Title of Invention	A PROCESS FOR PREPARATION OF DUAL RELEASE COMBINATION OF CARDIOVASCULAR DRUG COMPRISING ANTHYPERTENSIVE AGENT AND DIURETIC AGENT
Abstract	The present invention relates to a process for dual release of cardiovascular drugs when in combination, wherein one of the active pharmaceutical agents is diuretic in the form of sustained release and the other agent is selective Bi blocker in the form of immediate release. Formulation is developed by using any of the technology like multilayer tablet or press coated tablet or drug loading or multirelease granules in capsule.

Title of Invention

A PROCESS FOR PREPARATION OF DUAL RELEASE COMBINATION OF CARDIOVASCULAR DRUG COMPRISING ANTHYPERTENSIVE AGENT AND DIURETIC AGENT

Abstract

The present invention relates to a process for dual release of cardiovascular drugs when in combination, wherein one of the active pharmaceutical agents is diuretic in the form of sustained release and the other agent is selective Bi blocker in the form of immediate release. Formulation is developed by using any of the technology like multilayer tablet or press coated tablet or drug loading or multirelease granules in capsule.

Full Text	FORM 2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION [See section 10] "A PROCESS FOR PREPARATION OF DUAL RELEASE COMBINATION OF CARDIOVASCULAR DRUG, COMPRISING ANTIHYPERTENSIVE AGENT AND DIURETIC AGENT" (a) IPCA LABORATORIES LTD. (b) 48, Kandivli Industrial Estate, Mumbai - 400 067, Maharashtra, India (c) Indian Company incorporated under the Companies Act 1956 The following specification describes the nature of the invention and the manner in which it is to be performed: GRANTED ORIGINAL 5-5-2004 Technical Field of Invention The present invention relates to a process for dual release of cardiovascular drugs when in combination, wherein one of the active pharmaceutical agents is diuretic in the form of sustained release and the other agent is selective pi blocker in the form of immediate release. Formulation is developed by using any of the technology like multilayer tablet or press coated tablet or drug loading or multirelease granules in capsule. Background and Prior Art ABOUT INDAPAMIDE: > Indapamide is the first of a new class of antihypertensive/diuretics, the indolines. > Indapamide is a white or almost white powder practically insoluble in water, soluble in alcohol, slightly soluble in ether. > Indapamide contains not less than 98.0% and not more than the equivalent of 102.0% of (RS)-chloro-3-sulphamoyl-N-(2_methyl-,3-dihydro-lH-indol-l-yl) benzamide, calculated with reference to anhydrous substance. > Its molecular formula is C16H16CIN3O3S and its molecular weight is 365.8. > mdapamide is preferentially and reversibly taken up by the erythrocytes in the peripheral blood. > Indapamide is an extensively metabolized drug with only about 7% of the total dose administered, recovered in the urine as unchanged drug during the first 48hrs after administration. > Thiazide diuretics increase urinary excretion of Sodium and water by inhibiting Sodium reabsorption in the cortical (thick) portion of the ascending limb of Henle's loop and in the early distal tubules. They also increase excretion of chloride, potassium and to a lesser extent, bicarbonate ions. ABOUT ATENOLOL: > Atenolol, a synthetic, Bi- selective (cardio selective) adrenoreceptor blocking agent, maybe chemically described as benzene acetamide, 4-[2y hydroxy -3y - 1 [(1- methyl ethyl) amino] propoxy]- phenyl acetamide. > (3-blockers are competitive inhibitors and interfere with the action of stimulating hormones on J3 - adrenergic receptors in the nervous system. > Atenolol is soluble in ethanol, sparingly soluble in water, slightly soluble in dichloromethane, practically insoluble in ether. > Atenolol contains not less than 99% and not more than 101% of C14H22N2O3 calculated with reference to the dried substance. > Atenolol is white or almost white crystalline powder which is almost odorless > Hypertension may be treated with these drugs because of their ability to increase the diameter of the blood to flow less under pressure. > Blockage of myocardial pi receptors causes sinoatrial brandycardia, suppression of some ectopic pacemakers, decreased force of myocardial contraction, slowing of atrioventricular conduction and atrioventricular refractoriness The effect to slow the heart rate increases the duration of diastole and thus increases coronary blood flow to the subendocardial region. Chinese Patent No. CN 13.94.60.4 to Yan Jie claims a slowly release tablet of Indapamide as a single - ingredient formulation with a core and a coating. Pharmaceutical composition designed in the form of membrane - covered center containing efficient quantity of Indapamide as active substance is descripted in the Russian Patent No, RU 22.Q1.7.51 .granted to Khim. UK Patent No. GB 2123293, to Molle Daniel and Labeyrie Etienne provides pharmaceutical compositions and preparations comprising a combination of thiachromans with Indapamide (Equivalent patents). KoreanJPatent.No, 9507207 to Park Sok-Ryon describes a drug composition for treatment of hypertension comprising a pi-blocking agent as a sympathetic nerve blocking agent, a B.1 -blocking agent, a ACE inhibitor and a diuretic. The pi-blocking agent is selected from acebutolol, atenolol, metoprolol, nanolol, propranolol, timolol, penputolol, cateolol or pindolol; the al-blocking agent is selected from prazosin, terazosin or doxazosin; the ACE inhibitor is selected from captopril, enalapril, lisinopril or cilazapril; and the diuretic is selected from bendroflumethiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichlormethiazide, chlorthalidone, Indapamide, metolazone, quinethazone or cyclothiazide. I However, none of the above patents deal with a combination of anti-hvdpertensive and I diuretic agents wherein one of the drugs namely the diuretic is suitably formulated for sustained release while the P-blocker antihypertensive agents is incorporated suitably for immediate release. Objectives ^+7 The objective of the present invention to provide immediate release of selective pi. adrenoreceptor blocker by using solubilising agent in an effective manner in - upper layer. 2. A further objective is to provide two drugs in combination therapy to have additive effect in lowering blood pressure in hypertensive patients. 3. Another objective is to reduce the dose of one of the active ingredient by sustaining over a period of time. 4. Further objective is to prolong t max, to reduce peak concentration and to decrease electrolyte disturbances of "drug by sustaining it for a specific period of time. 5. To improve patient compliance. Summary of the Invention The present invention relates to a process for dual release cardiovascular drug comprising of two active ingredients which are formulated in a single dosage form providing different release profile. The process involves use of hydroxypropyl methyl cellulose polymer with polyvinyl pyrrolidon which helps to sustain the release of drug over specific period of time and independent of pH. Detailed Description The process claimed in present invention comprises formulating in one of the compartment which is the lower layer and which releases the diuretic active agent, Indapamide, over a period of time, ensuring uniform & constant blood levels after absorption and the upper layer which compressed on to the lower layer and which is formulated for immediate release of the (3-blocker, atenolol. Until now, Indapamide has been orally administered at a dose of 2.5 mg per day by means of an immediate release form .The immediate release formulation leads to; Cmax in just two hours after administration of tablet and these results in the unfavorable hydro electrolytic type or metabolic disturbances. Due to this and in accordance with the international guidelines recommending the use of low doses of antihypertensive agents, new formulation of Indapamide i.e. Indapamide sustained release has-been developed. (P,Clinical Pharmacokinetic, 1999, 37, suppl 1: 13-9) This new formulation eliminates plasma peak, prolongs t max and reduces peak concentration while maintaining minimum concentration. The speed of release must be reproducible and correlated with the blood concentration observed after administration. The new SR formulation which allows reduction in the daily dose of Indapamide from 2.5 to 1.5 mg leads to an improvement in its efficacy or tolerability ratio (Fundamental & Clinical Pharmacology, 2000, 14/2, 139-146). The mechanism employed to control the release of a soluble active principle from the formulation may be by - 1) Controlling diffusion of drug through polymer or diffusion control of drug release by water soluble or insoluble polymer. 2) Dissolution control of drug release via dissolution rate & thickness of membrane barrier coat 3) Dissolution control of drug release by polymer core erosion or polymer coating erosion 4) Controlling the release of drug due to osmotic pressure gradient across semipermeable membrane. Release of active drug is controlled by embedding drug in matrix of hydrophilic polymers, melted mixture of fat & wax and capillary network of plastic material. Hydrophilic polymers utilised for building material are sodium carboxy methyl cellulose, hydroxy propyl cellulose, hydroxy ethyl cellulose, polyethylene oxide, polyvinyl pyrollidone, polyvinyl acetate, carboxy polymethlyne, algenic acid, gelatin & natural *ums. The matrix is compressed by direct compression of the blend of active ingredients and certain hydrophilic carriers, wet granulation containing the drug and hydrophilic matrix material. rhe diffusion of drug is through a gel formed after swelling of hydrophilic polymer Drought into contact with dissolving liquid (in vitro) or gastrointestinal fluid ( in vivo). fhe drug release is controlled by gel diffusion barrier that is formed and / or tablet erosion. rhe drug is incorporated into fat wax granulation by spray congealing in air, blend congealing in an aqueous media with or without aid of surfactant and spray drying Cechnique. The drug embedded into a melt of fat & waxes is released by leaching and /or hlydrolysis as well as dissolution of fats under the influences of enzymes and pH change in GIT in general; primary constituents of fat wax matrix are fatty acid and fatty esters. Release through plastic matrix is usually delayed because the dissolved drug has to diffuse through capillary network of compacted particles. Commonly used plastic materials are polyvinyl chloride, polyethylene, vinyl acetate /vinyl chloride copolymer, vinylidene chloride, acrylate/methacrylate copolymer, ethyl cellulose, cellulose acetate. Plastic matrix tablet, in which the active ingredient is embedded in tablet with coherent ind porous skeletal structure, is easily prepared by direct compression of drug with Mastic material provided the plastic material comminuted or granulated to desired oarticle size to facilitate mixing with drug particle. rhe matrix tablet described in present invention combines in a novel manner, two polymers of different chemical families, which allows a precisely controlled release of ptive principle. JI a preferred embodiment of the invention, the finished dosage form is accomplished hrough a drug delivery system suitable for oral administration with an immediate release compartment, which contains a compressed blend of an active agent and one or more jolymers, substantially enveloped by an extended release compartment which contains a compressed blend of the active agent and hydrophilic and hydrophobic constituents and substantially enveloped by an optional immediate release compartment, which provides a lose sufficient to exceed the livers metabolic capacity and to maintain therapeutic levels, preferably throughout a 24hr period. In another embodiment of the present invention, the active agent in the extended release compartment is diffuse out first, resulting in a first order release rate. As the active agent & soluble polymers in the extended release compartment disintegrate, water will penetrate through the extended compartment and cause the immediate release compartment to expand; creating a bursting effect that further disrupts any remaining integrity of the extended release compartment. The pharmaceutical preparation of present invention is prepared by press coating technique. It allows the compaction of a dry coating around the tablet core produced on the same machine. The technique is utilized in the present invention as to avoid use of solvent, whether aqueous or organic in nature. Press coated tablet having multiple layer, formed by press coating a core containing a medicinal active ingredient with one or more kind of polymers. Another layer, pressed around the core, containing different medicinal active ingredient. Core of press coated tablet provides sustained release of medicinal active ingredient for a period of 0 to 24 hrs. Other medicinal active ingredient coated on core provides immediate release. The pharmaceutical preparation of present invention is prepared by coating/loading medicinal active ingredient on the core containing another medicinal active ingredient with different kind of polymers that allows sustained release for period of 0 to 24 hrs. Core is in the form of dried granules, nonpareils pellets or drug crystals or tablet. There are a layer between core and coat that works as barrier for the excipient to interfere in the release of both the medicinal active ingredient. A film coat is applied to the core. The final coated particles are filled into two piece hard gelatin capsule or compacted into tablets. Example Example 1 For Lower Layer : (Indapamide) Lactose 54% w/w Hydroxy Propyl Methyl Cellulose K 15 M 37% w/w Polyvinyl pyrrlidone K 30 4.33% w/w Indapamide 1.0% w/w Colloidal silicon dioxide 0.2 % w/w Magnesium stearate 1.0% w/w Dissolve Indapamide in IPA and add it in mixture of powder except magnesium stearate. Granulation is carried out using aqueous and alcoholic solution in equal proportion. For Upper Layer: Atenolol 25% w/w Magnesium carbonate 36% w/w Sodium starch Glycollate 5.5% w/w Colloidal silicon dioxide 200 2.0 w/w Maize starch 30.5 w/w Magnesium stearate 0.5 w/w Lake of sunset yellow 0.5 w/w Drug is mixed with excipient and colour in Geometric mixing. (Geometric mixing is process wherein the active along with excipient and colour are mixed in proportions to achieve uniform distribution of colour and drug in powder mixture.) Binding is carried out by starch paste. The final blend is prepared by mixing the lubricants and glidants with above rasped granules. For bilayered tablet, weighing 300 mg (containing 102 mg of upper layer and 198 mg of lower layer) and 8.5 mm in dimension were produced on tablet pressed by two stage pressing procedure as described. The powder of lower layer is compressed by partial pressure in the press first and the upper layer is then added and the press is operated again. Example 2 For Lower Layer: (Indapamide) Lactose 55.86% w/w Hydroxy Propyl Methyl Cellulose K 15 M 36.90% w/w Polyvinyl pyrrlidone K 30 4.98% w/w Indapamide 0.76 % w/w Colloidal silicon dioxide 0.49 % w/w Magnesium stearate 0.99 % w/w Mixing of Indapamide, Polyvinyl pyrrolidone and lactose and then wetting of this mixture by means of aqueous or alcoholic solution. The dough is then wet milled, dried and lubricated so as to obtain granulate whose physical characteristic allows good filling of the dies of fast rotary bilayered machine. For Upper Layer: Atenolol 22.52 w/w Microcrystalline cellulose 36% w/w Lactose 33.78 % w/w Sodium lauryl sulphate 3.15% w/w Sodium starch Glycollate 5.85% w/w Cross carmelose sodium 3.60 % w/w Colloidal silicon dioxide 200 3.15 w/w Maize starch 4.5 w/w Magnesium stearate 0.5 w/w Lake of sunset yellow 0.45 w/w Drug is mixed with excipient and colour in Geometric mixing. (Geometric mixing is process wherein the active along with excipient and colour are mixed in proportions to achieve uniform distribution of colour and drug in powder mixture.) Binding is carried out by starch paste. The final blend is prepared by mixing the lubricants and glidants with above dried and rasped granules. For bilayered tablet, weighing 311 mg (containing 111 mg of upper layer and 200 mg of lower layer) and 9 mm in dimension were produced on tablet pressed by two stage pressing procedure as described. The powder of lower layer is compressed by partial pressure in the press first and the upper layer is then added and the press is operated again. Example 3 For Core of tablet: (Indapamide) Lactose 55% w/w Hydroxy Propyl Methyl Cellulose K 15 M 37.65% w/w Polyvinyl pyrrlidone K 30 4.07% w/w Indapamide 0.77 % w/w Colloidal silicon dioxide 0.50 % w/w Magnesium stearate 1.01 %w/w Mixing of Indapamide, polyvinyl pyrrolidone and lactose and then wetting of this mixture by means of aqueous or alcoholic solution. The dough is then wet milled, dried and lubricated so as to obtain granulate whose physical characteristic allows good filling of the dies of fast rotary tablet in tablet machine. For press coated Layer: Atenolol 12.5% w/w Lactose 62.5 % w/w Sodium lauryl sulphate 3.0% w/w Talc 1.0% w/w Maize starch 16.98 %w/w Poly vinyl pyrrolidone 3.0 % w/w Magnesium stearate 1.0 w/w Iron oxide red 0.15 w/w Drug is mixed with excipient and colour in Geometric mixing. (Geometric mixing is process wherein the active along with excipient and colour are mixed in proportions to achieve uniform distribution of colour and drug in powder mixture.) Binding is carried out by starch and poly vinyl pyrrolidone paste. The final blend is prepared by mixing the lubricants and glidants with above dried and rasped granules. For Tablet in tablet, weighing 396.5 mg (containing 200 mg of Press coat and 196.5 mg of core) and 8 mm in dimension for core and 10 mm dimension for press coat, were produced on tablet pressed by two stage pressing procedure as described. The powder of core layer is compressed by first rotary press using 8 mm round punch and then press coat is fill over core in 10 mm circular dimension in following second press machine to obtain tablet in tablet. Example 4 For core : Lactose 55% w/w Hydroxy Propyl Methyl Cellulose K 15 M 37.65% w/w Polyvinyl pyrrlidone K 30 4.07% w/w Indapamide 0.77 % w/w Colloidal silicon dioxide 0.50 % w/w Magnesium stearate 1.01 %w/w Binding is given by the aqueous or alcoholic solution with polyvinyl pyrrolidine K30 to the blend of lactose, hydroxy propyl methyl cellulose K 15 M and Indapamide. The dough is then wet milled, dried and lubricated so as to obtain granulate whose physical characteristic allows good filling of the dies of fast rotary tablet in tablet machine. For COAT 1) Seal Coat: Titanium dioxide 0.18 Hydroxy Propyl Methyl Cellulose 15 cps 0.92 Talc 0.092 Ethyl cellulose 0.18 PEG 400 0.01 IPA q.s. Methylene chloride q.s. Add Titanium dioxide & talc into the dispersion of hydroxyl porpyl methyl cellulose 15 cps & ethyl cellulose in IPA. Mix it well and coat above solution over the core tablet till 10 mg weight gain achieve. 2) Drug Loading : Atenolol 2.5-5.05% OY-IN 58901 3.2% Sodium lauryl sulphate 0.3% Water q.s. Disperse OY-IN -58901 in water and then add atenolol under vigorous stirring. To this solution add SLS & mix well. Use solution for drug loading tablet till 75-80 mg weight gain achieved. 3) Final coat: OY-IN 58901 0.16% Methylene chloride q.s. Water q.s. Finally coat the tablet using dispersion of OY-IN 58901 in IPA and methylene chloride. Description of Drawings Fig.l describes the sustained release of Indapamide. X axis (1) denotes time in hours and Y axis (2) denotes dissolution in percentage. The graph indicates the sustained release pattern of Indapamide from the combination in dissolution percentage. Fig.2 describes comparison between immediate and sustained release form of Indapamide tablet. As in Fig.l, the X axis (1) denotes time in hours and Y axis (2) denotes dissolution in percentage. The graph (3) denotes immediate release and graph (4) denotes slow release. Fig. 3 describes dissolution release pattern of Atenolol IR. and Indapamide SR. X axis (1) denotes time in hours and Y axis (2) denotes dissolution in percentage. The graph (3) denotes, immediate release pattern of Atenolol and graph (4) denotes sustained release pattern of Indapamide. Fig.4 describes the shape and dimension of the tablet formulation, wherein (1) denotes 9 mm circular S/C and (2) denotes 10.5 mm circular S/C. While the present invention is described above in connection with preferred or illustrative embodiments, these embodiments are not intended to be exhaustive or limiting of the invention. Rather, the invention is intended to cover all alternatives, modifications and equivalents included within its spirit and scope, as defined by the appended claims. We Claim: 1 A process for preparation of a dual release multilayered tablet comprising of a plurality of layers wherein, the said process comprises: a) preparing a granule of the first active substance from the pulveruleant mixture of the said active substance, one or more disintegrating agents and optionally one or more additives for preparation of a layer for immediate release b) preparing a granule of the second active substance from the pulveruleant mixture of the said second active substance, one or more non¬biodegradable inert polymeric materials and optionally one or more additives suitable for the preparation of layer for prolonged release c) compression of the granules obtained in steps (a) and (b) to obtain a tablet in which first layer results from compression of granules in step (a) and the second layer resulting from step (b) which is compressed on to the first layer 2. A process for preparation of multilayered tablet as claimed in claim 1 wherein the active substance in the upper layer is 4-[2-hydroxy-3-l{(l-methyl ethyl) amino} propoxy] phenyl acetamide (Atenolol). 3. A process for preparation of multilayered tablet as claimed in claim 1 wherein the active substance in the lower layer is chloro-3-sulphanoyl-N-(2-methyl-2,3-dihydro-1 H-indol-1 -yl)benzamide (Indapamide). 4. A process for preparation of multilayered tablet as claimed in claim 1 wherein one or more of diluents, binders, lubricants, colourants and polymers are incorporated. 5. A process for preparation of multilayered tablet as claimed in claim 1 wherein the lubricants are incorporated in concentration of about 1 to 10 % w/w. 6. A process for preparation of multilayered tablet as claimed in claim 1 wherein active substances used singly and concomitantly for the treatment of hypertension wherein their antihypertensive effects are additive and wherein no interference with bioavailability occurs when these agents are given together in single combination as a convenient dosage form for the concomitant administration of these two entities. 7. A process for preparation of multilayered tablet as claimed in claim 1 wherein formulation is prepared by compression spraying technology or encapsulation in a pharmaceutically acceptable presentation. 8. A process for preparation of multilayered tablet as claimed in claim 1 wherein the two active ingredients are provided in the two strengths of (25+1.5 mg) and (50+1.5 mg) respectively for the first and second active ingredients. 9. A process for preparation of multilayered tablet as claimed in claim 1 and 8 wherein tablet for the strength of 25 mg + 1.5 mg is compressed by using punch of s/c 9 mm. 10. A process for preparation of multilayered tablet as claimed in claim 1 and 8 wherein tablet for the strength of 50 mg + 1.5 mg is compressed by using punch s/c 10.5 mm. 11. A process for preparation of multilayered tablet as claimed in claim 1 wherein the said tablet is circular in shape and the two layers are superimposed one on top of the other. 12. A process for preparation of multilayered tablet as claimed in claim 1 wherein the hydrophilic carrier is selected from the group consisting of heteropolysaccharide, xanthan gum, propylene glycol ester, homopolysaccharide, guar gum, gumacacia, gum tragacanth, alkali metal caraginates alginates, cellulose alkyl carboxylate, carboxymethyl cellulose, alkali metal salts of cellulose alkali carboxylate, sodium carboxymethyl cellulose, carboxypolymethylene, hydroxy propyl methyl cellulose, hydroxy propyl cellulose, hydroxy ethyl cellulose, hydroxy ethyl methyl cellulose, polyethylene glycol, polyethylene oxides, alginate oxides, alginate salts, natural polysaccharide, gum arabica and combination thereof. 13. A process for preparation of multilayered tablet as claimed in claim 1 and 12 wherein the hydrophilic carrier is hydroxy propyl methyl cellulose. 14. A process for preparation of multilayered tablet as claimed in claim 1, 12 and 13 wherein the hydroxy propyl methyl cellulose has a viscosity between 5 cps and 100000 cps, a hydroxyl propyl content between 20-80%. 15. A process for preparation of multilayered tablet as claimed in claim 1 and 4 wherein the polymer to excipient ratio vary from 60:40 to 40:60 with respect to low & high molecular weights of the used polymers to excipient. 16. A process for preparation of multilayered tablet as claimed in claim 1 wherein the seal coating membrane is present in the concentration of about 0.01 to 1 % w/w of the weight of the core. 17. A process for preparation of multilayered tablet as claimed in claim 1 wherein the top coating membrane is an aq. coating dispersion in a concentration of about 0.01 to 1 % w/w of the weight of the core. 18. A process for preparation of multilayered tablet as claimed in claim 1 and 17 wherein the aq. coating dispersion further comprises dispersed colors. 19. A process for preparation of multilayered tablet as claimed in claim 1 substantially as herein described with reference to the foregoing example. Dated this the 5th Sept 2003 Dr. Gopakumr G. Nair Agent for the Applicant 14. A process for preparation of multilayered tablet as claimed in claim 1,12 and 13 wherein the hydroxy propyl methyl cellulose has a viscosity between 5 cps and 100000 cps, a hydroxyl propyl content between 20-80% 15. A process for preparation of multilayered tablet as claimed in claim 1 and 4 wherein the polymer to excipient ratio vary from 60:40 to 40:60 with respect to low & high molecular weights of the used polymers to excipient 16. A process for preparation of multilayered tablet as claimed in claim 1 wherein the seal coating membrane is present in the concentration of about 0.01 to 1 % w/w of the weight of the core 17. A process for preparation of multilayered tablet as claimed in claim 1 wherein the top coating membrane is an aqueous coating dispersion in a concentration of about 0.01 to 1 % w/w of the weight of the core 18. A process for preparation of multilayered tablet as claimed in claim 1 and 17 wherein the aqueous coating dispersion further comprises dispersed colors 19. A process for preparation of dual release multilayered tablet as substantially described herein with reference to the foregoing examples 1 to 4. Dated this the 5th day of Sept 2003 To, The Controller of Patents The Patent Office, At Mumbai Dr. Gopakumr G. Nair Agent for the Applicant GOPAKUMAR NAIR ASSOCIATES Nair Baug, Akurli Road, Kandivli (East) Mumbai 400 101

Full Text

FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
COMPLETE SPECIFICATION
[See section 10]
"A PROCESS FOR PREPARATION OF DUAL RELEASE COMBINATION OF CARDIOVASCULAR DRUG, COMPRISING ANTIHYPERTENSIVE AGENT
AND DIURETIC AGENT"
(a) IPCA LABORATORIES LTD.
(b) 48, Kandivli Industrial Estate, Mumbai - 400 067, Maharashtra, India
(c) Indian Company incorporated under the Companies Act 1956
The following specification describes the nature of the invention and the manner in which it is to be performed:
GRANTED
ORIGINAL
5-5-2004

Technical Field of Invention
The present invention relates to a process for dual release of cardiovascular drugs when in combination, wherein one of the active pharmaceutical agents is diuretic in the form of sustained release and the other agent is selective pi blocker in the form of immediate release. Formulation is developed by using any of the technology like multilayer tablet or press coated tablet or drug loading or multirelease granules in capsule.
Background and Prior Art
ABOUT INDAPAMIDE:
> Indapamide is the first of a new class of antihypertensive/diuretics, the indolines.
> Indapamide is a white or almost white powder practically insoluble in water, soluble in alcohol, slightly soluble in ether.
> Indapamide contains not less than 98.0% and not more than the equivalent of 102.0% of (RS)-chloro-3-sulphamoyl-N-(2_methyl-,3-dihydro-lH-indol-l-yl) benzamide, calculated with reference to anhydrous substance.
> Its molecular formula is C16H16CIN3O3S and its molecular weight is 365.8.
> mdapamide is preferentially and reversibly taken up by the erythrocytes in the peripheral blood.
> Indapamide is an extensively metabolized drug with only about 7% of the total dose administered, recovered in the urine as unchanged drug during the first 48hrs after administration.
> Thiazide diuretics increase urinary excretion of Sodium and water by inhibiting Sodium reabsorption in the cortical (thick) portion of the ascending limb of Henle's loop and in the early distal tubules. They also increase excretion of chloride, potassium and to a lesser extent, bicarbonate ions.
ABOUT ATENOLOL:
> Atenolol, a synthetic, Bi- selective (cardio selective) adrenoreceptor blocking agent, maybe chemically described as benzene acetamide, 4-[2y hydroxy -3y - 1 [(1- methyl ethyl) amino] propoxy]- phenyl acetamide.
> (3-blockers are competitive inhibitors and interfere with the action of stimulating hormones on J3 - adrenergic receptors in the nervous system.
> Atenolol is soluble in ethanol, sparingly soluble in water, slightly soluble in dichloromethane, practically insoluble in ether.
> Atenolol contains not less than 99% and not more than 101% of C14H22N2O3 calculated with reference to the dried substance.

> Atenolol is white or almost white crystalline powder which is almost odorless
> Hypertension may be treated with these drugs because of their ability to increase the diameter of the blood to flow less under pressure.
> Blockage of myocardial pi receptors causes sinoatrial brandycardia, suppression of some ectopic pacemakers, decreased force of myocardial contraction, slowing of atrioventricular conduction and atrioventricular refractoriness
The effect to slow the heart rate increases the duration of diastole and thus increases coronary blood flow to the subendocardial region.
Chinese Patent No. CN 13.94.60.4 to Yan Jie claims a slowly release tablet of Indapamide as a single - ingredient formulation with a core and a coating.
Pharmaceutical composition designed in the form of membrane - covered center containing efficient quantity of Indapamide as active substance is descripted in the Russian Patent No, RU 22.Q1.7.51 .granted to Khim.
UK Patent No. GB 2123293, to Molle Daniel and Labeyrie Etienne provides pharmaceutical compositions and preparations comprising a combination of thiachromans with Indapamide (Equivalent patents).
KoreanJPatent.No, 9507207 to Park Sok-Ryon describes a drug composition for treatment of hypertension comprising a pi-blocking agent as a sympathetic nerve blocking agent, a B.1 -blocking agent, a ACE inhibitor and a diuretic. The pi-blocking agent is selected from acebutolol, atenolol, metoprolol, nanolol, propranolol, timolol, penputolol, cateolol or pindolol; the al-blocking agent is selected from prazosin, terazosin or doxazosin; the ACE inhibitor is selected from captopril, enalapril, lisinopril or cilazapril; and the diuretic is selected from bendroflumethiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichlormethiazide, chlorthalidone, Indapamide, metolazone, quinethazone or cyclothiazide.
I However, none of the above patents deal with a combination of anti-hvdpertensive and
I diuretic agents wherein one of the drugs namely the diuretic is suitably formulated for
sustained release while the P-blocker antihypertensive agents is incorporated suitably for
immediate release.

Objectives
^+7 The objective of the present invention to provide immediate release of selective pi. adrenoreceptor blocker by using solubilising agent in an effective manner in - upper layer.
2. A further objective is to provide two drugs in combination therapy to have additive effect in lowering blood pressure in hypertensive patients.
3. Another objective is to reduce the dose of one of the active ingredient by sustaining over a period of time.

4. Further objective is to prolong t max, to reduce peak concentration and to decrease electrolyte disturbances of "drug by sustaining it for a specific period of time.
5. To improve patient compliance.
Summary of the Invention
The present invention relates to a process for dual release cardiovascular drug comprising of two active ingredients which are formulated in a single dosage form providing different release profile. The process involves use of hydroxypropyl methyl cellulose polymer with polyvinyl pyrrolidon which helps to sustain the release of drug over specific period of time and independent of pH.
Detailed Description
The process claimed in present invention comprises formulating in one of the compartment which is the lower layer and which releases the diuretic active agent, Indapamide, over a period of time, ensuring uniform & constant blood levels after absorption and the upper layer which compressed on to the lower layer and which is formulated for immediate release of the (3-blocker, atenolol.
Until now, Indapamide has been orally administered at a dose of 2.5 mg per day by means of an immediate release form .The immediate release formulation leads to; Cmax in just two hours after administration of tablet and these results in the unfavorable hydro electrolytic type or metabolic disturbances. Due to this and in accordance with the international guidelines recommending the use of low doses of antihypertensive agents, new formulation of Indapamide i.e. Indapamide sustained release has-been developed. (P,Clinical Pharmacokinetic, 1999, 37, suppl 1: 13-9) This new formulation eliminates plasma peak, prolongs t max and reduces peak concentration while maintaining minimum concentration. The speed of release must be reproducible and correlated with the blood concentration observed after administration. The new SR formulation which allows reduction in the daily dose of Indapamide from 2.5 to 1.5 mg leads to an improvement in its efficacy or tolerability ratio (Fundamental & Clinical Pharmacology, 2000, 14/2, 139-146). The mechanism employed to control the release of a soluble active principle from the formulation may be by -
1) Controlling diffusion of drug through polymer or diffusion control of drug release by water soluble or insoluble polymer.
2) Dissolution control of drug release via dissolution rate & thickness of membrane barrier coat
3) Dissolution control of drug release by polymer core erosion or polymer coating erosion
4) Controlling the release of drug due to osmotic pressure gradient across semipermeable membrane.
Release of active drug is controlled by embedding drug in matrix of hydrophilic polymers, melted mixture of fat & wax and capillary network of plastic material.

Hydrophilic polymers utilised for building material are sodium carboxy methyl cellulose, hydroxy propyl cellulose, hydroxy ethyl cellulose, polyethylene oxide, polyvinyl pyrollidone, polyvinyl acetate, carboxy polymethlyne, algenic acid, gelatin & natural *ums.
The matrix is compressed by direct compression of the blend of active ingredients and certain hydrophilic carriers, wet granulation containing the drug and hydrophilic matrix material.
rhe diffusion of drug is through a gel formed after swelling of hydrophilic polymer Drought into contact with dissolving liquid (in vitro) or gastrointestinal fluid ( in vivo).
fhe drug release is controlled by gel diffusion barrier that is formed and / or tablet erosion.
rhe drug is incorporated into fat wax granulation by spray congealing in air, blend congealing in an aqueous media with or without aid of surfactant and spray drying Cechnique. The drug embedded into a melt of fat & waxes is released by leaching and /or hlydrolysis as well as dissolution of fats under the influences of enzymes and pH change in GIT in general; primary constituents of fat wax matrix are fatty acid and fatty esters.
Release through plastic matrix is usually delayed because the dissolved drug has to diffuse through capillary network of compacted particles. Commonly used plastic materials are polyvinyl chloride, polyethylene, vinyl acetate /vinyl chloride copolymer, vinylidene chloride, acrylate/methacrylate copolymer, ethyl cellulose, cellulose acetate.
Plastic matrix tablet, in which the active ingredient is embedded in tablet with coherent ind porous skeletal structure, is easily prepared by direct compression of drug with Mastic material provided the plastic material comminuted or granulated to desired oarticle size to facilitate mixing with drug particle.
rhe matrix tablet described in present invention combines in a novel manner, two polymers of different chemical families, which allows a precisely controlled release of ptive principle.
JI a preferred embodiment of the invention, the finished dosage form is accomplished hrough a drug delivery system suitable for oral administration with an immediate release compartment, which contains a compressed blend of an active agent and one or more jolymers, substantially enveloped by an extended release compartment which contains a compressed blend of the active agent and hydrophilic and hydrophobic constituents and substantially enveloped by an optional immediate release compartment, which provides a lose sufficient to exceed the livers metabolic capacity and to maintain therapeutic levels, preferably throughout a 24hr period.

In another embodiment of the present invention, the active agent in the extended release compartment is diffuse out first, resulting in a first order release rate.
As the active agent & soluble polymers in the extended release compartment disintegrate, water will penetrate through the extended compartment and cause the immediate release compartment to expand; creating a bursting effect that further disrupts any remaining integrity of the extended release compartment.
The pharmaceutical preparation of present invention is prepared by press coating technique. It allows the compaction of a dry coating around the tablet core produced on the same machine. The technique is utilized in the present invention as to avoid use of solvent, whether aqueous or organic in nature. Press coated tablet having multiple layer, formed by press coating a core containing a medicinal active ingredient with one or more kind of polymers. Another layer, pressed around the core, containing different medicinal active ingredient. Core of press coated tablet provides sustained release of medicinal active ingredient for a period of 0 to 24 hrs. Other medicinal active ingredient coated on core provides immediate release.
The pharmaceutical preparation of present invention is prepared by coating/loading medicinal active ingredient on the core containing another medicinal active ingredient with different kind of polymers that allows sustained release for period of 0 to 24 hrs. Core is in the form of dried granules, nonpareils pellets or drug crystals or tablet. There are a layer between core and coat that works as barrier for the excipient to interfere in the release of both the medicinal active ingredient. A film coat is applied to the core. The final coated particles are filled into two piece hard gelatin capsule or compacted into tablets.
Example
Example 1
For Lower Layer : (Indapamide)

Lactose 54% w/w
Hydroxy Propyl Methyl Cellulose K 15 M 37% w/w
Polyvinyl pyrrlidone K 30 4.33% w/w
Indapamide 1.0% w/w
Colloidal silicon dioxide 0.2 % w/w
Magnesium stearate 1.0% w/w
Dissolve Indapamide in IPA and add it in mixture of powder except magnesium stearate. Granulation is carried out using aqueous and alcoholic solution in equal proportion.

For Upper Layer:

Atenolol 25% w/w
Magnesium carbonate 36% w/w
Sodium starch Glycollate 5.5% w/w
Colloidal silicon dioxide 200 2.0 w/w
Maize starch 30.5 w/w
Magnesium stearate 0.5 w/w
Lake of sunset yellow 0.5 w/w
Drug is mixed with excipient and colour in Geometric mixing.
(Geometric mixing is process wherein the active along with excipient and colour are
mixed in proportions to achieve uniform distribution of colour and drug in powder
mixture.)
Binding is carried out by starch paste.
The final blend is prepared by mixing the lubricants and glidants with above rasped
granules.
For bilayered tablet, weighing 300 mg (containing 102 mg of upper layer and 198 mg of lower layer) and 8.5 mm in dimension were produced on tablet pressed by two stage pressing procedure as described. The powder of lower layer is compressed by partial pressure in the press first and the upper layer is then added and the press is operated again.
Example 2
For Lower Layer: (Indapamide)

Lactose 55.86% w/w
Hydroxy Propyl Methyl Cellulose K 15 M 36.90% w/w
Polyvinyl pyrrlidone K 30 4.98% w/w
Indapamide 0.76 % w/w
Colloidal silicon dioxide 0.49 % w/w
Magnesium stearate 0.99 % w/w
Mixing of Indapamide, Polyvinyl pyrrolidone and lactose and then wetting of this mixture by means of aqueous or alcoholic solution. The dough is then wet milled, dried and lubricated so as to obtain granulate whose physical characteristic allows good filling of the dies of fast rotary bilayered machine.

For Upper Layer:

Atenolol 22.52 w/w
Microcrystalline cellulose 36% w/w
Lactose 33.78 % w/w
Sodium lauryl sulphate 3.15% w/w
Sodium starch Glycollate 5.85% w/w
Cross carmelose sodium 3.60 % w/w
Colloidal silicon dioxide 200 3.15 w/w
Maize starch 4.5 w/w
Magnesium stearate 0.5 w/w
Lake of sunset yellow 0.45 w/w
Drug is mixed with excipient and colour in Geometric mixing.
(Geometric mixing is process wherein the active along with excipient and colour are
mixed in proportions to achieve uniform distribution of colour and drug in powder
mixture.)
Binding is carried out by starch paste.
The final blend is prepared by mixing the lubricants and glidants with above dried and
rasped granules.
For bilayered tablet, weighing 311 mg (containing 111 mg of upper layer and 200 mg of lower layer) and 9 mm in dimension were produced on tablet pressed by two stage pressing procedure as described. The powder of lower layer is compressed by partial pressure in the press first and the upper layer is then added and the press is operated again.
Example 3
For Core of tablet: (Indapamide)

Lactose 55% w/w
Hydroxy Propyl Methyl Cellulose K 15 M 37.65% w/w
Polyvinyl pyrrlidone K 30 4.07% w/w
Indapamide 0.77 % w/w
Colloidal silicon dioxide 0.50 % w/w
Magnesium stearate 1.01 %w/w
Mixing of Indapamide, polyvinyl pyrrolidone and lactose and then wetting of this mixture by means of aqueous or alcoholic solution. The dough is then wet milled, dried

and lubricated so as to obtain granulate whose physical characteristic allows good filling of the dies of fast rotary tablet in tablet machine.
For press coated Layer:

Atenolol 12.5% w/w
Lactose 62.5 % w/w
Sodium lauryl sulphate 3.0% w/w
Talc 1.0% w/w
Maize starch 16.98 %w/w
Poly vinyl pyrrolidone 3.0 % w/w
Magnesium stearate 1.0 w/w
Iron oxide red 0.15 w/w
Drug is mixed with excipient and colour in Geometric mixing.
(Geometric mixing is process wherein the active along with excipient and colour are
mixed in proportions to achieve uniform distribution of colour and drug in powder
mixture.)
Binding is carried out by starch and poly vinyl pyrrolidone paste.
The final blend is prepared by mixing the lubricants and glidants with above dried and
rasped granules.
For Tablet in tablet, weighing 396.5 mg (containing 200 mg of Press coat and 196.5 mg of core) and 8 mm in dimension for core and 10 mm dimension for press coat, were produced on tablet pressed by two stage pressing procedure as described. The powder of core layer is compressed by first rotary press using 8 mm round punch and then press coat is fill over core in 10 mm circular dimension in following second press machine to obtain tablet in tablet.
Example 4
For core :

Lactose 55% w/w
Hydroxy Propyl Methyl Cellulose K 15 M 37.65% w/w
Polyvinyl pyrrlidone K 30 4.07% w/w
Indapamide 0.77 % w/w
Colloidal silicon dioxide 0.50 % w/w
Magnesium stearate 1.01 %w/w
Binding is given by the aqueous or alcoholic solution with polyvinyl pyrrolidine K30 to the blend of lactose, hydroxy propyl methyl cellulose K 15 M and Indapamide. The

dough is then wet milled, dried and lubricated so as to obtain granulate whose physical characteristic allows good filling of the dies of fast rotary tablet in tablet machine.
For COAT
1) Seal Coat:

Titanium dioxide 0.18
Hydroxy Propyl Methyl Cellulose 15 cps 0.92
Talc 0.092
Ethyl cellulose 0.18
PEG 400 0.01
IPA q.s.
Methylene chloride q.s.
Add Titanium dioxide & talc into the dispersion of hydroxyl porpyl methyl cellulose 15 cps & ethyl cellulose in IPA. Mix it well and coat above solution over the core tablet till 10 mg weight gain achieve.
2) Drug Loading :

Atenolol 2.5-5.05%
OY-IN 58901 3.2%
Sodium lauryl sulphate 0.3%
Water q.s.
Disperse OY-IN -58901 in water and then add atenolol under vigorous stirring. To this solution add SLS & mix well. Use solution for drug loading tablet till 75-80 mg weight gain achieved.
3) Final coat:

OY-IN 58901 0.16%
Methylene chloride q.s.
Water q.s.
Finally coat the tablet using dispersion of OY-IN 58901 in IPA and methylene chloride.

Description of Drawings
Fig.l describes the sustained release of Indapamide. X axis (1) denotes time in hours and Y axis (2) denotes dissolution in percentage. The graph indicates the sustained release pattern of Indapamide from the combination in dissolution percentage.
Fig.2 describes comparison between immediate and sustained release form of Indapamide tablet. As in Fig.l, the X axis (1) denotes time in hours and Y axis (2) denotes dissolution in percentage. The graph (3) denotes immediate release and graph (4) denotes slow release.
Fig. 3 describes dissolution release pattern of Atenolol IR. and Indapamide SR. X axis (1) denotes time in hours and Y axis (2) denotes dissolution in percentage. The graph (3) denotes, immediate release pattern of Atenolol and graph (4) denotes sustained release pattern of Indapamide.
Fig.4 describes the shape and dimension of the tablet formulation, wherein (1) denotes 9 mm circular S/C and (2) denotes 10.5 mm circular S/C.
While the present invention is described above in connection with preferred or illustrative embodiments, these embodiments are not intended to be exhaustive or limiting of the invention. Rather, the invention is intended to cover all alternatives, modifications and equivalents included within its spirit and scope, as defined by the appended claims.

We Claim:
1 A process for preparation of a dual release multilayered tablet comprising of a
plurality of layers wherein, the said process comprises:
a) preparing a granule of the first active substance from the pulveruleant mixture of the said active substance, one or more disintegrating agents and optionally one or more additives for preparation of a layer for immediate release
b) preparing a granule of the second active substance from the pulveruleant mixture of the said second active substance, one or more non¬biodegradable inert polymeric materials and optionally one or more additives suitable for the preparation of layer for prolonged release
c) compression of the granules obtained in steps (a) and (b) to obtain a tablet in which first layer results from compression of granules in step (a) and the second layer resulting from step (b) which is compressed on to the first layer

2. A process for preparation of multilayered tablet as claimed in claim 1 wherein the active substance in the upper layer is 4-[2-hydroxy-3-l{(l-methyl ethyl) amino} propoxy] phenyl acetamide (Atenolol).
3. A process for preparation of multilayered tablet as claimed in claim 1 wherein the active substance in the lower layer is chloro-3-sulphanoyl-N-(2-methyl-2,3-dihydro-1 H-indol-1 -yl)benzamide (Indapamide).
4. A process for preparation of multilayered tablet as claimed in claim 1 wherein one or more of diluents, binders, lubricants, colourants and polymers are incorporated.
5. A process for preparation of multilayered tablet as claimed in claim 1 wherein the lubricants are incorporated in concentration of about 1 to 10 % w/w.
6. A process for preparation of multilayered tablet as claimed in claim 1 wherein active substances used singly and concomitantly for the treatment of hypertension wherein their antihypertensive effects are additive and wherein no interference with bioavailability occurs when these agents are given together in single combination as a convenient dosage form for the concomitant administration of these two entities.
7. A process for preparation of multilayered tablet as claimed in claim 1 wherein formulation is prepared by compression spraying technology or encapsulation in a pharmaceutically acceptable presentation.
8. A process for preparation of multilayered tablet as claimed in claim 1 wherein the two active ingredients are provided in the two strengths of (25+1.5 mg) and (50+1.5 mg) respectively for the first and second active ingredients.
9. A process for preparation of multilayered tablet as claimed in claim 1 and 8 wherein tablet for the strength of 25 mg + 1.5 mg is compressed by using punch of s/c 9 mm.
10. A process for preparation of multilayered tablet as claimed in claim 1 and 8 wherein tablet for the strength of 50 mg + 1.5 mg is compressed by using punch s/c 10.5 mm.

11. A process for preparation of multilayered tablet as claimed in claim 1 wherein the said tablet is circular in shape and the two layers are superimposed one on top of the other.
12. A process for preparation of multilayered tablet as claimed in claim 1 wherein the hydrophilic carrier is selected from the group consisting of heteropolysaccharide, xanthan gum, propylene glycol ester, homopolysaccharide, guar gum, gumacacia, gum tragacanth, alkali metal caraginates alginates, cellulose alkyl carboxylate, carboxymethyl cellulose, alkali metal salts of cellulose alkali carboxylate, sodium carboxymethyl cellulose, carboxypolymethylene, hydroxy propyl methyl cellulose, hydroxy propyl cellulose, hydroxy ethyl cellulose, hydroxy ethyl methyl cellulose, polyethylene glycol, polyethylene oxides, alginate oxides, alginate salts, natural polysaccharide, gum arabica and combination thereof.
13. A process for preparation of multilayered tablet as claimed in claim 1 and 12 wherein the hydrophilic carrier is hydroxy propyl methyl cellulose.
14. A process for preparation of multilayered tablet as claimed in claim 1, 12 and 13 wherein the hydroxy propyl methyl cellulose has a viscosity between 5 cps and 100000 cps, a hydroxyl propyl content between 20-80%.
15. A process for preparation of multilayered tablet as claimed in claim 1 and 4 wherein the polymer to excipient ratio vary from 60:40 to 40:60 with respect to low & high molecular weights of the used polymers to excipient.
16. A process for preparation of multilayered tablet as claimed in claim 1 wherein the seal coating membrane is present in the concentration of about 0.01 to 1 % w/w of the weight of the core.
17. A process for preparation of multilayered tablet as claimed in claim 1 wherein the top coating membrane is an aq. coating dispersion in a concentration of about 0.01 to 1 % w/w of the weight of the core.
18. A process for preparation of multilayered tablet as claimed in claim 1 and 17 wherein the aq. coating dispersion further comprises dispersed colors.
19. A process for preparation of multilayered tablet as claimed in claim 1 substantially as herein described with reference to the foregoing example.
Dated this the 5th Sept 2003
Dr. Gopakumr G. Nair
Agent for the Applicant

14. A process for preparation of multilayered tablet as claimed in claim 1,12 and 13 wherein the hydroxy propyl methyl cellulose has a viscosity between 5 cps and 100000 cps, a hydroxyl propyl content between 20-80%
15. A process for preparation of multilayered tablet as claimed in claim 1 and 4 wherein the polymer to excipient ratio vary from 60:40 to 40:60 with respect to low & high molecular weights of the used polymers to excipient
16. A process for preparation of multilayered tablet as claimed in claim 1 wherein the seal coating membrane is present in the concentration of about 0.01 to 1 % w/w of the weight of the core
17. A process for preparation of multilayered tablet as claimed in claim 1 wherein the top coating membrane is an aqueous coating dispersion in a concentration of about 0.01 to 1 % w/w of the weight of the core
18. A process for preparation of multilayered tablet as claimed in claim 1 and 17 wherein the aqueous coating dispersion further comprises dispersed colors
19. A process for preparation of dual release multilayered tablet as substantially described herein with reference to the foregoing examples 1 to 4.
Dated this the 5th day of Sept 2003

To,
The Controller of Patents
The Patent Office,
At Mumbai

Dr. Gopakumr G. Nair
Agent for the Applicant GOPAKUMAR NAIR ASSOCIATES
Nair Baug, Akurli Road, Kandivli (East) Mumbai 400 101

Documents:

927-mum-2003-abstract(05-05-2004).pdf

927-mum-2003-abstract(5-5-2004).doc

927-mum-2003-cancelled pages(05-05-2004).pdf

927-mum-2003-claims(granted)-(05-05-2004).pdf

927-mum-2003-claims(granted)-(5-5-2004).doc

927-mum-2003-correspondence(06-07-2004).pdf

927-mum-2003-correspondence(ipo)-(03-04-2007).pdf

927-mum-2003-drawing(05-05-2004).pdf

927-mum-2003-form 1(08-09-2003).pdf

927-mum-2003-form 1(10-10-2003).pdf

927-mum-2003-form 19(10-10-2003).pdf

927-mum-2003-form 2(granted)-(05-05-2004).pdf

927-mum-2003-form 2(granted)-(5-5-2004).doc

927-mum-2003-form 26 (05-04-2003).pdf

927-mum-2003-form 3 (05-05-2004).pdf

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Patent Number

205470

Indian Patent Application Number

927/MUM/2003

PG Journal Number

43/2008

Publication Date

24-Oct-2008

Grant Date

03-Apr-2007

Date of Filing

08-Sep-2003

Name of Patentee

M/S. IPCA LABORATORIES LIMITED

Applicant Address

48, KANDIVLI INDUSTRIAL ESTATE, MUMBAI - 400 067, MAHARASHTRA, INDIA.

Inventors:

#	Inventor's Name	Inventor's Address
1	THEMBALATH, RAMACHANDRAN	6/35, PRAKASH CO. HOUSING SOCITY, RELIEF ROAD, SANTACRUZ (WEST), MUMBAI - 400 054.
2	BANSAL, YATISH KUMAR	FLAT NO. 3,SIRAS VILLA, PLOT NO. 40,SAI BABA PARK, EVERSHINE NAGAR, MALAD(WEST), MUMBAI 400 064
3	TAWDE VAISHALI MANISH	B-2, 14TH FORJETT TERRACE, OPP. BHATYA HOSPITAL, GRANT ROAD, MUMBAI 400 036
4	DODIYA SHAMSUNDER SATYANARAYAN	B. NO.53, GANGOTRI, SURANANAGAR, JALNA ROAD, AURANGABAD, MAHARASHTRA-431 001,
5	PHADKE MANISHA UMESH	B/104, SHIVYOG CO-OP HSG. SOCIETY, SHIVALABH ROAD, SAMBHAJI NAGAR, DAHISAR(EAST), MUMBAI 400 068.

PCT International Classification Number

A 61 K 31/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA