DESC:FIELD OF THE INVENTION
The present invention relates to a stable pharmaceutical composition for sublingual and/or buccal administration of Asenapine and process for preparation of said pharmaceutical composition.
BACKGROUND OF THE INVENTION
Asenapine is an antipsychotic drug used for the treatment of schizophrenia and bipolar and acute mania associated with bipolar disorder. Asenapine in form of maleate salt (Asenapine Maleate) is available in market for such treatment under the brand name of Saphris®, Sycrest®.

Asenapine (i.e. trans-5-Chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole) is a pyrrolidino tetracyclic compound with potent dopamine, serotonin and adrenergic antagonist properties. In particular, the compound has high affinity for dopamine 1, 2, 3 and 4 receptors, and for serotonin 2A, 2C, 1A, 6 and 7 receptors as well as noradrenaline- 1 and 2 receptor types.
US4145434 discloses about Asenapine and its salt and method of synthesis of Asenapine and its maleate salt. Asenapine is characterized by low bioavailability and show extensive first pass metabolism when taken up via the gastrointestinal tract.
During experimentation of the present invention it has found that Asenapine is unstable and produce impurities during manufacturing and in final formulation specifically "N-oxide impurity";
Several attempts have been done in past to solve the issue of low bioavailability, to avoid first pass metabolism and to reduce the impurity of asenapine in the final formulation by preparing composition using expensive and tedious method like freeze drying or by developing new polymorphic form or by reducing or controlling particle size of active substance.
US5763476 discloses sublingual or buccal tablet that contains 5 mg or 10 mg of Asenapine or salt thereof, mannitol and partially hydrolysed gelatin prepared by freeze-drying. US5763476 is silent about method other than freeze-drying to prepare said composition. However, a significant drawback of this freeze-drying process is that it leads to an expensive production, in particular due to the long duration of each freeze drying cycle (normally 24 to 48 hours) and the necessity to use sophisticated equipment for carrying out the process. Moreover, freeze-dried compositions are generally not stable enough to be easily handled by the modern high-speed packaging machines.
US7741358, EP1710245 and WO 2006106135 disclose a pharmaceutical composition comprising the orthorhombic form (form-L, having melting point in range of 138-142 °C) of asenapine Maleate prepared by freez drying method and US 7741358 also discloses about monoclinic form (Form-H having melting point in range of 141-145°C). It is also mentioned that the reason for the use of form L - despite its lower solubility - is that for sublingual or buccal administration, a drug substance with a small particle size is desired (see page 2, lines 8 to 16 of WO2006/106135 A1). This is because when drug substance particles are small it takes only short periods of time for the small particles to dissolve and thus to achieve high concentrations in the saliva. WO2006/106135 A1 discloses that only form L can be reproducibly obtained by micronisation in high polymorph purity whereas micronisation of monoclinic form H resulted in a non reproducible product (page 2, lines 22 to 32 and examples 9 and 10 of WO2006/106135 A1).
US20080090892 discloses the preparation of Amorphous Asenapine maleate by using spray drying method and freeze drying method. US20080090892 further discloses the use of other excipients to prepare amorphous asenapine maleate and also mentioned that as per the invention of US20080090892, Asenapine maleate is at least 50%, 75%, 90%, 95%, or 99% amorphous, based on the total weight of the compound. Hence, the crystalline asenapine maleate might be present in the final composition. US20080090892 also disclose the use of different pharmaceutical excipient disintegrants, surfactant, glidants, lubricants, binding agent, diluents, flavorant and sweetener for preparation of tablet dosage form.
WO2011159903A1 discloses about a monoclinic form of asenapine maleate, which is stable to micronization, and processes for preparation thereof. WO2011159903A1 also taught about pharmaceutical compositions comprising a microcrystalline monoclinic form of asenapine maieate, using at least one pharmaceutically acceptable excipient.
WO2012066565A2 discloses about substantially pure monoclinic form of asenapine maleate having particle size of d95 less than about 100 microns and process for preparation of same. WO2012066565A2 mentioned that “The particle size of the drug substance influences biopharmaceutical properties of the drug product. For example, the particle size of the drug substance affects drug product manufacturing and dissolution and hence its bioavailability. Since asenapine dissolves in the saliva the particle size is important. When drug substance particles are small, it takes only short periods of time to achieve high concentrations. From this perspective small particles are preferred. In addition, smaller particle size tends to improve the homogeneity of powder blends, which may result in improved uniformity of the contents of the drug product.” WO2012066565A2 also discloses “process for preparing amorphous asenapine maleate comprising slurrying asenapine maleate in a solvent selected from a group consisting of organic solvent such as aromatic hydrocarbons, glycerol, tetrahydrofuran, esters, ethers, ketones, alcohols and water or a mixture thereof. Another embodiment of the invention encompasses a process for preparing amorphous asenapine maleate comprising spray drying a solution of asenapine maleate in alcoholic solvent” and preparation of pharmaceutical composition containing substantially pure monoclinic form of asenapine maleate having particle size of d95 less than about 100 microns or amorphous asenapine maleate.
WO2012123325A1 discloses about new crystalline polymorphic forms of asenapine maleate (Form-M and Form-T), which can be micronized to a suitable particle size without a substantial conversion into the orthorhombic form (form-L) and which show an improved water solubility when compared the orthorhombic form (Form-L) and the monoclinic form (Form-H). WO2012123325A1 also revealed that the crystalline asenapine maleate Form-M and Form-T show excellent properties in term of stability, bioavailability, solubility and flowability, which contributes to a successful drug development and that these crystalline polymorphic Form-M and Form-T are suitable to be formulated, for example in the form of tablets for sublingual or buccal administration.
WO2012114325A1 discloses about a new crystalline form and a amorphous form of asenapine maleate. As per the disclosure of WO2012114325A1 the new crystalline form (Form II) having good bioavailability as well as adequate stability characteristics like less hygroscopic, has improved chemical stability at high humidity-conditions (75% RH) and shows enhanced aqueous solubility as compared to the known amorphous asenapine maleate of US 2008/0090892 enabling their incorporation into a variety of solid dosage forms (e.g. sub-lingual tablets). WO2012114325A1 also taught about amorphous asenapine maleate having average particle size about 25-50 µm with D90 of about 60-70 µm and use of vaccum drying, melting method and freeze drying method for preparation of amorphous asenapine maleate and general disclosure about preparation of pharmaceutical composition.
WO2012080195A2 discloses anhydrous polymorphic Form G, G1 and G2 of asenapine maleate that are stable at room temperature, reproducible and suitable for pharmaceutical dosage form and general disclosure about use of said polymorphic form for preparation of pharmaceutical composition.
WO2012038975A2 discloses about stable crystalline Form-H of Asenapine maleate that does not convert in to crystalline Form-L during micronisation or its storage after micronisation. WO2012038975A2 further discloses about orally disintegrating tablet having low friability, dispersion time of 35-60 seconds, 80-100% dissolution rate within 5 to 10 minutes comprising essentially of F-Melt and use of simple wet granulation technique to prepare said tablet wherein asenapine maleate is in crystalline or amorphous form. As per the disclosure of WO2012038975A2, asenapine maleate according to invention having purity greater than 99% by HPLC and the level of different impurities including N-Oxide impurity are well controlled with in the limits as per the ICH guidelines.
WO2012156676A1 discloses about a stable monoclinic crystalline form of asenapine maleate having low particle size (d90 of 40 µm or less) which avoids the need to use a micronisation process and discloses about different pharmaceutical dosage form comprises of stable monoclinic crystalline form of asenapine maleate.
WO2012156677A1 discloses about a stable monoclinic crystalline form of asenapine maleate having low particle size (d90 equal to or below 40 µm) prepared by using gas jet milling method under specific micronisation condition of temperature and pressure and also discloses that the said monoclinic crystalline form may contains orthorhombic form less than 1% by weight.
WO2012150538A1 relates to asenapine phosphate and a novel monoclinic crystalline form of asenapine maleate characterized by specific XRPD, IR and DSC (132.8 °C) which is differs from the orthorhombic and monoclinic polymorphic form disclosed in US 7741358. WO2012150538A1 discloses that the novel monoclinic crystalline form having chemico-physical and biopharmaceutical property such as stability, dissolution rate and bioavailability and preparation of pharmaceutical composition comprises of said crystalline form.
WO2013024492A2 taught about process for preparation of asenapine or its acid addition salt, asenapine sulphate, novel crystalline form of asenapine sulphate and asenapine maleate. WO2013024492A2 also discloses about co-precipitate of amorphous form of asenapine sulphate and asenapine maleate and process for preparation of co-precipitate wherein solution of asenapine sulphate or maleate and pharmaceutical excipient is prepared and solvent is removed from said solution to obtain solid residue or co-precipitate. The pharmaceutical excipient(s) used for preparation of co-precipitate is selected form polyvinylpyrrolidone, gum, cellulose derivatives, cyclodextrins, gelatins, hypromellose phthalate, sugar and polyvinyl alcohols.
WO2013041604A1 discloses about crystalline Form-S of Asenapine Maleate and use of Form S as a starting material for preparation of crystalline monoclinic form of Asenapine Maleate having particle size distribution d95 at 50 µm preferably at most 30 µm having less than 10% orthorhombic crystalline form optionally less than 5% or no detectable amount. WO2013041604A1 also discloses use of monoclinic form of Asenapine maleate for sublingual or buccal formulation.
WO2013041435A1 discloses about compressed dosage form of asenapine maleate for sublingual or buccal administration comprises of microcrystalline monoclinic asenapine maleate (characterized by a d95 of less than 75 µm, and contains less than 5 % w/w of asenapine maleate in the crystalline orthorhombic form), said dosage form should not comprises a significant amount of amorphous asenapine maleate. According to disclosure of WO2013041435A1, amorphous asenapine maleate is hygroscopic and less stable than the crystalline forms.
As discussed above different approaches have been used in past to provide stable pharmaceutical composition of asenapine having high dissolution rate and improved bioavailability and low level of impurity in final dosage form among that most frequently used approach was to use different polymorphic form of asenapine maleate. However, it is know in the art that distinct physical properties of different polymorphs of the compound can render different polymorphs more or less, useful for a particular purpose, such as for a pharmaceutical formulation. Moreover, particular polymorphic form might be converting into another polymorphic form during process like micronisation, storage of active substance or manufacturing of pharmaceutical composition or storage of final composition and such transformation of one polymorphic form to another polymorphic form may result in poor stability and bioavailability of active substance. Another approach was to reduce the particle size of active substance. The process of particle size reduction and controlling of such specific particle size is very expensive technique with high variability and less reproducibility of specific particle size of active substance. Third approach was use of special and expensive technique like freeze-drying or lyophilization for preparation dosage form. However, a significant drawback of this lyophilization process is that it leads to an expensive production, in particular due to the long duration of each freeze-drying cycle (normally 24 to 48 hours) and the necessity to use sophisticated equipment for carrying out the process. Moreover, freeze-dried compositions are generally not stable enough to be easily handled by the modern high-speed packaging machines.
Hence, there is unmet need to provide a stable pharmaceutical composition of Asenapine or pharmaceutically acceptable salt thereof having improved bioavailability or is bioequivalent to marketed dosage form and having low level of impurity specifically N-Oxide impurity which can be prepared by a simple procedure in an efficient manner.
The present invention provide a novel composition and process for preparation of a stable pharmaceutical composition of asenapine or acceptable salt thereof having improved bioavailability or is bioequivalent to marketed product, wherein asenapine or pharmaceutical acceptable salt thereof can be used in any form i.e. any crystalline or amorphous form without any specific particle size. Further, the present invention provides a stable pharmaceutical composition wherein the level of impurity in final dosage form is low or negligible.
OBJECT OF THE INVENTION
An object of the present invention is to provide a stable pharmaceutical composition of asenapine or pharmaceutical acceptable salt thereof for sublingual or buccal administration having improved bioavailability or is bioequivalent to marketed product.
Another object of the invention is to provide composition, which can reduce or prevent the increase in level of impurities impurity in final pharmaceutical compositions.
Another object of the invention is to provide simple and efficient process for preparation of said pharmaceutical composition of asenapine or pharmaceutical acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
Unexpectedly, a stable pharmaceutical composition, which meets the above requirement, has been found in the form of pharmaceutical composition comprising asenapine or pharmaceutically acceptable salt thereof, antioxidant, water soluble diluent, water soluble/swellable binder, disintegrant and optionally one or more surfactant and/or one or more pharmaceutically acceptable excipient.
For the purpose of the present invention, asenapine is as base or pharmaceutically acceptable salt of asenapine selected from maleate, palmitate, pamoate, acetate, benzoate, hemi-pamaote, naphtoate, fumarate, succinate, oxalate, hydrochloride, hydrobromide, phosphate or sulphate.
As per the preferred embodiment, for the purpose of the invention asenapine is used in the form of maleate salt i.e. asenapine maleate.
As per the more preferred embodiment, asenapine used for the purpose of the invention is asenapine maleate in polymorphic form know in US7741358/EP1710245/WO2006106135 (monoclinic form (Form-H) or orthorhombic form (Form-L)), amorphous form, WO2012123325A1 (Form M or form T), WO2012114325A1 (Form II), WO2012080195A2 (Anhydrous polymorphic Form G, G1 and G2), WO2012150538A1, WO2013024492A2, WO2013041604A1 (From-S), CN102952144A (Form-A or Form B) or any polymorphic form of asenapine maleate know to the person skilled in the art as a input material for preparation of pharmaceutical composition as per the invention.
As per the more preferred embodiment, asenapine maleate whether in amorphous or polymorphic form as mentioned above is used without any limitation of particle size or of any particle size as a input material for the preparation of pharmaceutical composition as per the invention.
As per the most preferred embodiment, asenapine maleate is monoclinic crystalline form (Form-H) without any limitation of particle size or of any particle size used as a input material for the preparation of pharmaceutical composition as per the invention.
Further, during experimentation, the following impurities were found in active substance or during preparation of pharmaceutical composition.
(3aRS,12bRS)-2-methyl-2,3,3a,12b-b-tetrahydro-1Hdibenzo[2,3:67] oxepino[4,5-c]pyrrole herein designated as "deschloroimpurity"; (3aRS,12bRS)-5-chloro-2,3,3a,12b-tetrahydro-lHdibenzo[2,3:6,7]oxepino [4,5-c] pyrrole, herein designated as "desmethylimpurity"; (33aRS,12bRS)-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-lHdibenzo[2,3:6,7]oxepino[4,5-c]pyrrole-N-oxide, herein designated as "N-oxide impurity"; 2-chloro-phenyl acetic acid, herein designated as "Impurity-A".

Surprisingly it is found that level of impurity could be reduced or prevented from increasing in the final composition by using antioxidant during preparation of pharmaceutical composition of asenapine or pharmaceutically acceptable salt thereof.
As per the preferred embodiment, a stable pharmaceutical composition comprising asenapine or pharmaceutically acceptable salt thereof and antioxidant.
As per the more preferred embodiment, a stable pharmaceutical composition comprising asenapine or pharmaceutically acceptable salt thereof, antioxidant, water soluble diluent, water soluble/swellable binder, disintegrant and one or more pharmaceutically acceptable excipient.
As per another embodiment, a stable pharmaceutical composition comprising asenapine or pharmaceutically acceptable salt thereof, antioxidant, water soluble diluent, water soluble/swellable binder, disintegrant and optionally one or more surfactant and/or one or more pharmaceutically acceptable excipient.
As per another embodiment a stable pharmaceutical composition consisting essentially of asenapine or pharmaceutically acceptable salt thereof, antioxidant and one or more pharmaceutically acceptable excipient.
Another aspect of the invention is to provide a pharmaceutical composition of asenapine or pharmaceutical acceptable salt thereof for sublingual or buccal administration having improved bioavailability or is bioequivalent to marketed product.
Another aspect of the invention is to provide, a rapidly dissolving stable pharmaceutical composition of asenapine or pharmaceutically acceptable salt thereof.
As per preferred embodiment, a stable pharmaceutical composition as per the present invention release at least about 65% of asenapine within 5 min.
As per preferred embodiment, a stable pharmaceutical composition as per the present invention release at least about 80% of asenapine within 15 min.
Another aspect of the invention is to provide, a stable pharmaceutical composition of asenapine or pharmaceutically acceptable salt thereof wherein total impurity is less than 0.2% and N-oxide impurity is less than 0.04%.
Another aspect of the invention is to provide, a stable pharmaceutical composition of asenapine or pharmaceutically acceptable salt thereof wherein total impurity is less than 0.45% and N-oxide impurity is less than 0.3% after 3 month accelerated stability study.
A stable pharmaceutical composition of asenapine or pharmaceutically acceptable salt thereof with above mentioned level of impurity is achieved by using antioxidant during preparation of pharmaceutical composition.
For the purpose of present invention, an antioxidant is at least about 0.10% by weight of total composition, more preferably at least about 0.12% of total composition.
For the purpose of present invention, an antioxidant is in range of 0.10 to 0.25 % of total composition.
As per the preferred embodiment of the invention, antioxidant is selected from, but not limited to Butylated hydroxytoluene (BHT) and Butylated hydroxyanisole (BHA) or mixture thereof.
From the experiment, it was found that it is advantageous to use water-soluble/swellable excipients to prepare pharmaceutical composition for sublingual or buccal administration of Asenapine or pharmaceutically acceptable salt thereof. The use of water soluble/swellable excipients optionally with or without surfactant helps to improve the dissolution and ultimately bioavailability or to prepare bioequivalent pharmaceutical composition of Asenapine to marketed product.
As per the preferred embodiment of the invention, a stable pharmaceutical composition of Asenapine or pharmaceutically acceptable salt thereof comprises water soluble diluent, water soluble/swellable binder, disintegrant along with anti-oxidants optionally one or more surfactant and/or one or more pharmaceutically acceptable excipients.
For the purpose of the present invention, a water soluble diluent is at least about 50% by weight of total composition.
As per the more preferred embodiment of the invention, water soluble diluent is selected from, but not limited to lactose, mannitol, xylitol, sorbitol, calcium sulfate dihydrate, inositol, dextrin, calcium sulfate anhydrous, fructose, kaolin, sugar compressible, sucrose, lactitol, dextrates, confectioner's sugar, sucrose, sodium chloride, dextrose, cyclodextrin or any combination thereof.
As per the most preferred embodiment of the invention, water soluble diluent is selected from, but not limited to lactose, mannitol, xylitol, sorbitol or any combination thereof.
For the purpose of the present invention, a water soluble/swellable binder is about at least about 2.5% by weight of total composition
As per the more preferred embodiment of the invention, water soluble/swellable binder is selected from but not limited to polyvinyl pyrrolidone, starch, gelatin, sucrose, lactose, cellulose derivative like Hydroxypropyl methyl cellulose, Hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxylmethyl cellulose or mixture of any thereof.
As per the most preferred embodiment of the invention, water soluble/swellable binder is selected from polyvinyl pyrrolidone, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose or mixture of thereof.
For the purpose of the present invention, a disintegrant is at least about 15% by weight of total composition.
As per the more preferred embodiment of the invention, disintegrant is selected form, but not limited to cross-linked carboxymethylcellulose sodium, cross-linked polyvinylpyrrolidone, pregelatinized starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium alginate, sodium starch glycolate, crospovidone, croscarmellose sodium and low substituted hydroxyl propyl cellulose or mixture thereof.
As per the preferred embodiment of the invention, disintegrant is used intra-granular and extragranular in the pharmaceutical composition.
As per another embodiment of the invention, intra-granular and extragranular disintegrant is same or different.
As per another embodiment of the invention, one or more pharmaceutically acceptable excipient are selected from, but not limited to lubricant, glidant, sweeteners, flavoring agent, coloring agent, antiadherents and mixture thereof. Other excipients known in the field of pharmaceutical composition may be also used.
For the purpose of the present invention, a surfactant is at least about 0.4% by weight of total composition.
As per another embodiment of the invention, one or more surfactant is selected from, but not limited to ionic, nonionic.
For the purpose of the present invention, Ionic surfactants may include one or more of anionic, cationic or zwitterionic surfactants.
For the purpose of the present invention, anionic surfactant is selected from, but not limited to one or more of sodium lauryl sulphate, sodium dodecyl sulphate, ammonium lauryl sulphate, alkyl benzene sulfonate, perfluorooctanoate, perfluorooctanesulfonate etc.; cationic surfactants may be selected from benzalkonium chloride, benzethonium chloride, polyethoxylated tallow amine, cetylpyridinium chloride, cetyl trimethylammonium bromide, hexadecyl trimethyl ammonium bromide and other alkyltrimethyl ammonium salts etc.; or amphoteric surfactants may be selected from dodecyl betaine, cocamidopropyl betaine, cocoampho glycinate etc. The ionic surfactants may also include alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithins and hydrogenated lecithins; lysolecithins and hydrogenated lysolecithins; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; acyl lactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides, and the like.
For the purpose of the present invention, cationic surfactants is selected from, but not limited to one or more of quaternary ammonium compounds, such as benzalkonium chloride, cetyl trimethyl ammonium bromide and dodecyl dimethyl ammonium bromide, hexadecyl (cetyl) trimethylammonium bromide, dodecyl pyridinium chloride, lauryl dimethyl benzyl ammonium chloride, acyl carnitine hydrochlorides, alkyl pyridinium halides, dodecylamine hydrochloride, and the like.
For the purpose of the present invention, zwitterionic surfactants is selected from, but not limited to one or more of alkyl betaines, alkyl amidopropyl betaines, alkyl sulphobetaines, alkyl glycinates, alkyl carboxyglycinates, alkyl amphopropionates, alkyl amidopropyl hydroxysultaines, acyl taurates and acyl glutamates wherein the alkyl and acyl groups have from 8 to 18 carbon atoms such as cocamidopropyl betaine, sodium cocoamphoacetate, cocamidopropyl hydroxysultaine, and sodium cocamphopropionate, and the like.
For the purpose of the present invention, non-ionic surfactant is selected from, but not limited to one or more of ethyleneoxide/propyleneoxide copolymers referred to hereinbelow as poloxamers, such as poloxamer 124 sold under the brand name Synperonic.RTM. PE/L44; poloxamer 188 sold under the brand name Pluronic.RTM. F68 or Synperonic.RTM. PE/F68; poloxamer 237 sold under the brand name Pluronic.RTM. F87 or Synperonic.RTM. PE/F87; poloxamer 338 sold under the brand name Synperonic.RTM. PE/F108 or poloxamer 407 sold under the brand name Pluronic.RTM. F127, Synperonic.RTM. PE/F127 or Lutrol.RTM. F127. polyethoxylated castor oils such as those sold under the brand name Cremophor.RTM. RH40. ethoxylated polysorbates, such as polysorbate 20, polysorbate 40, polysorbate 60 and polysorbate 80 sold respectively under the brand names Tween.RTM. 20, Tween.RTM. 40, Tween.RTM. 60 and Tween.RTM. 80. or alternatively polyethylene hydroxystearates such as polyethylene hydroxystearate 660 sold under the brand name Solutol.RTM. HS15.
As per more preferred embodiment, a stable pharmaceutical composition comprising Asenapine or pharmaceutically acceptable salt thereof and an antioxidant selected from Butylated hydroxytoluene and Butylated hydroxyanisole or mixture thereof
As per more preferred embodiment, a stable pharmaceutical composition comprising Asenapine or pharmaceutically acceptable salt thereof, an antioxidant is at least about 0.10%, a water soluble diluent is at least about 50%, a water soluble/swellable binder is at least about 2.5%, disintegrant is at least about 15% and optionally surfactant is at least about 0.4% by weight of total composition.
As per more preferred embodiment, a stable pharmaceutical composition comprising Asenapine maleate, an antioxidant is selected from Butylated hydroxytoluene, Butylated hydroxyanisole or combination thereof, a water soluble diluent is selected from lactose, mannitol, xylitol, and sorbitol, a water soluble/sellable binder is selected from polyvinylpyrrolidone and hydroxypropyl cellulose and disintegrant.
As per more preferred embodiment, a stable pharmaceutical composition comprising Asenapine maleate, butylated hydroxytoluene butylated hydroxyanisole, mannitol, polyvinylpyrrolidone or hydroxypropyl cellulose, low-substituted hydroxyproopyl cellulose and optionally polysorbate 80.
As per the another aspect of the invention is to provide a process for preparation of pharmaceutical composition of asenapine or pharmaceutical acceptable salt thereof for sublingual or buccal administration having improved bioavailability or is bioequivalent to marketed product.
It has been found that the inventive process of the invention offer advantage compared to prior art process to use asenapine or pharmaceutically acceptable salt thereof in any form i.e. irrespective of any polymorphic form or amorphous form or combination of any two polymorphic form or combination of amorphous and polymorphic form and without any limitation or of specific particle size as input material for preparation of pharmaceutical composition.
The advantage of invented process is that irrespective of any form (i.e. any polymorphic or amorphous with any particle size) of asenapine or pharmaceutically acceptable salt thereof used as input material, in the final pharmaceutical composition asenapine or pharmaceutically acceptable salt thereof would be in amorphous form only.
As per the preferred embodiment of the invention, process for preparation of pharmaceutical composition of asenapine or pharmaceutically acceptable salt thereof comprises the step of:
a). Dissolve anti-oxidant with or without water soluble/swellable binder(s) and/or surfactant in organic solvent or mixture of organic solvent;
b). add asenapine or pharmaceutically acceptable salt thereof with or without water soluble/swellable binder(s) in solution of step a);
c). granulate the mixture of water soluble diluent(s) and disintegrant(s) with solution of step b) and dry the resulted granules;
d). mix the granules of step c) with one or more pharmaceutically acceptable excipient selected from disintegrant, lubricant, glidant, sweeteners, flavoring agent, coloring agent, antiadherents or mixture thereof and
e). fill the granules of step d) in capsules or compressed in to tablet.
For the purpose of present invention granulation can be performed in rapid mixture granulator (RMG) or top spray granulation in Fluid bed processor (FBP)
As per the preferred embodiment of the invention, organic solvent is selected form, but not limited to dicholormethane, alcohols such as methanol, ethanol, n-propanol, isopropanol, and various isomers of butanol; ketones, such as acetone, methyl ethyl ketone, methyl iso-butyl ketone, and cyclohexanone; esters, such as methyl acetate, ethyl acetate, and propyl acetate; ethers, such as dimethyl ether, tetrahydrofuran, methyl tetrahydrofuran, 1,3-dioxolane, and 1,4-dioxane; alkanes, such as butane and pentane; alkenes, such as pentene and cyclohexene; nitriles, such as acetonitrile; alkyl halides, such as Dichloromethane (methylene chloride) , trichloroethane, chloroform, and trichloroethylene; aromatics, such as toluene; and mixtures thereof.
As per the more preferred embodiment of the invention, organic solvent is mixture of one or more organic solvent.
As per the more preferred embodiment of the invention, organic solvent is mixture of dicholormethane or isopropylalcohol.
As per the most preferred embodiment, a pharmaceutical composition comprising asenapine or pharmaceutically acceptable salt thereof, antioxidant, water soluble/swellable binder, water soluble diluent, disintegrant and optionally one or more surfactant and/or one or more pharmaceutically acceptable excipient as per the present invention is bioequivalent to marketed product Saphris® /Sycrest®.
As per another embodiment of the invention, a pharmaceutical composition comprising asenapine or pharmaceutically acceptable salt thereof, antioxidant. water soluble/swellable binder, water soluble diluent, disintegrant, surfactant and optionally one or more pharmaceutically acceptable excipient as per the present invention is bioequivalent to marketed product Saphris® /Sycrest®.
Comparative Example: In following examples Asenapine Maleate tablet is prepared without using antioxidant and/or surfactant in composition and prior art process of spray drying.
Comparative Example 1 & 2
Sr. No. Name of Ingredients % w/w
Example 1 Example 2
Intra-granular
1 Asenapine Maleate 8.47 15.63
2 Polyvinylpyrrolidone (Povidone) 7.23 6.67
3 Mannitol 52.37 48.26
4 Low substituted -HPC 12.05 11.11
Extra-granular
5 Low substituted -HPC 18.07 16.67
6 Sodium Stearyl Fumarate 1.81 1.67
Total 100 100
Process for manufacturing:
a). Dissolve polyvinylpyrrolidone and asenapine maleate in Methanol;
b). mix mannitol and low substituted-HPC and load in Fluid bed processor (FBP);
c). spray solution of Step a) on blend of step b) and dry the granules;
d). mix the granules of step c) with low substituted-HPC and sodium stearyl fumarate and
e). compress the granules of step d) in to tablet.
The following example is intended to be illustrative and non-limiting, and represent specific embodiments of the present invention.
Example 1
Sr. No. Name of Ingredients % w/w
Intra-granular
1 Asenapine Maleate 10.81
2 Hydroxypropyl Cellulose (HPC) 3.08
3 Mannitol 65.80
4 Butylated Hydroxytoluene 0.15
5 Low substituted -HPC 9.61
Extra-granular
6 Low substituted -HPC 9.61
7 Sodium Stearyl Fumarate 0.92
Total 100
Process for manufacturing: Granulation in RMG
a). Dissolve butylated hydroxytoluene in mixture of dichloromethane and isopropyl alcohol;
b). add asenapine maleate and HPC in solution of step a);
c). granulate the mixture of mannitol and low substituted-HPC with solution of step b) and dry the resulted granules;
d). mix the granules of step c) with low substituted-HPC and sodium stearyl fumarate and
e). compress the granules of step d) in to tablet.

Example 2
Sr. No. Name of Ingredients % w/w
Intra-granular
1 Asenapine Maleate 10.82
2 Polyvinylpyrrolidone (Povidone) 4.61
3 Mannitol 63.84
4 Butylated Hydroxytoluene 0.15
5 Butylated Hydroxy Anisole 0.19
5 Low substituted -HPC 9.62
Extra-granular
6 Low substituted -HPC 9.62
7 Sodium Stearyl Fumarate 1.15
Total 100
Process for manufacturing: Top Spray Granulation
a). Dissolve polyvinylpyrrolidone, butylated hydroxytoluene and butylated hydroxy anisole in methanol;
b). add asenapine maleate in solution of step a);
c). granulate the mixture of mannitol and low substituted-HPC with solution of step b) and dry the resulted granules;
d). mix the granules of step c) with low substituted-HPC and sodium stearyl fumarate and
e). compress the granules of step d) in to tablet.
Example 3
Sr. No. Name of Ingredients % w/w
Intra-granular
1 Asenapine Maleate 10.82
2 Hydroxypropyl Cellulose (HPC) 3.07
3 Mannitol 64.57
4 Butylated Hydroxytoluene 0.15
5 Butylated Hydroxy Anisole 0.19
6 Polysorbate 80 0.81
7 Low substituted -HPC 9.62
Extra-granular
8 Low substituted -HPC 9.62
9 Sodium Stearyl Fumarate 1.15
Total 100
Process for manufacturing: Granulation in RMG
a). Dissolve HPC, butylated hydroxytoluene, butylated hydroxy anisole and Polysorbate 80 in mixture of dichloromethane and isopropyl alcohol;
b). add asenapine or pharmaceutically acceptable salt thereof in solution of step a);
c). granulate mixture of Mannitol and low substituted-HPC with solution of step b) and dry the resulted granules;
d). mix the granules of step c) with low substituted-HPC and sodium stearyl fumarate and
e). compress the granules of step d) in to tablet.
Example 4
Sr. No. Name of Ingredients % w/w
Intra-granular
1 Asenapine Maleate 10.82
2 Hydroxypropyl Cellulose (HPC) 3.07
3 Mannitol 64.84
4 Butylated Hydroxytoluene 0.15
5 Butylated Hydroxy Anisole 0.19
6 Polysorbate 80 0.54
7 Low substituted -HPC 9.62
Extra-granular
8 Low substituted -HPC 9.62
9 Sodium Stearyl Fumarate 1.15
Total 100

Process for manufacturing: Granulation in RMG
a). Dissolve HPC, butylated hydroxytoluene, butylated hydroxy anisole and Polysorbate 80 in mixture of dichloromethane and isopropyl Alcohol;
b). add asenapine or pharmaceutically acceptable salt thereof in solution of step a);
c). granulate mixture of mannitol and low substituted-HPC with solution of step b) and dry the resulted granules;
d). mix the granules of step c) with low substituted-HPC and sodium stearyl fumarate and
e). compress the granules of step d) in to tablet.

Example 5: Stability Results
The stability study was performed on tablets prepared according to above comparative examples, example 1-5 and marketed product Saphris®
Table: 1: Stability Study
Impurity profile (%) Saphris® Comparative Example
Time Initial 3M ACC* Initial 2W 60°C 1M ACC* 3M ACC*
N-Oxide 0.32 1.096 0.11 1.776 0.536 1.084
Highest Unknown ND 0.024 0.045 0.157 0.064 0.119
Total 0.32 1.271 0.325 2.452 0.828 1.597
Impurity profile (%) Example 1
Time Initial 1W 60°C 2W 60°C 1M ACC* 3M ACC*
N-Oxide 0.016 0.023 0.021 0.016 0.187
Highest Unknown 0.074 0.037 0.015 0.019 0.027
Total 0.163 0.095 0.114 0.048 0.364
Impurity profile (%) Example 2
Time Initial 1W 60°C 2W 60°C 1M ACC* 3M ACC*
N-Oxide 0.026 0.162 0.271 0.11 0.275
Highest Unknown 0.023 0.006 0.084 0.062 0.035
Total 0.066 0.279 0.473 0.31 0.399
Impurity profile (%) Example 3
Time Initial 1W 60°C 2W 60°C 1M ACC* 3M ACC*
N-Oxide 0.038 0.035 0.193 0.11 0.126
Highest Unknown - 0.02 0.091 0.053 0.067
Total 0.059 0.077 0.361 0.223 0.236
Impurity profile (%) Example 4
Time Initial 1W 60°C 2W 60°C 1M ACC*
N-Oxide 0.022 0.024 0.017 0.036
Highest Unknown 0.022 0.016 0.011 0.036
Total 0.08 0.088 0.026 0.095
*Accelerated condition: 40°C ± 2°C/75% RH ± 5% RH
The results of Table 1 reveled that antioxidant used in the pharmaceutical compositions as per the present invention is able to maintain the level of N-Oxide impurity less than 0.04 compare to comparative example wherein the level of N-Oxide impurity is greater than 0.1.

Example 6
Sr. No. Name of Ingredients % w/w
Intra-granular
1 Asenapine Maleate 11.72
2 Polyvinylpyrrolidone (Povidone) 5.00
3 Mannitol 60.83
4 Butylated Hydroxytoluene 0.17
5 Butylated Hydroxy Anisole 0.21
5 Low substituted -HPC 10.42
Extra-granular
6 Low substituted -HPC 10.42
7 Sodium Stearyl Fumarate 1.25
Total 100

Process for manufacturing: Top Spray Granulation
a). Dissolve polyvinylpyrrolidone, butylated hydroxytoluene and butylated hydroxy Anisole in methanol;
b). add asenapine maleate in solution of step a);
c). granulate the mixture of mannitol and low substituted-HPC with solution of step b) and dry the resulted granules;
d). mix the granules of step c) with low substituted-HPC and sodium stearyl fumarate and
e). compress the granules of step d) in to tablet.

Example 7: Comparative dissolution study

The Comparative dissolution study was performed on tablet as per the Example 2 and 4 and marketed product Saphris® 10 mg Tablet in USP Type II at 50 RPM.

Table 3: Comparative dissolution study

% Drug Release
Media 0.1N HCl
Time (min) Saphris® 10 mg Example 2 Example 4
3 76 100 97
5 97 103 104
15 101 102 104

Media pH 4.5 Acetate Buffer
Time (min) Saphris® 10 mg Example 2 Example 4
3 73 90 99
5 96 99 101
15 100 102 102

Media pH 6.8 Phosphate Buffer
Time (min) Saphris® 10 mg Example 2 Example 4
3 66 55 70
5 81 68 81
15 88 81 82

Media Purified Water
Time (min) Saphris® 10 mg Example 2 Example 4
3 60 39 61
5 93 80 95
15 101 94 100

,CLAIMS:We Claim,

1. A stable pharmaceutical composition comprising asenapine or pharmaceutically acceptable salt thereof and antioxidant.
2. The stable pharmaceutical composition as claimed in claim 1 further comprising water soluble diluent, water soluble/swellable binder, disintegrant, optionally one or more surfactant and one or more pharmaceutically acceptable excipient.
3. The stable pharmaceutical composition as claimed in claim 1 is for sublingual or buccal administration.
4. The stable pharmaceutical composition as claimed in claim 1, wherein total impurity is less than 0.2% and N-oxide impurity is less than 0.04%.
5. The stable pharmaceutical composition as claimed in claim 1, wherein an antioxidant is selected from butylated hydroxytoluene and butylated hydroxyanisole or mixture thereof.
6. The stable pharmaceutical composition as claimed in claim 1, wherein an antioxidant is at least about 0.10 % by weight of total composition.
7. The stable pharmaceutical composition as claimed in claim 2, wherein a water soluble diluent is at least about 50%, a water soluble/swellable binder is at least about 2.5%, disintegrant is at least about 15% and optionally surfactant is at least about 0.4% by weight of total composition.
8. A process for preparation of the stable pharmaceutical composition as claimed in claim 2 comprising the step of
a). dissolve anti-oxidant with or without water soluble/swellable binder(s) and/or surfactant in organic solvent or mixture of organic solvent;
b). add asenapine or pharmaceutically acceptable salt thereof with or without water soluble/swellable binder(s) in solution of step a);
c). granulate the mixture of water soluble diluent(s) and disintegrant(s) with solution of step b) and dry the resulted granules;
d). mix the granules of step c) with one or more pharmaceutically acceptable excipient selected from disintegrant, lubricant, glidant, sweeteners, flavoring agent, coloring agent, antiadherents or mixture thereof and
e). fill the granules of step d) in capsules or compressed in to tablet.
9. The stable pharmaceutical composition as claimed in claim 2 releases at least about 80% of asenapine within 15 min.