US20180193283A1 - Transdermal therapeutic system containing asenapine - Google Patents

Transdermal therapeutic system containing asenapine Download PDF

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US20180193283A1
US20180193283A1 US15/847,360 US201715847360A US2018193283A1 US 20180193283 A1 US20180193283 A1 US 20180193283A1 US 201715847360 A US201715847360 A US 201715847360A US 2018193283 A1 US2018193283 A1 US 2018193283A1
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asenapine
hours
therapeutic system
transdermal
matrix layer
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Patrick Mohr
René RIETSCHER
René Eifler
Olga BOURQUAIN
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LTS Lohmann Therapie Systeme AG
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Assigned to LTS LOHMANN THERAPIE-SYSTEME AG reassignment LTS LOHMANN THERAPIE-SYSTEME AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BOURQUAIN, Olga, Eifler, René , MOHR, PATRICK, RIETSCHER, René
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    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
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    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
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Definitions

  • the present invention relates to a transdermal therapeutic system (TTS) for the transdermal administration of asenapine to the systemic circulation, and processes of manufacture, method of treatments and uses thereof.
  • TTS transdermal therapeutic system
  • 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 dibenzo-oxepino pyrrole family, 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 the dopamine D2 and serotonin 5-HT2A receptors with high affinity to the latter and has been developed by Schering-Plough/Organon for the treatment of schizophrenia and acute mania associated with bipolar disorder.
  • asenapine is commercially available in the form of sublingual tablets, 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).
  • the sublingual administration route avoids the first-pass metabolism of an oral administration in order to increase bioavailability, which is at 35% when taken sublingually and ⁇ 2% if ingested.
  • sublingual administration is associated with bitter or unpleasant taste as well as tongue/oral mucosal numbness induced by a local anesthetic effect, nausea and headaches.
  • eating, drinking and smoking are not allowed immediately after sublingual dosing for 10 min.
  • These inconveniences may lead to reduced patient compliance and improper administration such as dose reduction, dose skipping, irregular drug intake or a complete abstinence from the intended asenapine intake.
  • Sublingual administration is also difficult to monitor in institutionalized psychiatric patients and may not be suitable for children, elderly and other patients with difficulty in swallowing, or for those not capable of taking medication on their own.
  • Asenapine shows side effects which are not unusual for a neuroleptic drug. Somnolence and anxiety are very common (observed in ⁇ 10% of the patients). Other common ( ⁇ 1% to ⁇ 10% of the patients) adverse effects include weight gain and increased appetite, nervous system disorders such as dystonia, akathisia, dyskinesia, parkinsonism, sedation, dizziness, dysgeusia; gastrointestinal disorders such as oral hypoesthesia, nausea, increased salivation; increases in alanine aminotransferase (ALT), muscle rigidity, and fatigue (tiredness).
  • ALT alanine aminotransferase
  • Asenapine is metabolized hepatically, mainly via CYP1A2 and UGT1A4 (glucuronidation).
  • the clinical relevance of the main human metabolites N-desmethyl-asenapine and asenapine N+ glucuronide remain controversial. It at least appears that the metabolites would not substantially participate in the therapeutic effect. Thus, a decrease in the amount of these metabolites appears generally desirable.
  • asenapine is rapidly absorbed with peak blood plasma concentrations occurring within 0.5 to 1.5 hours and (in 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 around 1 day or longer.
  • the blood plasma concentration thus exhibits a certain degree of fluctuation with peaks about 1 h post-dose, followed by a concentration decrease resulting in a low point just before the next dose, even in steady state.
  • the relatively rapid concentration decrease also inevitably leads to multiple daily doses (currently twice daily), which are associated with poor patient compliance, in particular in chronic conditions.
  • transdermal administration of asenapine which prevents plasma concentration decrease between two doses to some extent by providing an extended release of the active.
  • Transdermal delivery of asenapine has been investigated, but it appears that passive transdermal delivery of asenapine, and in particular a constant release over an extended 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 surface of the skin and the concentration in the blood stream.
  • TTS transdermal therapeutic system
  • Such passive transport is advantageous in view of complexity of the TTS and the convenience of administration compared to TTS making use of active transportation such as iontophoresis or microporation.
  • no commercial asenapine TTS is available.
  • TTS transdermal administration of asenapine providing a permeation rate which is sufficient for achieving a therapeutically effective dose.
  • TTS transdermal administration of asenapine with an improved bioavailability of asenapine.
  • 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:
  • 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 delivery a mean release rate of 0.5 to 20 mg/day over at least 48 hours of administration.
  • 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 delivery an AUC 0-48 from 20 to 300 (ng/ml) h or from more than 300 to 450 (ng/ml) h, preferably from 30 to 200 (ng/ml) h.
  • 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 delivery an AUC 0-72 from 30 to 400 (ng/ml) h or from more than 400 to 600 (ng/ml) h, preferably from 50 to 300 (ng/ml) h.
  • 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 delivery an AUC 0-84 from 35 to 450 (ng/ml) h or from more than 450 to 700 (ng/ml) h, preferably from 60 to 350 (ng/ml) h.
  • 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 delivery a C max to C 48 ratio of less than 2.0, preferably of less than 1.5 and more preferably of less than 1.3.
  • 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 delivery a C max to C 72 ratio of less than 3.0, preferably of less than 2.5 and more preferably of less than 2.0.
  • 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 delivery a C max to C 84 ratio of less than 3.5, preferably of less than 3.0, more preferably of less than 2.5 and most preferably of less than 2.0.
  • 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:
  • the transdermal therapeutic system according to the invention is for use in a method of treatment, in particular for use in a method of treating schizophrenia and/or bipolar disorder, in particular during administration for an extended period of time.
  • the transdermal therapeutic system according to the invention is for use in a method of treating schizophrenia and/or bipolar disorder during an administration period of about 24 h to about 168 h, or 1 to 7 days, and in particular for use in a method of treating schizophrenia and/or bipolar disorder during an administration period of about 24 h, or 1 day, of about 48 hours, or 2 days, or of about 84 h, or 3.5 days.
  • the transdermal therapeutic system according to the invention is for use in a method of treating psychosis in general, and in particular for use in a method of treating one or more conditions selected from schizophrenia, bipolar disorder, posttraumatic stress disorder, major depressive disorder, dementia related psychosis, agitation and manic disorder, in particular during administration for an extended period of time, e.g. during an administration period of about 24 h to about 168 h, or 1 to 7 days, and in particular during an administration period of about 24 h, or 1 day, of about 48 hours, or 2 days, or of about 84 h, or 3.5 days.
  • the present invention relates to a method of treatment, in particular to a method of treating 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.
  • the invention relates to a method of treating schizophrenia and/or bipolar disorder including applying a transdermal therapeutic system according to the invention for about 24 h to about 168 h or for 1 to 7 days, or for about 24 h, 48 h or 84 h, or for 1 day, 2 days or 3.5 days to the skin of a patient.
  • Such modes of administration require a once a day, once each two days, twice a week or a once a week exchange of the TTS in an around-the-clock treatment.
  • the present invention relates to a method of treating psychosis in general, and in particular to a method of treating one or more conditions selected from schizophrenia, bipolar disorder, posttraumatic stress disorder, major depressive disorder, dementia related psychosis, agitation and manic disorder, in particular during administration for an extended period of time, e.g. during an administration period of about 24 h to about 168 h, or 1 to 7 days, and in particular during an administration period of about 24 h, or 1 day, of about 48 hours, or 2 days, or of about 84 h, or 3.5 days.
  • the present invention relates to asenapine for use in a method of treating a human patient by transdermal administration of asenapine for a dosing interval of at least about 48 hours or 2 days, or of at least about 72 hours or 3 days.
  • 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 for a dosing interval of at least about 48 hours or 2 days, or of at least about 72 hours or 3 days.
  • the present invention relates to a method of treating a human patient by transdermal administration of asenapine for a dosing interval of at least about 48 hours or 2 days, or of at least about 72 hours or 3 days.
  • the invention relates to a process of manufacture of a matrix layer for use in a transdermal therapeutic system comprising the steps of:
  • the term “transdermal therapeutic system” refers to a system by which the active agent (asenapine) is administered to the systemic circulation via transdermal delivery and refers to the entire individual dosing unit that is applied to the skin of a patient, and which comprises a therapeutically effective amount of asenapine in a self-adhesive layer structure and optionally an additional adhesive overlay on top of the asenapine-containing self-adhesive layer structure.
  • the self-adhesive layer structure may be located on a release liner (a detachable protective layer), thus, the TTS may further comprise a release liner.
  • the term “TTS” in particular refers to a system providing passive transdermal delivery excluding active transport as in methods including iontophoresis or microporation.
  • the term “asenapine-containing self-adhesive layer structure” or “self-adhesive layer structure containing a therapeutically effective amount of asenapine” refers to the active agent-containing structure providing the area of release for asenapine during administration.
  • the adhesive overlay adds to the overall size of the TTS but does not add to the area of release.
  • the asenapine-containing self-adhesive layer structure comprises a backing layer and at least one asenapine-containing layer.
  • the term “therapeutically effective amount” refers to a quantity of active agent in the TTS sufficient to provide, if administered by the TTS to a patient, asenapine blood levels of a similar range (e.g. of about 10% to about 1000% as measured as an AUC) when compared to blood levels obtained in steady state administration of twice daily 5 mg sublingual asenapine over a predefined extended period of time (e.g. 1, 3.5 and 7 days).
  • a TTS usually contains more active in the system than is in fact provided to the skin and the systemic circulation. This excess amount of active agent is usually necessary to provide enough driving force for the passive transportation from the TTS to the systemic circulation.
  • 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. These forms include without limitation asenapine in its free base form, protonated or partially protonated asenapine, asenapine salts 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.
  • the asenapine where contained in a medium such as a solvent, may be dissolved or dispersed or in part dissolved and in part dispersed.
  • the amount of asenapine in the self-adhesive layer structure relates to the amount of asenapine included in the TTS during manufacture of the TTS and is calculated based on asenapine in the form of the free base.
  • 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.
  • the asenapine starting material included in the TTS during manufacture of the TTS may be in the form of particles.
  • Asenapine may e.g. be present in the self-adhesive layer structure in the form of particles and/or dissolved.
  • particles refers to a solid, particulate material comprising individual particles, the dimensions of which are negligible compared to the material.
  • the particles are solid, including plastic/deformable solids, including amorphous and crystalline materials.
  • dispersing refers to a step or a combination of steps wherein a starting material (e.g. asenapine) is not totally dissolved.
  • Dispersing in the sense 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).
  • TTS transdermal therapeutic systems
  • matrix-type TTS the active agent is included in a matrix
  • reservoir-type TTS the active agent is included in a liquid or semi-liquid reservoir.
  • the release of the active agent in a matrix-type TTS is mainly controlled by the matrix including the active agent itself.
  • a reservoir-type TTS needs a rate-controlling membrane controlling the release of the active agent.
  • Matrix-type TTS are advantageous in that, compared to reservoir type TTS, usually no rate determining membranes are necessary and no dose dumping can occur due to membrane rupture.
  • matrix-type transdermal therapeutic systems are less complex in manufacture and easy and convenient to use by patients.
  • matrix-type TTS refers to a system or structure wherein the active is homogeneously dissolved and/or dispersed within a polymeric carrier, i.e. the matrix, which forms with the active agent and optionally 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.
  • Reservoir-type TTS are not to be understood as being of matrix-type within the meaning of the invention.
  • microreservoir-systems biphasic systems having an inner active-containing phase in an outer matrix-phase
  • 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 wherein the active is homogeneously dissolved and/or dispersed within a pressure-sensitive adhesive matrix.
  • matrix layer refers to any layer containing the active homogeneously dissolved and/or dispersed within a polymeric carrier.
  • a matrix layer is present in a matrix-type TTS as the active agent-containing layer.
  • a reservoir-type TTS may comprise, in addition to a reservoir layer and a rate-controlling membrane, an additional adhesive layer which serves as a skin contact layer.
  • the additional adhesive layer often is manufactured as an active agent-free layer.
  • the additional adhesive layer contains the active agent and is to be regarded as a matrix layer in the sense of the present invention.
  • the matrix layer is the final, solidified layer e.g. obtained after coating and drying the solvent-containing coating composition.
  • the matrix layer may also be manufactured by laminating two or more such solidified layers (e.g. dried 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 for providing sufficient tack.
  • the matrix layer is a pressure sensitive adhesive matrix.
  • pressure-sensitive adhesive refers to a material that 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 further aid for fixation on the skin is needed.
  • a “self-adhesive” layer structure includes a pressure sensitive adhesive layer for skin contact 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 overlay may still be employed to advance adhesion.
  • the term “skin contact layer” refers to a layer included in the TTS to be in direct contact with the skin of the patient during administration.
  • the TTS comprises a skin contact layer
  • the other layers do not contact the skin and do not necessarily have self-adhesive properties.
  • the skin contact layer may over time absorb parts of the active agent and then may be regarded as a matrix layer.
  • the area of release is provided by the area of the matrix layer.
  • a skin contact layer may be used to enhance adherence.
  • the sizes of an additional skin contact layer and the matrix layer are usually coextensive and correspond to the area of release.
  • area weight refers to the dry weight of a specific layer, e.g. of the matrix layer, provided in g/m 2 .
  • the area weight values are subject to a tolerance of ⁇ 10%, preferably ⁇ 7.5%, due to manufacturing variability.
  • polymer refers to any substance consisting of so-called repeating units obtained by polymerizing one or more monomers, and includes homopolymers which consist of one type of monomer and copolymers which consist of two or more types of monomers.
  • Polymers may be of any architecture such as linear polymers, star polymer, comb polymers, brush polymers, of any monomer arrangements in case of copolymers, e.g. alternating, statistical, block copolymers, or graft polymers.
  • the minimum molecular weight varies depending on the polymer type and is known to the skilled person. Polymers may e.g. have a molecular weight above 2,000, preferably above 5,000 and more preferably above 10,000 Dalton.
  • compounds with a molecular weight below 2,000, preferably below 5,000 or more preferably below 10,000 Dalton are usually referred to as oligomers.
  • cross-linking agent refers to a substance which is able to cross-link functional groups contained within the polymer.
  • the term “adhesive overlay” refers to a self-adhesive layer structure that is free of active agent and larger in area than the active agent-containing structure and provides additional area adhering to the skin, but no area of release of the active agent. It enhances thereby the overall adhesive properties of the TTS.
  • the adhesive overlay comprises a backing layer and an adhesive layer.
  • backing layer refers to a layer, which supports e.g. the asenapine-containing layer or forms the backing of the adhesive overlay. At least one backing layer in the TTS and usually the backing layer of the 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 thus prevents active loss or cross-contamination in accordance with regulatory requirements.
  • the TTS according to the present invention can be characterized by certain parameters as measured in an in vitro skin permeation test.
  • the in vitro permeation test is performed in a Franz diffusion cell, with human or animal skin and preferably with dermatomed split-thickness human skin with a thickness of 800 ⁇ m 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 vol-% organic solvent e.g. ethanol, acetonitrile, isopropanol, dipropylenglycol, PEG 400 so that a receptor medium may e.g. contain 60 vol-% phosphate buffer pH 5.5, 30 vol-% dipropylenglycol and 10 vol-% acetonitrile.
  • a receptor medium may e.g. contain 60 vol-% phosphate buffer pH 5.5, 30 vol-% dipropylenglycol and 10 vol-% acetonitrile.
  • the in vitro permeation test is performed with dermatomed split-thickness human skin with a thickness of 800 ⁇ m 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 in regular intervals using a validated HPLC method with a UV photometric detector by taking a sample volume.
  • the receptor medium is completely or in part replaced by fresh medium when taking the sample volume, and the measured amount of active permeated relates to the amount permeated between the two last sampling points and not the total amount permeated so far.
  • the parameter “permeated amount” is provided in ⁇ g/cm 2 and relates to the amount of active permeated in a sample interval at certain elapsed time.
  • the “permeated amount” of active can be given e.g. for the sample interval from hour 8 to hour 12 and corresponds to the measurement at hour 12.
  • the permeated amount can also be given as a “cumulative permeated amount”, corresponding to the cumulated amount of active permeated at a certain point in time.
  • a “cumulative permeated amount” corresponding to the cumulated amount of active permeated at a certain point in time.
  • the “cumulative permeated amount” of active at hour 12 corresponds to the sum of the permeated amounts from hour 0 to hour 2, hour 2 to hour 4, hour 4 to hour 8 and hour 8 to hour 12.
  • the parameter “skin permeation rate” for a certain sample interval at certain elapsed time is provided in ⁇ g/(cm 2 h) and is calculated from the permeated amount in said sample interval as measured by in vitro permeation test as described above in ⁇ g/cm 2 , divided by the hours of said sample interval.
  • a “cumulative skin permeation rate” can be calculated from the respective cumulative permeated amount by dividing the cumulative permeated amount by the elapsed time. E.g. in an in vitro permeation test as described above, wherein the amount of active permeated into the receptor medium has been e.g. measured at hours 0, 2, 4, 8, 12 and 24, the “cumulative skin permeation rate” at hour 12 is calculated as the cumulative permeated amount for hour 12 (see above) divided by 12 hours.
  • permeated amount and skin permeation rate refer to mean values calculated from 3 in vitro permeation test experiments.
  • the TTS according to the present invention can also be characterized by certain parameters as measured in an in vivo clinical study.
  • the parameter “mean release rate” refers to the mean release rate in ⁇ g/h, in mg/h, in ⁇ g/24 h, in mg/24 h, in ⁇ g/day or in mg/day over the period of administration (e.g. 1 to 7 day(s)) by which the active agent is released through the human skin into the systemic circulation and is based on the AUC obtained over said period of administration in a clinical study.
  • the mean release rate is a parameter used to identify the dose or the strength of a TTS. Since, in contrast to e.g.
  • a TTS usually contains more active in the system than is in fact provided to the skin and the systemic circulation, the amount of active contained in the TTS is not meaningful as a parameter for the dose. This is why for a TTS the dose or strength is usually characterized by the mean release rate, which describes more accurately the amount of active delivered to the subject over time.
  • extended period of time relates to a period of at least or about 24 h, at least or about 48 h, at least or about 84 h, at least or about 168 h, 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 h to about 168 h or 1 to 7 day(s), or about 24 h to about 84 h or 1 to 3.5 day(s).
  • the frequency of drug administration is preferably kept sufficiently high so as to maintain a therapeutically effective blood plasma concentration.
  • the interval between two dosage form administrations also called dosing interval, needs to be adapted accordingly.
  • the term “dosing interval” refers to the period of time between two consecutive TTS administrations, i.e. the interval between two consecutive points in time a TTS is applied to the skin of the patient. Once applied, the TTS is usually maintained on the skin of the patient for the entire dosing interval and only removed at the end of the dosing interval, at which time a new TTS is applied to the skin.
  • the TTS is applied to and maintained on the skin of the patient 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.
  • a dosing interval of 168 hours or 7 days allows a once-a-week TTS exchange mode in an around-the-clock treatment.
  • room temperature refers to the unmodified temperature found indoors in the laboratory where the experiments are conducted and usually lies within 15 to 35° C., preferably about 18 to 25° C.
  • the term “patient” refers to a subject who has presented a clinical manifestation of a particular symptom or symptoms suggesting the need for treatment, who is treated preventatively or prophylactically for a condition, or who has been diagnosted with a condition to be treated.
  • pharmacokinetic parameters refers to parameters describing the blood plasma curve, e.g. C max , C t and AUC t1-t2 obtained in a clinical study, e.g. by single-dose, multi-dose or steady state administration of the active agent TTS, e.g. the asenapine TTS to healthy human subjects.
  • the pharmacokinetic parameters of the individual subjects are summarized using arithmetic and geometric means, e.g. a mean C max , a mean AUC t and a mean AUC INF , and additional statistics such as the respective standard deviations and standard errors, the minimum value, the maximum value, and the middle value when the list of values is ranked (Median).
  • pharmacokinetic parameters e.g. the C max , C t and AUC t1-t2 refer to arithmetic or geometric mean values and preferably refer to geometric mean values. It cannot be precluded that the absolute mean values obtained for a certain TTS in a clinical study vary to a certain extent from study to study.
  • a reference formulation e.g. in the future any product based on the invention, may be used as internal standard. A comparison of the AUC per area of release of the respective reference product in the earlier and later study can be used to obtain a correction factor to take into account differences from study to study.
  • Clinical studies according to the present invention refer to studies performed in full compliance with the International Conference for Harmonization of Clinical Trials (ICH) and all applicable local Good Clinical Practices (GCP) and regulations.
  • ICH International Conference for Harmonization of Clinical Trials
  • GCP global Good Clinical Practices
  • the term “healthy human subject” refers to a male or female subject 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 inclusion and exclusion criteria which are based on and in accordance with recommendations of the ICH.
  • BMI body mass index
  • subject population refers to at least ten individual healthy human subjects.
  • geometric mean refers to the mean of the log transformed data back-transformed to the original scale.
  • the term “arithmetic mean” refers to the sum of all values of observation divided by the total number of observations.
  • 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 blood circulation in total and is hence a measure for the bioavailability.
  • the parameter “AUC t1-t2 ” is provided in (ng/ml) h and relates to the area under the plasma concentration-time curve from hour t 1 to t 2 and is calculated by the linear trapezoidal method.
  • C max is provided in (ng/ml) and relates to the maximum observed blood plasma concentration of the active agent.
  • the parameter “C e ” is provided in (ng/ml) and relates to the blood plasma concentration of the active agent observed at hour t.
  • t max is provided in h and relates to the time point at which the C max value is reached.
  • t max is the time point of the maximum observed plasma concentration.
  • the t lag can be calculated approximately as the mean arithmetic value of the first point in time when a measurable (i.e. non-zero) active agent blood plasma concentration is obtained or represented by a median value.
  • mean plasma concentration is provided in (ng/ml) and is a mean of the individual plasma concentrations of active agent, e.g. asenapine, at each point in time.
  • coating composition refers to a composition comprising all components of the matrix layer in a solvent, which may be coated onto the backing layer or release liner to form the matrix layer upon drying.
  • solvent refers to the process of obtaining a solution, which is clear and does not contain any particles, as visible to the naked eye.
  • 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.
  • the term “about” refers to an amount that is ⁇ 10% of the disclosed amount. In some embodiments, the term “about” refers to an amount that is ⁇ 5% of the disclosed amount. In some embodiments, the term “about” refers to an amount that is ⁇ 2% of the disclosed amount.
  • FIG. 1 a depicts the asenapine skin permeation rate of TTS prepared according to Examples 1a, 1b, 1c and 1d for hours 0 to 72.
  • FIG. 1 b depicts the asenapine skin permeation rate of TTS prepared according to Examples 1a, 1b, 1c and 1d for hours 0 to 168.
  • FIG. 1 c depicts the utilisation of asenapine of TTS prepared according to Examples 1a, 1b, 1c and 1d after 72 h.
  • FIG. 2 a depicts the asenapine skin permeation rate of TTS prepared according to Examples 2a, 2b, 2c and 2d for hours 0 to 72.
  • FIG. 2 b depicts the asenapine skin permeation rate of TTS prepared according to Examples 2a, 2b, 2c and 2d for hours 0 to 168.
  • FIG. 2 c depicts the utilisation of asenapine of TTS prepared according to Examples 2a, 2b, 2c and 2d after 72 h.
  • FIG. 2 d depicts the asenapine skin permeation rate of TTS prepared according to Examples 2e to 2j for hours 0 to 72.
  • FIG. 2 e depicts the utilisation of asenapine of TTS prepared according to Examples 2e to 2j after 72 h.
  • FIG. 3 a depicts the asenapine skin permeation rate of TTS prepared according to Examples 3a, 3b, 3c, 3d and 3e.
  • FIG. 3 b depicts the utilisation of asenapine of TTS prepared according to Examples 3a, 3b, 3c, 3d and 3e after 56 h.
  • FIG. 4 a depicts the asenapine skin permeation rate of TTS prepared according to Examples 4a and 4b for hours 0 to 72.
  • FIG. 4 b depicts the asenapine skin permeation rate of TTS prepared according to Examples 4a and 4b for hours 0 to 168.
  • FIG. 4 c depicts the utilisation of asenapine of TTS prepared according to Examples 4a and 4b after 72 h and 168 h.
  • FIG. 5 a depicts the asenapine skin permeation rate of TTS prepared according to Examples 5a, 5b and 5c for hours 0 to 72.
  • FIG. 5 b depicts the utilisation of asenapine of TTS prepared according to Examples 5a, 5b and 5c after 72 h.
  • FIG. 6 a depicts the asenapine skin permeation rate of TTS prepared according to Examples 6a, 6b and 6c for hours 0 to 72.
  • FIG. 6 b depicts the utilisation of asenapine of TTS prepared according to Examples 6a, 6b and 6c after 72 h.
  • FIG. 7 a depicts the asenapine skin permeation rate of TTS prepared according to Examples 7a, 7b and 7c for hours 0 to 72.
  • FIG. 7 b depicts the utilisation of asenapine of TTS prepared according to Examples 7a, 7b and 7c after 72 h.
  • FIG. 8 a depicts the asenapine skin permeation rate of TTS prepared according to Examples 8a, 8b and 8c for hours 0 to 72.
  • FIG. 8 b depicts the utilisation of asenapine of TTS prepared according to Examples 8a, 8b and 8c after 72 h.
  • FIG. 9 a depicts the asenapine skin permeation rate of TTS prepared according to Examples 9a and 9b for hours 0 to 72.
  • FIG. 9 b depicts the utilisation of asenapine of TTS prepared according to Examples 9a and 9b after 72 h.
  • FIG. 10 a depicts the asenapine skin permeation rate of TTS prepared according to Example 10 for hours 0 to 72.
  • FIG. 10 b depicts the utilisation of asenapine of TTS prepared according to Example 10 after 72 h.
  • FIG. 11 depicts the asenapine blood plasma concentration of TTS prepared according to Examples 11a, 11b, 11c and 11d.
  • FIG. 12 a depicts the asenapine skin permeation rate of TTS prepared according to Examples 12a and 12b for hours 0 to 72.
  • FIG. 12 b depicts the utilisation of asenapine of TTS prepared according to Examples 12a and 12b after 72 h.
  • FIG. 13 a depicts the asenapine blood plasma concentration (arithmetic mean values with standard deviation as error bars) obtained in an in vivo clinical study of the TTS prepared according to Examples 13a and 13b for hours 0 to 168.
  • FIG. 13 b depicts the asenapine blood plasma concentration (arithmetic mean values with standard deviation as error bars) obtained in an in vivo clinical study of the TTS prepared according to Examples 13a and 13b for hours 0 to 84.
  • FIG. 13 c depicts the asenapine-glucuronide blood plasma concentration (geometric mean values with geometric mean multiplied with/divided by the geometric standard deviation as error bars) obtained in an in vivo clinical study of the TTS prepared according to Examples 13a and 13b for hours 0 to 168.
  • FIG. 13 d depicts the asenapine-glucuronide blood plasma concentration (geometric mean values with geometric mean multiplied with/divided by the geometric standard deviation as error bars) obtained in an in vivo clinical study of the TTS prepared according to Examples 13a and 13b for hours 0 to 96.
  • FIG. 13 e depicts the N-desmethyl-asenapine blood plasma concentration (geometric mean values with geometric mean multiplied with/divided by the geometric standard deviation as error bars) obtained in an in vivo clinical study of the TTS prepared according to Examples 13a and 13b for hours 0 to 108.
  • the present invention is related to a transdermal therapeutic system for the transdermal administration of asenapine comprising a self-adhesive layer structure containing asenapine.
  • the self-adhesive layer structure may comprise therapeutically effective amounts of asenapine.
  • the self-adhesive layer structure according to the present invention comprises A) a backing layer, and B) an asenapine-containing matrix layer consisting of a matrix layer composition comprising 1. asenapine and 2. a polymer.
  • 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:
  • 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:
  • the backing layer is in particular substantially asenapine-impermeable.
  • 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.
  • the asenapine and preferably a therapeutically effective amount of asenapine, is included in the asenapine-containing matrix layer.
  • the self-adhesive layer structure in such a matrix-type TTS can include one or more further layers such as a skin contact layer.
  • the active agent may be included or may not be included.
  • a skin contact layer can, even if manufactured as an active agent-free layer, after equilibration, comprise asenapine and then may also be regarded as a (further) matrix layer.
  • the further layer and the asenapine-containing matrix layer may comprise the same polymer or different polymers.
  • any of the asenapine-containing matrix layer and the further layer(s) may be directly contacting each other or separated by a membrane such as a rate controlling membrane. If an asenapine-containing layer is prepared by laminating two asenapine-containing matrix layers, which are of substantially the same composition, the resulting double layer is to be regarded as one matrix layer.
  • the asenapine is included in a liquid or semi-liquid reservoir.
  • the self-adhesive layer structure in such a reservoir-type TTS can include one or more further layers such as a skin contact layer.
  • the active agent may be included or may not be included.
  • a skin contact layer can, even if manufactured as an active agent-free layer, after equilibration, comprise asenapine and then may also be regarded as a matrix layer.
  • the reservoir-type TTS further includes a rate controlling membrane separating the reservoir and skin contact layer.
  • the self-adhesive layer structure comprises an additional reservoir layer which is located between the backing layer and the matrix layer, and a further rate controlling membrane which is located between the additional reservoir layer and the matrix layer.
  • the self-adhesive layer structure according to the invention comprises an additional skin contact layer.
  • the additional skin contact layer is self-adhesive and provides for adhesion between the self-adhesive layer structure and the skin of the patient during administration.
  • the self-adhesive layer structure may or may not comprise a membrane which is located between the matrix layer and the additional skin contact layer, wherein the membrane is preferably a rate controlling membrane.
  • the self-adhesive layer structure according to the invention does not comprise an additional skin contact layer. Sufficient adhesion between the self-adhesive layer structure and the skin of the patient during administration is then provided for by other means, e.g. an asenapine-containing matrix layer and/or an adhesive layer.
  • the TTS may further comprise an adhesive overlay or does not comprise an adhesive overlay, and preferably does not comprise an adhesive overlay.
  • This adhesive overlay is in particular larger than the asenapine-containing self-adhesive layer structure and is attached thereto for enhancing the adhesive properties of the overall transdermal therapeutic system.
  • Said adhesive overlay comprises also a backing layer. The area of said adhesive overlay adds to the overall size of the TTS but does not add to the area of release.
  • the adhesive overlay comprises a self-adhesive polymer or a self-adhesive polymer mixture selected from the group of acrylic polymers, polyisobutylenes, styrene-isoprene-styrene copolymers, polysiloxanes, and mixtures thereof, which may be identical to or different from any polymer or polymer mixture included in the active agent-containing self-adhesive layer structure.
  • the self-adhesive layer structure according to the invention is normally located on a detachable protective layer (release liner) from which it is removed immediately before application to the surface of the patient's skin.
  • the TTS may further comprise a release liner.
  • a TTS protected this way is usually stored in a seam-sealed pouch.
  • the packaging may be child resistant and/or senior friendly.
  • the TTS comprises a self-adhesive layer structure comprising an asenapine-containing matrix layer consisting of a matrix layer composition.
  • the matrix layer composition comprises:
  • the matrix layer composition comprises asenapine and a polymer selected from acrylic polymers, wherein the transdermal therapeutic system has an area of release of from 5 to 100 cm 2 .
  • the area of release ranges from 5 to 100 cm 2 , preferably from 10 to 80 cm 2 , and more preferably from 10 to 25 cm 2 or from 10 to 20 cm 2 , from 25 to 55 cm 2 or from 25 to 35 cm 2 or from 55 to 65 cm 2 , i.e. the transdermal therapeutic system has an area of release of from 5 to 100 cm 2 , preferably from 10 to 80 cm 2 , and more preferably from 10 to 25 cm 2 or from 10 to 20 cm 2 , from 25 to 55 cm 2 or from 25 to 35 cm 2 or from 55 to 65 cm 2 .
  • the matrix layer composition comprises asenapine in the form of the free base and a polymer, wherein the area weight of the matrix layer is at least 90 g/m 2 and wherein the asenapine-containing matrix layer does not comprise isopropyl palmitate.
  • the area weight of the matrix layer ranges from 90 to 230 g/m 2 , preferably from 110 to 210 g/m 2 , and most preferably from 120 to 170 g/m 2 .
  • the advantageous features of the TTS according to the present invention are inter alio achieved by the amount of asenapine contained in the TTS, which can be controlled two-way by adjusting concentration and/or the area weight of the asenapine-containing layers such as the matrix layer.
  • the transdermal therapeutic system contains at least 0.70 mg/cm 2 , preferably at least 0.80 mg/cm 2 , more preferably at least 0.82 mg/cm 2 and most preferably at least 0.83 mg/cm 2 asenapine per area of release. In certain further embodiments of the invention, the transdermal therapeutic system contains at least 0.90 mg/cm 2 , at least 1.00 mg/cm 2 , at least 1.2 mg/cm 2 , at least 1.5 mg/cm 2 or at least 2.0 mg/cm 2 asenapine per area of release.
  • the transdermal therapeutic system contains from 0.70 mg/cm 2 to 4.0 mg/cm 2 , preferably from 0.80 mg/cm 2 to 3.0 mg/cm 2 , more preferably from 0.82 mg/cm 2 to 2.0 mg/cm 2 and most preferably from 0.83 mg/cm 2 to 1.7 mg/cm 2 asenapine.
  • the matrix layer composition is a pressure-sensitive adhesive composition.
  • the matrix layer composition may comprise a second polymer or may comprise two or more further polymers.
  • the total polymer content in the matrix layer composition ranges from 75 to 97%, preferably from 80 to 96% and more preferably from 85 to 95% of the matrix layer composition. In any event does the matrix layer include sufficient amounts of polymer to provide sufficient cohesion.
  • the amount of asenapine contained in the TTS, in particular in the matrix layer of the TTS ranges from 5 to 100 mg, preferably from 10 to 80 mg, and most preferably from 15 to 60 mg.
  • the transdermal therapeutic system has an area of release of from 5 to 100 cm 2 , and the amount of asenapine contained in the TTS ranges from 5 to 100 mg.
  • the asenapine-containing matrix layer does not comprise isopropyl palmitate in an amount of 10% of the matrix layer composition, preferably does not comprise isopropyl palmitate in an amount of 5-15% of the matrix layer composition and most preferably does not comprise isopropyl palmitate.
  • the asenapine-containing matrix layer does not comprise isopropyl myristate in an amount of 5% of the matrix layer composition, preferably does not comprise isopropyl myristate in an amount of 1-10% of the matrix layer composition and most preferably does not comprise isopropyl myristate.
  • the asenapine-containing matrix layer does not comprise ethyl cellulose in an amount of 10-20% of the matrix layer composition and preferably does not comprise ethyl cellulose.
  • the asenapine-containing matrix layer does not comprise hydrogen chloride.
  • the asenapine-containing matrix layer does not comprise sodium acetate or sodium diacetate. In yet another embodiment, the asenapine-containing layer does not comprise a dicarboxylic acid alkali salt. In yet another embodiment, the asenapine-containing layer does not comprise a maleic acid alkali salt.
  • the matrix layer composition does not comprise any of polysiloxanes and polyisobutylenes in an amount of more than 50% of the matrix layer composition.
  • the asenapine-containing matrix layer is obtainable by drying a coated coating composition wherein no hydrochloric acid has been included in the coating composition.
  • the asenapine-containing matrix layer does not comprise toluene.
  • the asenapine-containing matrix layer is obtainable by drying a coated coating composition comprising no toluene.
  • the self-adhesive layer structure contains asenapine, in particular in a therapeutically effective amount.
  • the self-adhesive layer structure comprises an asenapine-containing matrix layer consisting of a matrix layer composition comprising asenapine.
  • the active agent may be present in the TTS in protonated or in free base form, the free base form is preferred.
  • the asenapine in the matrix layer composition is included in the form of the free base.
  • the matrix layer composition is obtainable by incorporating the asenapine in the form of the free base.
  • 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.
  • the asenapine in the matrix layer may be completely dissolved, or the matrix layer composition may contain asenapine particles, preferably constituted of asenapine free base.
  • the amount of asenapine in the TTS is believed to be important for a good release of the active, and can be e.g. adjusted by the asenapine concentration.
  • 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.
  • the asenapine has a purity of at least 95%, preferably of at least 98% and more preferably of at least 99% as determined by quantitative HPLC.
  • Quantitative HPLC may be performed with Reversed-Phase-HPLC with UV detection. In particular, the following conditions can be used if HPLC is performed isocratically:
  • the TTS 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.
  • 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.
  • the polymer is selected from pressure-sensitive adhesive polymers.
  • Polymers which are suitable as the polymer in accordance with the invention are polysiloxanes, polyisobutylenes, styrene-isoprene-styrene block copolymers and acrylic polymers.
  • Bio-PSAs polysiloxanes
  • Oppanol B10/B100 a polyisobutylene polymer, 85:15
  • JSR-SIS a styrene-isoprene-styrene copolymer
  • Duro-TakTM acrylic polymers, see below for details.
  • Suitable polyisobutylenes according to the invention are available under the tradename Oppanol®. Combinations of high-molecular weight polyisobutylenes (B100/B80) and low-molecular weight polyisobutylenes (B10, B11, B12, B13) may be used. Suitable ratios of low-molecular weight polyisobutylene to high-molecular weight polyisobutylene are in the range of from 100:1 to 1:100, preferably from 95:5 to 40:60, more preferably from 90:10 to 80:20.
  • the low molecular weight polyisobutylene has a viscosity average molecular weight of from 10,000 to 70,000 g/mol and/or a weight average molecular weight of from 10,000 to 70,000 g/mol
  • the high molecular weight polyisobutylene has a viscosity average molecular weight of from 1,000,000 to 1,200,000 g/mol and/or a weight average molecular weight of from 1,400,000 to 1,600,000 g/mol.
  • a preferred example for a polyisobutylene combination is B10/B100 in a ratio of 85/15 or 90/10.
  • Oppanol® B100 has a viscosity average molecular weight M v of 1,110,000, and a weight average molecular weight M w of 1,550,000.
  • Oppanol® B10 has a viscosity average molecular weight M v of 40,000, and a weight average molecular weight M w of 36,000.
  • polybutene may be added to the polyisobutylenes.
  • the polymer is selected from acrylic polymers, wherein the acrylic polymers comprise or do not comprise functional groups.
  • 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
  • Duro-TakTM 387-9301 an acrylic copolymer comprising no functional groups
  • 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.
  • the functional groups are limited to hydroxyl groups.
  • 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.
  • 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.
  • 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 (provided as a solution in ethyl acetate without cross-linking agent) and Duro-TakTM 387-2516 (provided as a solution in ethyl acetate, ethanol, n-heptane and methanol with a titanium cross-linking agent).
  • the polymer in the finalized matrix layer is cross-linked (and preferably is cross-linked by a titanium cross-linking agent) or is not cross-linked by a cross-linking agent.
  • 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.
  • 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 (provided as a solution in ethyl acetate).
  • 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 (provided as a solution in ethyl acetate).
  • the amount of the polymer ranges from 60 to 97%, preferably from 65 to 80% or from 70 to 96% and more preferably from 75 to 88% or from 91 to 96%, and most preferably from 77 to 82% or from 81 to 85% of the matrix layer composition. These amounts are in particular preferred in case the matrix layer composition does not comprise any further, additional polymer(s).
  • 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).
  • Additional polymers and additives may also be added to enhance cohesion and/or adhesion.
  • Certain polymers in particular reduce the cold flow and are thus in particular suitable as additional polymer.
  • a polymeric matrix may show a cold flow, since such polymer compositions often exhibit, despite a very high viscosity, the ability to flow very slowly. Thus, during storage, the matrix may flow to a certain extent over the edges of the backing layer. This is a problem with storage stability and can be prohibited by the addition of certain polymers.
  • a basic acrylate polymer e.g. Eudragit E100 which is a copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate
  • the matrix layer composition comprises additionally a basic polymer, in particular an amine-functional acrylate as e.g. Eudragit E100.
  • 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.
  • 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.
  • the matrix layer composition of the TTS according to the invention may comprise further excipients or additives selected from the group consisting of cross-linking agents, solubilizers, fillers, tackifiers, plasticizers, stabilizers, softeners, substances for skincare, permeation enhancers, i.e. substances which influence the barrier properties of the stratum corneum in the sense of increasing the active agent permeability, pH regulators, and preservatives.
  • Particularly preferred additives are tackifiers and stabilizers.
  • Such additives may be present in the asenapine-containing layer in an amount of from 0.001% to 15% of the matrix layer composition per additive. In a certain embodiment, the total amount of all additives is from 0.001% to 25% of the matrix layer composition.
  • a range for an amount of a specific additive refers to the amount per individual additive.
  • the formulation components are categorized according to their physicochemical and physiological properties, and in accordance with their function. This means in particular that a substance or a compound falling into one category is not excluded from falling into another category of formulation component.
  • a certain polymer can be a crystallization inhibitor but also a tackifier.
  • Some substances may e.g. be a typical softener but at the same time act as a permeation enhancer.
  • the skilled person is able to determine based on his general knowledge in which category or categories of formulation component a certain substance or compound belongs to. In the following, details on the excipients and additives are provided which are, however, not to be understood as being exclusive.
  • Other substances not explicitly listed in the present description may be as well used in accordance with the present invention, and substances and/or compounds explicitly listed for one category of formulation component are not excluded from being used as another formulation component in the sense of the present invention.
  • the cross-linking agent may be selected from the group consisting of aluminium and titanium cross-linking agents such as aluminium acetylacetonate, titanium acetylacetonate or polybutyltitanate, and preferably is a titanium cross-linking agent.
  • the amount of cross-linking agent may range from 0.005 to 1%, and preferably from 0.01 to 0.1% of the matrix layer composition.
  • the matrix layer composition may also comprise a polymer which is self-crosslinking, i.e. comprises a cross-linking functional group such as glycidyl groups, which reacts upon heating.
  • the matrix layer composition comprises a cross-linking agent as above and a self-crosslinking polymer.
  • the matrix layer composition further comprises a solubilizer.
  • the solubilizer preferably improves the solubility of the asenapine in the asenapine-containing layer.
  • Preferred solubilizers include, e.g., glycerol-, polyglycerol-, propylene glycol- and polyoxyethylene-esters of medium chain and/or long chain fatty acids, such as glyceryl monolinoleate, medium chain glycerides and medium chain triglycerides, non-ionic solubilizers made by reacting castor oil with ethylene oxide, and any mixtures thereof which may further contain fatty acids or fatty alcohols; cellulose and methylcellulose and derivatives thereof such as hydroxypropylcellulose and hypromellose acetate succinate; various cyclodextrins and derivatives thereof; non-ionic tri-block copolymers having a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene known
  • permeation enhancers mentioned below can act as solubilizers.
  • crystallization inhibitors may act as solubilizers.
  • Fillers such as silica gels, titanium dioxide and zinc oxide may be used in conjunction with the polymer in order to influence certain physical parameters, such as cohesion and bond strength, in the desired way.
  • a tackifier is added.
  • the tackifier may be selected from polyvinylpyrrolidone (which, due to its ability to absorb water, is able to maintain the adhesive properties of the matrix layer and thus can be regarded as a tackifier in a broad sense), triglycerides, polyethylene glycols, dipropylene glycol, resins, resin esters, terpenes and derivatives thereof, ethylene vinyl acetate adhesives, dimethylpolysiloxanes and polybutenes, preferably polyvinylpyrrolidone and more preferably soluble polyvinylpyrrolidone.
  • the matrix layer composition comprises a tackifier in an amount of from 5 to 15% of the matrix layer composition.
  • soluble polyvinylpyrrolidone refers to polyvinylpyrrolidone, also known as povidone, which is soluble with more than 10% in at least ethanol, preferably also in water, diethylene glycol, methanol, n-propanol, 2-propanol, n-butanol, chloroform, methylene chloride, 2-pyrrolidone, macrogol 400, 1,2 propylene glycol, 1,4 butanediol, glycerol, triethanolamine, propionic acid and acetic acid.
  • polyvinylpyrrolidones which are commercially available include Kollidon® 12 PF, Kollidon® 17 PF, Kollidon® 25, Kollidon® 30 and Kollidon® 90 F supplied by BASF, or povidone K90F.
  • the different grades of Kollidon® are defined in terms of the K-Value reflecting the average molecular weight of the polyvinylpyrrolidone grades.
  • Kollidon® 12 PF is characterized by a K-Value range of 10.2 to 13.8, corresponding to a nominal K-Value of 12.
  • Kollidon® 17 PF is characterized by a K-Value range of 15.3 to 18.4, corresponding to a nominal K-Value of 17.
  • Kollidon® 25 is characterized by a K-Value range of 22.5 to 27.0, corresponding to a nominal K-Value of 25
  • Kollidon® 30 is characterized by a K-Value range of 27.0 to 32.4, corresponding to a nominal K-Value of 30
  • Kollidon® 90 F is characterized by a K-Value range of 81.0 to 97.2, corresponding to a nominal K-Value of 90.
  • Preferred Kollidon® grades are Kollidon® 12 PF, Kollidon® 30 and Kollidon® 90 F.
  • K-Value refers to a value calculated from the relative viscosity of polyvinylpyrrolidone in water according to the European Pharmacopoeia (Ph. Eur.) and USP monographs for “Povidone”.
  • 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 ⁇ -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.
  • the matrix layer composition further comprises a softener/plasticizer.
  • softeners/plasticizers include linear or branched, saturated or unsaturated alcohols having 6 to 20 carbon atoms, triglycerides and polyethylene glycols.
  • the matrix layer composition further comprises a substance for skincare.
  • a substance for skincare may be used to avoid or reduce skin irritation as determined by assessment of the skin using dermal response scores.
  • Suitable substances for skincare include sterol compounds such as cholesterol, dexpanthenol, alpha-bisabolol, and antihistamines.
  • Substances for skincare are preferably used in amounts of from 1 to 10% of the matrix layer composition.
  • the matrix layer composition comprises a permeation enhancer selected from diethylene glycol monoethyl ether, diisopropyl adipate, isopropyl myristate, isopropyl palmitate, lauryl lactate, dimethylpropylene urea and a mixture of propylene glycol monoesters and diesters of fatty acids.
  • a permeation enhancer selected from diethylene glycol monoethyl ether, diisopropyl adipate, isopropyl myristate, isopropyl palmitate, lauryl lactate, dimethylpropylene urea and a mixture of propylene glycol monoesters and diesters of fatty acids.
  • a permeation enhancer selected from diethylene glycol monoethyl ether, diisopropyl adipate, isopropyl myristate, isopropyl palmitate, lauryl lactate, dimethylpropylene urea and a mixture of propylene glyco
  • Capryol which is a propylene glycol monocaprylate (type II), a mixture of propylene glycol monoesters and diesters of fatty acids with a ratio of >90% monoesters and ⁇ 10% diesters, wherein the fatty acids mainly consist of caprylic acid.
  • 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.
  • the matrix layer composition does not comprise sodium acetate or sodium diacetate.
  • the asenapine-containing layer does not comprise a dicarboxylic acid alkali salt.
  • the matrix layer composition does not comprise a maleic acid alkali salt.
  • the matrix layer composition according to the invention may comprise a pH regulator.
  • the pH regulator is selected from amine derivatives, inorganic alkali derivatives, polymers with basic and acidic functionality, respectively.
  • the TTS in accordance with the invention are designed for transdermally administering asenapine to the systemic circulation for a predefined extended period of time.
  • the TTS according to the invention provide a mean release rate of 0.5 to 20 mg/day, 0.5 to 20 mg/24 h, 500 to 20,000 ⁇ g/day, 500 to 20,000 ⁇ g/24 h, 0.021 to 0.833 mg/h or 21 to 833 ⁇ g/h, preferably of 1.0 to 15 mg/day, 1.0 to 15 mg/24 h, 1,000 to 15,000 ⁇ g/day, 1,000 to 15,000 ⁇ g/24 h, 0.042 to 0.625 mg/h or 42 to 625 ⁇ g/h, and more preferably of 2.0 to 10 mg/day, 2.0 to 10 mg/24 h, 2,000 to 10,000 ⁇ g/day, 2,000 to 10,000 ⁇ g/24 h, 0.083 to 0.417 mg/h or 83 to 417 ⁇ g/h over at least 24 hours of administration, preferably over at least 48 hours of administration, more preferably over at least 72 hours of administration, and most preferably over at least 84 hours of administration.
  • the TTS according to the invention provide a cumulative skin permeation rate of asenapine at hour 48 or at hour 72 as measured in a Franz diffusion cell with dermatomed human skin of 1 ⁇ g/(cm 2 h) to 20 ⁇ g/(cm 2 h), preferably of 2 ⁇ g/(cm 2 h) to 15 ⁇ g/(cm 2 h) and more preferably of 4 ⁇ g/(cm 2 h) to 12 ⁇ g/(cm 2 h).
  • the TTS according to the invention as described above provides a skin permeation rate of asenapine as measured in a Franz diffusion cell with dermatomed human skin of
  • the transdermal therapeutic system provides a cumulative permeated amount of asenapine as measured in a Franz diffusion cell with dermatomed human skin of 0.05 mg/cm 2 to 1.0 mg/cm 2 , preferably of 0.1 mg/cm 2 to 0.7 mg/cm 2 over a time period of 48 hours.
  • the transdermal therapeutic system provides a cumulative permeated amount of asenapine as measured in a Franz diffusion cell with dermatomed human skin of 0.1 mg/cm 2 to 2.0 mg/cm 2 , preferably 0.2 mg/cm 2 to 1.0 mg/cm 2 over a time period of 72 hours.
  • the TTS according to the invention is for use in a method of treatment, and in particular in a method of treating a human patient.
  • the TTS according to the invention is preferably for use in a method of treating psychosis, and more preferably for use in a method of treating one or more conditions selected from schizophrenia, bipolar disorder, posttraumatic stress disorder, major depressive disorder, dementia related psychosis, agitation and manic disorder, in particular for use in a method of treating schizophrenia and/or bipolar disorder in a human patient, and in particular for use in a method of treating acute manic or mixed episodes of bipolar disorder in a human patient.
  • the TTS according to the invention is for use in a method of treating acute manic or mixed episodes of bipolar disorder in an adult or a pediatric patient 10 to 17 years of age. In certain embodiments, the TTS according to the invention is for use as an adjunctive treatment to lithium or valproate in a method of treating bipolar disorder in a human patient, in particular an adult. In certain embodiments, the TTS according to the invention is for use as a maintenance monotherapy treatment in a method of treating bipolar disorder in a human patient, in particular an adult.
  • the TTS according to the invention is further preferably for use in a method of treating schizophrenia or bipolar disorder in a subject in need thereof, the method comprising transdermally administering a therapeutically effective amount of asenapine to the subject, wherein the asenapine is contained in a transdermal therapeutic system for the transdermal administration of asenapine, and wherein the transdermal therapeutic system is in contact with at least one body surface on the subject for at least 48 hours or 2 days or for at least 72 hours or 3 days, or for about 48 hours or about 2 days, or about 72 hours or about 3 days, or about 84 hours or about 3.5 days.
  • the body surface may be located at any part of the body, and is in certain embodiments selected from the upper outer arm, upper chest, upper back or the side of the chest.
  • the TTS may be further for use in a method of treatment with a dosing interval of at least 24 hours or 1 day, at least 48 hours or 2 days, or at least 72 hours or 3 days, and/or with a dosing interval of up to 168 hours or 7 days, up to 120 hours or 5 days, or up to 96 hours or 4 days.
  • the dosing interval may in particular be 24 hours or 1 day, 48 hours or 2 days, or 84 hours or 3.5 days.
  • the invention is also related to TTS for use in a method of treatment, and in particular for use in a method of treating schizophrenia and/or bipolar disorder, and in particular acute manic or mixed episodes of bipolar disorder, in an around-the-clock treatment with a once-a-day TTS exchange mode (dosing interval of 24 hours or 1 day), a twice-a-week TTS exchange mode (dosing interval of 84 hours or 3.5 days) or a once-a-week TTS exchange mode (dosing interval of 168 hours, or 7 days).
  • a once-a-day TTS exchange mode dosing interval of 24 hours or 1 day
  • a twice-a-week TTS exchange mode dosing interval of 84 hours or 3.5 days
  • a once-a-week TTS exchange mode dosing interval of 168 hours, or 7 days.
  • the TTS according to the invention is further preferably for use in a method of treating a patient, wherein the transdermal therapeutic system provides a reduction in at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine.
  • Relative to an equivalent dose of sublingual asenapine should be understood as a comparison in the incidence and intensity of side effects in a clinical study when using a dose of transdermal and sublingual asenapine that leads substantially to the same blood plasma exposure of asenapine.
  • 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.
  • the transdermal therapeutic systems for use in a method of reducing at least one asenapine-related side effect the transdermal therapeutic systems for use in a method of reducing at least one asenapine-related side effect, the methods of treatment and methods of reducing at least one asenapine-related side effect as well as the asenapine for use in a method of treating a human patient as will be described below, the following may generally further apply:
  • the at least one asenapine-related side effect is in particular fatigue, somnolence, dizziness, oral hypoaesthesia, or any combination thereof.
  • the inventive methods and transdermal therapeutic systems for use in the methods are in particular suitable for a human patient already suffering from such a condition, i.e. suffering from fatigue, somnolence, dizziness, or any combination thereof.
  • the incidence of the at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine may be reduced by at least about 30%, at least about 40%, at least about 70% or at least about 80%, and/or the intensity of the at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine may be reduced.
  • the intensity of a side effect can be determined e.g. by classifying the side effects on a scale indicating “mild”, “moderate” or “severe” intensity, and a reduction of the intensity can be quantified by comparing the median intensity.
  • 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.
  • 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%.
  • the present invention is also related to a method of treatment, and in particular a method of treating a human patient.
  • the invention is in particular related to a method of treating psychosis, and in particular to a method of treating one or more conditions selected from schizophrenia, bipolar disorder, posttraumatic stress disorder, major depressive disorder, dementia related psychosis, agitation and manic disorder, and preferably to a method of treating schizophrenia and/or bipolar disorder in a human patient, and in particular acute manic or mixed episodes of bipolar disorder including applying a transdermal therapeutic system according to the invention to the skin of a human patient.
  • the invention is also related to a method of treating acute manic or mixed episodes of bipolar disorder in an adult or a pediatric patient 10 to 17 years of age. In certain embodiments, the invention is also related to a method of treating bipolar disorder in a human patient, in particular an adult, as an adjunctive treatment to lithium or valproate. In certain embodiments, the invention is also related to a maintenance monotherapy treatment in a method of treating bipolar disorder in a human patient, in particular an adult.
  • the invention is further preferably also related to a method of treating schizophrenia or bipolar disorder in a subject in need thereof, the method comprising transdermally administering a therapeutically effective amount of asenapine to the subject, wherein the asenapine is contained in a transdermal therapeutic system for the transdermal administration of asenapine, and wherein the transdermal therapeutic system is in contact with at least one body surface (as defined above) on the subject for at least 48 hours or 2 days or for at least 72 hours or 3 days, or for about 48 hours or about 2 days, or about 72 hours or about 3 days, or about 84 hours or about 3.5 days.
  • the invention is also related to a method of treatment by applying a transdermal therapeutic system according to the invention for at least 24 hours or 1 day, at least 48 hours or 2 days, or at least 72 hours or 3 days, and/or for up to 168 hours or 7 days, up to 120 hours or 5 days, or up to 96 hours or 4 days to the skin of a human patient.
  • the transdermal therapeutic system according to the invention may in particular be applied for 24 hours or 1 day, 48 hours or 2 days, or 84 hours or 3.5 days to the skin of a human patient.
  • the invention is also related to a method of treatment in an around-the-clock treatment with a once-a-day TTS exchange mode (dosing interval of 24 hours or 1 day), a twice-a-week TTS exchange mode (dosing interval of 84 hours or 3.5 days) or a once-a-week TTS exchange mode (dosing interval of 168 hours, or 7 days).
  • a once-a-day TTS exchange mode dosing interval of 24 hours or 1 day
  • a twice-a-week TTS exchange mode dosing interval of 84 hours or 3.5 days
  • a once-a-week TTS exchange mode dosing interval of 168 hours, or 7 days.
  • the transdermal therapeutic system may provide a reduction in at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine.
  • the present invention is also related to a method of reducing, in a patient, at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine, the method comprising administering a transdermal therapeutic system according to the invention.
  • the invention is also related to a method of reducing at least one asenapine-related side effect in a patient being treated with sublingual asenapine therapy, the method comprising
  • the transdermal therapeutic system may deliver an amount of asenapenaine equivalent to the amount of asenapine originally provided by the sublingual asenapine therapy.
  • the inventors have surprisingly shown that a relatively constant asenapine blood plasma concentration can be maintained for an extended period of time by transdermal delivery of asenapine.
  • the present invention is related to asenapine for use in a method of treating a human patient by transdermal administration of asenapine for a dosing interval of at least 48 hours or 2 days or for a dosing interval of at least 72 hours or 3 days.
  • 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.
  • the asenapine is preferably for use in a method of treating psychosis, and in particular for use in a method of treating one or more conditions selected from schizophrenia, bipolar disorder, posttraumatic stress disorder, major depressive disorder, dementia related psychosis, agitation and manic disorder, or for use in a method of treating schizophrenia and/or bipolar disorder, more preferably bipolar disorder and in particular acute manic or mixed episodes of bipolar disorder.
  • the asenapine is also preferably for use in a method of treating acute manic or mixed episodes of bipolar disorder in an adult or a pediatric patient 10 to 17 years of age, for use as an adjunctive treatment to lithium or valproate or for use as maintenance monotherapy treatment in a method of treating bipolar disorder in a human patient, in particular an adult.
  • the asenapine is further preferably for use in a method of treating schizophrenia or bipolar disorder in a subject in need thereof, the method comprising transdermally administering a therapeutically effective amount of asenapine to the subject, wherein the asenapine is contained in a transdermal therapeutic system for the transdermal administration of asenapine, and wherein the transdermal therapeutic system is in contact with at least one body surface (as defined above) on the subject for at least 48 hours or 2 days or for at least 72 hours or 3 days, or for about 48 hours or about 2 days, or about 72 hours or about 3 days, or about 84 hours or about 3.5 days.
  • the relatively constant asenapine blood plasma concentration can be described by several pharmacokinetic parameters as obtained in an in vivo clinical study on human subjects.
  • the present invention is related to asenapine for use in a method of treating a human patient by transdermal administration of asenapine as described above,
  • the present invention is related to asenapine for use in a method of treating a human patient by transdermal administration of asenapine as described above,
  • the present invention is related to asenapine for use in a method of treating a human patient by transdermal administration of asenapine as described above,
  • the present invention is related to asenapine for use in a method of treating a human patient by transdermal administration of asenapine as described above,
  • the present invention is further related to asenapine for use in a method of treating a human patient as outlined above, wherein at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced.
  • the present invention is related to a transdermal therapeutic system for the transdermal administration of asenapine for use in a method of treating a human patient for a dosing interval of at least 48 hours or 2 days or for a dosing interval of at least 72 hours or 3 days.
  • 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.
  • Such a transdermal therapeutic system for use in a method of treating a human patient as described above preferably comprises a self-adhesive layer structure containing a therapeutically effective amount of asenapine.
  • the transdermal therapeutic system is preferably for use in a method of treating psychosis, and in particular for use in a method of treating one or more conditions selected from schizophrenia, bipolar disorder, posttraumatic stress disorder, major depressive disorder, dementia related psychosis, agitation and manic disorder, or for use in a method of treating schizophrenia and/or bipolar disorder, more preferably bipolar disorder and in particular acute manic or mixed episodes of bipolar disorder.
  • the transdermal therapeutic system is also preferably for use in a method of treating acute manic or mixed episodes of bipolar disorder in an adult or a pediatric patient 10 to 17 years of age, for use as an adjunctive treatment to lithium or valproate or for use as maintenance monotherapy treatment in a method of treating bipolar disorder in a human patient, in particular an adult.
  • the transdermal therapeutic system is further preferably for use in a method of treating schizophrenia or bipolar disorder in a subject in need thereof, the method comprising transdermally administering a therapeutically effective amount of asenapine to the subject, wherein the asenapine is contained in a transdermal therapeutic system for the transdermal administration of asenapine, and wherein the transdermal therapeutic system is in contact with at least one body surface (as defined above) on the subject for at least 48 hours or 2 days or for at least 72 hours or 3 days, or for about 48 hours or about 2 days, or about 72 hours or about 3 days, or about 84 hours or about 3.5 days.
  • the present invention is related to a transdermal therapeutic system for the transdermal administration of asenapine for use in a method of treating a human patient as described above,
  • the present invention is related to a transdermal therapeutic system for the transdermal administration of asenapine for use in a method of treating a human patient as described above,
  • the present invention is related to a transdermal therapeutic system for the transdermal administration of asenapine for use in a method of treating a human patient as described above,
  • the present invention is related to a transdermal therapeutic system for the transdermal administration of asenapine for use in a method of treating a human patient as described above,
  • the TTS may be for use in a method of treating a human patient, wherein the transdermal therapeutic system provides a reduction in at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine.
  • the present invention is related to a method of treating a human patient by transdermal administration of asenapine for a dosing interval of at least 48 hours or 2 days or for a dosing interval of at least 72 hours or 3 days.
  • 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.
  • Such a method of treating a human patient by transdermal administration of asenapine as described above preferably includes applying a transdermal therapeutic system for the transdermal administration of asenapine for at least 48 hours or 2 days, for at least 72 hours or 3 days, for 48 hours or 2 days, for 72 hours or 3 days, or for 84 hours or 3.5 days to the skin of a patient.
  • 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.
  • the method described above is preferably a method of treating psychosis, and in particular a method of treating one or more conditions selected from schizophrenia, bipolar disorder, posttraumatic stress disorder, major depressive disorder, dementia related psychosis, agitation and manic disorder, or a method of treating schizophrenia and/or bipolar disorder, more preferably bipolar disorder and in particular acute manic or mixed episodes of bipolar disorder.
  • the method is also preferably a method of treating acute manic or mixed episodes of bipolar disorder in an adult or a pediatric patient 10 to 17 years of age, or a method of treating bipolar disorder in a human patient, in particular an adult, as an adjunctive treatment to lithium or valproate or as a maintenance monotherapy treatment.
  • the method is further preferably a method of treating schizophrenia or bipolar disorder in a subject in need thereof, the method comprising transdermally administering a therapeutically effective amount of asenapine to the subject, wherein the asenapine is contained in a transdermal therapeutic system for the transdermal administration of asenapine, and wherein the transdermal therapeutic system is in contact with at least one body surface (as defined above) on the subject for at least 48 hours or 2 days or for at least 72 hours or 3 days, or for about 48 hours or about 2 days, or about 72 hours or about 3 days, or about 84 hours or about 3.5 days.
  • the relatively constant asenapine blood plasma concentration can be described by several pharmacokinetic parameters as obtained in an in vivo clinical study on human subjects.
  • the present invention is related to a method of treating a human patient as described above,
  • the present invention is related to a method of treating a human patient as described above,
  • the present invention is related to a method of treating a human patient as described above,
  • the present invention is related to a method of treating a human patient as described above,
  • the transdermal therapeutic system may provide a reduction in at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine.
  • the present invention is related to a transdermal therapeutic system for the transdermal administration of asenapine
  • the present invention is directed to a method of treating a human patient by transdermal administration of asenapine, wherein at least one asenapine-related side effect relative to an equivalent dose of sublingual asenapine is reduced, and wherein
  • the human patient is suffering from fatigue, somnolence, dizziness, or any combination thereof, and/or the at least one asenapine-related side effect is fatigue, somnolence, dizziness, oral hypoaesthesia, or any combination thereof.
  • 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, somnolence, dizziness, or any combination thereof, and/or the at least one asenapine-related side effect is fatigue, somnolence, dizziness, oral hypoaesthesia, or any combination thereof.
  • 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
  • the invention further relates to a process of manufacture of a matrix layer for use in a transdermal therapeutic system and a corresponding matrix layer structure and a corresponding TTS.
  • the process of manufacture of a matrix layer for use in a transdermal therapeutic system comprises the steps of:
  • step 1) the asenapine is dissolved to obtain a coating composition.
  • the solvent is selected from alcoholic solvents, in particular methanol, ethanol, isopropanol and mixtures thereof, and from non-alcoholic solvents, in particular ethyl acetate, hexane, n-heptane, petroleum ether, toluene, and mixtures thereof, and more preferably is selected from ethanol and ethyl acetate.
  • the polymer in the above process is an acrylic polymer and preferably a copolymer based on vinyl acetate, 2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and glycidyl-methacrylate, which is provided as a solution and preferably as a solution in ethyl acetate, n-heptane, methanol or ethanol with a solids content of from 30 to 60% by weight.
  • step 3 drying is performed preferably at a temperature of from 50 to 90° C., more preferably from 60 to 80° C.
  • Solids content of 50.5% by weight (Duro-Tak TM 387-2287) Isopropyl myristate — — 0.49 6.55 — — — — Diethylene glycol — — — 0.51 6.67 — — monoethyl ether (Transcutol) Ethyl acetate 2.06 — 3.81 — 3.83 — 3.79 — Total 11.69 100.00 17.37 100.00 17.43 100.00 16.89 100.00 Area Weight [g/m 2 ] 200.1 141.5 136.9 149.0 Asenapine content 1.345 1.746 1.678 3.864 [mg/cm 2 ]
  • Example 1a-1c a beaker was loaded with the asenapine base and with the solvent (ethyl acetate), and the isopropyl myristate (Example 1b) or the diethylene glycol monoethyl ether (Example 1c) was added, if applicable.
  • the acrylic pressure sensitive adhesive Duro-TakTM 387-2287 was added and the mixture was then stirred at up to 500 rpm until a homogeneous mixture was obtained (stirring time is 60 min. or longer throughout the examples, if not indicated otherwise).
  • Example 1d For Example 1d, a beaker was loaded with approx. 1.41 g of the asenapine base and the solvent (ethyl acetate) was added. The acrylic pressure sensitive adhesive was added and the mixture was stirred at approx. 200 rpm for approx. 30 min. Further approx. 0.56 g of the asenapine base was added in two portions, while stirring continued at approx. 500 rpm for approx. 30 min.
  • solvent ethyl acetate
  • the resulting asenapine-containing coating composition was coated on a polyethylene terephthalate film (siliconised, 100 ⁇ m thickness, which may function as release liner) and dried for approx. 10 min at room temperature and 20 min at 60° C. The coating thickness gave an area weight of the matrix layer of 100.1 g/m 2 .
  • a first part of the dried film was laminated with a polyethylene terephthalate backing layer (23 ⁇ m thickness) to provide a first asenapine-containing self-adhesive layer structure.
  • a second, unmodified part of the dried film serves as the second asenapine-containing self-adhesive layer structure, comprising a release liner but not a backing layer.
  • the polyethylene terephthalate film (siliconised, 100 ⁇ m thickness, which may function as a release liner) of the first layer structure was removed and the adhesive site of the first layer structure was laminated on the adhesive site of the second layer structure. This results in an asenapine-containing self-adhesive layer structure with an area weight of the matrix layer of 200.1 g/m 2 , with a backing layer and a release liner.
  • the resulting asenapine-containing coating composition was coated on a polyethylene terephthalate film (siliconised, 100 ⁇ m thickness, which may function as release liner) and dried for approx. 15 min at room temperature and 25 min at 60° C.
  • the coating thickness gave an area weight of the matrix layer of 141.5 g/m 2 (Example 1b), 136.9 g/m 2 (Example 1c), and 149.0 g/m 2 (Example 1d), respectively.
  • the dried film was laminated with a polyethylene terephthalate backing layer (23 ⁇ m thickness) to provide an asenapine-containing self-adhesive layer structure.
  • TTS The individual systems
  • a TTS as described above can be provided with a further self-adhesive layer of larger surface area, preferably with rounded corners, comprising a pressure-sensitive adhesive matrix layer which is free of active agent.
  • This is of advantage when the TTS, on the basis of its physical properties alone, does not adhere sufficiently to the skin and/or when the asenapine-containing matrix layer, for the purpose of avoiding waste, has pronounced corners (square or rectangular shapes).
  • the TTS are then punched out and sealed into pouches of the primary packaging material.
  • TTS permeated amount and the corresponding skin permeation rates of TTS prepared according to Examples 1a-d were determined by in vitro experiments in accordance with the OECD Guideline (adopted Apr. 13, 2004) carried out with a 7.0 ml Franz diffusion cell.
  • Split thickness Goettingen minipig skin (female) was used.
  • a dermatome was used to prepare skin to a thickness of 800 ⁇ m, with an intact epidermis for all TTS. Diecuts with an area of 1.156 cm 2 were punched from the TTS.
  • the asenapine permeated amount in the receptor medium of the Franz cell solution containing 60% phosphate buffer pH 5.5, 30% dipropylene glycol and 10% acetonitrile) at a temperature of 32 ⁇ 1° C. was measured and the corresponding skin permeation rate calculated. The results are shown in Table 1.2 and FIGS. 1 a and 1 b .
  • Example 1a Example 1b
  • Example 2a the coating compositions were prepared as described in Example 1c except that the diethylene glycol monoethyl ether was added before the solvent ethyl acetate.
  • Example 2b the beaker was loaded with the solvent (petroleum ether) first and the polyisobutylene adhesive was added.
  • the polyvinylpyrrolidone (Kollidon® 90 F) was added while stirring at approx. 200 rpm.
  • the asenapine base was added while stirring at up to 1500 rpm until a homogeneous mixture was obtained.
  • the resulting asenapine-containing coating composition was coated on a polyethylene terephthalate film (siliconised, 100 ⁇ m thickness, which may function as release liner) and dried for approx. 10 min at room temperature and 20 min at 60° C. (Examples 2a and 2c) or at 90° C. (Example 2b).
  • the coating thickness gave an area weight of the matrix layer of 91.3 g/m 2 (Example 2a), 85.7 g/m 2 (Example 2b), and 90.15 g/m 2 (Example 2c), respectively.
  • the dried film was laminated with a polyethylene terephthalate backing layer (23 ⁇ m thickness) to provide an asenapine-containing self-adhesive layer structure.
  • Example 2d a double layer self-adhesive layer structure was prepared as described for Example 1a, starting from two layers as prepared for Example 2c. This results in an asenapine-containing self-adhesive layer structure with an area weight of the matrix layer of 159.6 g/m 2 , with a backing layer and a release liner.
  • TTS permeated amount and the corresponding skin permeation rates of TTS prepared according to Examples 2a-d were determined by in vitro experiments in accordance with the OECD Guideline (adopted Apr. 13, 2004) carried out with a 7.0 ml Franz diffusion cell.
  • Split thickness Goettingen minipig skin (female) was used.
  • a dermatome was used to prepare skin to a thickness of 800 ⁇ m, with an intact epidermis for all TTS. Diecuts with an area of 1.145 cm 2 were punched from the TTS.
  • the asenapine permeated amount in the receptor medium of the Franz cell phosphate buffer solution pH 5.5 with 0.1% saline azide as antibacteriological agent
  • the results are shown in Table 2.2 and FIGS. 2 a and 2 b .
  • Example 2a Example 2b
  • Example 2b the beaker was loaded with the polyvinylpyrrolidone (Kollidon® 90 F) first and ethanol was added while stirring at approx. 100-200 rpm. The polyisobutylene adhesive was then added while stirring at approx. 400 rpm. Further, the asenapine base was added while stirring at approx. 400 rpm and finally, n-heptane was added while stirring at approx. 400-500 rpm until a homogeneous mixture was obtained.
  • the polyvinylpyrrolidone Kerdon® 90 F
  • the resulting asenapine-containing coating composition was coated on a polyethylene terephthalate film (siliconised, 75 ⁇ m thickness, which may function as release liner) and dried for approx. 10 min-20 min at room temperature and 20 min-25 min at 80° C.
  • the coating thickness gave an area weight of the matrix layer of 52.8 g/m 2 (Example 2e), 129.6 g/m 2 (Example 20, 188.4 g/m 2 (Example 2g), 51.6 g/m 2 (Example 2h), 128.2 g/m 2 (Example 2i), and 185.9 g/m 2 (Example 2j), respectively.
  • the dried film was laminated with a polyethylene terephthalate backing layer (23 ⁇ m thickness) to provide an asenapine-containing self-adhesive layer structure.
  • TTS permeated amount and the corresponding skin permeation rates of TTS prepared according to Examples 2e to 2j were determined by in vitro experiments in accordance with the OECD Guideline (adopted Apr. 13, 2004) carried out with a 7.0 ml Franz diffusion cell. Split thickness human skin from cosmetic surgeries (female abdomen, date of birth 1969) was used. A dermatome was used to prepare skin to a thickness of 800 ⁇ m, with an intact epidermis for all TTS. Diecuts with an area of 1.151 cm 2 were punched from the TTS. The asenapine permeated amount in the receptor medium of the Franz cell (phosphate buffer solution pH 5.5 with 0.1% saline azide as antibacteriological agent) at a temperature of 32 ⁇ 1° C. was measured and the corresponding skin permeation rate calculated. The results are shown in Tables 2.5 and 2.6 and FIG. 2 d .
  • Example 3a The coating composition of Example 3a was prepared as described in Example 1c.
  • a beaker was loaded with the excipients polyethylene glycol 400, diisopropyl adipate or propylene glycol monocaprylate type II, as applicable, and with the solvent (ethyl acetate).
  • the acrylic pressure sensitive adhesive Duro-TakTM 387-2287 was added and the mixture was then stirred at up to 500 rpm until a homogeneous mixture was obtained.
  • the asenapine base was added and the mixture again stirred at up to 500 rpm until a homogeneous mixture was obtained.
  • Example 3c a beaker was loaded with the acrylic pressure sensitive adhesive Duro-TakTM 387-2287.
  • the solvent ethyl acetate
  • the polyvinylpyrrolidone was added and the mixture was then stirred at approx. 500 rpm until a homogeneous mixture was obtained.
  • the asenapine base was added and the mixture again stirred at up to 500 rpm until a homogeneous mixture was obtained.
  • Example 3a The coating thickness gave an area weight of the matrix layer of 137.3 g/m 2 (Example 3a), 144.1 g/m 2 (Example 3b), 146.05 g/m 2 (Example 3c), 152.1 g/m 2 (Example 3d), and 147.6 g/m 2 (Example 3e) respectively.
  • the dried film was laminated with a polyethylene terephthalate backing layer (23 ⁇ m thickness) to provide an asenapine-containing self-adhesive layer structure.
  • TTS permeated amount and the corresponding skin permeation rates of TTS prepared according to Examples 3a-e were determined by in vitro experiments in accordance with the OECD Guideline (adopted Apr. 13, 2004) carried out with a 7.0 ml Franz diffusion cell. Split thickness Goettingen minipig skin was used. A dermatome was used to prepare skin to a thickness of 800 ⁇ m, with an intact epidermis for all TTS. Diecuts with an area of 1.156 cm 2 were punched from the TTS. The asenapine permeated amount in the receptor medium of the Franz cell (phosphate buffer solution pH 5.5 with 0.1% saline azide as antibacteriological agent) at a temperature of 32 ⁇ 1° C. was measured and the corresponding skin permeation rate calculated. The results are shown in Table 3.2 and FIG. 3 a .
  • Example 3a Example 3b
  • Example 3c Example 3d
  • Solids content of 50.5% by weight (Duro-Tak TM 387-2287) Basic butylated — — 0.71 10.07 methacrylate copolymer (Eudragit ® E100) Ethyl acetate 2.91 4.35 Total 35.12 100.00 16.41 100.00 Area Weight [g/m 2 ] 146.7 126.85 Asenapine content 2.644 2.259 [mg/cm 2 ]
  • Example 4a a beaker was loaded with the acrylic pressure sensitive adhesive Duro-TakTM 387-2516 and with the asenapine. The solvent ethyl acetate was added and the mixture was then stirred at approx. 500 rpm until a homogeneous mixture was obtained.
  • Example 4b a beaker was loaded with the asenapine and the solvent ethyl acetate.
  • the acrylic pressure sensitive adhesive Duro-TakTM 387-2287 was added and the mixture was then stirred at approx. 500 rpm until a homogeneous mixture was obtained.
  • the basic butylated methacrylate copolymer Eudragit E100 was added while stirring at up to 1000 rpm.
  • Example 4a The coating thickness gave an area weight of the matrix layer of 146.7 g/m 2 (Example 4a) and 126.85 g/m 2 (Example 4b) respectively.
  • the dried film was laminated with a polyethylene terephthalate backing layer (23 ⁇ m thickness) to provide an asenapine-containing self-adhesive layer structure.
  • TTS permeated amount and the corresponding skin permeation rates of TTS prepared according to Examples 4a and 4b were determined by in vitro experiments in accordance with the OECD Guideline (adopted Apr. 13, 2004) carried out with a 7.0 ml Franz diffusion cell.
  • Split thickness Goettingen minipig skin (female) was used.
  • a dermatome was used to prepare skin to a thickness of 800 ⁇ m, with an intact epidermis for all TTS. Diecuts with an area of 1.156 cm 2 were punched from the TTS.
  • the asenapine permeated amount in the receptor medium of the Franz cell phosphate buffer solution pH 5.5 with 0.1% saline azide as antibacteriological agent
  • the results are shown in Table 4.2 and FIGS. 4 a and 4 b .
  • Example 5a a beaker was loaded with the asenapine and with the acrylic pressure sensitive adhesive Duro-TakTM 387-9301. The solvent ethyl acetate was added in two portions and the mixture was then stirred at approx. 200 rpm until a homogeneous mixture was obtained.
  • Example 5b a beaker was loaded with the acrylic pressure sensitive adhesive Duro-TakTM 387-2287, the acrylic pressure sensitive adhesive Duro-TakTM 387-4098, with the asenapine and with the diethylene glycol monoethyl ether.
  • the solvent ethyl acetate was added in two portions and the mixture was then stirred at approx. 200 rpm until a homogeneous mixture was obtained.
  • Example 5c a beaker was loaded with the polyisobutylene adhesive Oppanol B10/B100 and with the acrylic pressure sensitive adhesive Duro-TakTM 387-2287. A first portion (1.50 g) of the solvent ethyl acetate was added and the mixture was then stirred at approx. 100 rpm until a homogeneous mixture was obtained. The diethylene glycol monoethyl ether was added and the mixture was then stirred at approx. 200 rpm until a homogeneous mixture was obtained. The asenapine base was added and the mixture was again stirred at approx. 1000 rpm and the remaining portion of the solvent ethyl acetate (0.67 g) was added while stirring.
  • the resulting asenapine-containing coating composition was coated on a polyethylene terephthalate film (siliconised, 100 ⁇ m thickness, which may function as release liner) and dried for approx. 10 min at room temperature and 20 min at 60° C. (Examples 5a and 5b) or at 90° C. (Example 5c).
  • the coating thickness gave an area weight of the matrix layer of 99.6 g/m 2 (Example 5a), 102.55 g/m 2 (Example 5b), and 98.4 g/m 2 (Example 5c), respectively.
  • the dried film was laminated with a polyethylene terephthalate backing layer (23 ⁇ m thickness) to provide an asenapine-containing self-adhesive layer structure.
  • TTS permeated amount and the corresponding skin permeation rates of TTS prepared according to Examples 5a-c were determined by in vitro experiments in accordance with the OECD Guideline (adopted Apr. 13, 2004) carried out with a 7.0 ml Franz diffusion cell. Split thickness Goettingen minipig skin was used. A dermatome was used to prepare skin to a thickness of 800 ⁇ m, with an intact epidermis for all TTS. Diecuts with an area of 1.145 cm 2 were punched from the TTS. The asenapine permeated amount in the receptor medium of the Franz cell (solution containing 60% phosphate buffer pH 5.5, 30% dipropylene glycol and 10% acetonitrile) at a temperature of 32 ⁇ 1° C. was measured and the corresponding skin permeation rate calculated. The results are shown in Table 5.2 and FIG. 5 a .
  • Example 5a Example 5b
  • a beaker was loaded with the asenapine and with the acrylic pressure sensitive adhesive Duro-TakTM 387-2287 and with the polysiloxane adhesive Bio-PSA Q7-4301.
  • the solvent (petroleum ether for Example 6a and ethyl acetate for Examples 6b and 6c) was added and the mixture was then stirred at up to 1500 rpm until a homogeneous mixture was obtained.
  • the resulting asenapine-containing coating composition was coated on a polyester film (fluoro polymer coated, 75 ⁇ m thickness, which may function as release liner) and dried for approx. 10 min at room temperature and 20 min at 90° C.
  • the coating thickness gave an area weight of the matrix layer of 93.7 g/m 2 (Example 6a), 130.2 g/m 2 (Example 6b), and 105.3 g/m 2 (Example 6c), respectively.
  • the dried film was laminated with a polyethylene terephthalate backing layer (23 ⁇ m thickness) to provide an asenapine-containing self-adhesive layer structure.
  • TTS permeated amount and the corresponding skin permeation rates of TTS prepared according to Examples 6a-c were determined by in vitro experiments in accordance with the OECD Guideline (adopted Apr. 13, 2004) carried out with a 7.0 ml Franz diffusion cell.
  • Split thickness Goettingen minipig skin (female) was used.
  • a dermatome was used to prepare skin to a thickness of 800 ⁇ m, with an intact epidermis for all TTS. Diecuts with an area of 1.145 cm 2 were punched from the TTS.
  • the asenapine permeated amount in the receptor medium of the Franz cell phosphate buffer solution pH 5.5 with 0.1% saline azide as antibacteriological agent
  • the results are shown in Table 6.2 and FIG. 6 a .
  • Example 6a Example 6b
  • Solids content of 50.5% by weight (Duro- Tak TM 387-2287) Polysiloxane adhesive in n- — — — — — — 6.07 86.85 heptane. Solids content of 72.40% by weight (DOW CORNING ® BIO-PSA Q7-4301) Isopropylmyristate — — 0.35 6.92 — — — — — Ethyl acetate 0.61 — 2.72 — 2.37 — 0.58 — Total 11.69 100.00 11.68 100.00 11.60 100.00 7.32 100.00 Area Weight [g/m 2 ] 94.15 99.85 100.9 90.3 Asenapine content 1.257 1.339 2.515 [mg/cm 2 ]
  • Example 7a a beaker was loaded with the asenapine base, the acrylic pressure sensitive adhesive Duro-TakTM 387-2516 was added and the mixture was then stirred at approx. 250 rpm until a homogeneous mixture was obtained. The solvent ethyl acetate was added and the mixture again stirred at up to 400 rpm.
  • Example 7b a beaker was loaded with the asenapine base and with the solvent (ethyl acetate), and the isopropyl myristate was added.
  • the acrylic pressure sensitive adhesive Duro-TakTM 387-2287 was added and the mixture was then stirred at approx. 400 rpm until a homogeneous mixture was obtained.
  • Example 7c For the first and second layer of Example 7c, a beaker was loaded with the asenapine base and with the solvent (ethyl acetate), and the acrylic pressure sensitive adhesive Duro-TakTM 387-2287 or the polysiloxane adhesive was added, respectively, and the mixture was then stirred at approx. 400 rpm until a homogeneous mixture was obtained.
  • solvent ethyl acetate
  • the resulting asenapine-containing coating composition was coated on a polyethylene terephthalate film (siliconised, 100 ⁇ m thickness, which may function as release liner) and dried for approx. 10 min at room temperature and 20 min at 60° C. (Example 7b) or at 90° C. (Example 7a).
  • the coating thickness gave an area weight of the matrix layer of 94.15 g/m 2 (Example 7a) and 99.85 g/m 2 (Example 7b), respectively.
  • the dried film was laminated with a polyethylene terephthalate backing layer (23 ⁇ m thickness) to provide an asenapine-containing self-adhesive layer structure.
  • Example 7c the resulting asenapine-containing coating compositions were coated on a polyethylene terephthalate film (siliconised, 100 ⁇ m thickness, for Layer 1, or fluoro polymer coated, 75 ⁇ m thickness, for Layer 2, which may function as release liner) and dried for approx. 10 min at room temperature and 20 min at 60° C. (Layer 1) or at 90° C. (Layer 2).
  • a double layer self-adhesive layer structure was then prepared as described for Example 1a, with Layer 1 intended to be the layer contacting the skin (i.e. the dried film of Layer 2 was laminated with a polyethylene terephthalate backing layer (23 ⁇ m thickness) and Layer 1 was used unmodified).
  • TTS permeated amount and the corresponding skin permeation rates of TTS prepared according to Examples 7a-c were determined by in vitro experiments in accordance with the OECD Guideline (adopted Apr. 13, 2004) carried out with a 7.0 ml Franz diffusion cell.
  • Split thickness Goettingen minipig skin (female) was used.
  • a dermatome was used to prepare skin to a thickness of 800 ⁇ m, with an intact epidermis for all TTS. Diecuts with an area of 1.156 cm 2 were punched from the TTS.
  • the asenapine permeated amount in the receptor medium of the Franz cell solution containing 60% phosphate buffer pH 5.5, 30% dipropylene glycol and 10% acetonitrile) at a temperature of 32 ⁇ 1° C. was measured and the corresponding skin permeation rate calculated. The results are shown in Table 7.2 and FIG. 7 a .
  • Example 7a Example 7b
  • Example 8a a beaker was loaded with the asenapine base and the solvent ethyl acetate.
  • the acrylic pressure sensitive adhesive Duro-TakTM 387-2516 was added and the mixture was then stirred at up to 500 rpm (Example 8a) or at approx. 300 rpm (Example 8b), until a homogeneous mixture was obtained.
  • Example 8c a beaker was loaded with the asenapine base.
  • the acrylic pressure sensitive adhesive Duro-TakTM 387-2516 was added and the mixture was then stirred at approx. 300 rpm until a homogeneous mixture was obtained.
  • the polyvinylpyrrolidone and the solvent ethanol were consecutively added while stirring at approx. 300 rpm and approx. 500 rpm, respectively.
  • the resulting asenapine-containing coating composition was coated on a polyethylene terephthalate film (siliconised, 100 ⁇ m thickness, which may function as release liner) and dried for approx. 15 min at room temperature and 25 min at 75° C.
  • the coating thickness gave an area weight of the matrix layer of 134.8 g/m 2 (Example 8a) and 134.9 g/m 2 (Example 8c), respectively.
  • the dried film was laminated with a polyethylene terephthalate backing layer (23 ⁇ m thickness) to provide an asenapine-containing self-adhesive layer structure.
  • the resulting asenapine-containing coating composition was coated on a polyethylene terephthalate film (siliconised, 100 ⁇ m thickness, which may function as release liner) and dried for approx. 15 min at room temperature and 25 min at 75° C., and additionally 25 min at 75° C.
  • a double layer self-adhesive layer structure was then prepared as described for Example 1a. This results in an asenapine-containing self-adhesive layer structure with an area weight of the matrix layer of 168.5 g/m 2 , with a backing layer and a release liner.
  • TTS permeated amount and the corresponding skin permeation rates of TTS prepared according to Examples 8a-c were determined by in vitro experiments in accordance with the OECD Guideline (adopted Apr. 13, 2004) carried out with a 7.0 ml Franz diffusion cell.
  • Split thickness human skin from cosmetic surgeries (female abdomen, date of birth 1954) was used.
  • a dermatome was used to prepare skin to a thickness of 800 ⁇ m, with an intact epidermis for all TTS. Diecuts with an area of 1.148 cm 2 were punched from the TTS.
  • the asenapine permeated amount in the receptor medium of the Franz cell phosphate buffer solution pH 5.5 with 0.1% saline azide as antibacteriological agent
  • the results are shown in Table 8.2 and FIGS. 8 a and 8 b .
  • Example 8a Example 8b
  • a beaker was loaded with the asenapine base and the ascorbyl palmitate (Example 9b), if applicable, and the acrylic pressure sensitive adhesive Duro-TakTM 387-2516 was added. The mixture was then stirred at approx. 250 rpm (Example 9a) or up to 1000 rpm (Example 9b), until a homogeneous mixture was obtained.
  • Example 9a the resulting asenapine-containing coating composition was coated on a polyethylene terephthalate film (siliconised, 100 ⁇ m thickness, which may function as release liner) and dried for approx. 10 min at room temperature and 15 min at 70° C.
  • Example 9b the resulting asenapine-containing coating composition was coated on a polyethylene terephthalate film (siliconised, 75 ⁇ m thickness, which may function as release liner) and dried for approx. 15 min at room temperature and 25 min at 70° C.
  • the coating thickness gave an area weight of the matrix layer of 85.8 g/m 2 (Example 9a) and 149.0 g/m 2 (Example 9b) respectively.
  • the dried film was laminated with a polyethylene terephthalate backing layer (23 ⁇ m thickness) to provide an asenapine-containing self-adhesive layer structure.
  • TTS permeated amount and the corresponding skin permeation rates of TTS prepared according to Examples 9a and 9b were determined by in vitro experiments in accordance with the OECD Guideline (adopted Apr. 13, 2004) carried out with a 7.0 ml Franz diffusion cell.
  • Split thickness human skin from cosmetic surgeries (female abdomen, date of birth 1981) was used.
  • a dermatome was used to prepare skin to a thickness of 800 ⁇ m, with an intact epidermis for all TTS. Diecuts with an area of 1.149 cm 2 were punched from the TTS.
  • the asenapine permeated amount in the receptor medium of the Franz cell phosphate buffer solution pH 5.5 with 0.1% saline azide as antibacteriological agent
  • the results are shown in Table 9.2 and FIG. 9 a .
  • the formulation of the asenapine-containing coating composition is summarized in Table 10.1 below.
  • the formulation is based on weight percent, as also indicated in Table 10.1.
  • a beaker was loaded with the asenapine base and the ⁇ -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.
  • the resulting asenapine-containing coating composition was coated on a polyethylene terephthalate film (siliconised, 75 ⁇ m thickness, which may function as release liner) and dried for approx. 15 min at room temperature and 25 min at 70° C.
  • the coating thickness gave an area weight of the matrix layer of 148.35 g/m 2 .
  • the dried film was laminated with a polyethylene terephthalate backing layer (23 ⁇ m thickness) to provide an asenapine-containing self-adhesive layer structure.
  • the permeated amount and the corresponding skin permeation rates of TTS prepared according to Example 10 were determined by in vitro experiments in accordance with the OECD Guideline (adopted Apr. 13, 2004) carried out with a 10.0 ml Franz diffusion cell. Split thickness human skin from cosmetic surgeries (male abdomen, date of birth 1955) was used. A dermatome was used to prepare skin to a thickness of 800 ⁇ m, with an intact epidermis for all TTS. Diecuts with an area of 1.154 cm 2 were punched from the TTS. The asenapine permeated amount in the receptor medium of the Franz cell (phosphate buffer solution pH 5.5 with 0.1% saline azide as antibacteriological agent) at a temperature of 32 ⁇ 1° C. was measured and the corresponding skin permeation rate calculated. The results are shown in Table 10.2 and FIG. 10 a .
  • Example 11a-11c a beaker was loaded with the asenapine base and with the solvent (ethyl acetate), and the diethylene glycol monoethyl ether (Example 11c) was added, if applicable.
  • the acrylic pressure sensitive adhesive Duro-TakTM 387-2516 (Example 11a) or Duro-TakTM 387-2287 (Examples 11b and 11c) was added and the mixture was then stirred at approx. 500 rpm (Examples 11a and 11b) or approx. 700 rpm (Example 11c) until a homogeneous mixture was obtained.
  • Example 11d a beaker was loaded with the asenapine base and with the solvent (ethyl acetate).
  • the acrylic pressure sensitive adhesive Duro-TakTM 387-2516 was added and the mixture was then stirred at approx. 500 rpm until a homogeneous mixture was obtained.
  • the basic butylated methacrylate copolymer Eudragit E100 was then added while stirring at approx. 500 rpm.
  • the resulting asenapine-containing coating composition was coated on a polyethylene terephthalate film (siliconised, 100 ⁇ m thickness, which may function as release liner) and dried for approx. 15 min at room temperature and 25 min at 60° C. (Examples 11b-11d) or 90° C. (Example 11a).
  • the coating thickness gave an area weight of the matrix layer of 146.0 g/m 2 (Example 11a), 135.7 g/m 2 (Example 11b), 137.3 g/m 2 (Example 11c), and 140.3 g/m 2 (Example 11d) respectively.
  • the dried film was laminated with a polyethylene terephthalate backing layer (23 ⁇ m thickness) to provide an asenapine-containing self-adhesive layer structure.
  • TTS skin permeation rates
  • Goettingen minipigs female, about 6 months, randomized by simple random sample method. Diecuts with an area of 10 cm 2 were punched from the TTS and one Goettingen minipig was used for one TTS formulation. Three drug containing and one placebo TTS (each 10 cm 2 ) were used per minipig. The total wear time of all 4 patches per minipig (3 active and 1 placebo) patches was 84 h.
  • the minipigs were kept at 22 ⁇ 3° C., at a relative humidity of 40 ⁇ 15%, lighted from 6 am to 6 pm with calorie reduced breeding food, sniff, twice daily of about 140-200 g per animal, and with water ad libitum.
  • Histopathological examination of the epidermis and the dermis revealed no morphological or pathological transformation indicating an irritation of the deeper tissue layers. Histological results also show no lesion or removal of stratum corneum.
  • the residual amount of asenapine was determined in the removed TTS by quantitative HPLC (see above) and the dermally delivered amount of asenapine calculated as the difference to the initial amount of asenapine included in the TTS. The results are shown in Tables 11.2, 11.3, and FIG. 11 .
  • a stainless steel vessel was loaded with the ⁇ -tocopherol, the asenapine and the ethanol.
  • the acrylic pressure sensitive adhesive Duro-TakTM 387-2516 was added and the mixture was then stirred until a clear solution was obtained (about 20 min).
  • the polyvinylpyrrolidone was added slowly while stirring and dissolved under stirring until a clear solution was obtained.
  • the resulting asenapine-containing coating composition was coated on a polyethylene terephthalate film (one side siliconized, 75 ⁇ m thickness, which may function as release liner) and dried for approx. 15 min at 80° C.
  • the coating thickness gave an area weight of 148.6 g/m 2 (Ex. 12a) and 149.6 g/m 2 (Ex. 12b), respectively.
  • the dried film was laminated with a polyethylene terephthalate backing layer (23 ⁇ m thickness) to provide an asenapine-containing self-adhesive layer structure.
  • TTS permeated amount and the corresponding skin permeation rates of TTS prepared according to Examples 12a and 12b were determined by in vitro experiments in accordance with the OECD Guideline (adopted Apr. 13, 2004) carried out with a 7.0 ml Franz diffusion cell.
  • Split thickness human skin from cosmetic surgeries (female abdomen, date of birth 1986) was used.
  • a dermatome was used to prepare skin to a thickness of 800 ⁇ m, with an intact epidermis for all TTS. Diecuts with an area of 1.154 cm 2 were punched from the TTS.
  • the asenapine permeated amount in the receptor medium of the Franz cell phosphate buffer solution pH 5.5 with 0.1% saline azide as antibacteriological agent
  • the results are shown in Table 12.2 and FIG. 12 a .
  • the stainless steel vessel was loaded with ⁇ -tocopherol.
  • the acrylic pressure sensitive adhesive Duro-TakTM 387-2516 was added and the mixture was then stirred until a clear solution was obtained.
  • the polyvinylpyrrolidone was added slowly while stirring and dissolved under stirring until a clear solution was obtained.
  • the asenapine was suspended in the ethanol and transferred to the stainless steel vessel. After addition of the asenapine, the mixture was stirred at until a clear, slightly yellow colored solution was obtained.
  • the resulting asenapine-containing coating composition was coated on a polyethylene terephthalate film (one side siliconized, 75 ⁇ m thickness, which may function as release liner) and dried for approx. 15 min at 80° C.
  • the coating thickness gave an area weight of about 140 g/m 2 in accordance with the label requirements (hereinafter, where reference is made to a label value, it is understood that the actual value is within a tolerance of ⁇ 7.5% of the label value).
  • the dried film was laminated with a polyethylene terephthalate backing layer (23 ⁇ m thickness) to provide an asenapine-containing self-adhesive layer structure. Residual solvents amounts fulfilled the requirement the ICH guideline Q3C (R3), i.e. methanol 3,000 ppm, ethanol 5,000 ppm, ethyl acetate 5,000 ppm and n-heptane 5,000 ppm.
  • TTS Individual systems of 10 cm 2 (Ex. 13a) as well as 15 cm 2 (Ex. 13b) were then punched out from the asenapine-containing self-adhesive layer structure.
  • the trial was conducted in a single center, Phase I, open-label design with 3 treatments, 3 treatment periods, a fixed treatment sequence in 16 healthy male and female subjects, comparing the relative bioavailability of asenapine in plasma after single dose transdermal application of the TTS prepared in Examples 13a and 13b to the currently marketed sublingual tablets (Sycrest®, 5 mg).
  • Positive drug screen 4. Positive alcohol breath test. 7. Consumption of xanthine-containing food or beverages as well as grapefruit juice or Seville oranges within 48 hours before first dosing. 8. Consumption of char-grilled food, broccoli, or Brussel sprouts within 72 h before first dosing.
  • the reference formulation administered in period 1 contains the active ingredient asenapine maleate and is marketed under the trade name Sycrest® 5 mg Sublingualtabletten by N.V. Organon, Oss, Netherlands.
  • the pharmacy central number (PZN) is 07728207.
  • Sublingual tablets were administered in the morning and in the evening of the first day only with 12 h in between the two administrations according to the administration instructions given in the summary of product characteristics. The subjects were instructed to place the tablets under the tongue for at least 10 min to allow dissolving of the sublingual tablet and not to chew or swallow the sublingual tablets.
  • the TTS were applied to intact skin on the upper chest or upper back. Hairs on the application area were trimmed with scissors (not shaved) before application, if necessary. The subjects were instructed to verify that the skin is free of detergents, oils and fat before TTS application.
  • the TTS was placed on the desired position and pressed for at least 30 sec with fingers or the palm to fixate the TTS on the skin surface. In case of need and to avoid further detachment, the TTS was additionally fixated with an adhesive overlay free of active agent.
  • the optional adhesive overlay was placed above the TTS in such a way that each side was equally covered by the adhesive overlay. Afterwards, to fixate the TTS, it was pressed again for at least 30 sec with fingers or the palm.
  • the TTS were removed after 3.5 days (84 h, Period 2 and Period 3). After removal, the used TTS (including the adhesive overlay, if applicable) were handled and stored under nitrogen in the refrigerator until they were further analyzed.
  • Period 1 On the first day of Period 1, no breakfast was served; the subjects fasted overnight before morning administration. A standardized lunch was given 4 h and dinner approximately 10 h after morning administration. Fluid intake was not allowed from 1 h before until 1 h after morning and evening administration. As food does not interact with the TTS, the subjects received standardized meals and beverages during in-house days at customary times during Period 2 and 3. During in-house days, the subjects were only allowed to consume food or beverages provided by the study unit.
  • Blood samples for the determination of the concentration of asenapine and its metabolites in blood plasma were collected at specified time points after administration.
  • a validated internally standardized liquid chromatography tandem mass spectrometry method was used for the determination of the blood plasma concentration of asenapine, N-desmethyl-asenapine and asenapine-glucuronide, which was carried out by a GLP (Good Laboratory Practice)—certified laboratory. Plasma concentrations of asenapine-glucuronide were only determined for 8 subjects, which had no influence on the validity of the results, or the interpretation of the trial results. The lower limits of quantification (LLOQs) were 0.1 ng/ml for asenapine and N-desmethyl-asenapine in plasma, and 0.25 ng/ml for asenapine-glucuronide.
  • Adverse events were ascertained by the investigator using non-leading questions, noted as spontaneously reported by the subjects to the medical staff or observed during any measurements on all study days after administration of the dosage form and rated by a study physician.
  • An AE was referred to the treatment and time point after which it occurred, i.e., any AE occurring before the first dosing was counted as baseline complaint/pre-treatment AE and is not included in the below analysis.
  • Arithmetic mean values of the asenapine blood plasma concentration based on all 16 subjects for period 1 and based on the 15 and 14 subjects that completed periods 2 and 3, respectively, along with the standard deviation values are presented in Table 14.2 as well as FIGS. 13 a and 13 b .
  • AUC values were calculated from the blood plasma concentration.
  • the t lag was calculated approximately as the mean arithmetic value of the first point in time when a measurable (i.e. non-zero) asenapine blood plasma concentration was obtained, and the results also indicated in Table 14.2.
  • the residual amount is determined by extraction of the active from a sample of the used TTS with an appropriate solvent followed by determination of the active amount using a validated HPLC method with a UV photometric detector.
  • the mean release rate is calculated based on the initial asenapine content in the TTS (according to the label composition) applied and on the residual amount in the TTS after 84 hours referring to the total dose administered (see Table 13.1).
  • the blood plasma concentration profile of the metabolites asenapine glucuronide and N-desmethyl-asenapine was depicted as geometric mean values and indicating the geometric mean multiplied with and divided by the geometric standard deviation as error bars in FIGS. 13 c , 13 d and 13 e.
  • Calculation of the pharmacokinetic characteristics were based on actual blood sampling times [h] (relative to the corresponding administration time—accepted deviations from planned blood sampling times were within 3.5%) rounded to 2 decimal digits and negative pre dose times set to zero.
  • concentrations below LLOQ were calculated as zero. Concentrations below LLOQ between 2 quantifiable concentrations were calculated with half the LLOQ. Trailing concentrations below LLOQ were not used in calculations.
  • the plasma concentration profile of asenapine shows that therapeutic concentrations may be maintained over the entire wearing period of the TTS without major fluctuations. Compared to sublingual administration, maximum concentrations were lower and reached later after transdermal application. The formation of the major metabolites, N-desmethyl-asenapine and asenapine-glucuronide, is markedly reduced compared to sublingual administration.
  • Tables 14.8 and 14.9 reflect the number of adverse events reported in the different categories.
  • treatment duration for the sublingual tablet was only 12 h (i.e., 2 administrations) compared to 3.5 days TTS application (Examples 13a and 13b)
  • common systemic side effects of asenapine treatment such as fatigue and dizziness, were observed less frequently after TTS application and, in case of fatigue, only with mild intensity.
  • the frequency and intensity of fatigue was notably lower after transdermal administration, and dizziness occurred with lower frequency.
  • the invention relates in particular to the following further items:
  • 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:

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020071207A1 (ja) * 2018-10-01 2020-04-09 久光製薬株式会社 アセナピン含有貼付剤
WO2020071205A1 (ja) * 2018-10-01 2020-04-09 久光製薬株式会社 アセナピン含有貼付剤
US10898449B2 (en) 2016-12-20 2021-01-26 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US11033512B2 (en) 2017-06-26 2021-06-15 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer
US11337932B2 (en) 2016-12-20 2022-05-24 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene
US20230034383A1 (en) * 2021-07-21 2023-02-02 Hisamitsu Pharmaceutical Co., Inc. Method for reducing skin sensitization of an asenapine-containing patch
US11648213B2 (en) 2018-06-20 2023-05-16 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210251914A1 (en) * 2018-06-20 2021-08-19 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
WO2020047205A1 (en) * 2018-08-31 2020-03-05 Arctic Therapeutics, Llc Novel topical formulation for intradermal application and uses thereof
JP7410490B2 (ja) 2019-07-24 2024-01-10 株式会社リスニ 閉鎖型陸上養殖装置及びそれを用いた陸上養殖方法
BR112022007651A2 (pt) * 2019-10-22 2022-07-12 Shinkei Therapeutics Llc Dispositivo de distribuição transdérmica de tetrabenazina
CN114302716B (zh) * 2019-10-28 2024-09-17 久光制药株式会社 抑制阿塞那平-n-氧化物的生成的方法
CN113959923B (zh) * 2021-10-25 2024-08-09 中国地质调查局油气资源调查中心 天然气水合物未固结储层多孔介质骨架强化材料评价方法
DE102021128911A1 (de) 2021-11-05 2023-05-11 Lts Lohmann Therapie-Systeme Ag. Diclofenac enthaltendes tts mit dimethylpropylenharnstoff

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5656286A (en) * 1988-03-04 1997-08-12 Noven Pharmaceuticals, Inc. Solubility parameter based drug delivery system and method for altering drug saturation concentration
US20150202183A1 (en) * 2012-07-26 2015-07-23 Hisamitsu Pharmaceutical Co., Inc. Patch
WO2016140087A1 (ja) * 2015-03-02 2016-09-09 久光製薬株式会社 貼付剤

Family Cites Families (303)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS531190B2 (ja) 1974-02-22 1978-01-17
US4158059A (en) 1976-05-24 1979-06-12 Akzona Incorporated Tension reducing 2,3,4,4a,9,136-hexahydro-dibenz[1,2;5,6]cyclohepta[3,4-c]py
NL7605526A (nl) 1976-05-24 1977-11-28 Akzo Nv Nieuwe tetracyclische derivaten.
AU576884B2 (en) * 1984-07-23 1988-09-08 Schering Corporation Transdermal delivery of azatadine
US5474783A (en) 1988-03-04 1995-12-12 Noven Pharmaceuticals, Inc. Solubility parameter based drug delivery system and method for altering drug saturation concentration
US5446070A (en) 1991-02-27 1995-08-29 Nover Pharmaceuticals, Inc. Compositions and methods for topical administration of pharmaceutically active agents
DE69009540T2 (de) 1989-03-15 1994-09-29 Nitto Denko Corp Arzneimittel enthaltendes Heftpflaster.
DE3937271A1 (de) 1989-11-09 1991-05-16 Boehringer Ingelheim Kg Transdermale applikation von 2-amino-6-n-propylamino-4,5,6,7-tetrahydrobenzothiazol
EP0569096A1 (en) 1992-05-08 1993-11-10 Akzo Nobel N.V. Depot preparation
RU2139051C1 (ru) 1994-03-02 1999-10-10 Акцо Нобель Н.В. Сублингвальная или трансбуккальная фармацевтическая композиция
JP3274579B2 (ja) 1995-01-12 2002-04-15 住友製薬株式会社 脳血管障害に伴う精神症候治療剤
KR100213465B1 (ko) 1996-11-01 1999-08-02 최좌진 케토프로펜 패취 조성물
AU7767598A (en) 1997-05-26 1998-12-30 Akzo Nobel N.V. Salts of aromatic sulphonic acids
US7150881B2 (en) 1997-06-26 2006-12-19 Mylan Technologies, Inc. Adhesive mixture for transdermal delivery of highly plasticizing drugs
GB9714650D0 (en) 1997-07-11 1997-09-17 Strakan Ltd Block copolymer
WO1999032108A1 (en) 1997-12-19 1999-07-01 Akzo Nobel N.V. Org-5222 in the treatment of depression
DE19814083C2 (de) 1998-03-30 2002-02-07 Lohmann Therapie Syst Lts Verfahren zur Herstellung von transdermalen therapeutischen Systemen unter Verwendung von basischen Alkalimetallsalzen zur Umwandlung von Wirkstoffsalzen in die freien Basen
DE69922257T2 (de) 1998-07-29 2005-11-10 Teijin Ltd. Druckempfindliche klebstoffzusammensetzung und feuchtigkeitsdurchlässiges, druckempfindliches klebeband, druckempfindliche, pharmazeutische klebstoffzusammensetzung und herstellung eines druckempfindlichen klebebandes welches diese zusammensetzung enthält
US20040142024A1 (en) 1999-07-27 2004-07-22 Hisamitsu Pharmaceutical Co., Inc. Patch formulation for external use
US20020004065A1 (en) 2000-01-20 2002-01-10 David Kanios Compositions and methods to effect the release profile in the transdermal administration of active agents
AU2002214364B2 (en) 2000-11-06 2004-08-19 Samyang Biopharmaceuticals Corporation Transdermal drug delivery system with improved water absorbability and adhesion properties
CA2431041A1 (en) 2001-01-02 2002-07-11 Pharmacia & Upjohn Company New drug combinations of norepinehrine reuptake inhibitors and neuroleptic agents
EP1366762B1 (en) 2001-03-07 2015-12-30 Hisamitsu Pharmaceutical Co., Inc. Adhesive patch
WO2002087590A1 (en) 2001-04-26 2002-11-07 Ortho-Mcneil Pharmaceutical, Inc. Treatment of psychotic disorders comprising co-therapy with anticonvulsant derivatives and atypical antipsychotics
GB0119012D0 (en) 2001-08-03 2001-09-26 Strakan Group Plc Transdermal delivery of drugs
JP4323138B2 (ja) 2002-06-05 2009-09-02 日東電工株式会社 経皮吸収型製剤およびその製造方法
MXPA05000294A (es) 2002-07-30 2005-08-19 Peter Migaly Terapia combinada para la depresion, prevencion de suicidios y varias condiciones medicas y psiquiatricas.
DK1530469T3 (da) * 2002-08-20 2009-05-04 Euro Celtique Sa Transdermal dosisform omfattende et aktivt middel og et salt og fri baseform af en antagonist
AU2003268376A1 (en) 2002-08-30 2004-11-26 Watson Pharmaceuticals, Inc. Transdermal delivery systems and methods
AU2003284899A1 (en) 2002-10-29 2004-05-25 Miicro, Inc. Novel combination therapy for schizophrenia focused on improved cognition: 5-ht-2a/d2 blockade with adjunctive blockade of prefrontal da reuptake
GB0302662D0 (en) 2003-02-05 2003-03-12 Strakan Ltd Transdermal granisetron
GB0306604D0 (en) 2003-03-21 2003-04-30 Curidium Ltd Second medical use
BRPI0410271A (pt) 2003-05-16 2006-05-16 Pfizer Prod Inc combinações terapêuticas de antipsicóticos atìpicos com moduladores de gaba, anticonvulsivantes ou benzodiazepinas
TWI327915B (en) 2003-06-12 2010-08-01 Organon Nv Pharmaceutical composition comprising antipsychotic agent and use of the antipsychotic agent for treating patients with overweight
US20080020028A1 (en) * 2003-08-20 2008-01-24 Euro-Celtique S.A. Transdermal dosage form comprising an active agent and a salt and a free-base form of an adverse agent
JP2007508297A (ja) 2003-10-10 2007-04-05 オリックス 経皮の高分子量化合物及び低分子量化合物
JP2007509951A (ja) 2003-10-28 2007-04-19 ノーヴェン ファーマシューティカルズ インコーポレイテッド 経皮的なドラッグデリバリーシステムにおける医薬品の損失及び送達を制御するための組成物及び方法
CA2546200A1 (en) 2003-11-18 2005-06-02 3M Innovative Properties Company Olanzapine containing transdermal drug delivery compositions
EP1547650A1 (en) 2003-12-02 2005-06-29 B & B Beheer NV Use of D4 and 5-HT2A antagonists, inverse agonists or partial agonists
PL1708790T3 (pl) 2003-12-02 2010-10-29 Pharmaneuroboost N V Zastosowanie pipamperonu oraz antagonisty receptora D2 lub antagonisty receptora serotoniny/dopaminy do leczenia zaburzeń psychotycznych
EP1576985A1 (en) 2004-03-18 2005-09-21 B&B Beheer NV Use of D4 and 5-HT2A antagonists, inverse agonists or partial agonists
US7884096B2 (en) 2003-12-02 2011-02-08 Pharmaneuroboost N.V. Method of treating mental disorders using of D4 and 5-HT2A antagonists, inverse agonists or partial agonists
JP2007516275A (ja) 2003-12-23 2007-06-21 ファイザー・プロダクツ・インク 認知増強および精神病性障害のための治療的組合せ
WO2005082370A1 (en) 2004-01-29 2005-09-09 Pfizer Products Inc. Combinations of an atypical antipsychotic and an aminomethylpyridyloxymethyl/benzisoxazole azabicyclic derivatives for treating cns disorders
CN1917882A (zh) 2004-02-13 2007-02-21 辉瑞产品公司 非典型抗精神病药物与促肾上腺皮质激素释放因子拮抗剂的治疗剂组合
US7650848B2 (en) 2004-02-17 2010-01-26 University Of Florida Research Foundation, Inc. Surface topographies for non-toxic bioadhesion control
BRPI0508254A (pt) 2004-03-02 2007-07-24 Pharmacia Corp métodos e composições para o tratamento ou prevenção de distúrbios psiquiátricos com inibidores de cox-2 sozinhos e em combinação com agentes antidepressivos
GB0405200D0 (en) 2004-03-08 2004-04-21 Pfizer Ltd Combinations comprising alpha-2-delta ligands
US9205062B2 (en) 2004-03-09 2015-12-08 Mylan Pharmaceuticals, Inc. Transdermal systems containing multilayer adhesive matrices to modify drug delivery
WO2005102393A1 (ja) 2004-04-21 2005-11-03 Hisamitsu Pharmaceutical Co., Inc. 粘着基剤中の吸収促進剤の含有率を高めた外用貼付剤
AU2005235422B2 (en) 2004-04-22 2011-08-11 Boehringer Ingelheim International Gmbh New pharmaceutical compositions for the treatment of sexual disorders II
WO2005107808A2 (en) 2004-05-11 2005-11-17 Pfizer Products Inc. Combination of atypical antipsychotics and 5-ht1b receptor antagonists
WO2006000222A2 (en) 2004-06-24 2006-01-05 H. Lundbeck A/S The combination of an antipsychotic and a glycine transporter type i inhibitor for the treatment of schizophrenia
US20060019969A1 (en) 2004-07-24 2006-01-26 Laboratorios Dr. Esteve S.A. Use of compounds active on the sigma receptor for the treatment of allodynia
ITMI20041628A1 (it) 2004-08-06 2004-11-06 Bouty S P A Sistema terapeutico a rilascio controllato per uso topico transdermico
GB0417702D0 (en) 2004-08-09 2004-09-08 Merck Sharp & Dohme New uses
US20060039869A1 (en) * 2004-08-17 2006-02-23 Daniel Wermeling Intranasal delivery of antipsychotic drugs
US20060078604A1 (en) 2004-10-08 2006-04-13 Noven Pharmaceuticals, Inc. Transdermal drug delivery device including an occlusive backing
WO2006041911A2 (en) 2004-10-08 2006-04-20 Noven Pharmaceuticals, Inc. Device transdermal administration of drugs including acrylic polymers
WO2006040314A1 (en) 2004-10-15 2006-04-20 Pfizer Inc. Treatment of bipolar disorders and associated symptoms
DE602005010812D1 (de) 2004-11-22 2008-12-18 Hisamitsu Pharmaceutical Co Transdermales Pflaster enthaltend einen schmelzpunktsenkenden Hilfsstoff
US20060150989A1 (en) 2005-01-12 2006-07-13 Peter Migaly Method of diagnosing, treating and educating individuals with and/or about depression
EP1841417A2 (en) 2005-01-28 2007-10-10 Schwarz Pharma Ag Spm 927 for add-on therapy of schizophrenia
US20080138388A1 (en) 2005-02-04 2008-06-12 Hisamitsu Pharmaceutical Co., Inc. Transdermal Absorption Patch
AU2006219643A1 (en) 2005-03-01 2006-09-08 Pfizer Limited Use of PDE7 inhibitors for the treatment of neuropathic pain
WO2006096439A2 (en) 2005-03-04 2006-09-14 Boehringer Ingelheim International Gmbh Pharmaceutical compositions for the treatment and/or prevention of schizophrenia and related diseases
GB0506139D0 (en) * 2005-03-24 2005-05-04 Transphase Ltd A transdermal topical composition and its uses
US7872147B2 (en) 2005-04-07 2011-01-18 N. V. Organon Intermediate compounds for the preparation of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole
EP1710245B1 (en) 2005-04-07 2007-08-22 N.V. Organon Crystal form of asenapine maleate
CN101175741B (zh) 2005-04-07 2011-06-22 欧加农股份有限公司 用于制备反式-5-氯-2-甲基-2,3,3a,12b-四氢-1H-二苯并[2,3:6,7]-氧杂䓬并[4,5-C]吡咯的中间体化合物
US7741358B2 (en) 2005-04-14 2010-06-22 N.V. Organon Crystal form of asenapine maleate
WO2006118212A1 (ja) 2005-04-27 2006-11-09 Umn Pharma Inc. 膵炎の予防および治療剤
EP1731143B1 (en) 2005-06-06 2008-11-26 Nitto Denko Corporation Percutaneous absorption-type pharmaceutical preparation using a metal chloride, preferably sodium chloride, for preventing cohesive failure
CA2548864C (en) 2005-06-06 2012-12-11 Nitto Denko Corporation Percutaneous absorption-type pharmaceutical preparation
JP5000932B2 (ja) 2005-06-21 2012-08-15 日東電工株式会社 ニコチン含有経皮吸収製剤
US20070015763A1 (en) 2005-07-12 2007-01-18 Pfizer Inc Treatment of psychosis associated with parkinson's disease and subcortical dementias using a combination of an atypical antipsychotic with a dopamine agonist
WO2007017750A1 (en) 2005-08-08 2007-02-15 Pfizer Products Inc. Benzoate salt of 4-(5-methyl-oxazolo[4,5-b]pyridin-2-yl)-1,4-diaza-bicyclo[3.2.2]nonane
WO2007046554A1 (ja) 2005-10-21 2007-04-26 Sumitomo Chemical Company, Limited ジベンゾオキセピノピロール化合物の製造方法、その中間体及び該中間体の製造方法
DE102005050431A1 (de) 2005-10-21 2007-04-26 Lts Lohmann Therapie-Systeme Ag Transdermales therapeutisches System zur Verabreicherung lipophiler und/oder wenig hautpermeabler Wirkstoffe
US7888422B2 (en) 2005-11-09 2011-02-15 Mylan Technologies Inc. Long-wearing removable pressure sensitive adhesive
TWI389709B (zh) * 2005-12-01 2013-03-21 Novartis Ag 經皮治療系統
JP5037831B2 (ja) 2006-02-15 2012-10-03 久光製薬株式会社 凝集力向上及び徐放化の外用貼付剤
RS20080439A (en) 2006-03-27 2009-05-06 Panacea Biotec Ltd., Sustained release pharmaceutical composition on the basis of a release system comprising an acid-soluble polymer and a ph-dependent polymer
US20070259952A1 (en) 2006-05-02 2007-11-08 H. Lundbeck A/S Uses of escitalopram
TW200812993A (en) 2006-05-02 2008-03-16 Lundbeck & Co As H New uses of escitalopram
WO2007137224A2 (en) 2006-05-22 2007-11-29 Vanda Pharmaceuticals, Inc. Method of treatment
WO2007142295A1 (ja) 2006-06-09 2007-12-13 Dainippon Sumitomo Pharma Co., Ltd. 新規テープ製剤
TW200817414A (en) 2006-07-05 2008-04-16 Organon Nv Process for the preparation of asenapine and intermediate products used in said process
US7750167B2 (en) 2006-07-05 2010-07-06 N.V. Organon Process for the preparation of asenapine and intermediate products used in said process
CA2657640A1 (en) 2006-07-14 2008-01-24 Pfizer Products Inc. Tartrate salt of (7s)-7-[(5-fluoro-2-methyl-benzyl)oxy]-2-[(2r)-2-methylpiperazin-1-yl]-6,7-dihydro-5h-cyclopenta[b]pyridine
US20080045512A1 (en) 2006-08-09 2008-02-21 Pfizer Inc. Benzoate salt of 4-(5-methyl-oxazolo[4,5-b]-pyridin-2-yl)-1,4-diazabicyclo[3.2.2]nonane
PE20081457A1 (es) 2006-10-06 2008-10-18 Organon Nv Asenapina amorfa, procesos para prepararlas y su uso para tratar trastornos del sistema nervioso central
DE102006050558B4 (de) * 2006-10-26 2009-03-26 Lts Lohmann Therapie-Systeme Ag Transdermales therapeutisches System enthaltend Norelgestromin zur Kontrazeption und Hormonsubstitution
BRPI0719308A2 (pt) 2006-12-01 2014-02-04 Nitto Denko Corp Método para supressão da coloração de preparação adesiva contendo donepzil e método para redução da quantidade de substâncias formadas relacionadas à donepezil.
EP2098233A4 (en) 2006-12-01 2012-03-21 Nitto Denko Corp PREPARATION OF SKIN ADHESIVE COMPRISING DERESEPZIL STABILIZED
CN101563312A (zh) 2006-12-22 2009-10-21 住友化学株式会社 阿塞那平合成中间体的制备方法
US7875729B2 (en) 2007-01-05 2011-01-25 Synthon Bv Process for making asenapine
KR101460820B1 (ko) 2007-01-16 2014-11-11 아이피아이엔티엘, 엘엘씨 대사 증후군의 치료를 위한 신규한 조성물
US20080226698A1 (en) 2007-03-16 2008-09-18 Mylan Technologies, Inc. Amorphous drug transdermal systems, manufacturing methods, and stabilization
FR2913882B1 (fr) 2007-03-20 2009-05-01 Oreal Utilisation pour la coloration des fibres keratiniques d'une composition comprenant un compose halochromique et/ou le colorant correspondant a ce compose
WO2008141438A1 (en) 2007-05-17 2008-11-27 Sunnybrook Health Sciences Centre Gabaergic modulators for treating airway conditions
EP2170399A1 (en) 2007-06-05 2010-04-07 Synthon B.V. Intranasal administration of asenapine and pharmaceutical compositions therefor
WO2009000890A2 (en) 2007-06-27 2008-12-31 N.V. Organon Medication container
JP5245428B2 (ja) 2007-07-06 2013-07-24 住友化学株式会社 トランス−ジベンゾオキセノピロール化合物の製造方法およびその中間体
US20100178323A1 (en) 2007-07-10 2010-07-15 Agis Kydonieus Dermal Delivery Device
JP5224163B2 (ja) 2007-07-24 2013-07-03 コスメディ製薬株式会社 経皮吸収テープ製剤
WO2009017453A1 (en) 2007-07-30 2009-02-05 Astrazeneca Ab New therapeutic combination of an antipsychotic and a gsk3 inhibitor 958
BRPI0815850A2 (pt) 2007-08-01 2014-10-07 Medivation Neurology Inc "método para tratar, retardar a progressão, prevenir ou atrasar o desenvolvimento de esquizofrenia em um individuo, composiçã farmaceuticamente aceitável, kit e método para reforçar uma resposta de um individuo a um antipsicótico"
US20090209608A1 (en) 2007-08-29 2009-08-20 Protia, Llc Deuterium-enriched asenapine
EP2198049A1 (en) 2007-09-10 2010-06-23 Vanda Pharmaceuticals Inc. Antipsychotic treatment based on snp genotype
US8652776B2 (en) 2007-09-10 2014-02-18 Vanda Pharmaceuticals, Inc. Prediction of QT prolongation based on SNP genotype
US8318813B2 (en) 2007-09-13 2012-11-27 Lcs Group, Llc Method of treating binge eating disorder
US20100297181A1 (en) 2007-12-26 2010-11-25 Eisai R&D Management Co., Ltd. AMPA Receptor Antagonists for Epilepsy, Mental Disorders or Deficits in Sensory Organ
US7964739B2 (en) 2008-01-04 2011-06-21 N.V. Organon Process for the preparation of asenapine and intermediate products used in said process
GB2456183A (en) 2008-01-04 2009-07-08 Gw Pharma Ltd Anti-psychotic composition comprising cannabinoids and anti-psychotic medicament
US8529441B2 (en) * 2008-02-12 2013-09-10 Innurvation, Inc. Ingestible endoscopic optical scanning device
PT2254598E (pt) 2008-02-13 2013-10-16 Targacept Inc Combinação de agonistas nicotínicos alfa 7 e antipsicóticos
EP2255809B1 (en) 2008-02-27 2017-08-23 Hisamitsu Pharmaceutical Co., Inc. Medicated patch
WO2009121031A1 (en) 2008-03-27 2009-10-01 Vascular Biosciences, Inc. Methods of novel therapeutic candidate identification through gene expression analysis in vascular-related diseases
JP5301190B2 (ja) 2008-03-31 2013-09-25 積水メディカル株式会社 貼付剤
WO2009135091A1 (en) 2008-04-30 2009-11-05 Medivation Technologies, Inc. Use of asenapine and related compounds for the treatment of neuronal or non-neuronal diseases or conditions
NZ589542A (en) 2008-05-30 2012-10-26 Mylan Inc Transdermal drug delivery system comprising an active agent in amorphous form and polyvinylpyrrolidone
AU2008359725A1 (en) 2008-07-24 2010-01-28 Handa Pharmaceuticals, Llc Stabilized atypical antipsychotic formulation
US9267151B2 (en) 2008-08-20 2016-02-23 Brainco Biopharma, S.L. STXBP1 overexpressing mouse and its uses in screening of treatments for neuropsychiatric illness
WO2010026154A1 (en) 2008-09-04 2010-03-11 Neurosearch A/S A method for combating adverse effects arising from antipsychotic treatment
WO2010060742A1 (en) 2008-11-03 2010-06-03 Solvay Pharmaceuticals B.V. Combination of bifeprunox and an antipsychotic drug with d2/5-ht2a receptor antagonistic activity for treating cns disorders
WO2010073326A1 (ja) 2008-12-24 2010-07-01 ニチバン株式会社 経皮吸収型製剤
WO2010080757A2 (en) 2009-01-07 2010-07-15 Astrazeneca Ab Combinations with an alpha-4beta-2 nicotinic agonist
EP3006023B1 (en) 2009-01-20 2019-06-26 Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center Sorbic acid and derivatives thereof to enhance the activity of a neuropharmaceutical
ES2838012T3 (es) 2009-03-12 2021-07-01 Delpor Inc Dispositivo implantable durante un período largo de tiempo de fármacos
KR101597672B1 (ko) 2009-03-20 2016-02-25 앤태어스 파머, 인코퍼레이티드 위험 약제 주사 장치
WO2010110914A2 (en) 2009-03-27 2010-09-30 Zirus, Inc. Mammalian genes involved in infection
EP2236157A1 (en) 2009-03-30 2010-10-06 PharmaNeuroBoost N.V. Pipamperone and a second agent in treating mood and anxiety disorders
EP2413935A1 (en) 2009-03-30 2012-02-08 PharmaNeuroBoost N.V. Low dose pipamperone in treating mood disorders
EP2236138A1 (en) 2009-03-30 2010-10-06 PharmaNeuroBoost N.V. Low dose pipamperone in treating mood and anxiety disorders
WO2010119455A2 (en) 2009-04-15 2010-10-21 Sun Pharma Advanced Research Company Ltd. An injectable sustained release pharmaceutical composition
CA2759481A1 (en) 2009-04-21 2010-10-28 Sanomune Inc. Tissue kallikrein for the treatment of schizophrenia and bipolar disorder
TWI471127B (zh) 2009-04-29 2015-02-01 Intervet Int Bv 供人類使用之口服崩解錠劑的製備方法、所製得之口服崩解錠劑、以及含有該口服崩解錠劑的包裝物
US8512742B2 (en) 2009-05-01 2013-08-20 Hisamitsu Pharmaceutical Co., Inc. Transdermal preparation
WO2010127674A1 (en) * 2009-05-06 2010-11-11 Sunin K/S Transdermal compositions of asenapine for the treatment of psychiatric disorders
EP2453870A2 (en) 2009-06-24 2012-05-23 MSD Oss B.V. Injectable formulations containing asenapine and method of treatment using same
US20110306596A1 (en) 2009-07-27 2011-12-15 Auspex Pharmaceuticals, Inc. Benzazepine inhibitors of gamma-secretase
TW201118102A (en) 2009-07-29 2011-06-01 Organon Nv Hydroxyasenapine compounds, derivatives thereof and pharmaceutical compositions comprising same
CN102481283A (zh) 2009-08-31 2012-05-30 埃里克·B·施耐德 创伤或损伤后中枢神经系统继发性损伤的预防和治疗
WO2011047341A2 (en) 2009-10-16 2011-04-21 University Of South Florida Treatment of suicidal ideation or behavior using inhibitors of nicotinic acetylcholine receptors
US20110262442A1 (en) 2009-11-06 2011-10-27 Adenios, Inc. Compositions for treating cns disorders
US9629920B2 (en) 2009-12-18 2017-04-25 Exodos Life Sciences Limited Partnership Methods and compositions for stable liquid drug formulations
US8202525B2 (en) 2009-12-22 2012-06-19 Pondera Biotechnologies, LLC Methods and compositions for treating distress dysfunction and enhancing safety and efficacy of specific medications
AR079814A1 (es) 2009-12-31 2012-02-22 Otsuka Pharma Co Ltd Compuestos heterociclicos, composiciones farmaceuticas que los contienen y sus usos
AU2010339689B2 (en) 2010-01-07 2015-02-19 Alkermes Pharma Ireland Limited Quaternary ammonium salt prodrugs
US20110166194A1 (en) 2010-01-07 2011-07-07 Alkermes, Inc. Asenapine Prodrugs
WO2011085188A1 (en) 2010-01-07 2011-07-14 Eurand, Inc. Pharmaceutical compositions comprising anti-psychotic drugs
ITMI20100260A1 (it) 2010-02-19 2011-08-20 Giulio Scigliano Composizione farmaceutica contenente un farmaco per ridurre gli effetti collaterali dei farmaci antipsicotici
JP5615898B2 (ja) 2010-02-24 2014-10-29 久光製薬株式会社 貼付剤
US9707188B2 (en) 2010-02-24 2017-07-18 Hisamitsu Pharmaceutical Co., Inc. Transdermal preparation
WO2011107855A2 (en) 2010-03-04 2011-09-09 Torrent Pharmaceuticals Limited Sustained release oral liquid suspension dosage form
US20130245253A1 (en) 2010-03-26 2013-09-19 Department Of Veterans Affairs Conjugated Neuroactive Steroid Compositions And Methods Of Use
JP5654006B2 (ja) 2010-04-28 2015-01-14 久光製薬株式会社 皮膚刺激抑制剤及び経皮吸収製剤
WO2011143755A1 (en) 2010-05-21 2011-11-24 Serdar Dursun Compositions and methods of treating schizophrenia
CN101851242B (zh) 2010-05-25 2013-07-24 上海皓元生物医药科技有限公司 阿塞那平中间体的制备方法
EP2582704A4 (en) 2010-06-18 2014-04-02 Reddys Lab Ltd Dr Asenapine MALEATE
CA2805542C (en) 2010-07-29 2017-12-12 Laboratorios Lesvi, S.L. Novel process for the preparation of asenapine
JP2013540748A (ja) 2010-09-16 2013-11-07 コーネル ユニバーシティー 血液脳関門の透過性を調節するためのアデノシン受容体シグナル伝達の使用法
WO2012038975A2 (en) 2010-09-22 2012-03-29 Msn Laboratories Limited Process for the preparation of (3ars,12brs)-5-chloro-2-methyl-2,3,3a12b-tetrahydro-1hdibenzo[2,3:6,7] oxepino [4,5-c]pyrrole maleate and it's pharmaceutical composition thereof
WO2012040845A1 (en) 2010-09-27 2012-04-05 Alphora Research Inc. Process for the preparation of tetracyclic derivatives and intermediate products used in the process
EP2638005A4 (en) 2010-11-12 2015-04-01 Promentis Pharm Inc S-T-BUTYL-CYSTONE-PROTECTED DI-PEPTIDE ANALOGS AND ASSOCIATED COMPOUNDS
WO2012065110A2 (en) 2010-11-12 2012-05-18 Promentis Pharmaceuticals, Inc. S-protected cysteine analogs and related compounds
WO2012066565A2 (en) 2010-11-16 2012-05-24 Cadila Healthcare Limited Asenapine maleate amorphous and crystalline form and process for preparation thereof
CN103200944B (zh) 2010-11-17 2016-05-04 赫克萨尔股份公司 包含丁丙诺啡的经皮治疗系统
CN103370059A (zh) 2010-11-26 2013-10-23 约翰内斯堡威特沃特斯兰德大学 一种药物递送装置
EP2642988A1 (en) 2010-11-26 2013-10-02 Ramot at Tel-Aviv University Ltd Method and composition for weight-gain management
EP2468750A1 (en) 2010-12-13 2012-06-27 Chemo Ibérica, S.A. Polymorphic forms of asenapine maleate and processes for their preparation
WO2012088441A1 (en) 2010-12-23 2012-06-28 Alkermes, Inc. Multi- api loading prodrugs
ES2575544T3 (es) 2010-12-24 2016-06-29 Medichem, S.A. Procedimientos para la preparación de 5-cloro-2-metil-2,3,3a,12b-tetrahidro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pirrol
US9737531B2 (en) 2012-07-12 2017-08-22 Glytech, Llc Composition and method for treatment of depression and psychosis in humans
WO2012114325A1 (en) 2011-02-23 2012-08-30 Mapi Pharma Limited Polymorphs of asenapine maleate
WO2012123325A1 (en) 2011-03-11 2012-09-20 Medichem S.A. NEW CRYSTAL FORMS OF THE SALT OF TRANS-5-CHLORO-2-METHYL-2,3,3A,12b-TETRAHYDRO-1H-DIBENZO[2,3:6,7]OXEPINO[4,5-c]PYRROLE WITH MALEIC ACID
CA2833474C (en) 2011-04-18 2017-09-19 Hisamitsu Pharmaceutical Co., Inc. Method for producing patch, and patch
ITMI20110734A1 (it) 2011-05-02 2012-11-03 Olon Spa Sali cristallini di asenapina
EP2524919A1 (en) 2011-05-17 2012-11-21 Sandoz AG Novel crystalline salts of Asenapine with organic Di-acids and Tri-acids
EP2524921A1 (en) 2011-05-17 2012-11-21 Sandoz AG Novel Crystalline Salts of Asenapine
EP2524920A1 (en) 2011-05-17 2012-11-21 Sandoz AG Novel Crystalline Asenapine Hydrochloride Salt Forms
EP2709615A1 (en) 2011-05-18 2014-03-26 Laboratorios Lesvi, S.L. Monoclinic crystalline form of asenapine maleate with a specific particle size distribution
EP2709616B1 (en) 2011-05-18 2018-01-24 Laboratorios Lesvi, S.L. Synthesis of a stable micronised monoclinic form of asenapine maleate
DE102011076653A1 (de) 2011-05-27 2012-11-29 Acino Ag Transdermales therapeutisches System enthaltend Buprenorphin und eine alpha-Hydroxysäure
JP5893135B2 (ja) 2011-06-28 2016-03-23 ビボゾーン インコーポレイテッド 多重ターゲッティングの相乗効果を誘発する有効物質の組合せ及びその用途
AR086798A1 (es) 2011-06-29 2014-01-22 Otsuka Pharma Co Ltd Derivados quinazolinicos utiles para tratar trastornos del sistema nervioso central y composiciones farmaceuticas que los contienen
WO2013024492A2 (en) 2011-07-01 2013-02-21 Megafine Pharma (P) Ltd. A process for the preparation of asenapine and novel salts thereof
US9145421B2 (en) 2011-07-20 2015-09-29 Ranbaxy Laboratories Limited Process for the preparation of asenapine maleate
CA2842106A1 (en) 2011-07-28 2013-01-31 Promentis Pharmaceuticals, Inc. Cysteine prodrugs
AR082640A1 (es) * 2011-08-25 2012-12-19 Amarin Technologies S A Un dispositivo para la administracion transdermal de compuestos alcalinos susceptibles a la degradacion en su forma no salificada
WO2013035109A1 (en) 2011-09-08 2013-03-14 Mylan Laboratories Ltd Improved process for the preparation of asenapine maleate
US20150224120A1 (en) 2011-09-14 2015-08-13 Catherine Clelland Compositions and methods for treating hyperprolinemia-associated mental disorders
EP2572703A1 (en) 2011-09-21 2013-03-27 Hexal AG Compressed oral dosage form for asenapine maleate
WO2013041604A1 (en) 2011-09-21 2013-03-28 Sandoz Ag Crystal form of asenapine maleate
TWI583401B (zh) 2011-10-24 2017-05-21 布雷本製藥股份有限公司 可植入替紮尼定組合物及其治療方法
WO2013061247A1 (en) 2011-10-24 2013-05-02 Alembic Pharmaceuticals Limited Novel process for the preparation of asenapine
US20140350081A1 (en) 2011-11-04 2014-11-27 Purdue Research Foundation Insect g-coupled receptors useful as targets for insecticides and compounds and reagents identified using the same
US20140336391A1 (en) 2011-11-28 2014-11-13 Ranbaxy Laboratories Limited Process for the preparation of asenapine intermediate
US20130143867A1 (en) 2011-12-02 2013-06-06 Sychroneuron Inc. Acamprosate formulations, methods of using the same, and combinations comprising the same
WO2013114400A2 (en) 2012-01-20 2013-08-08 Rubicon Research Private Limited Compressed pharmaceutical compositions of atypical antipsychotics
CN103254201B (zh) 2012-02-21 2016-04-13 四川科伦药物研究有限公司 一种阿塞那平的制备方法
SI2825208T1 (sl) 2012-03-14 2017-10-30 Levicept Ltd. P75ntr nevrotrofin vezavni protein za terapevtsko rabo
DE102012205493A1 (de) 2012-04-03 2013-10-10 Acino Ag Einen Dopamin-Agonisten enthaltendes transdermales Applikationssystem
CA2908622A1 (en) 2012-04-18 2013-10-24 Hemoshear, Llc In vitro model for pathological or physiologic conditions
KR20130120648A (ko) 2012-04-26 2013-11-05 에스에프씨 주식회사 벤조사이클로플루오렌계 화합물 및 이를 포함하는 유기전계발광소자
US20150141274A1 (en) 2012-05-09 2015-05-21 The Rockefeller University Methods and Compositions for Activity Dependent Transcriptome Profiling
WO2013190481A1 (en) 2012-06-21 2013-12-27 Alembic Pharmaceuticals Limited Process for preparing asenapine and salts of intermediates thereof
US8986677B2 (en) 2012-07-30 2015-03-24 Pop Test Cortisol Llc Therapeutic compositions and methods
JP6538559B2 (ja) 2012-09-28 2019-07-03 デルポー，インコーポレイティド 抗精神病薬の徐放のための装置及び方法
ITMI20121810A1 (it) 2012-10-24 2014-04-25 Chemo Iberica Sa Poliformi di maleato di asenapina e processo per la loro preparazione
JOP20210047A1 (ar) 2012-10-25 2017-06-16 Otsuka Pharma Co Ltd عامل وقائي و/أو علاجي للأعراض السلوكية والنفسية المصحوبة بمرض تنكسي عصبي أو الأعراض الإندفاعية المصحوبة بمرض ذهني، يحتوي على بريكسبيرازول أو ملحه
WO2014078377A1 (en) 2012-11-14 2014-05-22 Agenebio, Inc. Methods and compositions for treating schizophrenia
US10154988B2 (en) * 2012-11-14 2018-12-18 The Johns Hopkins University Methods and compositions for treating schizophrenia
RU2663289C2 (ru) 2012-11-26 2018-08-03 Юниверсити Оф Кейптаун Производные фенотиазина и их применение против туберкулеза
JP2014105205A (ja) 2012-11-30 2014-06-09 Medical Front Co Ltd 医用貼付剤
US9597291B2 (en) 2012-12-11 2017-03-21 Alfred E. Tiefenbacher (Gmbh & Co. Kg) Orally disintegrating tablet containing asenapine
US9868707B2 (en) 2012-12-20 2018-01-16 Sanford-Burnham Medical Research Institute Small molecule agonists of neurotensin receptor 1
EP2938335B1 (en) 2012-12-28 2021-03-17 Noven Pharmaceuticals, INC. Multi-polymer compositions for transdermal drug delivery
TWI646091B (zh) 2012-12-28 2019-01-01 日商衛斯克慧特股份有限公司 鹽類及晶形
CN103893139B (zh) 2012-12-28 2018-06-08 石药集团中奇制药技术（石家庄）有限公司 一种阿塞那平组合物及其制备方法
CN103965206A (zh) 2013-01-29 2014-08-06 北京京卫燕康药物研究所有限公司 一种阿色纳品马来酸盐的新晶型及制备方法
WO2014121332A1 (en) 2013-02-06 2014-08-14 Sillender Mark Therapeutic substance transfer catheter and method
WO2014127786A1 (en) 2013-02-22 2014-08-28 Zentiva, K.S. Orally disintegrating pharmaceutical composition comprising asenapine
WO2014165136A1 (en) 2013-03-12 2014-10-09 Antares Pharma, Inc. Constant volume prefilled syringes and kits thereof
US20140276479A1 (en) * 2013-03-14 2014-09-18 Noven Pharmaceuticals, Inc. Transdermal drug delivery system with overlay
WO2014160155A2 (en) 2013-03-14 2014-10-02 Endo Pharmaceuticals Solutions Inc. Implantable drug delivery compositions comprising non-polymeric sorption enhancers and methods of treatment thereof
WO2014160026A2 (en) 2013-03-14 2014-10-02 Endo Pharmaceuticals Solutions Inc. Implantable drug delivery compositions comprising sugar-based sorption enhancers and methods of treatment thereof
US20140271923A1 (en) 2013-03-14 2014-09-18 Christopher Brian Reid Compositions & formulations for preventing and treating chronic diseases that cluster in patients such as cardiovascular disease, diabetes, obesity, polycystic ovary syndrome, hyperlipidemia and hypertension, as well as for preventing and treating other diseases and conditions
WO2014160167A1 (en) 2013-03-14 2014-10-02 Endo Pharmaceuticals Solutions Inc. Implantable drug delivery compositions comprising aromatic polyurethanes and methods of treatment thereof
WO2014152965A2 (en) 2013-03-14 2014-09-25 The Children's Hospital Of Philadelphia Schizophrenia-associated genetic loci identified in genome wide association studies and use thereof as novel therapeutic targets
JP2016512890A (ja) 2013-03-15 2016-05-09 アメリトックス，エルティーディー． 測定された薬物濃度を正規化する方法、及び薬物治療計画の不遵守の可能性を試験する方法
TW201444552A (zh) 2013-03-15 2014-12-01 Chien-Hung Chen 一種包含ａｍｐｋ激活劑及血清素活性製劑之醫藥組合物及其用途
AR095259A1 (es) 2013-03-15 2015-09-30 Noven Pharma Composiciones y métodos para la administración transdérmica de fármacos de amina terciaria
US20140274764A1 (en) 2013-03-15 2014-09-18 Pathway Genomics Corporation Method and system to predict response to treatments for mental disorders
WO2014152454A1 (en) * 2013-03-15 2014-09-25 Nal Pharmaceuticals, Ltd. Transdermal drug delivery system containing rivastigmine
JP6129632B2 (ja) 2013-04-24 2017-05-17 帝國製薬株式会社 貼付剤
HUE031662T2 (en) * 2013-06-04 2017-07-28 Lts Lohmann Therapie Systeme Ag Transdermal drug delivery system
JP2016520653A (ja) 2013-06-05 2016-07-14 シンクロニューロン インコーポレイテッド アカンプロサート製剤、それを用いる方法、およびそれを含む合剤
WO2014207664A2 (en) 2013-06-28 2014-12-31 Alembic Pharmaceuticals Limited Stable pharmaceutical composition of asenapine
WO2015027342A1 (en) 2013-08-30 2015-03-05 Mcmaster University Microgel compositions for delivery of substances to the brain
CN104447770A (zh) 2013-09-12 2015-03-25 天津市汉康医药生物技术有限公司 阿塞那平化合物
CN104447771A (zh) 2013-09-12 2015-03-25 天津市汉康医药生物技术有限公司 一种稳定的马来酸阿塞那平化合物
US10098893B2 (en) 2013-10-03 2018-10-16 Northwestern University Methods of administering a trace amine-associated receptor 1 (TAAR1) agonist to patients having the minor allele of the single nucleotide polymorphism rs2237457
US9757330B2 (en) 2013-10-18 2017-09-12 Industrial Technology Research Institute Recipe for in-situ gel, and implant, drug delivery system formed thereby
IN2013MU03596A (ja) 2013-11-18 2015-07-24 Piramal Entpr Ltd
WO2015085004A1 (en) 2013-12-03 2015-06-11 Intra-Cellular Therapies, Inc. Novel methods
US20160303102A1 (en) 2013-12-05 2016-10-20 Alrise Biosystems Gmbh Process for the production of drug formulations for oral administration
JP6360494B2 (ja) * 2013-12-12 2018-07-18 久光製薬株式会社 積層型貼付剤
CN103772401A (zh) 2014-01-07 2014-05-07 万特制药(海南)有限公司 11-氯-2,3,3a,12b-四氢-2-甲基-1H-二苯并[2,3:6,7]氧杂卓并[4,5-c]吡咯-1-酮的一种新精制方法
CN103772402A (zh) 2014-01-07 2014-05-07 万特制药(海南)有限公司 一种新的阿塞那平马来酸盐粗品精制方法
CN103772400A (zh) 2014-01-07 2014-05-07 万特制药(海南)有限公司 反式-5-氯-2,3,3a,12b-四氢-1H-二苯并[2,3:6,7]氧杂卓并[4,5-c]吡咯的制备方法
CN103760280A (zh) 2014-01-10 2014-04-30 万特制药(海南)有限公司 一种用液相色谱法分离测定阿塞那平中间体有关物质的方法
NZ723107A (en) 2014-02-07 2022-11-25 Neurocrine Biosciences Inc Pharmaceutical compositions comprising an antipsychotic drug and a vmat2 inhibitor and uses thereof
WO2015125152A2 (en) 2014-02-18 2015-08-27 Hetero Research Foundation Pharmaceutical compositions of asenapine
US20170189443A1 (en) 2014-02-24 2017-07-06 C. Lowell Parsons Compositions and methods for treatment of diseases and conditions employing oral administration of sodium pentosan polysulfate and other pentosan polysulfate salts
WO2015127556A1 (en) 2014-02-28 2015-09-03 UNIVERSITé LAVAL Methods and uses for inducing or facilitating defecation in a patient in need thereof
WO2015127557A1 (en) 2014-02-28 2015-09-03 Centre For Addiction And Mental Health Compositions and methods for the treatment and prevention of antipsychotic medication-induced weight gain
WO2015127558A1 (en) 2014-02-28 2015-09-03 UNIVERSITé LAVAL Methods and uses for inducing or facilitating micturition in a patient in need thereof
CN103864802B (zh) 2014-03-31 2016-08-17 四川科伦药业股份有限公司 马来酸阿塞那平的制备方法
CN104974167B (zh) 2014-04-02 2019-01-04 洋浦慧谷医药有限公司 阿塞那平的制备方法以及用于制备阿塞那平的中间体
CN104974168B (zh) 2014-04-02 2019-01-04 洋浦慧谷医药有限公司 阿塞那平的制备方法以及用于制备阿塞那平的中间体
CN106456638A (zh) 2014-04-04 2017-02-22 细胞内治疗公司 有机化合物
PL3125893T3 (pl) 2014-04-04 2024-02-12 Intra-Cellular Therapies, Inc. Deuterowane gamma-karboliny w fuzji z heterocyklami jako antagoniści receptorów 5-HT2A
CN104000800A (zh) 2014-04-28 2014-08-27 万特制药(海南)有限公司 马来酸阿塞那平口腔速溶膜剂及其制备方法
EP3145503A1 (en) 2014-05-20 2017-03-29 LTS Lohmann Therapie-Systeme AG Method for adjusting the release of active agent in a transdermal delivery system
US11752110B2 (en) 2014-05-20 2023-09-12 Lts Lohmann Therapie-Systeme Ag Transdermal delivery system including an interface mediator
EP3151906B1 (en) 2014-06-03 2019-12-11 Pop Test Abuse Deterrent Technology LLC Drug device configured for wireless communication
WO2015191554A1 (en) 2014-06-09 2015-12-17 Intra-Cellular Therapies, Inc. Compounds and methods of use to treat schizophrenia
CN104133010B (zh) 2014-07-01 2019-11-29 北京万全德众医药生物技术有限公司 高效液相色谱法分离分析阿西马朵林中间体及光学异构体
CN104133012B (zh) 2014-07-02 2020-01-07 北京万全德众医药生物技术有限公司 一种高效液相色谱法测定马来酸阿塞那平消旋体的方法
ES2784756T3 (es) * 2014-07-18 2020-09-30 Buzzz Pharmaceuticals Ltd Parche transdérmico opioide/antagonista de opioides disuasivo del abuso
CN104098580B (zh) 2014-07-22 2016-04-13 成都百裕科技制药有限公司 一种阿塞那平关键中间体的制备方法
AU2015296807A1 (en) 2014-07-31 2017-03-09 Noven Pharmaceuticals, Inc. Silicone-containing acrylic polymers for transdermal drug delivery compositions
ES2562684B1 (es) 2014-08-04 2017-02-06 Consejo Superior De Investigaciones Científicas (Csic) Método de monitorización de tratamiento antipsicótico
EP3193837A1 (en) 2014-08-14 2017-07-26 Alrise Biosystems GmbH Injectable formulations of asenapine
JP2016056142A (ja) 2014-09-11 2016-04-21 第一三共株式会社 Ｐｄｅ１０ａ阻害薬と抗精神病薬の組み合わせ
CN104297366A (zh) 2014-09-24 2015-01-21 万特制药(海南)有限公司 马来酸阿塞那平及其杂质的液相分析方法
PT3206678T (pt) 2014-10-14 2020-03-23 Sculpt B V Escultura corporal
TW201615221A (zh) 2014-10-24 2016-05-01 朗齊生物醫學股份有限公司 炎症用藥臨床新應用
EP3020782B1 (en) 2014-11-11 2018-08-01 SFC Co., Ltd. An electroluminescent compound and an electroluminescent device comprising the same
CA2965157A1 (en) 2014-11-25 2016-06-02 Nanocopoeia, Llc Method of converting a crystalline compound to an amorphous compound, method of increasing the solubility of a crystalline compound in a biorelevant fluid, and nanoparticles that achieve supersaturation
WO2016089737A1 (en) 2014-12-01 2016-06-09 The Feinstein Institute For Medical Research Use of striatal connectivity patterns for evaluating antipsychotic agents
WO2016090228A1 (en) 2014-12-05 2016-06-09 Myriad Genetics, Inc. Biomarkers for distinguishing mood disorders
EP3031458A1 (en) 2014-12-09 2016-06-15 Iproteos S.L. Use of 1-[(2-phenylcycloprop-1-yl)carbonyl]-2-[(1,3-thiazolidin-3-yl)carbonyl]perhydroindole in the treatment of schizophrenia-associated cognitive deficits
US9656441B2 (en) * 2015-01-08 2017-05-23 Alfred E. Tiefenbacher ( Gmbh & Co. Kg) Transdermal patch
WO2016114655A1 (en) 2015-01-12 2016-07-21 Ry Pharma B.V. Treating neuromuscular or neurologic disease through reducing gabaergic and/or glycinergic inhibitory neurotransmitter overstimulation
US20180028464A1 (en) 2015-01-30 2018-02-01 Toyo Ink Sc Holdings Co., Ltd. Adhesive patch
CA3204599A1 (en) 2015-02-25 2016-09-01 The Regents Of The University Of California 5ht agonists for treating disorders
KR20160107610A (ko) 2015-03-04 2016-09-19 한국과학기술원 대사 질환의 예방 또는 치료용 조성물
ITUB20150635A1 (it) 2015-04-14 2016-10-14 Giuseppe Lotito Uso di un inibitore dell’aceticolinesterasi e composizioni farmaceutiche contenenti detto inibitore.
WO2016170102A1 (en) 2015-04-22 2016-10-27 Cemm - Forschungszentrum Für Molekulare Medizin Gmbh Combination of an antiandrogen with a vitamin k antagonist or with a gamma -glutamyl carboxylase inhibitor for the therapy of androgen receptor positive cancer
US20190055603A1 (en) 2015-04-28 2019-02-21 Proove Biosciences, Inc. System and method for processing genotype information relating to drug metabolism
ES2598248B1 (es) 2015-06-26 2017-12-18 Centro De Investigación Biomédica En Red Método in vitro y kit para el pronóstico o predicción de la respuesta al tratamiento con agentes antipsicóticos por parte de pacientes que han sufrido un primer episodio psicótico
CN107847487B (zh) * 2015-07-27 2021-11-02 久光制药株式会社 含有阿塞那平的贴剂
KR102005201B1 (ko) * 2015-07-27 2019-07-29 히사미쓰 세이야꾸 가부시키가이샤 아세나핀 함유 첩부제의 제조 방법
CN105566336A (zh) 2016-01-08 2016-05-11 万特制药(海南)有限公司 一种制备阿塞那平去甲基杂质的新方法
CN105693735A (zh) 2016-01-15 2016-06-22 万特制药(海南)有限公司 马来酸阿塞那平一种制备方法
JP6556873B2 (ja) 2016-01-28 2019-08-07 久光製薬株式会社 経皮吸収製剤
JP6658201B2 (ja) 2016-03-28 2020-03-04 東洋インキＳｃホールディングス株式会社 貼付剤
KR20160108258A (ko) 2016-06-20 2016-09-19 한국과학기술원 대사 질환의 예방 또는 치료용 조성물
AU2017302305A1 (en) 2016-07-27 2019-02-14 Corium, LLC. Transdermal delivery systems with pharmacokinetics bioequivalent to oral delivery
US20180193283A1 (en) 2016-12-20 2018-07-12 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5656286A (en) * 1988-03-04 1997-08-12 Noven Pharmaceuticals, Inc. Solubility parameter based drug delivery system and method for altering drug saturation concentration
US20150202183A1 (en) * 2012-07-26 2015-07-23 Hisamitsu Pharmaceutical Co., Inc. Patch
WO2016140087A1 (ja) * 2015-03-02 2016-09-09 久光製薬株式会社 貼付剤

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10898449B2 (en) 2016-12-20 2021-01-26 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US10980753B2 (en) 2016-12-20 2021-04-20 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US11337932B2 (en) 2016-12-20 2022-05-24 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene
US11033512B2 (en) 2017-06-26 2021-06-15 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer
US11648213B2 (en) 2018-06-20 2023-05-16 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
JPWO2020071205A1 (ja) * 2018-10-01 2021-09-02 久光製薬株式会社 アセナピン含有貼付剤
CN112789039A (zh) * 2018-10-01 2021-05-11 久光制药株式会社 含有阿塞那平的贴剂
CN113226308A (zh) * 2018-10-01 2021-08-06 久光制药株式会社 含有阿塞那平的贴剂
WO2020071207A1 (ja) * 2018-10-01 2020-04-09 久光製薬株式会社 アセナピン含有貼付剤
JPWO2020071207A1 (ja) * 2018-10-01 2021-09-02 久光製薬株式会社 アセナピン含有貼付剤
KR20210049147A (ko) * 2018-10-01 2021-05-04 히사미쯔 제약 주식회사 아세나핀 함유 첩부제
JP7152499B2 (ja) 2018-10-01 2022-10-12 久光製薬株式会社 アセナピン含有貼付剤
JP7152500B2 (ja) 2018-10-01 2022-10-12 久光製薬株式会社 アセナピン含有貼付剤
US11590106B2 (en) 2018-10-01 2023-02-28 Hisamitsu Pharmaceutical Co., Inc. Asenapine-containing adhesive patch
WO2020071205A1 (ja) * 2018-10-01 2020-04-09 久光製薬株式会社 アセナピン含有貼付剤
KR102593864B1 (ko) * 2018-10-01 2023-10-24 히사미쯔 제약 주식회사 아세나핀 함유 첩부제
US11850311B2 (en) 2018-10-01 2023-12-26 Hisamitsu Pharmaceutical Co., Inc. Asenapine-containing adhesive patch
US20230034383A1 (en) * 2021-07-21 2023-02-02 Hisamitsu Pharmaceutical Co., Inc. Method for reducing skin sensitization of an asenapine-containing patch

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