FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
COMPLETE SPECIFICATION
(SECTION 10)
"MODIFIED RELEASE PHARMACEUTICAL COMPOSITIONS OF
MEMANTINE HCL"
UNICHEM LABORATORIES LIMITED, A COMPANY REGISTERED UNDER
THE INDIAN COMPANY ACT, 1956, HAVING ITS REGISTERED OFFICE
LOCATED AT UNICHEM BHAVAN, PRABHAT ESTATE, OFF S. V. ROAD,
JOGESHWARI (WEST), MUMBAI-400 102,
MAHARASTRA, INDIA
The following specification particularly describes the invention and the manner in which it is to be performed.

MODIFIED RELEASE PHARMACEUTICAL COMPOSITIONS OF
MEMANTINE HCL
FIELD OF INVENTION
The present invention relates to the preparation of stable, modified release, solid oral pharmaceutical composition comprising memantine or its pharmaceutically acceptable salt, enantiomers or mixtures thereof. Memantine HC1 is a non-competitive (open-channel) N-methyl-D-aspartate (NMDA)-receptor antagonist. It is used in the treatment of Alzheimer's disease, Parkinson's disease and other neurological disorders. In particular, the present invention is related to pharmaceutical technology, which discloses the novel methods of manufacturing of modified release pharmaceutical compositions of memantine HC1.
BACKGROUND OF THE INVENTION
Memantine HC1 is a non-competitive NMDA-receptor antagonist having low to moderate affinity for the receptor with strong voltage dependency and rapid blocking/unblocking kinetics. These pharmacological features allow memantine HC1 to block sustained activation of the receptor under pathological conditions and to rapidly leave the NMDA channel during normal physiological activation of the channel.
The reported IUPAC name for memantine HC1 is 3, 5-dimethyladamantane-l-amine hydrochloride. The molecular formula of memantine HC1 is C12H21N.HCI with a molecular weight of 215.76.
Memantine is commercially available as, immediate release systems in the form of tablets of 5, 10, 15 & 20 mg strengths, extended release systems in the form of capsules of 7, 14, 21 and 28 mg strengths & oral drops in the form of solution of 2 mg/ml, 10 mg/g strengths.
Immediate release systems of memantine are currently marketed by Forest Labs under the brand name of Namenda 5 mg and 10 mg tablets in the USA and by Lundbeck Limited under the brand name of Ebixa 5, 10, 15 and 20 mg film coated tablets in Europe. Oral drops of memantine is marketed by Forest Labs under the brand name of Namenda 2

mg/ml oral solution in the USA and by Lundbeck Limited under the brand name of Ebixa 10mg/g oral drops solution in Europe.
Extended release systems of memantine are currently marketed by Forest Labs under the brand name of Namenda XR 7, 14, 21 & 28mg extended release capsules in the USA.
US Patent 5,382,601 (Eberhard Niirnberg et al.; 1995) discloses solid pharmaceutical composition in the dosage forms having, matrix extended two-stage release profile. This composition utilizes water soluble and insoluble salts of casein. Casein has an unpleasant taste. Casein being protein may lead to increased microbial load on storage of the dosage form. In addition, as it is obtained from animal origin, may lead to complications like Transmissible spongiform encephalopathy.
WO 2005/079748 A2 (Jurado Sanchez et al,; 2005) discloses sustained release pharmaceutical composition of memantine HC1 in the form capsules or tablets or granules, which are prepared by coating of inert cores with the active ingredient and release modifying polymer. One aspect of this composition comprises compression coated pellets to form tablets. Compression of the coated pellets may rupture the modified release coating and hence may lead to dose dumping. Conditions like Alzheimer's and Parkinson's disease require effective plasma drug concentrations for prolonged period of time along with drug available for immediate action. From the disclosed pharmaceutical composition of '748, there is a very less chance of having drug for immediate action and hence making the therapy ineffective.
US 2006/0051416 Al (Suneel K. Rastogi et al; 2006) discloses sustained release pharmaceutical composition of memantine HC1 with no drug available for immediate action. As conditions like Alzheimer's and Parkinson's disease require effective plasma drug concentrations for prolonged period of time along with drug available for immediate action. From the disclosed pharmaceutical composition of '416, there is a very less chance of having drug for immediate action and hence making the therapy ineffective. Disclosed pharmaceutical composition releases more than about 80% of the drug after 12 hrs in pH 1.2 buffer. In house developed novel pharmaceutical composition contains immediate release portion and modified release portion wherein modified release portion contains from about 20% about 80% of the active ingredient, hence the in house developed formulation may not release 80% of the drug even after 12 hrs.

WO 2006/138227 Al (Periclou Antonia et al.; 2006) discloses pharmaceutical composition in the form of composite dosage form comprising plurality of immediate release component and plurality of modified release component. This composition utilizes coating of inert cores with the active ingredient, providing immediate release beads. Coating of immediate release beads with release modifying polymer, providing modified release beads. This composition comprises compression immediate release beads and prolonged release beads to form tablets. Compression of the coated beads may rupture the modified release coating and hence may lead to dose dumping. Even though the dissolution rate from disclosed composition was mentioned i.e., from about 70% to from about 80% in from about 4 hrs to about 24 hrs, dissolution conditions were not mentioned.
Even though many technologies with different compositions are disclosed for the manufacture of sustained release oral compositions of memantine HC1, they however suffer from problems like usage of complex and costlier manufacturing equipment, usage of excipients which may lead to undesirable effects and non-availability of the active ingredient for immediate action. Therefore, there is a need for simple and cost effective pharmaceutical composition and novel process for preparing the same, which could eliminate all these disadvantages.
OBJECT OF THE INVENTION
The object of the present invention is to provide an improved, simple and effective modified release pharmaceutical composition of Memantinee or its pharmaceutically acceptable salt(s), solvate(s), enantiomers or mixtures thereof.
Another object of the present invention is to provide an improved process for the manufacture of modified release, stable, solid, oral pharmaceutical composition of memantine or its pharmaceutically acceptable salt(s), solvate(s), enantiomers or mixtures thereof.
SUMMARY OF THE INVENTION
The present invention relates to an stable, modified release solid oral pharmaceutical composition comprises, an immediate release portion and modified release portion of memantine or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof.

According to the present invention the solid oral pharmaceutical compositions comprising memantine or its pharmaceutical acceptable salt, solvate, enantiomers or mixtures thereof manufactured by filling plurality of tablets in capsule for both immediate release and modified release of memantine HCI.
The present invention provides processes used for the preparation of the novel pharmaceutical composition for the modified release of memantine HC1 which involves addition of active substance to placebo granules, adsorption method using conventional wet granulation or adsorption method using spray granulation method..
BRIEF DESCRIPTION OF THE DRAWINGS :
Figure 1: A comparative drug release profile of Example 1 Memantine MR Capsules 7/14/21/28 in 900 ml'of Simulated gastric fluid without enzyme (pH 1.2) for 0.5, 1, 1.5 & 2 hours followed by Phosphate buffer (pH 7.4) 0.5, 1, 1.5,2, 3,"4, 6, 8 & 12 hours in 900 ml using USP Type I Apparatus (Basket) at 100RPM maintained 37±0.5°C.
DETAILED DESCRIPTION OF THE PRESENT INVENTION
The present invention relates to the solid oral pharmaceutical compositions comprising memantine or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof manufactured by filling plurality of tablets in capsule for both immediate release and modified release portion.
In accordance with the present invention, stable, modified release solid oral pharmaceutical composition comprises, an immediate release portion and modified release portion of memantine or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof, more preferably, the memantine is memantine HC1 and one or more of pharmaceutically acceptable excipients.
The novel pharmaceutical composition of the present invention contains memantine HCI in the range of about 1 mg to about 40 mg.
The present invention provides processes used for the preparation of the novel pharmaceutical composition for the modified release of memantine HCI.

In accordance with the present invention, novel pharmaceutical composition of memantine HC1 in the form of capsule comprises,
1. Drug granulates or pellets or blend or un-coated tablet(s) or optionally film-coated tablet(s) un-coated minitablet(s) or optionally film-coated minitablet(s) for immediate release of active ingredient.
2. Drug granulates or pellets or optionally enteric coated granules or pellets or coated tablets or minitablets for modified release of active ingredient.
In accordance with the present invention, composition of immediate release portion comprises,
1. Drug granulates or pellets or blend or un-coated tablet or un-coated minitablet
essentially contains one or more of,
i. Active ingredient,
ii. Pharmaceutically acceptable diluents,
iii. Pharmaceutically acceptable binders,
iv. Pharmaceutically acceptable disintegrants,
v. Optionally pharmaceutically acceptable anti-oxidants
vi. Optionally pharmaceutically acceptable plasticizers,
vii. Optionally pharmaceutically acceptable super disintegrants.
viii. Pharmaceutically acceptable glidants and lubricants.
2. Optional coating around the said uncoated tablet or minitablets, which essentially
consists of a protective layer of pharmaceutically acceptable water soluble or
dispersible polymer along with one or more of other pharmaceutically acceptable
excipients like opacifier, plasticizer and antitacking agent etc.
In accordance with the present invention, composition. of modified release portion comprises,
1. Drug granulates or pellets or uncoated tablets or uncoated mintablets, which essentially contains,
i. Active ingredient, ii. Pharmaceutically acceptable diluents,

iii. Pharmaceutically acceptable binders,
iv. pharmaceutically acceptable disintegrants
v. Optionally pharmaceutically acceptable release retarding or modifying
agents.
vi. Optionally.pharmaceutically acceptable anti-oxidants
vii. Optionally pharmaceutically acceptable plasticizers
viii. Optionally pharmaceutically acceptable antitacking agents
ix. Pharmaceutically acceptable glidants and lubricants.
2. Coating around the drug granulates or pellets or uncoated tablet oruncoated mintablets, which essentially consists either of the following coatings:
i. A layer of pH dependent enteric polymer
ii. . A protective layer of pharmaceutically acceptable water soluble polymer along with one or more of other pharmaceutically acceptable excipients like opacifier and plasticizer & a layer of pH dependent enteric polymer along with one or more of other pharmaceutically acceptable excipients like opacifier and, plasticizer etc.
In accordance with the present invention, immediate release portion of the novel pharmaceutical composition of memantine HC1 is prepared by either of procedures as given below.
A. Addition of active ingredient to placebo granules
1. Preparation of the placebo granules.
'a. Sifting of the inactive ingredients.
b. Mixing of the inactive ingredients
c. Preparation of binder solution and granulation of step-b dry mix.
d. Drying and sifting of the granules of step-c.
2. Adsorption of the active ingredient onto the placebo granules by co-sifting and mixing. Optionally filling of drug granulates into capsules.
3. Lubrication of the blend of step-2.

4. Compression of the lubricated blend of step-3 into tablets or optionally direct filling of the lubricated blend into capsules.
5. Optionally film coating of the compressed tablets of step-4.
B. Adsorption of active ingredient by spray-granulation method
1. Sifting of the inactive ingredients.
2. Preparation of drug solution.
3. Mixing of the inactive ingredients and spraying of the drug solution with simultaneous drying.
4. Sifting of the granules of step-3. Optionally filling of drug granulates into capsules.
5. Lubrication of blend of step-4.
6. Compression of the lubricated blend of step-5 into tablets or optionally direct filling of lubricated blend into capsules.
7. Optionally film coating of the compressed tablets of step-6.
C. Adsorption of active ingredient by wet granulation method
1. Sifting of the inactive ingredients.
2. Preparation of drug solution.
3. Mixing of the inactive ingredients, preparation of granules and drying of the granules.
4. Sifting of the granules of step-3. Optionally filling of the drug granulates into the capsules.
5. Lubrication of step-4 granules.
6. Compression of the lubricated blend of step-5 into tablets or optionally filling of lubricated blend into capsules.
7. Optionally film coating of the compressed tablets of step-6.
In accordance with the present invention, modified release portion of the novel pharmaceutical composition of memantine HC1 is prepared by either of the following processes.
A. Preparation of modified release portion from drug granulates
1. Sifting and mixing of the inactive ingredients and active ingredient.

2. Preparation of binder solution.
3. Granulation of step-1 dry mix with step-2 binder solution.
4. Drying & sifting of the step-3 drug granulates. Optionally direct filling drug granulates into capsules.
5. Lubrication of step-4 drug granulates
6. Compression of the lubricated blend of step-5 into tablets or optionally filling of lubricated blend into capsules.
7. Film coating and optionally enteric coating (functional coating) of the compressed tablets of step-6.
B. Preparation of modified release from pellets.
1. Sifting and mixing of the inactive ingredients and active ineredient.
2. Preparation of drug pellets by extrusion.
3. Milling & sifting of extrudes of step-2. Optionally direct filling drug granulates into capsules.
4. Lubrication of step-4 drug granulates
5. Compression of the lubricated blend of step-5 into tablets or optionally filling of lubricated blend into capsules.
6. Film coating and optionally enteric coating (functional coating) of the compressed tablets of step-6.
C. Preparation of modified release portion from immediate release portion by coating
around the drug granulates or pellets or uncoated tablets, which essentially consists either
of the following coatings:
i. Optional non-functional coating and functional coating (enteric coating)
1. Preparation of the solution/dispersion of non-functional coating composition.
2. Coating of the drug granulates or pellets or uncoated tablets with the coating composition of step-1.
3. Preparation of solution/dispersion of functional coating (enteric coating) composition
4. Coating of the drug granulates or pellets or uncoated tablets with the coating composition of step-3.

ii. Functional coating
1. Preparation of the solution/dispersion of functional coating (enteric coating) composition.
2. Coating of the drug granulates or pellets or uncoated tablets or uncoated minitablets with the coating composition of step-1.
In accordance with present invention, placebo granules are prepared by dry granulation method or wet granulation method. Dry granulation method of preparing placebo granules may include slugging or roller compaction. Wet granulation method of preparing placebo granules may include conventional granulation method using high shear/low shear mixers or spray granulation method using fluid bed processor.
The process of preparing pharmaceutical composition comprises placebo granules which can be manufactured by granulating one or more diluents with a disintegrant and a binder using a liquid. The placebo granules are dried, and then co-sifted with active ingredient, mixed with lubricant and a glidant. The final lubricated blend is then compressed into tablets or filled into capsules, which serves as the immediate release portion of the novel pharmaceutical composition.
In accordance with the present invention, novel pharmaceutical composition comprises, active ingredient and at least one or more pharmaceutically acceptable excipients viz., diluents, disintegrants, binders, release retarding of modifying polymers, colorants, antioxidants, plasticizers, glidants, lubricants and antitacking agent and one or more of coating agents for protecting the active ingredient from external environment and for controlling the release of the active ingredient in gastric acidic conditions.
In one preferred embodiment of the present invention, immediate release portion may be manufactured by addition of active ingredient present in the solid form to placebo granules or by adding or spraying of active ingredient present in the liquid form to excipients mixture (adsorption method).
In one preferred embodiment adsorption method can involve either addition of drug solution to excipient mixture or spraying the drug solution on to excipient mixture, using suitable equipments like high shear or low shear mixers can be used for adsorption method

by adding solution on to excipients mixture and fluid bed processor can be used for adsorption method by spraying the drug solution on to excipients mixture.
According to the present invention, pharmaceutical compositions manufactured by either addition of active ingredient to placebo granules or adsorption method comprise, memantine or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof and placebo granules or excipients mixture. These pharmaceutical compositions also comprise at least one or more of pharmaceutically acceptable excipients along with placebo granules and/or excipients blend, which are selected from the group consisting of glidant§ and lubricants.
In accordance with the present invention, placebo granules used along with active ingredient or excipients blend used for adsorption of active ingredient comprises two or. more of pharmaceutically acceptable excipients, preferably comprises diluents, binder and disintegrant.
In accordance with the present invention, diluents..comprises at least one or more of calcium phosphate (dibasic/tribasic), calcium sulphate, calcium sulphate dihydrate, lactose, fructose, sucrose, mannitol, sorbitol, xylitol, dextrose, compressible sugar, dextrates, dextrin, starch, microcrystalline cellulose, powdered cellulose, cellulose acetate, polymethacrylates, sodium alginate and tragacanth. Preferred diluents may be one or more of calcium phosphate (dibasic/tribasic), lactose, mannitol, dextrose, compressible sugar, dextrates, dextrin, starch, microcrystalline cellulose, powdered cellulose. More preferred diluents may be one or more of powdered cellulose, microcrystalline cellulose, lactose and starch.
In accordance with the present invention, the mean particle size range of different grades of microcrystalline cellulose in the pharmaceutical composition can be ranging from about 20 {im to about 180 urn. Preferred mean particle size range of microcrystalline cellulose used in the pharmaceutical composition is from about 50 fim to about 180 urn More preferred mean particle size range of microcrystalline cellulose in the pharmaceutical composition can be from about 100μm to about 180 μm.
In one of the preferred embodiment of the present invention, ratio of different grades of microcrystalline celluloses with different mean particle size can be about 5:95 % w/w. Preferred ratio of microcrystalline celluloses with different mean particle size can be

about 10: 90 % w/w. More preferred ratio of microcrystalline celluloses with different mean particle size can be about 20: 80 % w/w.
In accordance with the present invention, binder comprises at least one or more of polyvinyl pyrrolidone, co-povidone, acacia gum, guar gum, xanthan gum, karaya gum, gellan gum, hupu gum, carob bum, caramania gum, gelatin, glucose, sugar, dextrin, sorbitol, maltose, pregelatinised starch, carboxymethyl cellulose sodium, methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, ethyl cellulose, cellulose acetate, agar, alginic acid, sodium alginate, carbomers, carrageenan, ceratonia, chitosan, poloxamer, polyethylene oxide, magnesium aluminum silicate and glyceryl behenate. Preferred binders used in the pharmaceutical compositions can be one or more of polyvinyl pyrrolidone, copovidone, pregelatinised starch, hydroxypropylmethyl cellulose, methyl cellulose, and hydroxypropyl cellulose. More preferred binders used in the pharmaceutical composition can be polyvinyl pyrrolidone and copovidone.
In accordance with the present invention, disintegrant comprises at least one or more of croscarmellose . sodium, crospovidone, sodium starch glycolate, low-substituted hydroxypropyl cellulose, starch, pregelatinized starch, microcrystalline cellulose, emcosoy (Soya polysaccharide) and potassium polacrilin. More preferred disintegrants used in the pharmaceutical composition can be crospovidone,: croscaramellose sodium and sodium starch glycolate.
In accordance with the present invention Anti-oxidants comprises at least one or more of salts of citric acid, L-ascorbic acid, ascorbyl palmitate, citric acid, tocopherols such as a-or β- or γ-tocopherol, tocopherol esters, propyl gallate, octyl gallate, dodecyl gallate, butylated hydroxyl anisole, butylated hydroxyl toluene.
In accordance with the present invention, the glidant comprises at least one or more of colloidal silicon dioxide, silicon dioxide, calcium silicate, magnesium silicate, calcium phosphate tribasic, talc, pregelatinized starch and starch. More preferred glidants comprise one or more of colloidal silicon dioxide and talc
In accordance with the present invention, lubricant comprises at least one or more of magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumerate, hydrogenated vegetable oils, magnesium lauryl sulfate, talc, wax, polyethylene glycol, glyceryl behenate, glyceryl palmitostearate, palmitic acid, poloxamer, sodium benzoate and sodium

lauryl sulfate. More preferred lubricants comprise one or more of magnesium stearate, calcium stearate, and sodium stearyl fumerate.
The immediate release portion contains 1 to 25% of the active ingredient. The modified release portion contains 1 to 25% of the active ingredient. The term 'active ingredient' refers memantine or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof; preferably the active ingredient is memantine HCI.
According to present invention, novel modified release pharmaceutical composition may contain by weight comprises active ingredient about 1 to 25%, preferably about 1 to 20 % and more preferably about 1 to 10%; placebo granules about 1 to 99% , preferably about 25 to 99%, and more preferably about 50 to 99%; about 0.1 to 5% of glidants, more preferably about 0.1 to 3%, and about 0.1 to 5% of lubricant, more preferably about 0.1 to 3%
According to the present invention, placebo granules may contain diluents from about 1 to 99% , of one or more of diluents, more preferably between about 1 to 96% of one or more of diluents; disintegrants from about 0.1 to 25%; preferably about 0.1 to 10% of disintegrants, more preferably between about 0.1 to 6% of disintegrants, binders from about 0.1 to 25%; preferably from about 0.1 to 10% of one or more of binders, more preferably between about 0.1 to 4% of one or more of binders
The immediate release formulation may contain from about 1 to 99 % of placebo granules used for addition of active ingredient or excipients blend used for adsorption of active ingredient.
In accordance with the present invention, pharmaceutically acceptable excipients may comprise between 5 to 99 % by weight of the pharmaceutical composition.
In accordance with the present invention, memantine HCI may present in an amount of about 1 mg to about 40 mg. Preferably the pharmaceutical composition may contain from about 1 mg to about 30 mg of memantine HCI, and more preferably the pharmaceutical composition contains from about 1 mg to 25 mg of memantine HCI.
One aspect of the present invention involves the manufacturing of compositions of memantine or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures

thereof; preferably memantine HCI by adsorption method using conventional wet granulation method or spray granulation method. Tablets prepared by this method are cost effective, simple, and independent of particle size of active ingredient. Disclosed method of manufacturing helps in adsorbing the active ingredient more uniformly throughout the blend of pharmaceutically acceptable excipients, which ensures uniformity of active ingredient among the final dosage forms.
In one aspect of disclosed process for preparing immediate release portion of pharmaceutical composition comprises, dissolving or dispersing the active ingredient in aqueous or hydro alcoholic or non-aqueous solvent, adsorbing the active ingredient solution onto the mixture of pharmaceutically acceptable excipients using high shear mixers or low shear mixers. The memantine or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof; preferably memantine HCI granulate is then dried, sifted and lubricated with lubricant and glidant(s). The final lubricated blond is then compressed into tablets or filled into capsules.
In another aspect of present invention for preparing immediate release portion of the pharmaceutical, using spray granulating process comprises, solubilizing the active ingredient in aqueous or hydro alcoholic or non-aqueous solvent, spraying the active ingredient solution onto the mixture of pharmaceutically acceptable excipients in fluid bed processor. The spray dried granules of memantine or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof; preferably memantine HCI are dried, sifted and lubricated with lubricant and glidant. The final lubricated blend of memantine HCI may then be compressed into tablets or filled into capsules.
In accordance with the present invention, the immediate release pharmaceutical composition is in the form of drug granulates or blend or pellets or un-coated tablet or optionally film coated tablet comprising memantine or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof; preferably memantine HCI.
In accordance with the present invention, the modified release pharmaceutical composition is in the form of drug granulates or pellets or enteric coated drug granulates or enteric coated pellets or enteric coated tablet comprising memantine or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof; preferably memantine HCI.

In accordance with the present invention, the coating may be applied as dispersion/solution of coating ingredients using one of the coating techniques such as spray coating, dip coating and conventional pan coating.
In accordance with the present invention, film coating is about 1 to 40%, preferably about 1 to 30 % and more preferably about 2 to 30%.
In accordance with the present invention, one or more coating layers are applied for protecting the active ingredient from degradation due to external environment and for controlling the release of the active ingredient in the gastro intestinal tract.
In accordance with the present invention, coating agent for controlling the release of active ingredient in gastro intestinal tract comprises, release retarding or modifying polymer, antitaking agent, plasticizer, opacifier & colorant etc.
In accordance with the present invention; film coating comprises of 1 to 50% of one or more of release retarding or modifying polymers, from about 0.01 to 6% of colorants, from about 0.01 to 25% of plasticizers.
The film coating comprises release modifying polymers from one or more of cellulose derivatives like, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, cellulose acetate phthalate, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, polyvinyl acetate phthalate, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, one or more of methacrylic co-polymers like, poly (ethyl acrylate, methyl methacrylate) 2:1; Poly(methacrylic acid, methyl methacrylate)1:1; Polyfmethacrylic acid, ethyl acrylate) 1:1; Poly(methacylic acid-co-methyl methacrylate) 1:2; Poly (methyl acrylate, methyl methacrylate, methacrylic acid) 7:3:1; and polyethylene glycol, polyvinyl alcohol, povidone, copovidone, chitosan, maltodextrin, isomalt, ammonium alginate, gelatin, carrageen, ethyl lactate and mixture thereof. Preferrably film coating comprises release modifying hydrophilic polymers from one or more of methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, cellulose acetate phthalate, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, polyvinyl acetate phthalate, hydroxypropylmethyl

cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, one or more of methacrylic co-polymers like, poly (ethyl acrylate, methyl methacrylate) 2:1; Poly(methacrylic acid, methyl methacrylate)1:1, Poly(methacrylic acid, ethyl acrylate) 1:1; Poly(methacylic acid-co-methyl methacrylate) 1:2; Poly (methyl acrylate, methyl methacrylate, methacrylic acid) 7:3:1; and polyethylene glycol, polyvinyl alcohol, copovidone, chitosan, ammonium alginate, gelatin, carrageen, and mixture thereof. More preferably film coating comprises release modifying hydrophilic polymers from one or more of ethyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, cellulose acetate, one or more of methacrylic co-polymers like, poly (ethyl acrylate, methyl methacrylate) 2:1; Poly(methacrylic acid, methyl methacry]ate)l;]; Poly(methacrylic acid, ethyl acrylate) 1:1; Poly(methacylic acid-co-methyl methacrylate) 1:2; Poly (methyl acrylate, methyl methacrylate, methacrylic acid) 7:3:1; and polyethylene glycol, polyvinyl alcohol, copovidone, chitosan, ammonium alginate, gelatin, carrageen, and mixture thereof & most preferably Poly(methacylic acid-co-methyl methacrylate) 1:2.
In accordance with the present invention, antitacking agent of film coating comprises of one or more of talc, magnesium stearate, calcium stearate, stearic acid, calcium carbonate, magnesium carbonate, ground limestone, magnesium silicate, aluminum silicate, clay, alumina, titanium oxide, mono-calcium phosphate, di-calcium phosphate, tri-calcium phosphate and/or combinations thereof; more preferable anti-tacking agent comprises of one or more of talc, magnesium stearate, calcium stearate, stearic acid, calcium carbonate, magnesium carbonate, magnesium silicate, aluminum silicate, alumina, titanium oxide and/or combinations thereof; most preferred anti-tacking agent comprises of at least one or more talc, magnesium stearate and titanium oxide.
In accordance with the present invention, optional opacifier of film coating layer comprises of one or more of titanium dioxide, silicates such as talc and aluminium silicate, ethylene glycol palmitostearate, acetates such as zinc acetate, carbonates such as magnesium carbonate, calcium carbonate, stearates such as aluminium stearate and zinc stearate, sulfates such as calcium sulfate, oxides such as magnesium oxide and hydroxides such as aluminiuim hydroxides; more preferred comprises of at least one or more of titanium dioxide, silicates such as talc and aluminium silicate, ethylene glycol carbonates such as magnesium carbonate, calcium carbonate, stearates such as aluminium stearate and zinc stearate; most preferred opacifier used is selected from at least one or more of

titanium dioxide, silicates such as talc and aluminium silicate, stearates such as aluminium stearate and zinc stearate.
In accordance with the present invention plasticizers of film coating layer comprises at least one or more of triethyl citrate, polyethylene glycols, propylene glycol, glycerine, caster oil, acetyltriethyl citrate, benzyl benzoate, chlorbutanol, dextrin, acetyltributyl citrate, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, glyceryl monooleate, glyceryl monostearate, 2-pyrrolidone, sorbitol., stearic acid,, palmitic acid, triacetin, tributyl citrate, triethanolamine, lecithin, surfactants like polysorbates, sorbitan esters and organic acid esters and/or mixtures thereof; more preferably comprises of one or more triethyl citrate, polyethylene glycols, propylene glycol, stearic acid, triacetin and/or mixtures thereof; most preferably plasticizers comprises of at least one or more one or more of triethyl citrate, polyethylene glycols and Triacetin.
Suitable coloring agents include one or more colors approved by FDA.
Suitable solvents used in the manufacturing of pharmaceutical composition include one or more of water, ethyl acetate, acetone, isopropyl alcohol, n-propanol, methanol, methyline dichloride, ethanol and mixtures thereof, preferably one or more of water, acetone, isopropyl alcohol and methylene dichloride and mixtures thereof.
In accordance with the present invention, pharmaceutical composition is in the form of a solid oral dosage form.
In accordance with present invention solid dosage form comprises granules, pellets, tablets, minitablets, capsules, preferably minitablets.
In accordance with present invention, minitablets have diameter from about 1 mm to 7 mm
In accordance with the present invention, process for the preparation of modified release pharmaceutical composition comprises one to twelve encapsulated tablets or minitablets.
In accordance with the present invention, from one to twelve uncoated immediate release tablets or minitablets and or modified release coated tablets or minitablets may encapsulated alone or in combination in any ratio.

In accordance with the present invention, pharmaceutical composition is in the form of a solid oral dosage form.
In accordance with the present invention, wherein the dosage form releases, less than about 55 % of the drug in about 2 hour, more than about 40 % of the drug in about 4 hours, more than about 70 % of the drug in about 6 hours, more than about 85 % of the drug in 12 hours, as measured in 900 ml of Simulated gastric fluid without enzyme for upto 2 hours followed by 900 ml of Phosphate buffer using USP Type I apparatus (basket), at 37±0.5°C.
The compositions of the present invention may be administered to a mammal. Preferably, the mammal is a human, and the composition is administered as pharmaceutical compositions. Preferably, the pharmaceutical composition is administered to treat Alzheimer's disease, Parkinson's disease, as per the approved indications for NAMENDA XR capsules.
The amount of the memantine HC1 in the present pharmaceutical composition is preferably an amount that provides a therapeutically effective amount of memantine HC1. The amount of memantine HC1 used differs according to the amount needed for effective therapeutic response.
Although the invention has been described with reference to specific embodiments, this description is not meant to be construed in a limiting sense. Various modifications of the disclosed embodiments, as well as alternate embodiments of the invention, will become apparent to persons skilled in the art upon reference to the description of the invention. It is therefore contemplated that such modifications can be made without departing from the spirit or scope of the present invention as defined.

Examples:
The following examples are presented for illustration only, and are not intended to limit the scope of the invention or appended claims.
Example-1: Combination containing an un-coated immediate release tablets of Memantine HCl and modified release tablets of memantine HC1
Table 1: Composition of uncoated Immediate Release Memantine HCl tablet of Example-1

Sr. No. Ingredients Quantity/Unit (mg)
Intra-granular (Placebo granules)
1. Microcrystalline cellulose (Avicel PH 200) 8.75
2. Microcrystalline cellulose (Avicel PH 112) ' 34.00
3. Crospovidone 2.00
4. Polyvinyl pyrrolidone (PVP K 29-32) 0.50
5. Purified water* q.s.
Extra-granular
6. Memantine hydrochloride 3.50
7. Talc 0.25
8. Colloidal silicon dioxide (Aerosil 200) 0.50
9. Magnesium stearate 0.50
Total weight (mg) 50.00
■* Remove d during the process.

Table 2: Composition of Modified Release Tablets of Memantine HC1 of Example-1
Sr.
No. Ingredients Quantity /Unit (mg)
1. One uncoated immediate release tablet of memantine HC1 containing 3.5mg of memantine HC1 50.0
2. Polymethacrylic acid copolymer (Eudragit S100) 6.00
3. Triethyl citrate 1.00
4. Talc 3.00
5. Isopropyl alcohol* q.s.
6. Acetone* q.s.
7. Purified Water* q.s.
Total weight (mg) 60.00
* Removed 3 during the process.
Capsule content:
Capsules were filled with the required number(s) of immediate release tablet(s) and modified release tablet(s) based on the strength of the dosage form.
Manufacturing process:
I. Manufacturing of Immediate Release Core Tablets:
1. Preparation of placebo granules: Avicel PH 200, Avicel PH 112, crospovidone and povidone were sifted through 40 mesh ASTM, loaded into high shear mixer, mixed and then granulated by using purified water as a granulating agent to form wet granules.
2. Wet granules of step 1 were dried using fluid bed processor till the LOD reached to 2-3 % w/w. Dried granules were sifted through 40 mesh ASTM.
3. Dried granules of step 2 were subjected to sifting using 60 mesh sieve ASTM; granules retained on sieve and passing through sieve (fines) were collected in separately.
4. Memantine HC1 and fine placebo granules of step 3 were co-sifted through 60 mesh ASTM mesh for 3 times.

5. Blend of step 4 was mixed with 60 mesh retained placebo granules of step 3 in a blender.
6. Talc, colloidal silicone dioxide and magnesium stearate were sifted through 60 mesh ASTM and mixed with blend of step 5.
7. Blend of step 6 was compressed into tablets by using 5.00 mm Round standard concave punches.
II. Manufacturing of Modified Release Tablets by Coating of Immediate Release Core Tablets:
1. Preparation of coating dispersion: Eudragit was dispersed in isopropyl alcohol and acetone mixture in a stainless steel container and stirred for about 45 minutes to get dispersion.
2. Add tirethyl citrate to the dispersion of step 1 with stirring.
3. Add about 3% purified water to the dispersion of step 2.
4. Sifted talc through 200 mesh ASTM and dispersed into isopropyl alcohol and acetone mixture.
5. Added dispersion of step 3 to the dispersion of step 3 with continuous stirring.
6. Sifted dispersion of step 12 through 200 mesh ASTM.
7. Modified release tablet were manufactured by coating immediate release core tablets obtained above with dispersion of step 6.
Example 1A: Filled one immediate release tablet and one modified release tablet into suitable capsule to prepare 7mg strength capsules.
Example 1B: Filled two immediate release tablets and two modified release tablets into suitable capsules to prepare 14mg strength capsules.
Example 1C: Filled three immediate release tablets and three modified release tablets into suitable capsules to prepare 21mg strength capsules.
Example 1D: Filled four immediate release tablets and four modified release tablets into capsules suitable to prepare 28mg strength capsules.
Dissolution studies of tablets of Example 1 were carried out in Simulated gastric fluid without enzyme (pH 1.2) for 0.5, 1,1.5 & 2 hours followed by Phosphate buffer (pH 7.4)

0.5, 1, 1.5, 2, 3, 4, 6, 8 & 12 hours in 900 ml using USP Type I Apparatus (Basket) at 100RPM maintained 37±0,5°. Comparative dissolution profiles are given in Table 3.
Table 3: Comparative Data of the Memantine HCI Modified Release Capsules of Example-l in Simulated gastric fluid without enzyme (pH 1.2) followed by Phosphate buffer (pH 7.4)

Time (Hrs) Percent Memantine HCI released

Memantine HCI Modified Release Capsules

7mg 14 mg 21 mg 28 mg
Simulated gastric fluid without enzyme (pH 1.2)
0.5 44.1 39.0 45.3 36.8
1 46.2 45.4 45.2 45.2
1.5 46.6 44.1 44.5 44.8
2 45.1 45.4 45.0 44.0
Phosphate buffer (pH 7.4)
0.5 45.1 45.4 47.1 48.5
1 45.1 45.4 47.6 46.7
1.5 71.4 57.2 . 60.4 50.6
2 90.0 91.9 89.3 76.9
3 94.2 98.1 95.9 92.2
4 94.0 98.0 96.6 94.4
6 93.8 98.2 96.4 94.7
8 93.1 98.1 96.1 93.7
12 95.0 97.7 94.8 92.9
Stability studies were also conducted for the capsules of Example 1 after packing in HDPE bottle for 3 months at accelerated conditions (40°C/75% RH) to evaluate the changes in related substances as well as changes in the dissolution profile in 900 ml of Simulated gastric fluid without enzyme (pH 1.2) for 0.5, 1, 1.5 & 2 hours followed by Phosphate buffer (pH 7.4) 0.5, 1, 1.5, 2, 3, 4, 6, 8 & 12 hours in 900 ml using USP Type I Apparatus (Basket) at 100RPM maintained 37±0.5°. The results related substances of stability studies are summarized in Table 4 and results of dissolution study are summarized in Table 5 & 6.

Table 4: Initial & Accelerated stability study results of tablets of Example 1
Sr. No. Parameters Initial Accelerated conditions (40°C/75% RH)

1 Month 2 Months 3 Months
Example 1A (Memantine HC1 Modified Release Capsule 7 mg)
1. Assay (%) 99.6 104.6 100.4 96.5
2. Related substances

% Amide Impurity BDL BDL BDL BDL

% Unknown Impurity BQL BQL BQL BQL

% Total Impurities BRT BRT BRT BRT
Example IB (Memantine HC1 Modified Release Capsule 14 mg)
1. Assay (%) 103.5 98.9 98.5 99.1
2. Related substances

% Amide Impurity BDL BDL BDL BDL

.% Unknown Impurity 0.02, 0.03, 0.02 BQL BQL BQL

% Total Impurities BDL BRT BRT BRT
Example 1C (Memantine HC1 Modified Release Capsule 21 mg)
1. Assay (%) 104.0 101.9 96.2 100.3
2. Related substances

% Amide Impurity BDL BDL BDL BDL

% Unknown Impurity 0.03 BQL BQL BQL

% Total Impurities BRT BRT BRT BRT
Example ID (Memantine HCI Modified Release Capsule 28 mg)
1. Assay (%) 100.0 99.9 99.2 97.2
2. Related substances

% Amide Impurity BDL BDL BDL BDL

% Unknown Impurity BQL BQL BQL BQL

% Total Impurities BRT BRT BRT BRT
BDL: thresho Below detection limit; BQL:
ld Below quantita tion limit; BRT Below reporti ng

Table 5: Dissolution profiles of the Memantine HCI Modified Release Capsules of Example-l in Simulated gastric fluid without enzyme (pH 1.2) followed by Phosphate buffer (pH 7.4) during stability study

Time
(Hrs) Percent Memantine HCI released

Memantine HCI MR Capsules 7 mg Memantine HCI MR Capsules 14 mg

Initial 1 Month 2 Months 3 Months Initial 1 Month 2 Months 3 Months
Simulated gastric fluid without enzyme (pH 1.2 '
0.5 44.1 46.9 45.2 43.1 39.0 45.1 44.9 44.1
1 46.2 46.3 45.0 43.9 45.4 45.5 45.8 43.9
1.5 46.6 46.3 44.9 44.2 44.1 45.0 46.2 45.3
2 45.1 45.8 . 45.2 45.6 45.4 45.8 45.7 45.6
Phosphate buffer (pH 7.4)
0.5 45.1 45.8 46.1 47.4 45.4 45.8 53.7 45.6
1 45.1 45.8 52.9 49.1 45.4 45.8 92.4 48.3
1.5 71.4 65.4 86.6 68.5 57.2 45.8 95.3 65.7
2 90.0 91.9 89.3 90.1 91.9 82.7 97.0 93.6
3 94.2 96.7 89.5 91.8 98.1 97.1 9S.6 96.4
4 94.0 96.1 90.6 94.8 .98.0 98.1 98.2 97.2
6 93.8 96.1 90.6 96.7 98.2 97.5 99.0 97.1
8 93.1 96.4 91.0 95.9 98.1 97.4 99.1 97.4
12 95.0 96.9 90.1 96.8 97.7 96.2 98.8 96.7

Table 6: Dissolution profiles of the Memantine HC1 modified release capsules of Example-l in Simulated gastric fluid without enzyme (pH 1.2) followed by Phosphate buffer (pH 7.4) during stability study

Time (Hrs) Percent Memant ne HC1 released

Memantine HC1 MR Capsules 21 mg Memantine HC1 MR Capsules 28 mg

Initial 1 Month 2 Months 3 Months Initial 1 Month 2 Months 3 Months
Simulated gastric fluid without enzyme (pH 1.2 >
0.5 45.3 44.2 45.2 46.3 36.8 44.4 43.7 37.0
1 45.2 45.5 46.3 47.6 45.2 45.0 43.9 44.6
1.5 44.5 45.5 45.3 46.2 44.8 44.4 42.8 45.1
2 45.0 44.8 45.4 46.8 44.0 46.0 42.4 45.6
Phosphate buffer (pH 7.4)
0.5 47.1 46.1 47.9 48.3 48.5 47.4 44.1 46.6
1 47.6 48.0 65.6 49.3 46.7 48.0 44.5 47.2
1.5 60.4 66,4 94,3 68.5 50.6 56.2 53.9 53.2
2 89.3 92.9 98.8 92.5 76.9 89.0 85.5 90.9
3 95.9 96.5 99.J 98.4 92.2 96.0 93.0 97.0
4 96.6 96.4 98.5 98.8 94.4 96.7 94.2 98.8
6 96.4 94.6 98.1 98.9 94.7 96.7 94.1 99.0
8 96.1 94.6 98.4 98.0 93.7 95.5 93.1 98.4
12 94.8 93.6 99.4 98.4 92.9 94.1 92.6 97.2

CLAIMS:
1. Modified release pharmaceutical composition of memantine or its pharmaceutically acceptable salts, solvates, enantiomers or mixtures thereof comprising immediate release portion and modified release portion in single unit dosage form.
2. Modified release pharmaceutical compositions according to claim 1, wherein the dosage forms of immediate release portion and modified release portion comprises of granules, pellets, tablets, mini tablets, or capsules, suitable for oral administration;
3. Modified release pharmaceutical compositions according to claim 2, wherein dosage form filled in capsule or sachet; preferably in capsule.
4. Modified release pharmaceutical compositions according to claim 1, wherein memantine or its pharmaceutically acceptable salts, solvates, enantiomers or mixtures thereof is in the range of about 1% to about 25% by weight.
5. Modified release pharmaceutical compositions according to claim 1, wherein the pharmaceutically acceptable excipients comprises of diluents, binders, disintegrants, glidants & lubricants.
6. Modified release pharmaceutical compositions according to claim 1, wherein memantine or its pharmaceutically acceptable salts, solvates, enantiomers or mixtures thereof comprising in a therapeutically effective amount, placebo granules comprising of diluents, disintegrants and optionally binders, and one or more pharmaceutically acceptable excipients comprising of glidants & lubricants, and in said compositions modified release portion being further coated with a release modifying or release retarding polymers.
7. Modified release pharmaceutical compositions according to claim 3, wherein pharmaceutical composition can be prepared by co-sifting the active substance along with placebo granules manufactured using pharmaceutically acceptable excipients or adsorbing the active substance onto the pharmaceutically acceptable placebo granules.
8. Modified release pharmaceutical compositions of claim 6, wherein placebo granules prepared by dry granulation or wet granulation method, preferably prepared by wet granulation using high shear mixers or low shear mixers or fluid bed processor.

9. Modified release pharmaceutical compositions according to claim 8, wherein adsorption method involves either addition of drug solution to excipient mixture by using suitable equipments like high shear or low shear mixers or spraying the drug solution on to excipient mixture by using fluid bed processor.
10. Modified release pharmaceutical compositions of claim 5, wherein the diluents comprises of at least one or more of calcium phosphate (dibasic/tribasic), calcium sulphate, calcium sulphate dihydrate, lactose, fructose, sucrose, mannitol, sorbitol, xylitol, dextrose, compressible sugar, dextrates, dextrin, starch, microcrystalline cellulose, powdered cellulose, cellulose acetate, polymethacrylates, sodium alginate and tragacanth; preferred diluents comprises of one or more of calcium phosphate (dibasic/tribasic), lactose, mannitol, dextrose, compressible sugar, dextrates, dextrin, starch, microcrystalline cellulose, powdered cellulose; more preferred diluents comprises of one or more of powdered cellulose, microcrystalline cellulose, lactose and starch.
11. Modified release pharmaceutical compositions of claim 11, wherein microcrystalline cellulose used with one or more grades, with different mean particle size in different ratios, wherein mean particle size is ranging from about 20 μm to about 180 μm, preferably mean particle size range of from about 50 μm to about 180 μm, more preferably is from about 100 μm to about 180 μm.
12. Modified release pharmaceutical compositions of claim 11, wherein ratio of different grades of microcrystalline celluloses with different mean particle size used in the pharmaceutical composition is about 5:95 % w/w, preferably ratio is about 10:90 % w/w; more preferably ratio of is about 20: 80 % w/w.
13. Modified release pharmaceutical compositions of claim 5, wherein binder comprises at least one or more of polyvinyl pyrrolidone, co-povidone, acacia gum, guar gum, xanthan gum, karaya gum, gellan gum, hupu gum, carob bum, caramania gum, gelatin, glucose, sugar, dextrin, sorbitol, maltose, pregelatinised starch, carboxymethyl cellulose sodium, methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, ethyl cellulose, cellulose acetate, agar, alginic acid, sodium alginate, carbomers, carrageenan, ceratonia, chitosan, poloxamer, polyethylene oxide, magnesium aluminum silicate and glyceryl behenate; preferrsble binders comprises of one or more of polyvinyl pyrrolidone, copovidone, pregelatinised starch,

hydroxypropylmethyl cellulose, methyl cellulose, and hydroxypropyl cellulose; more preferable binders comprises of polyvinyl pyrrolidone and copovidone.
34. Modified release pharmaceutical compositions of claim 5, wherein disintegrant comprises at least one or more of croscarmellose sodium, crospovidone, sodium starch glycolate, low-substituted hydroxypropyl cellulose, starch, pregelatinized starch, microcrystalline cellulose, emcosoy (Soya polysaccharide) and potassium polacrilin; more preferred disintegrants comprises of crospovidone, croscarameliose sodium and sodium starch glycolate.
15. Modified release pharmaceutical compositions of claim 5. wherein the glidant comprises at least one or more of colloidal silicon dioxide, silicon dioxide, calcium silicate, magnesium silicate, calcium phosphate tribasic, talc, pregelatinized starch and starch; more preferred glidants comprises of one or more of colloidal silicon dioxide and talc.
16. Modified release pharmaceutical compositions of claim 5, wherein the lubricant comprises at least one or more of magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumerate, hydrogenated vegetable oils, magnesium lauryl sulfate, talc, wax, polyethylene glycol, glyceryl behenate, glyceryl palmitostearate, palmitic acid, poloxamer, sodium benzoate and sodium lauryl sulfate; more preferable lubricants comprise of one or more of magnesium stearate, calcium stearate, and sodium stearyl fumerate.
17. Modified release pharmaceutical compositions of claim 1, wherein memantine HC1 present is in an amount of about 1 mg to about 40 mg; preferably from about 1 mg to about 30 mg of memantine HC1; and more preferably from about 1 mg to 25 mg.
18. Modified release pharmaceutical compositions of claim 1, wherein the pharmaceutically acceptable excipients comprises between 5 to 99% by weight of the pharmaceutical composition.
19. Modified release pharmaceutical compositions of claim 1, wherein the composition by weight comprises active ingredient about 1 to 25%, preferably about 1 to 20 % and more preferably about 1 to 10%; placebo granules about 1 to 99% , preferably about 25 to 99%, and more preferably about 50 to 99%; about 0.1 to 5% of glidants, more

preferably about 0.1 to 3%, and about 0.1 to 5% of lubricant, more preferably about 0.1 to 3%.
20. Modified release pharmaceutical compositions of claim 19, wherein placebo granules comprises of diluents from about 1 to 99%, more preferably about 1 to 96%; disintegrants from about 0.1 to 25%, preferably about 0.1 to 10%, and more preferably about 0.1 to 6%, binders from about 0.1 to 25%; preferably from about 0.1 to 10%, and more preferably between about 0.1 to 4% .
21. Modified release pharmaceutical compositions of claims 1, wherein modified release portion can be prepared by film coating using one or more of techniques like spray coating, dip coating or conventional pan coating,
22. Modified release pharmaceutical compositions of claims 21, wherein, film coating is about 1 to 40%, preferably about 1 to 30 % and more preferably about 2 to 30%.
23. Modified release pharmaceutical compositions of claim 22, wherein film coating comprises one or more of release retardant or modifying polymers, antitaking agent, plasticizers optionally opacifying agents.
24. Modified release pharmaceutical compositions of claim 23, wherein film coating comprises of 1 to 50% of one or more of release retarding or modifying polymers, from about 0.01 to 6% of colorants, from about 0.01 to 25% of plasticizers.
25. Modified release pharmaceutical compositions of claim 22, wherein film coating comprises of release modifying polymers comprises of one or more of cellulose derivatives like, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxymethyl cellulose, hydroxyethy! cellulose, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, cellulose acetate phthalate, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, polyvinyl acetate phthalate, hydroxypropylmethyl cellulose phthalate, hydroxypropylm ethyl cellulose acetate succinate, one or more of methacrylic co-polymers like, poly (ethyl acrylate, methyl methacrylate) 2:1; Poly(methacrylic acid, methyl methacrylate)l:l; Poly(methacrylic acid, ethyl acrylate) 1:1; Poly(methacylic acid-co-methyl methacrylate) 1:2; Poly (methyl acrylate, methyl methacrylate, methacrylic acid) 7:3:1; and polyethylene glycol, polyvinyl alcohol, povidone, copovidone, chitosan, maltodextrin, isomalt, ammonium alginate, gelatin, carrageen, ethyl lactate and

mixture thereof. Preferred release modifying hydrophilic polymers comprises one or more of methyl cellulose, ethyl cellulose. hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, cellulose acetate phthalate, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, polyvinyl acetate phthalate, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, one or more of methacrylic co-polymers like, poly (ethyl acrylate, methyl methacrylate) 2:1; Poly(methacrylic acid, methyl methacrylate)l:l; Poly(methacrylic acid, ethyl acrylate) 1:1; Poly(methacylic acid-co-methyl methacrylate) 1:2; Poly (methyl acrylate, methyl methacrylate, methacrylic acid) 7:3:1; and polyethylene glycol, polyvinyl alcohol, copovidone, chitosan, ammonium alginate, gelatin, carrageen, and mixture thereof; more preferably release modifying hydrophilic polymers comprises one or more of ethyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, cellulose acetate, one or more of methacrylic co-polymers like, poly (ethyl acrylate, methyl methacrylate) 2:1; Poly(methacrylic acid, methyl methacrylate)I:I; Poly(methacryIic acid, ethyl acrylate) 1:1; Poly(methacyiic acid-co-methyl methacrylate) 1:2; Poly (methyl acrylate, methyl methacrylate, methacrylic acid) 7:3:1; and polyethylene glycol, polyvinyl alcohol, copovidone, chitosan, ammonium alginate, gelatin, carrageen, and mixture thereof & most preferably Poly(methacylic acid-co-methyl methacrylate) 1:2.
26. Modified release pharmaceutical compositions of claim 22, wherein plasticizer in film coating comprises of at least one or more triethyl citrate, polyethylene glycols, propylene glycol, glycerine, caster oil, acetyltriethyl citrate, benzyl benzoate, chlorbutanol, dextrin, acetyltributyl citrate, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, glyceryl monooleate, glyceryl monostearate, 2-pyrrolidone, sorbitol, stearic acid, palmitic acid, triacetin, tributyl citrate, triethanolamine, lecithin, surfactants like polysorbates, sorbitan esters and organic acid esters and/or mixtures thereof; more preferably comprises of one or more triethyl citrate, polyethylene glycols, propylene glycol, stearic acid, triacetin and/or mixtures thereof; most preferably plasticizers comprises of at least one or more one or more of triethyl citrate, polyethylene glycols and triacetin.
27. Modified release pharmaceutical compositions of claim 22, wherein antitacking agent of film coating comprises of one or more of talc, magnesium stearate, calcium stearate,

stearic acid, calcium carbonate,, magnesium carbonate, ground limestone, magnesium silicate, aluminum silicate, clay, alumina, titanium oxide, mono-calcium phosphate, di-calcium phosphate, tri-calcium phosphate and/or combinations thereof; more preferable anti-tacking agent comprises of one or more of talc, magnesium stearate, calcium stearate, stearic acid, calcium carbonate, magnesium carbonate, magnesium silicate, aluminum silicate, alumina, titanium oxide and/or combinations thereof; most preferred anti-tacking agent comprises of at least one or more talc, magnesium stearate and titanium oxide.
28. Modified release pharmaceutical compositions of claim 22. wherein optional opacifier of film coating layer comprises of one or more of titanium dioxide, silicates such as talc and aluminium silicate, ethylene glycol palmitostearate, acetates such as zinc acetate, carbonates such as magnesium carbonate, calcium carbonate, stearates such as aluminium stearate and zinc stearate, sulfates such as calcium sulfate, oxides such as magnesium oxide and hydroxides such as aluminiuim hydroxides;, more preferred comprises of at least one or more of titanium dioxide, silicates such as talc and aluminium silicate, ethylene glycol carbonates such as magnesium carbonate, calcium carbonate, stearates such as aluminium stearate and zinc stearate; most preferred opacifier used is selected from at least one or more of titanium dioxide, silicates such as talc and aluminium silicate, stearates such as aluminium stearate and zinc stearate.
29. Modified release pharmaceutical compositions of claim 1, wherein suitable solvents used in the manufacturing of pharmaceutical compositions; comprises one or more of water, ethyl acetate, acetone, isopropyl alcohol, ethanol, methylene chloride, n-propanol, and mixtures thereof; preferably one or more of water, acetone, isopropyl alcohol and methylene dichloride and mixtures thereof
30. The process for preparation of modified release pharmaceutical compositions according to claim 1, prepared by addition of active substance to placebo granules, wherein steps comprises of,
a. Sifting of pharmaceutically inactive ingredients other than glidant and
lubricant.
b. Preparing placebo granules of above excipient mixture using binder solution.
c. Drying of the prepared placebo granules.

d. Adsorption of placebo granules with active substance and mixing with giidant and lubricant.
,e. Compress the above blend or can be direct filled into, capsules or sachets.
f. Film coated the part of compressed tablets of step (e).
g. Fill the uncoated and film coated tablets into capsules or sachets.
31. The process for preparation of pharmaceutical composition according to claim 1,
prepared by adsorption method using conventional wet granulation method, wherein
steps comprises of,
a. Sifting of pharmaceutically inactive ingredients.
b. Preparation of drug solution.
c. Mixing of the ingredients other than giidant and lubricant and adsorbing the
drug on to excipient mixture by simple addition.
d. Drying of the prepared active granulate and lubricating the granulate with
giidant and lubricant.
e. Compress the above blend or can be direct filled into capsules or sachets
f. Film coated the part of compressed tablets of step (e).
g. Fill the uncoated and film coated tablets into capsules or sachets.
32. The process for preparation of pharmaceutical composition according to claim 1,
prepared by adsorption method using spray granulation method, wherein steps
comprises of,
a. Sifting of pharmaceutically inactive ingredients.
b. Preparation of drug solution.
c. Mixing of the ingredients other than giidant and lubricant and adsorbing the
drug on to excipient mixture by spray granulation technique.
d. Drying of the prepared active granulate and lubricating the granulate with
giidant and lubricant.

e. Compress the above blend or can be direct filled into capsules or sachets
f. Film coated the part of compressed tablets of step (e).
g. Fill the uncoated and film coated tablets into capsules or sachets.
33. Modified release pharmaceutical composition according to claim 1, wherein from one to twelve uncoated immediate release minitablets and or modified release coated minitablets are encapsulated alone or in combination in any ratio.
34. Modified release pharmaceutical compositions according to claim 2, wherein the minitablets have diameter from about 1 mm to 7 mm.
35. Modified release pharmaceutical composition according to claim 1, wherein the dosage form releases, less than about 55 % of the drug in about 2 hour, more than about 40 % of the drug in about 4 hours, more than about 70 % of the drug in about 6 hours, more than about 85 % of the drug in 12 hours, as measured in 900 ml of simulated gastric fluid without enzyme for upto 2 hours followed by 900 ml of Phosphate buffer using USP Type I apparatus (basket), at 37±0.5 °C.
36. Pharmaceutical compositions according to claim 1, wherein the dosage form is used in the treatment of Alzheimer's disease, Parkinson's disease and other neurological disorders.
37. The oral pharmaceutical composition substantially as herein described and illustrated with reference to the accompanying examples.