FORM 2
THE PATENTS ACT 1970 (39 of 1970)
& THE PATENTS RULE 2003 PROVISIONAL SPECIFICATION
(Section 10 and rule 13)
"PHARMACEUTICAL COMPOSITIONS OF AMORPHOUS ASENAPINE
MALEATE"
Glenmark Generics Limited
an Indian Company, registered Under the Indian company's Act 1957-
having office at
Glenmark House,
HDO - Corporate Bldg,
Wing -A, B. D. Sawant Marg, Chakala,
Andheri (East), Mumbai - 400 099, INDIA
THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED

FIELD OF INVENTION
[0001] The present invention relates to the pharmaceutical compositions comprising amorphous asenapine maleate and a process for preparing the same.
BACKGROUND OF THE INVENTION
[0002] Asenapine belongs to the class dibenzo-oxepino pyrroles. Asenapine is a racemic mixture of molecules in the trans orientation. Chemically it is designated as trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-lH-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole.The compound and pharmaceutically acceptable salts thereof were disclosed in U.S. Pat .No.4145434. Asenapine is a broad-spectrum, high potency serotonin, noradrenaline and dopamine antagonist. As described in patent application WO 1999032108, asenapine exhibits potential antipsychotic activity and may be useful for treating depression. Asenapine is marketed under the trade name SAPHRIS® by Merck and Co. for the treatment of schizophrenia and for acute management, as monotherapy of adjunctive therapy, of manic or mixed episodes associated with bipolar I disorder.
[0003] U.S. Pat. No.7741358 discloses crystalline polymorphs of asenapine maleate namely monoclinic form (Form H) and orthorhombic form (Form L). For the sublingual administration of asenapine, it is highly desired that asenapine composition disintegrates and dissolves faster in an oral cavity. In accordance with the present invention, inventor provides asenapine sublingual tablets containing alternative polymorph such as amorphous polymorph which disintegrates and dissolves faster in an oral cavity.
SUMMARY OF INVENTION
[0004] The present invention relate to a novel sublingual pharmaceutical composition comprising amorphous asenapine maleate.

[0005] In one of the aspect, the present invention provides a novel sublingual pharmaceutical composition comprising amorphous asenapine maleate and one or more excipients.
[0006] In another aspect, the present invention provides a novel sublingual pharmaceutical composition comprising amorphous asenapine maleate and one or more excipients wherein the composition disintegrates within 30 seconds to 60 seconds.
[0007] In another aspect, the present invention provides a novel sublingual pharmaceutical composition comprising amorphous asenapine maleate and one or more excipients wherein asenapine dissolves within 5 to 10 minutes.
[0008] In another aspect, the present invention also provides a method of manufacturing of a novel sublingual composition comprising amorphous asenapine maleate and one or more excipients.
DETAILED DESCRIPTION OF INVENTION
[0009] It is to be understood that the descriptions of the present invention have been simplified to illustrate elements that are relevant for a clear understanding of the present invention, while eliminating, for the purpose of clarity, many other elements found in typical pharmaceutical compositions and methods of stabilization. Those of ordinary skill in the art will recognize that other elements and/or steps are desirable and/or required in implementing the present invention. Furthermore, the embodiments identified and illustrated herein are for exemplary purposes only, and are not meant to be exclusive or limited in their description of the present invention.
[0010] The phrase "commercially relevant times" as used herein, meant that throughout the reasonable shelf time.

[0011] As used herein, the term "drug" or "active ingredient" or "active" shall refer to asenapine base or asenapine maleate.
[0012] Orally administered dosage forms e.g., tablets, capsules are convenient dosage form for many drugs but they are challenging to formulate. The sublingual route of administration produces faster onset of action than orally ingested tablet and portion absorbed through the sublingual blood vessels bypasses the hepatic first pass processes. The tablets that are fast disintegrate or dissolve rapidly in patients mouth are convenient for young children, old patients and patients with swallowing difficulties. For these formulations small volume of saliva is usually sufficient to result in tablet disintegration in the oral cavity. They are popular as novel drug delivery system because they are easy to administer and lead to better patient compliance. The time for disintegration of orally disintegrated tablets are generally considered as less than one minute. They are categorized by high porosity, low density and low hardness. When administered, an in-situ suspension is created in oral cavity as tablet disintegrates and is subsequently swallowed.
[0013] The present invention relates to a novel sublingual pharmaceutical composition comprising amorphous asenapine maleate.
[0014] U.S. 5763476 discloses sublingual or buccal tablet of asenapine maleate which is prepared by freeze drying (Lyophilization) method. Composition described in this patent disintegrates within 10 seconds in water at 37°C. However the composition described in 5763476, are expensive, difficult to optimize and manufacture, and are equally time consuming,
[0015] Based on the above disadvantages, there exists a need for an easy to manufacture and cost effective sublingual composition of asenapine or its pharmaceutical acceptable salts thereof which will be bioequivalent to marketed preparation.
[0016] Polymorphic forms occur where the same composition of matter crystallizes in a different lattice arrangement resulting in different thermodynamic properties and stabilities specific to the particular polymorph form. In cases where two or more polymorph substances can be

produced, it is desirable to have a method to make both polymorphs in pure form. In deciding which polymorph is preferable, the numerous properties of the polymorphs must be compared and the preferred polymorph chosen based on the many physical property variables. It is entirely possible that one polymorph form can be preferable in some circumstances where certain aspects such as ease of preparation, stability, etc. are deemed to be critical. In other situations, a different polymorph maybe preferred for greater solubility and/or superior pharmacokinetics.
[0017] Literature suggests that asenapine or its pharmaceutical acceptable salts thereof exists in different polymorphs. Its crystalline polymorphs are disclosed in US7741358, US8022228. These patents also cover pharmaceutical composition comprising these polymorphs. A sublingual tablet comprising amorphous asenapine maleate is not disclosed anywhere.
[0018] In one embodiment- present invention, an amorphous polymorph of asenapine maleate is used as a starting material for manufacturing of the dosage form.
[0019] In a preferred embodiment amorphous asenapine maleate is used for the purpose of this invention.
[0020] Polymorphic form of active can be identified using analytical methods such as PXRD, infrared spectrophotometry, thermal analysis techniques, etc., all of which are familiar to those skilled in the art.
[0021] In another aspect, the present application provides a novel sublingual pharmaceutical formulations comprising amorphous asenapine maleate together with one or more excipients.
[0022] In addition to the active ingredient, the tabletting powder also contains number of inert materials known as excipients. They may be classified according to the role they play in the tablet. The primary composition includes fillers, binders or diluents, lubricants,

disintegrants and glidant. Other excipients which give physical characteristics to the finished tablet are coloring agents, and flavors. Typically, excipients are added to a formulation to impart good flow and compression characteristics to the material being compressed. Such properties are imparted to these excipients through pretreatment steps, such as wet granulation, slugging, spray drying etc.
[0023] In one of the preferred embodiment of the invention amorphous asenapine maleate is present in an amount ranging from 5 % to 25% of total weight of the composition.
[0024] One or more fillers or diluents can be selected. Examples of pharmaceutically acceptable fillers or diluents include, but are not limited to, sucrose, and lactose, in particular lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose, powdered cellulose. Different grades of lactose, mannitol or microcrystalline cellulose can be used. Combination of mannitol and microcrystalline cellulose is the preferred diluents for this invention. The total weight percentage of filler ranges between about 50 % and about 80% by weight, preferably from about 60 to about 70 %.
[0025] Disintegrants are often included to ensure that the tablet has an acceptable rate of disintegration. One or more disintegrants can be selected. Examples of pharmaceutically acceptable disintegrants include, but are not limited to, starches; clays; celluloses; alginates; gums; cross-linked polymers, e.g., crospovidone, cross-linked Ca-CMC and Na-CMC, Sodium starch glycoalte. Disintegrants are included to ensure that the tablet has an acceptable rate of disintegration, crospovidone is the preferred disintegrant for this formulation. Preferably the disintegrant is present in the tablet formulation in an amount of from about 1% to about 10 % by weight, and can be from about 3 % to about 8% by weight, and most preferred, can be from about 4.5% to about 5.5% by weight.
[0026] In addition, it may be desirable to use an effervescent couple, in combination with the other recited ingredients to improve the disintegration profile, the organoleptic properties of the material and the like. Preferably, the effervescent couple is provided in an amount of

between about 0.5 and about 50%, and more preferably, between about 3.25 and about 15% by weight, based on the weight of the finished tablet.
[0027] The term "effervescent couple" includes compounds which evolve gas. The preferred 30 effervescent couple evolves gas by means of a chemical reaction which takes place upon exposure of the effervescent disintegration couple to water and/or to saliva in the mouth.
[0028] The term "effervescent agent" includes compounds which evolve gas. The preferred effervescent agents evolve gas by means of a chemical reaction which takes place upon exposure of the effervescent agent (an effervescent couple) to water and/or to saliva in the mouth. This reaction is most often the result of the reaction of a soluble acid source and a source of carbon dioxide such as an alkaline carbonate or bicarbonate. The reaction of these two general compounds produces carbon dioxide gas upon contact with water or saliva. Such water-activated materials must be kept in a generally anhydrous state and with little or no absorbed moisture or in a stable hydrated form, since exposure to water will prematurely disintegrate the tablet. The acid sources may be any which are safe for human consumption and may generally include food acids, acid and hydrite antacids such as, for example: citric, tartaric, amalic, adipic, and succinics.
[0029] Another commonly used class of excipients in tablets is binders. Binders are agents, which impart cohesive qualities to the powdered material. The compositions described herein also can comprise binders, examples of pharmaceutically acceptable binders include, but are not limited to, povidones (e.g., PVP K-30, PVP K-60, and PVP K-90), cellulose derivatives (e.g.,- methylcellulose and sodium carboxymethylcellulose), gelatin, polyethylene glycol, polymethacrylates, ethyl cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, pregelatinized starch and sodium alginate, wherein povidones are preferred, and wherein PVP K -30 is particularly preferred. . The total weight percentage of binder ranges between about 1 % and about 5% by weight. Most preferred range is about 3 %.

[0030] A glidant can be used to improve powder flow properties prior to and during tabletting and to reduce caking. Suitable glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, talc, tribasic calcium phosphate and the like. Talc is preferably included as a glidant in an amount up to about 4%, preferably about 3% to about 2.0%, by weight of the tablet, more preferably from about 1 to about 0.5%.
[0031] Lubricants are typically added to prevent the tabletting materials from sticking to punches, minimize friction during tablet compression, and allow for removal of the compressed tablet from the die. Examples of pharmaceutically acceptable lubricants include, but are not limited to, magnesium stearate, calcium stearate, canola oil, glyceryl palmitostearate, hydrogenated vegetable oil, magnesium oxide, mineral oil, poloxamer, polyethylene glycol, polyvinyl alcohol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, hydrogenated vegetable oil, zinc stearate and the like. In one embodiment, magnesium stearate is included as a lubricant in an amount of about 0.2% to about 2.0%, preferably about 1 %, by weight of the tablet.
[0032] Colouring agents may include titanium dioxide, and dyes suitable for food such as those known as F.D & C. dyes and natural coloring agents such as grape skin extract, beet red powders beta-carotene, annato, carmine, turmeric, paprika, etc. The amount of colouring used may range from about 0.1 to about 3.5 weight percent of the total composition.
[0033] Flavoring agents and/or sweeteners useful in the epinephrine formulations described herein, include, but are not limited to, compounds such as acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream, berry, black currant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glyrrhizinate maltol, mannitol, maple, marshmallow, menthol, mint cream,

mixed berry, neohesperidine DC, neotame, orange, pear, peach, peppermint, peppermint cream, Powder, raspberry, root beer, rum, saccharin, safrole, sorbitol, spearmint, spearmint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfame potassium, talin, sylitol, sucralose, sorbitol, Swiss cream, tagatose, tangerine, thaumatin, tutti fruitti, vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol, or any combination of these flavoring ingredients, e.g., anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint, and mixtures thereof.
[0034] In one of the preferred embodiment, a novel sublingual composition of present invention comprises amorphous asenapine maleate in combination with
a) Diluents/fillers
b) Disintegrating agent
c) Sweetener
d) Glidant
e) Lubricant and
f) Optionally effervescent couple, binder, flavor and colors.
[0035] In a more preferred embodiment of the invention, a novel sublingual composition of the invention comprises
a) Amorphous asenapine maleate 2-25%
b) Diluents / fillers 55-85%
c) Disintegrant 2-8%
d) Sweetener 0.5-2%
e) Glidant 0.1-1%
f) Lubricant 0.5-1%
[0036] As described above, this dosage form is becoming popular because of the convenience it offers to patients. One of the biggest advantages it offers over conventional dosage form is

that it disintegrates in oral cavity within a minute to provide rapid absorption of drug through oral mucosal lining.
[0037] In another preferred aspect, the present invention provides a novel sublingual pharmaceutical composition comprising amorphous asenapine maleate and one or more excipients wherein disintegration time of the composition is more than 30 seconds to 60 seconds.
[0038] Disintegration time for sublingual tablets of the invention was determined using USP disintegration apparatus with water as a disintegrating medium at 37± 0.2 °C'-
[0039] In a preferred embodiment of the invention, disintegration time of the sublingual tablet of the present invention was 55 seconds, more preferably 45-50 seconds and most preferably
40 seconds.
[0040] In another preferred aspect, the present invention provides a novel sublingual pharmaceutical composition comprising amorphous asenapine maleate and one or more excipients wherein dissolution time of the composition is from 5 to 10 minutes.
[0041] In a preferred embodiment of the invention, more than 80% of the drug was dissolve in 5 minutes and more than 90% of the drug in lOminutes, more preferably more than 85% of the drug was dissolved in 5 minutes and more than 95% of the drug was dissolved in 10 minutes.
[0042] In another aspect, the present invention also provides a method of manufacturing of a novel sublingual pharmaceutical composition comprising amorphous asenapine maleate with one or more excipients.
[0043] In a preferred embodiment, the present invention provides the pharmaceutical composition comprising asenapine maleate in an amorphous form with the pharmaceutically acceptable

excipients, is prepared by any conventional methods know in the art. The method of manufacturing a novel sublingual tablet of the present invention comprises direct compression, dry granulation or wet granulation.
EXAMPLES
[0044] The following examples describe compositions of the present invention containing amorphous asenapine maleate, but they are not to be interpreted as limiting the scope of the claims
EXAMPLE 1: Preparation of Asenapine sublingual tablet by direct compression

Ingredient Qty/Tab (in mg)
Asenapine Maleate 14.1
Mannitol (Pearlitol SD 200) 50.778
Microcrystalline cellulose (Avicel PH 102) 11.84
Crospovidone (Polyplasdone XL 10) 2.4
Colloidal silicon dioxide (Aersoil 200) 0.082
Magnesium Stearate 0.8
Total 80.00
The manufacturing process consists of following steps:
Co-sifted asenapine maleate, mannitol, MCC, crospovidone and colloidal silicon dioxide (through #30 sieve) were loaded into Bin Blender and mixed for 5 minutes, then Mg-stearate (sifted through sieve #40) was added and mixed for about 3 minutes. The blend from was then compressed to tablets.
EXAMPLE 2: Preparation of Asenapine sublingual tablet by direct compression

Ingredient Qty/Tab (in mg)
Asenapine Maleate 14.10
Mannitol (Pearlitol SD 200) 46.22
Microcrystalline cellulose (Avicel PH 102) 10.50
Aspartame 1.6
Citric Acid Anhydrous 1.8
Sodium Bicarbonate 2.5

Crospovidone (Polyplasdone XL 10) 2.4
Colloidal silicon dioxide (Aersoil 200) 0.08
Magnesium Stearate 0.8
Total 80.00
The manufacturing process consists of following steps:
Co-sifted asenapine maleate, mannitol, MCC, crospovidone, colloidal silicon dioxide, citric acid anhydrous and sodium bicarbonate (through #30 sieve) were loaded into Bin Blender and mixed for 5 minutes, then Mg-stearate (sifted through sieve #40) was added and mixed for about 3 minutes. The blend from was then compressed to tablets.
EXAMPLE 3: Preparation of Asenapine sublingual tablet by dry granulation

Ingredient Qty/Tab (in mg)
Asenapine maleate 14.10
Mannitol (Pearlitol SD 200) 46.22
Microcrystalline cellulose (Avicel PH 102) 10.50
Crosppvidone (Polyplasdone XL 10) 2.4
Aspartame (Nutrasweet) 1.6
Colloidal silicon dioxide (Aerosil 200) 0.08
Citric acid anhydrous 1.8
Sodium bicarbonate 2.5
Magnesium stearate 0.8
Total 80.00
Co-sifted asenapine maleate, mannitol, MCC, citric acid anhydrous, sodium bicarbonate and part of crospovidone (through #30 sieve) were loaded into Bin Blender and mixed for about 5 minutes. Part of Mg-stearate sifted through sieve #60 was then added to the above blend and mixed for about 2 minutes. The above blend was then roll compacted and milled through 1.5 mm screen and then mixed with aspartame, remaining part of crospovidone, pre-sifted colloidal silicon dioxide (through # 40 sieve) and Mg-stearate. The blend was then compressed to tablets.
EXAMPLE 4: Preparation of Asenapine sublingual tablet by wet granulation

Ingredient Qty/Tab (in mg)
Asenapine maleate 14.1
Mannitol (Pearlitol) 48.37
Microcrystalline cellulose (Avicel PH 101) 15.00
Sodium starch glycolate (Primojel) 2.00
Povidone (PVP K-30) 1.00
Purified water qs
Sodium starch glycolate (Promojel) 1.400
Microcrystalline cellulose (Avicel PH 102) 1.0
Aspartame (Nutrasweet) 1.28
Magnesium Stearate 0.85
Total 85.00
Co-sifted asenapine maleate, mannitol, MCC and SSG (# 30 sieve) were loaded into fluidized bed processor (FBP) and mixed for about 5 minutes. Said mixture was then granulated using povidone solution in purified water. The wet mass was dried at about 60°C and passed through #30. Dried granules from above step were mixed with presifted SSG, MCC and aspartame and were added to blender and blended for about 5 minutes. Then Mg stearate sifted through sieve #60 was added to 5 and blended for about 3 minutes. The blend was then compressed to tablets.

Claims:
1. A solid pharmaceutical composition comprising asenapine maleate wherein the composition is formulated using amorphous asenapine maleate.
2. The composition of claim 1 wherein solid pharmaceutical composition is sublingual composition.
3. The composition of claim 2 wherein composition comprises amorphous asenapine maleate.
4. The composition of claim 2 wherein the composition disintegrates within 30 seconds to 60 seconds.
5. The composition of claim 4 wherein the composition disintegrates between 45 to 55 seconds.
6. A solid pharmaceutical composition comprising asenapine maleate wherein the composition is formulated using amorphous asenapine maleate and diluents/fillers, disintegrating agent, sweetener, glidant, lubricant and optionally effervescent couple, binder, flavor and colors.
7. The composition of claim 6 wherein solid pharmaceutical composition is sublingual composition.
8. The composition of claim 6 comprises amorphous asenapine maleate 2-25%, diluents / fillers 55-85%, disintegrant 2-8%, sweetener 0.5-2%, glidant 0.1-1%, lubricant 0.5-1% of the mean weight of the composition.
9. The composition of claim 1 is prepared by direct compression or dry granulation or wet granulation method.