included in the TTS to be in direct contact with the patient's skin during administration. When the TTS comprises the skin contact layer, the other layers do not contact the skin and do not necessarily have self-adhesive properties. As outlined above, the skin contact layer may over time absorb parts of the active agent and can then be considered as a matrix layer. The release area is provided by the area of the matrix layer. The skin contact layer can be used to enhance adhesion. The sizes of an additional skin contact layer and the matrix layer are generally coextensive and correspond to the release area.

[0061] Within the meaning of this invention, the term "area weight" refers to the dry weight of a specific layer, for example of the matrix layer, given in g/m2. The area weight values are subject to a tolerance of ± 10%, preferably ± 7.5%, due to manufacturing variability.

[0062] If not otherwise indicated "%" refers to % by weight.

[0063] Within the meaning of this invention, the term "polymer" refers to any substance consisting of so-called repeating units obtained by polymerization of one or more monomers, and includes homopolymers consisting of one type of monomer and copolymers consisting of two or more types of monomers. The polymers can be of any architecture, such as linear polymers, star polymers, comb polymers, brush polymers, of any arrangements of monomers, in the case of copolymers, for example, alternating, statistical, block copolymers, or graft polymers. The minimum molecular weight varies depending on the type of polymers and is known to the skilled person. Polymers can, for example, have a molecular weight above 2,000, preferably above 5,000 and more preferably above 10,000 Daltons. Correspondingly, compounds with a molecular weight below 2,000, preferably below 5,000, or more preferably below 10,000 Daltons are generally referred to as oligomers.

[0064] Within the meaning of this invention, the term "functional groups" refers to hydroxylic and carboxylic acid groups.

[0065] Within the meaning of this invention, the term "crosslinking agent" refers to a substance that is capable of crosslinking functional groups contained within the polymer.

[0066] Within the meaning of this invention, the term "adhesive overlayer" refers to a self-adhesive layer structure that is free of active agent and of larger area than the active agent-containing structure and provides additional area for adhering to the skin but no area for releasing the active agent. It thereby enhances the overall adhesive properties of the TTS. The adhesive overlayer comprises a reinforcement layer and an adhesive layer.

[0067] Within the meaning of this invention, the term "reinforcing layer" refers to a layer, which supports, for example, the asenapine-containing layer or forms the reinforcement of the adhesive overlayer. At least one reinforcing layer in the TTS and generally the reinforcing layer of an asenapine-containing layer is occlusive, i.e. substantially impermeable to the active agent contained in the layer during the period of storage and administration and thereby prevents active loss or cross-contamination in accordance with regulatory requirements.

[0068] The TTS according to the present invention can be characterized by certain parameters when measured in an in vitro skin permeation test.

[0069] The in vitro permeation test is carried out in a Franz diffusion cell, with human or animal skin and preferably with dermatomized split-thickness human skin with a thickness of 800 μm and an intact epidermis, and with phosphate buffer, pH 5.5 or 7.4 as receptor medium (32°C with 0.1% saline azide) with or without addition of a maximum of 40 percent volumes of organic solvent, e.g. ethanol, acetonitrile, isopropanol, dipropylene glycol, PEG 400, so that a receptor medium may, for example, contain 60 percent volumes of phosphate buffer, pH 5.5, 30 percent volumes of dipropylene glycol and 10 percent volumes of acetonitrile.

[0070] Where not otherwise indicated, the in vitro permeation test is performed with dermatomized split-thickness human skin with a thickness of 800 μm and an intact epidermis, and with phosphate buffer, pH 5.5 as receptor medium (32°C with 0.1% saline azide). The amount of active permeated into the receptor medium is determined at regular intervals using a validated HPLC method with a UV photometric detector taking a sample volume. The receptor medium is completely or partly replaced with fresh medium when taking the sample volume, and the measured amount of active permeated refers to the amount permeated between the last two sampling points and not the total amount permeated so far.

[0071] Thus, within the meaning of this invention, the parameter "permeated quantity" is given in μg/cm2 and refers to the quantity of active permeated in a sample interval in a certain elapsed time. For example, in an in vitro permeation test, as described above, in which the quantity of active permeated in the receiving medium was, for example, measured in 0, 2, 4, 8, 12 and 24 hours, the "permeated quantity" of active can be given, for example, for the sample interval from 8 hours to 12 hours, and corresponds to the measurement in 12 hours.

[0072] The permeated amount may also be given as a "cumulative permeated amount", corresponding to the cumulative amount of active permeated at a given point in time. For example, in an in vitro permeation test as described above, in which the amount of active permeated into the receiving medium was, for example, measured at 0, 2, 4, 8, 12 and 24 hours, the "cumulative permeated amount" of active at 12 hours corresponds to the sum of the amounts permeated from 0 hours to 2 hours, 2 hours to 4 hours, 4 hours to 8 hours and 8 hours to 12 hours.

[0073] Within the meaning of this invention, the parameter "skin permeation rate" during a given sample interval at a given elapsed time is given in μg/(cm2 h) and is calculated from the amount permeated in said sample interval, when measured by the in vitro permeation test as described above in μg/cm2, divided by the hours of said sample interval. For example, the skin permeation rate in an in vitro permeation test as described above, in which the amount of active permeated into the receptor medium was, for example, measured at 0, 2, 4, 8, 12 and 24 hours, the "skin permeation rate" at 12 hours is calculated as the amount permeated in the sample interval from 8 hours to 12 hours, divided by 4 hours.

[0074] A "cumulative skin permeation rate" can be calculated from the respective cumulative permeated amount by dividing the cumulative permeated amount by the elapsed time. For example, in an in vitro permeation test as described above, in which the amount of active permeated into the receptor medium was, for example, measured at 0, 2, 4, 8, 12 and 24 hours, the "cumulative skin permeation rate" at 12 hours is calculated as the cumulative permeated amount during 12 hours (see above) divided by 12 hours.

[0075] Within the meaning of this invention, the above parameters of permeated amount and skin permeation rate (as well as cumulative permeated amount and cumulative skin permeation rate) refer to average values calculated from 3 in vitro permeation test experiments.

[0076] The TTS according to the present invention can also be characterized by certain parameters when measured in an in vivo clinical study.

[0077] Within the meaning of this invention, the parameter "mean release rate" refers to the mean release rate in μg/h, in mg/h, in μg/24 h, in mg/24 h, in μg/day or in mg/day during the administration period (e.g. 1 to 7 days) by which the active agent is released through the human skin into the systemic circulation and is based on the AUC obtained during said administration period in a clinical study. The mean release rate is a parameter used to identify the dose or intensity of a TTS. Since, unlike intravenous or oral administration, for example, and as also described above, a TTS generally contains more active in the system than is actually delivered to the skin and systemic circulation, the amount of active compound in the TTS is not significant as a parameter for the dose. It is for this reason that for a TTS the dose or intensity is generally characterized by the mean release rate, which more accurately describes the amount of active released to the individual over time.

[0078] Within the meaning of this invention, the term "extended period of time" refers to a period of at least or about 24 hours, at least or about 48 hours, at least or about 84 hours, at least or about 168 hours, at least or about 1 day, at least or about 3.5 days, or at least or about 7 days, or to a period of about 24 hours to about 168 hours, or 1 to 7 days, or about 24 hours to about 84 hours, or 1 to 3.5 days.

[0079] For continuous drug treatment, the frequency of drug administration is preferably kept sufficiently high in order to maintain a therapeutically effective blood plasma concentration. In other words, the interval between two administrations of the dosage form, also called dosage interval, needs to be adapted accordingly. Within the meaning of the present invention, the term "dosage interval" refers to the period of time between two consecutive administrations of TTS, i.e. the interval between two consecutive points in time at which a TTS is applied to the patient's skin. Once applied, the TTS is generally kept on the patient's skin throughout the dosage interval and only removed at the end of the dosage interval, at which time a new TTS is applied to the skin. For example, if the dosage interval is 168 hours or 7 days, the TTS is applied to, and kept on, the patient's skin for 168 hours or 7 days. After 168 hours or 7 days, the TTS is removed from the skin and a new TTS is applied. Thus, a dosing interval of 168 hours or 7 days allows for a once-weekly TTS exchange mode in a timed treatment.

[0080] Within the meaning of this invention, the term "room temperature" refers to the unmodified temperature found inside the laboratory where the experiments are conducted, and is generally between 15 to 35°C, preferably around 18 to 25°C.

[0081] Within the meaning of this invention, the term "patient" refers to an individual who has presented a clinical manifestation of a particular symptom or symptoms suggesting the need for treatment, which is employed preventively or prophylactically for a condition, or who has been diagnosed with a condition to be treated.

[0082] Within the meaning of this invention the term "pharmacokinetic parameters" refers to parameters describing the blood plasma curve, e.g., Cmax, Ct and AUCt1-t2 obtained in a clinical study, e.g., by administering a single dose, multiple doses or steady state of the TTS of an active agent, e.g., an asenapine TTS to healthy human subjects. The pharmacokinetic parameters of individual subjects are summarized using arithmetic and geometric means, e.g., a mean Cmax, a mean AUCt and a mean AUCINF, and additional statistics such as the respective standard deviations and standard errors, the minimum value, the maximum value, and the median value when the list of values is sorted (Mean). In the context of the present invention, pharmacokinetic parameters, e.g., Cmax, Ct and AUCt1-t2 refer to arithmetic or geometric mean values and preferably refer to geometric mean values. It cannot be excluded that the absolute mean values obtained for a given TTS in a clinical study vary to a certain extent from study to study. In order to enable a comparison of absolute mean values between studies, a reference formulation, e.g. in the future any product based on the invention, can be used as an internal standard. A comparison of the AUC per release area of the respective reference product in the previous and subsequent study can be used to obtain a correction factor to take into account differences from study to study.

[0083] Clinical studies according to the present invention refer to studies carried out in full compliance with the International Conference for Harmonization of Clinical Trials (ICH) and all applicable Good Clinical Practices (GCP) and local regulations.

[0084] Within the meaning of this invention, the term "healthy human subject" refers to a man or woman with a body weight ranging from 55 kg to 100 kg and a body mass index (BMI) ranging from 18 to 29 and normal physiological parameters such as blood pressure, etc. Healthy human subjects for the purposes of the present invention are selected according to the inclusion and exclusion criteria that are based on, and in accordance with, the recommendations of the ICH.

[0085] Within the meaning of this invention, the term "subject population" refers to at least ten individual healthy human subjects.

[0086] Within the meaning of this invention, the term "geometric mean" refers to the mean of log-transformed data retransformed to the original scale.

[0087] Within the meaning of this invention, the term "arithmetic mean" refers to the sum of all observation values, divided by the total number of observations.

[0088] Within the meaning of this invention, the parameter "AUC" corresponds to the area under the plasma concentration time curve. The AUC value is proportional to the amount of active agent absorbed into the total blood circulation and is therefore a measure for bioavailability.

[0089] Within the meaning of this invention, the parameter "AUCt1- t2" is given in (ng/mL) h and refers to the area under the plasma concentration-time curve in hours t1 to t2 and is calculated by the linear trapezoidal method.

[0090] Within the meaning of this invention, the parameter "Cmax" is given in (ng/mL) and refers to the maximum observed blood plasma concentration of the active agent.

[0091] Within the meaning of this invention, the parameter "Ct" is given in (ng/mL) and refers to the blood plasma concentration of the active agent observed at time t.

[0092] Within the meaning of this invention, the parameter "tmax" is given in h and refers to the point in time at which the Cmax value is reached. In other words, tmax is the point in time of the maximum observed plasma concentration.

[0093] Within the meaning of this invention, the parameter "tlag" is given in h and refers to the delay between the administration time (in the case of a TTS, the time at which the TTS is first applied to the skin, i.e. t = 0) and the time of appearance of a measurable blood plasma concentration. The tlag can be calculated approximately as the arithmetic mean value of the first point in time at which a measurable (i.e. non-zero) blood plasma concentration of active agent is obtained or represented by an average value.

[0094] Within the meaning of this invention, the term "mean plasma concentration" is given in (ng/mL) and is an average of the individual plasma concentrations of active agent, e.g., asenapine, at each time point.

[0095] Within the meaning of this invention, the term "coating composition" refers to a composition comprising all the components of the matrix layer in a solvent, which can be coated over the reinforcement layer or release liner to form the matrix layer after drying.

[0096] Within the meaning of this invention, the term "dissolve" refers to the process of obtaining a solution, which is clear and does not contain any particles, as visible to the naked eye.

[0097] Within the meaning of this invention, the term "solvent" refers to any liquid substance, which preferably is a volatile organic liquid, such as methanol, ethanol, isopropanol, acetone, ethyl acetate, methylene chloride, hexane, n-heptane, toluene and mixtures thereof.

[0098] Within the meaning of this invention, and unless otherwise specified, the term "about" refers to an amount that is ± 10% of the described amount. In some embodiments, the term "about" refers to an amount that is ± 5% of the described amount. In some embodiments, the term "about" refers to an amount that is ± 2% of the described amount.

Brief Description of the Drawings

[0099] Fig. 1a depicts the skin permeation rate of asenapine from TTS prepared according to Examples 1a, 1b, 1c and 1d over 0 to 72 hours.

[00100] Fig. 1b depicts the skin permeation rate of asenapine from TTS prepared according to Examples 1a, 1b, 1c and 1d over 0 to 168 hours.

[00101] Fig. 1c depicts the utilization of asenapine TTS prepared according to Examples 1a, 1b, 1c and 1d after 72 hours.

[00102] Fig. 2a depicts the skin permeation rate of asenapine from TTS prepared according to Examples 2a, 2b, 2c and 2d over 0 to 72 hours.

[00103] Fig. 2b depicts the skin permeation rate of asenapine from TTS prepared according to Examples 2a, 2b, 2c and 2d over 0 to 168 hours.

[00104] Fig. 2c depicts the utilization of asenapine TTS prepared according to Examples 2a, 2b, 2c and 2d after 72 hours.

[00105] Fig. 2d depicts the skin permeation rate of asenapine from TTS prepared according to Examples 2e to 2j for 0 to 72 hours.

[00106] Fig. 2e depicts the use of asenapine TTS prepared according to Examples 2e to 2j after 72 hours.

[00107] Fig. 3a depicts the skin permeation rate of asenapine from TTS prepared according to Examples 3a, 3b, 3c, 3d and 3e.

[00108] Fig. 3b depicts the use of asenapine TTS prepared according to Examples 3a, 3b, 3c, 3d and 3e after 56 hours.

[00109] Fig. 4a depicts the skin permeation rate of asenapine from TTS prepared according to Examples 4a and 4b over 0 to 72 hours.

[00110] Fig. 4b depicts the skin permeation rate of asenapine from TTS prepared according to Examples 4a and 4b over 0 to 168 hours.

[00111] Fig. 4c depicts the utilization of asenapine from TTS prepared according to Examples 4a and 4b after 72 hours and 168 hours.

[00112] Fig. 5a depicts the skin permeation rate of asenapine from TTS prepared according to Examples 5a, 5b and 5c over 0 to 72 hours.

[00113] Fig. 5b depicts the utilization of asenapine TTS prepared according to Examples 5a, 5b and 5c after 72 hours.

[00114] Fig. 6a depicts the skin permeation rate of asenapine from TTS prepared according to Examples 6a, 6b and 6c over 0 to 72 hours.

[00115] Fig. 6b depicts the use of asenapine TTS prepared according to Examples 6a, 6b and 6c after 72 hours.

[00116] Fig. 7a depicts the skin permeation rate of asenapine from TTS prepared according to Examples 7a, 7b and 7c over 0 to 72 hours.

[00117] Fig. 7b depicts the utilization of asenapine TTS prepared according to Examples 7a, 7b and 7c after 72 hours.

[00118] Fig. 8a depicts the skin permeation rate of asenapine from TTS prepared according to Examples 8a, 8b and 8c over 0 to 72 hours.

[00119] Fig. 8b depicts the utilization of asenapine TTS prepared according to Examples 8a, 8b and 8c after 72 hours.

[00120] Fig. 9a depicts the skin permeation rate of asenapine from TTS prepared according to Examples 9a and 9b over 0 to 72 hours.

[00121] Fig. 9b depicts the use of asenapine TTS prepared according to Examples 9a and 9b after 72 hours.

[00122] Fig. 10a depicts the skin permeation rate of asenapine from TTS prepared according to Example 10 over 0 to 72 hours.

[00123] Fig. 10b depicts the use of asenapine TTS prepared according to Example 10 after 72 hours.

[00124] Fig. 11 depicts the blood plasma concentration of asenapine from TTS prepared according to Examples 11a, 11b, 11c and 11d.

[00125] Fig. 12a depicts the skin permeation rate of asenapine from TTS prepared according to Examples 12a and 12b over 0 to 72 hours.

[00126] Fig. 12b depicts the use of asenapine TTS prepared according to Examples 12a and 12b after 72 hours.

[00127] Fig. 13a represents the blood plasma concentration of asenapine (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 during 0 to 168 hours.

[00128] Fig. 13b depicts the blood plasma concentration of asenapine (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 0 to 84 hours.

[00129] Fig. 13c depicts a blood plasma concentration of asenapine-glucuronide (geometric mean values with the 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 0 to 168 hours.

[00130] Fig. 13d depicts a blood plasma concentration of asenapine-glucuronide (geometric mean values with the 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 0 to 96 hours.

[00131] Fig. 13e depicts the blood plasma concentration of N-desmethyl-asenapine (geometric mean values with the 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 0 to 108 hours.

Detailed Description TTS Structure

[00132] The present invention relates to a transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure containing asenapine.

[00133] In particular, the self-adhesive layer structure may comprise a therapeutically effective amount of asenapine.

[00134] Preferably, the self-adhesive layer structure according to the present invention comprises A) a reinforcing layer, and B) a matrix layer containing asenapine consisting of a matrix layer composition comprising 1. asenapine and 2. a polymer.

[00135] 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: A) a reinforcing layer; B) a matrix layer containing asenapine consisting of a matrix layer composition comprising: 1. asenapine; and 2. a polymer selected from acrylic polymers; wherein the transdermal therapeutic system has a release area of 5 to 100 cm2.

[00136] 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: A) a reinforcing layer; B) a matrix layer containing asenapine consisting of a matrix layer composition comprising: 1. asenapine in the form of the free base; and 2. a polymer; wherein the areal weight of the matrix layer is at least 90 g/m2, and wherein the matrix layer containing asenapine does not comprise isopropyl palmitate.

[00137] The reinforcement layer is, in particular, substantially impermeable to asenapine.

[00138] 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.

[00139] In such a matrix-type TTS, asenapine, and preferably a therapeutically effective amount of asenapine, is included in a matrix layer containing asenapine. The self-adhesive layer structure in such a matrix-type TTS may include one or more other layers, such as a skin contact layer. In such an additional layer, the active agent may or may not be included. As outlined above, the skin contact layer may, even if manufactured as an active agent-free layer, after equilibration, comprise asenapine and thus may also be considered as an (additional) matrix layer. The additional layer and the asenapine-containing matrix layer may comprise the same polymer or different polymers. Any asenapine-containing matrix layer and the additional layer(s) may be directly in contact with 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 that are substantially of the same composition, the resulting double layer shall be considered as one matrix layer.

[00140] In a reservoir type TTS according to the present invention, asenapine is included in a liquid or semi-liquid reservoir. The self-adhesive layer structure in such a reservoir type TTS may include one or more additional layers, such as a skin contact layer. In such an additional layer, the active agent may or may not be included. As outlined above, the skin contact layer may, even if manufactured as an active agent-free layer, after equilibration, comprise asenapine and thus may also be considered as a matrix layer. The reservoir type TTS also includes a rate-controlling membrane separating the reservoir and the skin contact layer.

[00141] Thus, in certain embodiments, the self-adhesive layer structure comprises an additional reservoir layer that is located between the reinforcement layer and the matrix layer, and an additional rate control membrane that is located between the additional reservoir layer and the matrix layer.

[00142] 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 adhesion between the self-adhesive layer structure and the patient's skin during administration.

[00143] In such embodiments, the self-adhesive layer structure may or may not comprise a membrane that is located between the matrix layer and the additional skin contact layer, wherein the membrane is preferably a rate controlling membrane.

[00144] 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 patient's skin during administration is then provided by other means, for example a matrix layer containing asenapine and/or an adhesive layer.

[00145] Thus, according to certain embodiments of the invention, the TTS may also comprise an adhesive overlayer or not comprise an adhesive overlayer, and preferably not comprise an adhesive overlayer. This adhesive overlayer is, in particular, larger than a self-adhesive layer structure containing asenapine and is bonded thereto to enhance the adhesive properties of the overall transdermal therapeutic system. Said adhesive overlayer also comprises a reinforcing layer. The area of said adhesive overlayer adds to the overall size of the TTS, but does not add to the release area. The adhesive overlayer comprises a self-adhesive polymer or a self-adhesive polymer blend selected from the group of acrylic polymers, polyisobutylenes, styrene-isoprene-styrene copolymers, polysiloxanes, and blends thereof, which may be identical to, or different from, any polymer or polymer blend included in the self-adhesive layer structure containing active agent.

[00146] The self-adhesive layer structure according to the invention is usually located on a peelable protective layer (release liner) from which it is removed immediately before application to the patient's skin surface. Thus, the TTS may also comprise a release liner. A TTS thus protected is usually stored in a seam-sealed bag. The packaging may be child-resistant and/or senior-friendly.

Matrix layer and matrix layer composition

[00147] As outlined in greater 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.

[00148] In these embodiments, the matrix layer composition comprises: 1. asenapine; and 2. a polymer;

[00149] 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 a release area of 5 to 100 cm2.

[00150] In certain embodiments of the invention, the release area ranges from 5 to 100 cm2, preferably from 10 to 80 cm2, and more preferably from 10 to 25 cm2 or from 10 to 20 cm2, from 25 to 55 cm2 or from 25 to 35 cm2 or from 55 to 65 cm2, i.e., the transdermal therapeutic system has a release area of 5 to 100 cm2, preferably from 10 to 80 cm2, and more preferably from 10 to 25 cm2 or from 10 to 20 cm2, from 25 to 55 cm2 or from 25 to 35 cm2 or from 55 to 65 cm2.

[00151] In another specific embodiment of the invention, the matrix layer composition comprises asenapine in free base form and a polymer, wherein the areal weight of the matrix layer is at least 90 g/m2 and wherein the matrix layer containing asenapine does not comprise isopropyl palmitate.

[00152] In certain embodiments of the invention, the area weight of the matrix layer ranges from 90 to 230 g/m2, preferably from 110 to 210 g/m2, and more preferably from 120 to 170 g/m2.

[00153] Without wishing to be bound by theory, it is believed that the advantageous characteristics 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 in two ways, by adjusting the concentration and/or the area weight of the layers containing the asenapine such as the matrix layer.

[00154] Thus, in certain embodiments of the invention, the transdermal therapeutic system contains at least 0.70 mg/cm2, preferably at least 0.80 mg/cm2, more preferably at least 0.82 mg/cm2, and most preferably at least 0.83 mg/cm2 asenapine per release area. In certain other embodiments of the invention, the transdermal therapeutic system contains at least 0.90 mg/cm2, at least 1.00 mg/cm2, at least 1.2 mg/cm2, at least 1.5 mg/cm2, or at least 2.0 mg/cm2 asenapine per release area.

[00155] In particular, the transdermal therapeutic system contains from 0.70 mg/cm2 to 4.0 mg/cm2, preferably from 0.80 mg/cm2 to 3.0 mg/cm2, more preferably from 0.82 mg/cm2 to 2.0 mg/cm2 and most preferably from 0.83 mg/cm2 to 1.7 mg/cm2 of asenapine.

[00156] 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 other polymers.

[00157] 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 the matrix layer includes sufficient amounts of polymer to provide sufficient cohesion.

[00158] 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 more preferably from 15 to 60 mg.

[00159] In certain embodiments, the transdermal therapeutic system has a release area of 5 to 100 cm2, and the amount of asenapine contained in the TTS ranges from 5 to 100 mg.

[00160] In certain embodiments of the invention, the matrix layer containing asenapine 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 to 15% of the matrix layer composition, and most preferably does not comprise isopropyl palmitate.

[00161] In certain embodiments of the invention, the matrix layer containing asenapine 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 to 10% of the matrix layer composition, and most preferably does not comprise isopropyl myristate.

[00162] In certain embodiments of the invention, the matrix layer containing asenapine does not comprise ethyl cellulose in an amount of 10 to 20% of the matrix layer composition and preferably does not comprise ethyl cellulose.

[00163] In certain embodiments of the invention, the matrix layer containing asenapine does not comprise hydrogen chloride.

[00164] 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 an alkali salt of dicarboxylic acid. In yet another embodiment, an asenapine-containing layer does not comprise an alkali salt of maleic acid.

[00165] 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.

[00166] In certain embodiments, the matrix layer containing asenapine is obtainable by drying the coated coating composition wherein no hydrochloric acid has been included in the coating composition.

[00167] In certain embodiments of the invention, the matrix layer containing asenapine does not comprise toluene.

[00168] In certain embodiments of the invention, the matrix layer containing asenapine is obtainable by drying the coated coating composition comprising no toluene.

Asenapine

[00169] According to the invention, the self-adhesive layer structure contains asenapine, in particular in a therapeutically effective amount.

[00170] In certain embodiments, the self-adhesive layer structure comprises an asenapine-containing matrix layer consisting of a matrix layer composition comprising asenapine.

[00171] While according to the present invention, the active agent may be present in the TTS in free base or protonated form, the free base form is preferred.

[00172] Thus, in certain embodiments, the asenapine in the matrix layer composition is included in the free base form.

[00173] In certain embodiments, the matrix layer composition is obtainable by incorporating an asenapine in free base form.

[00174] 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 free base form.

[00175] The asenapine in the matrix layer may be completely dissolved, or the matrix layer composition may contain asenapine particles, preferably consisting of asenapine free base.

[00176] As outlined above, the amount of asenapine in the TTS is believed to be important for good release of the active, and can be, for example, adjusted by a concentration of asenapine. 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.

[00177] In certain embodiments, asenapine has a purity of at least 95%, preferably at least 98%, and more preferably 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 may be employed if the HPLC is performed isocratically: Column: Octadecyl phase acc. Ph. Eur. 2.2.29 (USP phase L1) Kromasil C18 125 mm x 4.0 mm; 5 μm or equivalent Mobile phase: KH2PO4/Methanol/TEA (45:55:0.1; v:v:v); pH 2.5 ± 0.05 (TEA = triethylamine) Gradient: isocratic Flow rate: Column temperature: 40 °C Wavelength: 225 nm, 270 nm and 3-D field; Evaluation is performed at 270 nm Run time: 10 min [0178] Additionally, the following conditions can be employed if HPLC is performed with a gradient: Column: Octadecyl phase acc. Ph. Eur. 2.2.29 (USP phase L1) Kinetex C18 EVO 100 mm x 4.6 mm; 2.1 μm or equivalent Mobile phase: A: 0.02 mol KH2PO4 /Methanol/TEA buffer (70:30:0.1; v:v:v) adj. for pH 2.5 B: 0.02 mol KH2PO4/Methanol/TEA buffer (30:70:0.1; v:v:v); adj. for pH 2.5 (TEA = triethylamine) Flow rate: 1.0 mL Injection volume: 30 μl Column temperature: 40 °C Wavelength: 225 nm, 270 nm and 3-D field; The 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

[00178] 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.

[00179] 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.

[00180] In a preferred embodiment, the polymer is selected from pressure-sensitive adhesive polymers.

[00181] Polymers that are suitable as the polymer according to the invention are polysiloxanes, polyisobutylenes, styrene-isoprene-styrene block copolymers and acrylic polymers.

[00182] Corresponding commercial products are available, for example, under the brand names Bio-PSAs (polysiloxanes), Oppanol B10/B100 (a polyisobutylene polymer, 85:15), JSR-SIS (a styrene-isoprene-styrene copolymer) or Duro-TakTM (acrylic polymers, see below for details).

[00183] Suitable polyisobutylenes according to the invention are available under the brand name Oppanol®. Combinations of high molecular weight polyisobutylenes (B100/B80) and low molecular weight polyisobutylenes (B10, B11, B12, B13) can be employed. Suitable ratios of low molecular weight polyisobutylene to high molecular weight polyisobutylene are in the range of 100:1 to 1:100, preferably from 95:5 to 40:60, more preferably from 90:10 to 80:20. Typically, low molecular weight polyisobutylene has a viscosity-average molecular weight of 10,000 to 70,000 g/mol and/or a weight-average molecular weight of 10,000 to 70,000 g/mol, and high molecular weight polyisobutylene has a viscosity-average molecular weight of 1,000,000 to 1,200,000 g/mol and/or a weight-average molecular weight of 1,400,000 to 1,600,000 g/mol. A preferred example of a polyisobutylene blend is B10/B100 in a ratio of 85/15 or 90/10. Oppanol® B100 has a viscosity-average molecular weight Mv of 1,110,000, and a weight-average molecular weight Mw of 1,550,000. Oppanol® B10 has a viscosity average molecular weight Mv of 40,000, and a weight average molecular weight Mw of 36,000. In certain embodiments, polybutene may be added to polyisobutylenes.

[00184] Preferably, the polymer is selected from acrylic polymers, wherein the acrylic polymers comprise or do not comprise functional groups.

[00185] Corresponding commercial products are available, for example, under the brand names Duro-TakTM 387-2287 (an acrylic copolymer comprising hydroxyl groups), Duro-TakTM 387-2516 (an acrylic copolymer comprising hydroxyl groups), Duro-TakTM 387-2051 (an acrylic copolymer comprising carboxylic acid groups), Duro-TakTM 387-2353 (an acrylic copolymer comprising carboxylic acid groups), Duro-TakTM 387-4098 (an acrylic copolymer comprising no functional groups) and Duro-TakTM 387-9301 (an acrylic copolymer comprising no functional groups).

[00186] 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.

[00187] 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.

[00188] In other 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.

[00189] Such a copolymer based on vinyl acetate, 2-ethylhexyl acrylate, 2-hydroxyethyl acrylate and glycidyl methacrylate is commercially available under the brand names Duro-TakTM 387-2287 (supplied as a solution in ethyl acetate without a crosslinking agent) and Duro-TakTM 387-2516 (supplied as a solution in ethyl acetate, ethanol, n-heptane and methanol with a titanium crosslinking agent). Thus, depending on the type of commercially available acrylic polymer employed and depending on whether a crosslinking agent is added to the coating composition, the polymer in the finished matrix layer is either crosslinked (and preferably is crosslinked by a titanium crosslinking agent) or is not crosslinked by a crosslinking agent.

[00190] In other certain 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.

[00191] In other 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-TakTM 387-9301 (supplied as a solution in ethyl acetate).

[00192] In other preferred embodiments, the polymer is a copolymer based on 2-ethylhexyl acrylate and vinyl acetate, which is commercially available under the brand name Duro-TakTM 387-4098 (supplied as a solution in ethyl acetate).

[00193] 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 particularly preferred in the case where the matrix layer composition does not comprise any additional polymer(s) besides.

[00194] 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).

[00195] Additional additives and polymers may also be added to enhance cohesion and/or adhesion.

[00196] Certain polymers in particular reduce cold flow and are therefore in particular suitable as additional polymer. A polymer matrix may exhibit cold flow, since such polymer compositions often exhibit, despite a high viscosity, the ability to flow very slowly. Thus, during storage, the matrix may flow to a certain extent over the edges of the reinforcement layer. This is a problem with storage stability and may 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 for example be used to reduce cold flow. Thus, in certain embodiments, the matrix layer composition additionally comprises a basic polymer, in particular an amine functional acrylate such as for example Eudragit E100.

[00197] 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.

Other additives

[00198] 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 crosslinking agents, solubilizers, fillers, tackifiers, plasticizers, stabilizers, softeners, skin care substances, permeation enhancers, i.e., substances that influence the barrier properties of the stratum corneum in the sense of increasing the permeability of the active agent, pH regulators, and preservatives. Particularly preferred additives are tackifiers and stabilizers. Such additives may be present in an asenapine-containing layer in an amount of 0.001% to 15% of the matrix layer composition per additive. In a given embodiment, the total amount of all additives is from 0.001% to 25% of the matrix layer composition. Thereafter, where a range for a specific additive amount is provided, such range refers to the amount per individual additive.

[00199] It should be noted that in pharmaceutical formulations, the formulation components are categorized according to their physicochemical and physiological properties, and according to 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. For example, a certain polymer can be a crystallization inhibitor, but also an adhesion agent. Some substances can, for example, be a typical softener, but at the same time act as a permeation enhancer. The skilled person will be able to determine on the basis of his general knowledge, to which category of formulation component a certain substance or compound belongs. In the following, details on excipients and additives are given which are, however, not to be construed as being exclusive. Other substances not explicitly listed in the present description can also be 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 within the meaning of the present invention.

[00200] The crosslinking agent may be selected from the group consisting of aluminum and titanium crosslinking agents such as aluminum acetylacetonate, titanium acetylacetonate or polybutyltitanate, and preferably is a titanium crosslinking agent. The amount of crosslinking 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 that is self-crosslinking, i.e., comprises a crosslinking functional group such as glycidyl groups, which reacts upon heating. According to another specific embodiment, the matrix layer composition comprises a crosslinking agent as described above, and a self-crosslinking polymer.

[00201] In one embodiment, the matrix layer composition also comprises a solubilizer. The solubilizer preferably improves the solubility of an asenapine in a layer containing asenapine. Preferred solubilizers include, for example, 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; nonionic solubilizers made by reacting castor oil with ethylene oxide, and any mixtures thereof which may contain fatty acids or fatty alcohols; cellulose and methylcellulose and derivatives thereof such as hydroxypropylcellulose and hypromellose acetate succinate; various cyclodextrins and derivatives thereof; nonionic tri-block copolymers having a central hydrophobic polyoxypropylene chain flanked by two hydrophilic polyoxyethylene chains known as poloxamers; a polyethylene glycol, polyvinyl acetate and polyvinylcaprolactam based graft copolymer, also abbreviated as PVAc-PVCap-PEG and known as Soluplus®; purified grades of naturally derived castor oil, polyethylene glycol 400, polyoxyethylene sorbitan monooleate (such as polysorbate 80) or propylene glycols; diethylene glycol monoethyl ether; as well as any of the soluble polyvinylpyrrolidones mentioned below, but also insoluble/crosslinked 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.

[00202] However, the permeation enhancers mentioned below can also act as solubilizers. Furthermore, crystallization inhibitors can also act as solubilizers.

[00203] Fillers such as silica gel, titanium dioxide and zinc oxide may be employed in conjunction with the polymer in order to influence certain physical parameters, such as cohesion and bonding strength, in the desired manner.

[00204] In the event that the matrix layer is required to have self-adhesive properties, and one or more polymers are selected to provide sufficient self-adhesive properties or not, a tackifier is added. The tackifier may be selected from polyvinylpyrrolidone (which, due to its ability to absorb water, is capable of maintaining the adhesive properties of the matrix layer and thus may be considered as a tackifier in a broad sense), triglycerides, polyethylene glycols, dipropylene glycol, resins, rosin 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 5 to 15% of the matrix layer composition.

[00205] The term "soluble polyvinylpyrrolidone" refers to polyvinylpyrrolidone, also known as povidone, which is soluble to 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 that 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 from 10.2 to 13.8, corresponding to a nominal K-value of 12. Kollidon® 17 PF is characterized by a K-value range from 15.3 to 18.4, corresponding to a nominal K-value of 17. Kollidon® 25 is characterized by a K-value range from 22.5 to 27.0, corresponding to a nominal K-value of 25, Kollidon® 30 is characterized by a K-value range from 27.0 to 32.4, corresponding to a nominal K-value of 30. Kollidon® 90 F is characterized by a K-value range from 81.0 to 97.2, corresponding to a nominal K-value of 90. The preferred Kollidon® grades are Kollidon® 12 PF, Kollidon® 30 and Kollidon® 90 F.

[00206] Within the meaning of this invention, the term "K-value" refers to a calculated value of the relative viscosity of polyvinylpyrrolidone in water according to European Pharmacopoeia (Ph.Eur.) and USP monographs for "Povidone".

[00207] 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.

[00208] In one embodiment, the matrix layer composition also comprises a softener/plasticizer. Exemplary softeners/plasticizers include linear or branched, saturated or unsaturated alcohols having from 6 to 20 carbon atoms, triglycerides, and polyethylene glycols.

[00209] In one embodiment, the matrix layer composition also comprises a skin care substance. Such substances can be employed to prevent or reduce skin irritation as determined by evaluating the skin using dermal response scores. Suitable skin care substances include sterol compounds such as cholesterol, dexpanthenol, alpha-bisabolol, and antihistamines. The skin care substances are preferably employed in amounts of 1 to 10% of the matrix layer composition.

[00210] 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 fatty acid diesters. Such a mixture of propylene glycol monoesters and fatty acid diesters is commercially available, for example, under the brand name Capryol, which is a propylene glycol monocaprylate (type II), a mixture of propylene glycol monoesters and diesters of fatty acids having a ratio of >90% monoesters and <10% diesters, wherein the fatty acids consist of caprylic acid.

[00211] 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, an asenapine-containing layer does not comprise an alkali salt of dicarboxylic acid. In yet another embodiment, the matrix layer composition does not comprise an alkali salt of maleic acid.

[00212] 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

[00213] The TTS according to the invention is designed to transdermally deliver asenapine to the systemic circulation over a predefined prolonged period of time.

[00214] In one aspect, the TTS according to the invention provides an average 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, and more preferably 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 for at least 24 hours of administration, preferably for at least 48 hours of administration, more preferably for at least 72 hours of administration, and most preferably for at least 84 hours of administration.

[00215] According to certain embodiments, the TTS according to the invention provides a cumulative skin permeation rate of asenapine at 48 hours or at 72 hours as measured in a Franz diffusion cell with dermatomized human skin of from 1 μg/(cm2 h) to 20 μg/(cm2 h), preferably from 2 μg/(cm2 h) to 15 μg/(cm2 h), and more preferably from 4 μg/(cm2 h) to 12 μg/(cm2 h).

[00216] 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 dermatomized human skin of 0 μg/(cm2 h) to 10 μg/(cm2 h) in the first 8 hours, 2 μg/(cm2 h) to 20 μg/(cm2 h) from 8 hours to 24 hours, 3 μg/(cm2 h) to 20 μg/(cm2 h) from 24 hours to 32 hours, 3 μg/(cm2 h) to 20 μg/(cm2 h) from 32 hours to 48 hours, 2 μg/(cm2 h) to 15 μg/(cm2 h) from 48 hours to 72 hours.

[00217] 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 dermatomized human skin of 0.05 mg/cm2 to 1.0 mg/cm2, preferably of 0.1 mg/cm2 to 0.7 mg/cm2 over a time period of 48 hours.

[00218] 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 dermatomized human skin of 0.1 mg/cm2 to 2.0 mg/cm2, preferably of 0.2 mg/cm2 to 1.0 mg/cm2 over a time period of 72 hours.

Treatment method/medical use

[00219] According to 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 for the treatment of a human patient.

[00220] In certain embodiments, the TTS according to the invention is preferably for use in a method for the treatment of psychosis, and more preferably for use in a method for the treatment of one or more conditions selected from schizophrenia, bipolar disorder, post-traumatic stress disorder, major depressive disorder, dementia-related psychosis, agitation and manic disorder, in particular for use in a method for the treatment of schizophrenia and/or bipolar disorder in a human patient, and in particular for use in a method for the treatment of acute mixed or manic episodes of bipolar disorder in a human patient.

[00221] In certain embodiments, the TTS according to the invention is for use in a method for treating acute mixed or manic 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 adjunct treatment to lithium or valproate in a method for 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 for treating bipolar disorder in a human patient, in particular an adult.

[00222] The TTS according to the invention is also preferably for use in a method for 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 surface of the subject's body 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.

[00223] Within the meaning of the present invention, the body surface may be located anywhere on the body, and is, in certain embodiments, selected from the upper outer arm, upper chest, upper back, or the side of the chest.

[00224] The TTS may also be for use in a treatment method 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.

[00225] Accordingly, the invention also relates to TTS for use in a method of treatment, and in particular for use in a method for the treatment of schizophrenia and/or bipolar disorder, and in particular acute mixed or manic episodes of bipolar disorder, in a timed treatment with a once-daily TTS switching mode (24-hour, or 1-day, dosing interval), a twice-weekly TTS switching mode (84-hour, or 3.5-day, dosing interval) or a once-weekly TTS switching mode (168-hour, or 7-day, dosing interval).

[00226] The TTS according to the invention is also preferably for use in a method for 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.

[00227] 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 employing a transdermal and sublingual dose of asenapine that induces substantially the same blood plasma exposure of asenapine.

[00228] 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.

[00229] In such a method for treating a patient or in such a method of reducing at least one asenapine-related side effect, but also in all transdermal therapeutic systems for use in a method of treatment, transdermal therapeutic systems for use in a method of reducing at least one asenapine-related side effect, methods of treatment and methods of reducing at least one asenapine-related side effect, as well as asenapine for use in a method for treating a human patient as will be described below, the following may generally also apply: (i) "the at least one" asenapine-related side effect is, in particular, fatigue, drowsiness, dizziness, oral hypoesthesia, or any combination thereof. (ii) Because such 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, drowsiness, dizziness, or any combination thereof. (iii) Furthermore, the incidence of at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine can 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 at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine can be reduced. The intensity of a side effect can be determined, for example, by rating the side effects on a scale indicating "mild", "moderate", or "severe" intensity, and a reduction in intensity can be quantified by comparing the median intensity. (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. (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%.

[00230] As regards the type of side effects, it should be noted that fatigue and drowsiness, whilst designating clinically different conditions, have common and/or similar symptoms and may therefore be difficult to distinguish, particularly if not followed over a long period.

[00231] According to another specific aspect, the present invention also relates to a method of treatment, and in particular a method for treating a human patient.

[00232] The invention relates in particular to a method for the treatment of psychosis, and in particular to a method for the treatment of one or more conditions selected from schizophrenia, bipolar disorder, post-traumatic stress disorder, major depressive disorder, dementia-related psychosis, agitation or manic disorder, and preferably to a method for the treatment of schizophrenia and/or bipolar disorder in a human patient, and in particular acute mixed or manic episodes of bipolar disorder including applying a transdermal therapeutic system according to the invention to the skin of a human patient.

[00233] In certain embodiments, the invention also relates to a method for treating acute mixed or manic episodes of bipolar disorder in an adult or a pediatric patient 10 to 17 years of age. In certain embodiments, the invention also relates to a method for treating bipolar disorder in a human patient, in particular an adult, as an adjunct treatment to lithium or valproate. In certain embodiments, the invention also relates to a maintenance monotherapy treatment in a method for treating bipolar disorder in a human patient, in particular an adult.

[00234] The invention also preferably relates to a method for 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) of 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.

[00235] The invention also relates 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 can 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.

[00236] Accordingly, the invention also relates to a treatment method in a timed treatment with a once-daily TTS switching mode (24-hour or 1-day dosing interval), a twice-weekly TTS switching mode (84-hour or 3.5-day dosing interval) or a once-weekly TTS switching mode (168-hour or 7-day dosing interval).

[00237] 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.

[00238] In another embodiment, the present invention also relates 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.

[00239] The invention also relates to a method for reducing at least one asenapine-related side effect in a patient being treated with sublingual asenapine therapy, the method comprising a) discontinuing sublingual asenapine therapy; and 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.

[00240] In such a method, the transdermal therapeutic system may release an amount of asenapine equivalent to the amount of asenapine originally delivered by sublingual asenapine therapy.

[00241] The inventors have surprisingly shown that a relatively constant blood plasma concentration of asenapine can be maintained for an extended period of time by transdermal delivery of asenapine.

[00242] Thus, according to a specific aspect, the present invention relates to asenapine for use in a method for 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.

[00243] 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.

[00244] Furthermore, asenapine is preferably for use in a method for the treatment of psychosis, and in particular for use in a method for the treatment of one or more conditions selected from schizophrenia, bipolar disorder, post-traumatic stress disorder, major depressive disorder, dementia-related psychosis, agitation or manic disorder, or for use in a method for the treatment of schizophrenia and/or bipolar disorder, more preferably bipolar disorder and in particular acute mixed or manic episodes of bipolar disorder. Asenapine is also preferably for use in a method for the treatment of acute mixed or manic episodes of bipolar disorder in an adult or a pediatric patient 10 to 17 years of age, for use as an adjunct treatment to lithium or valproate or for use as maintenance monotherapy treatment in a method for the treatment of bipolar disorder in a human patient, in particular an adult.

[00245] Asenapine is also preferably for use in a method for 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) of 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.

[00246] The relatively constant blood plasma concentration of asenapine can be described by severe pharmacokinetic parameters as obtained in an in vivo clinical study in human subjects.

[00247] Thus, in certain embodiments, the present invention relates to asenapine for use in a method of treating a human patient by transdermal administration of asenapine as described above, providing, upon transdermal delivery, an average 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/hr or 42 to 625 μg/hr, more preferably 2.0 to 10 mg/day, 2.0 to 10 mg/24 hr, 2,000 to 10,000 μg/day, 2,000 to 10,000 μg/24 hr, 0.083 to 0.417 mg/hr or 83 to 417 μg/hr for at least 48 hours or 2 days of administration, or providing, by transdermal delivery, an average release rate of 0.5 to 20 mg/day, 0.5 to 20 mg/24 hr, 500 to 20,000 μg/day, 500 to 20,000 μg/24 hr, 0.021 to 0.833 mg/hr or 21 to 833 μg/hr, preferably 1.0 to 15 mg/day, 1.0 to 15 mg/24 hr, 1,000 to 15,000 μg/day, 1,000 to 15,000 μg/24 hr, 0.042 to 0.625 mg/hr or 42 to 625 μg/hr, more preferably 2.0 to 10 mg/day, 2.0 to 10 mg/24 hr, 2,000 to 10,000 μg/day, 2,000 to 10,000 μg/24 hr, 0.083 to 0.417 mg/hr or 83 to 417 μg/hr for at least 72 hours or 3 days of administration, or providing, by release transdermal, an average 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 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 for at least 84 hours or 3.5 days of administration.

[00248] Furthermore, in certain embodiments, the present invention relates to asenapine for use in a method for treating a human patient by transdermal administration of asenapine as described above, providing, by transdermal delivery, an AUC0-48 of 20 to 300 (ng/mL) h or of greater than 300 to 450 (ng/mL) h and preferably of 30 to 200 (ng/mL) h, or providing, by transdermal delivery, an AUC0-72 of 30 to 400 (ng/mL) h or of greater than 400 to 600 (ng/mL) h and preferably of 50 to 300 (ng/mL) h, or providing, by transdermal delivery, an AUC0-84 of 35 to 450 (ng/mL) h or of greater than 450 to 700 (ng/mL) h and preferably 60 to 350 (ng/mL) h.

[00249] Still further, in certain embodiments, the present invention relates to asenapine for use in a method for treating a human patient by transdermal administration of asenapine as described above, providing, upon transdermal delivery, a ratio of Cmax to C48 of less than 2.0, preferably less than 1.5, and more preferably less than 1.3, or providing upon transdermal delivery a ratio of Cmax to C72 of less than 3.0, preferably less than 2.5, and more preferably less than 2.0, or providing upon transdermal delivery a ratio of Cmax to C84 of less than 3.5, preferably less than 3.0, more preferably less than 2.5, and most preferably less than 2.0.

[00250] Still further, in certain embodiments, the present invention relates to asenapine for use in a method for treating a human patient by transdermal administration of asenapine as described above, providing upon transdermal release a Cmax value of from 0.5 to 10 ng/mL and preferably from 1 to 8 ng/mL.

[00251] In other embodiments, the present invention also relates to asenapine for use in a method for 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.

[00252] According to another specific aspect, the present invention relates to a transdermal therapeutic system for the transdermal administration of asenapine for use in a method for 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.

[00253] 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.

[00254] Such a transdermal therapeutic system for use in a method for treating a human patient as described above preferably comprises a self-adhesive layer structure containing a therapeutically effective amount of asenapine.

[00255] Furthermore, the transdermal therapeutic system is preferably for use in a method for the treatment of psychosis, and in particular for use in a method for the treatment of one or more conditions selected from schizophrenia, bipolar disorder, post-traumatic stress disorder, major depressive disorder, dementia-related psychosis, agitation or manic disorder, or for use in a method for the treatment of schizophrenia and/or bipolar disorder, more preferably bipolar disorder and in particular acute mixed or manic episodes of bipolar disorder. The transdermal therapeutic system is also preferably for use in a method for the treatment of acute mixed or manic episodes of bipolar disorder in an adult or a pediatric patient 10 to 17 years of age, for use as an adjunct treatment to lithium or valproate or for use as a maintenance monotherapy treatment in a method for the treatment of bipolar disorder in a human patient, in particular an adult.

[00256] The transdermal therapeutic system is also preferably for use in a method for 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) of 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.

[00257] Thus, in certain embodiments, the present invention relates to a transdermal therapeutic system for the transdermal delivery of asenapine for use in a method of treating a human patient as described above, providing, upon transdermal delivery, an average 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, or 2.5 to 3.0 mg/day. h, 0.042 to 0.625 mg/h or 42 to 625 μg/h, more preferably 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 for at least 48 hours or 2 days of administration, or providing, by transdermal delivery, an average 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/hr or 21 to 833 μg/hr, 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/hr or 42 to 625 μg/hr, more preferably 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/hr or 83 to 417 μg/hr for at least 72 hours or 3 days of administration, or providing, by transdermal delivery, an average 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 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 for at least 84 hours or 3.5 days of administration.

[00258] Furthermore, in certain embodiments, the present invention relates to a transdermal therapeutic system for the transdermal administration of asenapine for use in a method for treating a human patient as described above, providing, by transdermal delivery, an AUC0-48 of 20 to 300 (ng/mL) h or of greater than 300 to 450 (ng/mL) h and preferably of 30 to 200 (ng/mL) h, or providing, by transdermal delivery, an AUC0-72 of 30 to 400 (ng/mL) h or of greater than 400 to 600 (ng/mL) h and preferably of 50 to 300 (ng/mL) h, or providing, by transdermal delivery, an AUC0-84 of 35 to 450 (ng/mL) h or of greater than 450 to 700 (ng/mL) h and preferably 60 to 350 (ng/mL) h.

[00259] Still further, in certain embodiments, the present invention relates to a transdermal therapeutic system for the transdermal administration of asenapine for use in a method for treating a human patient as described above, providing, upon transdermal delivery, a ratio of Cmax to C48 of less than 2.0, preferably less than 1.5, and more preferably less than 1.3, or providing upon transdermal delivery a ratio of Cmax to C72 of less than 3.0, preferably less than 2.5, and more preferably less than 2.0, or providing upon transdermal delivery a ratio of Cmax to C84 of less than 3.5, preferably less than 3.0, more preferably less than 2.5, and most preferably less than 2.0.

[00260] Further, in certain embodiments, the present invention relates to a transdermal therapeutic system for the transdermal administration of asenapine for use in a method for treating a human patient as described above, providing upon transdermal release a Cmax value of 0.5 to 10 ng/mL and preferably of 1 to 8 ng/mL.

[00261] In all such embodiments, as previously described, the TTS may be for use in a method for 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.

[00262] According to yet another specific aspect, the present invention relates to a method for 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.

[00263] 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.

[00264] Such a method for treating a human patient by transdermal administration of asenapine as described above preferably includes applying a transdermal therapeutic system for 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.

[00265] 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.

[00266] Furthermore, the above-described method is preferably a method for treating psychosis, and in particular a method for treating one or more conditions selected from schizophrenia, bipolar disorder, post-traumatic stress disorder, major depressive disorder, dementia-related psychosis, agitation or manic disorder, or a method for treating schizophrenia and/or bipolar disorder, more preferably bipolar disorder and in particular acute mixed or manic episodes of bipolar disorder. In certain embodiments, the method is also preferably a method for treating acute mixed or manic episodes of bipolar disorder in an adult or a pediatric patient 10 to 17 years of age, or a method for treating bipolar disorder in a human patient, in particular an adult, as an adjunct treatment to lithium or valproate or as a maintenance monotherapy treatment.

[00267] In certain embodiments, the method is also preferably a method for 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) of 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.

[00268] The relatively constant blood plasma concentration of asenapine can be described by severe pharmacokinetic parameters as obtained in an in vivo clinical study in human subjects.

[00269] Thus, in certain embodiments, the present invention relates to a method for treating a human patient as described above, providing, by transdermal delivery, an average 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/hr, more preferably 2.0 to 10 mg/day, 2.0 to 10 mg/24 hr, 2,000 to 10,000 μg/day, 2,000 to 10,000 μg/24 hr, 0.083 to 0.417 mg/hr or 83 to 417 μg/hr for at least 48 hours or 2 days of administration, or providing, by transdermal delivery, an average release rate of 0.5 to 20 mg/day, 0.5 to 20 mg/24 hr, 500 to 20,000 μg/day, 500 to 20,000 μg/24 hr, 0.021 to 0.833 mg/hr or 21 to 833 μg/hr, 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 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 for at least 72 hours or 3 days of administration, or providing, by transdermal delivery, an average 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 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 for at least 84 hours or 3.5 days of administration.

[00270] Furthermore, in certain embodiments, the present invention relates to a method for treating a human patient as described above, providing, by transdermal delivery, an AUC0-48 of 20 to 300 (ng/mL) h or of greater than 300 to 450 (ng/mL) h and preferably of 30 to 200 (ng/mL) h, or providing, by transdermal delivery, an AUC0-72 of 30 to 400 (ng/mL) h or of greater than 400 to 600 (ng/mL) h and preferably of 50 to 300 (ng/mL) h, or providing, by transdermal delivery, an AUC0-84 of 35 to 450 (ng/mL) h or of greater than 450 to 700 (ng/mL) h and preferably of 60 to 350 (ng/mL) h.

[00271] Still further, in certain embodiments, the present invention relates to a method for treating a human patient as described above, providing, by transdermal delivery, a ratio of Cmax to C48 of less than 2.0, preferably less than 1.5, and more preferably less than 1.3, or providing by transdermal delivery a ratio of Cmax to C72 of less than 3.0, preferably less than 2.5, and more preferably less than 2.0, or providing by transdermal delivery a ratio of Cmax to C84 of less than 3.5, preferably less than 3.0, more preferably less than 2.5, and most preferably less than 2.0.

[00272] Furthermore, in certain embodiments, the present invention relates to a method for treating a human patient as described above, providing by transdermal delivery a Cmax value of 0.5 to 10 ng/mL and preferably 1 to 8 ng/mL.

[00273] In such methods as described above, the transdermal therapeutic system can provide a reduction in at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine. In yet another aspect, the present invention relates to a transdermal therapeutic system for the transdermal administration of asenapine 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, and wherein the human patient is suffering from fatigue, drowsiness, dizziness, or any combination thereof, and/or the "at least one" asenapine-related side effect is fatigue, drowsiness, dizziness, oral hypoesthesia, or any combination thereof.

[00274] In another aspect, the present invention is directed to a method for 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 the human patient is suffering from fatigue, drowsiness, dizziness, or any combination thereof, and/or "the at least one" asenapine-related side effect is fatigue, drowsiness, dizziness, oral hypoesthesia, or any combination thereof.

[00275] 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 the human patient is suffering from fatigue, drowsiness, dizziness, or any combination thereof, and/or "the at least one" asenapine-related side effect is fatigue, drowsiness, dizziness, oral hypoesthesia, or any combination thereof.

[00276] In yet another 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 a) discontinuing sublingual asenapine therapy; and b) transdermally administering asenapine, wherein the patient is suffering from fatigue, drowsiness, dizziness, or any combination thereof, and/or "the at least one" asenapine-related side effect is fatigue, drowsiness, dizziness, oral hypoesthesia, or any combination thereof. Manufacturing process

[00277] The invention also relates to a process for manufacturing a matrix layer for use in a transdermal therapeutic system and a corresponding matrix layer structure and a corresponding TTS.

[00278] According to the invention, the process of manufacturing a matrix layer for use in a transdermal therapeutic system comprises the steps of: 1) combining at least the asenapine and polymer components, in a solvent to obtain a coating composition; 2) coating the coating composition over the backing layer or release liner or any intermediate coating; and 3) drying the coated coating composition to form the matrix layer.

[00279] In this manufacturing process, preferably in step 1) asenapine is dissolved to obtain a coating composition.

[00280] In the process described above, 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 it is selected from ethanol and ethyl acetate.

[00281] 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 having a solids content of 30 to 60 wt%.

[00282] In step 3), drying is preferably carried out at a temperature of 50 to 90 °C, more preferably of 60 to 80 °C. EXAMPLES

[00283] 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. The numerical values given in the examples with respect to the amount of the ingredients in the composition or the area weight may vary slightly due to manufacturing variability.

EXAMPLES 1A-D Coating composition

[00284] The formulations of 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 1.1

Preparation of coating composition

[00285] For Examples 1a-1c, a beaker was charged with asenapine base and solvent (ethyl acetate), and isopropyl myristate (Example 1b) or diethylene glycol monoethyl ether (Example 1c) was added, if applicable. Duro-TakTM 387-2287 acrylic pressure sensitive adhesive was added and the mixture was then stirred at 500 rpm until a homogeneous mixture was obtained (stirring time is 60 minutes or longer throughout the examples, if not otherwise indicated).

[00286] For Example 1d, a beaker was charged with approximately 1.41 g of an asenapine base and the solvent (ethyl acetate) was added. The acrylic pressure sensitive adhesive was added and the mixture was stirred at approximately 200 rpm for approximately 30 min. An additional approximately 0.56 g of an asenapine base was added in two portions while stirring continued at approximately 500 rpm for approximately 30 min. Coating of the coating composition, Example 1a

[00287] The resulting asenapine-containing coating composition was coated onto a polyethylene terephthalate film (siliconized, 100 μm thick, which can function as a release liner) and dried for approximately 10 minutes at room temperature and 20 minutes at 60 °C. The coating thickness provided a matrix layer areal weight of 100.1 g/m2. A first portion of the dried film was laminated with a polyethylene terephthalate reinforcement layer (23 μm thick) to provide a first self-adhesive layer structure containing asenapine. A second, unmodified portion of the dried film serves as the second self-adhesive layer structure containing asenapine, comprising a release liner but not a reinforcement layer.

[00288] The polyethylene terephthalate film (siliconized, 100 μm thick, which can function as a release liner) of the first layer structure was removed and the adhesive site of the first layer structure was laminated onto the adhesive site of the second layer structure. This results in a self-adhesive layer structure containing asenapine with a matrix layer area weight of 200.1 g/m2, with a reinforcing layer and a release liner. Coating of the coating composition, Examples 1b-d

[00289] The resulting asenapine-containing coating composition was coated onto a polyethylene terephthalate film (siliconized, 100 μm thick, which can function as a release liner) and dried for approximately 15 minutes at room temperature and 25 minutes at 60 °C. The coating thickness provided a matrix layer areal weight of 141.5 g/m2 (Example 1b), 136.9 g/m2 (Example 1c), and 149.0 g/m2 (Example 1d), respectively. The dried film was laminated with a polyethylene terephthalate backing layer (23 μm thick) to provide a self-adhesive layer structure containing asenapine. Preparation of TTS (relating to all examples)

[00290] Individual systems (TTS) were then punched out of the self-adhesive layer structure containing asenapine. In specific embodiments, a TTS as described above may be provided with a further self-adhesive layer of greater surface area, preferably with rounded corners, comprising a pressure-sensitive adhesive layer matrix that is free of active agent. This is advantageous when the TTS, on the basis of its physical properties alone, does not adhere sufficiently to the skin and/or when a matrix layer containing asenapine, in order to avoid waste, has pronounced corners (square or rectangular shapes). The TTS are then removed and sealed in pouches of the primary packaging material. Measurement of skin permeability rate

[00291] The permeated amount and corresponding skin permeability rates of TTS prepared according to Examples 1a-d were determined by in vitro experiments according to the OECD guideline (adopted on April 13, 2004) performed with a 7.0 mL Franz diffusion cell. Split-thickness Goettingen minipig skin (female) was used. A dermatome was used to prepare the skin to a thickness of 800 μm, with an intact epidermis for all TTS. Sections with an area of 1.156 cm2 were taken from the TTS. A permeated amount of asenapine into the Franz cell receptor medium (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 permeability rate calculated. The results are shown in Table 1.2 and Figures 1a and 1b. Table 1.2 Use of asenapine

[00292] The 72-hour asenapine utilization was calculated based on the cumulative permeation amount at 72 hours and the initial asenapine content. The results are shown in Table 1.3 and Figure 1c. Table 1.3

EXAMPLES 2A-D Coating composition

[00293] 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 2.1 Preparation of coating composition

[00294] For Examples 2a, c, and d, the coating compositions were prepared as described in Example 1c except that diethylene glycol monoethyl ether was added before the ethyl acetate solvent.

[00295] For Example 2b, the beaker was charged with the solvent (petroleum ether) first and the polyisobutylene adhesive was added. Polyvinylpyrrolidone (Kollidon® 90 F) was added while stirring at approximately 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

[00296] The resulting asenapine-containing coating composition was coated onto a polyethylene terephthalate film (siliconized, 100 μm thick, which can function as a release liner) and dried for approximately 10 minutes at room temperature and 20 minutes at 60 °C (Examples 2a and 2c) or 90 °C (Example 2b). The coating thickness provided a matrix layer areal weight of 91.3 g/m2 (Example 2a), 85.7 g/m2 (Example 2b), and 90.15 g/m2 (Example 2c), respectively. The dried film was laminated with a polyethylene terephthalate reinforcement layer (23 μm thick) to provide a self-adhesive layer structure containing asenapine. Preparation of the self-adhesive layer structure, Example 2d

[00297] For Example 2d, a bilayer self-adhesive layer structure was prepared as described for Example 1a, starting from two layers as prepared for Example 2c. This results in a self-adhesive layer structure containing asenapine with a matrix layer area weight of 159.6 g/m2, with a reinforcing layer and a release liner. Preparation of TTS

[00298] See Example 1. Measurement of skin permeability rate

[00299] The permeated amount and corresponding skin permeability rates of TTS prepared according to Examples 2a-d were determined by in vitro experiments according to the OECD guideline (adopted on April 13, 2004) performed with a 7.0 mL Franz diffusion cell. Split-thickness Goettingen minipig skin (female) was used. A dermatome was used to prepare the skin to a thickness of 800 μm, with an intact epidermis for all TTS. Sections with an area of 1.145 cm2 were taken from the TTS. A permeated amount of asenapine into the Franz cell receptor medium (phosphate buffer solution pH 5.5 with 0.1% saline azide as an antibacterial agent) at a temperature of 32 ± 1°C was measured and the corresponding skin permeability rate calculated. The results are shown in Table 2.2 and Figures 2a and 2b. Table 2.2 Use of asenapine

[00300] The 72-hour asenapine utilization was calculated based on the cumulative permeation amount at 72 hours and the initial asenapine content. The results are shown in Table 2.3 and Figure 2c. Table 2.3 EXAMPLES 2E-J Coating composition

[00301] 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. Preparation of coating composition

[00302] For Example 2b, the beaker was charged with polyvinylpyrrolidone (Kollidon® 90 F) first and ethanol was added while stirring at approximately 100 to 200 rpm. The polyisobutylene adhesive was then added while stirring at approximately 400 rpm. Additionally, the asenapine base was added while stirring at approximately 400 rpm and finally, n-heptane was added while stirring at approximately 400 to 500 rpm until a homogeneous mixture was obtained. Coating of the coating composition, Examples 2a-2c

[00303] The resulting asenapine-containing coating composition was coated onto a polyethylene terephthalate film (siliconized, 75 μm thick, which can function as a release liner) and dried for approximately 10 minutes to 20 minutes at room temperature and 20 minutes to 25 minutes at 80 °C. The coating thickness provided a matrix layer areal weight of 52.8 g/m2 (Example 2e), 129.6 g/m2 (Example 2f), 188.4 g/m2 (Example 2g), 51.6 g/m2 (Example 2h), 128.2 g/m2 (Example 2i), and 185.9 g/m2 (Example 2j), respectively. The dried film was laminated with a polyethylene terephthalate reinforcing layer (23 μm thick) to provide a self-adhesive layer structure containing asenapine. Preparation of TTS

[00304] See Example 1. Measurement of skin permeability rate

[00305] The permeated amount and corresponding skin permeability rates of TTS prepared according to Examples 2e to 2j were determined by in vitro experiments according to the OECD guideline (adopted April 13, 2004) performed 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 the skin to a thickness of 800 μm, with an intact epidermis for all TTS. Sections with an area of 1,151 cm2 were taken from the TTS. A permeated amount of asenapine into the Franz cell receptor medium (phosphate buffer solution pH 5.5 with 0.1% saline azide as antibacterial agent) at a temperature of 32 ± 1°C was measured and the corresponding skin permeability rate calculated. The results are shown in Tables 2.5 and 2.6 and Figure 2d. Table 2.5 Use of asenapine

[00306] The 72-hour asenapine utilization was calculated based on the cumulative permeation amount at 72 hours and the initial asenapine content. The results are shown in Table 2.7 and Figure 2e. Table 2.7 EXAMPLES 3A-E Coating composition

[00307] 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 3.1 Preparation of coating composition

[00308] The coating composition of Example 3a was prepared as described in Example 1c.

[00309] For Examples 3b, 3d and 3e, a beaker was charged with the excipients polyethylene glycol 400, diisopropyl adipate or propylene glycol monocaprylate type II, where applicable, and the solvent (ethyl acetate). Duro-TakTM 387-2287 acrylic pressure sensitive adhesive was added and the mixture was then stirred at up to 500 rpm until a homogeneous mixture was obtained. Asenapine base was added and the mixture was again stirred at up to 500 rpm until a homogeneous mixture was obtained.

[00310] For Example 3c, a beaker was charged with Duro-TakTM 387-2287 acrylic pressure sensitive adhesive. 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 approximately 500 rpm until a homogeneous mixture was obtained. Finally, the asenapine base was added and the mixture was again stirred at up to 500 rpm until a homogeneous mixture was obtained. Coating of the coating composition

[00311] See Examples 1b-d for the coating process. The coating thickness provided a matrix layer areal weight of 137.3 g/m2 (Example 3a), 144.1 g/m2 (Example 3b), 146.05 g/m2 (Example 3c), 152.1 g/m2 (Example 3d), and 147.6 g/m2 (Example 3e) respectively. The dried film was laminated with a polyethylene terephthalate reinforcement layer (23 μm thick) to provide a self-adhesive layer structure containing asenapine. Preparation of TTS

[00312] See Example 1. Measurement of skin permeability rate

[00313] The permeated amount and corresponding skin permeability rates of TTS prepared according to Examples 3a-e were determined by in vitro experiments according to the OECD guideline (adopted on April 13, 2004) performed with a 7.0 mL Franz diffusion cell. Split-thickness Goettingen minipig skin was used. A dermatome was used to prepare the skin at a thickness of 800 μm, with an intact epidermis for all TTS. Sections with an area of 1.156 cm2 were cut from the TTS. A permeated amount of asenapine into the Franz cell receptor medium (phosphate buffer solution pH 5.5 with 0.1% saline azide as an antibacterial agent) at a temperature of 32 ± 1°C was measured and the corresponding skin permeability rate calculated. The results are shown in Table 3.2 and Figure 3a. Table 3.2 Use of asenapine

[00314] The 56-hour asenapine utilization was calculated based on the cumulative permeation amount at 72 hours and the initial asenapine content. The results are shown in Table 3.3 and Figure 3b. Table 3.3 EXAMPLES 4A, 4B Coating composition

[00315] 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 4.1 Preparation of coating composition

[00316] For Example 4a, a beaker was charged with Duro-TakTM 387-2516 acrylic pressure sensitive adhesive and asenapine. The solvent ethyl acetate was added and the mixture was then stirred at approximately 500 rpm until a homogeneous mixture was obtained.

[00317] For Example 4b, a beaker was charged with the solvent asenapine and ethyl acetate. Duro-TakTM 387-2287 acrylic pressure sensitive adhesive was added and the mixture was then stirred at approximately 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

[00318] See Examples 1b-d for the coating process. The coating thickness provided a matrix layer areal weight of 146.7 g/m2 (Example 4a) and 126.85 g/m2 (Example 4b) respectively. The dried film was laminated with a polyethylene terephthalate reinforcement layer (23 μm thick) to provide a self-adhesive layer structure containing asenapine. Preparation of TTS

[00319] See Example 1. Measurement of skin permeability rate

[00320] The permeated amount and corresponding skin permeability rates of TTS prepared according to Examples 4a and 4b were determined by in vitro experiments according to the OECD guideline (adopted on April 13, 2004) performed with a 7.0 mL Franz diffusion cell. Split-thickness Goettingen minipig skin (female) was used. A dermatome was used to prepare the skin at a thickness of 800 μm, with an intact epidermis for all TTS. Sections with an area of 1.156 cm2 were taken from the TTS. A permeated amount of asenapine into the Franz cell receptor medium (phosphate buffer solution pH 5.5 with 0.1% saline azide as an antibacterial agent) at a temperature of 32 ± 1°C was measured and the corresponding skin permeability rate calculated. The results are shown in Table 4.2 and Figures 4a and 4b. Table 4.2 Use of asenapine

[00321] The 72-hour and 168-hour asenapine utilization was calculated based on the cumulative permeation amount at 72 hours and the initial asenapine content. The results are shown in Table 4.3 and Figure 4c. Table 4.3 EXAMPLES 5A-C Coating composition

[00322] 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 5.1 Preparation of coating composition

[00323] For Example 5a, a beaker was charged with asenapine and Duro-TakTM 387-9301 acrylic pressure sensitive adhesive. The solvent ethyl acetate was added in two portions and the mixture was then stirred at approximately 200 rpm until a homogeneous mixture was obtained.

[00324] For Example 5b, a beaker was charged with Duro-Tak™ 387-2287 acrylic pressure sensitive adhesive, Duro-Tak™ 387-4098 acrylic pressure sensitive adhesive, asenapine, and diethylene glycol monoethyl ether. The solvent ethyl acetate was added in two portions and the mixture was then stirred at approximately 200 rpm until a homogeneous mixture was obtained.

[00325] For Example 5c, a beaker was charged with Oppanol B10/B100 polyisobutylene adhesive and Duro-TakTM 387-2287 acrylic pressure sensitive adhesive. The first portion (1.50 g) of the solvent ethyl acetate was added and the mixture was then stirred at approximately 100 rpm until a homogeneous mixture was obtained. Diethylene glycol monoethyl ether was added and the mixture was then stirred at approximately 200 rpm until a homogeneous mixture was obtained. Asenapine base was added and the mixture was again stirred at approximately 1000 rpm and the remaining portion of the solvent ethyl acetate (0.67 g) was added while stirring. Coating of the coating composition

[00326] The resulting asenapine-containing coating composition was coated onto a polyethylene terephthalate film (siliconized, 100 μm thick, which can function as a release liner) and dried for approximately 10 minutes at room temperature and 20 minutes at 60°C (Examples 5a and 5b) or 90°C (Example 5c). The coating thickness provided a matrix layer areal weight of 99.6 g/m2 (Example 5a), 102.55 g/m2 (Example 5b), and 98.4 g/m2 (Example 5c), respectively. The dried film was laminated with a polyethylene terephthalate reinforcement layer (23 μm thick) to provide a self-adhesive layer structure containing asenapine. Preparation of TTS

[00327] See Example 1. Measurement of skin permeability rate

[00328] The permeated amount and corresponding skin permeability rates of TTS prepared according to Examples 5a-c were determined by in vitro experiments according to the OECD guideline (adopted on April 13, 2004) performed with a 7.0 mL Franz diffusion cell. Split-thickness Goettingen minipig skin was used. A dermatome was used to prepare the skin to a thickness of 800 μm, with an intact epidermis for all TTS. Sections with an area of 1.145 cm2 were taken from the TTS. A permeated amount of asenapine into the Franz cell receptor medium (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 permeability rate calculated. The results are shown in Table 5.2 and Figure 5a. Table 5.2 Use of asenapine

[00329] The 72-hour asenapine utilization was calculated based on the cumulative permeation amount at 72 hours and the initial asenapine content. The results are shown in Table 5.3 and Figure 5b. Table 5.3 EXAMPLES 6A-C Coating composition

[00330] 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 6.1 Preparation of coating composition

[00331] A beaker was charged with asenapine and Duro-TakTM 387-2287 acrylic pressure sensitive adhesive and Bio-PSA Q7-4301 polysiloxane adhesive. 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

[00332] The resulting asenapine-containing coating composition was coated onto a polyester film (fluoropolymer coated, 75 μm thick, which can function as a release coating) and dried for approximately 10 minutes at room temperature and 20 minutes at 90 °C. The coating thickness provided a matrix layer area weight of 93.7 g/m2 (Example 6a), 130.2 g/m2 (Example 6b), and 105.3 g/m2 (Example 6c), respectively. The dried film was laminated with a polyethylene terephthalate reinforcement layer (23 μm thick) to provide a self-adhesive layer structure containing asenapine. Preparation of TTS

[00333] See Example 1. Measurement of skin permeability rate

[00334] The permeated amount and corresponding skin permeability rates of TTS prepared according to Examples 6a-c were determined by in vitro experiments according to the OECD guideline (adopted on April 13, 2004) performed with a 7.0 mL Franz diffusion cell. Split-thickness Goettingen minipig skin (female) was used. A dermatome was used to prepare the skin to a thickness of 800 μm, with an intact epidermis for all TTS. Sections with an area of 1.145 cm2 were taken from the TTS. A permeated amount of asenapine into the Franz cell receptor medium (phosphate buffer solution pH 5.5 with 0.1% saline azide as an antibacterial agent) at a temperature of 32 ± 1°C was measured and the corresponding skin permeability rate calculated. The results are shown in Table 6.2 and Figure 6a. Table 6.2 Use of asenapine

[00335] The 72-hour asenapine utilization was calculated based on the cumulative permeation amount at 72 hours and the initial asenapine content. The results are shown in Table 6.3 and Figure 6b. Table 6.3 EXAMPLES 7A-C Coating composition

[00336] 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 7.1 Preparation of coating composition

[00337] For Example 7a, a beaker was charged with asenapine base, Duro-TakTM 387-2516 acrylic pressure sensitive adhesive was added, and the mixture was then stirred at approximately 250 rpm until a homogeneous mixture was obtained. The solvent ethyl acetate was added, and the mixture was again stirred at up to 400 rpm.

[00338] For Example 7b, a beaker was charged with the asenapine base and the solvent (ethyl acetate), and the isopropyl myristate was added. Duro-TakTM 387-2287 acrylic pressure sensitive adhesive was added and the mixture was then stirred at approximately 400 rpm until a homogeneous mixture was obtained.

[00339] For the first and second layers of Example 7c, a beaker was charged with the asenapine base and the solvent (ethyl acetate), and the Duro-TakTM 387-2287 acrylic pressure sensitive adhesive or the polysiloxane adhesive was added, respectively, and the mixture was then stirred at approximately 400 rpm until a homogeneous mixture was obtained.

[00340] The resulting asenapine-containing coating composition was coated onto a polyethylene terephthalate film (siliconized, 100 μm thick, which can function as a release liner) and dried for approximately 10 minutes at room temperature and 20 minutes at 60°C (Example 7b) or 90°C (Example 7a). The coating thickness provided a matrix layer areal weight of 94.15 g/m2 (Example 7a) and 99.85 g/m2 (Example 7b), respectively. The dried film was laminated with a polyethylene terephthalate reinforcement layer (23 μm thick) to provide a self-adhesive layer structure containing asenapine. Coating of the coating composition of Examples 7c

[00341] For Example 7c, the resulting coating compositions containing asenapine were coated onto a polyethylene terephthalate film (siliconized, 100 μm thick, for Layer 1, or fluoropolymer coated, 75 μm thick, for Layer 2, which can function as a release liner) and dried for approximately 10 minutes at room temperature and 20 minutes at 60 °C (Layer 1) or 90 °C (Layer 2). A bilayer self-adhesive layer structure was then prepared as described for Example 1a, with Layer 1 intended to be the skin contacting layer (i.e., the dried Layer 2 film was laminated with a polyethylene terephthalate reinforcement layer (23 μm thick) and Layer 1 was used unmodified). Preparation of TTS

[00342] See Example 1. Measurement of skin permeability rate

[00343] The permeated amount and corresponding skin permeability rates of TTS prepared according to Examples 7a-c were determined by in vitro experiments according to the OECD guideline (adopted on April 13, 2004) performed with a 7.0 mL Franz diffusion cell. Split-thickness Goettingen minipig skin (female) was used. A dermatome was used to prepare the skin to a thickness of 800 μm, with an intact epidermis for all TTS. Sections with an area of 1.156 cm2 were taken from the TTS. A permeated amount of asenapine into the Franz cell receptor medium (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 permeability rate calculated. The results are shown in Table 7.2 and Figure 7a. Table 7.2 Use of asenapine

[00344] The 72-hour asenapine utilization was calculated based on the cumulative permeation amount at 72 hours and the initial asenapine content. The results are shown in Table 7.3 and Figure 7b. Table 7.3 EXAMPLES 8A-C Coating composition

[00345] 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 8.1 Preparation of coating composition

[00346] For Examples 8a and 8b, a beaker was charged with asenapine base and the solvent ethyl acetate. Duro-TakTM 387-2516 acrylic pressure sensitive adhesive was added and the mixture was then stirred at up to 500 rpm (Example 8a) or at approximately 300 rpm (Example 8b) until a homogeneous mixture was obtained.

[00347] For Example 8c, a beaker was charged with asenapine base. Duro-Tak™ 3872516 acrylic pressure sensitive adhesive was added and the mixture was then stirred at approximately 300 rpm until a homogeneous mixture was obtained. The solvent polyvinylpyrrolidone and ethanol were consecutively added while stirring at approximately 300 rpm and approximately 500 rpm, respectively. Coating of the coating composition of Examples 8a and 8c

[00348] The resulting asenapine-containing coating composition was coated onto a polyethylene terephthalate film (siliconized, 100 μm thick, which can function as a release liner) and dried for approximately 15 minutes at room temperature and 25 minutes at 75°C. The coating thickness provided a matrix layer area weight of 134.8 g/m2 (Example 8a) and 134.9 g/m2 (Example 8c), respectively. The dried film was laminated with a polyethylene terephthalate reinforcement layer (23 μm thick) to provide a self-adhesive layer structure containing asenapine. Coating of the coating composition of Example 8b

[00349] The resulting asenapine-containing coating composition was coated onto a polyethylene terephthalate film (siliconized, 100 μm thick, which can function as a release liner) and dried for approximately 15 minutes at room temperature and 25 minutes at 75°C, and an additional 25 minutes at 75°C. A double-layer self-adhesive layer structure was then prepared as described for Example 1a. This results in an asenapine-containing self-adhesive layer structure with a matrix layer area weight of 168.5 g/m2, with a reinforcing layer and a release liner. Preparation of TTS

[00350] See Example 1. Measurement of skin permeability rate

[00351] The permeated amount and corresponding skin permeability rates of TTS prepared according to Examples 8a-c were determined by in vitro experiments according to the OECD guideline (adopted April 13, 2004) performed 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 the skin to a thickness of 800 μm, with an intact epidermis for all TTS. Sections with an area of 1.148 cm2 were taken from the TTS. A permeated amount of asenapine into the Franz cell receptor medium (phosphate buffer solution pH 5.5 with 0.1% saline azide as antibacterial agent) at a temperature of 32 ± 1°C was measured and the corresponding skin permeability rate calculated. The results are shown in Table 8.2 and Figures 8a and 8b. Table 8.2 Use of asenapine

[00352] The 72-hour asenapine utilization was calculated based on the cumulative permeation amount at 72 hours and the initial asenapine content. The results are shown in Table 8.3 and Figure 8c. Table 8.3 EXAMPLES 9A, 9B Coating composition

[00353] 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 9.1

[00354] A beaker was charged with the asenapine base and ascorbyl palmitate (Example 9b), if applicable, and the Duro-TakTM 387-2516 acrylic pressure sensitive adhesive was added. The mixture was then stirred at approximately 250 rpm (Example 9a) or up to 1000 rpm (Example 9b), until a homogeneous mixture was obtained. Coating of the coating composition

[00355] For Example 9a, the resulting asenapine-containing coating composition was coated onto a polyethylene terephthalate film (siliconized, 100 μm thick, which may function as a release liner) and dried for approximately 10 minutes at room temperature and 15 minutes at 70°C. For Example 9b, the resulting asenapine-containing coating composition was coated onto a polyethylene terephthalate film (siliconized, 75 μm thick, which may function as a release liner) and dried for approximately 15 minutes at room temperature and 25 minutes at 70°C. The coating thickness provided a matrix layer areal weight of 85.8 g/m2 (Example 9a) and 149.0 g/m2 (Example 9b), respectively. The dried film was laminated with a polyethylene terephthalate reinforcing layer (23 μm thick) to provide a self-adhesive layer structure containing asenapine. Preparation of TTS

[00356] See Example 1. Measurement of skin permeability rate

[00357] The permeated amount and corresponding skin permeability rates of TTS prepared according to Examples 9a and 9b were determined by in vitro experiments according to the OECD guideline (adopted on April 13, 2004) performed 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 the skin to a thickness of 800 μm, with an intact epidermis for all TTS. Sections with an area of 1.149 cm2 were taken from the TTS. A permeated amount of asenapine into the Franz cell receptor medium (phosphate buffer solution pH 5.5 with 0.1% saline azide as antibacterial agent) at a temperature of 32 ± 1°C was measured and the corresponding skin permeability rate calculated. The results are shown in Table 9.2 and Figure 9a. Table 9.2 Use of asenapine

[00358] The 72-hour asenapine utilization was calculated based on the cumulative permeation amount at 72 hours and the initial asenapine content. The results are shown in Table 9.3 and Figure 9b. Table 9.3

EXAMPLE 10 Coating composition

[00359] The formulation of a coating composition containing asenapine is summarized in Table 10.1 below. The formulation is based on weight percent as also indicated in Table 10.1. Table 10.1 Preparation of coating composition

[00360] A beaker was charged with the asenapine base and the α-tocopherol and the acrylic pressure sensitive adhesive Duro-TakTM 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

[00361] The resulting asenapine-containing coating composition was coated onto a polyethylene terephthalate film (siliconized, 75 μm thick, which can function as a release liner) and dried for approximately 15 minutes at room temperature and 25 minutes at 70 °C. The coating thickness provided a matrix layer area weight of 148.35 g/m2. The dried film was laminated with a polyethylene terephthalate reinforcement layer (23 μm thick) to provide a self-adhesive layer structure containing asenapine. Preparation of TTS

[00362] See Example 1. Measurement of skin permeability rate

[00363] The permeated amount and corresponding skin permeability rates of TTS prepared according to Example 10 were determined by in vitro experiments according to the OECD guideline (adopted on April 13, 2004) performed 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 the skin to a thickness of 800 μm, with an intact epidermis for all TTS. Sections with an area of 1.154 cm2 were taken from the TTS. A permeated amount of asenapine into the Franz cell receptor medium (phosphate buffer solution pH 5.5 with 0.1% saline azide as antibacterial agent) at a temperature of 32 ± 1°C was measured and the corresponding skin permeability rate calculated. The results are shown in Table 10.2 and Figure 10a. Table 10.2 Use of asenapine

[00364] The 72-hour asenapine utilization was calculated based on the cumulative permeation amount at 72 hours and the initial asenapine content. The result is shown in Table 10.3 and Figure 10b. Table 10.3

EXAMPLE 11 Coating composition

[00365] 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 11.1 Preparation of Coating Composition [0406] For Examples 11a-11c, a beaker was charged with the asenapine base and the solvent (ethyl acetate), and diethylene glycol monoethyl ether (Example 11c) was added, if applicable. Duro-TakTM 387-2516 (Example 11a) or Duro-TakTM 387-2287 (Examples 11b and 11c) acrylic pressure sensitive adhesive was added and the mixture was then stirred at approximately 500 rpm (Examples 11a and 11b) or approximately 700 rpm (Example 11c) until a homogeneous mixture was obtained.

[00366] For Example 11d, a beaker was charged with the asenapine base and the solvent (ethyl acetate). Duro-TakTM 387-2516 acrylic pressure sensitive adhesive was added and the mixture was then stirred at approximately 500 rpm until a homogeneous mixture was obtained. The basic butylated methacrylate copolymer Eudragit E100 was then added while stirring at approximately 500 rpm. Coating of the coating composition

[00367] The resulting asenapine-containing coating composition was coated onto a polyethylene terephthalate film (siliconized, 100 μm thick, which can function as a release liner) and dried for approximately 15 minutes at room temperature and 25 minutes at 60 °C (Examples 11b-11d) or 90 °C (Example 11a). The coating thickness provided a matrix layer areal weight of 146.0 g/m2 (Example 11a), 135.7 g/m2 (Example 11b), 137.3 g/m2 (Example 11c), and 140.3 g/m2 (Example 11d) respectively. The dried film was laminated with a polyethylene terephthalate backing layer (23 μm thick) to provide a self-adhesive layer structure containing asenapine. TTS Preparation

[00368] See Example 1. In vivo study using Goettingen minipigs

[00369] The in vivo releases and corresponding skin permeability rates of TTS prepared according to Examples 11a-11d were determined by in vivo experiments using Goettingen minipigs (females, about 6 months old, randomized by the simple random sampling method). Sections with an area of 10 cm2 were taken from the TTS and one Goettingen minipig was used for one TTS formulation. Three drugs containing one placebo TTS (each 10 cm2) were used per minipig. The total wear time of all 4 patches per minipig patch (3 active and 1 placebo) was 84 hours.

[00370] During the study, the minipigs were kept at 22 ± 3°C, at a relative humidity of 40 ± 15%, lit from 6 am to 6 pm with reduced-calorie, sniffed rearing food twice a day of approximately 140 to 200 g per animal, and with water ad libitum.

[00371] After application of the above single dose of TTS (3*verum and 1 placebo, each 10 cm2), 3 mL of 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 min at 2000 xg in order to obtain blood plasma. A blood plasma concentration of asenapine was determined by an LC method with MS/MS detection. AUC values were calculated from the blood plasma concentration. After removal of TTS, the skin condition was macroscopically determined and a Draize score obtained based on the scoring scheme mentioned below. Histopathological examination of the epidermis and dermis did not reveal any morphological or pathological transformation indicating an irritation of the deeper tissue layers. Histological results also showed no lesion or removal of the stratum corneum. The residual amount of asenapine was determined in the removed TTS by quantitative HPLC (see above) and the dermally released 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 Figure 11. Table 11.2 *: Draize scoring schemes for the assessment of skin irritation potential: 0 = No erythema, no edema, 1 = very mild erythema (barely noticeable), very mild edema (barely noticeable), 2 = well-defined erythema, mild edema, 3 = moderate to severe erythema, moderate edema, 4 = severe erythema, severe edema. Table 11.3

EXAMPLES 12A, 12B Coating composition

[00372] 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 12.1 Preparation of coating composition

[00373] For Examples 12a and 12b, a stainless steel vial was charged with the α-tocopherol, asenapine, and ethanol. Duro-Tak™ 387-2516 acrylic pressure sensitive adhesive was added and the mixture was then stirred until a clear solution was obtained (approximately 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

[00374] The resulting asenapine-containing coating composition was coated onto a polyethylene terephthalate film (one side siliconized, 75 μm thick, which can function as a release liner) and dried for approximately 15 minutes at 80°C. The coating thickness provided an areal weight of 148.6 g/m2 (Ex. 12a) and 149.6 g/m2 (Ex. 12b), respectively. The dried film was laminated with a polyethylene terephthalate reinforcement layer (23 μm thick) to provide a self-adhesive layer structure containing asenapine. Preparation of TTS

[00375] See Example 1. Measurement of skin permeability rate

[00376] The permeated amount and corresponding skin permeability rates of TTS prepared according to Examples 12a and 12b were determined by in vitro experiments according to the OECD guideline (adopted on April 13, 2004) performed 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 the skin to a thickness of 800 μm, with an intact epidermis for all TTS. Sections with an area of 1.154 cm2 were taken from the TTS. A permeated amount of asenapine into the Franz cell receptor medium (phosphate buffer solution pH 5.5 with 0.1% saline azide as antibacterial agent) at a temperature of 32 ± 1°C was measured and the corresponding skin permeability rate calculated. The results are shown in Table 12.2 and Figure 12a. Table 12.2 *: Standard deviation in this Example was as in all other Examples, calculated based on the n method. **: n = 2. Asenapine use

[00377] The 72-hour asenapine utilization was calculated based on the cumulative permeation amount at 72 hours and the initial asenapine content. The results are shown in Table 12.3 and Figure 12b. Table 12.3 EXAMPLES 13A, 13B Coating composition

[00378] 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 13.1 Preparation of coating composition

[00379] For Examples 13a and 13b, the stainless steel vial was charged with α-tocopherol. Duro-TakTM 387-2516 acrylic pressure sensitive adhesive was added and the mixture was then stirred until a clear solution was obtained. Polyvinylpyrrolidone was added slowly while stirring and dissolved under stirring until a clear solution was obtained. Asenapine was suspended in the ethanol and transferred to the stainless steel vial. After addition of asenapine, the mixture was stirred until a clear, slightly yellow colored solution was obtained. Coating of the coating composition of Examples 13A and 13B

[00380] The resulting asenapine-containing coating composition was coated onto a polyethylene terephthalate film (one side siliconized, 75 μm thick, which can be used as a release liner) and dried for approximately 15 minutes at 80°C. The coating thickness provided an area weight of about 140 g/m2 in accordance with label requirements (hereinafter, where reference is made to a label value, it is understood that the actual value is within a tolerance of ± 7.5% of the label value). The dried film was laminated with a polyethylene terephthalate backing layer (23 μm thick) to provide a self-adhesive layer structure containing asenapine. Residual amounts of solvents met the requirements of ICH Q3C (R3) guideline, i.e. Methanol < 3,000 ppm, Ethanol < 5,000 ppm, Ethyl acetate < 5,000 ppm and n-Heptane < 5,000 ppm. Preparation of TTS

[00381] Individual systems (TTS) of 10 cm2 (Ex. 13a) as well as 15 cm2 (Ex. 13b) were then taken from the self-adhesive layer structure containing asenapine. EXAMPLE 14 In vivo clinical study

[00382] An in vivo clinical experiment was conducted to investigate the relative bioavailability of asenapine following transdermal application of the inventive TTS (Examples 13a and 13b) compared to sublingual administration. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki. Experimental design

[00383] The trial was conducted in an open-label, Phase I, single-center 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 following transdermal application of a single dose of the TTS prepared in Examples 13a and 13b to the currently marketed sublingual tablets (Sycrest®, 5 mg).

[00384] For each subject, the trial consisted of: • A walk-in screening period in which informed consent was obtained and the subjects' eligibility assessed. Depending on the outcome of the assessment, subjects were enrolled in the trial. • A treatment and observation period consisting of 3 sequential treatment periods (each of several days). • A walk-in follow-up visit after completion of the last treatment.

[00385] With respect to 3 sequential treatment periods, subjects received asenapine 5 mg sublingual tablets 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 cm2 each) during period 2 and a single dose of the TTS prepared in Example 13b (1 TTS of 15 cm2) during period 3. Selection of the experimental population

[00386] Only individuals meeting all inclusion criteria and none of the exclusion criteria were included in the treatment phase. The criteria were assessed at screening and a recheck was performed on Day -1 of Period 1. Inclusion Criteria

[00387] Subjects had to meet all of the following criteria to be eligible for participation in the treatment period. 1. Subjects who are able to understand and follow instructions during the study. 2. Signed informed consent. 3. White. 4. Age >18 and <55 years. 5. Non-smoker. 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. 7. Weight within the normal range according to accepted values for body mass index (BMI) within 18.0 to 29.4 kg/m2. 8. Normal blood pressure (Systolic Blood Pressure (SBP) >90 <139 mmHg; Diastolic Blood Pressure >55 <89 mmHg) measured after 5 minutes of rest in the supine position. 9. A pulse rate of >50 and <99 b/min measured after 5 minutes of rest in the supine position. 10. ECG recording without clinically significant abnormalities. 11. Having had no febrile or infectious illness for at least 7 days before the first administration. Exclusion Criteria

[00388] To ensure that subjects were healthy and in a comparable state, the following exclusion criteria were applied. Lifestyle Restrictions 1. Demonstrating excessive xanthine intake (more than 5 cups of coffee or equivalent per day). 2. More than moderate alcohol consumption (> 35 g of ethanol regularly per day or > 245 g regularly per week). 3. Any history of alcohol or drug abuse. 4. Vegetarian. 5. Positive drug screen. 6. Positive alcohol breath test. 7. Consumption of xanthine-containing food or beverages, such as grapefruit juice or Seville oranges within 48 hours prior to the first dosing. 8. Consumption of grilled broccoli or Brussels sprouts within 72 hours prior to the first dosing. Previous Medication 9. Use of any medication (self-medication or prescription medication) except hormonal contraception within 4 weeks prior to the first dosage (or at least 10 times the respective elimination half-life, whichever is longer). Medical and Surgical History 10. Demonstrating any active physical disease, acute or chronic. 11. Any history of drug hypersensitivity, asthma, urticaria or other severe allergic diathesis, as well as current hay fever. 12. Any history of hypersensitivity to any component of the dosage forms investigated. 13. Any history of chronic gastritis or peptic ulcers. 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, skin diseases, and bleeding tendency. 15. Gilbert's syndrome. 16. Any gastrointestinal complaints within 7 days prior to the first dose. 17. Any scars, moles, tattoos, skin irritation, or excessive hair growth at the TTS injection site. 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 thinking, active suicidal thinking with method, active suicidal thinking with intent but without specific planning, or active suicidal thinking with planning and intent). Laboratory Tests 19. Laboratory values outside the reference range that are of clinical relevance (e.g., suggesting an unknown disease and requiring further clinical evaluation by the investigator), especially with respect to aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl transpeptidase (GGT). 20. Positive test for human immunodeficiency virus (HIV) antibody/p24 antigen. 21. Positive hepatitis B virus surface antigen (HBsAg) test. 22. Positive anti-hepatitis C virus antibody (anti-HCV) test. Other 23. Blood donation within 30 days prior to signing the informed consent for this trial. 24. Participation in the treatment phase of a 30-day clinical trial or blocked by the follow-up period of a previous clinical trial prior to signing the informed consent for this trial. 25. Women of childbearing potential not using a highly effective method of birth control. Highly effective methods of birth control are defined as those that result in a low failure rate, i.e., less than 1% per year, when used consistently and correctly (e.g., combination intrauterine device and condom). Women are considered to be of childbearing potential unless surgically sterilized by hysterectomy or bilateral tubal ligation, or postmenopausal for at least 2 years. 26. Pregnant or breastfeeding women. Treatments for the study

[00389] The treatments administered for the study are summarized in Table 14.1 below and their characteristics are detailed below. Table 14.1 bid = twice a day; q12h = every 12 hours

[00390] The reference formulation administered in period 1 contains the active ingredient asenapine maleate and is marketed under the trade name Sycrest® 5 mg sublingual tablet by N.V. Organon, Oss, Netherlands. The central pharmacy number (PZN) is 07728207. Administration of the sublingual tablets (reference)

[00391] Sublingual tablets were administered in the morning and evening of the first day with only 12 hours between the two administrations according to the administration instructions provided in the summary of product characteristics. Subjects were instructed to place the tablets under the tongue for at least 10 minutes to allow dissolution of the sublingual tablet and not to chew or swallow the sublingual tablets.

TTS Application

[00392] TTS were applied to intact skin on the upper chest or upper back. Hair in the application area was trimmed with scissors (not shaved) prior to application, if necessary. Subjects were instructed to check that the skin was free from detergents, oils and grease prior to application of the TTS. The TTS was placed in the desired position and pressed for at least 30 seconds with the fingers or palm of the hand to fix the TTS to the skin surface. If necessary and to avoid further detachment, the TTS was additionally fixed with an active agent-free adhesive overlay. 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 fix the TTS, it was pressed again for at least 30 seconds with fingers or the palm of the hand. The TTS were removed after 3.5 days (84 h, period 2 and period 3). After removal, used TTS (including the adhesive overlay, if applicable) were handled and stored under nitrogen in the refrigerator until further analysis. Dose time for each individual

[00393] On the first day of period 1, no breakfast was served; subjects fasted overnight prior to morning administration. A standardized lunch was given 4 hours after administration and dinner approximately 10 hours after administration. No fluid intake was allowed from 1 hour before until 1 hour after morning and afternoon administration. Because food does not interact with TTS, subjects received standardized meals and beverages during the inpatient days at the usual times during periods 2 and 3. During the inpatient days, subjects were only allowed to consume food or beverages provided by the study unit. Restrictions and Precautions

[00394] During the test, subjects were instructed to refrain from all activities that could increase body temperature, i.e. physical exertion, sauna, very hot environments. During the time of TTS use, subjects were not allowed to perform any activities that could influence TTS compliance, such as any activities that increased sweating. Additional restrictions on food and beverage intake were placed, e.g. according to the exclusion criteria. Sample collection and determination of blood plasma concentrations

[00395] Blood samples for determination of the concentration of asenapine and its metabolites in blood plasma were collected at specific time points after administration.

[00396] An internally standardized, validated liquid chromatography-tandem mass spectrometry method was used for the determination of blood plasma concentrations of asenapine, N-desmethyl-asenapine and asenapine-glucuronide, which was performed 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 test 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)

[00397] Adverse events were ascertained by the investigator through non-leading questions, noted as spontaneously reported by subjects to medical staff or observed during any measurements on all study days following administration of the dosage form and assessed by a study physician.

[00398] In addition, suicide risk was monitored. All positive reports during the trial were documented as adverse events. Suicidal ideation of types 1-3 was documented as a non-serious AE. Suicidal ideation of types 4 and 5 and all suicidal behavior during the trial were documented as a serious adverse event (SAE) and reported.

[00399] An AE referred to the time point and treatment after which it occurred, i.e., any AE occurring before the first dose was counted as a baseline complaint/pretreatment AE and is not included in the analysis below. Results and analysis

[00400] All 16 subjects completed period 1 (baseline) of the trial. After period 1 (baseline) and before the start of period 2 (Ex. 13a), 1 subject withdrew. Another subject withdrew during period 3 (Ex. 13b) but could be evaluated for adverse event analysis. Safety laboratory parameters, vital signs, and ECG parameters showed no clinically relevant changes. The results of the study are shown in Tables 14.2 to 14.9 and Figures 13a to 13e. Arithmetic mean blood plasma concentration of asenapine

[00401] The arithmetic mean values of asenapine blood plasma concentration based on all 16 subjects during period 1 and based on the 15 and 14 subjects who completed periods 2 and 3, respectively, together with the standard deviation values are presented in Table 14.2 as well as Figures 13a and 13b. The AUC values were calculated from the blood plasma concentration. The tlag was calculated approximately as the arithmetic mean value of the first time point when a measurable (i.e., non-zero) asenapine blood plasma concentration was obtained, and the results are also shown in Table 14.2. Table 14.2 * : The AUC(0-84) value is calculated over the reference period by multiplying the AUC(0-24) value by 3.5. **: The residual amount is determined by extraction of the active substance from a sample of the used TTS with an appropriate solvent followed by determination of the active substance using a validated HPLC method with a UV photometric detector. **: The mean release rate is calculated based on the initial content of Asenapine in the applied TTS (according to the label composition) and the residual amount in the TTS after 84 hours referring to the total administered dose (see Table 13.1). Pharmacokinetic analysis of asenapine and metabolites

[00402] 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, where Cav represents the mean concentration observed over the relevant dosing interval (12 hours for period 1/Reference and 84 hours for periods 2 and 3/Examples 13a and 13b), and where tlag represents the time of first quantifiable concentration after administration. For Cav and tlag of the reference formulation, only the first dosing interval (0-12 h) was considered. Furthermore, the blood plasma concentration profile of the metabolites asenapine glucuronide and N-desmethyl-asenapine were depicted as geometric mean values and indicating the geometric mean multiplied with and divided by the geometric standard deviation as error bars in Figures 13c, 13d and 13e.

[00403] Biometric assessment was performed using SAS software, Version 9.3 of the SAS System for Windows. Pharmacokinetic calculations were performed using Phoenix WinNonlin version 6.4. The pharmacokinetic calculation was based on all subjects who completed at least 2 treatment periods, i.e. who had data assessed for the reference and at least one of Examples 13a or 13b for asenapine and N-desmethyl-asenapine. Thus, the number of subjects was n = 15 for periods 1 and 2 (Reference and Example 13a) and n = 14 for period 3 (Example 13b). For asenapine-glucuronide, the number of subjects was n = 8 for all periods. Values below the LLOQ were excluded from any calculations for descriptive statistics. Descriptive statistics for concentrations were calculated if at least 1/2 of the individual data points were measured at or above the LLOQ.

[00404] Calculations of 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.

[00405] At time points in the lag time between time zero and the first quantifiable concentration, concentrations below the LLOQ were calculated as zero. Concentrations below the LLOQ between 2 quantifiable concentrations were calculated as half the LLOQ. Concentrations to the right below the LLOQ were not used in the calculations.

[00406] Descriptive statistics of pharmacokinetic parameters were calculated separately for each of periods 1, 2 and 3. For tmax, frequency tables were drawn by treatment based on the nominal time of tmax.

[00407] For each of References and Examples 13a and 13b, the pharmacokinetic parameters of asenapine and metabolites were compared using an exploratory analysis of variance (ANOVA) model. Geometric and arithmetic means used for the calculation of point estimators, such as differences or ratios between treatments, were derived from ANOVA as mean squares (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 α adjustment was performed.

[00408] Based on the fundamental pharmacokinetic relationships, the multiplicative model was applied for all concentration-related parameters. This implied that these characteristics were preferably log-normally rather than normally distributed. ANOVA was therefore performed after logarithmic transformation. Exemplary results are shown in Tables 14.6 and 7.

[00409] The plasma concentration profile of asenapine shows that therapeutic concentrations can be maintained throughout the period of TTS use without major fluctuations. Compared with sublingual administration, peak 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 with sublingual administration. Table 14.3 AUC, Cmax, Cav and t/xz given as geometric mean (standard deviation), Minimum - Maximum; Standard deviation (SD) given in geometric standard deviation factor for both descriptive statistics and key PK characteristics. **: tmax and tlag as mean (Minimum - Maximum) Table 14.4 : AUC, Cmax and t½ λz given as geometric mean (Standard Deviation), Minimum – Maximum; Standard Deviation given in geometric standard deviation factor **: tmax and tlag as mean (Minimum – Maximum) Table 14.5 *: AUC and Cmax given as geometric mean (Standard Deviation), Minimum - Maximum; Standard Deviation given is the geometric standard deviation factor **: tmax and tlag as mean (Minimum - Maximum) Table 14.6 Table 14.7 Ad verso events (AE)

[00410] Tables 14.8 and 14.9 reflect the number of adverse events reported in the different categories.

[00411] Although the duration of treatment for the sublingual (reference) tablet was only 12 h (i.e. 2 administrations) compared to the 3.5 days TTS application (examples 13a and 13b), common systemic side effects of asenapine treatment, such as fatigue and dizziness, were less frequently observed after TTS application and, in the case of fatigue, only of mild intensity. Compared to sublingually administered treatment, the frequency and intensity of fatigue were notably lower after transdermal administration, and dizziness occurred less frequently.

[00412] Symptoms of oral discomfort, such as hypoesthesia and dry mouth, as observed after administration of the reference treatment, were not observed in the application of TTS (Examples 13a and 13b).

[00413] Local tolerance at the application site was good, only mild reactions were occasionally observed (five AEs) which subsided without intervention.

[00414] The dysmenorrhea reported during Period 3, which was moderate in intensity, was unrelated to the administered Example 13b TTS.

[00415] No SAEs were reported and none of the subjects had suicidal ideation.

[00416] Overall, transdermal application of asenapine was safe and well tolerated. AEs observed after TTS administration (Periods 2 and 3) were mostly transient and mild, resolved without intervention, and the frequency of AEs was lower compared to baseline Period 1. Table 14.8 *: Numbers in parentheses indicate incidences by intensity (mild/moderate/severe) The invention relates in particular to the following other items: 1. A transdermal therapeutic system for the transdermal delivery of asenapine comprising a self-adhesive layer structure containing a therapeutically effective amount of asenapine, said self-adhesive layer structure comprising: A) a reinforcing layer; B) a matrix layer containing asenapine consisting of a matrix layer composition comprising: 1. asenapine; and 2. a polymer selected from acrylic polymers; wherein the transdermal therapeutic system has a release area of 5 to 100 cm2. 3. Transdermal therapeutic system according to item 1, wherein the transdermal therapeutic system contains at least 0.70 mg/cm2, preferably at least 0.80 mg/cm2, more preferably at least 0.82 mg/cm2 and most preferably at least 0.83 mg/cm2 of asenapine. 4. Transdermal therapeutic system according to item 1 or 2, wherein the transdermal therapeutic system contains from 0.70 mg/cm2 to 4.0 mg/cm2, preferably from 0.80 mg/cm2 to 3.0 mg/cm2, more preferably from 0.82 mg/cm2 to 2.0 mg/cm2 and most preferably from 0.83 mg/cm2 to 1.7 mg/cm2 of asenapine. 5. Transdermal therapeutic system according to any one of items 1 to 3, in which the area weight of the matrix layer ranges from 90 to 230 g/m2, preferably from 110 to 210 g/m2, and more preferably from 120 to 170 g/m2. 6. Transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure containing asenapine, wherein the transdermal therapeutic system provides by transdermal release, an average release rate of 0.5 to 20 mg/day during at least 48 hours of administration. 7. Transdermal therapeutic system according to item 5, in which the transdermal therapeutic system provides, by transdermal release, an average release rate of 0.5 to 20 mg/day for at least 72 hours, preferably for 84 hours of administration. 8. Transdermal therapeutic system according to item 5 or 6, in which the transdermal therapeutic system provides by transdermal release, an average release rate of 1.0 to 15 mg/day, preferably from 2.0 to 10 mg/day for at least 48 hours of administration, or in which the transdermal therapeutic system provides by transdermal release, an average release rate of 1.0 to 15 mg/day, preferably from 2.0 to 10 mg/day for at least 72 hours of administration, or in which the transdermal therapeutic system provides by transdermal release, an average release rate of 1.0 to 15 mg/day, preferably from 2.0 to 10 mg/day for 84 hours of administration. 9. Transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure containing asenapine, wherein the transdermal therapeutic system provides by transdermal release, an AUC0-48 of 20 to 300 (ng/mL) h or of more than 300 to 450 (ng/mL) h. 10. Transdermal therapeutic system according to item 8, in which the transdermal therapeutic system provides, by transdermal release, an AUC0-48 of 30 to 200 (ng/mL) h. 11. Transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure containing asenapine, wherein the transdermal therapeutic system provides by transdermal release, an AUC0-72 of 30 to 400 (ng/mL) h or of more than 400 to 600 (ng/mL) h. 12. Transdermal therapeutic system according to item 10, in which the transdermal therapeutic system provides, by transdermal release, an AUC0-72 of 50 to 300 (ng/mL) h. 13. Transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure containing asenapine, wherein the transdermal therapeutic system provides upon transdermal release, an AUC0-84 of 35 to 450 (ng/mL) h or of greater than 450 to 700 (ng/mL) h. 14. Transdermal therapeutic system according to item 12, in which the transdermal therapeutic system provides, by transdermal release, an AUC0-84 of 60 to 350 (ng/mL) h. 15. A transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure containing asenapine, wherein the transdermal therapeutic system provides upon transdermal release a Cmax to C48 ratio of less than 2.0. 16. Transdermal therapeutic system according to item 14, wherein the transdermal therapeutic system provides, by transdermal release, a ratio of Cmax to C48 of less than 1.5 and preferably less than 1.3. 17. A transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure containing asenapine, wherein the transdermal therapeutic system provides upon transdermal release a Cmax to C72 ratio of less than 3.0. 18. Transdermal therapeutic system according to item 16, wherein the transdermal therapeutic system provides, by transdermal release, a ratio of Cmax to C72 of less than 2.5 and preferably less than 2.0. 19. Transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure containing asenapine, wherein the transdermal therapeutic system provides upon transdermal release a Cmax to C84 ratio of less than 3.5. 20. Transdermal therapeutic system according to item 18, wherein the transdermal therapeutic system provides, by transdermal release, a ratio of Cmax to C84 of less than 3.0, preferably less than 2.5 and more preferably less than 2.0. 21. A 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: A) a reinforcing layer; B) a matrix layer containing asenapine which consists of a matrix layer composition comprising: 1. asenapine; and 2. a polymer. 21. Transdermal therapeutic system according to any one of items 1 to 4 and 20, wherein the matrix layer containing asenapine 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 to 15% of the matrix layer composition and more preferably does not comprise isopropyl palmitate. 22. A transdermal therapeutic system for the transdermal delivery of asenapine comprising a self-adhesive layer structure containing a therapeutically effective amount of asenapine, said self-adhesive layer structure comprising: A) a reinforcing layer; B) a matrix layer containing asenapine consisting of a matrix layer composition comprising: 1. asenapine in the form of the free base; and 2. a polymer; 3. that the area weight of the matrix layer is at least 90 g/m2, and wherein the matrix layer containing asenapine does not comprise isopropyl palmitate. 23. Transdermal therapeutic system according to any one of items 5 to 22, wherein the transdermal therapeutic system contains at least 0.70 mg/cm2, preferably at least 0.80 mg/cm2, more preferably at least 0.82 mg/cm2 and most preferably at least 0.83 mg/cm2 of asenapine. 24. Transdermal therapeutic system according to any one of items 5 to 23, wherein the transdermal therapeutic system contains from 0.70 mg/cm2 to 4.0 mg/cm2, preferably from 0.80 mg/cm2 to 3.0 mg/cm2, more preferably from 0.82 mg/cm2 to 2.0 mg/cm2 and most preferably from 0.83 mg/cm2 to 1.7 mg/cm2 of asenapine. 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/m2, preferably from 110 to 210 g/m2, and more preferably from 120 to 170 g/m2. 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 polysiloxanes and polyisobutylenes in an amount of more than 50% of the matrix layer composition. 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. 28. Transdermal therapeutic system according to any one of items 20 to 26, wherein the polymer is selected from acrylic polymers. 29. Transdermal therapeutic system according to any one of items 5 to 28, wherein the transdermal therapeutic system has a delivery area of 5 to 100 cm2. 30. Transdermal therapeutic system according to any one of items 1 to 4 and 20 to 29, wherein the matrix layer containing asenapine 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 more preferably does not comprise isopropyl myristate. 31. Transdermal therapeutic system according to any one of items 1 to 4 and 20 to 30, wherein the matrix layer containing asenapine does not comprise ethyl cellulose in an amount of 10 to 20% of the matrix layer composition and preferably does not comprise ethyl cellulose. 32. Transdermal therapeutic system according to any one of items 1 to 4 and 20 to 31, in which the matrix layer containing asenapine does not comprise hydrogen chloride. 33. Transdermal therapeutic system according to any one of items 1 to 4 and 20 to 32, wherein the matrix layer containing asenapine does not comprise toluene. 34. Transdermal therapeutic system according to any one of items 1 to 4 and 20 to 33, in which the matrix layer containing asenapine is obtained by drying a coated coating composition in which no hydrochloric acid has been included in the coating composition. 35. Transdermal therapeutic system according to any one of items 1 to 4 and 20 to 34, wherein the matrix layer containing asenapine is obtained by drying a coated coating composition not comprising any toluene. 36. Transdermal therapeutic system according to any one of items 1 to 4 and 20 to 35, in which asenapine in the matrix layer composition is included in the form of the free base. 37. Transdermal therapeutic system according to any one of items 1 to 4 and 20 to 36, in which the matrix layer composition is obtained by incorporating asenapine in the form of the free base. 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. 39. Transdermal therapeutic system according to any one of items 1 to 4 and 20 to 38, in which the asenapine in the matrix layer is completely dissolved. 40. Transdermal therapeutic system according to any one of items 1 to 4 and 20 to 39, in which the matrix layer composition contains asenapine particles, preferably consisting of asenapine free base. 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. 42. Transdermal therapeutic system according to any one of items 1 to 41, wherein asenapine has a purity of at least 95%, preferably at least 98% and more preferably at least 99% as determined by quantitative HPLC. 43. A 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. 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. 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. 46. Transdermal therapeutic system according to item 45, in which the functional groups are selected from hydroxyl groups, carboxylic acid groups, neutralized carboxylic acid groups and mixtures thereof. 47. Transdermal therapeutic system according to item 46, in which the functional groups are limited to hydroxyl groups. 48. Transdermal therapeutic system according to any one of items 1 to 4 and 20 to 47, in which the polymer is selected from acrylic polymers that do not comprise carboxylic acid groups or neutralized carboxylic acid groups or both groups. 49. Transdermal therapeutic system according to any one of items 1 to 4 and 20 to 48, in which the polymer is selected from acrylic polymers that do not comprise acidic groups. 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. 51. Transdermal therapeutic system according to item 50, in which the polymer is a copolymer based on vinyl acetate, 2-ethylhexyl acrylate, 2-hydroxyethyl acrylate and glycidyl methacrylate. 52. Transdermal therapeutic system according to item 51, wherein the polymer is crosslinked by a crosslinking agent and preferably is crosslinked by a titanium crosslinking agent. 53. Transdermal therapeutic system according to item 51, in which the polymer is not crosslinked by a crosslinking agent. 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 group and no carboxylic acid group. 55. Transdermal therapeutic system according to item 54, wherein the polymer is selected from acrylic polymers comprising no functional groups. 56. Transdermal therapeutic system according to item 55, in which 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. 57. Transdermal therapeutic system according to any one of items 1 to 4 and 20 to 56, in which the amount of polymer varies 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. 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. 59. Transdermal therapeutic system according to any one of items 1 to 58, wherein the transdermal therapeutic system has a release area of 5 to 100 cm2, preferably 10 to 80 cm2, and more preferably 10 to 20 cm2, 25 to 35 cm2 and 55 to 65 cm2. 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 more preferably from 15 to 60 mg. 61. Transdermal therapeutic system according to any one of items 1 to 60, wherein the transdermal therapeutic system has a release area of 5 to 100 cm2, and the amount of asenapine contained in the transdermal therapeutic system ranges from 5 to 100 mg. 62. Transdermal therapeutic system according to any one of items 1 to 4 and 20 to 61, in which the matrix layer composition comprises other excipients or additives selected from the group consisting of crosslinking agents, solubilizers, fillers, adhesion agents, plasticizers, stabilizers, softeners, skin care substances, permeation enhancers, pH regulators, and preservatives. 63. Transdermal therapeutic system according to item 62, in which the adhesion agent 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. 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 ester of fatty acids and tocopherol, and most preferably is ascorbyl palmitate or α-tocopherol or a combination thereof. 65. Transdermal therapeutic system according to item 62, in which 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 fatty acid diesters. 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. 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. 68. Transdermal therapeutic system according to any one of items 1 to 4 and 20 to 67, in which the matrix layer composition also comprises a copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate. 69. Transdermal therapeutic system according to any one of items 1 to 68, wherein the transdermal therapeutic system provides an average release rate of 0.5 to 20 mg/day, preferably 1.0 to 15 mg/day, and more preferably 2.0 to 10 mg/day for at least 24 hours of administration, preferably for at least 48 hours of administration, more preferably for at least 72 hours of administration. 70. A transdermal therapeutic system according to any one of items 1 to 69, providing a cumulative skin permeation rate of asenapine at hour 48 or hour 72 as measured in a Franz diffusion cell with dermatomized human skin of from 1 μg/(cm2 h) to 20 μg/(cm2 h), preferably from 2 μg/(cm2 h) to 15 μg/(cm2 h) and more preferably from 4 μg/(cm2 h) to 12 μg/(cm2 h). 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 dermatomized human skin of 0 μg/(cm2 h) to 10 μg/(cm2 h) in the first 8 hours, 2 μg/(cm2 h) to 20 μg/(cm2 h) from 8 hours to 24 hours, 3 μg/(cm2 h) to 20 μg/(cm2 h) from 24 hours to 32 hours, 3 μg/(cm2 h) to 20 μg/(cm2 h) from 32 hours to 48 hours, 2 μg/(cm2 h) to 15 μg/(cm2 h) from 48 hours to 72 hours. 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 dermatomized human skin of 0.05 mg/cm2 to 1.0 mg/cm2, preferably of 0.1 mg/cm2 to 0.7 mg/cm2 over a time period of 48 hours. 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 dermatomized human skin of 0.1 mg/cm2 to 2.0 mg/cm2, preferably 0.2 mg/cm2 to 1.0 mg/cm2 over a time period of 72 hours. 74. Transdermal therapeutic system according to any one of items 1 to 73, also comprising a release coating. 75. Transdermal therapeutic system according to any one of items 1 to 74, also comprising an adhesive overlayer or not comprising any adhesive overlayer, and preferably not comprising any adhesive overlayer. 76. A transdermal therapeutic system according to any one of items 1 to 75, wherein the backing layer is substantially impermeable to asenapine. 77. A 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. 78. A transdermal therapeutic system according to any one of items 1 to 76, wherein the self-adhesive layer structure comprises an additional skin contact layer. 79. The transdermal therapeutic system of item 78, wherein the self-adhesive layer structure comprises a membrane that is located between the matrix layer and the additional skin contact layer, wherein the membrane is preferably a rate controlling membrane. 80. A transdermal therapeutic system according to any one of items 1 to 79, wherein the self-adhesive layer structure comprises an additional reservoir layer that is located between the reinforcement layer and the matrix layer, and another rate control membrane that is located between the additional reservoir layer and the matrix layer. 81. A transdermal therapeutic system according to any one of items 1 to 80, wherein the transdermal therapeutic system is a matrix-type TTS. 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 for the treatment of psychosis and more preferably for use in a method for the treatment of one or more conditions selected from schizophrenia, bipolar disorder, post-traumatic stress disorder, major depressive disorder, dementia-related psychosis, agitation and manic disorder. 83. Transdermal therapeutic system according to item 82, for use in a method for the treatment of schizophrenia and/or bipolar disorder. 84. Transdermal therapeutic system according to item 82, for use in a method for the treatment of bipolar disorder, in particular acute manic or mixed episodes of bipolar disorder. 85. Transdermal therapeutic system according to any one of items 82 to 84, for use in a method of treatment with a dosage interval of at least 24 hours or 1 day, at least 48 hours or 2 days, or at least 72 hours or 3 days. 86. Transdermal therapeutic system according to any one of items 82 to 85, for use in a method of treatment with a dosage interval of up to 168 hours or 7 days, up to 120 hours or 5 days, or up to 96 hours or 4 days. 87. Transdermal therapeutic system according to item 85 for use in a treatment method with a dosage interval of 24 hours or 1 day. 88. Transdermal therapeutic system according to item 85 for use in a treatment method with a dosage interval of 48 hours or 2 days. 89. Transdermal therapeutic system according to item 85 for use in a treatment method with a dosing interval of 84 hours or 3.5 days. 90. A transdermal therapeutic system according to any one of items 82 to 89, 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. 91. Transdermal therapeutic system according to item 90 for use in a method for treating a patient, wherein the patient is a human patient suffering from fatigue, drowsiness, dizziness, or any combination thereof, or at least one asenapine-related side effect is fatigue, drowsiness, dizziness, oral hypoesthesia, or any combination thereof, or the incidence of 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 at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced, or 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 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%. 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. 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 the patient is a human patient suffering from fatigue, somnolence, dizziness, or any combination thereof, or the at least one asenapine-related side effect is fatigue, somnolence, dizziness, oral hypoesthesia, or any combination thereof, or 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 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 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%. 94. A method of treatment, and in particular a method for the treatment of psychosis and more preferably a method for the treatment of one or more conditions selected from schizophrenia, bipolar disorder, post-traumatic stress disorder, major depressive disorder, dementia-related psychosis, agitation and manic disorder, comprising applying a transdermal therapeutic system according to any one of items 1 to 81 to the skin of a patient. 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. 96. A method for the treatment of 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. 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. 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. 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. 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. 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. 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. 103. The method of treatment according to item 102, wherein the patient is a human patient suffering from fatigue, drowsiness, dizziness, or any combination thereof. 104. The method of treatment according to item 102 or 103, wherein at least one asenapine-related side effect is fatigue, somnolence, dizziness, oral hypoesthesia, or any combination thereof. 105. The treatment method according to any one of items 102 to 104, wherein the incidence of 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 at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced. 106. The treatment method according to item 105, wherein 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 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%. 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. 108. The method according to item 107, wherein the patient is a human patient suffering from fatigue, drowsiness, dizziness, or any combination thereof. 109. The method according to item 107 or 108, wherein at least one side effect related to asenapine is fatigue, somnolence, dizziness, oral hypoesthesia, or any combination thereof. 110. The method according to any one of items 107 to 109, wherein the incidence of 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 at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced. 111. The method according to item 110, wherein 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 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%. 112. A method of reducing at least one asenapine-related side effect in a patient who is being treated with sublingual asenapine therapy, the method comprising: a) discontinuing sublingual asenapine therapy; and 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. 113. The method of item 112, wherein the transdermal therapeutic system releases an amount of asenapine equivalent to an amount of asenapine originally delivered by sublingual asenapine therapy. 114. Asenapine for use in a method for the treatment of a human patient by transdermal administration of asenapine for a dosing interval of at least 48 hours or 2 days. 115. Asenapine for use in a method for the treatment of a human patient by transdermal administration of asenapine for a dosing interval of at least 72 hours or 3 days. 116. Asenapine for use in a method for the treatment of a human patient according to item 114 or 115, wherein the dosage interval is up to 168 hours or 7 days, up to 120 hours or 5 days, or up to 96 hours or 4 days. 117. Asenapine for use in a method for the treatment of 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. 118. Asenapine for use in a method for the treatment of a human patient according to any one of items 114 to 117, for use in a method for the treatment of psychosis, and in particular for use in a method for the treatment of one or more conditions selected from schizophrenia, bipolar disorder, post-traumatic stress disorder, major depressive disorder, dementia-related psychosis, agitation and manic disorder, or for use in a method for the treatment of schizophrenia and/or bipolar disorder, preferably bipolar disorder and in particular acute manic or mixed episodes of bipolar disorder. 119. Asenapine for use in a method for the treatment of a human patient according to any one of items 114 to 118, providing, by transdermal delivery, an average release rate of 0.5 to 20 mg/day, preferably 1.0 to 15 mg/day, more preferably 2.0 to 10 mg/day for at least 48 hours or 2 days of administration, or providing, by transdermal delivery, an average release rate of 0.5 to 20 mg/day, preferably 1.0 to 15 mg/day, more preferably 2.0 to 10 mg/day for at least 72 hours or 3 days of administration, or providing, by transdermal delivery, an average release rate of 0.5 to 20 mg/day, preferably 1.0 to 15 mg/day, more preferably 2.0 to 10 mg/day for at least 84 hours or 3.5 days of administration. 120. Asenapine for use in a method for the treatment of a human patient according to any one of items 114 to 119, providing, by transdermal release, an AUC0-48 of 20 to 300 (ng/mL) h or of greater than 300 to 450 (ng/mL) h and preferably of 30 to 200 (ng/mL) h, or providing, by transdermal release, an AUC0-72 of 30 to 400 (ng/mL) h or of greater than 400 to 600 (ng/mL) h and preferably of 50 to 300 (ng/mL) h, or providing, by transdermal release, an AUC0-84 of 35 to 450 (ng/mL) h or of greater than 450 to 700 (ng/mL) h and preferably of 60 to 350 (ng/mL) h. 121. Asenapine for use in a method for the treatment of a human patient according to any one of items 114 to 120, providing, by transdermal delivery, a ratio of Cmax to C48 of less than 2.0, preferably less than 1.5 and more preferably less than 1.3, or providing by transdermal delivery the ratio of Cmax to C72 of less than 3.0, preferably less than 2.5 and more preferably less than 2.0, or providing by transdermal delivery the ratio of Cmax to C84 of less than 3.5, preferably less than 3.0, more preferably less than 2.5 and most preferably less than 2.0. 122. Asenapine for use in a method for the treatment of a human patient according to any one of items 114 to 121, wherein at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced. 123. Asenapine for use in a method for treating a human patient according to item 122, wherein the human patient is suffering from fatigue, drowsiness, dizziness, or any combination thereof, or at least one asenapine-related side effect is fatigue, drowsiness, dizziness, oral hypoesthesia, or any combination thereof, or the incidence of 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 at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced, or 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 at least one side effect related to asenapine 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%. 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. 125. Transdermal therapeutic system for the transdermal administration of asenapine, for use in a method for the treatment of a human patient for a dosing interval of at least 72 hours or 3 days. 126. A transdermal therapeutic system for use in a method of treating a human patient according to item 124 or 125 wherein the dosage interval is up to 168 hours or 7 days, up to 120 hours or 5 days, or up to 96 hours or 4 days. 127. A transdermal therapeutic system for use in a method of treating a human patient according to item 124 or 125, wherein the dosing interval is 48 hours or 2 days, or 72 hours or 3 days, or 84 hours or 3.5 days. 128. A transdermal therapeutic system for use in a method of treating a human patient according to any one of items 124 to 127, comprising a self-adhesive layer structure containing a therapeutically effective amount of asenapine. 129. A transdermal therapeutic system for use in a method for the treatment of a human patient according to any one of items 124 to 128, for use in a method for the treatment of psychosis, and in particular for use in a method for the treatment of one or more conditions selected from schizophrenia, bipolar disorder, post-traumatic stress disorder, major depressive disorder, dementia-related psychosis, agitation and manic disorder, or for use in a method for the treatment of schizophrenia and/or bipolar disorder, preferably bipolar disorder and in particular acute manic or mixed episodes of bipolar disorder. 130. A transdermal therapeutic system for use in a method of treating a human patient according to any one of items 124 to 129, providing, by transdermal delivery, an average release rate of 0.5 to 20 mg/day, preferably 1.0 to 15 mg/day, more preferably 2.0 to 10 mg/day over at least 48 hours of administration, or providing, by transdermal delivery, an average release rate of 0.5 to 20 mg/day, preferably 1.0 to 15 mg/day, more preferably 2.0 to 10 mg/day over at least 72 hours of administration, or providing, by transdermal delivery, an average release rate of 0.5 to 20 mg/day, preferably 1.0 to 15 mg/day, more preferably 2.0 to 10 mg/day over at least 84 hours of administration. 131. A transdermal therapeutic system for use in a method for treating a human patient according to any one of items 124 to 130 providing, by transdermal release, an AUC0-48 of 20 to 300 (ng/mL) h or of greater than 300 to 450 (ng/mL) h and preferably of 30 to 200 (ng/mL) h, or providing, by transdermal release, an AUC0-72 of 30 to 400 (ng/mL) h or of greater than 400 to 600 (ng/mL) h and preferably of 50 to 300 (ng/mL) h, or providing, by transdermal release, an AUC0-84 of 35 to 450 (ng/mL) h or of greater than 450 to 700 (ng/mL) h and preferably of 60 at 350 (ng/mL) h. 132. A transdermal therapeutic system for use in a method for treating a human patient according to any one of items 124 to 131, providing, by transdermal delivery, a ratio of Cmax to C48 of less than 2.0, preferably less than 1.5 and more preferably less than 1.3, or providing by transdermal delivery a ratio of Cmax to C72 of less than 3.0, preferably less than 2.5 and more preferably less than 2.0, or providing by transdermal delivery a ratio of Cmax to C84 of less than 3.5, preferably less than 3.0, more preferably less than 2.5 and most preferably less than 2.0. 133. A transdermal therapeutic system according to any one of items 124 to 132, 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. 134. Transdermal therapeutic system according to item 133 for use in a method for treating a patient, wherein the patient is a human patient suffering from fatigue, drowsiness, dizziness, or any combination thereof, or at least one asenapine-related side effect is fatigue, drowsiness, dizziness, oral hypoesthesia, or any combination thereof, or the incidence of 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 at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced, or 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 by at least about 30% or at least about 40%, ... equivalent dose of sublingual asenapine is reduced, or 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%. 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. 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. 137. A method of treating a human patient by transdermal administration of asenapine according to item 135 or 136, wherein the dosage interval is up to 168 hours or 7 days, up to 120 hours or 5 days, or up to 96 hours or 4 days. 138. A method of treating a human patient by transdermal administration of asenapine according to item 135 or 136, wherein the dosing interval is 48 hours or 2 days, or 72 hours or 3 days, or 84 hours or 3.5 days. 139. A method of treating a human patient by transdermal administration of asenapine according to any one of items 135 to 138, including applying a transdermal therapeutic system for 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. 140. A method of treating a human patient by transdermal administration of asenapine according to any one of items 135 to 139, wherein the transdermal therapeutic system for transdermal administration of asenapine comprises a self-adhesive layer structure containing a therapeutically effective amount of asenapine. 141. The method of treating psychosis, and in particular the method of treating one or more conditions selected from schizophrenia, bipolar disorder, post-traumatic 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. 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. 143. A method of treating a human patient according to any one of items 135 to 142 providing, by transdermal delivery, an average release rate of 0.5 to 20 mg/day, preferably 1.0 to 15 mg/day, more preferably 2.0 to 10 mg/day over at least 48 hours of administration, or providing, by transdermal delivery, an average release rate of 0.5 to 20 mg/day, preferably 1.0 to 15 mg/day, more preferably 2.0 to 10 mg/day over at least 72 hours of administration, or providing, by transdermal delivery, an average release rate of 0.5 to 20 mg/day, preferably 1.0 to 15 mg/day, more preferably 2.0 to 10 mg/day over at least 84 hours of administration. 144. A method of treating a human patient according to any one of items 135 to 143 providing, by transdermal delivery, an AUC0-48 of 20 to 300 (ng/mL) h or of more than 300 to 450 (ng/mL) h and preferably of 30 to 200 (ng/mL) h, or providing, by transdermal delivery, an AUC0-72 of 30 to 400 (ng/mL) h or of more than 400 to 600 (ng/mL) h and preferably of 50 to 300 (ng/mL) h, or providing, by transdermal delivery, an AUC0-84 of 35 to 450 (ng/mL) h or of more than 450 to 700 (ng/mL) h and preferably of 60 to 350 (ng/mL) h. 145. A method of treating a human patient according to any one of items 135 to 144 providing, by transdermal delivery, a ratio of Cmax to C48 of less than 2.0, preferably less than 1.5 and more preferably less than 1.3, or providing by transdermal delivery a ratio of Cmax to C72 of less than 3.0, preferably less than 2.5 and more preferably less than 2.0, or providing by transdermal delivery a ratio of Cmax to C84 of less than 3.5, preferably less than 3.0, more preferably less than 2.5 and most preferably less than 2.0. 146. A 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. 147. A method of treating a human patient according to item 146, wherein the human patient is suffering from fatigue, drowsiness, dizziness, or any combination thereof. 148. A method of treating a human patient according to item 146 or 147, wherein at least one asenapine-related side effect is fatigue, somnolence, dizziness, oral hypoesthesia, or any combination thereof. 149. A method of treating a human patient according to any one of items 146 to 148 wherein the incidence of 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 at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced. 150. A method of treating a human patient according to item 149, wherein 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 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%. 151. A transdermal therapeutic system for the transdermal delivery of asenapine 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, and wherein 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 hypoesthesia, or any combination thereof. 152. The transdermal therapeutic system of item 151 for use in a method for treating a human patient, wherein the incidence of 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 at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced, or 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 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% or at least about 40% 30%, at least about 40%, at least about 70% or at least about 80%. 153. A method for 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 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 hypoesthesia, or any combination thereof. 154. A method of treating a human patient according to item 153, wherein the incidence of 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 at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced, or 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 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 80%, and/or the incidence of fatigue ... 70% or at least about 80%. 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 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 hypoesthesia, or any combination thereof. 156. A method of treating a human patient according to item 155, wherein the incidence of 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 at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced, or 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 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 80%, or at least about 90%. 70% or at least about 80%. 157. A method of reducing at least one asenapine-related side effect in a patient who is being treated with sublingual asenapine therapy, the method comprising: a) discontinuing sublingual asenapine therapy; and b) transdermal administration of asenapine, wherein the patient is suffering from fatigue, somnolence, dizziness, or any combination thereof, and/or at least one asenapine-related side effect is fatigue, somnolence, dizziness, oral hypoesthesia, or any combination thereof. 158. The method of item 157, wherein the transdermal therapeutic system releases an amount of asenapine equivalent to the amount of asenapine originally delivered by sublingual asenapine therapy. 159. Process for manufacturing 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: 1) combining at least the asenapine and polymer components, in a solvent to obtain a coating composition; 2) coating the coating composition over the backing layer or release liner or any intermediate coating; and 3) drying the coated coating composition to form the matrix layer. 160. Process for manufacturing a matrix layer according to item 159, in which in step 1 asenapine is dissolved to obtain the coating composition. 161. The process according to item 159 or 160, 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 most preferably is selected from ethanol and ethyl acetate. 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 supplied as a solution and preferably as a solution in ethyl acetate, n-heptane, methanol, ethanol, or any mixtures thereof, with a solids content of 30 to 60% by weight. 163. The process according to any one of items 159 to 162, wherein the drying is carried out at a temperature of 50 to 90 °C, more preferably 60 to 80 °C. 164. A transdermal therapeutic system for the transdermal delivery of asenapine comprising a self-adhesive layer structure comprising: A) a reinforcing layer; B) a matrix layer containing asenapine consisting of a matrix layer composition comprising: 1. asenapine included in the form of the free base; 2. a copolymer based on vinyl acetate, 2-ethylhexyl acrylate, 2-hydroxyethyl acrylate and glycidyl methacrylate; and 3. a stabilizer. 165. A transdermal therapeutic system for the transdermal delivery of asenapine comprising a self-adhesive layer structure comprising: 1. a reinforcing layer; 8. a matrix layer containing asenapine consisting of a matrix layer composition comprising: 9. asenapine included in the form of the free base in an amount of 3% to 9% of the matrix layer composition; 10. a copolymer based on vinyl acetate, 2-ethylhexyl acrylate, 2-hydroxyethyl acrylate and glycidyl methacrylate in an amount of 90 to 96.5% of the matrix layer composition; and 11. a stabilizer in an amount of 0.1% to 2% of the matrix layer composition; wherein the areal weight of the matrix layer ranges from 120 to 170 g/m2. 166. A transdermal therapeutic system for the transdermal delivery of asenapine comprising a self-adhesive layer structure comprising: A) a reinforcing layer; B) a matrix layer containing asenapine consisting of a matrix layer composition comprising: 1. asenapine included in the form of the free base; 2. a copolymer based on vinyl acetate, 2-ethylhexyl acrylate, 2-hydroxyethyl acrylate and glycidyl methacrylate; 3. a stabilizer; and 4. a polyvinyl pyrrolidone. 167. A transdermal therapeutic system for the transdermal delivery of asenapine comprising a self-adhesive layer structure comprising: A) a reinforcing layer; B) a matrix layer containing asenapine consisting of a matrix layer composition comprising: 1. asenapine included in the form of the free base in an amount of 3% to 9% of the matrix layer composition; 2. a copolymer based on vinyl acetate, 2-ethylhexyl acrylate, 2-hydroxyethyl acrylate and glycidyl methacrylate in an amount of 80 to 90% of the matrix layer composition; 3. a stabilizer in an amount of 0.1% to 2% of the matrix layer composition; and 4. a polyvinyl pyrrolidone in an amount of 5 to 15% of the matrix layer composition. where the area weight of the matrix layer varies from 120 to 170 g/m2. 168. A transdermal therapeutic system for the transdermal delivery of asenapine comprising a self-adhesive layer structure comprising: A) a reinforcing layer; B) a matrix layer containing asenapine consisting of a matrix layer composition comprising: 1. asenapine included in the form of the free base in an amount of 7% to 13% of the matrix layer composition; 2. a copolymer based on vinyl acetate, 2-ethylhexyl acrylate, 2-hydroxyethyl acrylate and glycidyl methacrylate in an amount of 75% to 85% of the matrix layer composition; 3. a stabilizer in an amount of 0.1% to 2% of the matrix layer composition; and 4. a polyvinyl pyrrolidone in an amount of 5 to 15% of the matrix layer composition. where the area weight of the matrix layer varies from 120 to 170 g/m2. 169. A transdermal therapeutic system for the transdermal delivery of asenapine comprising a self-adhesive layer structure comprising: 1. a reinforcing layer; 8. a matrix layer containing asenapine consisting of a matrix layer composition comprising: 9. asenapine included in the form of the free base in an amount greater than 13% to 20% of the matrix layer composition; 10. a copolymer based on vinyl acetate, 2-ethylhexyl acrylate, 2-hydroxyethyl acrylate and glycidyl methacrylate in an amount of 65% to 82% of the matrix layer composition; 11. a stabilizer in an amount of 0.001% to 2% of the matrix layer composition; and 12. a polyvinyl pyrrolidone in an amount of 5 to 15% of the matrix layer composition. where the area weight of the matrix layer varies from 120 to 230 g/m2. 170. A transdermal therapeutic system for the transdermal delivery of asenapine comprising a self-adhesive layer structure comprising: A) a reinforcing layer; B) a matrix layer containing asenapine consisting of a matrix layer composition comprising: 1. asenapine included in the form of the free base in an amount of 7% to 20% of the matrix layer composition; 2. a copolymer based on vinyl acetate, 2-ethylhexyl acrylate, 2-hydroxyethyl acrylate and glycidyl methacrylate in an amount of 75% to 85% of the matrix layer composition; 3. a stabilizer in an amount of 0.001% to 2% of the matrix layer composition; and 4. a polyvinyl pyrrolidone in an amount of 5 to 15% of the matrix layer composition. where the areal weight of the matrix layer ranges from more than 170 to 230 g/m2. The invention relates in particular to the following other embodiments: 1. A 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: a) a reinforcing layer; b) a matrix layer containing asenapine consisting of a matrix layer composition comprising: i) asenapine; and ii) at least one acrylic polymer; wherein the transdermal therapeutic system has a release area of 5 to 100 cm2. 2. Transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure containing asenapine, wherein the transdermal therapeutic system provides by transdermal release, an average release rate of 0.5 to 20 mg/day during at least 48 hours of administration. 3. Transdermal therapeutic system according to embodiment 2, in which the transdermal therapeutic system provides by transdermal release, an average release rate of 0.5 to 20 mg/day for at least 72 hours, or during 84 hours of administration, and/or in which the transdermal therapeutic system provides by transdermal release, an average release rate of 1.0 to 15 mg/day, or of 2.0 to 10 mg/day for at least 48 hours of administration. 4. A transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure containing asenapine, wherein the transdermal therapeutic system provides upon transdermal release, one or more pharmacokinetic parameter(s) selected from the group consisting of an asenapine AUC0-48 of 20 to 300 (ng/mL) h or of greater than 300 to 450 (ng/mL) h, an asenapine AUC0-72 of 30 to 400 (ng/mL) h or of greater than 400 to 600 (ng/mL) h, an asenapine AUC0-84 of 35 to 450 (ng/mL) h or of greater than 450 to 700 (ng/mL) h, an asenapine Cmax to C48 ratio of less than 2.0, an asenapine Cmax to C72 ratio of less than 3.0, an asenapine Cmax to C84 ratio of less than 3.5, and an asenapine Cmax value of 0.5 to 10 ng/mL. 5. A 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: a) a reinforcing layer; b) a matrix layer containing asenapine consisting of a matrix layer composition comprising: i) asenapine; and ii) a polymer. 6. A transdermal therapeutic system for the transdermal delivery of asenapine comprising a self-adhesive layer structure containing a therapeutically effective amount of asenapine, said self-adhesive layer structure comprising: a) a reinforcing layer; b) an asenapine-containing matrix layer consisting of a matrix layer composition comprising: i) asenapine free base; and ii) a polymer; wherein the asenapine-containing matrix layer has an areal weight that is at least 90 g/m2, and wherein the asenapine-containing matrix layer does not comprise isopropyl palmitate. 7. The transdermal therapeutic system of any one of embodiments 1 to 6, wherein the transdermal therapeutic system contains at least 0.70 mg/cm2, at least 0.80 mg/cm2, at least 0.82 mg/cm2, or at least 0.83 mg/cm2 asenapine, and/or wherein the transdermal therapeutic system contains from 0.70 mg/cm2 to 4.0 mg/cm2, from 0.80 mg/cm2 to 3.0 mg/cm2, from 0.82 mg/cm2 to 2.0 mg/cm2, or from 0.83 mg/cm2 to 1.7 mg/cm2 asenapine, and/or wherein the asenapine-containing matrix layer has an areal weight ranging from 90 to 230 g/m2, from 110 to 210 g/m2, or from 120 to 170 g/m2. 8. Transdermal therapeutic system according to any one of embodiments 1 and 5 to 7, wherein the matrix layer composition containing asenapine does not comprise any polysiloxanes and polyisobutylenes in an amount of more than 50% of the matrix layer composition containing asenapine. 9. The transdermal therapeutic system of any one of embodiments 1 and 5 to 8, 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 to 10% of the asenapine-containing matrix layer composition or does not comprise isopropyl myristate, and/or wherein the asenapine-containing matrix layer does not comprise ethyl cellulose in an amount of 10 to 20% of the asenapine-containing matrix layer composition or does not comprise ethyl cellulose, or wherein the asenapine-containing matrix layer does not comprise hydrogen chloride. 10. Transdermal therapeutic system according to any one of embodiments 1 and 5 to 9, wherein the asenapine in the matrix layer composition containing asenapine is included in the form of the free base, or wherein the matrix layer composition containing asenapine is obtained by incorporating asenapine free base, and/or 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 containing asenapine is present in the form of the free base, and/or wherein the amount of asenapine in the matrix layer composition containing senapine ranges from 2 to 20 %, from 3 to 15 % or from 4 to 12 % of the matrix layer composition containing asenapine. 11. Transdermal therapeutic system according to any one of modalities 1 to 3, in which 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. 12. Transdermal therapeutic system according to any one of embodiments 5 to 10, 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. 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 matrix layer composition containing asenapine, or wherein the total polymer content in the matrix layer composition containing asenapine ranges from 75 to 97%, from 80 to 96% or from 85 to 95% of the matrix layer composition containing asenapine. 14. Transdermal therapeutic system according to any one of embodiments 1 and 5 to 13, wherein the matrix layer composition containing asenapine comprises other excipients or additives selected from the group consisting of crosslinking agents, solubilizers, fillers, adhesion agents, plasticizers, stabilizers, softeners, skin care substances, permeation enhancers, pH regulators, and preservatives. 15. The transdermal therapeutic system of embodiment 14, wherein the adhesion agent is selected from polyvinylpyrrolidone, triglycerides, dipropylene glycol, resins, rosin esters, terpenes and derivatives thereof, ethylene vinyl acetate adhesives, dimethylpolysiloxanes and polybutenes, preferably polyvinylpyrrolidone and more preferably soluble polyvinylpyrrolidone, 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 derivative thereof and ascorbic acid and ester derivative thereof, and is most preferably selected from ascorbyl esters of fatty acids and tocopherol. and more preferably is ascorbyl palmitate or α-tocopherol or a combination thereof, or 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 fatty acid diesters. 16. The transdermal therapeutic system of any one of embodiments 1 to 15, providing a skin permeation rate of asenapine as measured in a Franz diffusion cell with dermatomized human skin of 0 μg/(cm2 h) to 10 μg/(cm2 h) in the first 8 hours, 2 μg/(cm2 h) to 20 μg/(cm2 h) from 8 hours to 24 hours, 3 μg/(cm2 h) to 20 μg/(cm2 h) from 24 hours to 32 hours, 3 μg/(cm2 h) to 20 μg/(cm2 h) from 32 hours to 48 hours, 2 μg/(cm2 h) to 15 μg/(cm2 h) from 48 hours to 72 hours, or providing a cumulative permeated amount of asenapine as measured in a Franz diffusion cell with dermatomized human skin of 0.05 mg/cm2 to 1.0 mg/cm2, or of 0.1 mg/cm2 to 0.7 mg/cm2 over a 48-hour time period, or providing a cumulative permeated amount of asenapine as measured in a Franz diffusion cell with dermatomized human skin of 0.1 mg/cm2 to 2.0 mg/cm2, or of 0.2 mg/cm2 to 1.0 mg/cm2 over a 72-hour time period. 17. A transdermal therapeutic system according to any one of embodiments 1 to 16 for use in a method of treatment, for use in a method for the treatment of psychosis, for use in a method for the treatment of one or more conditions selected from schizophrenia, bipolar disorder, post-traumatic stress disorder, major depressive disorder, dementia-related psychosis, agitation and manic disorder, for use in a method for the treatment of schizophrenia and/or bipolar disorder or for use in a method for the treatment of bipolar disorder, in particular acute manic or mixed episodes of bipolar disorder. 18. A transdermal therapeutic system according to embodiment 17 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. 19. The transdermal therapeutic system of embodiment 18 for use in a method for treating a patient, wherein the patient is a human patient suffering from fatigue, drowsiness, dizziness, or any combination thereof, or at least one asenapine-related side effect is fatigue, drowsiness, dizziness, oral hypoesthesia, or any combination thereof, or the incidence of 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 at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced, or 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 ... sublingual asenapine equivalent is reduced, or 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%. 20. A transdermal therapeutic system according to embodiment 17 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. 21. The transdermal therapeutic system of 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 the patient is a human patient suffering from fatigue, drowsiness, dizziness, or any combination thereof, or the at least one asenapine-related side effect is fatigue, drowsiness, dizziness, oral hypoesthesia, or any combination thereof, or 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 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%, 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 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%. 30% or at least about 40% and/or the intensity of fatigue relative to an equivalent dose of sublingual asenapine is reduced, or 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%. 22. A method of treatment, a method for treating psychosis, a method for treating one or more conditions selected from schizophrenia, bipolar disorder, post-traumatic stress disorder, major depressive disorder, dementia-related psychosis, agitation and manic disorder, a method for treating schizophrenia and/or bipolar disorder, or a method for 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. 23. The treatment method of embodiment 22, wherein the transdermal therapeutic system provides a reduction in at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine. 24. The method of treatment according to embodiment 23, wherein the patient is a human patient suffering from fatigue, drowsiness, dizziness, or any combination thereof. 25. The method of treatment according to embodiment 23, wherein at least one asenapine-related side effect is fatigue, somnolence, dizziness, oral hypoesthesia, or any combination thereof. 26. The treatment method according to embodiment 23, wherein the incidence of 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 at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced. 27. The treatment method according to embodiment 26, wherein 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 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%. 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. 29. The method according to embodiment 28, wherein the patient is a human patient suffering from fatigue, drowsiness, dizziness, or any combination thereof. 30. The method according to embodiment 28 or 29, wherein at least one asenapine-related side effect is fatigue, somnolence, dizziness, oral hypoesthesia, or any combination thereof. 31. The method of any one of embodiments 28 to 30, wherein the incidence of 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 at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced. 32. The method according to embodiment 31, wherein 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 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%. 33. A method of reducing at least one asenapine-related side effect in a patient being treated with sublingual asenapine therapy, the method comprising: a) discontinuing sublingual asenapine therapy; and 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. 34. The method of embodiment 33, wherein the transdermal therapeutic system releases an amount of asenapine equivalent to the amount of asenapine originally delivered by sublingual asenapine therapy. 35. Asenapine for use in a method for the treatment of a human patient by transdermal administration of asenapine for a dosing interval of at least 48 hours or 2 days. 36. Asenapine for use in a method for 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 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 providing, by transdermal delivery, an average release rate of 0.5 to 20 mg/day, 1.0 to 15 mg/day, or 2.0 to 10 mg/day over at least 48 hours or 2 days of administration, or providing, by transdermal delivery, an average release rate of 0.5 to 20 mg/day, 1.0 to 15 mg/day, or 2.0 to 10 mg/day over at least 72 hours or 3 days of administration, or providing, by transdermal delivery, an average release rate of 0.5 to 20 mg/day, 1.0 to 15 mg/day, or 2.0 to 10 mg/day over at least 84 hours or 3.5 days of administration, or providing, by transdermal delivery, an AUC0-48 of 20 to 300 (ng/mL) hr, of greater than 300 to 450 (ng/mL) hr, or of 30 to 200 (ng/mL) hr, or providing, by transdermal delivery, an AUC0-72 of 30 to 400 (ng/mL) hr, of greater than 400 to 600 (ng/mL) hr, or of 50 to 300 (ng/mL) hr, or providing, by transdermal delivery, an AUC0-84 of 35 to 450 (ng/mL) h, from greater than 450 to 700 (ng/mL) h or from 60 to 350 (ng/mL) h, or providing, by transdermal delivery, a Cmax ratio for C48 of less than 2.0, less than 1.5 or less than 1.3, or providing, by transdermal delivery, a Cmax ratio for C72 of less than 3.0, less than 2.5 or less than 2.0, or providing, by transdermal delivery, a Cmax ratio for C84 of less than 3.5, less than 3.0, less than 2.5 or less than 2.0, or providing by transdermal delivery a Cmax value of 0.5 to 10 ng/mL or 1 to 8 ng/mL. 37. Asenapine for use in a method for treating a human patient according to embodiment 35 or 36, wherein at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced. 38. Asenapine for use in a method for treating a human patient according to embodiment 37, wherein the human patient is suffering from fatigue, drowsiness, dizziness, or any combination thereof, or at least one asenapine-related side effect is fatigue, drowsiness, dizziness, oral hypoesthesia, or any combination thereof, or the incidence of 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 at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced, or 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 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 by at least about 30%, at least about 40%, at least about 70%, or at least about 80%, and/or the intensity of fatigue relative to an equivalent dose of sublingual asenapine is reduced by at least about 30%, at least about 4 ... reduced, or at least one side effect related to asenapine 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%. 39. Transdermal therapeutic system for the transdermal administration of asenapine for use in a method for the treatment of a human patient for a dosing interval of at least 48 hours or 2 days. 40. A transdermal therapeutic system for use in a method for treating a human patient according to embodiment 39, 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 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 providing, upon transdermal delivery, an average release rate of 0.5 to 20 mg/day, 1.0 to 15 mg/day, or 2.0 to 10 mg/day over at least 48 hours of administration, or providing, upon transdermal delivery, an average release rate of 0.5 to 20 mg/day, 1.0 to 15 mg/day, or 2.0 to 10 mg/day over at least 72 hours of administration, or providing, by transdermal release, an average release rate of 0.5 to 20 mg/day, 1.0 to 15 mg/day, or 2.0 to 10 mg/day over at least 84 hours of administration, or providing, by transdermal release, an AUC0-48 of 20 to 300 (ng/mL) h, of greater than 300 to 450 (ng/mL) h, or of 30 to 200 (ng/mL) h, or providing, by transdermal release, an AUC0-72 of 30 to 400 (ng/mL) h, of greater than 400 to 600 (ng/mL) h, or of 50 to 300 (ng/mL) h, or providing, by transdermal release, an AUC0-84 of 35 to 450 (ng/mL) h, of more than 450 to 700 (ng/mL) h or of 60 to 350 (ng/mL) h, or providing, by transdermal delivery, a Cmax ratio for C48 of less than 2.0, less than 1.5 or less than 1.3, or providing, by transdermal delivery, a Cmax ratio for C72 of less than 3.0, less than 2.5 or less than 2.0, or providing, by transdermal delivery, a Cmax ratio for C84 of less than 3.5, less than 3.0, less than 2.5 or less than 2.0, or providing by transdermal delivery a Cmax value of 0.5 to 10 ng/mL or 1 to 8 ng/mL. 41. A transdermal therapeutic system according to embodiment 39 or 40 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. 42. The transdermal therapeutic system of embodiment 41 for use in a method for treating a patient, wherein the patient is a human patient suffering from fatigue, drowsiness, dizziness, or any combination thereof, or at least one asenapine-related side effect is fatigue, drowsiness, dizziness, oral hypoesthesia, or any combination thereof, or the incidence of 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 at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced, or 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 ... sublingual asenapine equivalent is reduced, or 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%. 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. 44. A 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 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 providing, by transdermal delivery, an average release rate of 0.5 to 20 mg/day, 1.0 to 15 mg/day, or 2.0 to 10 mg/day over at least 48 hours of administration, or providing, by transdermal delivery, an average release rate of 0.5 to 20 mg/day, 1.0 to 15 mg/day, or 2.0 to 10 mg/day over at least 72 hours of administration. administration, or providing, by transdermal delivery, an average release rate of 0.5 to 20 mg/day, 1.0 to 15 mg/day, or 2.0 to 10 mg/day over at least 84 hours of administration, or providing, by transdermal delivery, an AUC0-48 of 20 to 300 (ng/mL) h, of greater than 300 to 450 (ng/mL) h, or of 30 to 200 (ng/mL) h, or providing, by transdermal delivery, an AUC0-72 of 30 to 400 (ng/mL) h, of greater than 400 to 600 (ng/mL) h, or of 50 to 300 (ng/mL) h, or providing, by transdermal delivery, an AUC0-84 of 35 to 450 (ng/mL) h, of greater than than 450 to 700 (ng/mL) h or 60 to 350 (ng/mL) h, or providing, by transdermal release, a Cmax to C48 ratio of less than 2.0, less than 1.5 or less than 1.3, or providing, by transdermal release, a Cmax to C72 ratio of less than 3.0, less than 2.5 or less than 2.0, or providing, by transdermal release, a Cmax to C84 ratio of less than 3.5, less than 3.0, less than 2.5 or less than 2.0, or providing by transdermal release a Cmax value of 0.5 to 10 ng/mL or 1 to 8 ng/mL. 45. A method of treating a human patient according to embodiment 43 or 44, wherein transdermal administration of asenapine provides a reduction in at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine. 46. A method of treating a human patient according to embodiment 45, wherein the human patient is suffering from fatigue, drowsiness, dizziness, or any combination thereof. 47. A method of treating a human patient according to embodiment 45 or 46, wherein at least one asenapine-related side effect is fatigue, drowsiness, dizziness, oral hypoesthesia, or any combination thereof. 48. A method of treating a human patient according to any one of embodiments 45 to 47, wherein the incidence of 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 at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced. 49. The method of treating a human patient according to embodiment 48, wherein 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 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%. 50. A transdermal therapeutic system for the transdermal delivery of asenapine, 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, and wherein 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 hypoesthesia, or any combination thereof. 51. The transdermal therapeutic system of embodiment 50 for use in a method for treating a human patient, wherein the incidence of 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 at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced, or 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 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% or at least about 40% 30%, at least about 40%, at least about 70% or at least about 80%. 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 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 hypoesthesia, or any combination thereof. 53. A method of treating a human patient according to embodiment 52, wherein the incidence of 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 at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced, or 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 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 80%, or at least about 90%. 70% or at least about 80%. 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 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 hypoesthesia, or any combination thereof. 55. A method of treating a human patient according to embodiment 54, wherein the incidence of 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 at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced, or 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 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 80%, or at least about 90%. 70% or at least about 80%. 56. A method of reducing at least one asenapine-related side effect in a patient who is being treated with sublingual asenapine therapy, the method comprising: a) discontinuing sublingual asenapine therapy; and 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 hypoesthesia, or any combination thereof. 57. A process for manufacturing 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: 1) combining at least the asenapine and polymer components, in a solvent to obtain a coating composition; 2) coating the coating composition over the backing layer or release coating or any intermediate coating; and 3) drying the coated coating composition to form the matrix layer. 58. The transdermal therapeutic system of any one of embodiments 1, 5-17, and 22 wherein the matrix layer composition comprises: i) 3 to 9 wt % asenapine free base; ii) 80 to 90 wt % of a copolymer based on vinyl acetate, 2-ethylhexyl acrylate, 2-hydroxyethyl acrylate, and glycidyl methacrylate; iii) 0.1 to 2 wt % tocopherol; and iv) 5 to 15 wt % polyvinylpyrrolidone. 59. The transdermal therapeutic system of any one of embodiments 1, 5-17, 22, and 58, wherein the matrix layer composition comprises: i) about 6 wt % asenapine free base; ii) about 83.5 wt % an acrylic polymer; iii) about 0.5 wt % tocopherol; and iv) about 10 wt % polyvinylpyrrolidone. 60. The transdermal therapeutic system of any one of embodiments 1, 5-17, and 22 wherein the matrix layer composition comprises: i) 7 to 13% by weight of asenapine free base; ii) 75 to 85% by weight of a copolymer based on vinyl acetate, 2-ethylhexyl acrylate, 2-hydroxyethyl acrylate, and glycidyl methacrylate; iii) 0.1 to 2% by weight of tocopherol; and iv) 5 to 15% by weight of polyvinylpyrrolidone. 61. The transdermal therapeutic system of any one of embodiments 1, 5-17, 22, and 60, wherein the matrix layer composition comprises: i) about 10 wt % asenapine free base; ii) 77 to 82 wt % an acrylic polymer; iii) about 0.5 wt % tocopherol; and iv) about 10 wt % polyvinylpyrrolidone. 62. A method for 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: a) a reinforcing layer; b) a matrix layer containing asenapine consisting of a matrix layer composition comprising: i) a therapeutically effective amount of asenapine; and j) an acrylic polymer. 63. The method according to embodiment 62, wherein the transdermal therapeutic system provides by transdermal delivery an average release rate of 0.5 to 20 mg/day for at least 48 hours of administration. 64. The method according to any of embodiments 62 or 63, wherein the transdermal therapeutic system provides by transdermal delivery an average release rate of 0.5 to 20 mg/day over at least 84 hours of administration. 65. The method according to any of embodiments 6264, wherein the transdermal therapeutic system provides by transdermal delivery an average release rate of 1.0 to 15 mg/day over at least 48 hours of administration. 66. The method according to any of embodiments 6265, wherein the transdermal therapeutic system provides by transdermal delivery an average release rate of 2.0 to 10 mg/day over at least 48 hours of administration. 67. The method of any one of embodiments 62 to 66, wherein the transdermal therapeutic system provides by transdermal delivery one or more pharmacokinetic parameter(s) selected from the group consisting of an asenapine AUC0-48 of 20 to 300 (ng/mL) h, or of greater than 300 to 450 (ng/mL) h, an asenapine AUC0-72 of 30 to 400 (ng/mL) h or of greater than 400 to 600 (ng/mL) h, an asenapine AUC0-84 of 35 to 450 (ng/mL) h or of greater than 450 to 700 (ng/mL) h, an asenapine Cmax to C48 ratio of less than 2.0, an asenapine Cmax to C72 ratio of less than 3.0, an asenapine Cmax to C84 ratio of less than 3.5, and an asenapine Cmax value of 0.5 to 10 ng/mL. 68. The method of any one of embodiments 62 to 67, wherein the matrix layer containing asenapine has an areal weight that is at least 90 g/m2. 69. The method of any one of embodiments 62 to 68, wherein the transdermal therapeutic system contains at least 0.70 mg/cm2 of asenapine. 70. The method of any one of embodiments 62 to 69, wherein the matrix layer containing asenapine has an areal weight ranging from 90 to 230 g/m2. 71. The method according to any one of embodiments 62-70, wherein the asenapine in the asenapine-containing matrix layer composition is asenapine free base. 72. The method of any one of embodiments 62 to 71, wherein at least 90 mole % of the asenapine in the asenapine-containing matrix layer is asenapine free base. 73. The method of any one of embodiments 62 to 72, wherein the matrix layer composition comprises other excipients or additives selected from the group consisting of crosslinking agents, solubilizers, fillers, tackifiers, plasticizers, stabilizers, softeners, skin care substances, permeation enhancers, pH regulators, and preservatives, wherein: the tackifier is selected from polyvinylpyrrolidone, triglycerides, dipropylene glycol, resins, rosin esters, terpenes and derivatives thereof, ethylene vinyl acetate adhesives, dimethylpolysiloxanes and polybutenes; the stabilizer is selected from tocopherol and ester thereof and ascorbic acid and ester thereof; and 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 fatty acid diesters. 74. The method of any one of embodiments 62 to 73, wherein the transdermal therapeutic system provides a skin permeation rate of asenapine as measured in a Franz diffusion cell with dermatomized human skin of 0 μg/(cm2 h) to 10 μg/(cm2 h) in the first 8 hours, 2 μg/(cm2 h) to 20 μg/(cm2 h) from 8 hours to 24 hours, 3 μg/(cm2 h) to 20 μg/(cm2 h) from 24 hours to 32 hours, 3 μg/(cm2 h) to 20 μg/(cm2 h) from 32 hours to 48 hours, or 2 μg/(cm2 h) to 15 μg/(cm2 h) from 48 hours to 72 hours. 75. The method of any one of embodiments 62 to 74, wherein the transdermal therapeutic system is administered at a dosing interval of at least 48 hours or 2 days. 76. The method of any one of embodiments 62 to 75, wherein the transdermal therapeutic system provides, by transdermal delivery, an average release rate of 0.5 to 20 mg/day for at least 48 hours or 2 days of administration. 77. The method of any one of embodiments 62 to 76, wherein the transdermal therapeutic system provides, by transdermal release, an AUC0-48 of 20 to 300 (ng/mL) h or of more than 300 to 450 (ng/mL) h. 78. The method of any one of embodiments 62 to 77, wherein the transdermal therapeutic system provides, by transdermal release, a ratio of Cmax to C48 of less than 2.0. 79. The method of any one of embodiments 62 to 78, wherein the matrix layer composition comprises: i) 4 to 12 wt % asenapine free base; ii) 75 to 88 wt % an acrylic polymer; iii) 0.01 to 1.0 wt % tocopherol; and iv) 7 to 13 wt % polyvinylpyrrolidone. 80. The method of any one of embodiments 62 to 79, wherein the matrix layer composition comprises: i) about 6 wt % asenapine free base; ii) 81 to 85 wt % an acrylic polymer; iii) about 0.5 wt % tocopherol; and iv) about 10 wt % polyvinylpyrrolidone. 81. The method of any one of embodiments 62 to 80, wherein the matrix layer composition comprises: i) about 10% by weight asenapine; ii) 77 to 82% by weight of an acrylic polymer; iii) about 0.5% by weight tocopherol; and iv) about 10% by weight polyvinylpyrrolidone. 82. A method for 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: a) a reinforcing layer; and b) a matrix layer containing asenapine consisting of a matrix layer composition comprising: i) a therapeutically effective amount of asenapine; and j) an acrylic polymer. 83. The method according to embodiment 82, wherein the bipolar disorder is acute manic bipolar disorder. 84. The method according to embodiment 82, wherein the bipolar disorder is mixed episodes of bipolar disorder. 85. The method of any of embodiments 8284, wherein the transdermal therapeutic system provides by transdermal delivery an average release rate of 0.5 to 20 mg/day over at least 48 hours of administration. 86. The method according to any of embodiments 8285, wherein the transdermal therapeutic system provides by transdermal delivery an average release rate of 0.5 to 20 mg/day over at least 84 hours of administration. 87. The method of any of embodiments 8286, wherein the transdermal therapeutic system provides, by transdermal delivery, an average release rate of 1.0 to 15 mg/day over at least 48 hours of administration. 88. The method according to any of embodiments 82-87, wherein the transdermal therapeutic system provides by transdermal delivery an average release rate of 2.0 to 10 mg/day over at least 48 hours of administration. 89. The method of 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 an asenapine AUC0-48 of 20 to 300 (ng/mL) hr, or of greater than 300 to 450 (ng/mL) hr, an asenapine AUC0-72 of 30 to 400 (ng/mL) hr, or of greater than 400 to 600 (ng/mL) hr, an asenapine AUC0-84 of 35 to 450 (ng/mL) hr, or of greater than 450 to 700 (ng/mL) hr, an asenapine Cmax to C48 ratio of less than 2.0, an asenapine Cmax to C72 ratio of less than than 3.0, an asenapine Cmax to C84 ratio of less than 3.5, and an asenapine Cmax value of 0.5 to 10 ng/mL. 90. The method of any one of embodiments 82-89, wherein the matrix layer containing asenapine has an areal weight that is at least 90 g/m2. 91. The method of any one of embodiments 82-90, wherein the transdermal therapeutic system contains at least 0.70 mg/cm2 of asenapine. 92. The method of any one of embodiments 82-91, wherein the matrix layer containing asenapine has an areal weight ranging from 90 to 230 g/m2. 93. The method according to any one of embodiments 82-92, wherein the asenapine in the matrix layer composition containing asenapine is asenapine free base. 94. The method of any one of embodiments 82-93, wherein at least 90 mole % of the asenapine in the asenapine-containing matrix layer is asenapine free base. 95. The method of any one of embodiments 82-94, wherein the matrix layer composition comprises other excipients or additives selected from the group consisting of crosslinking agents, solubilizers, fillers, tackifiers, plasticizers, stabilizers, softeners, skin care substances, permeation enhancers, pH regulators, and preservatives, wherein the tackifier is selected from polyvinylpyrrolidone, triglycerides, dipropylene glycol, resins, rosin esters, terpenes and derivatives thereof, ethylene vinyl acetate adhesives, dimethylpolysiloxanes and polybutenes; the stabilizer is selected from tocopherol and ester thereof and ascorbic acid and ester thereof; and 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 fatty acid diesters. 96. The method of 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 dermatomized human skin of 0 μg/(cm2 h) to 10 μg/(cm2 h) in the first 8 hours, 2 μg/(cm2 h) to 20 μg/(cm2 h) from 8 hours to 24 hours, 3 μg/(cm2 h) to 20 μg/(cm2 h) from 24 hours to 32 hours, 3 μg/(cm2 h) to 20 μg/(cm2 h) from 32 hours to 48 hours, or 2 μg/(cm2 h) to 15 μg/(cm2 h) from 48 hours to 72 hours. 97. The method of any one of embodiments 82-96, wherein the transdermal therapeutic system provides, by transdermal delivery, an average release rate of 0.5 to 20 mg/day for at least 48 hours of administration. 98. The method of any one of embodiments 82-97, wherein the transdermal therapeutic system provides, by transdermal delivery, an average release rate of 0.5 to 20 mg/day over at least 84 hours of administration. 99. The method of any one of embodiments 82-98, wherein the transdermal therapeutic system provides, by transdermal delivery, an average release rate of 1.0 to 15 mg/day for at least 48 hours of administration. 100. The method of any one of embodiments 82-99, wherein the transdermal therapeutic system provides, by transdermal delivery, an average release rate of 2.0 to 10 mg/day for at least 48 hours of administration. 101. The method of any one of embodiments 82-100, wherein the matrix layer composition comprises: i) 4 to 12 wt % asenapine free base; ii) 75 to 88 wt % of an acrylic polymer; iii) 0.01 to 1.0 wt % tocopherol; and iv) 7 to 13 wt % polyvinylpyrrolidone. 102. The method of any one of embodiments 82-101, wherein the matrix layer composition comprises: i) about 6 wt % asenapine free base; ii) 81 to 85 wt % of an acrylic polymer; iii) about 0.5 wt % tocopherol; and iv) about 10 wt % polyvinylpyrrolidone. 103. The method of any one of embodiments 82-102, wherein the matrix layer composition comprises: i) about 10 wt % asenapine free base; ii) 77 to 82 wt % of an acrylic polymer; iii) about 0.5 wt % tocopherol; and iv) about 10 wt % polyvinylpyrrolidone. 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 of the subject for about 84 hours. 105. The method of embodiment 104, wherein the transdermal therapeutic system provides by transdermal delivery one or more pharmacokinetic parameter(s) selected from the group consisting of an asenapine AUC0-48 of 20 to 300 (ng/mL) hr, or of greater than 300 to 450 (ng/mL) hr, an asenapine AUC0-72 of 30 to 400 (ng/mL) hr, or of greater than 400 to 600 (ng/mL) hr, an asenapine AUC0-84 of 35 to 450 (ng/mL) hr, or of greater than 450 to 700 (ng/mL) hr, an asenapine Cmax to C48 ratio of less than 2.0, an asenapine Cmax to C72 ratio of less than 3.0, an asenapine Cmax to C84 ratio of less than 3.5, and an asenapine Cmax value of 0.5 to 10 ng/mL. 106. The method according to any of embodiments 104 or 105, wherein the transdermal therapeutic system provides by transdermal delivery an average release rate of 0.5 to 20 mg/day. 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: a) a reinforcing layer; and b) a matrix layer containing asenapine consisting of a matrix layer composition comprising: i) a therapeutically effective amount of asenapine; and j) an acrylic polymer. 108. The method of embodiment 107, wherein the asenapine in the asenapine-containing matrix layer is asenapine free base. 109. The method of embodiment 107 or 108, wherein at least 90 mole % of the asenapine in the asenapine-containing matrix layer is asenapine free base. 110. The method according to any one of embodiments 107 to 109, wherein the matrix layer composition comprises other excipients or additives selected from the group consisting of crosslinking agents, solubilizers, fillers, tackifiers, plasticizers, stabilizers, softeners, skin care substances, permeation enhancers, pH regulators, and preservatives. 111. The method according to any one of embodiments 107 to 110, wherein the transdermal therapeutic system provides a skin permeation rate of asenapine as measured in a Franz diffusion cell with dermatomized human skin of 0 μg/(cm2 h) to 10 μg/(cm2 h) in the first 8 hours, 2 μg/(cm2 h) to 20 μg/(cm2 h) from 8 hours to 24 hours, 3 μg/(cm2 h) to 20 μg/(cm2 h) from 24 hours to 32 hours, 3 μg/(cm2 h) to 20 μg/(cm2 h) from 32 hours to 48 hours, or 2 μg/(cm2 h) to 15 μg/(cm2 h) from 48 hours to 72 hours. 112. The method according to any one of embodiments 107 to 111, wherein the matrix layer composition comprises: i) 4 to 12 wt % asenapine free base; ii) 75 to 88 wt % of an acrylic polymer; iii) 0.01 to 1.0 wt % tocopherol; and iv) 7 to 13 wt % polyvinylpyrrolidone. 113. The method of any one of embodiments 107 to 112, wherein the matrix layer composition comprises: i) about 6 wt % asenapine free base; ii) 81 to 85 wt % an acrylic polymer; iii) about 0.5 wt % tocopherol; and iv) about 10 wt % polyvinylpyrrolidone. 114. The method of any one of embodiments 107 to 113, wherein the matrix layer composition comprises: i) about 10 wt % asenapine free base; ii) 77 to 82 wt % an acrylic polymer; iii) about 0.5 wt % tocopherol; and iv) about 10 wt % polyvinylpyrrolidone.

Claims (14)

1. A transdermal therapeutic system for transdermal administration of asenapine comprising a self-adhesive layer structure containing a therapeutically effective amount of asenapine, wherein said self-adhesive layer structure comprises: A) a reinforcing layer; B) a matrix layer containing asenapine, consisting of a matrix layer composition comprising: 1) asenapine in an amount ranging from 2 to 20% by weight of the matrix layer composition; and 2) a polymer selected from acrylic polymers comprising hydroxyl groups and no carboxylic acid groups, acrylic polymers comprising no functional groups, and any mixture thereof, in an amount ranging from 60 to 97% by weight of the matrix layer composition; wherein said transdermal therapeutic system has a release area of 5 to 100 cm2 and contains at least 0.70 mg/cm2 of asenapine; and the area weight of the matrix layer varies between 90 and 230 g/cm2. 2. Transdermal therapeutic system according to claim 1, characterized in that it: contains at least 0.80 mg/cm2, or at least 0.82 mg/cm2, or at least 0.83 mg/cm2 asenapine, and/or contains from 0.70 mg/cm2 to 4.0 mg/cm2, or from 0.80 mg/cm2 to 3.0 mg/cm2, or from 0.82 mg/cm2 to 2.0 mg/cm2, or from 0.83 mg/cm2 to 1.7 mg/cm2 asenapine, and/or the areal weight of the matrix layer ranges from 110 to 210 g/m2, or from 120 to 170 g/m2. 3. Transdermal therapeutic system according to claim 1 or 2, characterized in that: asenapine, in the matrix layer composition, is included in the form of the free base, or the matrix layer composition is obtainable by incorporating asenapine in the form of the free base, and/or at least 90 mol %, or at least 95 mol %, or at least 98 mol %, or at least 99 mol %, of asenapine in the matrix layer is present in the form of the free base. 4. Transdermal therapeutic system according to any one of claims 1 to 3, characterized in that: the amount of asenapine in the matrix layer composition ranges from 3 to 15% by weight, or from 4 to 12% by weight, of the matrix layer composition. 5. Transdermal therapeutic system according to any one of claims 1 to 4, characterized in that the polymer is 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. 6. Transdermal therapeutic system, according to claim 5, characterized by the fact that the polymer is a copolymer based on vinyl acetate, 2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and glycidyl-methacrylate. 7. Transdermal therapeutic system according to claim 6, characterized in that the polymer is crosslinked by a crosslinking agent, or is crosslinked by a titanium crosslinking agent. 8. Transdermal therapeutic system according to any one of claims 1 to 7, characterized in that: the amount of polymer varies from 70 to 96% by weight, or from 75 to 88% by weight, or from 91 to 96% by weight, of the matrix layer composition, or the total polymer content in the matrix layer composition varies from 75 to 97% by weight, or from 80 to 96% by weight, or from 85 to 95% by weight, of the matrix layer composition. 9. Transdermal therapeutic system according to any one of claims 1 to 8, characterized in that: the matrix layer composition comprises further excipients or additives selected from the group consisting of crosslinking agents, fillers, tackifiers, plasticizers, stabilizers, softeners, skin care substances, permeation enhancers, pH regulators, and preservatives, the tackifier is selected from polyvinylpyrrolidone, triglycerides, dipropylene glycol, resins, rosin esters, terpenes and derivatives thereof, ethylene vinyl acetate adhesives, dimethylpolysiloxanes and polybutenes, or from polyvinylpyrrolidone, or from soluble polyvinylpyrrolidone, and/or the stabilizer is selected from sodium metabisulfite, ascorbic acid and ester derivatives thereof, butylated hydroxytoluene, tocopherol and ester derivatives thereof, such as such as tocopheryl acetate and tocopheryl linoleate, as well as a combination of tocopherol and ascorbyl palmitate, or of tocopherol and ester derivatives thereof and ascorbic acid and ester derivatives thereof, or of ascorbyl esters of fatty acids and tocopherol, or is ascorbyl palmitate or α-tocopherol or a combination thereof, and/or 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 fatty acid diesters. 10. The transdermal therapeutic system of any one of claims 1 to 9, providing a skin permeation rate of asenapine when measured in a Franz diffusion cell with dermatomized human skin of: 0 μg/(cm2 h) to 10 μg/(cm2 h) in the first 8 hours, 2 μg/(cm2 h) to 20 μg/(cm2 h) from 8 hours to 24 hours, 3 μg/(cm2 h) to 20 μg/(cm2 h) from 24 hours to 32 hours, 3 μg/(cm2 h) to 20 μg/(cm2 h) from 32 hours to 48 hours, 2 μg/(cm2 h) to 15 μg/(cm2 h) from 48 hours to 72 hours. 11. The transdermal therapeutic system of any one of claims 1 to 10, providing a cumulative permeate amount of asenapine when measured in a Franz diffusion cell with dermatomized human skin of 0.05 mg/cm2 to 1.0 mg/cm2, or of 0.1 mg/cm2 to 0.7 mg/cm2, over a period of 48 hours, or providing a cumulative permeate amount of asenapine when measured in a Franz diffusion cell with dermatomized human skin of 0.1 mg/cm2 to 2.0 mg/cm2, or of 0.2 mg/cm2 to 1.0 mg/cm2, over a period of 72 hours. 12. Transdermal therapeutic system according to any one of claims 1 to 11, characterized in that it is for the treatment of schizophrenia and/or bipolar disorder, or in the treatment of bipolar disorder, in particular acute manic or mixed episodes of bipolar disorder. 13. Use of a transdermal therapeutic system as defined in any one of claims 1 to 11, characterized in that it is for the manufacture of a medicament for the treatment of schizophrenia and/or bipolar disorder, or of a medicament for the treatment of bipolar disorder, in particular acute mixed or manic episodes of bipolar disorder. 14. A process for manufacturing a matrix layer for use in a transdermal therapeutic system as defined in any one of claims 1 to 11, comprising the steps of: (1) combining at least the asenapine and polymer components in a solvent to obtain a coating composition; (2) coating the coating composition over the backing layer or release liner or any intermediate coating; and (3) drying the coated coating composition to form the matrix layer.