Title of Invention	PHARMACEUTICAL COMPOSITION OF MEMANTINE AND PROCESS FOR THE PREPARATION THEREOF
Abstract	The present invention relates to the field of pharmaceutical technology and describes novel methods of manufacturing of stable pharmaceutical composition comprising Memantine or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof. In particular the invention is directed to manufacture memantine composition through innovative process namely by adsorption method or spray drying method or placebo granules method. This composition shall be taken orally for the treatment of Alzheimer"s disease. 3§li JUL ZOOI 14

Title of Invention

PHARMACEUTICAL COMPOSITION OF MEMANTINE AND PROCESS FOR THE PREPARATION THEREOF

Abstract

The present invention relates to the field of pharmaceutical technology and describes novel methods of manufacturing of stable pharmaceutical composition comprising Memantine or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof. In particular the invention is directed to manufacture memantine composition through innovative process namely by adsorption method or spray drying method or placebo granules method. This composition shall be taken orally for the treatment of Alzheimer"s disease. 3§li JUL ZOOI 14

Full Text	FORM 2 THE PATENTS ACT 1970 (39 OF 1970) PROVISIONAL SPECIFICATION (SECTION 10) PHARMACEUTICAL COMPOSITION OF MEMANTINE AND PROCESS FOR THE PREPARATION THEREOF" 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, MAHARASHTRA, INDIA The following specification describes the invention "PHARMACEUTICAL COMPOSITION CONTAINING MEMANTINE AND PROCESS FOR THE PREPARATION THEREOF" FIELD OF INVENTION The present invention relates to prepare stable, dose proportional, easily disintegrated & dissolved immediate release oral pharmaceutical composition comprising memantine or its pharmaceutically acceptable salt, enantiomers or mixtures thereof, an uncompetitive (open-channel) NMDA-Receptor antagonist for the treatment of Alzheimer's disease. In particular, invention related to pharmaceutical technology, which discloses the novel methods of manufacturing of pharmaceutical compositions of memantine. BACKGROUND OF THE INVENTION Memantine hydrochloride is a adamantine derivative, uncompetitive NMDA receptor antagonist that belong to the chemical class of l-amino-3,5-dimethyladamentane hydrochloride. The reported IUPAC name for memantine hydrochloride is 3,5-dimethyladamantane-1-amine hydrochloride. The molecular formula of memantine hydrochloride is C12H21N.HCI, and the molecular weight is 215.76. Memantine hydrochloride is currently marketed by Forest Labs in the form of film coated tablets under the trade name NAMENDA® in USA. In Europe, Memantine hydrochloride is marketed under the brand names of AUXURA® and EBIXA®. NAMENDA has been approved by the USFDA for the treatment of moderate to severe Alzeimer's disease. 2 US20060002999 A1 (Yang Y. et al, 2005), discloses pharmaceutical compositions of 1-aminocyclohexanes, such as memantine or neramexane, prepared by a direct compression method for preparing tablets, which are released at a dissolution rate of at least about 80 percent in 60 minutes, and have a hardness between 3 and 40 kp, i.e., between about 4.2 and 56 SCU (Stong Cobb Units). In this invention formulations suffered from problems like sticking and capping. Our invention completely does not involve all these problems and shown superiority over direct compression strategy. WO 2008005036 (Hrakovsky et al, 2006) discloses the manufacturing of solid dosage form of memantine by wet granulation method. Even though wet granulation method widely used in the manufacturing of various pharmaceutical dosage forms, it suffers from various disadvantages such as loss of drug during various processing steps like granulation, drying, milling and exposure of drug to harsh environment like granulating solvent, heat, which may lead to rise in impurity levels in the formulation. US20060251717 (Firestone et al, 2004) discloses the manufacturing of solid dosage form containing memantine, by milling memantine with microcrystalline cellulose. Milling of any active pharmaceutical ingredient during manufacturing of pharmaceutical dosage form is not preferable because, it may results in loss of drug during milling or polymorphic conversion may takes place. Even though many technologies with different compositions are disclosed to manufacture memantine oral compositions, however suffers from problems like sticking & capping tendency, drug loss and high production costs . Therefore there is a need of, simple and effective composition which eliminates all these disadvantages. 3 OBJECT OF THE INVENTION The object of the present invention is to provide an improved, simple and cost effective process and composition for the preparation of memantine or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof, which is easily dissolved, stable and dose proportional. SUMMARY OF THE INVENTION The present invention relates to the composition and process of an immediate release oral pharmaceutical composition comprising, memantine or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof. The present invention discloses method of manufacturing, which is cost effective, simple and produces most stable pharmaceutical dosage forms of memantine. The present invention also discloses one of the methods of manufacturing, which is cost effective and simple and independent of particle size of active ingredient. Disclosed method of manufacturing is helps in adsorbing the drug more uniformly throughout the blend of pharmaceutically acceptable excipients, which ensures uniformity of drug among the final dosage forms. The present invention is directed to use placebo granules to prepare compositions of memantine, where in at about 95 percent of the memantine is released with in about 60 minutes of being placed in 0.1 N HCI at 37°C. Preferably, about 95 percent of the memantine is released within about 45 minutes, more preferably within about 30 minutes, most preferably within about 15 minutes of being placed in 0.1 N HCI at 37°C. 4 The present invention is also directed to prepare compositions of memantine by adsorbing or dispersing the memantine on one or more pharmaceutically acceptable excipients, where in at about 95 percent of the memantine is released with in about 60 minutes of being placed in 0.1 N HCI at 37°C. Preferably, about 95 percent of the memantine is released within about 45 minutes, more preferably within about 30 minutes, most preferably within about 15 minutes of being placed in 0.1 N HCI at 37°C. According to the present invention, memantine composition preferably comprises memantine and placebo granules, which are made up of two or more pharmaceutically acceptable excipients. More preferably, the memantine is memantine hydrochloride. Preferably, memantine composition may also comprises at least one or more pharmaceutically acceptable excipients along with placebo granules, which is selected from the group consisting of glidants and lubricants. In accordence with the invention, placebo granules preferbly comprises diluent, binder and disintegrant. The diluent used in placebo granules are at least one of the lactose, starch, calcium phosphate (dibasic/tribasic), calcium sulphate, powdered cellulose, dextratres, dextrin, fructose, sucrose, mannitol, sorbitol, calcium sulphate dihydrate, dextrose, cellulose acetate, compressible sugar, polymethacrylates, sodium alginate, tragacanth, xylitol and microcrystalline cellulose. Preferred diluents used in the preparation of placebo granules are microcrystalline cellulose, lactose, starch, mannitol and powdered cellulose. The binder used in the preparation of placebo granules, are at least one of polyvinyl pyrrolidone, magnesium aluminum silicate, co-povidone, acacia, agar, alginic acid, carbomers, carboxymethyl cellulose sodium, carrageenan, cellulose acetate, ceratonia, chitosan, glucose, sugar, dextrin, ethyl cellulose, glyceryl behenate, guar gum, gelatin hydroxypropyl methylcellulose, methyl cellulose, hydroxypropyl cellulose, poloxamer, polyethylene oxide, sodium alginate, sorbitol, maltose and pregelatinised starch. Preferred binders used in the preparation of placebo granules are 5 polyvinyl pyrrolidone, copovidone, pregelatinised starch, hydroxypropyl methylcellulose, methyl cellulose, and hydroxypropyl cellulose . The disintegrant used in the placebo granules include those disintegrants commonly used in solid pharmaceutical compositions. Disintegrants used are like at least one of croscarmellose sodium, crospovidone, microcrystalline cellulose, emcosoy ( Soya polysaccharide), potassium polacrilin, sodium starch glycolate, low-substituted hydroxypropyl cellulose, and starch, pregelatinized starch. Preferred disintegrants used in the preparation of placebo granules are crospovidone, croscarmellose sodium and sodium starch glycolate . The lubricant may be one or more of magnesium stearate, talc, stearic acid, wax, sodium stearyl fumerate, polyethylene glycol, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, magnesium lauryl sulfate, palmitic acid, poloxamer, sodium benzoate, sodium lauryl sulfate, and calcium stearate. The glidant may be one or more colloidal silicon dioxide, calcium phosphate tribasic, calcium silicate, magnesium silicate, silicon dioxide, talc, pregelatinized stach and starch. The memantine composition may contain 1-20% of memantine hydrochloride, 1-95 % of placebo granules, 0.1-5 % of colloidal silicone dioxide, 0.1-5 % of talc and 0.1-5 % of magnesium stearate. Placebo granules to be used in the manufacturing of memantine composition may contain 1-98 % of one or more grades of microcrystalline cellulose, 0.1-10 % of povidone and 0.1- 10 % of crospovidone. The memantine composition of the present invention may include the active ingredient in a range of about 1 mg to about 40 mg. Preferably, present invention may include 1 to 20 mg of memantine. More preferred dosage form may contain either 5 mg or 10 mg of the active ingredient. The 'active ingredient' refers to memantine hydrochloride or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof. 6 The formulation may contain 1-20% of the active ingredient. Preferably formulation may contain 1-10 % of the active ingredient. More preferably, formulation may contain 1-5 % of the active ingredient The 'active ingredient' may be memantine hydrochloride or pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof. The formulation may contain 1-95 % of placebo granules. Preferably formulation may contain 10-95 % of placebo granules. More preferably, formulation may contain 40-95 % of placebo granules. Placebo granules may contain 1-98 % of one or more diluents, 0.1- 10 % of one or more binders and 0.1-10 % of one or more disintegrants. More preferably, placebo granules may contain 1-96 % of one or more diluents, 0.1-4 % of one or more binders and 0.1-6 % of one or more disintegrants. The formulation may also contain 0.1-5 % of the glidants. Preferably formulation may contain 0.1-3% of the glidants. The formulation may also contain 0.1-5 % of the lubricants. Preferably formulation may contain 0.1-3% of the lubricants. In one preferred embodiment, memantine composition may include memantine hydrochloride or pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof in amounts ranging from about 1% to about 20% w/w, placebo granules in amount ranging from about 1-95% w/w, talc in amount ranging from about 0.1 - 3 % w/w, colloidal silicone dioxide in amount ranging from about 0.1 -• 3 % w/w, magnesium stearate in amount ranging from about 0.1-3 % w/w. Placebo granules to be used in the manufacturing of memantine composition may contain one or more grades of microcrystalline cellulose in amount ranging from about 1-96 % w/w , povidone in amount ranging from about 0.1-4 % w/w and crospovidone in amount ranging from about 0.1- 6% w/w. In accordance with the invention, memantine composition is preferably in the form of a solid oral dosage form. Preferably, the solid oral dosage form is a tablet or a capsule or a sachet of granules. 7 In accordenee with present invention, placebo granules can be prepared by dry granulation method or wet granulation method. Dry granulation method of preparing placebo granules may include slugging method or roller compaction. Wet granulation method of preparing placebo granules may include conventional granulation method using rapid mixer granulator or spray granulation method using fluid bed processor. Suitable solvents used for wet granulation include water, ethyl acetate, acetone, isopropyl alcohol, methanol, ethanol and mixtures thereof. In accordance with the invention, the memantine composition is preferably in the form of a film-coated tablet comprising memantine, placebo granules, which in turn comprises of povidone, microcrystalline cellulose & crospovidone, and colloidal silicon dioxide, talc, magnesium stearate, and a coating agent. The coating layers over the tablet may be applied as dispersion/solution'of coating ingredients using any technique known as spray coating, fluidized bed processor or dip coating and conventional pan coating. Suitable solvents used for coating solution/dispersion include water, ethyl acetate, acetone, isopropyl alcohol, methanol ethanol and mixtures thereof. Suitable coloring agents include one or more colors approved by FDA. , Suitable pharmaceutically acceptable excipients used for coating include carrageen, ethyl cellulose, hydroxypropyl methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, methyl cellulose, hydroxypropyl methyl phthalate, cellulose acetate phthalate, polyethylene glycol, methacrylic acid polymers, kollidone and mixture thereof. Preferably, the coating may also comprises polyethylene glycol, titanium dioxide and/or iron oxide. The invention is also provides a process for preparing a memantine composition using placebo granules. The process of preparing placebo granules comprises granulating one or more diluents with a disintegrant and a binder in a liquid to form a granulate. The granulate is then preferably dried and sifted. Memantine mixed with sifted placebo granules and lubricated with lubricant and glidant. The 8 final blend may then be compressed into tablets or filled into capsules or filled in a sachet. The invention is also provides a process for preparing a memantine composition by adsorption method . The process of preparing memantine composition comprises dissolving the drug in aqueous or hydroalcoholic or non-aquaeous solvent, adsorbing the active ingredient solution on the mixture of pharmaceutically acceptable excipients using rapid mixer granulator. The memantine granulate is then preferably dried and sifted and lubricated with lubricant and glidant. The final granulate may then be compressed into tablets or filled into capsules or filled in a sachet. In another aspect, the invention is also provides a process for preparing a memantine composition by spray drying method . The process of preparing memantine composition comprises dissolving the drug in aqueous or hydroalcoholic or non-aquaeous solvent, spraying the active ingredient solution on the mixture of pharmaceutically acceptable excipients in fluid bed processor. The spray dried granuls of memantine is then preferably dried and sifted and lubricated with lubricant and glidant. The final spray dried granuls of memantine may then be compressed into tablets or filled into capsules or filled in a sachet. The compositions of the 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, as per the approved indications for NAMEND A ® see prescribing information. The amount of the memantine in a pharmaceutical composition is preferably an amount that provides a therapeutically effective amount of memantine. It will be appreciated that the amount of memantine used will differ according to the amount needed to effect the therapeutic response. 9 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 Example 1 Table 1: Formulation of example 1 Sr. No. Ingradients Quantity per tablet in mg 1 MemantineHCI IH 10.0 2 Microcrystalline cellulose USP (Avicel PH200) 41.0 3 Microcrystalline cellulose USP (Avicel PH 112) 170.0 4 Crospovidone USP 10.0 5 Povidone K 29/32 USP 2.0 6 Colloidal silicone dioxide USP 2.0 7 Talc USP 1.0 8 Magnesium stearate USP 2.0 9 Hydroxypropyl methylcellulose 3 cps USP 3.6 10 Titanium dioxide USP 1.8 11 Polyethylene glycol 400 USP 0.6 12 Purified water USP qs Tablet weight 244 Manufacturing process: Placebo granules were prepared by using Avicel PH 200, Avicel PH 112, Crosspovidone and Povidone using purified water as a granulating agent to form wet 10 granulate in Rapid Mixer Granulator. Wet granulate was dried using Fluid Bed Processor till the LOD reach to 2-3 % w/w. Dried granules were sifted through the mesh # 40 ASTM. Fine placebo granules are separated by using mesh # 60 ASTM and over sized granules were collected in separate polybag. Fine placebo granules were sifted together with Memantine HCl through mesh # 60 ASTM for 3 times. This blend was lubricated with Talc, Colloidal silicone dioxide and Magnesium stearate (40 #). The above mixture was compressed into tablets by using 11.9X5.3 mm capsule shaped standard concave punches. Tablets were then spray coated with coating dispersion, which comprises Hydroxypropyl methyiceilulose, Titanium dioxide and Polyethylene glycol 400. Example 2 Table 2: Formulation of example 2 Sr. No3. Ingradients Quantity per tablet in mg 1 Memantine HCl IH 10 2 Microcrystalline cellulose USP (Avicel PHI 02) 199 3 Crospovidone USP 10 4 Povidone K 29/32 USP 2 5 Colloidal silicone dioxide USP 2 6 Talc USP 1 7 Magnesium stearate USP 2 8 Hydroxypropyl methyiceilulose 5 cps USP 3.5 9 Titanium dioxide USP 1.4 10 Polyethylene glycol 400 USP 1.1 11 Purified water USP qs Tablet weight 232 Manufacturing process: Memantine HCI was dissolved in purified water and sprayed on mixture of Avicel PH 102, Crospovidone and Povidone using Fluid bed processor. Wet granules were dried till the LOD reach to 2-3 % w/w. Dried granules were sifted through the mesh # 40 ASTM. This blend was lubricated with Talc, Colloidal silicone dioxide and Magnesium stearate (40 #). The above mixture was compressed into tablets by using 11.9X5.3 mm capsule shaped standard concave punches. Tablets were then spray coated with coating dispersion, which comprises Hydroxypropyl methylcellulose, Titanium dioxide and Polyethylene glycol 400. Example 3 Table 3: Formulation of example 3 Sr. No. Ingradients Quantity per tablet in mg 1 Memantine HCI IH 10 2 Corn starch 30 3 Microcrystalline cellulose USP (Avicel PH101) 134 4 Povidone K 29/32 USP 12 5 Microcrystalline cellulose USP (Avicel PH 102) 12 6 Magnesium stearate USP 2 7 Hydroxypropyl methylcellulose 3 cps USP 3.5 8 Titanium dioxide USP 1.4 9 Polyethylene glycol 400 USP 1.1 10 Purified water USP qs . Tablet weight 206 Manufacturing process: Memantine HCI was dissolved in warm purified water and adsorbed on mixture of Avicel PH 101, Corn starch and Povidone using Rapid Mixer Granulator. Wet adsorbent was dried using Fluid Bed Processor till the LOD reach to 2-3 % w/w. Dried granules were sifted through the mesh # 40 ASTM. These dried granules were lubricated with Magnesium stearate (40 #). The above mixture was compressed into 12 tablets by using 11.9X5.3 mm capsule shaped standard concave punches. Tablets were then spray coated with coating dispersion, which comprises Hydroxypropyl methylcellulose, Titanium dioxide and Polyethylene glycol 400. Dated this 29th day of July, 2008 For Unichem Laboratories Limited K. Subharaman Head - Legal & Company Secretary 13

Full Text

FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
PROVISIONAL SPECIFICATION
(SECTION 10)
PHARMACEUTICAL COMPOSITION OF MEMANTINE AND PROCESS FOR THE PREPARATION THEREOF"

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,
MAHARASHTRA, INDIA

The following specification describes the invention
"PHARMACEUTICAL COMPOSITION CONTAINING
MEMANTINE AND PROCESS FOR THE PREPARATION THEREOF"
FIELD OF INVENTION
The present invention relates to prepare stable, dose proportional, easily disintegrated & dissolved immediate release oral pharmaceutical composition comprising memantine or its pharmaceutically acceptable salt, enantiomers or mixtures thereof, an uncompetitive (open-channel) NMDA-Receptor antagonist for the treatment of Alzheimer's disease. In particular, invention related to pharmaceutical technology, which discloses the novel methods of manufacturing of pharmaceutical compositions of memantine.
BACKGROUND OF THE INVENTION
Memantine hydrochloride is a adamantine derivative, uncompetitive NMDA receptor antagonist that belong to the chemical class of l-amino-3,5-dimethyladamentane hydrochloride. The reported IUPAC name for memantine hydrochloride is 3,5-dimethyladamantane-1-amine hydrochloride. The molecular formula of memantine hydrochloride is C12H21N.HCI, and the molecular weight is 215.76.
Memantine hydrochloride is currently marketed by Forest Labs in the form of film coated tablets under the trade name NAMENDA® in USA. In Europe, Memantine hydrochloride is marketed under the brand names of AUXURA® and EBIXA®. NAMENDA has been approved by the USFDA for the treatment of moderate to severe Alzeimer's disease.
2

US20060002999 A1 (Yang Y. et al, 2005), discloses pharmaceutical compositions of 1-aminocyclohexanes, such as memantine or neramexane, prepared by a direct compression method for preparing tablets, which are released at a dissolution rate of at least about 80 percent in 60 minutes, and have a hardness between 3 and 40 kp, i.e., between about 4.2 and 56 SCU (Stong Cobb Units). In this invention formulations suffered from problems like sticking and capping. Our invention completely does not involve all these problems and shown superiority over direct compression strategy.
WO 2008005036 (Hrakovsky et al, 2006) discloses the manufacturing of solid dosage form of memantine by wet granulation method. Even though wet granulation method widely used in the manufacturing of various pharmaceutical dosage forms, it suffers from various disadvantages such as loss of drug during various processing steps like granulation, drying, milling and exposure of drug to harsh environment like granulating solvent, heat, which may lead to rise in impurity levels in the formulation.
US20060251717 (Firestone et al, 2004) discloses the manufacturing of solid dosage form containing memantine, by milling memantine with microcrystalline cellulose. Milling of any active pharmaceutical ingredient during manufacturing of pharmaceutical dosage form is not preferable because, it may results in loss of drug during milling or polymorphic conversion may takes place.
Even though many technologies with different compositions are disclosed to manufacture memantine oral compositions, however suffers from problems like sticking & capping tendency, drug loss and high production costs . Therefore there is a need of, simple and effective composition which eliminates all these disadvantages.
3

OBJECT OF THE INVENTION
The object of the present invention is to provide an improved, simple and cost effective process and composition for the preparation of memantine or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof, which is easily dissolved, stable and dose proportional.
SUMMARY OF THE INVENTION
The present invention relates to the composition and process of an immediate release oral pharmaceutical composition comprising, memantine or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof.
The present invention discloses method of manufacturing, which is cost effective, simple and produces most stable pharmaceutical dosage forms of memantine.
The present invention also discloses one of the methods of manufacturing, which is cost effective and simple and independent of particle size of active ingredient. Disclosed method of manufacturing is helps in adsorbing the drug more uniformly throughout the blend of pharmaceutically acceptable excipients, which ensures uniformity of drug among the final dosage forms.
The present invention is directed to use placebo granules to prepare compositions of memantine, where in at about 95 percent of the memantine is released with in about 60 minutes of being placed in 0.1 N HCI at 37°C. Preferably, about 95 percent of the memantine is released within about 45 minutes, more preferably within about 30 minutes, most preferably within about 15 minutes of being placed in 0.1 N HCI at 37°C.
4

The present invention is also directed to prepare compositions of memantine by adsorbing or dispersing the memantine on one or more pharmaceutically acceptable excipients, where in at about 95 percent of the memantine is released with in about 60 minutes of being placed in 0.1 N HCI at 37°C. Preferably, about 95 percent of the memantine is released within about 45 minutes, more preferably within about 30 minutes, most preferably within about 15 minutes of being placed in 0.1 N HCI at 37°C.
According to the present invention, memantine composition preferably comprises memantine and placebo granules, which are made up of two or more pharmaceutically acceptable excipients. More preferably, the memantine is memantine hydrochloride. Preferably, memantine composition may also comprises at least one or more pharmaceutically acceptable excipients along with placebo granules, which is selected from the group consisting of glidants and lubricants.
In accordence with the invention, placebo granules preferbly comprises diluent, binder and disintegrant. The diluent used in placebo granules are at least one of the lactose, starch, calcium phosphate (dibasic/tribasic), calcium sulphate, powdered cellulose, dextratres, dextrin, fructose, sucrose, mannitol, sorbitol, calcium sulphate dihydrate, dextrose, cellulose acetate, compressible sugar, polymethacrylates, sodium alginate, tragacanth, xylitol and microcrystalline cellulose. Preferred diluents used in the preparation of placebo granules are microcrystalline cellulose, lactose, starch, mannitol and powdered cellulose.
The binder used in the preparation of placebo granules, are at least one of polyvinyl pyrrolidone, magnesium aluminum silicate, co-povidone, acacia, agar, alginic acid, carbomers, carboxymethyl cellulose sodium, carrageenan, cellulose acetate, ceratonia, chitosan, glucose, sugar, dextrin, ethyl cellulose, glyceryl behenate, guar gum, gelatin hydroxypropyl methylcellulose, methyl cellulose, hydroxypropyl cellulose, poloxamer, polyethylene oxide, sodium alginate, sorbitol, maltose and pregelatinised starch. Preferred binders used in the preparation of placebo granules are
5

polyvinyl pyrrolidone, copovidone, pregelatinised starch, hydroxypropyl methylcellulose, methyl cellulose, and hydroxypropyl cellulose .
The disintegrant used in the placebo granules include those disintegrants commonly used in solid pharmaceutical compositions. Disintegrants used are like at least one of croscarmellose sodium, crospovidone, microcrystalline cellulose, emcosoy ( Soya polysaccharide), potassium polacrilin, sodium starch glycolate, low-substituted hydroxypropyl cellulose, and starch, pregelatinized starch. Preferred disintegrants used in the preparation of placebo granules are crospovidone, croscarmellose sodium and sodium starch glycolate .
The lubricant may be one or more of magnesium stearate, talc, stearic acid, wax, sodium stearyl fumerate, polyethylene glycol, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, magnesium lauryl sulfate, palmitic acid, poloxamer, sodium benzoate, sodium lauryl sulfate, and calcium stearate.
The glidant may be one or more colloidal silicon dioxide, calcium phosphate tribasic, calcium silicate, magnesium silicate, silicon dioxide, talc, pregelatinized stach and starch.
The memantine composition may contain 1-20% of memantine hydrochloride, 1-95 % of placebo granules, 0.1-5 % of colloidal silicone dioxide, 0.1-5 % of talc and 0.1-5 % of magnesium stearate.
Placebo granules to be used in the manufacturing of memantine composition may contain 1-98 % of one or more grades of microcrystalline cellulose, 0.1-10 % of povidone and 0.1- 10 % of crospovidone.
The memantine composition of the present invention may include the active ingredient in a range of about 1 mg to about 40 mg. Preferably, present invention may include 1 to 20 mg of memantine. More preferred dosage form may contain either 5 mg or 10 mg of the active ingredient. The 'active ingredient' refers to memantine hydrochloride or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof.
6

The formulation may contain 1-20% of the active ingredient. Preferably formulation may contain 1-10 % of the active ingredient. More preferably, formulation may contain 1-5 % of the active ingredient The 'active ingredient' may be memantine hydrochloride or pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof.
The formulation may contain 1-95 % of placebo granules. Preferably formulation may contain 10-95 % of placebo granules. More preferably, formulation may contain 40-95 % of placebo granules. Placebo granules may contain 1-98 % of one or more diluents, 0.1- 10 % of one or more binders and 0.1-10 % of one or more disintegrants. More preferably, placebo granules may contain 1-96 % of one or more diluents, 0.1-4 % of one or more binders and 0.1-6 % of one or more disintegrants.
The formulation may also contain 0.1-5 % of the glidants. Preferably formulation may contain 0.1-3% of the glidants.
The formulation may also contain 0.1-5 % of the lubricants. Preferably formulation may contain 0.1-3% of the lubricants.
In one preferred embodiment, memantine composition may include memantine hydrochloride or pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof in amounts ranging from about 1% to about 20% w/w, placebo granules in amount ranging from about 1-95% w/w, talc in amount ranging from about 0.1 - 3 % w/w, colloidal silicone dioxide in amount ranging from about 0.1 -• 3 % w/w, magnesium stearate in amount ranging from about 0.1-3 % w/w. Placebo granules to be used in the manufacturing of memantine composition may contain one or more grades of microcrystalline cellulose in amount ranging from about 1-96 % w/w , povidone in amount ranging from about 0.1-4 % w/w and crospovidone in amount ranging from about 0.1- 6% w/w.
In accordance with the invention, memantine composition is preferably in the form of a solid oral dosage form. Preferably, the solid oral dosage form is a tablet or a capsule or a sachet of granules.
7

In accordenee with present invention, placebo granules can be prepared by dry granulation method or wet granulation method. Dry granulation method of preparing placebo granules may include slugging method or roller compaction. Wet granulation method of preparing placebo granules may include conventional granulation method using rapid mixer granulator or spray granulation method using fluid bed processor.
Suitable solvents used for wet granulation include water, ethyl acetate, acetone, isopropyl alcohol, methanol, ethanol and mixtures thereof.
In accordance with the invention, the memantine composition is preferably in the form of a film-coated tablet comprising memantine, placebo granules, which in turn comprises of povidone, microcrystalline cellulose & crospovidone, and colloidal silicon dioxide, talc, magnesium stearate, and a coating agent.
The coating layers over the tablet may be applied as dispersion/solution'of coating ingredients using any technique known as spray coating, fluidized bed processor or dip coating and conventional pan coating.
Suitable solvents used for coating solution/dispersion include water, ethyl acetate, acetone, isopropyl alcohol, methanol ethanol and mixtures thereof. Suitable coloring agents include one or more colors approved by FDA. ,
Suitable pharmaceutically acceptable excipients used for coating include carrageen, ethyl cellulose, hydroxypropyl methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, methyl cellulose, hydroxypropyl methyl phthalate, cellulose acetate phthalate, polyethylene glycol, methacrylic acid polymers, kollidone and mixture thereof.
Preferably, the coating may also comprises polyethylene glycol, titanium dioxide and/or iron oxide.
The invention is also provides a process for preparing a memantine composition using placebo granules. The process of preparing placebo granules comprises granulating one or more diluents with a disintegrant and a binder in a liquid to form a granulate. The granulate is then preferably dried and sifted. Memantine mixed with sifted placebo granules and lubricated with lubricant and glidant. The
8

final blend may then be compressed into tablets or filled into capsules or filled in a sachet.
The invention is also provides a process for preparing a memantine composition by adsorption method . The process of preparing memantine composition comprises dissolving the drug in aqueous or hydroalcoholic or non-aquaeous solvent, adsorbing the active ingredient solution on the mixture of pharmaceutically acceptable excipients using rapid mixer granulator. The memantine granulate is then preferably dried and sifted and lubricated with lubricant and glidant. The final granulate may then be compressed into tablets or filled into capsules or filled in a sachet.
In another aspect, the invention is also provides a process for preparing a memantine composition by spray drying method . The process of preparing memantine composition comprises dissolving the drug in aqueous or hydroalcoholic or non-aquaeous solvent, spraying the active ingredient solution on the mixture of pharmaceutically acceptable excipients in fluid bed processor. The spray dried granuls of memantine is then preferably dried and sifted and lubricated with lubricant and glidant. The final spray dried granuls of memantine may then be compressed into tablets or filled into capsules or filled in a sachet.
The compositions of the 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, as per the approved indications for NAMEND A ® see prescribing information.
The amount of the memantine in a pharmaceutical composition is preferably an amount that provides a therapeutically effective amount of memantine. It will be appreciated that the amount of memantine used will differ according to the amount needed to effect the therapeutic response.
9

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 Example 1
Table 1: Formulation of example 1

Sr.
No. Ingradients Quantity per tablet in mg
1 MemantineHCI IH 10.0
2 Microcrystalline cellulose USP (Avicel PH200) 41.0
3 Microcrystalline cellulose USP (Avicel PH 112) 170.0
4 Crospovidone USP 10.0
5 Povidone K 29/32 USP 2.0
6 Colloidal silicone dioxide USP 2.0
7 Talc USP 1.0
8 Magnesium stearate USP 2.0
9 Hydroxypropyl methylcellulose 3 cps USP 3.6
10 Titanium dioxide USP 1.8
11 Polyethylene glycol 400 USP 0.6
12 Purified water USP qs
Tablet weight 244
Manufacturing process:
Placebo granules were prepared by using Avicel PH 200, Avicel PH 112,
Crosspovidone and Povidone using purified water as a granulating agent to form wet
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granulate in Rapid Mixer Granulator. Wet granulate was dried using Fluid Bed Processor till the LOD reach to 2-3 % w/w. Dried granules were sifted through the mesh # 40 ASTM. Fine placebo granules are separated by using mesh # 60 ASTM and over sized granules were collected in separate polybag. Fine placebo granules were sifted together with Memantine HCl through mesh # 60 ASTM for 3 times. This blend was lubricated with Talc, Colloidal silicone dioxide and Magnesium stearate (40 #). The above mixture was compressed into tablets by using 11.9X5.3 mm capsule shaped standard concave punches. Tablets were then spray coated with coating dispersion, which comprises Hydroxypropyl methyiceilulose, Titanium dioxide and Polyethylene glycol 400.
Example 2
Table 2: Formulation of example 2

Sr. No3. Ingradients Quantity per tablet in mg
1 Memantine HCl IH 10
2 Microcrystalline cellulose USP (Avicel PHI 02) 199
3 Crospovidone USP 10
4 Povidone K 29/32 USP 2
5 Colloidal silicone dioxide USP 2
6 Talc USP 1
7 Magnesium stearate USP 2
8 Hydroxypropyl methyiceilulose 5 cps USP 3.5
9 Titanium dioxide USP 1.4
10 Polyethylene glycol 400 USP 1.1
11 Purified water USP qs
Tablet weight 232
Manufacturing process:

Memantine HCI was dissolved in purified water and sprayed on mixture of Avicel PH 102, Crospovidone and Povidone using Fluid bed processor. Wet granules were dried till the LOD reach to 2-3 % w/w. Dried granules were sifted through the mesh # 40 ASTM. This blend was lubricated with Talc, Colloidal silicone dioxide and Magnesium stearate (40 #). The above mixture was compressed into tablets by using 11.9X5.3 mm capsule shaped standard concave punches. Tablets were then spray coated with coating dispersion, which comprises Hydroxypropyl methylcellulose, Titanium dioxide and Polyethylene glycol 400.
Example 3
Table 3: Formulation of example 3

Sr. No. Ingradients Quantity per tablet in mg
1 Memantine HCI IH 10
2 Corn starch 30
3 Microcrystalline cellulose USP (Avicel PH101) 134
4 Povidone K 29/32 USP 12
5 Microcrystalline cellulose USP (Avicel PH 102) 12
6 Magnesium stearate USP 2
7 Hydroxypropyl methylcellulose 3 cps USP 3.5
8 Titanium dioxide USP 1.4
9 Polyethylene glycol 400 USP 1.1
10 Purified water USP qs .
Tablet weight 206
Manufacturing process:
Memantine HCI was dissolved in warm purified water and adsorbed on mixture of Avicel PH 101, Corn starch and Povidone using Rapid Mixer Granulator. Wet adsorbent was dried using Fluid Bed Processor till the LOD reach to 2-3 % w/w. Dried granules were sifted through the mesh # 40 ASTM. These dried granules were lubricated with Magnesium stearate (40 #). The above mixture was compressed into
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tablets by using 11.9X5.3 mm capsule shaped standard concave punches. Tablets were then spray coated with coating dispersion, which comprises Hydroxypropyl methylcellulose, Titanium dioxide and Polyethylene glycol 400.
Dated this 29th day of July, 2008
For Unichem Laboratories Limited
K. Subharaman
Head - Legal & Company Secretary
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Documents:

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Patent Number

270878

Indian Patent Application Number

1631/MUM/2008

PG Journal Number

05/2016

Publication Date

29-Jan-2016

Grant Date

25-Jan-2016

Date of Filing

31-Jul-2008

Name of Patentee

UNICHEM LABORATORIES LIMITED

Applicant Address

UNICHEM BHAVAN, PRABHAT ESTAT, OFF. S.V. ROAD, JOGESHWARI WEST, MUMBAI,

Inventors:

#	Inventor's Name	Inventor's Address
1	MAHESH KUMAR GUPTA	VISHNU OIL MILL, PLOT NO G-1-63 INDUSTRIAL AREA, HINDAUN CITY, DIST. KAROLI-322230,
2	ARAVIND VISHWESHWAR KERUDI	36, KHB COLONY, NAVANAGAR, HUBLI-580 025,
3	GEDALA VENKATA MURALI MOHAN BABU	H. NO. 1-120, CHEEDIPUDI, BUDITHI, SRIKAKULAM, 532427,

PCT International Classification Number

A61K9/22; A61K31/13; A61K47/38

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA