Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
  • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
  • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
  • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
  • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
  • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

Definitions

• the present invention relates to compressed pharmaceutical compositions of asenapine or pharmaceutically acceptable salts thereof for sublingual, buccal or oromucosal administration.
• the present invention further relates to processes for preparing such compositions.
• Schizophrenia is a severe debilitating mental disorder characterized by symptoms such as hallucinations, delusions, disorganized speech, thinking and behavior, reduced motivation and blunted effect. Schizophrenia significantly impairs mental and social functioning and often leads to the development of comorbid diseases. Symptoms of schizophrenia usually begin in late adolescence or early adulthood. In both adults and children, the symptoms of schizophrenia can be divided into positive, negative and cognitive symptoms. Positive symptoms of schizophrenia include loss of contact with reality where patients have beliefs or perceptual experiences not shared by other members of their culture (delusions and hallucinations, respectively) or they engage in playful behavior.
• Negative symptoms such as blunted affect, anhedonia, apathy, and a reduced quantity or content of speech (alogia) are associated with disruptions to normal emotions and behaviors.
• Cognitive symptoms of schizophrenia are characterized by difficulties in attention, learning, and memory, and a variety of executive functions. Based on the kind of symptoms, schizophrenia can be categorized as paranoid, disorganized, catatonic and undifferentiated schizophrenia. Though exact etiopathology of schizophrenia has not been identified, currently it is believed to be result of combination of both brain vulnerabilities (either inherited or acquired) and life events.
• Bipolar disorder is also known as manic-depressive disorder characterized by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or more depressive episodes. It is a condition of severe mood swings that affects an individual for periods of time in a way that interferes with normal functioning.
• the elevated moods are clinically referred to as mania.
• Individuals who experience manic episodes may also commonly experience depressive episodes, or symptoms, or a mixed state in which features of both mania and depression are present at the same time.
• Bipolar disorder has been subdivided into bipolar I, bipolar II, cyclothymia, and other types, based on the nature and severity of mood episodes experienced.
• Bipolar I disorder is a mood disorder that is characterized by at least one manic or mixed episode. Genetic factors contribute substantially to the likelihood of developing bipolar disorder, while environmental factors have also been implicated.
• Antipsychotic drugs are principally used to treat psychoses particularly schizophrenia and bipolar disorder. Antipsychotics are broadly divided into two groups, the typical (conventional or first generation) antipsychotics and atypical (second generation) antipsychotics respectively. Typical antipsychotic agents act as high affinity antagonists for the type 2 dopamine like receptors with consequences of extrapyramidal side effects such as Parkinsonism, acute muscular dystonia, akathisia and tardive dyskinesia. The introduction of atypical antipsychotic drugs proved to be a significant advancement in the pharmacotherapy of schizophrenia and bipolar disorder.
• antipsychotic drugs have enhanced therapeutic action and reduced incidences of extrapyramidal motor control disabilities than typical antipsychotics because they are potent antagonists of serotonin type 2A and type 2 dopamine receptors with higher affinity for the former.
• Atypical antipsychotics are proved to be effective not only in the treatment of positive symptoms of schizophrenia but also found to be more efficacious against negative as well as cognitive symptoms of schizophrenia than conventional antipsychotics.
• Asenapine is an atypical antipsychotic approved in US and Europe for the acute treatment of adults with schizophrenia and acute treatment of manic or mixed episodes associated with bipolar I disorder with or without psychotic features in adults.
• Asenapine belongs to the class dibenzo-oxepino pyrroles and is known chemically as (3aRS,12bRS)-5-Chloro-2-methyl-2,3,3a,12b-tetrahydro-1 H-dibenzo[ 2,3:6,7] oxepino [4,5-c]pyrrole (2Z)-2-butenedioate (1 :1). It was first disclosed in U.S. Pat. No.
• Asenapine as asenapine maleate is therefore currently marketed in the form of sublingual tablets of 5 mg and 10 mg strengths under the brand name Saphris in the US and Sycrest in Europe by N.V. Organon. These sublingual tablets need to be placed under the tongue and left to dissolve completely. Eating and drinking needs to be avoided for 10 minutes after administration.
• U.S. Patent No. 5,763,476 covering the above sublingual product states that oral doses of asenapine may have cardiovascular side effects and further provides a sublingual or buccal pharmaceutical composition thereof which is manufactured by freeze-drying an aqueous suspension of asenapine, gelatin and mannitol in pre-formed aluminium blister pockets. The patent further discusses use of the composition in treating or managing diseases including mental disorders, such as tension, excitation, anxiety, psychosis and schizophrenia.
• Sublingual or buccal formulations are designed to cause absorption of the active through the oral mucosa so that the active directly enters into the systemic circulation thereby avoiding the first pass metabolism.
• Freeze-dried formulations are commonly employed for sublingual administration to obtain improved bioavailability and rapid onset of action.
• the marketed product is a freeze-dried formulation. Freeze-drying technique, however, is a cumbersome, time consuming and expensive process.
• freeze dried formulations tend to lack mechanical strength and fracture easily during handling and packaging.
• compositions of asenapine or pharmaceutically acceptable salts thereof for sublingual, buccal or oromucosal administration that have adequate mechanical strength, desired taste, requisite disintegration time and desired in-vitro dissolution and bioavailability.
• Such compositions are compressed dosage forms comprising asenapine or pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable excipient.
• the compositions of the present invention are manufactured by simple and cost effective manufacturing process and are stable.
• the present invention relates to compressed pharmaceutical compositions of asenapine or pharmaceutically acceptable salts thereof for sublingual, buccal or oromucosal administration comprising asenapine or pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.
• Such compressed compositions may be in the form of monolithic, bilayered or multilayered dosage forms.
• the present invention further relates to processes for preparing such compositions.
• compositions of the present invention are stable under ambient and accelerated storage conditions. Furthermore, in the pharmaceutical compositions of the present invention, the bitter, unpleasant or otherwise undesirable taste of the active is masked, without compromising on its stability, release and absorption requirements.
• the compositions of the present invention are prepared by simple and cost-effective process.
• composition of the present invention comprises asenapine or pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable excipient wherein the composition is in the form of a compressed dosage form.
• Asenapine may be incorporated in the compositions of the present invention in the form of free base or pharmaceutically acceptable salts, prodrugs, active metabolites, polymorphs, amorphous form, crystalline forms, combination of crystalline and amorphous forms, solvates, hydrates, enantiomers, optical isomers, tautomers or racemic mixtures thereof.
• asenapine in the form of maleate salt is incorporated in the compositions of the present invention.
• compositions of the present invention are employed in the composition of the present invention.
• effective amount refers to an amount effective to achieve desired therapeutic and/or beneficial effect in schizophrenia, bipolar disorder, psychotic disorders, tension, excitation or anxiety.
• asenapine is incorporated in the compositions of the present invention in an amount of about 0.01 weight % to about 95 weight %, based on the total weight of the composition.
• asenapine is incorporated in the compositions of the present invention in an amount of about 0.02 weight % to about 85 weight %, based on the total weight of the composition.
• compositions of the present invention are incorporated in the compositions of the present invention in an amount of about 0.05 weight % to about 80 weight %, based on the total weight of the composition.
• the compositions of the present invention may be » administered at a dose of about 0.01 mg to about 150 mg of asenapine for antipsychotic, antihistamine or antiserotonin action.
• the compositions of the present invention may be administered at a dose of about 0.1 mg to about 120 mg of asenapine.
• the compositions of the present invention may be administered at a dose of about 0.5 mg to about 100 mg of asenapine.
• the compositions' of the present invention may be administered at a dose of about 5 mg or 10 mg of asenapine for antipsychotic, antihistamine or antiserotonin action.
• Asenapine may be in the form of, but not limited to, powder, granules, pellets, beads, or the like.
• the asenapine granules may be prepared by methods such as, but not limited to, wet granulation, melt granulation, dry granulation or roll compaction or the like.
• granulations such as, but not limited to, aqueous, hydroalcoholic or alcoholic granulations may be employed.
• pellets of asenapine may be prepared using extrusion spheronization.
• asenapine can be loaded on an inert carrier.
• the inert carrier can be selected from, but not limited to, beads, pellets, spheres or similar particles that do not contain an active ingredient.
• Non-limiting examples of inert carriers include microcrystalline cellulose, sugar or silicon dioxide.
• asenapine, in the powder form may be incorporated in the composition of the present invention.
• asenapine, in the powder form may be blended, coated or treated with at least one pharmaceutically acceptable excipient.
• the pharmaceutical formulation of the present invention further comprises at least one pharmaceutically acceptable excipient such as, but not limited to, binders, disintegrants, superdisintegrants, diluents, surfactants, solubilizers, pH modifiers, flavors, sweeteners, colorants, salivating agents, souring agents, glidants, lubricants, absorption enhancers, mucoadhesive agents, taste-modifiers or the like.
• pharmaceutically acceptable excipient such as, but not limited to, binders, disintegrants, superdisintegrants, diluents, surfactants, solubilizers, pH modifiers, flavors, sweeteners, colorants, salivating agents, souring agents, glidants, lubricants, absorption enhancers, mucoadhesive agents, taste-modifiers or the like.
• Disintegrants that may be employed include, but are not limited to, crospovidone, microcrystalline cellulose, calcium silicate, starch and the like or combinations thereof.
• superdisintegrants that may be employed include, but are not limited to, natural, modified or pregelatinized starch, crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose, effervescent disintegrating systems and the like or combinations thereof.
• Effervescent disintegrating systems that may be employed include a gas generating agent and an acid source. Suitable acid source that may be employed as part of effervescent disintegrating system includes, but is not limited to, citric acid, citric acid anhydrous, maleic acid and the like or combinations thereof.
• Gas generating agents that may be used in the present invention include, but are not limited to, sodium bicarbonate, sodium glycine carbonate, potassium bicarbonate, ammonium bicarbonate, sodium bisulfite, sodium metabisulfite, and the like or combinations thereof.
• suitable binders include, but are not limited to, starch,, pregelatinized starch, polyvinyl pyrrolidone, copovidone, cellulose derivatives, such as hydroxypropylmethyl cellulose, hydroxypropyl cellulose and carboxymethyl cellulose and their salts and the like or combinations thereof.
• Suitable diluents include, but are not limited to, starch, microcrystalline cellulose, lactose, xylitol, mannitol, maltose, polyols, fructose, dicalcium phosphate, directly compressible composites, and the like or any combinations thereof.
• Directly compressible composites that may be employed include, but are not limited to, directly compressible coprocessed composite of calcium silicate and mannitol and the like.
• lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, talc, sodium stearyl fumarate and the like or combinations thereof.
• the formulations of the present invention may also include a glidant such as, but not limited to, colloidal silica, colloidal silicon dioxide, silica gel, precipitated silica, and the like or combinations thereof.
• a glidant such as, but not limited to, colloidal silica, colloidal silicon dioxide, silica gel, precipitated silica, and the like or combinations thereof.
• the said compositions may also include salivating agents such as, but not limited to, micronized polyethylene glycol, citric acid, citric acid anhydrous, sodium chloride or precipitated micronized silica, and the like or combinations thereof to improve the disintegration properties of the said compositions.
• solubilizers include, but are not limited to cetostearyl alcohol, cholesterol, diethanolamine, ethyl oleate, ethylene glycol palmitostearate, glycerin, polysorbate, polysorbate 20, polysorbate 80, polyethylene glycol, glyceryl monostearate, isopropyl myristate, lecithin, medium-chain glyceride, monoethanolamine, oleic acid, propylene glycol, polyoxyethylene alkyl ether, poloxamer, poly (oxyethylene)-poly(oxypropylene) block copolymers, polyoxyethylene castor oil glycoside', polyethylene sorbitan fatty acid ester, polyoxyethylene stearate, propylene glycol alginate, sorbitan fatty acid ester, macrogol glycerides, caprylcaproyl macrogol glycerides, stearic acid, sunflower oil, polyethylene glycol triethanolamine, cyclodextrins such as ⁇ -
• surfactants include, but are not limited to, cationic, anionic or zwitterionic surfactants such as, but not limited to, sodium docusate, glyceryl monooleate, polyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, sorbic acid, sorbitan fatty acid ester, and the like or mixtures thereof.
• Souring agents include, but are not limited to, monosodium fumarate and/or citric acid and the like or combinations thereof.
• compositions of the present invention may further optionally comprise a pH modifier or buffering agent such as, but not limited to, benzoic acid, sodium benzoate, tartaric acid, citric acid, citric acid anhydrous, fumaric acid, sodium citrate, potassium citrate, phosphoric acid and the like or combinations thereof.
• a pH modifier or buffering agent such as, but not limited to, benzoic acid, sodium benzoate, tartaric acid, citric acid, citric acid anhydrous, fumaric acid, sodium citrate, potassium citrate, phosphoric acid and the like or combinations thereof.
• Absorption enhancers include, but are not limited to, sodium caprate, sodium glycocholate, chitosans, polysorbate 80, Cremophor ® EL, D-a-tocopheryl polyethylene glycol succinate, and the like or combinations thereof.
• Mucoadhesive agents include, but are not limited to, cellulose derivatives such as, but not limited to, hydroxyethylcellulose, hydroxypropylcellulose, methyl cellulose, sodium carboxymethylcellulose and the like; poly (acrylic acid) polymers such as, but not limited to, carbopol and the like; natural polymers such as, but not limited to, shellac, tragacanth, pectin, lectin, sodium alginate, acacia, guar gum, karaya gum and the like; alginate-polyethylene glycol acrylate (alginate-PEGAc), poloxamer, pluronics, polyacrylates; polymethacrylates, vinyl derivatives or polymers and copolymers thereof such as, but not limited to, poly (vinyl pyrrolidone), poly (vinyl alcohol) and the like.
• poly (acrylic acid) polymers such as, but not limited to, carbopol and the like
• natural polymers such as, but not limited to
• compositions of the present invention comprise at least one sweetener such as, but not limited to, aspartame, stevia extract, glycyrrhiza, saccharine, saccharine sodium, acesulfame, sucralose and dipotassium glycyrrhizinate; and/or one or more flavors, such as, but not limited to, mint flavour, orange flavour, lemon flavors, strawberry aroma, vanilla flavour, raspberry aroma, cherry flavor, tutty frutty flavor, magnasweet 135, key lime flavor, grape flavor, trusil art 51 1815, and fruit extracts.
• sweetener such as, but not limited to, aspartame, stevia extract, glycyrrhiza, saccharine, saccharine sodium, acesulfame, sucralose and dipotassium glycyrrhizinate
• flavors such as, but not limited to, mint flavour, orange flavour, lemon flavors, strawberry aroma, vanilla flavour, raspberry aroma, cherry flavor, tutty fr
• Taste-modifiers that may optionally be incorporated in the compositions of the present invention include, but are not limited to, water soluble, water dispersible, water insoluble polymeric or non- polymeric agents and the like or combinations thereof.
• Water soluble, water dispersible, water insoluble polymeric or non-polymeric agents include, but are not limited to, cellulose derivatives, saccharides or polysaccharides, polyhydric alcohols, poly (oxyethylene)-poly(oxypropylene) block copolymers (poloxamers), vinyl derivatives or polymers or copolymers thereof, acrylic acid derivatives, fats, oils, waxes, fatty acids, fatty acid esters, long chain monohydric alcohols and their testers, phospholipids, terpenes, and the like or any combinations thereof.
• the pharmaceutically acceptable excipient is present in the composition of the present invention in an amount of about 1 % to about 95% by weight of . the dosage form.
• the active is blended, coated or granulated with at least one taste-modifier.
• the active is complexed or blended with at least one cyclodextrin such as, but not limited to, ⁇ - cyclodextrin, hydroxypropyl ⁇ -cyclodextrin.
• the pharmaceutical composition of the present invention of asenapine is a compressed dosage form.
• a compressed dosage form can be prepared by methods such as, but not limited to, direct compression, wet granulation, dry granulation, roll compaction, extrusion spheronization, melt granulation, melt extrusion, fluid bed coating, spray coating, compression coating and the like.
• the pharmaceutical compositions of the present invention for sublingual, buccal or oromucosal administration can be in the form of, but not limited to, orally or rapidly disintegrating or dissolving tablets, minitablets, pellets or lozenges or mucoadhesive tablets or pellets, pellets in capsule or minitablets in capsule.
• the pharmaceutical formulation of the present invention is in the form of a monolithic tablet. In another embodiment, the pharmaceutical formulation is in the form of multilayered tablet. In one embodiment, the composition of the present invention is a bilayered tablet. In another embodiment, the bilayered pharmaceutical composition of the present invention comprises one active layer and the other layer or the second layer devoid of the active. In one embodiment, both the layers of the bilayered tablet composition comprise the active. In another embodiment, one active layer of the bilayered tablet composition comprises more active than another.
• composition of the present invention is in the form of a bilayered tablet wherein one layer comprises asenapine or pharmaceutically acceptable salt thereof in an amount of more than 50% by weight of the dose of asenapine to be delivered and the other layer comprises the remaining dose of asenapine.
• composition of the present invention is in the form of a bilayered tablet wherein one layer comprises asenapine or pharmaceutically acceptable salt thereof in an amount of more than 75% by weight of the dose of asenapine to be delivered and the other layer comprises the remaining dose of asenapine.
• the composition of the present invention is in the form of a bilayered tablet wherein one layer comprises asenapine or pharmaceutically acceptable salt thereof in an amount of more than 85% by weight of the dose of asenapine to be delivered and the other layer comprises the remaining dose of asenapine.
• the bilayered tablet composition of the present invention comprises in one active layer more than about 90% by weight of the dose of asenapine to be delivered and the other layer comprises the remaining dose of asenapine.
• the bilayered tablet composition of the present invention comprises in one active layer more than about 95% by weight of the dose of asenapine to be delivered and the other layer comprises the remaining dose of asenapine.
• the pharmaceutical composition of the present invention is in the form of a tablet-in-tablet dosage form or compressed core with compression coated type of dosage form or inlay tablet type of dosage form.
• the compressed pharmaceutical formulation of asenapine of the present invention disintegrates within about 3 minutes as per USP in-vitro disintegration test. In a further embodiment, the compressed pharmaceutical formulation of asenapine of the present invention disintegrates within about 2 minutes as per USP in-vitro disintegration test. In another embodiment, the compressed pharmaceutical formulation of asenapine of the present invention disintegrates within about 60 seconds as per USP in-vitro disintegration test. In a further embodiment, the compressed pharmaceutical formulation of asenapine of the present invention disintegrates within about 45 seconds as per USP in-vitro disintegration test.
• the compressed pharmaceutical formulation of asenapine of the present invention disintegrates within about 30 seconds as per USP in-vitro disintegration test. In yet another embodiment, the compressed pharmaceutical formulation of asenapine of the present invention disintegrates in more than 30 seconds as per USP in-vitro disintegration test. In yet another embodiment, the compressed pharmaceutical formulation of asenapine of the present invention disintegrates in more than 45 seconds as per USP in-vitro disintegration test.
• one layer of the bilayered tablet formulation of the present invention comprising all the active or more amount of the active than the other layer is a rapidly disintegrating layer and the other layer not comprising the active or comprising less amount of active than the other layer is a slow disintegrating layer.
• the two layers of the bilayered tablet of the present invention have different in-vitro disintegration times as measured by USP in-vitro disintegration test.
• the outer tablet or outer compressed coating in a tablet-in-tablet or inlay tablet type of dosage form, is rapidly disintegrating one, while the inner tablet or compressed core can be a slow disintegrating one.
• outer tablet or outer compressed coating disintegrates rapidly and the inner tablet or compressed core disintegrates slowly.
• outer tablet or outer compressed coating disintegrates rapidly and the inner tablet or compressed core disintegrates slowly.
• the in vitro disintegration time of the compositions of the present invention is measured as per United States Pharmacopoeia (USP e.g. USP35).
• USP United States Pharmacopoeia
• the disintegration time is measured in vivo by placing the compressed dosage form e.g. tablet in the sublingual, buccal or oromucosal cavity, and measuring, using a stopwatch, the time that elapses between the beginning of the measurement and the moment when the tablet has completely disintegrated under the action of saliva and without chewing.
• the later disintegrating part or the slow disintegrating part of the compressed pharmaceutical composition of asenapine or pharmaceutically acceptable salt thereof retains the dosage form at the desired site in the oral cavity for sublingual, buccal or oromucosal administration.
• composition of the present invention releases asenapine or pharmaceutically acceptable ⁇ salt thereof immediately for absorption across the oral mucosa.
• composition of the present invention releases asenapine or pharmaceutically acceptable salt thereof in a modified manner for absorption across the oral mucosa.
• the dosage form may be optionally coated.
• Surface coating may be employed for aesthetic purposes or for dimensionally stabilizing the compressed dosage form.
• the coating may be carried out using any conventional technique employing conventional pharmaceutically acceptable polymers.
• tablet andtablet composition and “tablet formulation” are used synonymously within the context of the present invention. These terms should be construed to include a compacted or compressed powder composition obtained by compressing or otherwise forming the composition to form a solid having a defined shape.
• the tablet may vary in shape such as oval, triangle, almond, peanut, parallelogram, round, pentagonal, hexagonal, and trapezoidal. The preferred shapes are round, oval and parallelogram forms.
• the present invention discloses a process for preparing the compressed pharmaceutical formulation of asenapine or pharmaceutically acceptable salts thereof comprising: (a) blending asenapine or pharmaceutically acceptable salt thereof with at least one pharmaceutically acceptable excipient; (b) lubricating the blend of step (a); and (c) compressing the lubricated blend of step (b) to form tablets for buccal, sublingual or oromucosal administration.
• the present invention discloses a process for preparing the compressed pharmaceutical formulation of asenapine or pharmaceutically acceptable salts thereof comprising: (a) blending asenapine or pharmaceutically acceptable salt thereof with at least one pharmaceutically acceptable excipient; (b) dry or wet granulating the blend of step (a) to form granules; (c) lubricating the blend of step (b); and (d) compressing the lubricated blend of step (c) to form for buccal, sublingual or oromucosal administration.
• the present invention discloses a process for preparing the compressed pharmaceutical formulation of asenapine or pharmaceutically acceptable salts thereof comprising: (a) blending asenapine or pharmaceutically acceptable salt thereof with at least one pharmaceutically acceptable excipient; (b) lubricating the blend of step (a) to form the active layer; (c) blending at least one pharmaceutically acceptable excipient with lubricant to form layer devoid of active agent; (d) compressing the active layer of step (b) and the layer devoid of the active agent of step (c) to form a bilayered tablet for buccal, sublingual or oromucosal administration.
• the present invention discloses a process for preparing the compressed pharmaceutical formulation of asenapine or pharmaceutically acceptable salts thereof comprising: (a)blending more than 50% by weight, in a further embodiment more than 75% by weight, in yet another embodiment more than 85% by weight, in a still further embodiment more than 90% by weight, in still another embodiment more than 95% by weight, of the dose of asenapine to be delivered with at least one pharmaceutically acceptable excipient; (b) lubricating the blend of step (a) to form the first active layer; (c) blending the remaining dose of asenapine and at least one pharmaceutically acceptable excipient; (d) lubricating the blend of step (c) to form the second active layer; (e) compressing the first active layer of step (b) and the second active layer of step (d) to form a bilayered tablet for buccal, sublingual or oromucosal administration.
• the present invention discloses a process for preparing the compressed pharmaceutical formulation of asenapine or pharmaceutically acceptable salts thereof comprising: (a)blending more than 50% by weight, in a further embodiment more than 75% by weight, in yet another embodiment more than 85% by weight, in a still further embodiment more than 90% by weight, in still another embodiment more than 95% by weight, of the dose of asenapine to be delivered with at least one pharmaceutically acceptable excipient; (b) granulating the blend of step (a) with at least one binder to form granules (c) blending the granules of step (b) with the remaining excipients and then lubricant to form the first active layer; (d) blending the remaining dose of asenapine and at least one pharmaceutically acceptable excipient; (e) granulating the blend of step (d) with at least one binder to form granules (f) blending the granules of step (e) with the remaining excipients and then lubricant
• the present invention discloses a process for preparing the compressed pharmaceutical formulation of atypical antipsychotic agent such as asenapine or pharmaceutically acceptable salts thereof comprising: (a) blending at least one pharmaceutically acceptable excipient with lubricant and compressing the blend to form compressed tablet devoid of active agent; (b) blending the active agent with at least one pharmaceutically acceptable excipient, lubricating the blend, and compressing the lubricated blend in the form of coating over the compressed tablet of step (a) to form tablet in tablet dosage form for buccal, sublingual or oromucosal administration.
• atypical antipsychotic agent such as asenapine or pharmaceutically acceptable salts thereof comprising: (a) blending at least one pharmaceutically acceptable excipient with lubricant and compressing the blend to form compressed tablet devoid of active agent; (b) blending the active agent with at least one pharmaceutically acceptable excipient, lubricating the blend, and compressing the lubricated blend in the form of coating over the compressed tablet of step (a
• the present invention further provides a method for the treatment of tension, excitation, anxiety or psychotic disorders such as but not limited to schizophrenia, bipolar disorder, and the like comprising administering to the patient in need thereof compressed pharmaceutical formulations of the present invention comprising asenapine or pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable excipient.
• compressed pharmaceutical formulation of the present invention comprising asenapine or pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable excipient for the manufacture of a medicament for the treatment of tension, excitation, anxiety or psychotic disorders such as but not limited to schizophrenia, bipolar disorder, and the like.
• the compressed pharmaceutical compositions of the present invention may be adapted to deliver one or more active agents in addition to asenapine or pharmaceutically acceptable salts thereof.
• the compressed pharmaceutical formulation of the present invention may be co-administered with compositions of other active agents, such as, but not limited to, lithium, valproate, dimebon and the like. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. Details of the present invention, including its objects and advantages, are provided in the non-limiting exemplary illustrations below. Examples:
• Example 1 Bilayered orally disintegrating sublingual tablet of asenapine maleate
• Example 2 Orally disintegrating sublingual tablet of asenapine maleate
• Example 4 Orally disintegrating sublingual tablet of asenapine maleate
• Example 5 Bilayered orally disintegrating sublingual tablet of asenapine maleate

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• 2013
  • 2013-01-21 WO PCT/IN2013/000040 patent/WO2013114400A2/fr not_active Ceased

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