Title of Invention	"AN EXTENDED RELEASE PHARMACEUTICAL COMPOSITIONS COMPRISING CYCLOBENZAPRINE HYDROCHLORIDE"
Abstract	The present invention provides extended release pharmaceutical compositions structured for once a day administration comprising skeletal muscle relaxant such as cyclobenzaprine or its pharmaceutically acceptable salt thereof that extends the release of the drug under in-vitro conditions for at least 8 to 12 hours. The invention also provides process for the preparation of such structured compositions.

Title of Invention

"AN EXTENDED RELEASE PHARMACEUTICAL COMPOSITIONS COMPRISING CYCLOBENZAPRINE HYDROCHLORIDE"

Abstract

The present invention provides extended release pharmaceutical compositions structured for once a day administration comprising skeletal muscle relaxant such as cyclobenzaprine or its pharmaceutically acceptable salt thereof that extends the release of the drug under in-vitro conditions for at least 8 to 12 hours. The invention also provides process for the preparation of such structured compositions.

Full Text	FORM-2 THE PATENTS ACT. 1970 (39 OF 1970) & The Patent Rules, 2003 PROVISIONAL SPECIFICATION (See Section 10 and Rule 13) "EXTENDED RELEASE PHARMACEUTICAL COMPOSITIONS" I Inventia Healthcare Private Limited having its administrative office at Unit No. S - 4 Khira Industrial Estate, B.M Bhargava Road, Santacruz West, Mumbai 400054, Maharashtra, India an Indian Company The following specification describes the invention. FIELD OF THE INVENTION This invention relates to extended release pharmaceutical compositions for enhanced patient compliance comprising a skeletal muscle relaxant and process for producing the compositions. BACKGROUND OF THE INVENTION Cyclobehzaprine Hydrochloride, a skeletal muscle relaxant is currently available as immediate release tablets containing 5mg or 10mg of the active. These tablets are recommended to be administered three times a day to achieve relief from muscle spasm. Administration of such tablet three times a day is a major compliance issue especially in elderly patients. To substantially enhance patient compliance, it is desirable to provide Cyclobehzaprine Hydrochloride in extended release dosage form for once a day administration. US Patent 7287793, US Patent Application 2008/0124398, US Patent Application 2008/0124399, US Patent Application 2009/0017126 and US Patent Application 2009/0017127 discloses multi-particulate pharmaceutical dosage form of a skeletal muscle relaxant for once a day administration. These compositions provide modified release profile comprising a population of extended release beads, wherein said extended release jbeads comprise an active-containing core particle comprising a skeletal muscle i relaxant selected from the group consisting of Cyclobenzaprine, pharmaceutical^ acceptable salts or derivatives thereof and mixtures thereof; and an extended release coating .comprising a water insoluble polymer membrane surrounding said core. These compositions when analyzed in-vitro in USP apparatus 2 (paddles @ 50 rpm) in 900 ml of 0.1N HGI at 37°C exhibits the following dissolution profile: • not more than 40% of the total active is released at 2 hour; i • from about 40-65% of the total active is released at 4 hour; • from about 60-85% of the total active is released at 8 hour. i The dosage form in the prior art are essentially structured to have an active containing core particle coated with a polymer membrane which is prone to rupture thereby causing dose dumping. 2 OBJECTS OF THE INVENTION The object of the invention is to provide extended release pharmaceutical compositions for once a day administration comprising Cyclobenzaprine or its pharmaceutically acceptable salt thereof that extends the release of the active under in-vitro conditions for at least 8 to 12 hours for better patient compliance. It is another object of the invention to provide composition with substantially reduced numbenof ingredients to make the composition cost effective. i i It is yet I another object of the invention to structure the dosage form with minimum or no layeringj so as to provide simple and cost effective process options with less number of i processing steps. It is yet another object of the invention to provide the above compositions in the form of pellets capable of being filled in capsules or compressed into tablets. It is yet! another object of the invention to provide extended release compositions which i would substantially minimize the incidence of dose dumping. It is yet; another object of the invention to provide process for the preparation of extended release: pharmaceutical composition comprising Cyclobenzaprine or its pharmaceutically acceptable salts thereof that exhibits in-vitro drug release for at least 8 to 12 hours for better patient compliance. DESCRIPTION OF THE INVENTION Description of figures: Figures; 1(a), 1(b), 1(c) and 1(d) illustrate the manner in which the compositions of the present invention can be structured. The pharmaceutical composition of the present invention comprises of Cyclobenzaprine or its pharmaceutically acceptable salt thereof such as Cyclobenzaprine HCI and one or more agents for extended release that exhibits in-vitro drug release for at least 8 to 12 hours for better patient compliance. The composition optionally comprises at least one additive selected from binder, diluent, surfactant, plasticizer, anti-tack agent, lubricants, colors, Ipigments, dyes, or mixtures thereof. 3 Cyclobenzaprine salt is addition salt of Cyclobenzaprine with an inorganic acid such as hydrochloric, hydrobromic, phosphoric, nitric and / or sulphuric or of organic acid such as tartaric, acetic, propionic, hydroxyacetic, oxaloacetic, oxalic, pyruvic, succinic, malic, malonic,,fumaric, lactic, glutaric, maleic, sulphonic, benzenesulphonic and the like. The preferred Cyclobenzaprine salt is Cyclobenzaprine HCI and is usually administered in 15mg and 30mg strength. Cyclobenzaprine salt such as Cyclobenzaprine HCI of any particle sizes and shape can be used in the invention. However, the preferable particle size ranges from 0.1 microns to 1000 microns, more preferably from 0.5 micron to 500 microns and most preferably from 1 micron to 200 microns. The pharmaceutical composition comprises of Cyclobenzaprine HCI up to 50% by weight of the composition, preferably from 0.01% to 40% w/w, more preferably from 0.1% to 25%w/w and most preferably from 2.5% to 15% w/w. The age^nt for extended release is selected from water soluble agent, water insoluble agent, o' mixtures thereof. Agents for extended release are selected from the group of cellulose derivatives; acrylic acid derivatives; polymethacrylates; cellulose esters such as cellulose acetate; starch; modified starch; polyvinyl alcohol; polyvinyl acetate; povidone; polyalkylene glycol such as polyethylene glycol; gums such as xanthan gum, guar gum, locust bean gum; alginates such as sodium alginate and calcium alginate; hydrogenated castor oil; cetyl alcohol; waxes such as bees wax, carnauba wax; fatty acid; fatty alcohols and esters of fatty acids; stearic acid and its salt such as magnesium s tearate and calcium stearate; shellac; polyethylene oxides; vinyl pyrrolidone-vinyl acetate copolymer (Kollidon VA 64); carbomer such as] carbomer 934P, carbomer 971P, and carbomer 974P; or mixtures thereof. i i i Cellulose derivative are available in various grades depending on their viscosities from i about 3>cps to about 1,00,000cps. Various commonly available viscosity grades are of 3cps, 5cps, 6cps, 15cps, 100cps, 4000cps, 15000cps and about 1,00,000 cps. Cellulose derivatives are selected from ethylcellulose, hydroxypropylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, sodiumi carboxymethylcellulose, calcium carboxymethylcellulose, methylcellulose, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, 4 hydroxypropylmethylcellulose acetate succinate, cellulose acetate butyrate, cellulose i acetate frimellitate, or mixtures thereof. Ethylcellulose as a dry powder or aqueous dispersion marketed under the trade name of Ethocel RTM of Dow, U.S.A., Aquacoat RTM of FMC, USA and Surelease RTM of Colorcon, USA may also be used. This ready dispersion further contains plasticizers, surfactants (sodium lauryl sulfate), stabilizing agents, ammonium hydroxide, oleic acid, fumed silica, anti-foaming agent, cetyl alcohol as additives. Ethyl cellulose of various viscosities grades such as 3cps, 5cps, 7cps, 10cps, 20cps, 45cps, 50cps, 100cps can be used. Polymethacrylates used in the present invention is preferably selected from methacrylic acid copolymers and its esters. Such polymers are readily available from Rohm Pharma under trie brand name of Eudragit L30D55, Eudragit L100 55, Eudragit L100, Eudragit S100, Eudragit RL, Eudragit RS, and Eudragit NE 30D or 40D. The agent for extended release is present in an amount from about 0.5% to 90% by weight of the composition, preferably from 1% to 75% w/w, more preferably from 2.5% to 60% w/w, most preferably from 5% to 50% w/w. In one of the embodiments of the invention the agents for extended release are mixture of two or more different viscosity grade material. Mixtures of extended release agents are used in the ratio of 1:0.01 to 0.01: 1. Plasticizers are selected from the group of hydrophilic and hydrophobic plasticizer i selected from triacetin, triethylcitrate, polyethylene glycol, acetyltribytylcitrate, miglyol, hydrogenated oils, propylene glycol, acetyltriethylcitrate, polysorbate, oleic acid, propylene i glycol, 'p!ibutylsebacate, diethylphthalate, meglumine, cetyl alcohol and their mixtures i thereof.! Plasticizers in the composition is up to 30% w/w of the composition, preferably from 1% to 20%w/w of the composition, more preferably from 5% to 10%w/w of the composition. Anti-tack agents are selected from talc, colloidal silicon dioxide, glyceryl monostearate, sodium benzoate, sodium lauryl sulfate, waxes, glyceryl behenate, stearic acid and its salt such as' magnesium stearate, calcium stearate and their suitable mixture. i Diluents are selected from the group of monosaccharides; disaccharides; cross linked povidone; sodium starch glycolate; crosslinked carboxymethylcellulose and its sodium, 5 potassium and calcium salt; pregelatinized starch; starch 1500; natural gums and its derivatives such as sodium alginate; clays; cyclodextrins and its derivatives; alkali metal salts such as monobasic sodium phosphate, dibasic sodium phosphate, tribasic sodium phosphate, calcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate; carbonates such as calcium carbonate; oxides of metal such as magnesium oxide, microcrystalline cellulose, and mixtures thereof. i i The monosaccharides or disaccharides are selected from glucose, dextrose, fructose, mannitoj, sucrose, compressible sugar, sorbitol, lactose, galactose, maltose, arabinose, ribose, xylose, erythrose, threose, mannose, and mixtures thereof. i Binder used in the composition is selected from cellulose ethers xanthan gum, guar gum, acacia, tragacanth, gelatin, carrageenan, carbomer, locust bean gum, karaya gum, agar, chitosari, polyvinyl alcohol, polymethacrylic acid copolymers, polymethacrylates, methacrylic acid copolymers, alginic acid and its pharmaceutical acceptable salts such as i sodium, potassium and calcium salt, polyvinylpyrrolidone, copovidone, gelatin, and their suitable! mixture. i Cellulose ethers are selected from the group of hydroxypropylcellulose (HPC), methylcellulose (MC), hydroxyethylcellulose (HEC), hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC), carboxymethylcellulose (CMC) and its salt such as sodium, potassium, calcium, etc. i Surfactant used in the present invention is selected from but not limited to cationic surfactants, anionic surfactants and non - ionic surfactants. The preferred surfactants are sorbitan esters, poiysorbates, poloxamers, fatty acid esters and ethers of polyethylene glycol,! alkyl phenoxy polyethylene glycols, block polymers of polyethylene and i polyprc-pylene oxides, oleic acid and its salt, bile salts and their conjugates, octoxynol, polyoxyethylene and its derivatives such as castor oil derivatives polyoxyethylene monoakyl ethers, sucrose esters, lanolin esters and ethers, lauric acid and its salts, alkyl sulfate and its salts such as sodium lauryl sulfate and fatty acid and its salts and their suitable mixture. Lubricant is selected from but not limited to talc, colloidal silicon dioxide, glyceryl monostearate, sodium benzoate, sodium lauryl sulfate, hydrogenated castor oil, glyceryl 6 behenate, stearic acid and its salt such as magnesium stearate, calcium stearate and their suitable mixture. Colors, I pigments and dyes used in the present invention are selected from pharmaceutically acceptable colors, pigments and dyes. Structuring the Composition: In one of the embodiments of the invention, the extended release pharmaceutical composition comprises of an inert core, first layer comprising of Cyclobenzaprine or its i pharmaceutically acceptable salt thereof on the inert core, and second layer comprising of one or !more agents for extended release on the first layer, the second layer being substantially free of plasticizer. i As shown in figure 1(a), the compositions are structured to form an inert core (i), first layer (ii) comprising of Cyclobenzaprine or its pharmaceutically acceptable salt thereof such as Cyclobenzaprine Hydrochloride on the inert core and second layer (iii) comprising one or more agents for extended release on the first layer, the second layer being substantially free of plasticizer. i i The process for the preparation of the compositions to obtain structures as shown in figure 1 (a) comprises steps of: 1) providing an inert core selected from substantially water soluble, water insoluble, or water swellable material; 2) creating a first layer comprising of Cyclobenzaprine or its pharmaceutically acceptable salt thereof such as Cyclobenzaprine Hydrochloride on the inert core to bbtain drug core; and 3) creating a second layer comprising of one or more agents for extended release on the first layer, the second layer being substantially free of plasticizer to obtain extended release pellets. Creation of the said first layer on the inert core comprises steps of: dispersing and or dissolving Cyclobenzaprine or its pharmaceutically acceptable salt thereof such as Cyclobenzaprine Hydrochloride in a solvent selected from water, alcohol, organic solvent, or mixtures thereof to obtain drug dispersion or solution; 7 2) optionally dispersing and or dissolving at least one additive selected from binder, diluent, surfactant, plasticizer, anti-tack agent, or mixtures thereof in a solvent selected from water, alcohol, organic solvent, or mixtures thereof; 3) mixing dispersion or solution of step 2 with drug dispersion or solution obtained in step 1; 4) optionally adding pharmaceutical at least one additive selected from anti-tack agent, pigments, colorants, surfactants, diluents, or mixtures thereof to dispersion of solution of step 3; 5) spraying the resulting dispersion or solution on inert core to obtain drug core; i 6) drying and sizing the drug core. i Creation of the second layer (extended release layer) on the drug core comprises steps of: \| 1) dispersing and or dissolving one or more agent for extended release in a solvent selected from water, alcohol, organic solvent, or mixtures thereof to obtain dispersion or solution; 2) optionally adding at least one additive selected from anti-tack agent, pigments, colorants, surfactants, diluents, or mixtures thereof; 3) spraying the resulting dispersion or solution on drug pellets to obtain extended release pellets; 4) drying and sizing of extended release pellets. i i In another embodiment of the invention, the extended release pharmaceutical composition comprises of core of Cyclobenzaprine or its pharmaceutically acceptable salt thereof, the core being coated with a layer comprising of one or more agents for extended release, the said coating layer being substantially free of plasticizer. As shown in figure 1(b), the compositions are structured to form a core (i) of Cyclobenzaprine or its pharmaceutically acceptable salt thereof such as Cyclobenzaprine Hydrochloride, the core being coated with a layer (ii) comprising of one or more agents for extended release, the said coating layer being substantially free of plasticizer. The process for the preparation of the compositions as shown in figure 1 (b) comprises steps of: 1) providing a matrix core comprising of Cyclobenzaprine or its pharmaceutically Acceptable salt thereof such as Cyclobenzaprine Hydrochloride and optionally at 8 le'ast one additive selected from binder, anti-tack agent, plasticizers, pigments, colorants, surfactants, diluents or mixtures thereof; 2) creating a layer comprising of one or more agents for extended release on the matrix core to obtain extended release pellets, the layer optionally comprises of at least one additive selected from anti-tack agent, pigments, colorants, surfactants, diluents, or mixtures thereof, the said layer being substantially free of plasticizer; i Preparation of the said matrix core comprises steps of. 1) mixing Cyclobenzaprine or its pharmaceutically acceptable salt thereof such as Cyclobenzaprine Hydrochloride optionally with at least one additive selected from binder, anti-tack agent, plasticizers, pigments, colorants, surfactants, diluents, or ifnixtures thereof in a mixer to obtain drug mixture; 2) granulating drug mixture with a granulating solvent selected from water, alcohol, organic solvent, or mixtures thereof to obtain granules; 3) extruding the granules in an extruder to obtain extrudates; 4) spheronizing the extrudates in the spheronizer to obtain matrix core. i 5) frying and sizing the matrix core. Creation of the said extended release layer on the said matrix core comprises steps of: 1) dispersing and or dissolving one or more agent for extended release in a solvent selected from water, alcohol, organic solvent, or mixtures thereof to obtain dispersion or solution; 2) optionally adding pharmaceutical additives selected from anti-tack agent, pigments, colorants, surfactants, diluents and mixtures thereof; 3) spraying the resulting dispersion or solution on matrix core to obtain extended release pellets; 4) drying and sizing of extended release pellets. In another embodiment of the invention, the extended release pharmaceutical composition is in the form of matrix wherein the matrix comprises of Cyclobenzaprine or its pharmaceutically acceptable salt thereof and one or more agents for extended release. As shown in figure 1(c), the compositions are structured to form a matrix (i) that comprises i of Cyclobenzaprine or its pharmaceutically acceptable salt thereof such as Cyclobenzaprine Hydrochloride and one or more agents for extended release. 9 The process for the preparation of the compositions to obtain structures as shown in figure 1 (c) comprises steps of: 1) mixing Cyclobenzaprine or its pharmaceutically acceptable salt thereof such as Cyclobenzaprine Hydrochloride, one or more agents for extended release and optionally at least one additive selected from binder, anti-tack agent, plasticizers, pigments, colorants, surfactants, diluents, or mixtures thereof in a mixer to obtain drug mixture; 2) granulating drug mixture with a granulating solvent selected from water, alcohol, organic solvent, or mixtures thereof to obtain granules; 3) extruding the granules in an extruder to obtain extrudates and spheronizing the extrudates in the spheronizer to obtain extended release pellets followed by drying i and sizing; or optionally mixing the granules with lubricants and compressing the lubricated granules to obtain tablets. In yet another embodiment of the invention, the extended release pharmaceutical composition comprises of an inert core coated with a matrix comprising Cyclobenzaprine or its pharmaceutically acceptable salt thereof and one or more agents for extended release As shown in figure 1(d), the composition is structured to form a matrix that comprises of an inert core (i), the inert core being coated with a layer (ii) comprising of Cyclobenzaprine or its pharmaceutically acceptable salt thereof such as Cyclobenzaprine Hydrochloride and one or more agents for extended release. The process for the preparation of the compositions to obtain structures as shown in figure 1 (d) comprises steps of. 1) providing an inert core selected from substantially water soluble, water insoluble, or water swellable material," 2) applying a layer comprising of Cyclobenzaprine or its pharmaceutically acceptable salt thereof such as Cyclobenzaprine Hydrochloride, one or more agents for extended release and optionally at least one additive selected from binder, anti-tack agent, plasticizers, pigments, colorants, surfactants, diluents, or mixtures thereof on the inert i coi;e to obtain extended release pellets. 10 Creation of the said layer on the inert core comprises steps of: 1) dispersing and / or dissolving Cyclobenzaprine or its pharmaceutically acceptable salt thereof such as Cyclobenzaprine Hydrochloride in a solvent selected from water, alcor ol, organic solvent, or mixtures thereof to obtain drug dispersion or solution; 2) optionally dispersing and or dissolving binder in a solvent selected from water, alcohol, organic solvent, or mixtures thereof; 3) dispersing and or dissolving one or more agent for extended release in a solvent selected from water, alcohol, organic solvent, or mixtures thereof to obtain dispersion or solution; 4) mixing dispersion or solution of step 2 and 3 with drug dispersion or solution obtained in step 1; 5) optionally adding at least one additive selected from binder, anti-tack agent, plasticizers, pigments, colorants, surfactants, diluents, or mixtures thereof to dispersion or solution of step 4; i 6) spraying the resulting dispersion or solution on inert core to obtain extended release pellets; 7) dryirg and sizing the extended release pellets. The inert core used in the composition may be made up of any pharmaceutically acceptable inert excipient such as water soluble, water insoluble or water swellable excipients of average particle size of 1680 microns to 150 microns preferably between 1000 microns to 250 microns. The inert core is preferably made of microcrystalline cellulose or sugar and starch. The solvent is selected from water, alcohol, organic solvent, or mixtures thereof. Alcohol used is iselected from methanol, ethanol, isopropanol, or mixtures thereof. Organic solvent is selected from dichloromethane, acetone, halogenated hydrocarbon, ethylmethylketone, or mixtures thereof and the likes. Extended release compositions comprising Cyclobenzaprine hydrochloride when analyzed in-vitroin USP apparatus 2, in 0.1 N HCI should ideally exhibit an in-vitro dissolution profile of: • at least 5% of Cyclobenzaprine HCI at 1st hour; • at least 15% of Cyclobenzaprine HCI at 2nd hour; 11 • at least 30% of Cyclobenzaprine HCI at 4th hour; • at least 70% of Cyclobenzaprine HCI at 24th hour. If a batch of extended release pellets comprising Cyclobenzaprine HCI releases Cyclobenzaprine HCI too slowly to match with the desired in-vitro dissolution profile, a portion of drug core or extended release pellets comprising lower polymer levels may be added to comply with the desired dissolution profile. If the extended release pellets comprising Cyclobenzaprine HCI releases drug too fast to match the desired in-vitro dissolution profile, it may receive an additional coat or extended release pellets comprising higher polymer levels to achieve the desired in-vitro dissolution profile. Extended release pellets comprising Cyclobenzaprine HCI complying with the desired dissolution profile are filled in capsule or compressed into tablets using the process known in the art to deliver the therapeutic dose of Cyclobenzaprine HCI. The invention further provides non-limiting examples. Example 1: A) Preparation of extended release pellets: 30 g of Cyclobenzaprine HCI was dissolved in 100 g of purified water to obtain drug solution; 75 g of Eudragit L 100 was dissolved in 300 g of acetone and 30 g of water whereas 75 g of Eudragit RSPO was separately dissolved in 160 g of acetone and were added to the drug solution. The resulting solution was sprayed on 150 g of inert core (20 -25 mesh ASTM) in fluid bed bottom spray processor with inlet air temperature of about 20°C to.about 80°C, outlet air temperature of about 20°C to about 60°C, atomization air pressure of about 0.5 - 3.5 bars, fluidization flap open from about 10% to about 90% w/w to obtain extended release pellets. These extended release pellets so obtained were dried in fluid bed bottom spray processor to have moisture content of less than 5%, preferably less than 3% and more preferably less than 2%w/w. Example 2: Preparation of Tablets: 7.5 g of Cyclobenzaprine HCI was mixed with 45 g of hydroxypropylmethylcelluiose K4M i and 40g of lactose in a planetary mixer to obtain drug mixture. The said drug mixture was i granulated with the mixture of isopropanol and water in the ratio of 80:20 to obtain wet mass. The wet mass was dried in fluid bed dryer, milled and sifted through 40 mesh 12 ASTM. The sifted granules were compressed into tablets using single rotary compression machine. These compressed tablets were filled into capsule of suitable size to deliver the dose of 15mg and 30mg of Cyclobenzaprine HCI. Example 3: 30 g of Cyclobenzaprine HCI was dissolved in 340 g of purified water to obtain drug solution. 67.5 g of ethylcellulose (10cps) and 15 g of ethylcellufose (45cps) was added to the drug solution followed by addition of 1360 g of isopropanol. 4 g of diethylphthalate was added to the resulting solution and was sprayed on 123.5 g of inert core (40 - 60 mesh ASTM) in fluid bed bottom spray processor with inlet air temperature of about 20°C to about 80°C, outlet air temperature of about 20°C to about 60°C, atomization air pressure of about 0.5 - 3.5 bars, fluidization flap open from about 10% to about 90% w/w to obtain extended release pellets. These extended release pellets so obtained were dried in fluid bed bottom spray processor to have moisture content of less than 5%, preferably less than 3% and more preferably less than 2%w/w. The extended release pellets so obtained were filled in different sized capsules to deliver the dose of 15mg and 30mg. Extended release compositions comprising Cyclobenzaprine hydrochloride when analyzed in-vitro in USP apparatus 2, in 0.1 N HCI (900ml) exhibits in-vitro dissolution profile of: • at least 5% of Cyclobenzaprine HCI released at 1st hour; • at' least 15% of Cyclobenzaprine HCI released at 2nd hour; • at least 30% of Cyclobenzaprine HCI released at 4th hour; • at least 70% of Cyclobenzaprine HCI released at 24lh hour. Dated this 22nd day of May 2009 Dr. Ankur J. Shah Executive Director, Inventia Healthcare Private Limited 13

Full Text

FORM-2
THE PATENTS ACT. 1970
(39 OF 1970)
&
The Patent Rules, 2003
PROVISIONAL SPECIFICATION
(See Section 10 and Rule 13)
"EXTENDED RELEASE PHARMACEUTICAL COMPOSITIONS"

I
Inventia Healthcare Private Limited having its administrative office at Unit No. S - 4 Khira Industrial Estate, B.M Bhargava Road, Santacruz West, Mumbai 400054, Maharashtra, India an Indian Company
The following specification describes the invention.

FIELD OF THE INVENTION
This invention relates to extended release pharmaceutical compositions for enhanced patient compliance comprising a skeletal muscle relaxant and process for producing the compositions.
BACKGROUND OF THE INVENTION
Cyclobehzaprine Hydrochloride, a skeletal muscle relaxant is currently available as immediate release tablets containing 5mg or 10mg of the active. These tablets are recommended to be administered three times a day to achieve relief from muscle spasm. Administration of such tablet three times a day is a major compliance issue especially in
elderly patients. To substantially enhance patient compliance, it is desirable to provide

Cyclobehzaprine Hydrochloride in extended release dosage form for once a day administration.
US Patent 7287793, US Patent Application 2008/0124398, US Patent Application 2008/0124399, US Patent Application 2009/0017126 and US Patent Application 2009/0017127 discloses multi-particulate pharmaceutical dosage form of a skeletal muscle relaxant for once a day administration. These compositions provide modified release profile comprising a population of extended release beads, wherein said extended
release jbeads comprise an active-containing core particle comprising a skeletal muscle
i
relaxant selected from the group consisting of Cyclobenzaprine, pharmaceutical^ acceptable salts or derivatives thereof and mixtures thereof; and an extended release coating .comprising a water insoluble polymer membrane surrounding said core. These compositions when analyzed in-vitro in USP apparatus 2 (paddles @ 50 rpm) in 900 ml of 0.1N HGI at 37°C exhibits the following dissolution profile:
• not more than 40% of the total active is released at 2 hour;
i
• from about 40-65% of the total active is released at 4 hour;
• from about 60-85% of the total active is released at 8 hour.
i The dosage form in the prior art are essentially structured to have an active containing
core particle coated with a polymer membrane which is prone to rupture thereby causing
dose dumping.
2

OBJECTS OF THE INVENTION
The object of the invention is to provide extended release pharmaceutical compositions for once a day administration comprising Cyclobenzaprine or its pharmaceutically acceptable salt thereof that extends the release of the active under in-vitro conditions for at least 8 to 12 hours for better patient compliance.
It is another object of the invention to provide composition with substantially reduced
numbenof ingredients to make the composition cost effective.
i i
It is yet I another object of the invention to structure the dosage form with minimum or no
layeringj so as to provide simple and cost effective process options with less number of
i processing steps.

It is yet

another object of the invention to provide the above compositions in the form of

pellets capable of being filled in capsules or compressed into tablets.
It is yet! another object of the invention to provide extended release compositions which
i
would substantially minimize the incidence of dose dumping.
It is yet; another object of the invention to provide process for the preparation of extended release: pharmaceutical composition comprising Cyclobenzaprine or its pharmaceutically acceptable salts thereof that exhibits in-vitro drug release for at least 8 to 12 hours for better patient compliance.
DESCRIPTION OF THE INVENTION Description of figures:
Figures; 1(a), 1(b), 1(c) and 1(d) illustrate the manner in which the compositions of the
present invention can be structured.

The pharmaceutical composition of the present invention comprises of Cyclobenzaprine or its pharmaceutically acceptable salt thereof such as Cyclobenzaprine HCI and one or more agents for extended release that exhibits in-vitro drug release for at least 8 to 12 hours for better patient compliance. The composition optionally comprises at least one additive selected from binder, diluent, surfactant, plasticizer, anti-tack agent, lubricants, colors, Ipigments, dyes, or mixtures thereof.
3

Cyclobenzaprine salt is addition salt of Cyclobenzaprine with an inorganic acid such as hydrochloric, hydrobromic, phosphoric, nitric and / or sulphuric or of organic acid such as tartaric, acetic, propionic, hydroxyacetic, oxaloacetic, oxalic, pyruvic, succinic, malic, malonic,,fumaric, lactic, glutaric, maleic, sulphonic, benzenesulphonic and the like. The preferred Cyclobenzaprine salt is Cyclobenzaprine HCI and is usually administered in 15mg and 30mg strength.
Cyclobenzaprine salt such as Cyclobenzaprine HCI of any particle sizes and shape can be used in the invention. However, the preferable particle size ranges from 0.1 microns to 1000 microns, more preferably from 0.5 micron to 500 microns and most preferably from 1 micron to 200 microns.
The pharmaceutical composition comprises of Cyclobenzaprine HCI up to 50% by weight of the composition, preferably from 0.01% to 40% w/w, more preferably from 0.1% to 25%w/w and most preferably from 2.5% to 15% w/w.
The age^nt for extended release is selected from water soluble agent, water insoluble agent, o' mixtures thereof.
Agents for extended release are selected from the group of cellulose derivatives; acrylic acid derivatives; polymethacrylates; cellulose esters such as cellulose acetate; starch; modified starch; polyvinyl alcohol; polyvinyl acetate; povidone; polyalkylene glycol such as polyethylene glycol; gums such as xanthan gum, guar gum, locust bean gum; alginates such as sodium alginate and calcium alginate; hydrogenated castor oil; cetyl alcohol; waxes such as bees wax, carnauba wax; fatty acid; fatty alcohols and esters of fatty acids; stearic acid and its salt such as magnesium s tearate and calcium stearate; shellac; polyethylene oxides; vinyl pyrrolidone-vinyl acetate copolymer (Kollidon VA 64); carbomer such as] carbomer 934P, carbomer 971P, and carbomer 974P; or mixtures thereof.
i i
i
Cellulose derivative are available in various grades depending on their viscosities from
i
about 3>cps to about 1,00,000cps. Various commonly available viscosity grades are of
3cps, 5cps, 6cps, 15cps, 100cps, 4000cps, 15000cps and about 1,00,000 cps. Cellulose
derivatives are selected from ethylcellulose, hydroxypropylcellulose, microcrystalline
cellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose,
sodiumi carboxymethylcellulose, calcium carboxymethylcellulose, methylcellulose,
cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate,
4

hydroxypropylmethylcellulose acetate succinate, cellulose acetate butyrate, cellulose
i
acetate frimellitate, or mixtures thereof. Ethylcellulose as a dry powder or aqueous dispersion marketed under the trade name of Ethocel RTM of Dow, U.S.A., Aquacoat RTM of FMC, USA and Surelease RTM of Colorcon, USA may also be used. This ready dispersion further contains plasticizers, surfactants (sodium lauryl sulfate), stabilizing agents, ammonium hydroxide, oleic acid, fumed silica, anti-foaming agent, cetyl alcohol as additives. Ethyl cellulose of various viscosities grades such as 3cps, 5cps, 7cps, 10cps, 20cps, 45cps, 50cps, 100cps can be used.
Polymethacrylates used in the present invention is preferably selected from methacrylic acid copolymers and its esters. Such polymers are readily available from Rohm Pharma under trie brand name of Eudragit L30D55, Eudragit L100 55, Eudragit L100, Eudragit S100, Eudragit RL, Eudragit RS, and Eudragit NE 30D or 40D.
The agent for extended release is present in an amount from about 0.5% to 90% by weight of the composition, preferably from 1% to 75% w/w, more preferably from 2.5% to 60% w/w, most preferably from 5% to 50% w/w.
In one of the embodiments of the invention the agents for extended release are mixture of two or more different viscosity grade material. Mixtures of extended release agents are used in the ratio of 1:0.01 to 0.01: 1.
Plasticizers are selected from the group of hydrophilic and hydrophobic plasticizer
i selected from triacetin, triethylcitrate, polyethylene glycol, acetyltribytylcitrate, miglyol,
hydrogenated oils, propylene glycol, acetyltriethylcitrate, polysorbate, oleic acid, propylene
i
glycol, 'p!ibutylsebacate, diethylphthalate, meglumine, cetyl alcohol and their mixtures
i
thereof.! Plasticizers in the composition is up to 30% w/w of the composition, preferably from 1% to 20%w/w of the composition, more preferably from 5% to 10%w/w of the composition.
Anti-tack agents are selected from talc, colloidal silicon dioxide, glyceryl monostearate,

sodium

benzoate, sodium lauryl sulfate, waxes, glyceryl behenate, stearic acid and its salt

such as' magnesium stearate, calcium stearate and their suitable mixture.
i Diluents are selected from the group of monosaccharides; disaccharides; cross linked
povidone; sodium starch glycolate; crosslinked carboxymethylcellulose and its sodium,
5

potassium and calcium salt; pregelatinized starch; starch 1500; natural gums and its derivatives such as sodium alginate; clays; cyclodextrins and its derivatives; alkali metal salts such as monobasic sodium phosphate, dibasic sodium phosphate, tribasic sodium phosphate, calcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate; carbonates such as calcium carbonate; oxides of metal such as
magnesium oxide, microcrystalline cellulose, and mixtures thereof.
i i
The monosaccharides or disaccharides are selected from glucose, dextrose, fructose, mannitoj, sucrose, compressible sugar, sorbitol, lactose, galactose, maltose, arabinose, ribose, xylose, erythrose, threose, mannose, and mixtures thereof.
i Binder used in the composition is selected from cellulose ethers xanthan gum, guar gum,
acacia, tragacanth, gelatin, carrageenan, carbomer, locust bean gum, karaya gum, agar,
chitosari, polyvinyl alcohol, polymethacrylic acid copolymers, polymethacrylates,
methacrylic acid copolymers, alginic acid and its pharmaceutical acceptable salts such as
i
sodium, potassium and calcium salt, polyvinylpyrrolidone, copovidone, gelatin, and their
suitable! mixture.
i
Cellulose ethers are selected from the group of hydroxypropylcellulose (HPC), methylcellulose (MC), hydroxyethylcellulose (HEC), hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC), carboxymethylcellulose (CMC) and its salt such as sodium, potassium, calcium, etc.
i Surfactant used in the present invention is selected from but not limited to cationic
surfactants, anionic surfactants and non - ionic surfactants. The preferred surfactants are
sorbitan esters, poiysorbates, poloxamers, fatty acid esters and ethers of polyethylene
glycol,! alkyl phenoxy polyethylene glycols, block polymers of polyethylene and
i
polyprc-pylene oxides, oleic acid and its salt, bile salts and their conjugates, octoxynol, polyoxyethylene and its derivatives such as castor oil derivatives polyoxyethylene monoakyl ethers, sucrose esters, lanolin esters and ethers, lauric acid and its salts, alkyl sulfate and its salts such as sodium lauryl sulfate and fatty acid and its salts and their
suitable mixture.

Lubricant is selected from but not limited to talc, colloidal silicon dioxide, glyceryl
monostearate, sodium benzoate, sodium lauryl sulfate, hydrogenated castor oil, glyceryl
6

behenate, stearic acid and its salt such as magnesium stearate, calcium stearate and their suitable mixture.
Colors, I pigments and dyes used in the present invention are selected from pharmaceutically acceptable colors, pigments and dyes.
Structuring the Composition:
In one of the embodiments of the invention, the extended release pharmaceutical
composition comprises of an inert core, first layer comprising of Cyclobenzaprine or its
i pharmaceutically acceptable salt thereof on the inert core, and second layer comprising of
one or !more agents for extended release on the first layer, the second layer being
substantially free of plasticizer.
i
As shown in figure 1(a), the compositions are structured to form an inert core (i), first layer (ii) comprising of Cyclobenzaprine or its pharmaceutically acceptable salt thereof such as Cyclobenzaprine Hydrochloride on the inert core and second layer (iii) comprising one or more agents for extended release on the first layer, the second layer being substantially
free of plasticizer.
i i
The process for the preparation of the compositions to obtain structures as shown in figure 1 (a) comprises steps of:
1) providing an inert core selected from substantially water soluble, water insoluble, or water swellable material;
2) creating a first layer comprising of Cyclobenzaprine or its pharmaceutically acceptable salt thereof such as Cyclobenzaprine Hydrochloride on the inert core to bbtain drug core; and
3) creating a second layer comprising of one or more agents for extended release on the first layer, the second layer being substantially free of plasticizer to obtain extended release pellets.
Creation of the said first layer on the inert core comprises steps of:

dispersing and or dissolving Cyclobenzaprine or its pharmaceutically acceptable salt thereof such as Cyclobenzaprine Hydrochloride in a solvent selected from water, alcohol, organic solvent, or mixtures thereof to obtain drug dispersion or solution;
7

2) optionally dispersing and or dissolving at least one additive selected from binder, diluent, surfactant, plasticizer, anti-tack agent, or mixtures thereof in a solvent selected from water, alcohol, organic solvent, or mixtures thereof;
3) mixing dispersion or solution of step 2 with drug dispersion or solution obtained in step 1;
4) optionally adding pharmaceutical at least one additive selected from anti-tack agent, pigments, colorants, surfactants, diluents, or mixtures thereof to dispersion of solution of step 3;
5) spraying the resulting dispersion or solution on inert core to obtain drug core;
i
6) drying and sizing the drug core.
i Creation of the second layer (extended release layer) on the drug core comprises steps of: |
1) dispersing and or dissolving one or more agent for extended release in a solvent selected from water, alcohol, organic solvent, or mixtures thereof to obtain dispersion or solution;
2) optionally adding at least one additive selected from anti-tack agent, pigments, colorants, surfactants, diluents, or mixtures thereof;
3) spraying the resulting dispersion or solution on drug pellets to obtain extended release pellets;
4) drying and sizing of extended release pellets.
i
i In another embodiment of the invention, the extended release pharmaceutical composition
comprises of core of Cyclobenzaprine or its pharmaceutically acceptable salt thereof, the
core being coated with a layer comprising of one or more agents for extended release, the
said coating layer being substantially free of plasticizer.
As shown in figure 1(b), the compositions are structured to form a core (i) of Cyclobenzaprine or its pharmaceutically acceptable salt thereof such as Cyclobenzaprine Hydrochloride, the core being coated with a layer (ii) comprising of one or more agents for extended release, the said coating layer being substantially free of plasticizer.
The process for the preparation of the compositions as shown in figure 1 (b) comprises steps of:
1) providing a matrix core comprising of Cyclobenzaprine or its pharmaceutically Acceptable salt thereof such as Cyclobenzaprine Hydrochloride and optionally at
8

le'ast one additive selected from binder, anti-tack agent, plasticizers, pigments, colorants, surfactants, diluents or mixtures thereof; 2) creating a layer comprising of one or more agents for extended release on the matrix core to obtain extended release pellets, the layer optionally comprises of at least one additive selected from anti-tack agent, pigments, colorants, surfactants,
diluents, or mixtures thereof, the said layer being substantially free of plasticizer;
i
Preparation of the said matrix core comprises steps of.
1) mixing Cyclobenzaprine or its pharmaceutically acceptable salt thereof such as Cyclobenzaprine Hydrochloride optionally with at least one additive selected from binder, anti-tack agent, plasticizers, pigments, colorants, surfactants, diluents, or ifnixtures thereof in a mixer to obtain drug mixture;
2) granulating drug mixture with a granulating solvent selected from water, alcohol, organic solvent, or mixtures thereof to obtain granules;
3) extruding the granules in an extruder to obtain extrudates;
4) spheronizing the extrudates in the spheronizer to obtain matrix core.
i
5) frying and sizing the matrix core.
Creation of the said extended release layer on the said matrix core comprises steps of:
1) dispersing and or dissolving one or more agent for extended release in a solvent selected from water, alcohol, organic solvent, or mixtures thereof to obtain dispersion or solution;
2) optionally adding pharmaceutical additives selected from anti-tack agent, pigments, colorants, surfactants, diluents and mixtures thereof;
3) spraying the resulting dispersion or solution on matrix core to obtain extended release pellets;
4) drying and sizing of extended release pellets.
In another embodiment of the invention, the extended release pharmaceutical composition is in the form of matrix wherein the matrix comprises of Cyclobenzaprine or its pharmaceutically acceptable salt thereof and one or more agents for extended release.
As shown in figure 1(c), the compositions are structured to form a matrix (i) that comprises
i
of Cyclobenzaprine or its pharmaceutically acceptable salt thereof such as Cyclobenzaprine Hydrochloride and one or more agents for extended release.
9

The process for the preparation of the compositions to obtain structures as shown in figure 1 (c) comprises steps of:
1) mixing Cyclobenzaprine or its pharmaceutically acceptable salt thereof such as Cyclobenzaprine Hydrochloride, one or more agents for extended release and optionally at least one additive selected from binder, anti-tack agent, plasticizers, pigments, colorants, surfactants, diluents, or mixtures thereof in a mixer to obtain drug mixture;
2) granulating drug mixture with a granulating solvent selected from water, alcohol, organic solvent, or mixtures thereof to obtain granules;
3) extruding the granules in an extruder to obtain extrudates and spheronizing the
extrudates in the spheronizer to obtain extended release pellets followed by drying
i
and sizing; or
optionally mixing the granules with lubricants and compressing the lubricated
granules to obtain tablets.
In yet another embodiment of the invention, the extended release pharmaceutical composition comprises of an inert core coated with a matrix comprising Cyclobenzaprine or its pharmaceutically acceptable salt thereof and one or more agents for extended release
As shown in figure 1(d), the composition is structured to form a matrix that comprises of an
inert core (i), the inert core being coated with a layer (ii) comprising of Cyclobenzaprine or
its pharmaceutically acceptable salt thereof such as Cyclobenzaprine Hydrochloride and
one or more agents for extended release.

The process for the preparation of the compositions to obtain structures as shown in figure

1 (d) comprises steps of.
1) providing an inert core selected from substantially water soluble, water insoluble, or water swellable material,"
2) applying a layer comprising of Cyclobenzaprine or its pharmaceutically acceptable salt thereof such as Cyclobenzaprine Hydrochloride, one or more agents for extended release and optionally at least one additive selected from binder, anti-tack agent,
plasticizers, pigments, colorants, surfactants, diluents, or mixtures thereof on the inert
i
coi;e to obtain extended release pellets.
10

Creation of the said layer on the inert core comprises steps of:
1) dispersing and / or dissolving Cyclobenzaprine or its pharmaceutically acceptable salt thereof such as Cyclobenzaprine Hydrochloride in a solvent selected from water, alcor ol, organic solvent, or mixtures thereof to obtain drug dispersion or solution;
2) optionally dispersing and or dissolving binder in a solvent selected from water, alcohol, organic solvent, or mixtures thereof;
3) dispersing and or dissolving one or more agent for extended release in a solvent selected from water, alcohol, organic solvent, or mixtures thereof to obtain dispersion or solution;
4) mixing dispersion or solution of step 2 and 3 with drug dispersion or solution obtained in step 1;
5) optionally adding at least one additive selected from binder, anti-tack agent, plasticizers, pigments, colorants, surfactants, diluents, or mixtures thereof to dispersion or solution of step 4;
i
6) spraying the resulting dispersion or solution on inert core to obtain extended release pellets;
7) dryirg and sizing the extended release pellets.
The inert core used in the composition may be made up of any pharmaceutically acceptable inert excipient such as water soluble, water insoluble or water swellable excipients of average particle size of 1680 microns to 150 microns preferably between 1000 microns to 250 microns. The inert core is preferably made of microcrystalline cellulose or sugar and starch.
The solvent is selected from water, alcohol, organic solvent, or mixtures thereof. Alcohol used is iselected from methanol, ethanol, isopropanol, or mixtures thereof. Organic solvent is selected from dichloromethane, acetone, halogenated hydrocarbon, ethylmethylketone, or mixtures thereof and the likes.
Extended release compositions comprising Cyclobenzaprine hydrochloride when analyzed in-vitroin USP apparatus 2, in 0.1 N HCI should ideally exhibit an in-vitro dissolution profile of:
• at least 5% of Cyclobenzaprine HCI at 1st hour;
• at least 15% of Cyclobenzaprine HCI at 2nd hour;
11

• at least 30% of Cyclobenzaprine HCI at 4th hour;
• at least 70% of Cyclobenzaprine HCI at 24th hour.

If a batch of extended release pellets comprising Cyclobenzaprine HCI releases Cyclobenzaprine HCI too slowly to match with the desired in-vitro dissolution profile, a portion of drug core or extended release pellets comprising lower polymer levels may be added to comply with the desired dissolution profile. If the extended release pellets comprising Cyclobenzaprine HCI releases drug too fast to match the desired in-vitro dissolution profile, it may receive an additional coat or extended release pellets comprising higher polymer levels to achieve the desired in-vitro dissolution profile. Extended release pellets comprising Cyclobenzaprine HCI complying with the desired dissolution profile are filled in capsule or compressed into tablets using the process known in the art to deliver the therapeutic dose of Cyclobenzaprine HCI.
The invention further provides non-limiting examples.
Example 1:
A) Preparation of extended release pellets:
30 g of Cyclobenzaprine HCI was dissolved in 100 g of purified water to obtain drug solution; 75 g of Eudragit L 100 was dissolved in 300 g of acetone and 30 g of water whereas 75 g of Eudragit RSPO was separately dissolved in 160 g of acetone and were added to the drug solution. The resulting solution was sprayed on 150 g of inert core (20 -25 mesh ASTM) in fluid bed bottom spray processor with inlet air temperature of about 20°C to.about 80°C, outlet air temperature of about 20°C to about 60°C, atomization air pressure of about 0.5 - 3.5 bars, fluidization flap open from about 10% to about 90% w/w to obtain extended release pellets. These extended release pellets so obtained were dried in fluid bed bottom spray processor to have moisture content of less than 5%, preferably less than 3% and more preferably less than 2%w/w.
Example 2:
Preparation of Tablets:
7.5 g of Cyclobenzaprine HCI was mixed with 45 g of hydroxypropylmethylcelluiose K4M
i
and 40g of lactose in a planetary mixer to obtain drug mixture. The said drug mixture was
i granulated with the mixture of isopropanol and water in the ratio of 80:20 to obtain wet
mass. The wet mass was dried in fluid bed dryer, milled and sifted through 40 mesh
12

ASTM. The sifted granules were compressed into tablets using single rotary compression machine. These compressed tablets were filled into capsule of suitable size to deliver the dose of 15mg and 30mg of Cyclobenzaprine HCI.
Example 3:
30 g of Cyclobenzaprine HCI was dissolved in 340 g of purified water to obtain drug solution. 67.5 g of ethylcellulose (10cps) and 15 g of ethylcellufose (45cps) was added to the drug solution followed by addition of 1360 g of isopropanol. 4 g of diethylphthalate was added to the resulting solution and was sprayed on 123.5 g of inert core (40 - 60 mesh ASTM) in fluid bed bottom spray processor with inlet air temperature of about 20°C to about 80°C, outlet air temperature of about 20°C to about 60°C, atomization air pressure of about 0.5 - 3.5 bars, fluidization flap open from about 10% to about 90% w/w to obtain extended release pellets. These extended release pellets so obtained were dried in fluid bed bottom spray processor to have moisture content of less than 5%, preferably less

than 3%

and more preferably less than 2%w/w.

The extended release pellets so obtained were filled in different sized capsules to deliver the dose of 15mg and 30mg.
Extended release compositions comprising Cyclobenzaprine hydrochloride when analyzed in-vitro in USP apparatus 2, in 0.1 N HCI (900ml) exhibits in-vitro dissolution profile of:
• at least 5% of Cyclobenzaprine HCI released at 1st hour;
• at' least 15% of Cyclobenzaprine HCI released at 2nd hour;
• at least 30% of Cyclobenzaprine HCI released at 4th hour;
• at least 70% of Cyclobenzaprine HCI released at 24lh hour.
Dated this 22nd day of May 2009
Dr. Ankur J. Shah
Executive Director,
Inventia Healthcare Private Limited
13

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Patent Number

270474

Indian Patent Application Number

1287/MUM/2009

PG Journal Number

01/2016

Publication Date

01-Jan-2016

Grant Date

23-Dec-2015

Date of Filing

22-May-2009

Name of Patentee

INVENTIA HEALTHCARE PRIVATE LIMITED

Applicant Address

Inventia Healthcare private Limited Unit No.703&704,7th floor, Hubtown Solaris, N S Phadke Marg, Andheri (East), Mumbai-400 069

Inventors:

#	Inventor's Name	Inventor's Address
1	SHAH VAIBHAVI ANKUR	30, "SAUJANYA", 3RD N.S ROAD, VALLABHNAGAR SOCIETY, VILE PARLE (WEST), MUMBAI—400056,
2	JAISWAL SUNIL BEHARILAL	3-4, PANCH WATIKA, CHITNAVIS LAYOUT, BYRAMJI TOWN, NAGPUR-440 013,
3	TIWARI SUNIL DEVIPRASAD	105, BUILDING NO. 3, GARDEN ENCLAVE, POKAHRAN ROAD NO. 2, VASANT VIHAR, THANE (WEST) —400601,

PCT International Classification Number

A01N37/12; A01N37/44; A61K31/195

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA