Field of the invention:

The present invention relates to novel and orally disintegrating sublingual pharmaceutical composition comprising asenapine and its pharmaceutically acceptable salts thereof, and methods of preparing the same. In particular, the invention relates to granulated pharmaceutical composition of asenapine and its salts thereof.

Background of the invention:

Asenapine is an atypical antipsychotic drug used to treat schizophrenia and bipolar disorders. Asenapine maleate is chemically known as trans-5-chloro-2-methyl-2,3,3a,12b- tetrahydro-lH-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole (2Z)-2-Butenediaote (1:1) and has the structural formula-1:

Asenapine maleate was first disclosed in US4,145,434. The compound is described as having CNS depressant activity and antihistamine and antiserotonin activities. Sublingual or buccal pharmaceutical compositions of asenapine maleate was disclosed in US5,763,476 (Herein after referred as '476' patent). It is marketed as maleate salt under the brand name "SAPHRIS" sublingual tablets containing 5mg and 10mg in the United States by Schering-Plough for the treatment of schizophrenia and acute mania associated with bipolar disorder. The SAPHRIS sublingual tablets reportedly contains asenapine maleate as active principle and the following inactive ingrediants such as gelatin,mannitol,sucralose and blackcherry flavour.

An Orally Disintegrating Tablet (ODT) was defined as 'solid-dosage form containing medicinal substances which disintegrates rapidly, usually within a matter of seconds when placed on the tongue. Orally disintegrating pharmaceutical compositions including granules, tablets are convenient oral delivery systems designed to disintegrate rapidly upon contact with aqueous fluids like water, saliva to form a dispersion which can be swallowd easily. Orally disintegrating pharmaceutical compositions are particularly advantageous for patients e.g. pediatric or geriatric patients, having difficulty in swallowing conventional tablets or capsules, or for individuals who may not have difficulty in swallowing but may have an aversion to swallowing conventional tablets or capsules. Orally disintegrating pharmaceutical compositions are also convenient under circumstances in which taking an oral dosage form with water may be inconvenient (e.g. while working or traveling).

Various methods have been used to manufacture orally disintegrating tablets. Many of these methods use unconventional equipment and complicated processing techniques such as lyophilization (freeze-drying) and compressed tableting method. The asenapine maleate (SAPHRIS) ODT's are manufactured by using Lyophilization(freeze-drying) technique. '476' patent discloses orally distintegrating solid compositions which disintegrates within 30 seconds more preferably within 10 seconds in water at 37 °C. '476' patent particularly delt with sublingual and buccal compositions of Asenapine maleate produced by using freeze-drying(Lypholization) process. '476' patent also discloses that, orodispersible tablets were prepared with active pharmaceutical ingredient and a water soluble carrier material like hydrolysed gelatin, mannitol and distill water comprising quickly freeze-drying (Lypholization) soluble composition.

The Lypholization process is an expensive and time consuming process, and the tablets manufactured by using this process are fragile and one cannot stored in backpacks or the bottom of the purse.Moreover, this type of tablets are not suitable for conventional packaging methods and needs sophisticated packaging technology.

Based on the above disadvantages of Lypholization technology which was used in innovators patent, there exists a need for a conventional orally disintegrating pharmaceutical compositions having sufficiently low friability and sufficiently hardness, while maintaining high porosity of the pharmaceutical compositions. The process should be economically viable and should be able to be carried out by conventional equipments and techniques.

The present invention overcomes the problems of prior art, provides orally disintegrating pharmaceutical composition which is having all the required features.

Brief description of the invention:

The present invention relates to novel orally disintegrating pharmaceutical composition comprising of a) Asenapine or its pharmaceutically acceptable salts thereof, one or more suitable b)diluent(s), c)binder, disintegrating agent(s) and e) optionally pharmaceutically acceptable excipient(s) such as lubricants, sweetening agents and flavouring agents.

The first aspect of the present invention provides orally disintegrating pharmaceutical composition comprising asenapine or its pharmaceutically acceptable salts thereof particularly asenapine maleate compound of formula-1 as an active ingredient in an amount from about 1% to 30% preferably 2% to 25% by total weight of the composition.

The second aspect of the present invention provides orally disintegrating pharmaceutical composition comprising asenapine or its pharmaceutically acceptable salts thereof, particularly asenapine maleate, wherein orally disintegrating pharmaceutical composition is an uncoated or coated tablet and the diameter of the tablet ranging from 5 mm to 7 mm.

The third aspect of the present invention provides orally disintegrating tablet comprising asenapine or its pharmaceutically acceptable salts thereof, particularly asenapine maleate having hardness not less than 20 N.

The fourth aspect of the present invention provides orally disintegrating tablet comprising asenapine or its pharmaceutically acceptable salts thereof having low friability not more than 0.5%.

The fifth aspect of the present invention provides orally disintegrating tablet comprising asenapine or its pharmaceutically accptable salts thereof and having dispersion time not more than 60 seconds.

The sixth aspect of the present invention provides orally disintegrating pharmaceutical composition comprising asenapine or its paharmaceutically acceptable salts thereof, wherein orally disintegrating pharmaceutical composition is in the form of granules.

The seventh aspect of the present invention provides a method of producing orally disintegrating pharmaceutical compositions of asenapine maleate by conventional methods known in the art. The method of producing orally disintegrating pharmaceutical compositions comprises direct compression, dry granulation or wet granulation.

The eighth aspect of the present invention relates to orally disintegrating pharmaceutical composition having dissolution time from 3 minutes (80% to 90%) to 5 minutes (90% to 100%).

Detailed description of the invention:

The present invention relates to Novel oral disintegrating sublingual pharmaceutical compostion comprising atypical antipsychotic drug asenapine and its pharmaceutically acceptable salts selected from maleate, oxalate, succinate salts, preferably maleate salt of asenapine.The orally disintegrating pharmaceutical compositon of the present invention optionally may comprise pharmaceutically acceptable complexes, salts, polymorphs, hydrates and solvates of compositions of the invention optionally may comprise pharmaceutically acceptable complexes, salts, polymorphs, hydrates and solvates of asenapine, preferably asenapine maleate.

The present invention provides orally disintegrating sublingual pharmaceutical compositions comprising asenapine or its pharmaceutically acceptable salts thereof, as an active ingredient, diluent(s) and disintegrating agent(s) and optionally other suitable pharmaceutically acceptable excipient(s).

The term "orally disintegrating pharmaceutical compositions " as used herein refers to the ability of a pharmaceutical composition (e.g., granules, a tablet for oral administration) to disintegrate rapidly when contacted with a fluid, particularly an aqueous fluid (e.g., water, bodily fluids (e.g., saliva), and the like), to form a suspension, slurry or dispersion, which facilitates administration of the contents of the composition (e.g., by forming a suspension, slurry or dispersion, which is easily swallowed). According to the present invention, oral granular formulations such as granules, powders and fine granules can also be prepared.

The term "orally" includes the region within the interior of the mouth, including, but not limited to, the buccal cavity (e.g., anterior to the teeth and gums) as well as the sublingual and supralingual spaces, and the like.

The first aspect of the present invention relates to an orally disintegrating pharmaceutical composition comprising asenapine or its pharmaceutically acceptable salts thereof, particularly asenapine maleate of formula-1 as an active ingredient in an amount from about 1% to 30% preferably 2% to 25% by total weight of the composition and diluents , binders , disintegrants, bindind fluids, lubricants, sweetening agents,flavouring agents and other excipients thereof.

The second aspect of the present invention provides orally disintegrating pharmaceutical compositions comprising asenapine and pharmaceutically acceptable salts thereof, particularly asenapine maleate, wherein the orally disintegrating pharmaceutical composition (e.g., granules, a tablet for oral administration),particularly in an uncoated or coated tablet form and the diameter of the tablet preferably ranging from 5 mm to 7 mm preferably 6 mm of diameter.

The third aspect of the present invention refers to hardness of orally disintegrating tablet comprising asenapine or its pharmaceutically acceptable salts thereof, particularly asenapine maleate. Hardness refers to the diametral breaking strength as measured by conventional pharmaceutical tablet hardness determination methods, which are well known in the art. A higher hardness value, sometimes measured in Newtons (N), the hardness of the tablet of the present invention preferably ranges from about 50 N to about 20 N, and more preferably from about 45 N to about 35 N, and most preferably from about 40 N to about 20 N.

The fourth aspect of the present invention provides orally disintegrating tablet comprising asenapine or its pharmaceutically acceptable salts thereof having low friability not more than 1%, preferably 0.8%, more preferably 0.5%.

The fifth aspect of the present invention provides orally disintegrating sublingual tablet comprising asenapine or its pharmaceutically accptable salts thereof and having dispersion time not more than 60 seconds, when contacted with an aqueous fluid (e.g., water, saliva, or abuffered solution), to form a slurry, a dispersion or a suspension, which can be administered (e.g., swallowed) easily. The dispersion time of the pharmaceutical compositions of the present invention can range from within about 30 seconds to within about 60 seconds, more preferably from within about 40 seconds to within about 50 seconds.

The sixth aspect of the present invention provides orally disintegrating pharmaceutical compositions comprising asenapine or its pharmaceutically acceptable salts thereof, wherein orally disintegrating pharmaceutical composition is in form of granules.

The seventh aspect of the present invention provides a method of producing orally disintegrating pharmaceutical compositions of Asenapine maleate by conventional methods known in the art. The method of producing orally disintegrating pharmaceutical compositions comprises direct compression, dry granulation or wet granulation, and the wet granulation process involves the following steps;

a) Asenapine maleate and diluent are mixing to get uniform mass,

b) the prefered binder was dissolving in suitable binder fluid or solvent,

c) adding the above formed binder solution to the step-a slowly and to make granules,

d) drying the obtained granules,

e) adding a mixture of the second diluent, disintegrant, sweetening agent and flavouring agent, to the above obtained granules,

f) adding the lubricant to the above mixture to get uniform mass,

g) compressing the above blend into tablets by using suitable punches.

The eighth aspect of the present invention relates to orally disintegrating pharmaceutical composition having dissolution time from 3 minutes (80% to 90%) to 5 minutes (90% to 100%).

The present invention relates to orally disintegrating pharmaceutical composition comprising asenapine and its pharmaceutically acceptable salts thereof, particularly asenapine maleate is in either crystalline or in amorphous form.

According to the first aspect of the present invention, the diluents are selected from but are not limited to various cellulose derivatives such as microcrystallinecellulose(MCC) and the like, mannitol, lactose, dextrose, sorbitol, starch, xylitol, pearlitol flash, F-Melt, maltose, dicalcium phosphate and their derivatives thereof, and the preferred diluents are microcrystalline cellulose,pearlitol flash and F-Melt.

The binders are selected from but are not limited to various cellulose derivatives such as low molecularweight hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose and the like, methacrylate copolymers, amino alkyl methacrylate copolymers and the like, povidone and the like, sodium alginate and the like, and the preferred binders are hydroxypropylmethyl cellulose , hydroxypropylcellulose and povidone K 30.

The dintegrants are selected from but are not limited to starch or its derivative like pregelatinised starch, sodium carboxymethyl starch, sodium starch glycolate and the like, various cellulose derivatives like crosslinked sodiumcarboxymethyl cellulose, low substituted hydroxypropylcellulose, croscarmellose calcium and the like, crosspovidone and the like, alginic acid and various ion exchange resins, and the preferred disintegrants are cross linked sodium carboxymethyl cellulose (Ac-di-sol),croscarmellose calcium and crospovidone.

The lubricants may be selected from but are not limited to talc, magnesium stearate, calcium stearate, stearic acid,sodium stearyl fumarate and the like, and the preferred lubricants are magnesium stearate, calcium stearate, stearic acid,sodium stearyl fumarate.

The sweeteners may be selected form but are not limited to aspartame, acesulfam potassium, sucralose, xylitol,saccharine, saccharine potassium, sugars and the like, and the preferred sweetners are aspartame, sucralose, acesulfam potassium and sugars. The flavors may be for example mint flavors, orange flavor, lemon flavor, banana flavor,strawberry flavor, magnasweet, grape flavor and the like, and the preferred flavouring agents are peppermint flavour , strawberry flavor, magnasweet, grape flavor and black cherry flavor.

The binder fluids or solvents are selected from but are not limited to aqueous or non-aqueous or their mixtures thereof, for example may be isopropyl alcohol, acetone and ethanol.

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.

Example-1:

Composition of Tablets equivalent to i0 mg and 5mg of asenapine.

Manufacturing process:

Asenapine maleate was mixed with microcrystalline cellulose to get uniform mass. Then povidone taken in isopropyl alcohol was added to the mixture of Asenapine maleate and microcrystalline cellulose to provide granules, which were air dried and and passed through 30 mesh The mixture of F-Melt, croscarmellose sodium, Aspartame, Peppermint was prepared and passed through 40 mesh. The mixture was then added to the the air dried granules. Magnesium stearate was then passed though 60 mesh and mixed with the above ingredients throughly to get a uniform mass, which was compressed into tablets.

Example-2:

Composition of Tablets equivalent to 10 mg and 5mg of asenapine.

Manufacturing process:

The above composition was prepared according to the Example-1, except that crospovidone was used in place of croscaramellose sodium

ExampIe-3:

Composition of Tablets equivalent to 10 mg and 5mg of asenapine.

Manufacturing process:

Asenapine maleate was mixed with microcrystalline cellulose to get uniform mass. Then povidone taken in isopropyl alcohol was added to the mixture of Asenapine maleate and microcrystalline cellulose to provide granules, which were air dried and and passed through 30 mesh The mixture of Pearlitol flash , croscarmellose sodium, Aspartame, Peppermint was prepared and passed through 40 mesh. The mixture was then added to the the air dried granules. Magnesium stearate was then passed though 60 mesh and mixed with the above ingredients throughly to get a uniform mass, which was compressed into tablets.

Example-4:

Manufacturing process:

The above composition was prepared according to the Example-3, except that crospovidone was used in place of croscaramellose sodium.

We claim:

1. A novel and orally disintegrating sublingual pharmaceutical composition comprising, asenapine or its salts thereof as an active ingredient,in combination with one or more of,

a) diluent(s),

b) binding agents,

c) solvents or binding fluids,

d) disintegrating agent(s) and

e) optionally one or more suitable pharmaceutically acceptable excipient(s) such as lubricants, sweetners and flavoring agents.

2. According to claim-1, wherein the preferred salt is selected from oxalate, maleate and succinate salts, preferably asenapine maleate which is characterized from about 1% to 30% , preferably 2% to 25% by weight of the total composition.

3. According to claim-1, wherein the orally disintegrating sublingual pharmaceutical composition is particularly in an uncoated or coated tablet form having hardness not less than 20 N, preferably 20 N - 40 N.

4. An orally disintegrating sublingual pharmaceutical composition according to claim-1, having the dispersion time of not more than 60 seconds, preferably in between 40-50 seconds.

5. An orally disintegrating sublingual pharmaceutical composition according to claim 1, wherein;

a) the diluents are selected from microcrystalline cellulose, pearlitol flash and F-Melt or their mixture thereof

b) the disintegrating agents are selected from either cross-linked sodium carboxymethyl cellulose (Ac-di-sol) and crospovidone,

c) the binding agent is preferably povidone,

e) the lubricant is magnesium stearate.

6. A method of manufacturing of an orally disintegrating sublingual pharmaceutical composition comprising wet granulation or dry granulation preferably wet granulation method comprising;

a) Asenapine maleate and diluent are mixing to get uniform mass,

b) the prefered binder was dissolving in a suitable binder fluid or solvent,

c) adding the above formed binder solution to the mixture of step-a,

d) drying the above obtained granules,

e) adding the mixture of second diluent, disintegrant, sweetening agent and flavouring agent to the step-d,

f) adding the lubricant to the above mixture,

g) compressing the above blend into tablets.

7. An orally disintegrating sublingual pharmaceutical composition which comprises the therapeutical amount of asenapine maleate, microcrystalline cellulose, F-melt, crospovidone, povidone, magnesium stearate, aspartame and peppermint flavour.

8. An orally disintegrating sublingual pharmaceutical composition which comprises the therapeutical amount of asenapine maleate, microcrystalline cellulose, F-melt, croscarmellose sodium, povidone, magnesium stearate, aspartame and peppermint flavour.

9. An orally disintegrating sublingual pharmaceutical composition is particularly in an uncoated or coated tablet having diameter ranging from 5 mm to 7 mm preferably of 6 mm.

10. An orally disintegrating sublingual pharmaceutical composition is particularly in a form of tablet having disollution time ranging from 3 min to 5 min with 80% to 98% disollution respectively.