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"Extended Release Pharmaceutical Composition Of Nifedipine"

Abstract: The present invention relates to the field of pharmaceutical technology and describes about extended release pharmaceutical composition which is simple and cost effective. It also provides methods of manufacturing of extended release solid oral dosage forms comprising nifedipine. This composition taken orally in the treatment of hypertension and angina.

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Patent Information

Application #
Filing Date
15 February 2010
Publication Number
07/2012
Publication Type
INA
Invention Field
PHARMACEUTICALS
Status
Email
Parent Application

Applicants

UNICHEM LABORATORIES LIMITED
UNICHEM BHAVAN, PRABHAR ESTATE, OFF. S. V. ROAD, JOGESHWARI (W), MUMBAI - 400 102. MAHARASHTRA, INDIA.

Inventors

1. DR. GEDALA VENKATA MURALI MOHAN BABU
H. NO: - 1 - 120, CHEEDIPUDI, BUDITHI, SRIKAKULAM, ANDHRA PRADESH-532427, INDIA
2. DR. BHIMRAO KESHAVRAO JADHAV
POST: RAYAMOHA, TALUKA- SHIRUR-KASAR, DISTRICT: BEED, MAHARASHTRA, PIN-414205, INDIA
3. MR. SOHAM SHRIKAR SAGAR
NEW RENAPUR NAKA, SAI ROAD, NAVARATNA NAGAR, LATUR, MAHARASHTRA, PIN-413512, INDIA

Specification

FORM 2 THE PATENTS ACT 1970 (39 OF 1970) COMPLETE SPECIFICATION (SECTION 10) "EXTENDED RELEASE PHARMACEUTICAL COMPOSITION OF NIFEDIPINE" UNICHEM LABORATORIES LIMITED, A COMPANY REGISTERED UNDER THE INDIAN COMPANY ACT, 1956, HAVING ITS REGISTERED OFFICE LOCATED AT UNICHEM BHAVAN, PRABHAT ESTATE, OFF S. V. ROAD, JOGESHWARI (WEST), MUMBAI - 400 102, MAHARASTRA, INDIA The following specification particularly describes the invention and the manner in which it is to be performed. EXTENDED RELEASE PHARMACEUTICAL COMPOSITION OF MFEDIPINE FIELD OF INVENTION The present invention relates to the pharmaceutical compositions of extended release tablets of nifedipine and novel method of manufacture thereof, useful for the treatment of hypertension and angina. BACKGROUND OF THE INVENTION Nifedipine is an anti-hypertensive and anti-anginal drug belonging to the class of dihydropyridine calcium channel blockers. Its chemical name is 3,5-pyridinedicarboxylic acid, I,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-, dimethyl ester. It has a molecular formula of C17H18N206 with a molecular weight of 346.3. Nifedipine is commercially available as, immediate release systems in the form of soft gelatin capsules in 10 and 20 mg strengths, extended release tablets in 30 and 60 and 90 mg strengths. Nifedipine has excellent coronary vasodilating and hypotensive activity. The mechanism of anti-hypertensive action of nifedipine involves reduction of arterial blood pressure by peripheral arterial vasodilatation and the resulting reduction in peripheral vascular resistance. It dilates the main coronary arteries and coronary arterioles, both in normal and ischemic regions and hence acts as a potent inhibitor of coronary artery spasm. It also reduces arterial pressure at rest and at a given level of exercise by dilating peripheral arterioles and reducing the total peripheral resistance (after load) against which the heart works. This unloading of the heart reduces myocardial energy consumption and oxygen requirements and probably accounts for the effectiveness of nifedipine in chronic stable angina. Immediate release systems of nifedipine in the form of soft gelatin capsules are currently marketed by Pfizer under the brand name of Procardia in 10 mg and 20 mg strengths in the USA, in Europe it is marketed under the brand names of Adalat-5 and Adalat-10 in 5 and 10 mg strengths respectively by Bayer plc. Extended release systems of nifedipine in the form of tablets are currently marketed under the brand name Adalat CC (30/60/90 mg) by Bayer Healthcare in the form of film coated extended release tablet, Procardia XL (30/60/90 mg) by Pfizer in the form of gastrointestinal therapeutic systems (GITS), Afeditab CR (30/60 mg) by Watson Labs in the form of film coated extended release tablet, in the USA. In Europe, it is marketed under the brand names of Adalat LA in 20, 30 and 60 mg strengths as prolonged release tablets by Bayer plc, Nifedipress MR in 10 and 20 mg strengths as modified release tablets by Dexcel Pharma Ltd. US 2004/0142035 Al (Rong-Kun Chang & Niraj Shah, July 22, 2004) discloses use of mixture of two or more enteric materials to regulate the drug release via membrane or matrix controlled systems. Composition of the matrix controlled systems contains, usage of enteric polymers in the preparation of matrix tablets with coating, which is sustained release coating. Because of usage of the enteric polymers in the matrix systems, release of the drug becomes pH dependent. Inter-subject variability in physiological conditions may lead to a wide variability in the in vivo release pattern and hence plasma drug concentrations. US6500459 (Chhabra, Harinderpal et al.; December 31, 2002) discloses pharmaceutical composition for controlled onset and sustained release of active pharmaceutical ingredient and the method of manufacturing the same. Core comprises active pharmaceutical ingredient along with hydrophilic carrier; hydrodynamic diffusion enhancer and optionally other excipients which is surrounded by seal coating, functional coating and top coating. Composition of '459 contains hydrodynamic diffusion enhancer, which is swellable in nature. This hydrodynamic diffusion enhancer may exert more pressure on the membrane and may lead to breakages in the coating membrane. In addition, after solubilization of coating membrane, it may aid in the disintegration of the core tablet leading to sudden release of the active pharmaceutical ingredient. Whereas, composition of present disclosure contains sodium chloride as channeling agent which prolongs the release of the active pharmaceutical ingredient from the coated tablet without exerting much pressure on the coating membrane. Composition of '459 contains colorant in the top coating whereas, as present disclosure colorant is present in the functional coating (enteric coating), reducing the number of coatings and hence the decreases the number of manufacturing steps. WO1999/029305 (Zhang Guohua et al., June 17, 1999) discloses sustained release matrix formulations of nifedipine containing three different types of polymers like pH dependent gelling agent, pH independent gelling agent and enteric polymer. Dosage form as per '305 is uncoated tablet however, nifedipine is photosensitive and it may get degraded during manufacturing, handling and storage due to absence of proper protective coating. Whereas, present disclosure contains opacifier and colorant in the functional coating which may protect the dosage form against the degradation due to exposure to light. US5922352 (Chih-Ming Chen & Joseph P.H. Chou; July 13, 1999) discloses composition and manufacturing process of extended release tablets of nifedipine prepared using compression coating technique. The extended release pharmaceutical composition contains: (1) a delayed release compressed core comprising enteric-coated nifedipine drug particles and solid pharmaceutical filler; (2) a continuous compressed outer layer comprising nifedipine dispersed in a pharmaceutically acceptable polymer capable of forming hydrogel. Manufacturing of extended release tablets of this invention uses active ingredient in two different forms i.e., enteric coated drug particles in the core tablet and non-enteric coated drug in the compression coating. An enteric-coated drug particles are compressed to form core which is gain press coated using rate controlling hydrogel forming polymer and enteric polymer. This may be cause to retard the drug release even present in the form of non-enteric coated form. Manufacturing of extended release tablets by compression coating requires complex and costlier machinery, which increases the production cost hence, the cost of the drug product in turn. Whereas, present disclosure claims simple, cost effective method of manufacture of Nifedipine extended release compositions. US4892741 (Andreas Ohm et al, January 09, 1990) discloses pharmaceutical composition and method of manufacturing of extended release tablets of dihydropyridines. In this invention extended release tablets were prepared by press coating technique, which contains, a core tablet in the form of rapid release formulation, coat in the form of sustained release formulation applied by press coating around the core. In addition, it also contains film coating for protecting drug from light. This film coating composition also contains drug for immediate availability. Active ingredient present in the film coating is not protected against light. As per '741 process of manufacturing of extended release tablet involves more number of unit operations and it also requires additional machinery for press coating. This in turn increases the manufacturing cost. US4783337 (Patrick S.L. et al.; November 8, 1988) discloses composition and manufacturing methods for the preparation of controlled release drug delivery systems in the form of osmotic tablets. Production of osmotic tablets involves costlier equipment and hence increases the manufacturing cost Though many technologies are available, which allows modulating the release kinetics of drug, however, these have problems such as higher production costs and difficulty in reproducing the release kinetics. Therefore, there is a need for simple and cost effective, novel extended release pharmaceutical compositions of nifedipine for eliminating all these disadvantages. OBJECT OF THE INVENTION The objective of the present invention is to provide a simple, stable and cost effective, extended release pharmaceutical composition of nifedipine and process for preparation thereof. Another objective of the present invention is to provide an extended release pharmaceutical composition of nifedipine for once-a-day administration. SUMMARY OF THE INVENTION The present invention relates to the composition of an extended release pharmaceutical composition comprises nifedipine in an amount of 1 to 50% by weight based on the total weight of the dosage form, one or more release retarding agents between 1 to 50%, diluent between 1 to 50%, 0,1 to 20% pH dependant or pH independent polymer and/or combination thereof, channeling agent between 1 to 10% and one or more of pharmaceutically acceptable excipients suitable for the preparation of solid oral dosage forms. The present invention also relates to novel extended release pharmaceutical composition of nifedipine; which is useful for once daily administration. The present invention also relates to process for the preparation of pH dependent extended release pharmaceutical composition comprises the following steps • Preparation of the aqueous granulating solution containing pharmaceutically acceptable channeling agent and binder. • Spraying the aqueous granulating solution on the mixture of active pharmaceutical ingredient and pharmaceutically acceptable excipients in fluidized bed processor and drying the granules. • Mixing of the spray-dried granules with extra granular excipients and finally lubricant to obtain lubricated blend. • Compression of the lubricated blend to form extended release matrix tablet. • Preparation of the aqueous or hydro-alcoholic or non-aqueous solution containing water soluble polymer so as to form a protective barrier or seal coat against environmental conditions. • Preparation of the aqueous or hydro-alcoholic or non-aqueous solution containing pH dependent enteric polymer so as to control the release of the drug in gastro intestinal tract. The present invention also involves the process for the preparation of pH independent extended release pharmaceutical composition comprises the steps of • Preparation of the aqueous granulating solution containing pharmaceutically acceptable channeling agent and binder. • Spraying the aqueous granulating solution on the mixture of active pharmaceutical ingredient and pharmaceutically acceptable excipients in fluidized bed processor and drying the granules • Mixing of the spray-dried granules with extra-granular excipients and finally with lubricant to obtain lubricated blend. • Compression of the lubricated blend to form a extended release matrix tablet. • Preparation of the aqueous or hydro-alcoholic or non-aqueous solution containing water soluble polymer so as to form a protective barrier or seal coat against environmental conditions. • Preparation of the aqueous or hydro-alcoholic or non-aqueous solution containing pH independent polymer so as to control the release of the drug in gastro intestinal tract. DESCRIPTION OF THE DRAWINGS: Figure 1 shows a comparative drug release profile of Example IB and Adalat XL60® in USP Test II (0.5% sodium lauryl sulphate Phosphate Buffer pH 6.8, 900 ml, 50RPM, Apparatus II) at 37±0.5°C. Figure 2 shows a comparative drug release profile of Example IB and Adalat XL60® in USP Test III (Phase I: 0.05M Phosphate Buffer pH 7.5, 900 ml, 100RPM, Apparatus II for 25 min; Phase II: 0.5% SLS in 0.1N SGF without enzymes pH 1.2, 900 ml, 100RPM, Apparatus II) at 37±0.5°C. Figure 3 shows a comparative drug release profile of Example 1B and Adalat XL60® in USP Test IV (0.5% Sodium lauryl sulphate in 0.1N SGF without enzymes pH 1.2, 900 ml, 100RPM, Apparatus II) at 37±0.5°C. Figure 4 shows a comparative drug release profile of Example 1B and Adalat XL60® in Acetate buffer (0.5% Sodium lauryl sulphate in Acetate Buffer pH 4.5 900 ml, 100RPM, Apparatus I) at 37±0.5°C. Figure 5 shows a comparative drug release profile of Example 2B and Adalat XL60® in USP Test II (0.5% sodium lauryl sulphate Phosphate Buffer pH 6.8, 900 ml, 50RPM, Apparatus II) at 37±0.5°C. Figure 6 shows a comparative drug release profile of Example 2B and Adalat XL60® in USP Test III (Phase I: 0.05M Phosphate Buffer pH 7.5, 900 ml, 100RPM, Apparatus II for 25 min; Phase II: 0.5% SLS in 0.1N SGF without enzymes pH 1.2, 900 mh 100RPM, Apparatus II) at 37±0.5°C. Figure 7 shows a comparative drug release profile of Example 2B and Adalat XL60® in USP Test IV (0.5% Sodium lauryl sulphate in 0.1 N SGF without enzymes pH 1.2, 900 ml, 100RPM, Apparatus II) at 3 7±0.5°C. Figure 8 shows a comparative drug release profile of Example 2B and Adalat XL60® in Acetate buffer (0.5% Sodium lauryl sulphate in Acetate Buffer pH 4.5 900 ml, 100RPM, Apparatus I) at 37±0.5°C. DETAILED DESCRIPTION OF THE INVENTION The present invention is related to novel extended release pharmaceutical composition of nifedipine, which is useful for once daily administration. The present invention describes the simple and cost effective extended release pharmaceutical composition of nifedipine with novel process for its preparation. In accordance with the present invention, novel extended release dosage form comprises: (1) Compressed core, which essentially contains, (i) Active pharmaceutical ingredient, (ii) Pharmaceutically acceptable diluent(s), (iii) Pharmaceutically acceptable channeling agent(s), (iv) Pharmaceutically acceptable binders), (v) Pharmaceutically acceptable release retardant polymer(s), (vi) Pharmaceutically acceptable glidant(s) and lubricant(s) and (2) Coating around the said core tablet which essentially consists either of the following coatings: (i) Protective layer of pharmaceutically acceptable water soluble polymer(s) and layer of pH dependent enteric polymer(s), (ii) Protective layer of pharmaceutically acceptable water soluble polymer and layer of pH independent polymer(s), In accordance with the present invention, manufacturing methods used are one or more of wet granulation technique or dry granulation technique or direct compression of active pharmaceutical ingredient along with one or more of pharmaceutically acceptable excipients. Method of manufacturing by wet granulation method includes, preparation of drug granulates comprising, active pharmaceutical ingredient, one or more of pharmaceutically acceptable excipients by using aqueous granulating solution containing binder and pharmaceutically acceptable channeling agent. Wet granulation method includes, spray granulation using fluidized bed processor or conventional wet granulation using rapid mixer granulator. After drying, milling and sieving, the resulted drug granulates are mixed with one or more of other extra granular pharmaceutically acceptable excipients, lubricated and then compressed into tablets. Method of manufacturing by dry granulation method includes, preparation of drug granulates by slugging the uniformly blended mixture of active pharmaceutical ingredient and one or more of pharmaceutically acceptable excipients. After sieving, the resulted drug granulates are mixed with one or more of other extra-granular pharmaceutically acceptable excipients, lubricated and then compressed into tablets or filled into capsules. Method of manufacturing by direct compression includes mixing of active pharmaceutical ingredient with other pharmaceutically acceptable excipients, lubricated, and then compressed into tablets In accordance with the present invention, novel extended release pharmaceutical composition comprises, nifedipine and at least one or more pharmaceutically acceptable excipients viz., drug release retardant(s), diluent(s), channeling agent(s), glidant(s), binder(s), lubricant(s) and one or more of coating agent(s) for protecting the drug from external environment and for controlling the release of the drug in acidic condition of stomach. Release retarding polymer(s) used in the present invention are at least one or more of cellulose derivatives, natural gums, carboxyvinyl polymers, chitosans, carrage'enans, methacrylates and copolymers, polyanhydrides, polyvinyl alcohol, glucans, dextran, waxes, vegetable oils, sodium alginate and alginic acid. More preferred release retarding polymers used in the present invention are at least one or more of cellulose derivatives, natural gums, carboxyvinyl polymers, methacrylates and copolymers, polyanhydrides, polyvinyl alcohol, waxes, vegetable oils, sodium alginate and alginic acid. Most preferred release retarding polymers used in the present invention are at least one or more of cellulose derivatives, natural gums, carboxyvinyl polymers and methacrylates and copolymers. The cellulose derivative used in the present invention may be one or more of ethyl cellulose, hydroxyethyl cellulose, hydroxymethylcellulose, hydroxypropylmethyl cellulose, hydroxypropylcellulose, carboxymethy! cellulose, methyl cellulose, cellulose acetate, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate and hydroxypropylmethyl cellulose acetate succinate. Preferred cellulose derivative used in the present invention may be one or more of ethyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, cellulose acetate, cellulose acetate phthalate and hydroxypropylmethyl cellulose acetate succinate. More preferred cellulose derivative used in the present invention may be one or more of ethyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose and cellulose acetate phthalate. Natural gums comprise one or more of xanthan gum, guar gum, karaya gum, locust bean gum, gellan gum, hupu gum, carob gum and caramania. Preferred natural gums used in the present invention may be one or more of xanthan gum, guar gum, karaya gum, locust bean gum, gellan gum and hupu gum. More preferred natural gums used in the present invention may be one or more of xanthan gum, guar gum, karaya gum, hupu gum Glucans used in the present invention may be one or more of lichenin, nigeran and glycogens. More preferred glucans used in the present invention may be one or more of lichenin and glycogens. Binders used in the present invention may be at least one or more of polyvinyl pyrrolidone, co-povidone, natural gums, cellulose derivatives, gelatin, glucose, sugar, dextrin, sorbitol, maltose, pregelatinised starch, agar, alginic acid, sodium alginate, carbomers, carrageenan, chitosan, poloxamer, polyethylene oxide and magnesium aluminum silicate. More preferred binders used in the present invention may be at least one or more of polyvinyl pyrrolidone, co-povidone, natural gums, cellulose derivatives, pregelatinised starch, alginic acid, sodium alginate, carbomers, chitosan, polyethylene oxide and magnesium aluminum silicate. Most preferred binders used in the present invention may be at least one or more of polyvinyl pyrrolidone, co-povidone, natural gums, cellulose derivatives, pregelatinised starch, carbomers and polyethylene oxide. Diluents used in the present invention are at least one or more of the microcrystalline cellulose, silicified microcrystalline cellulose, anhydrous lactose, directly compressible lactose, starch 1500, calcium phosphate (dibasic/tribasic), calcium sulphate, calcium sulphate dihydrate, fructose, sucrose, sorbitol, xylitol, dextrose, compressible sugar, dextrates, dextrin, starch, starch derivatives, powdered cellulose, sodium alginate, tragacanth, sodium chloride, potassium chloride, magnesium sulfate, magnesium chloride, sodium sulfate, lithium sulfate, urea, inositol, lactose, mannitol, magnesium succinate, potassium acid phosphate and the like. Preferred diluents used in the present invention are at least one or more of microcrystalline cellulose, silicified microcrystalline cellulose, anhydrous lactose, directly compressible lactose, starch 1500, calcium phosphate (dibasic/tribasic), sodium chloride, potassium chloride, magnesium sulfate, magnesium chloride, sodium sulfate, lithium sulfate, inositol, lactose, mannitol, magnesium succinate, potassium acid phosphate and the like. More preferred diluents used in the present invention are at least one or more of microcrystalline cellulose, silicified microcrystalline cellulose, anhydrous lactose, directly compressible lactose, sodium chloride, potassium chloride, inositol, lactose, mannitol and the like. Most preferred diluents used in the present invention are at least one or more of microcrystalline cellulose, silicified microcrystalline cellulose, anhydrous lactose, directly compressible lactose, lactose, mannitol and the like. Channeling agents used in the present invention are at least one or more of sodium chloride, potassium chloride, magnesium sulfate, magnesium chloride, sodium sulfate, fructose, sucrose, sorbitol, xylitol, dextrose, urea, inositol, lactose, mannitol, magnesium succinate, calcium phosphate (dibasic/tribasic), calcium sulphate, calcium sulphate dihydrate, potassium acid phosphate and the like. More preferred channeling agents used in the present invention are at least one or more of sodium chloride, potassium chloride, fructose, sucrose, sorbitol, xylitol, dextrose, inositol, lactose, mannitol, magnesium succinate, calcium phosphate (dibasic/tribasic), calcium sulphate, calcium sulphate dihydrate, potassium acid phosphate and the like. Most preferred channeling agents used in the present invention are at least one or more of sodium chloride, potassium chloride, sorbitol, inositol, lactose, mannitol, and the like. Glidants used in the present invention may be at least one or more of colloidal silicon dioxide, talc, stearic acid, magnesium stearate, calcium stearate, hydrogenated castor oil, sodium lauryl sulfate, precipitated silicon dioxide and starch. More preferred glidants used in the present invention may be at least one or more of colloidal silicon dioxide, talc, stearic acid, magnesium stearate, calcium stearate, precipitated silicon dioxide and starch. Most preferred glidants used in the present invention may be at least one or more of colloidal silicon dioxide, talc, stearic acid, magnesium stearate. Lubricants used in the present invention are one or more of magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumerate, hydrogenated vegetable oils, magnesium lauryl sulfate, wax, polyethylene glycol, glyceryl behenate, glyceryl palmitostearate, palmitic acid, poloxamer, sodium benzoate and sodium lauryl sulfate. More preferred lubricants used in the present invention are one or more of magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumerate, glyceryl behenate, glyceryl palmitostearate, palmitic acid. Most preferred lubricants used in the present invention are one or more of magnesium stearate, stearic acid, sodium stearyl fumerate. In accordance with the present invention, multiple coating layers are applied for protecting the drug from degradation due to external environment and for controlling the release of the drug in the gastro intestinal tract. In accordance with the present invention, protective coating agent for protecting the drug from degradation due to external environment comprises, film forming agent, plasticizer and opacifier and anti-taking agent. In accordance with the present invention, pH dependent coating agent for controlling the drug release in gastro intestinal tract comprises, pH dependent polymer (enteric polymer), plasticizer, opacifier and colorant. In accordance with the present invention, pH independent coating agent for controlling the drug release in gastro intestinal tract comprises, pH independent polymer (non-enteric polymer), plasticizer, opacifier and colorant. In accordance with the present invention, protective film forming agent contains one or more of hydroxypropylmethyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, polyethylene glycol, polyvinyl alcohol, povidone, chitosan, maltodextrin, isomalt, ammonium alginate, gelatin, carrageen, ethyl lactate. More preferred protective film forming agent used in the present invention contains one or more of hydroxypropylmethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyethylene glycol, polyvinyl alcohol, povidone, ammonium alginate, gelatin, carrageen, ethyl lactate. Most preferred protective film forming agent used in the present invention contains one or more of hydroxypropylmethyl cellulose, polyethylene giycol, polyvinyl alcohol and povidone. In accordance with the present invention, pH dependant enteric polymers include one or more of acrylate co-polymers like dimethyl aminoethyl methylmethacrylate, other neutral methacrylic acid esters, methacrylic co-polymer like poly (ethyl acrylate, methyl methacrylate) 2:1, poly (methacrylicacid, methyl methacrylate) 1:1, poly (ethyl acrylate, methacrylic acid) 1:1, poly (methacrylic acid, methyl methacrylate) 1:2, poly (methacrylic acid, methyl methacrylate, methacrylic acid) 7:3:1, poly (ethylacrylate, methyl methacrylate, trimethylammonioethylmethacryJate chloride) 1:2:0.2, poly (ethylacrylate, methyl methacrylate, trimethylammonioethylmethacrylate chloride) 1:2:0.1, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, polymethacrylates, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, and/or mixture thereof. More preferred pH dependant enteric polymers used in the present invention includes one or more of acrylate co-polymers like dimethyl aminoethyl methylmethacrylate, other neutral methacrylic acid esters, methacrylic co-polymer like poly (ethyl acrylate, methyl methacrylate) 2:1, poly (methacrylicacid, methyl methacrylate) 1:1, poly (ethyl acrylate, methacrylic acid) 1:1, poly (methacrylic acid, methyl methacrylate) 1:2, poly (methacrylic acid, methyl methacrylate, methacrylic acid) 7:3:1, poly (ethylacrylate, methyl methacrylate, trimethylammonioethylmethacrylate chloride) 1:2:0.2, poly (ethylacrylate, methyl methacrylate, trimethylammom'oethylmethacrylate chloride) 1:2:0.1, cellulose acetate phthalate, hydroxypropylmethyl hydroxypropylmethyl cellulose acetate succinate, polymethacrylates, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, and/or mixture thereof. Most preferred pH dependant enteric polymers used in the present invention includes one or more of acrylate co-polymers like dimethyl aminoethyl methylmethacrylate, other neutral methacrylic acid esters, methacrylic co-polymer (ike poly (ethyl acrylate, methyl methacrylate) 2:1, poly (methacrylicacid, methyl methacrylate) 1:1, poly (ethyl acrylate, methacrylic acid) 1:1, poly (methacrylic acid, methyl methacrylate) 1:2, poly (methacrylic acid, methyl methacrylate, methacrylic acid) 7:3; 1, poly (ethylacrylate, methyl methacrylate, trimethylammonioethylmethacrylate chloride) 1:2:0.2, poly (ethylacrylate, methyl methacrylate, trimethylammonioethylmethacrylate chloride) 1:2:0.1, cellulose acetate phthalate, hydroxypropylmethyl cellulose acetate succinate and/or mixture thereof. In accordance with the present invention, pH independent polymers includes, one or more of cellulose derivatives like ethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, cellulose acetate, poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.2 or 1:2:0.1 and poly (ethyl acrylate, methyl methacrylate) 2:1. More preferred pH independent polymers used in the present invention includes, one or more of cellulose derivatives ethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, cellulose acetate. Most Preferred pH independent polymers used in the present invention includes, one or more of cellulose derivatives like ethyl cellulose, hydroxypropyl methyl cellulose and cellulose acetate. Opacifiers used in the present invention may be one or more of titanium dioxide, silicates such as talc and aluminium silicate, ethylene glycol palmitostearate, acetates such as zinc acetate, carbonates such as magnesium carbonate, calcium carbonate, stearates such as aluminium stearate and zinc stearate, sulfates such as calcium sulfate, oxides such as magnesium oxide and hydroxides such as aluminiuim hydroxides. More Preferred opacifiers used in the present invention may be one or more of titanium dioxide, silicates such as talc and aluminium silicate, stearates such as aluminium stearate and zinc stearate, sulfates such as calcium sulfate, oxides such as magnesium oxide and hydroxides such as aluminiuim hydroxides. Most preferred opacifiers used in the present invention may be one or more of titanium dioxide, silicates such as talc and aluminium silicate, stearates such as aluminium stearate and oxides such as magnesium oxide. Plasticizers used in the present invention may be one or more of triethyl citrate, polyethylene glycols, propylene glycol, glycerine, caster oil, acetyltriethyl citrate, benzyl benzoate, chiorbutanol, dextrin, acetyltributyl citrate, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, glyceryl monooleate, glyceryl monostearate, 2-pyrrolidone, sorbitol, stearic acid, palmitic acid, triacetin, tributyl citrate, triethanolamine, lecithin, surfactants like polysorbates, sorbitan esters and organic acid esters and/or mixtures thereof. Preferred plasticizers used in the present invention may be one or more of triethyl citrate, polyethylene glycols, propylene glycol, glycerine, acetyltriethyl citrate, benzyl benzoate, glyceryl monooleate, glyceryl monostearate, 2-pyrrolidone, sorbitol, stearic acid, palmitic acid, triacetin, tributyl citrate, triethanolamine, surfactants like polysorbates, sorbitan esters and organic acid esters and/or mixtures thereof. More preferred plasticizers used in the present invention may be one or more of triethyl citrate, polyethylene glycols, propylene glycol, stearic acid, triacetin and/or mixtures thereof. Most preferred plasticizers used in the present invention may be one or more of triethyl citrate, polyethylene glycols, triacetin and/or mixtures thereof. Anti-tacking agent used in the present invention may be one or more of talc, magnesium stearate, calcium stearate, stearic acid, calcium carbonate, magnesium carbonate, ground limestone, magnesium silicate, aluminum silicate, clay, alumina, titanium oxide, mono-calcium phosphate, di-calcium phosphate, tri-calcium phosphate and combinations thereof. Preferred anti-tacking agent used in the present invention may be one or more of talc, magnesium stearate, calcium stearate, stearic acid, calcium carbonate, magnesium carbonate, magnesium silicate, aluminum silicate, alumina, titanium oxide, mono-calcium phosphate, di-calcium phosphate, tri-calcium phosphate and combinations thereof. More preferred anti-tacking agent used in the present invention may be one or more of talc, magnesium stearate, calcium stearate, stearic acid, calcium carbonate, magnesium carbonate, magnesium silicate, aluminum silicate, alumina, titanium oxide and combinations thereof. Most preferred anti-tacking agent used in the present invention may be one or more of talc, magnesium stearate, calcium stearate, stearic acid, magnesium silicate, aluminum silicate, alumina, titanium oxide and combinations thereof. Suitable coloring agents include one or more colors approved by FDA. Suitable solvents used in the manufacturing of pharmaceutical composition include one or more of water, ethyl acetate, acetone, isopropyl alcohol, n-propanol, ethanol and mixtures thereof. In accordance with the present invention, it is believed that the use of the channeling agent in core tablet formulation will allow water to be imbibed into the tablet even in the absence of a pre-formed aperture as present in the osmotic systems. As water is taken up into the core of the tablet, the water swellable polymer expands and increases the osmotic pressure inside the tablet. Initially expansion of the core causes small openings at the weakest points in the coating, which are typically at the edges of the tablet. Once the initial opening is formed around the edges of the tablet, the combination of factors such as diffusion, dissolution, erosion and osmotic effect will cause the contents of the core to extrude through the initial openings. With increase in the water uptake by the core, polymer in the core swells, leading to fracture of insoluble membrane ail around the circumference of the core tablet. Once core tablet is completely exposed to the medium, dissolution of the drug will be taken place by diffusion, dissolution and erosion, which may result in the required release profile of the drug. In accordance with the present invention, performance of the developed novel extended release matrix formulation is comparable to controlled release formulations of prior arts, developed by using much more complicated techniques like compression coating and osmotic drug delivery technology. According to the present invention, novel extended release pharmaceutical composition matrix system may contain between 1 to 50% of active ingredient, between 1 to 50% of one or more swellable release retardant polymers, between 1 to 15% of the binders, between 1 to 50% of the diluents, 0.1 to 5% of glidants, 0.1 to 5% of lubricants, 0,1 to 4% protective barrier coating agent, 0.1 to 20% pH dependant or pH independent polymer and/or combination of thereof in appropriate ratio, 0.1 to 20% plasticizer or combination thereof, 0.05 to 10% opacifiers, 0.1 to 20% anti-tacking agents and 0.01 to 5% colorants. Also, it comprises channeling agent between l to 10%, preferably between l to 5%, and more preferably between lto 3%. According to the present invention, novel extended release pharmaceutical composition, releases, less than about 25% of the drug in about 1 hour, less than about 50% of the drug in about 4 hours, less than about 75 % of the drug in about 8 hours, less than about 85% of the drug in 12 hours, and more than about 90% of the drug in about 24 hours, as measured in 900 ml of 0.01NHCI with 0.5% sodium lauryl sulfate using USP Type II apparatus (paddle), at 37±2°C. Novel extended release pharmaceutical composition of the present invention contains the active ingredient in the range of from about 10 mg to about 90 mg. The 'active ingredient' refers to nifedipine. The extended release pharmaceutical composition; wherein the extended release pharmaceutical composition of nifedipine is manufactured by direct compression, wet granulation or dry granulation method; preferably by direct compression or wet granulation method and more preferably by wet granulation. Wet granulation method includes, spray granulation using fluidized bed processor or conventional wet granulation using rapid mixer granulator using high sheer or low sheer granulation. According to the present invention, the novel extended release matrix formulation is in the form of tablets. In one embodiment, process for forming a coated extended release matrix system includes: • Sifting of active pharmaceutical ingredient, pharmaceutically acceptable excipients through ASTM mesh # 40 and mixing for 5 min. • Sifting of extra-granular pharmaceutically acceptable excipients through ASTM mesh # 40 and addition to the above blend and then mixing for 3 min. • Compression of the above blend to form a extended release matrix tablet. • Preparation of the aqueous or hydro-alcoholic or non-aqueous solution/dispersion containing water soluble polymer so as to form a protective barrier against environmental conditions. • Optionally, preparation of the aqueous or hydro-alcoholic or non-aqueous solution/dispersion containing pH dependent enteric polymer or pH independent polymer so as to control the release of the drug in gastro intestinal tract. In another embodiment, process for forming a coated extended release matrix system includes: • Sifting of active pharmaceutical ingredient, pharmaceutically acceptable excipients through ASTM mesh # 40 and mixing for 5 min. • Slugging of the above blend in miniroller compactor into slugs, sifting through ASTM mesh # 24 and collection of slugs and sizing of the slugs. • Sifting of extra-granular pharmaceutically acceptable excipients through ASTM mesh # 40, addition of the sifted extra-granular pharmaceutically acceptable Excipients to the above blend and mixing for 3 min • Compression of the above blend to form a extended release matrix tablet. • Preparation of the aqueous or hydro-alcoholic or non-aqueous solution/dispersion containing water soluble polymer so as to form a protective barrier against environmental conditions. • Optionally, preparation of the aqueous or hydro-alcoholic or non-aqueous solution /dispersion containing pH dependent enteric polymer or pH independent polymer so as to control the release of the drug in gastro intestinal tract. In one preferred embodiment, process for forming a coated extended release matrix system includes: • Preparation of the aqueous granulating solution containing pharmaceutically acceptable channeling agent and binder. • Spraying the aqueous granulating solution on the mixture of active pharmaceutical ingredient and pharmaceutically acceptable excipients in fluidized bed processor and drying the granules • Mixing of the spray-dried granules with extra granulate excipients, lubrication. • Compression of the lubricated blend to form a extended release matrix tablet. • Preparation of the aqueous or hydro-alcoholic or non-aqueous solution containing water soluble polymer so as to form a protective barrier against environmental conditions. • Preparation of the aqueous or hydro-alcoholic or non-aqueous solution containing pH dependent enteric polymer so as to control the release of the drug in gastro intestinal tract. In another preferred embodiment, process for forming a coated extended release matrix system includes: • Preparation of the aqueous granulating solution containing pharmaceutically acceptable channeling agent and binder. • Spraying the aqueous granulating solution on the mi xture of active pharmaceutical ingredient and pharmaceutically acceptable excipients in fluidized bed processor and drying the granules • Mixing of the spray-dried granules with extra granulate excipients, lubrication. • Compression of the lubricated blend to form a extended release matrix tablet. • Preparation of the aqueous or hydro-alcoholic or non-aqueous solution containing water soluble polymer so as to form a protective barrier against environmental conditions. • Preparation of the aqueous or hydro-alcoholic or non-aqueous solution containing pH independent polymer so as to control the release of the drug in gastro intestinal tract. According to the present invention, pharmaceutical composition and manufacturing process of extended release matrix tablets of nifedipine is simple and economical to that of controlled release systems in the form of compression coated tablets and osmotic tablets of the earlier reported prior arts. The novel extended release pharmaceutical composition of the present invention may be administered to the mammals. Preferably the mammal is a human, and the composition is administered as novel extended release tablet. Preferably, the pharmaceutical composition of present invention containing nifedipine, may be used in the treatment of hypertension and angina. The amount of the nifedipine in the novel extended release pharmaceutical composition of present invention, is preferably an amount that provides a therapeutically effective amount of nifedipine. Although the present invention has been described with reference to specific embodiments, this description is not meant to be construed in a limiting sense. Various modifications of the disclosed embodiments, as well as alternate embodiments of the invention, will become apparent to persons skilled in the art upon reference to the description of the invention. It is therefore, contemplated that such modifications can be made without departing from the spirit or scope of the present invention as defined. EXAMPLES The following examples are presented for illustration only, and are not intended to limit the scope of the invention or appended claims Example 1 Table 1: Formulations of Example 1A (Nifedipine Extended Release Tablets 30 mg] & Example IB [Nifedipine Extended Release Tablets 60 mg] Sr. No. Ingredients Quantity / tablet (mg) Example 1A (30 mg) Example IB (60 mg) 1 Nifedipine 30.00 60.00 2 Hydroxypropylmethyl cellulose (High viscosity) 27.50 27.50 3 Hydroxypropylmethyl cellulose (Low viscosity) 75.00 75.00 4 Microcrystalline Cellulose 49.25 19.25 5 Povidone 6.50 6.50 6 Colloidal Silicone dioxide 3.00 3.00 7 Sodium Chloride 9.00 9.00 8 Purified water q.s. q.s. Silicified microcrystalline cellulose 52.50 52.50 10 Hydroxy ethyl Cellulose 19.25 19.25 11 Magnesium stearate 3.00 3.00 Tablet weight (in mg) 275.00 275.00 12 Hydroxypropyfmethyl cellulose (Low viscosity) 3.00 3.00 Tablet weight (in mg) 278.00 278.00 13 Methacrylic acid copolymer, Type C 11.90 11.90 14 Methacrylic acid copolymer, Type B 0.90 0.90 15 Triethyl citrate 1.90 1.90 16 Titanium dioxide 0.70 0.70 17 Talc 6.46 6.46- 18 Iron oxide Red 0.34 0.34 19 Isopropyl alcohol q.s. q.s. 20 Purified water q.s. q.s. Total weight (in mg) 300.20 300.20 Brief manufacturing procedure: 1. Sift active pharmaceutical ingredient Nifedipine, iow viscosity hydroxypropyl methyl cellulose, high viscosity hydroxypropylmethyl cellulose, microcrystalline cellulose; three parts of povidone and colloidal silicon dioxide through 40 mesh ASTM (425 microns). 2. Sifted ingredients of Step 1 were mixed for 15 min. 3. Dissolved remaining one part of povidone and sodium chloride in purified water to obtain solution. 4. Blend of Step 2 was transferred into fluidized bed processor bowel and fiuidized till temperature reaches 35°C. 5. Sprayed the granulating solution from Step 3 on blend of Step 4. 6., After complete spraying of granulating solution, granules were dried and sifted through 20 mesh ASTM (850 microns). 7. Silicified microcrystalline cellulose and hydroxyl ethyl cellulose were sifted through 40 mesh ASTM (425 microns) and added to Step no 6 and mixed for 15 mins. 8. Magnesium stearate was sifted through 40 mesh ASTM (425 microns) and mixed with blend of Step 7 to obtain lubricated blend. 9. Lubricated blend of Step 8 was compressed into Tablets using 9.00mm round punch standard concave punch; upper punch embossed with "30" and lower punch plain for compressing 30mg strength tablets and upper punch embossed with "60" and lower punch plain for compressing 60 mg strength tablets. 10. Low viscosity hydroxypropylmethyl cellulose was dissolved in purified water to get seal coating solution. 11. Methacrylic acid copolymer, Type C and methacrylic acid copolymer, Type B were dissolved in isopropyl alcohol: purified water mixture (95:5). 12. Co-sifted titanium dioxide, talc and iron oxide red through 200 mesh ASTM (75 microns) and dispersed in isopropyl alcohol: purified water mixture (95:5) to obtain pigment dispersion. 13. Pigment dispersion of Step 12 was added to the methacrylic acid copolymer solution of Step 11, mixed and filtered. 14. Compressed Tablets of Step 9 were coated using coating solution of Step 10 followed by coating dispersion of Step 13. Dissolution studies of tablets of Example 1 and Adalat XL60 were carried out in four different dissolution media viz., (1) USP Test II (0.5% sodium lauryl sulphate Phosphate Buffer pH 6.8, 900 ml, 50RPM, Apparatus II), (2) USP Test HI (Phase I: 0.05M Phosphate Buffer pH 7.5, 900 ml, 100RPM, Apparatus II for 25 min; Phase II: 0.5% SLS in 0. IN SGF without enzymes pH 1.2, 900 ml, 100RPM, Apparatus II), (3) USP Test IV (0.5% Sodium lauryl sulphate in 0.1N SGF without enzymes pH 1.2, 900 ml, 100RPM, Apparatus II), (4) Acetate buffer (0.5% Sodium lauryl sulphate in Acetate Buffer pH 4.5 900 ml, 100RPM, Apparatus I) maintained 37±0.5°. Comparative dissolution profiles are given in Table 2 and Fig. 1 to Fig. 4. Table 2: Comparative dissolution profiles of the tablets of Example-IB and Adalat XL60 in (1) USP Test II

Documents

Application Documents

# Name Date
1 388-MUM-2010- AFR.pdf 2023-01-27
1 388-MUM-2010-DUPLICATE-FER-2017-09-13-17-21-30.pdf 2017-09-13
2 388-MUM-2010-AbandonedLetter.pdf 2018-08-10
2 388-MUM-2010-DUPLICATE-FER-2017-09-14-11-26-42.pdf 2017-09-14
3 ABSTRACT1.jpg 2018-08-10
3 388-MUM-2010-ABSTRACT(14-2-2011).pdf 2018-08-10
4 388-mum-2010-form 5.pdf 2018-08-10
4 388-mum-2010-abstract.pdf 2018-08-10
5 388-mum-2010-form 3.pdf 2018-08-10
5 388-MUM-2010-CLAIMS(14-2-2011).pdf 2018-08-10
6 388-mum-2010-form 2.pdf 2018-08-10
6 388-MUM-2010-CORRESPONDENCE(14-2-2011).pdf 2018-08-10
7 388-mum-2010-form 2(title page).pdf 2018-08-10
7 388-MUM-2010-CORRESPONDENCE(26-7-2013).pdf 2018-08-10
8 388-MUM-2010-FORM 2(TITLE PAGE)-(14-2-2011).pdf 2018-08-10
8 388-MUM-2010-Correspondence-181217.pdf 2018-08-10
9 388-mum-2010-correspondence.pdf 2018-08-10
9 388-mum-2010-form 2(14-2-2011).pdf 2018-08-10
10 388-MUM-2010-DESCRIPTION(COMPLETE)-(14-2-2011).pdf 2018-08-10
10 388-MUM-2010-FORM 18(26-7-2013).pdf 2018-08-10
11 388-mum-2010-description(provisional).pdf 2018-08-10
11 388-mum-2010-form 1.pdf 2018-08-10
12 388-MUM-2010-DRAWING(14-2-2011).pdf 2018-08-10
12 388-MUM-2010-FER.pdf 2018-08-10
13 388-MUM-2010-DRAWING(14-2-2011).pdf 2018-08-10
13 388-MUM-2010-FER.pdf 2018-08-10
14 388-mum-2010-description(provisional).pdf 2018-08-10
14 388-mum-2010-form 1.pdf 2018-08-10
15 388-MUM-2010-DESCRIPTION(COMPLETE)-(14-2-2011).pdf 2018-08-10
15 388-MUM-2010-FORM 18(26-7-2013).pdf 2018-08-10
16 388-mum-2010-correspondence.pdf 2018-08-10
16 388-mum-2010-form 2(14-2-2011).pdf 2018-08-10
17 388-MUM-2010-FORM 2(TITLE PAGE)-(14-2-2011).pdf 2018-08-10
17 388-MUM-2010-Correspondence-181217.pdf 2018-08-10
18 388-mum-2010-form 2(title page).pdf 2018-08-10
18 388-MUM-2010-CORRESPONDENCE(26-7-2013).pdf 2018-08-10
19 388-mum-2010-form 2.pdf 2018-08-10
19 388-MUM-2010-CORRESPONDENCE(14-2-2011).pdf 2018-08-10
20 388-mum-2010-form 3.pdf 2018-08-10
20 388-MUM-2010-CLAIMS(14-2-2011).pdf 2018-08-10
21 388-mum-2010-form 5.pdf 2018-08-10
21 388-mum-2010-abstract.pdf 2018-08-10
22 ABSTRACT1.jpg 2018-08-10
22 388-MUM-2010-ABSTRACT(14-2-2011).pdf 2018-08-10
23 388-MUM-2010-DUPLICATE-FER-2017-09-14-11-26-42.pdf 2017-09-14
23 388-MUM-2010-AbandonedLetter.pdf 2018-08-10
24 388-MUM-2010-DUPLICATE-FER-2017-09-13-17-21-30.pdf 2017-09-13
24 388-MUM-2010- AFR.pdf 2023-01-27

Search Strategy

1 searchstrategy_07-09-2017.pdf