TRANSDERMAL COMPOSITIONS OF ASENAPINE FOR THE TREATMENT OF PSYCHIATRIC DISORDERS

Field of the invention The present invention relates to the use of asenapine in pharmaceutical compositions for application to the skin.

Background of the invention

Asenapine is a psychopharmacologic agent for the treatment of schizophrenia and bipolar disorder. In vitro asenapine has high affinity for serotonin receptors, dopamine, alpha-adrenergic and histamine receptors, but in contrast to e.g. olanzapine and clozapine, asenapine shows minimal affinity for muscarinic receptors. Thus, asenapine incurs minimal risk of anticholinergic side effects. Asenapine has been subject of a phase III clinical trial and proved to be an efficacious and well-tolerated drug in the treatment of patients with acute exacerbation of schizophrenia.

Asenapine compositions have been developed for oral, sublingual or buccal administration (see e.g. US 5,763,476) and intranasal administration (see WO 2008/148515). The bioavailability after oral administration is very low (< 1%). The sublingual or buccal compositions, as well as the intranasal compositions which contain asenapine maleate in an aqueous carrier having pH of 5, are developed with the aim of avoiding first-pass metabolism in the liver.

However, there is still a need for developing compositions for alternative administration routes to avoid first-pass metabolism, to improve bioavailability, to decrease the frequency of administration, decrease variability in exposure, reduce side effects, such as tongue numbness, nausea, headache associated with buccal or sublingual dosage forms, reduce bitter or unpleasant taste, and/or to improve patient compliance.

The inventors of present invention have surprisingly found that topical compositions of asenapine, as described herein, result in an unexpectedly fast absorption via the transdermal route, a route, which due to the keratinized nature of the skin, is not conducive to fast rates of absorption when a passive transdermal delivery system is utilized. When administered through the transdermal route to pigs, the asenapine plasma levels increase rapidly (fast rate of absorption). Such unexpectedly fast absorption is commonly observed with sublingual or oral routes of delivery rather than passive transdermal route of delivery.

Description of the invention The present invention is based on the idea of administering asenapine to the systemic circulation via the skin, i.e. by transdermal absorption. Thus, the present invention relates to pharmaceutical asenapine-containing compositions for administration to the systemic circulation via the skin of a human. It is contemplated that this administration route will offer advantages over known asenapine regimens by improving one or more of i) bioavailability (compared with oral administration), ii) patient compliance (e.g. by eliminating bitter or unpleasant taste associated with buccal or sublingual dosage forms, reducing administration frequency and/or by facilitating easy and discreet administration), iii) reduce side effects such as headache, tongue numbness, nausea.

The invention also relates to a method for treating a subject suffering from a disorder that is susceptible to asenapine by administering to the skin an effective amount of asenapine. Such disorders include mental disorders such as tension, excitation, anxiety, psychosis, schizophrenia and bipolar disorders. The subject may also suffer from such a disorder and being overweight or having a predisposition for overweight.

As disclosed herein, the present invention provides means for administering asenapine transdermal^ in the form of a spray, an aerosol, a patch, a film, a gel, a creme, an ointment, a lotion, or a foam.

Both in vivo and in vitro transdermal studies performed by the Applicant show that asenapine, when administered according to present invention can be efficiently absorbed transdermally. Hence , the present invention provides an alternative mode for delivering asenapine that avoids the draw backs that are associated with the sublingual delivery of asenapine.

As presented herein, in vitro studies show that asenapine, when formulated according to the present invention, efficiently permeate the skin at levels and rates that would lend themselves to achieve fast absorption in-vivo that could translate into profiles that are comparable to oral and sublingual administration. When tested in vivo in pigs, it is further disclosed herein, that the compositions of the present invention provide a maximum plasma level after transdermal administration after only 10 to 20 minutes. This is directly comparable to the time for obtaining maximum plasma-levels with sublingual administration of Asenapine and is significantly shorter that the time expected with passive transermal delivery.

The fast absorption time, the potential to provide an extended release profile by the incorporation of film-forming materials, and the compositionsignificantly improved patient compliance illustrate that the present invention provides novel and inventive methods for administering asenapine systemically to a subject through the transdermal route.

Asenapine

Asenapine has the following chemical structure:

The chemical name is trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1 H- dibenz[2,3:6,7]oxepino-[4,5-c]pyrrole. It has two optically active centers leading to four isomers: (3afi, 12bR)-5-Chloro-2,3,3a, 12b-tetrahydro-

2-methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole (the active drug in treatment of schizophrenia and bipolar conditions). Consequently there are three other isomers:

Enantiomer: (3aS,12bS)-5-Chloro-2,3,3a,12b-tetrahydro-

2-methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole

Mesoforms:

(3aS,12bR)-5-Chloro-2,3,3a,12b-tetrahydro- 2-methyl-1 H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole (3aR, 12bS)-5-Chloro-2,3,3a, 12b-tetrahydro- 2-methyl-1/-/-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole Moreover, asenapine is a weak base, the pK _A value being reported to be in the range of 7.5 to 8.6. It forms salts with inorganic or organic acids. Often asenapine is employed in the form of a maleate salt, which may be in amorphous or various crystalline forms (see e.g. EP-B-1 710 245 to N.V. Organon).

In the present context, the term "asenapine" means asenapine in any form including any of its enantiomers or mesoforms, any mixture thereof including asenapine in racemic form, any asenapine salt, asenapine (or any of its enantiomers, or mixtures thereof of asenapine or salts of asenapine) in any crystal form, amorphous or polymorphous form, in any solvate form including hydrates of asenapine.

Pharmaceutically acceptable salts of asenapine include salts with hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, sulfamic acid, citric acid, lactic acid, maleic acid, malic acid, succinic acid, tartaric acid, cinnamic acid, acetic acid benzoic acid, gluconic acid, ascorbic acid etc.

In a particular aspect of the invention, asenapine is present in a concentration of 15- 30%w/w but may vary from 1-50% as exemplified herein.

In a preferred aspect asenapine is present in the composition as free base, notably at least 25% such as at least 50%, at least 75% or 80% or more is present as free asenapine. It is generally known that un-ionized substances has improved penetration and permeation through the skin and, accordingly, it is believed that the presence of free asenapine in the compositions facilitates entry into the systemic circulation after administration to the skin.

In the present context, the term "penetration" is intended to denote passage through the skin. Accordingly, the term covers permeation of asenapine into the various skin layer and through the layers into the systemic circulation.

In the present context, the term "permeation" is intended to denote permeation into one or more skin layer. In the present context, the term permeation enhancer or penetration enhancer is intended to denote an agent that enhances the penetration rate of drugs through the skin e.g. by temporarily diminishing the impermeability of the skin.

In the present context, the term "percutaneous absorption" or "transdermal absorption" is intended to mean absorption through the skin into the systemic circulation. Thus, when a drug substance is applied to the skin (e.g. in the form of a suitable pharmaceutical composition), the drug substance permeate into the various skin layers (stratum corneum, epidermis, and dermis) and penetrate through these layers into the blood. Transdermal absorption normally involves i) dissolution or solubilization of the drug substance in a suitable vehicle, ii) diffusion of the drug substance from the vehicle to the surface of the skin and iii) partitioning and penetration of the drug substance through the layers of the skin. The important factors influencing the penetration of a drug substance into the skin are: i) concentration of dissolved drug which affects the activity gradient and thereby penetration rate; ii) partition coefficient between the skin and the vehicle, which is a measure of the relative affinity of the drug substance for skin and vehicle; and iii) diffusion coefficients, which represent the resistance of the drug substance molecule movement through vehicle and skin barriers. iiii) the inclusion of penetration enhancers, which help the pharmaceutical ingredient to penetrate the skin..

As seen from the above, the concentration of asenapine may be a decisive factor in the penetration rate through the skin. Accordingly, asenapine may be present in the vehicle in as high a concentration as possible such as about 40%, 50%, 60%, 70%, 80% or more, 85% or more, 90%, or more, 95% or more or close to 100% of its saturation concentration.

In the present context, the term "vehicle" is used to denote the constitution of the composition without the content of asenapine or any other drug substance.

Compositions for administration to the skin

More specifically, the present invention provides a pharmaceutical composition for application to the skin, the composition comprises asenapine or a pharmaceutically acceptable salt thereof and at least one of i) one or more pharmaceutically acceptable adhesive agents, ii) one or more film-forming agents, ii) one or more dermally acceptable excipients.

In aspect of the invention, the composition above comprises both i) one or more film- forming agents, and ii) one or more dermally acceptable excipients.

As discussed herein, asenapine may be in base form and in some aspects of the invention at least 25% such as 50%, 75% or 100% of said asenapine is present in its free base form.

The total concentration of asenapine or a pharmaceutically acceptable salt thereof may be at least 40%, such as 80%, 85%, 90%, 95% or close to 100% of its saturation concentration in the composition.

A composition of the invention may also comprise one or more dermally acceptable excipients, such as e.g. ethanol or isopropyl alcohol (IPA) and optionally a cosolvent, such as e.g. water, ethanol, isopropyl alcohol, propylene glycol, polyethylene glycol, glycerin, acetone, cyclomethicone, benzyl alcohol, propylene carbonate, dimethyl sulfoxide, isopropyl myristate and oleic acid. The present invention also relates to compositions comprising a penetration enhancer such as e.g. lipophilic solvents e.g. dimethyl sulfoxide, dimethyl formamide, isopropyl myristate, a surfactant e.g. Tweens or sodium lauryl sulfate; menthol, oleic acid, octyl dimethyl para-amino benzoic acid, mixed esters of capric and caprylic acid; or a polyhydric alcohol such as propylene glycol or diethylene glycol monoethyl ether (Transcutol®) or combinations thereof

Additionally a composition according to present invention may comprise a pharmaceutically acceptable adhesive agent such as e.g. fatty acid esters, pressure- sensitive adhesives including acrylic-based and silicone-based adhesives and combinations thereof.

To deposit an amount of the pharmaceutical substance after administration a composition according to present invention may comprise one or more film-forming agents such as e.g. acrylic polymers or copolymers including methacrylic polymers or copolymers, povidone (PVP), povidone vinyl acetate, polyvinyl acetate, polyvinyl alcohol, cellulose acetate, hydroxypropyl methyl cellulose (HPMC), hydroxyethyl cellulose, methyl cellulose, ethyl cellulose and combinations thereof. The acrylic polymers or copolymers include non-ionic copolymers of methyl methacrylate and butyl methacrylate, copolymer of dimethylamine ethyl methacrylate and a neutral methacrylic acid ester, amino methacrylate copolymer type B, ammonio methacrylate copolymer type A, methacrylic acid copolymer type A, methacrylic acid copolymer type B and other Eudragit® polymers and combinations thereof.

As disclosed herein, the dermally acceptable excipient in a composition according to present invention may be, in addition to conventional excipients, be selected from solubilizers, permeation enhancers, plasticizers, propellants, humectants, suspending agents, emulsifying agents, surfactants, viscosity-adjusting agents, pH-regulating agents, solvents, preservatives, oils, waxes, glycerides including mono-, di- and triglycerides.

In a preferred aspect, the invention relates to a composition wherein the asenapine is administered in a spray that contains asenapine in a concentration of from 10 to 30% w/w, a volatile solvent in a concentration of from 10 to 40% w/w, a co-solvent in a concentration of from 0.1 to 30% w/w, a solubilizer in a concentration of from 0.1 to 10% w/w, optionally a skin penetration enhancer in a concentration of from 0.5 to 10% w/w, optionally an occlusive or non-occlusive film-formining agent in a concentration of from 0.1 to 10% w/w, and optionally a propellant in a concentration of from 15 to 95% w/w provided that the sum of concentrations does not exceed 100% w/w.

The formulations of present invention may be administered once or twice daily to the skin of a subject for the treatment of psychiatric disorders and may be intended for absorption into the systematic circulation via the skin.

In a further aspect of the invention, present invention relates to asenapine or a pharmaceutically acceptable salt thereof for administration once or twice daily to the skin of a subject for the treatment of psychiatric disorders. This may be obtained by absorption into the systemic circulation via the skin and by one or more of the methods disclosed herein. Hence an aspect of present invention also relates to a method for treating a subject suffering from psychiatric disorders, the method comprising administering once or twice daily to the skin of the subject asenapine or a pharmaceutically acceptable salt thereof. This may be performed by using one or more of the formulations as presented herein.

Regardless of composition type, stabilizers may be added to increase the chemical stability of asenapine and/or the physical stability of the composition.

After application to the skin, the composition may be occlusive or non-occlusive.

Sprays and aerosols

In spray and aerosol compositions, asenapine is delivered to the skin in a dosed amount through a nozzle or orifice. The composition may be delivered through a pump spray, a pressurized spray or as an aerosol. Moreover, it is easy to apply and by means of one or more film-forming agents it is possible to ensure the adherence of the composition to the skin for a certain period of time thereby providing a sustained release of the drug. Moreover, after application on the skin the composition is transparent, i.e. it leaves no major sign and, thus, it can be applied anywhere on the skin after the choice of the subject to be treated. A spray or aerosol composition may or may not contain a film-forming agent as Eudragit® or the like. Normally, they contain a suitable amount of one or more propellants in an organic solvent. In order to apply a spray or an aerosol to the skin, the composition normally contains one or more volatile solvents that evaporate upon application to the skin.

A "film-forming agent" is an agent, preferably a polymer that forms a film on a surface, when applied. The film is preferably stable, i.e. it is resistant to removal for a period of time by which the composition is intended to deliver the drug to the skin. Suitable film- forming agents include acrylic polymers or copolymers including methacrylic polymers or copolymers, povidone (PVP), povidone vinyl acetate, polyvinyl acetate, polyvinyl alcohol, cellulose acetate, hydroxyalkylcellulose including hydroxypropyl methyl cellulose (HPMC), hydroxyethyl cellulose, methyl cellulose, ethyl cellulose other cellulose based polymers and cellulose based co-polymers and combinations thereof.

The acrylic polymers or copolymers include non-ionic copolymers of methyl methacrylate and butyl methacrylate, copolymer of dimethylamine ethyl methacrylate and a neutral methacrylic acid ester, amino methacrylate copolymer type B, ammonio methacrylate copolymer type A, methacrylic acid copolymer type A, methacrylic acid copolymer type B and other Eudragit® polymers and combinations thereof.

Other dermally acceptable excipients for use in sprays and aerosols include:

"Plasticizer" refers to an agent that aids a composition in forming a flexible, adherent film on the skin. Plasticizers include triethyl citrate, citric acid, citric acid esters, oleic acid, fatty acid esters, glycol derivatives, hydrocarbons and derivatives thereof, adipic acid/butanediol polyesters, epoxides, soya oils, diethyl phthalate, dibutyl phthalate, dimethyl isosorbide, acetyltributyl citrate, castor oil, mineral oil, polybutene oil, glycerol, propylene glycol, polyethylene glycol (PEG), triacetin, chlorinated paraffins and combinations thereof. Some film-forming agents may have sufficient plasticizing properties. Others are suitably used in combination with one or more of the plasticizers mentioned above. Notably, Eudragit® polymers in combination with a PEG are suitable.

Skin penetration enhancing agents include lipophilic solvents e.g. dimethyl sulfoxide, dimethyl formamide, isopropyl myristate, a surfactant e.g. Tweens or sodium lauryl sulfate; menthol, oleic acid, octyl dimethyl para-amino benzoic acid, mixed esters of capric and caprylic acid; or a polyhydric alcohol such as propylene glycol or diethylene glycol monoethyl ether (Transcutol®) or combinations thereof.

Propellants that provide a suitable pressure within an aerosol dispenser include hydrocarbons such as propane, butane, isobutene, or dimethylether; hydrofluorocarbons (e.g. hydrofluoroalkanes) and hydrochloroflurocarbons (e.g. hydrochlorofluroalkanes) such as dichlorodifluoromethane, trichloromonofluromethane, dichlorofluroethan, monochlorodifluromethane, dichlorotetrafluoroethane, difluroethane, tetrafluorethane, heptafluropropane or combinations thereof; or compressed gases such as nitrogen or carbon dioxide or combinations thereof. Such propellants may also be used in spray systems.

Solvents and cosolvents including water, ethanol, isopropyl alcohol, propylene glycol, polyethylene glycol, glycerin, acetone, cyclomethicone, benzyl alcohol, propylene carbonate, dimethyl sulfoxide, isopropyl myristate and oleic acid. Solubilizers may also be included. Suitable examples include acrylate and methacrylate esters and copolymers, surfactants, polyhydric alcohols, vitamin E, vitamin E TPGS, polyethylene glycol, dipropylene glycol and labrasol. Further, solubilizers or penetration enhancers may include Propylene glycol; Polyethylene glycol; 1 ,2-butanediol; 1 ,3-butanediol; 2,3-butanediol; 1 ,4-butanediol; 2-ethoxyethanol (ethylene glycol mmonoethyl ether); 2,2-oxy-bis-ethanol (diethylene glycol); C3-C6 triols; Oleyl alcohol; lsocetyl alcohol; Glycerol; Ethanol; 2-propanol; Azone (1- dodecylazacycloheptan-2-one); Glycerol monoacetate; n-octyl, decyl, dodecyl and tetradecyl alcohols; methyl and ethyl esters of n-octanoic, decanoic, docecanoic, tetradecanoic and hexadecanoic acid; acetates of n-octanol, decanol, dodecanol, tetradecanol and hexadecanol, such as lauryl acetate and myristyl acetate methyl, ethyl, N,N-dimethyl, diethyl and methyl ethyl amides of n-octanoic, decanoic, dodecanoic, tetradecanoic and hexadecanoic acids; the decenyl, dodecenyl, tetradecenyl, hexadecenyl, octadecenyl, eicosaenyl and docosaenyl alcohols in which the double bond has the cis-configuration; cis-myristoleic, palmitoleic, oleic, linoleic, linolenic, arachidonic and erucic acids; tetradecenyl methyl sulfoxide, hexadecenyl methyl sulfoxide, octadecenyl methyl sulfoxide, eicosenyl methyl sulfoxide and docesenyl methyl sulfoxide; methyl cis-myristoleate, - palmitoleate, -oleate, -linoleate, - linolenate, -arachidonate, and -erucate; oleic isopropyl amide, dimethyl glycol oleate; polyethylene glycol 200 monolinoleate; dioxyethylene isostearyl ether; dioxyethylene oleyl ether; sorbitan monoleate; sorbitan monoisostearate; ethyl isostearate; mystoleyl palmitoleyl, oleyl, linoleyl, linolenyl, arachidonyl and erucyl dimethyl phosphine oxides; isohexadecyl dimethyl phosphine oxide; isooctadecyl dimethyl phosphine oxide; isoeicosenyl dimethyl phosphine oxide; isodocosyl dimethyl phosphine oxide; isohexadecyl monoethanolamide; isooctadenyl monoethanolamide; isoeicosyl monoethanolamide; isodocosyl monoethanolamide; propylene glycol monoisopalmitate; propylene glycol monoisostearate; propylene glycol monoisoarchidate; propylene glycol monoisobehenate; glycerol monoisopalmitate; glycerol monoisostearate; glycerol monooesoarach; glycerol monoisobehenate; phytol, bactoprenol, geraniol, isophytol and farnesol

pH regulating agents including buffers such as acetate, citrate, phosphate, borate, carbonate etc, sodium hydroxide, hydrochloric acid etc. Anti-nucleating agents may be included as well. Suitable anti-nucleating agents are well-known in the art, and may include PVA when PVP is used as the film-forming agent, as well as when methyl cellulose or ethyl cellulose is used as film-forming agent.

Specific concentration ranges for the individual excipients appear from, but are not limited to the examples herein. Further to what is disclosed in the examples herein, the compositions disclosed herein may contain penetration enhancers such as lipophilic solvents e.g. dimethyl sulfoxide, dimethyl formamide, isopropyl myristate, a surfactant e.g. Tween or sodium lauryl sulfate; menthol, oleic acid, octyl dimethyl para-amino benzoic acid, mixed esters of capric and caprylic acid; or a polyhydric alcohol such as propylene glycol or diethylene glycol monoethyl ether (Transcutol®) or combinations thereof may be present in rages from 1-15%w/w, solubilizers such as PEG 400 in ranges from 2-85%.

Solvents or cosolvents such as water, ethanol, isopropyl alcohol, propylene glycol, polyethylene glycol, glycerin, acetone, cyclomethicone, benzyl alcohol, propylene carbonate, dimethyl sulfoxide, isopropyl myristate and oleic acid may present in ranges from 0.1-95% and propellants as hydrocarbons such as propane, butane, isobutene, or dimethylether; hydrofluorocarbons (e.g. hydrofluoroalkanes) and hydrochloroflurocarbons (e.g. hydrochlorofluroalkanes) such as dichlorodifluoromethane, trichloromonofluromethane, dichlorofluroethan, monochlorodifluromethane, dichlorotetrafluoroethane, difluroethane, tetrafluorethane, heptafluropropane or combinations thereof; or compressed gases such as nitrogen or carbon dioxide or combinations thereof may be present in ranges from 10-95%. An aspect of the invention relates to an aerosol composition comprising asenapine, a solvent, a cosolvent and optionally a penetration enhancer. Further the composition may contain agents facilitating the formation of an occlusive reservoir on the skin after administration. Examples of such occlusive agents are film-forming agents as specified above.

Sprays and aerosols may be applied on several places on the human body. Due to the physical properties of the skin, when compared to mucosal membranes, the amount of drug administered to the skin is expected to be at least the same and presumably 2-20 times higher than when administered to a mucosal membrane of a patient. Similarly, to facilitate efficient transdermal permeation, the area of application may be adjusted e.g. increased, to allow faster and larger uptake (exposure) of asenapine. Patches or plasters

Patches or plasters are intended to be applied to the skin and remain on the skin for a period of time where after it is removed and replaced with another patch or plaster. Two types of patches are known, the reservoir and matrix type. In a matrix patch, asenapine is present in an adhesive layer from which it is released e.g. by diffusion. The adhesive layer is placed on a backing layer and normally the patch also has a release liner. A person skilled in the art knows how to formulate a patch and which materials to include, see e.g. Remington's Pharmaceutical Sciences, 18 ^th Edition, 1990, Mack Publishing Company.

A patch or plaster is adhered to the skin by means of one or more adhesive agents.

Such agents include fatty acid esters, pressure-sensitive adhesives including acrylic- based and silicone-based adhesives and combinations thereof.

Adhesive agents can include viscoelastic material that adheres instantaneously to most substrates with the application of very slight pressure and remains permanently tacky. A polymer is a pressure-sensitive adhesive in the present context if it has the properties of a pressure-sensitive adhesive per se or functions as a pressure-sensitive adhesive by admixture with tackifiers, plasticizers or other additives. The term includes polyisobutylenes of different molecular weights, rubber based pressure-sensitive adhesives including hydrocarbon polymers such as natural and synthetic polyisoprene, polybutylene and polyisobutylenes, styrene/butadiene polymers, styrene-isoprene- styrene block copolymers, hydrocarbon polymers such as butyl rubber, halogen- containing polymers such as polyacrylic-nitrile, polytetrafluoroethylene, polyvinylchloride, polyvinylidene chloride, and polychlorodiene, and other copolymers thereof. Other suitable adhesives include natural or synthetic polysaccharides and polyacrylic acid polymers, and mixtures thereof.

Other dermally acceptable excipients for use in patches and plasters include: Tackifiers such as rosin derivaties, hydrogenation and/or esterification products or hydrocarbon resins. Examples include abietic acid, fatty acid esters, hydrocarbon derivaties, terpene alcohols, di- or tetrahydroabeietic acid, glycine, glycerin, pentaerythorol esters, polyterpene, or aliphatic hydrocarbon resins. Plasticizers, skin penetration enhancing agents, pH regulating agents etc. may also be included such as those mentioned earlier herein.

Films Alternatively, drug-in-matrix films may be applied via releasable support liner(s) which are removed prior to use and/or during application. Such film may be prepared by applying a composition as described herein comprising one or more film-forming agents on such a support liner.

Other types of compositions

Semi-solids, including ointments, gels, pastes, cremes, lotions and soaps. Ointments are semisolid preparations intended for external application to the skin or mucous membranes. The preferred ointment composition may vary depending on the necessary properties and its interaction with asenapine, but may be composed of a base selected from the groups comprising: hydrocarbon-, absorption-, water-soluble-, emulsion- (VWO or OΛ/V) bases.

Examples of hydrocarbon bases may be petrolatum or petrolatum modified by addition of waxes. Hydrocarbon base ointments have a high compatibility with most pharmaceuticals and because of their low water content often provide an optimum stability for the active pharmaceutical ingredients. Since hydrocarbons, due to their occlusive properties, increases skin hydration and may increase the permeation and penetration of asenepine through the skin.

Water washable and emulsion ointment types, usually referred to as creams, most often comprise several phases such as the emulsifier-, water- and the oil phase.

Emulsifiers include anionic, cationic and nonionic emulsifiers

Besides the components described in, but not limited to, the examples, the ointments may comprise humectants. These may comprise glycerin, propylene glycol or polyethylene glycol.

Preservatives may comprise different types of parabenes such as methylparaben, ethylparaben, propylparaben, benzyl alcohol, sorbic acid or quaternary ammonium compounds. In a further embodiment, ointments may comprise additional stabilizers, antioxidants, buffers or additional components such as penetration enhancers if needed to ensure optimal delivery and penetration of asenapine.

Penetration enhancers include lipophilic solvents e.g. dimethyl sulfoxide, dimethyl formamide, isopropyl myristate, a surfactant e.g. Tweens or sodium lauryl sulfate; menthol, oleic acid, octyl dimethyl para-amino benzoic acid, mixed esters of capric and caprylic acid; or a polyhydric alcohol such as propylene glycol or diethylene glycol monoethyl ether (Transcutol®) or combinations thereof.

Additional examples on ointments may be found in Remington's Pharmaceutical Sciences, 18 ^th edt. Mack Publishing Company, 1990 with referral to Chapter 87, Medicated Applications.

The invention is illustrated by the following non-limiting examples.

Example 1

Spray-On composition Compositions comprising the following ingredients will be made

Example 2 Spray-On composition

In accordance with Example 1 , the following specific composition will be made:

Example 3

Spray-On composition

Compositions comprising the following ingredients will be made

Example 4

Spray-On composition In accordance with Example 3, the following specific composition will be made:

Ingredient Amount

Asenapine (free base) 5-40 mg

Film former preferably PVP 2 mg

Solvent /Solubilizer preferably ethanol 10-20 mg

Propellant preferably HFA q.s.

Total 100mg

Example 5

Spray-On composition

Compositions comprising the following ingredients will be made

Example 6

Spray-On composition In accordance with Example 5, the following specific composition will be made:

Ingredient Amount

Asenapine (free base) 5-40 mg

Example 7

Spray-On composition In accordance with Example 5, the following specific composition will be made:

Ingredient Amount

Asenapine (free base) 5-40 mg

Film former preferably PVP 2 mg

Solvent /Solubilizer preferably ethanol 10-20 mg

Plasticizer preferably PEG 400 5 mg

Propellant preferably HFA q.s.

Total 100mg

Example 8

Aerosol composition

Compositions comprising the following ingredients will be made

Example 9 Aerosol composition

In accordance with Example 8, the following specific composition will be made:

Example 10

Pump Dispenser Composition

Example 12

Pump Dispenser Composition

Example 13 Patch

The following will be made

The ingredients are mixed, applied to a backing layer and dried.

Example 14 Patch

The following will be made

The ingredients are mixed, applied to a backing layer and dried.

Example 15

Ointment, Hydrophilic Petrolatum

Example 16 Hydrophilic ointment

Example 17

Non-film forming spray

Example 18 Gel

Example 19 Patch

Example 20 Cream

Example 21

Spray-on composition, occlusive

Example 22

Spray-on composition, non-occlusive

Example 23

Saturated solution, with penetration enhancer (TP)

Example 24

Saturated solution, without TP

Example 25, In vitro testing Preparation of epidermal membrane

Human skin from cosmetic reduction surgery (taken from an abdominoplasty) was employed for the in vitro permeation experiment. The epidermal membrane was prepared as follows: Full thickness skin previously frozen (-20 ⁰ C) was defrosted at ambient temperature until malleable. 1. The subcutaneous fat was removed mechanically by blunt dissection.

2. Once the subcutaneous fat was removed the skin was immersed in deionised water previously heated to 60 ± 3 ^C C for 45 s.

3. The epidermal membrane (comprising the Stratum corneum and epidermis) was removed from the underlying dermis using a gloved finger and the dermis discarded.

4. The epidermal membrane was floated (Stratum corneum side up) in deionised water and onto filter paper.

5. The epidermal membrane mounted on filter paper was removed from the deionised water, any excess water was removed using tissue and the epidermal membrane was either used immediately or stored at -20 ⁰ C until use.

The skin used in the investigations was from a single donor and had only been subjected to one freeze thaw cycle.

Use of the Franz cell for comparative studies of epidermal permeation of the compositions as described in examples 17-24

The epidermal membrane prepared as above was mounted between the two halves of a Franz cell with the Stratum corneum facing the donor compartment as illustrated in figure 1.

Preliminary investigation

A preliminary investigation was performed in order to establish a suitable method to accurately determine the amount of asenapine which permeates into the receptor compartment over time. The integrity of the epidermal membrane was measured prior to dosing the cells using electrical impedance, where the upper and lower donor chambers were filled with PBS (pH 7.4, comprising of approximately 136.89 mM sodium chloride, 2.68 mM potassium chloride, 8.10 mM disodium hydrogen phosphate and 1.5 mM potassium dihydrogen phosphate), solution to allow for current conductance across the membrane. Skin samples showing an impedance of <2 k ^' Ω were discarded and replaced. Once the integrity of the epidermal membrane mounted in the Franz cells had been established, the PBS solution was removed from both the donor and receiver compartments, where the latter was subsequently replaced with 10% w/w ethanol in PBS. A PTFE coated magnetic follower was also added to receiver compartment of each Franz cell. The cells were then placed into a water bath which contained a submersible magnetic stirrer plate and equilibrated at 37 ⁰ C (to maintain a skin surface temperature of 32 ± 1 ⁰ C) whilst stirring for at least 30 min prior to dosing. Six Franz cells were mounted in total for the preliminary investigation with epidermal membrane. The cells were left un-occluded for the duration of the experiment. At t=0, 200 μl_ of the receiver fluid was removed prior to dosing and analysed by HPLC (this represented the t=0 sample). The cell were then dosed, where an infinite dose

(approximately 100 mg) of the saturated active solution (Example 24) was applied to three of the cells, 100 mg of the corresponding placebo was applied to the surface of the epidermal membrane in two of the cells and the final cell, had no solution applied and represented the negative control cell. The receiver fluid was then removed (200 μl_) at each time point using a 250 μl_ Hamilton syringe. After each sample was removed, an equal volume of pre-warmed (37°C) receiver fluid was replaced.

Sample preparations for comparative studies

To provide an in vitro test of the permeability of asenapine, a small Franz cell with 0.6 cm ² surface area and a 2 ml receiver volume was mounted with a epidermal membrane with Stratum corneum facing the donor compartment. The receiver fluid was 10% ethanol in PBS, whereof 0.2ml was removed at testing. The sampling points were: 0, 1 ,

2, 3, 4, 6, 8, 24, 30 and 48 h from application of the test composition. The different compositions were applied as outlined below:

Non-film forming spray (example 17): 100 mg applied directly to surface of skin using positive displacement pipette or using a metered dose pump action spray (2 x immediate actuations directly onto the surface of the skin using a 50 pi pump)

Gel (example 18): 100 mg applied evenly, directly to surface of skin using positive displacement pipette

Patch (example 19) A disc of 0.6 cm2 was cut and placed in direct contact with skin (where 100 mg of the composition was applied to the occlusive backing and dried before applying matrix side down onto the surface of the skin)

Cream (example 20) 100 mg applied evenly, directly to surface of skin using positive displacement pipette Spray-on (non-occlusive)(example 22): 2 x immediate actuations directly onto the surface of the skin using a 50 μl actuator pump and then allowed to dry .

Spray-on (occlusive)(example 21 ): 2 x immediate actuations directly onto the surface of the skin usinga 50 μl actuator pump and then allowed to dry

The saturated solutions were tested as outlined above under 'preliminary investigation'.

During the testing, a water bath was maintained at 37 ⁰ C to ensure constant temperature of the Franz cell. The number of replicates was N=6 for each composition, n=3 for placebos of each composition and 2 blank cells (56 cells in total).

Results: Comparative studies, epidermal permeation over δhours of the compositions prepared in examples 17-24

As outlined in figure 2 and in table 1 below, the gel composition (example 18) provided the highest maximum permeation level of asenapine, followed by the occlusive spray- on composition (example 21 ) , the cream (example 20) and fourthly the non-occlusive spray-on composition (example 22).

Table 1 : Summary of lag phase, flux and maximum response from the data presented in Figure 2.

Results Comparative studies, epidermal permeation over 48hours of the compositions prepared in examples 17-24

As outlined in figure 3 and in table 2 below, the gel composition (example 18) provided the highest maximum permeation level of asenapine, followed by the cream (example 20), and the non-occlusive spray-on (example 22) and the occlusive spray-on composition (example 21).

Table 2. Summary of maximum response at 48h from the data presented in Figure 3.

Example 26, In vivo pharmacokinetic study of transdermal absorption of Asenapine on pigs

A total of 3 weanling domestic pigs (a mixture of male and female; pink with no black colouration whatsoever) weighing approximately 10 kg at the PLS Test Site. The animals were tagged for identification. On arrival at the animals were subjected to a veterinary examination which included a detailed evaluation of each animal's condition by abdominal palpation, thoracic auscultation, rectal temperature and examination of skin and body orifices. The animals were approved for entry into the experiment on the basis of satisfactory veterinary examination (performed shortly after arrival), clinical observations records, body weight profile and clinical pathology investigations. The animals were allowed to acclimatise to the accommodation before the commencement of dosing. The pigs were installed in pens compliant with Portuguese Laboratory Animal Welfare legislation with wood shavings and straw as bedding material. The animals were housed individually during the pretrial period and throughout the treatment period. The pigs had access to suitable toys and chews. The target room temperature was set between 14 ⁰ C and 22 ⁰ C with a humidity of 45%-65%. The airflow was set to a minimum of 15 air changes per hour and the light hours from 0700-1900. The pen and animal room was cleaned once daily. The animals had access to a proprietary non- medicated protein concentrate feed offered twice daily (normally 150 to 250 g). However, the pigs were denied food and water for the first 120 minutes post dosing .

The spray on composition as described in example 21 , was spray dosed transdermal^, by a single application of a 50 μl dose.

The skin of all animals was shaved and washed 2 to 3 days before commencement of initial treatment. Wash was done using 4% w/v chlorhexidine gluconate (Hibiscrub ^® ) followed by 0.9% w/v sterile sodium chloride solution (Normasol ^® ).

Each pig was anaesthetised a day before the study commenced and their body weight was recorded in the study specific lab book. The condition of each animal was recorded in the study specific lab book immediately after anaesthesia. A 15 ml aliquot of blood was withdrawn from each of the animals to obtain plasma for the analytical method. The 15 ml was be split down into 2.5 ml microcentrifuge tubes, containing dry lithium heparin and immediately immersed in an ice bath. Plasma samples were prepared by centrifugation of the blood at 4,000 x g for 15 minutes at 4 ⁰ C and after aspirating into cryovials the samples were snap frozen in liquid nitrogen and subsequently placed in a -80 ⁰ C freezer for storage.

A test area was demarked on each pig with an indelible marker pen. On the day of the study the test composition container was cleaned with an alcoholic wipe, dried and weighed. It was held vertically (actuation button at the top) at an angle of 45 ^° with dose actuation head tilted towards the floor and 5 doses were applied to a A4 piece of paper at a distance of 30 cm. The mass loss from the canister after the five doses have been ejected was recorded. If the mass loss was in the range of 250 ± 5 mg the study could commence.

Spray on composition (occlusive) dosed transdermals The pigs were placed in holding slings. The pre-prepared clear plastic grid was applied to the pig at the demarked test site using adhesive tape to secure around the edges. The position of entire edge of each clear grid was demarked with an indelible marker pen. A dose of 50 mg of the spray was applied to the demarked site of each animal (holding the sprays approximately 5 cm from the surface of the skin, which covers an area of 3.8 cm ² ), this equates to a total of 1 spray. The spray canister was weighed prior to and after dosing and the weight loss recorded in the study specific laboratory book. Each group of animals received a single dermal application. Blood samples (approximately 5 ml_) were obtained from each animal for analysis of plasma drug concentration at: predose, 5, 10 20, 25, 30, 45, 60 min and 2, 4, 6 and 24 h post dose (total blood draw = 75 ml). The blood samples were collected from the jugular vein/cranial vena cava using sterile, disposable, plastic syringes and hypodermic needles. Each 5 ml sample was split into 2 x 2.5 ml microcentrifuge tubes, containing dry lithium heparin and immediately immersed in an ice bath. Plasma samples were prepared by centrifugation of the blood at 4,000 x g for 15 minutes at 4 ⁰ C and after aspirating into cryovials were snap frozen in liquid nitrogen and subsequently placed in a -8O ⁰ C freezer for storage.

Results As graphically depicted in Figure 4, the transdermal administration of the composition according to example 21 resulted in an increase of the plasma concentration of asenapine. The maximum plasma level obtained by the transdermal administration occurred after only 10 to 20 minutes which is surprisingly fast, when compared to previously described transdermal delivery systems that utilize passive diffusion.

Considering the physical properties of the skin, this permeation profile provides a promising proof of principle of transdermal administration of asenapine since the lag- time is relatively short and thus provides an efficient mean for rapid delivery of asenapine that can mimic the fast absorption expected when asenapine is administered sublingually.

Considering the limited area of application (3.8cm ² ) and the relatively small volume (50μl) that contained only 15% asenapine, the transdermal administration of asenapine as presented in present invention provides a scalable and effective route for administering asenapine to a subject. As the initial speed of permeation is satisfactory from the conducted experiments (Example 27, 28 and 30), parameters such as the area of application (spray area) and the amount of asenapine per cm ² (concentration, applied amount and reservoir size) may be changed in order to adjust the asenapine plasma-level curves and obtain higher plasma levels and larger exposure (AUC) if needed.

Legends to figures

Figure 1 : Schematic representation of a Franz cell.

Figure 2: Application of compositions from examples 17-24 all formulated with 15% w/w asenapine applied to epidermal membrane presented over an 8 h period, where n=6 ± SEM, with the exception of ^* where n=5 and ^** where n=4. No asenapine peaks observed in placebos or blanks run over same experimental duration.

Figure 3. Application of compositions containing 15% w/w asenapine applied to the skin over 48 period, where n=6 ± SEM, with the exception of ^* where n=5 and ^** where n=4. No asenapine peaks observed in placebos or blanks run over same experimental duration.

Figure 4. Plasma concentration time curve for Asenapine in (ng/mL) presented over time from pigs (n=3) following dosing with the Spray-on composition (occlusive).