Title of Invention	DELAYED RELEASE ASPIRIN FORMULATION & A PROCESS FOR ITS PREPARATION
Abstract	The invention disclosed in this application relates to an improved pharmaceutical formulation containing aspirin, which is useful for the prevention of cardiovascular diseases such as stroke and decrease in recurrence of a heart attack and other heart problems, and is protected against gastric juices, in the form of pellets filled into hard gelatin capsules or compressed into tablets. The pellets have an inert core comprising of sucrose, starch, and an active layer having drug along with alkali compound and an antiadherent, an intermediate layer comprising of a hydrophilic polymer along with an antiadherent and finally a coating of an enteric layer. The invention also relates to a process for the preparation of the above-defined improved pharmaceutical formulation containing aspirin.

Title of Invention

DELAYED RELEASE ASPIRIN FORMULATION & A PROCESS FOR ITS PREPARATION

Abstract

The invention disclosed in this application relates to an improved pharmaceutical formulation containing aspirin, which is useful for the prevention of cardiovascular diseases such as stroke and decrease in recurrence of a heart attack and other heart problems, and is protected against gastric juices, in the form of pellets filled into hard gelatin capsules or compressed into tablets. The pellets have an inert core comprising of sucrose, starch, and an active layer having drug along with alkali compound and an antiadherent, an intermediate layer comprising of a hydrophilic polymer along with an antiadherent and finally a coating of an enteric layer. The invention also relates to a process for the preparation of the above-defined improved pharmaceutical formulation containing aspirin.

Full Text	INTRODUCTION The invention disclosed in this application relates to an importing nulation containing aspirin. The formulation is useful for the prevention of cardiovascular diseases such as stroke and decrease in recurrence of a heart attack and other heart related problems. The formulation does not react with gastric juices thereby enhancing its pharmaceutical efficacy. The formulation may be in the form of tablets & capsules. The invention also relates to a process for the preparation of above said formulation. BACKGROUND OF THE INVENTION Aspirin or acetyl salicylic acid is a well-known therapeutic agent, which has been employed for many years as an analgesic as well as for its antipyretic and anti-inflammatory properties. It is also well known that aspirin is an acidic drug which can cause gastric distress. Such gastric distress is caused primarily because the aspirin particles do not dissolve and such particles attach to the walls of the stomach. Equally well known today is the significant role which aspirin plays in the successful treatment and management of two of the most common major diseases that afflict the world's population, i.e. arthritis and heart attacks. According to the PDR (Physicians Desk Reference) Asprin also temporarily relieves the minor aches and pains of arthritis, muscle aches, colds, flu and menstrual discomfort. In some patients, a small daily dose of aspirin may be used to ensure sufficient blood flow to the brain and prevent stroke. Aspirin may also be taken to decrease recurrence of a heart attack or other heart problems. In addition, the beneficial effect of aspirin on the human immune system may make it a promising drug for possible use in the treatment of cancer, AIDS, cataracts, allergies and a number of other diseases in which the immune system is involved These valuable pharmacological properties have made aspirin the most widely used drug in the world. "It is also being studied for cancer prevention'* as per the National Cancer Institutes Cancer GOV Dictionary. As per AIDS treatment news no. 109- dated August 17,1990, Laboratory studies have suggested that reducing certain inflammatory reactions as aspirin does, may affect the pathogenesis of the disease, improving some immune functions, and possibly showing the replication of HIV by reducing the levels of certain chemical messengers which may trigger the growth of the Virus. Nevertheless, it has been documented that aspirin does possess a number of undesirable side effects, although the true severity of these side effects has not been recognized until recently. For example, being a sparingly soluble substance (only 0.33 gm in 100 ml of water), the undissolved particles of aspirin will normally adhere to the gastrointestinal mucosa Such adherence can cause lesions, gastric and duodenal ulcers and bleeding. These undesirable side effects are usually persistent and cumulative and they occur in a number of patients in which aspirin is used as a ther^y. To meet the above situation and to make good use of the activity of aspirin, delayed release aspirin pellets have been developed to reduce gastric irritation by not releasing the drug in the stomach and releasing the drug in intestine. The corrosive effects that aspirin may display on the gastrointestinal mucosa were recognized early in the history of aspirin therapy. Consequently, attempts to produce a soluble form of this drug have been made almost continuously since then. As far as in 1903, Prior art U.S. Pat. No. 740,703 reveals efforts were made to develop the drug, exclusively on the preparation of various soluble salts, lithium, sodium, potassium, calcium and magnesium as well as with organic amines and amino acids (lysine and ornithine). The main disadvantages of these particular salt products were that, in contrast to the aspirin itself, they were not stable. In order to make aspirin more useful as an oral dosage form for its use as preventive agent in Cardiovascular diseases such as stroke and decrease in recurrence of a heart attack and other heart problems, it is necessary to protect it against gastric juices v^ich are acidic in nature. Such a protection will enable the formulation to release aspirin in the intestine. To prevent contact of aspirin with gastric juices, the formulation is to be enteric coated. In US patent No: 4,775,536 an enteric coated aspirin tablet and process for making is described, in v^ich the core of the tablet is coated with enteric coating layer of film forming polymers and an over coat layer of non enteric film forming polymers. The drawback of aqueous enteric coating of aspirin tablet may lead to the hydrolysis/cleavage of parent molecule increasing the free salicylic acid content during storage period. In US Patent No: 5,576,024 a buffered aspirin tablet composed of aqueous based polymer coated aspirin, a buffering system and a hydrophilic gel forming matrix material was described, in vAdch the buffering system and matrix material, provide a microenvironment of pH 5.0 thus increasing the solubility of the aspirin. Though the solublity may show improvement, the formulation can still cause gastric irritation. The US Patent No: 5,582,837 alkyl -substituted cellulose based sustained release oral dosage forms are described. Sustained release oral dosage form comprise a tablet or capsule containing a plurality of particles of solid state dispersed in alkyl cellulose such as hydroxyethylcellulose or hydroxypropylcellulose. The tablet / c^sule upon ingestion disintegrates to disperse the particles into stomach vAievQ they imbibe water to cause them swell thus enhancing their retention in stomach. Imbibed water dissolves the drug entrj^ped in the particles and the resulting solution diffuses from the dispersed particles, assuring no solid drug contacts the mucosal tissue. The US Patent No: 5,603,957 relates to a controlled release microtablets & capsules of acetyl salicylic acid coated with mixture of cellulose film formers, thus controlling release of acetyl salicylic acid throughout the length of gastrointestinal tract. JPO 2001-139469 dated 22/05/01, a novel sustained release preparation composition consists of Aspirin with coating material, which would be used in cardiovascular diseases, primarily a process of mixing sustained release particles, excipient and homogenizing them, used for oral adminstration. In all the above four patents the drug is released over a period of time , the drug in low doses may not provide immediate relief In US patent No: 5,683,721 a galenic preparation of therapeutic composition containing aspirin as sublingual administration was described, in which the active ingredient is in micro administration of aspirin may cause unpleasant taste and further keeping the large size dosage form beneath the tongue may cause discomfort to the consxmier. In US Patent No: 5,723,453 a stabilized , sodium free, alkaline and aspirin combination compound is described, in v^ch the compoimd is readily soluble in a preselected fluid i.e.water and produces potassium acetyl salicylate. This combination compound contains aspirin (USP 60 # mesh) within a range 325 -1000 mg per unit dose and alkaline compound between 250 -3000 mg per unit dose, having a pH generally within a range of between about 8.0 and about 10.0 and being present in a molar amount which is greater than a molar amount required to neutralize aspirin granules. As the tablet is effervescent and has to be dissolved in a large amount of water before administration, some users may find inconvenience and hence non- acceptable. In J^anese Publication Nbr 09-263538- 07/10/97 it is provided a stable pharmaceutical composition based on acetylsalicylic acid and tochoperol, for peroral administration, in treatment and prevention of cardiovascular and cancer ther^y. The pharmaceutical composition is based on capsule and is prepared by mixing with usually used additive used as excepients. The product appears to be a powder c^sule, which can cause gastric irritation. In our continued efforts to provide valuable and effective drug for effective prevention of cardiovascular disease such as stroke and decrease in recurrence of a heart attack and other heart problems, we directed our research towards developing dosage form aspirin which will have no effect by the gastric juices The present invention accordingly relates to a delayed release oral dosage form of aspirin which prevents gastric irritation in individuals taking it as well as a process for preparing such forms of aspirin Delayed release composition resists the action of the acidic stomach fluids on the drug. The coating can protect the gastric mucosa from the irritating effects of aspirin. However this coating dissolves in the neutral or alkaline milieu of the intestine and active ingredients become available for absorption into blood stream. Accordingly, the main objective of the present invention is to provide an improved stable formulation containing aspirin useful for the prevention of cardiovascular diseases such as stroke and decrease in recurrence of a heart attack and other heart problems, v^toch will be resistant to gastric juices Another objective of the present invention is to provide an improved stable formulation containing aspirin useful for the prevention of cardiovascular diseases such as stroke and decrease in recurrence of a heart attack and other heart problems, \\4iich delays release of aspirin in the stomach and facilitate immediate release in intestine for speedy absorption as against delayed release in the prior art. Yet another objective of the present invention is to provide a method for the preparation of an improved and stabilized formulation containing aspirin useful for the prevention of cardiovascular diseases such as stroke and decrease in recurrence of a heart attack and other heart problems, which will be resistant to gastric juices and will dissolve in neutral to alkaline media and has good stability. We have developed this invention based on our finding that if the core containing aspirin is effectively protected its stability as well as its resistance to the action of gastric juices can be enhanced. Accordingly, the present invention provides an improved stable pharmaceutical formulation containing aspirin wiiich is resistant to acid media in stomach and dissolves in neutral to alkaline media in intestines and having good stability and useful for the prevention of cardiovascular disease and wiiich comprises a) an inert core comprising ofsucrose and starch. b) a coating on the inert core with a drug layer comprising a mixture of aspirin and an alkaline agent or a mixture thereof and forming the resulting mixture into pellets or tablets. c) the drug layer comprising aspirin and an alkaline agent , a diluent, an antiadherent compound, binder, a preservative & a hydrophilic polymer. 1 d) an intermediate layer containing a hydrophilic polymer with a diluent, an antiadherent agent and a solvent. e) the resulting pellets / tablets having a coating of an enteric layer. If desired the pellets /tablets thus formed can be enc^sulated by conventional methods. The amount of sucrose & starch in the inner core may be intherangeof 2.00 to 20.00 mg per c^sule / tablet and from 1.00 to 10.00 mg per c^sule / tablet, respectively, more preferably, the amount ranges from 4.00 to 14.00 mg per capsule / tablet and 2.00 to 8.00 mg per cj^)sule / tablet respectively. The drug layer contains Aspirin in the range of 50.00 to 400.00 mg per c^sule / tablet preferably in the range of 75.00 mg to 325.00 mg per capsule / tablet The alkaline agent in the drug layer may be selected from magnesium oxide, magnesium carbonate, aluminum hydroxide, magnesium hydroxide, calcium carbonate, sodium carbonate, potassium carbonate and the like .The amount of alkaline agent used ranges from 5.00 to 60.00 mg per c^sule / tablet, more preferably 10.00 to 50.00 mg per capsule / tablet. The diluent used may be selected from microcrystalline cellulose. Lactose, Mannitol, dextrose, and the like .The amount of diluent employed in the active core of drug layer, ranges from 5.00 to 60.00 mg per capsule / tablet, preferably 8.00-40.00mg per cq)sule / tablet The drug layer may contain an anti-adherent agent selected from talc, aerosol, calcium stearate and the like. The amount ranges from 1.00 to 20.00 mg per capsule / tablet, more preferably 2.00 to 15.00 mg per c^sule / tablet The binder when used ay be selected from Hydroxypropyl methylcellulose, Hydroxy ethyl cellulose. Polyvinylpyrrolidone and the like .The amount ranges from 2.00 to SO.OOmg per capsule / tablet, more preferably 4.00 to 25.00mg per capsule / tablet The preservative when used may be selected from sodium benzoate, sodium metabisulfite, sodium sulfite, sodiimi bisulfite and the like. The amount ranges from 0.20 to S.OOmg per c^sule / tablet, more preferably 0.50 to 4.00 mg per capsule / tablet. The binder \^en used may be dissolved in an organic solvent which may be selected from Isopropyl alcohol, methylene chloride, ethyl alcohol, acetone and the like or a mixture thereof. The polymer employed in the intermediate layer may be selected from polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxy propyl cellulose, sodium carboxy methyl cellulose, carboxy methyl cellulose and the like or a mixture thereof The amount of polymer employed in the intermediate layer ranges from 2.00 to 50.00 mg per capsule / tablet , more preferably 5.00 to 40.00 mg per c^sule / tablet The diluent when used in the Intermediate layer may be selected from microcrystalline cellulose, lactose, mannitol and the like .The amount ranges from 2.00 to 50.00mg per capsule / tablet, more preferably 3.00 to 40.00mg per c^sule / tablet. The anti adherent agent when used may be selected from talc, aerosil, calcium carbonate and the like .The amount ranges from 1.00 to 20.00 mg per capsule / tablet more preferably 2.00 to 10.00 mg per cqjsule / tablet. The organic solvent used in intermediate layer is selected from isopropyl alcohol, ethyl alcohol, acetone, methylene chloride and the like or mixture thereof is used to dissolve the polymer. For the enteric coating , the polymer used may be selected from cellulose derivatives and acrylic derivatives. The cellulose derivatives are selected from Hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate and the like and the acrylic derivatives are selected from Eudragit L 100-55 and the like. The amount of polymer used ranges from 10.00 to 100.00 mg per capsule / tablet, more preferably 20.00 to 80.00 mg per cqDsule / tablet The plasticizer used may be selected from phthalate derivatives such as diethyl phthalate, dibutyl phthalate, dioctyl phthalate and the like and of fatty alcohol derivatives such as cetyl alcohol, stearyl alcohol and the like or mixture of phthalate & fatty alcohol. The amount of plasticizer used ranges from 3.00 to SO.OOmg per capsule / tablet, more preferably 4.00 to 24.00mg per capsule / tablet. The antiadherent when used may be selected from talc, colloidal silicon dioxide and the like and its amount ranges from 2.00 to 16.00mg per capsule / tablet, more preferably 3.00 to 12.00mg per capsule / tablet. The coloring agent for the enteric coating is selected from titanium dioxide, iron oxide and mixture thereof .The amount of coloring agent ranges from 0.025 to 4.00mg per capsule / tablet more preferably 0.05 to 3.00 mg per capsule / tablet. The organic solvent used in the enteric coating used to dissolve the polymer is selected from isopropyl alcohol, ethyl alcohol, acetone, methylene chloride and the like or mixture thereof. According to another feature of the invention, there is provided a process for the preparation of pharmaceutical formulation containing aspirin which is resistant to acid media and dissolves in neutral to alkaline media and having good stability and useful for the prevention of cardiovascular disease which comprises : a) forming an inert core comprising of sucrose and starch. b) Providing a coating on the inert core with a drug layer comprising a mixture of aspirin and an alkaline agent or a mixture thereof an alkaline agent , a diluent, an antiadherent compound , binder , a preservative & a hydrophilic polymer and forming the resulting mixture into pellets or tablets . c) Providing an intermediate layer containing a hydrophilic polymer with a diluent, an antiadherent agent and a solvent. d) Providing the resulting pellets / tablets with a coating of an enteric layer., if desired e) encapsulating the pellets / tablets thus formed by conventional methods. In a preferred embodiment of the present invention the amount of sucrose, starch used in the inert core range from 2.00 to 20.00 mg per c^sule / tablet and from 1.00 to 10.00 mg per c^sule /tablet, respectively, more preferably, the amount ranges from 4.00 to 14.00 mg per capsule / tablet and 2.00 to 8.00 mg per capsule / tablet respectively. The drug layer contains aspirin in the range from 50.00 to 400.00 mg per c^sule/ tablet, preferably in the range of 75.00 mg to 325.00 mg per capsule / tablet. In the drug layer alkaline agent is selected from magnesium oxide, magnesium carbonate, aluminum hydroxide, magnesium hydroxide, calcium carbonate, sodium carbonate, potassium carbonate. The amount of alkaline agent used ranges from 5.00 to 60.00 mg per cq)sule / tablet, more preferably 10.00 to 50.00 mg per capsule / tablet. The diluent used is selected from microcrystalline cellulose. Lactose, Mannitol, dextrose, and the like. The amount of diluent employed in the drug layer ranges from 5.00 to 60.00 mg per c^sule / tablet preferably 8.00-40.00 mg per c^sule / tablet. The anti-adherent agent is selected from talc, aerosol, calcium stearate and the like and its amount ranges from 1.00 to 20.00 mg per c^sule / tablet, more preferably 2.00 to 15.00 mg per capsule / tablet. The binder used is selected from Hydroxypropyl methylcellulose. Hydroxy ethyl cellulose. Polyvinylpyrrolidone and the like and its amount ranges from 2.00 to 30.00mg per c^sule / tablet more preferably 4.00 to 25.00mg per capsule / tablet. The preservative vAien employed is selected from sodium benzoate, sodium metabisulfite, sodium sulfite, sodium bisulfite and the like and its amount ranges from 0.20 to 5.00mg per c^sule / tablet, more preferably 0.50 to 4.00 mg per capsule / tablet The binder is dissolved in organic solvent selected from Isopropyl alcohol, methylene chloride, ethyl alcohol, acetone and the like or a mixture thereof The polymer employed in the Intermediate layer is selected from polj^nylpyrrolidone, hydroxypropyl methylcellulose, hydroxy propyl cellulose, sodium carboxy methyl cellulose, carboxy methyl cellulose and the like or a mixture thereof. The amount of polymer employed in intermediate layer ranges from 2.00 to 50.00 mg per c^sule / tablet, more preferably 5.00 to 40.00.mg per c^sule / tablet. The diluent used in the Intermeidate layer is selected from microcrystalline cellulose, lactose, maimitol and the like .The s amount ranges from 2.00 to SO.OOmg per c^sule / tablet, more preferably 3.00 to 40.00mg per capsule/ tablet The anti adherent agent is selected from talc, aerosil, calcium carbonate and the like.The amount ranges from 1.00 to 20.00 mg per c^sule / tablet more preferably 2.00 to 15.00 mg per c^sule / tablet The organic solvent such as isopropyl alcohol, ethyl alcohol, acetone, methylene chloride and the like or mixture thereof is used to dissolved the polymer. The enteric coating of the polymer is selected from cellulose derivatives and acrylic derivatives, v^^erein the cellulose derivatives are selected from Hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate and the like and the acrylic derivatives are selected from Eudragit L 100-55 and the like. The amoimt of polymer used ranges from 10.00 to lOO.OOmg per capsule or tablet, more preferably 20.00 to SO.OOmg per c^sule/ tablet. The plasticizer is selected from phthalate derivatives such as diethyl phthalate, dibutyl phthalate, dioctyl phthalate and the like and of fatty alcohol derivatives such as cetyl alcohol, stearyl alcohol and the like or mixture of phthalate & fatty alcohol. The amount of plasticizer used ranges from 3.00 to 30.00mg per capsule / tablet, more preferably 4.00 to 24.00 mg per c^sule/ tablet. The antiadherent used is selected from talc, colloidal silicon dioxide and the like and its amount ranges from 2.00 to 16.00mg per c^sule / tablet, more preferably 3.00 to 12.00mg per capsule/ tablet. The enteric coating contains a coloring agent such as titanium dioxide, iron oxide and mixture thereof. And its amount of coloring agent ranges from 0.025 to 4.00mg per capsule / tablet, more preferably 0.05 to 3.00 mg per capsule / tablet. The Organic solvent used in the enteric coating is selected from isopropyl alcohol, ethyl alcohol, acetone, methylene chloride and the like or mixture thereof is used to dissolve the polymer. The enteric coating may be applied on to intermediate layered pellets in mechanized perforated coating pan, or using any suitable coating equipment. Enteric coated pellets may be filled into hard gelatin c^sules or compressed into tablets in a conventional maimer and may be packed into a moisture resistant primary pack. For the long term stability of formulation, water content of the pellets in formulation is kept below 2.0% It would be observed that the active ingredient was available by using a buffered environment by enc^sulating the inert core surrounded by drug layer followed by intermediate layer and covered by enteric layer, that makes the drug stable over the entire shelf life of the product to enable it to pass from acidic layer in stomach to the alkali/neutral layer in the intestine. By doing so. Not only the stabilization of the drug is achieved but it also improve the solubility of drug, which facilitate the maximxjm bioavailability after the administration of dosage form. Another advantage of preparing the dosage form in the form of pellets is that there are less chances of degradation of the product, as it is an individual discrete particle unlike the tablets.. The pellets are enc^sulated or compressed into tablets with a low moisture content vviiich avoids the degradation of aspirin due to moisture. The incorporation of preservatives in the formulation makes the product free of any additional microbial burden throughout its shelf life. The invention is described in detail in the Examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention. It should be noted that in all the Examples the pellets formed according to the invention can be enc^sulated by any conventional method. EXAMPLE 1 Inert cores were prepared from sucrose and starch with the help of sugar syrup in a coating pan. The polymer solution was prepared by dissolving polyvinylpyrrolidone in isopropyl alcohol. Aspirin was mixed with aluminium hydroxide, sodium benzoate, microcrystaline cellulose powder, talc and is micronised. This micronized drug mixture was applied onto the inert core by dusting process employing polymer solution prepared as above as binder intermittently in conventional coating equipment Talc 2.00 Isopropyl alcohol* 25,00 AVi.t,ui^iOii Hydroxypropyl methylcellulose was dissolved in a solvent mix of isopropyl alcohol and methylene chloride and kept for about 2 hours for complete dissolution. Microcrystaline cellulose and talc were passed through 100# and dispersed in hydroxypropyl methylcellulose solution. The dispersion was applied to drug pellets employing a perforated coating pan. d) Composition of enteric coating mg/capsule Hydroxypropyl methylcellulose phthalate H55S 25.00 Diethyl phthalate 5.00 Talc 3.00 Isopropyl alcohol* 650.00 Methylene chloride* 1000.00 Titanium dioxide 1.00 Diethyl phthalate was dissolved in a solvent mixture of isopropyl alcohol and methylene chloride and, Hydroxypropyl methylcellulose phthalate H55S was added slowly and dissolved until a clear solution was obtained Titanium dioxide and talc were shifted through 200# and dispersed in this polymer solution. This dispersion was ^plied on intermediate layered pellets employing a perforated coating equipment Used in the process but the solvents ev^ourate during the processing and in the final pellets they are only present in traces within acceptable regulatory limits. EXAMPLE 2 a) Composition of Inert Core: mg/C^sule Sucrose 11.00 Starch 7.00 b) Composition of drug layer mg/c^sule Aspirin 150.00 magnesium hydroxide 35.00 Talc 10.00 Micro crystalline cellulose powder 25.00 Hydroxypropyl methylcellulose E5 10.00 Isopropyl alcohol 20.00 Methylene chloride 30.00 Inert cores were prepared from sucrose and starch with the help of sugar syrup in a coating pan. The Polymer solution was prepared by dissolving hydroxypropyl methylcellulose in a solvent mix of isopropyl alcohol and methylene chloride. Aspirin was mixed with magnesium hydroxide, sodium metabisulfite, microcrystaline cellulose powder, talc and the mixture was micronised. This micronized drug mixture was applied onto inert core by dusting process employing polymer solution prepared as above as binder intermittently in suitable coating equipment C) Composition of Intermediate layer mg/capsule Hydroxypropyl methylcellulose E5 32.00 Microcrystaline cellulose 10.00 Talc 4.00 Isopropyl alcohol 50.00 Methylene chloride* 80.00 Hydroxypropyl methylcellulose E5 was dissolved in a solvent mix of isopropyl alcohol and methylene chloride and kept for about 2 hours. Microcrystaline cellulose and talc were passed through 100# and dispersed in hydroxypropyl methylcellulose solution. This dispersion was applied onto drug pellets employing a conventional coating equipment. d) Composition of enteric coating mg/c^sule Hydroxypropyl methylcellulose phthalate H 55 S 58.00 Diethyl phthalate 11.00 Talc 10.00 Isopropyl alcohol* 1300.00 Methylene chloride* 2500.00 Titanium dioxide 2.50 Diethyl phthalate was dissolved in a solvent mixture of isopropyl alcohol and methylene chloride and Hydroxypropyl methylcellulose phthalate H55 until a clear solution was obtained. Titanium dioxide and talc are sifted through 200# and dispersed in the polymer solution. Applied the dispersion on intermediete layered pellets employing conventional coating equipment. Used in the process but the solvents ev^ourate during the processing and in the final pellets they are only present in traces within acceptable regulatory limits. EXAMPLE 3 a) Composition of Inert Core: mg/C^sule Sucrose 6.00 Starch 4.00 b) Composition of drug layer mg/capsule Aspirin 75.00 Calcium carbonate 15.00 Sodium sulfite 1.00 Talc 5.00 Maimitol 5.00 Hydroxypropyl methylcellulose E5 5.00 Isopropyl alcohol 10.00 Methylene chloride 15.00 Inert cores were prepared fi-om sucrose and starch with the help of sugar syrup in a coating pan. Polymer solution was prepared by dissolving hydroxypropyl methylcellulose E5 in a solvent mix of isopropyl alcohol and methylene chloride. Aspirin was mixed with calcium carbonate, sodium sulfite, marmitol, talc and the mixture was micronized. This drug mixture was ^plied onto the inert core by dusting process employing hydroxypropyl methylcellulose E5 solution prepared as above as binder intermitently in a conventional coating equipment c) Composition of Intermediate layer mg/capsule Hydroxypropyl methylcellulose E5 12.00 Microcrystaline cellulose powder 3.00 Talc 2.00 Isopropyl alcohol* 25.00 Hydroxypropyl methylcellulose E5 was dissolved in a solvent mix of isopropyl alcohol and kept for about 2 hours. Microcrystaline cellulose powder and talc were passed through 100# and dispersed in hydroxypropyl methylcellulose E5 solution. This dispersion was applied onto drug pellets employing a conventional coating equipment. d) Composition of enteric coating mg/capsule EudragitLlOO-55 30.00 Isopropyl alcohol* 60.00 Acetone* 90.00 Triethyl citrate 6.00 Triethyl citrate was dissolved in a solvent mix of isopropyl alcohol and acetone and Eudragit LlOO-55 was added to it until a clear solution was obtained. The solution was applied onto intermediate layered pellets employing a perforated coating pan. * Used in the process but the solvents ev^ourate during the processing and in the final pellets they are only present in traces within acceptable regulatory limits. EXAMPLE 4 a) Composition of Inert Core: mg/Capsule Sucrose 12.00 Starch 8.00 b) Composition of drug layer me/caosule Aspirin 150.00 Aluminium hydroxide 30.00 Sodium benzoate 2.00 Talc 10.00 Microcrystalline cellulose powder 20.00 Polyvinyl pyrrolidone 10.00 Isopropyl alcohol 40.00 Inert cores were prepared from sucrose and starch with the help of sugar syrup in a coating pan. Polymer solution was prepared by dissolving polyvinylpyrrolidone in isopropyl alcohol. Aspirin was mixed with aluminium hydroxide, sodium benzoate, microcrystaline cellulose powder, talc and micronised the mixture. This micronized drug mixture was applied onto the inert core by dusting process employing polymer solution prepared as above as binder intermittently in conventional coating equipment. c) Composition of intermediate layer mg/c^sule Hydroxypropyl methylcellulose E5 20.00 Microcrystaline cellulose powder 6.00 Talc 4.00 Isopropyl alcohol* 50.00 Methylene chloride* 80.00 Hydroxypropyl methylcellulose E5 was dissolved in a solvent mix of isopropyl alcohol and methylene chloride and kept for about 2 hours. Microcrystaline cellulose powder and talc was passed through 100# and dispersed in hydroxypropyl methylcellulose E5 solution. This dispersion was applied onto drug pellets employing a conventional coating machine. d) Composition of enteric coating mg/c^sule Eudragit LlOO-55 60.00 Isopropyl alcohol* 120.00 Acetone* 180.00 Triethyl citrate 12.00 Triethyl citrate was dissolved in a solvent mix of isopropyl alcohol and acetone and Eudragit LlOO-55 was added to it until a clear solution was obtained. This solution was applied onto intermediate layered pellets employing a perforated coating pan. * *Used in the process but the solvents ev^ourate during the processing and in the final pellets they are only present in traces within acceptable regulatory limits. The product is stable for 6 months at 30°C/ 60% RH and 25X/ 60% RH without any appreciable changes in the characteristics studied. Further studies at 30oC/ 60% RH and 25°C/ 60% RH are in progess. ADVANTAGES OF THE INVENTION 1. It prevents gastric upset / disorder. 2. Results in immediate release of the drug after passing the stomach. 3. Enchanced and assured stability of the drug 4. The formulation can be manufactured with normally available equipments. 5. Economy and cost benefits in the production. 1. An improved pharmaceutical formulation containing aspirin which is resistant to acid media and dissolves in neutral to alkaline media and having good stability and useful for the prevention of cardiovascular disease and which comprises a) an inert core comprising of sucrose and starch. b) a coating on the inert core with a drug layer comprising a mixture of aspirin and an alkaline agent or a mixture thereof and forming the resulting mixture into pellets or tablets. \c) the drug layer comprising aspirin and an alkaline agent , a diluent, an antiadherent / compound, binder, a preservative & a hydrophilic polymer. d) an intermediate layer containing a hydrophilic polymer with a diluent, an antiadherent agent and a solvent. the resulting pellets / tablets having a coating of an enteric layer. 2. A formulation as claimed in claim 1 wherein the amount of sucrose & starch used in the inert core range from 2.00 to 20.00 mg per capsule / tablet and from 1.00 to 10.00 mg per capsule / tablet, respectively, more preferably, the amounts range from 4.00 to 14.00 mg per capsule / tablet and 2.00 to 8.00 mg per capsule / tablet respectively. 3. A formulation as claimed in claim 2 wherein the amount of aspirin employed in the drug layer ranges from 50.00 to 400.00 mg per capsule / tablet, preferably in the range of 75.00 mg to 325.00 mg per capsule / tablet. 4.A formulation as claimed in claims 1 & 2 wherein the alkaline agent such as magnesium oxide, magnesium carbonate, aluminum hydroxide, magnesium hydroxide, calcium carbonate, sodium carbonate, potassium carbonate and the like is employed in the drug layer. 5. A formulation as claimed in claims 1 to 4 wherein the amount of alkaline agent used ranges from 5.00 to 60.00 mg per capsule / tablet, more preferably 10.00 to 50.00 mg per capsule/ tablet. 6.A formulation as claimed in claims 1 to 5 wherein the diluent used is selected from microcrystalline cellulose. Lactose, Mannitol, dextrose, and the like. 7. A formulation as claimed in claim 6 wherein the amount of diluent employed in the active core ranges from 5.00 to 60.00 mg per capsule / tablet , preferably 8.00 - 40.00 mg per capsule/tablet. 8. A formulation as claimed in claim 1 to 7 wherein the anti-adherent agent is selected from talc, aerosil, calcium stearate and the like, and its amount ranges from 1.00 to 20.00 mg per capsule / tablet, more preferably 2.00 to 15.00 mg per capsule / tablet. 9.A formulation as claimed in claim 1 to 8 wherein the binder used is selected from Hydroxypropyl methylcellulose, Hydroxy ethyl cellulose, Polyvinylpyrrolidone and the like and its amoimt ranges from 2.00 to 30.00mg per capsule / tablet, more preferably 4.00 to 25.00mg per capsule / tablet 10. A formulation as claimed in claim 1 to 9 wherein a preservative is employed which when employed is selected from sodium benzoate, sodium metabisulfite, sodium sulfite, sodium bisulfite and the like and its amount ranges from 0.20 to S.OOmg per capsule / tablet, more preferably 0.50 to 4.00 mg per capsule / tablet. 11. A formulation as claimed in claims 1 to 10 wherein the binder is dissolved in organic solvent selected from Isopropyl alcohol, methylene chloride, ethyl alcohol, acetone and the like or a mixture thereof, 12.A formulation as claimed in claims 1 to 11 wherein the polymer employed in the intermediate layer is selected from polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxy propyl cellulose, sodium carboxy methyl cellulose, carboxy methyl cellulose and the like or a mixture thereof 13. A formulation as claimed in claim 12 wiierein the amount of polymer employed in the intermediate layer ranges from 2.00 to 50.00 mg per capsule /. tablet, more preferably 5.00 to 40.00_mg per capsule/ tablet. 14. A formulation as claimed in claims 1 to 13 wherein the diluent used in the Intermediate layer is selected from microcrystalline cellulose, lactose, mannitol and the like and its amount ranges from 2.00 to 50.00mg per capsule / tablet, more preferably 3.00 to 40.00mg per capsule or tablet. 15. A formulation as claimed in claims 1 to 14wherein the organic solvent such as isopropyl alcohol, ethyl alcohol, acetone, methylene chloride and the like or mixture thereof is used to dissolved the polymer. 16.A formulation as claimed in claims 1 to 15wherein for the enteric coating of the polymer is selected from cellulose derivatives and acrylic derivatives. 17. A formulation as claimed in claim 16wherein the cellulose derivatives are selected from Hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate and the like and the acrylic derivatives are selected from Eudragit L 100-55 and the like. 18. A formulation as claimed in claims 16& 17wherein the amount of polymer used ranges from 10.00 to lOO.OOmg per capsule /tablet, more preferably 20.00 to 80.00 mg per capsule /tablet. 19. A formulation as claimed in claims 1 to 18 wherein the plasticizer is selected from phthalate derivatives such as diethyl phthalate, dibutyl phthalate, dioctyl phthalate and the like and of fatty alcohol derivatives such as cetyl alcohol, stearyl alcohol and the like or mixture of phthalate & fatty alcohol. 20. A formulation as claimed in claim 19 wherein the amount of plasticizer used ranges from 3.00 to 30.00mg per capsule /tablet, more preferably 4.00 to 24.00mg per capsule /tablet. 21. A formulation as claimed in claims 1 to 20 wherein antiadherent used is selected from talc, colloidal silicon dioxide and the like and its amount ranges from 2.00 to 16.00mg per capsule /tablet, more preferably 3.00 to 12.00mg per capsule /tablet. 22. A formulation as claimed in claims 1 to 21 wherein the formulation contains a coloring agent such as titanium dioxide, iron oxide and mixture thereof and its amount of coloring agent ranges from 0.025 to 4.00mg per capsule / tablet more preferably 0.05 to 3.00 mg per capsule / tablet. 23. A formulation as claimed in 1 to 22 wherein the formulation contains a organic solvent used in enteric coating is selected from isopropyl alcohol, ethyl alcohol, acetone, methylene chloride and the like or mixture thereof is used to dissolve the polymer. 24. An improved process for the preparation of pharmaceutical formulation containing aspirin which is resistant to acid media and dissolves in neutral to alkaline media and having good stability and useful for the prevention of cardiovascular disease which comprises a) forming an inert core comprising of sucrose and starch. b) Providing a coating on the inert core with a drug layer comprising a mixture of aspirin and an alkaline agent or a mixture thereof an alkaline agent , a diluent, an antiadherent compound , binder, a preservative & a hydrophilic polymer c) forming the resulting mixture into pellets or tablets . d) providing an intermediate layer containing a hydrophilic polymer with a diluent, an antiadherent agent and a solvent. e) Providing the resulting pellets / tablets with a coating of an enteric layer, t) encapsulating the pellets / tablets thus formed by conventional methods. 25. A process as claimed in claim 24 wherein the amount of sucrose & starch used in the inner core range from 2.00 to 20.00 mg per capsule / tablet and from 1.00 to 10.00 mg per capsule / tablet, respectively, more preferably, the amounts range from 4.00 to 14.00 mg per capsule / tablet and 2.00 to 8.00 mg per capsule or tablet respectively 26. A process as claimed in claims 24 and 25 wherein the amount of aspirin employed in the active core ranges from 50,00 to 400.00 mg per capsule / tablet, preferably in the range of 75.00 mg to 325.00 mg per capsule / tablet. 27. A process as claimed in claims 24 to 26 wherein the alkaline agent such as magnesium oxide, magnesium carbonate, aluminium hydroxide, magnesium hydroxide, calcium carbonate, sodium carbonate, potassium carbonate and the like is employed in the drug layer. 28. A process as claimed in claims 24 to 27 wherein the amount of alkaline agent used ranges from 5.00 to 60.00 mg per capsule / tablet, more preferably 10.00 to 50.00 mg per capsule / tablet. 29. A process as claimed in claims 24 to 28 wherein the diluent used is selected from microcrystalline cellulose. Lactose, Mannitol, dextrose, and the like. 30. A process as claimed in claim 29 whereinjhe amount of diluent employed in the drug layer ranges from 5.00 to 60.00 mg per capsule / tablet preferably 8.00-40.00mg per capsule / tablet. 31. A process as claimed in claim 24 to 30 wherein the drug layer contains an anti-adherent agent selected from talc, aerosil, calcium stearate and the like and its amount ranges from 1.00 to 20.00 mg per capsule / tablet, more preferably 2.00 to 15.00 mg per capsule / tablet. 32. A process as claimed in claim 24 to 31 wherein the binder used is selected from Hydroxypropyl methylcellulose, Hydroxy ethyl cellulose. Polyvinylpyrrolidone and the like and its e amount ranges from 2.00 to 30.00mg per capsule / tablet more preferably 4.00 to 25.00mg per capsule or tablet. 33. A process as claimed in claim 24 to 32 wherein the preservative when employed is selected from sodium benzoate, sodium metabisulfite, sodium sulfite, sodium bisulfite and the like and its amount ranges from 0.20 to 5.00mg per capsule / tablet , more preferably 0.50 to 4.00 mg per capsule / tablet 34. A process as claimed in claims 24 to 33 wherein the binder is dissolved in organic solvent selected from Isopropyl alcohol, methylene chloride, ethyl alcohol, acetone or a mixture thereof 35. A process as claimed in claims 24 to 34 wherein the polymer employed in the intermediate layer is selected from polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxy propyl cellulose, sodium carboxy methyl cellulose, carboxy methyl cellulose and the like or a mixture thereof. 36. A process as claimed in claim 35 wherein the amount of polymer employed in intermediate layer ranges from 2.00 to 50.00 mg per capsule / tablet, more preferably 5.00 to 40.00,mg per capsule / tablet. 37. A process as claimed in claims 24 to 36 wherein the diluent used in the Intermediate layer is selected from microcrystalline cellulose, lactose, mannitol and the like and its amount ranges from 2.00 to 50.00mg per capsule / tablet, more preferably 3.00 to 40.00mg per capsule/ tablet. 38. A process as claimed in claims 24 to 37 wherein the anti-adherent agent is selected from talc, aerosol, calcium stearate and the like and its amount ranges from 1.00 to 20.00 mg per capsule / tablet, more preferably 2.00 to 15.00 mg per capsule or tablet. 39. A process as claimed in claims 24 to 38 wherein the organic solvent such as isopropyl alcohol, ethyl alcohol, acetone, methylene chloride and the like or mixture thereof is used to dissolved the polymer. 40. A process as claimed in claims 24 to 39 v^erein for the enteric coating of the polymer is selected from cellulose derivatives and acrylic derivatives. 41. A process as claimed in claim 40 wherein the cellulose derivatives are selected from Hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate and the like and the acrylic derivatives are selected from Eudragit L 100-55 and the like. 42. A process as claimed in claims 39 & 40 wherein the amount of polymer used ranges from 10.00 to lOO.OOmg per capsule / tablet, more preferably 20.00 to 80.00mg per capsule / tablet. 43. A process as claimed in claims 24 to 42 wherein the plasticizer is selected from phthalate derivatives such as diethyl phthalate, dibutyl phthalate, dioctyl phthalate and the like and of fatty alcohol derivatives such as cetyl alcohol, stearyl alcohol and the like or mixture of phthalate & fatty alcohol. 44. A process as claimed in claim 43 wherein the amount of plasticizer used ranges from 3.00 to 30.00mg per capsule / tablet, more preferably 4.00 to 24.00 mg per capsule / tablet. 45. A process as claimed in claims 24 to 44 wherein antiadherent used is selected from talc, colloidal silicon dioxide and the like and its amount ranges from 2.00 to 16.00mg per capsule / tablet, more preferably 3.00 to 12.00mg per capsule / tablet. 46. A process as claimed in claims 24 to 45 wherein enteric coating contains a coloring agent such as titanium dioxide, iron oxide and mixture thereof and its amount of coloring agent ranges from 0.025 to 3.00mg per capsule / tablet, more preferably 0.05 to 2. 50 mg per capsule / tablet. 47. A process as claimed in 24 to 46 wherein the formulation contains a organic solvent used in enteric coating is selected from isopropyl alcohol, ethyl alcohol, acetone, methylene chloride and the like or mixture thereof is used to dissolve the polymer. 48. An improved pharmaceutical formulation containing aspirin which is resistant to acid media and dissolves in neutral to alkaline media and having good stability and useful for the prevention of cardiovascular disease substantially as herein described with reference to the Examples 1 to 4. 49. A process for the preparation of an improved pharmaceutical formulation containing aspirin which is resistant to acid media and dissolves in neutral to alkaline media and having good stability and useful for the prevention of cardiovascular disease.

Full Text

INTRODUCTION
The invention disclosed in this application relates to an importing nulation containing aspirin. The formulation is useful for the prevention of cardiovascular diseases such as stroke and decrease in recurrence of a heart attack and other heart related problems. The formulation does not react with gastric juices thereby enhancing its pharmaceutical efficacy. The formulation may be in the form of tablets & capsules. The invention also relates to a process for the preparation of above said formulation.
BACKGROUND OF THE INVENTION
Aspirin or acetyl salicylic acid is a well-known therapeutic agent, which has been employed for many years as an analgesic as well as for its antipyretic and anti-inflammatory properties. It is also well known that aspirin is an acidic drug which can cause gastric distress. Such gastric distress is caused primarily because the aspirin particles do not dissolve and such particles attach to the walls of the stomach. Equally well known today is the significant role which aspirin plays in the successful treatment and management of two of the most common major diseases that afflict the world's population, i.e. arthritis and heart attacks. According to the PDR (Physicians Desk Reference) Asprin also temporarily relieves the minor aches and pains of arthritis, muscle aches, colds, flu and menstrual discomfort. In some patients, a small daily dose of aspirin may be used to ensure sufficient blood flow to the brain and prevent stroke. Aspirin may also be taken to decrease recurrence of a heart attack or other heart problems.
In addition, the beneficial effect of aspirin on the human immune system may make it a promising drug for possible use in the treatment of cancer, AIDS, cataracts, allergies and a number of other diseases in which the immune system is involved These valuable pharmacological properties have made aspirin the most widely used drug in the world. "It is also being studied for cancer prevention'* as per the National Cancer Institutes Cancer GOV Dictionary. As per AIDS treatment news no. 109- dated August 17,1990, Laboratory studies have suggested that reducing certain inflammatory reactions as aspirin does, may affect the pathogenesis of the disease, improving some immune functions, and possibly showing the

replication of HIV by reducing the levels of certain chemical messengers which may trigger the growth of the Virus.
Nevertheless, it has been documented that aspirin does possess a number of undesirable side effects, although the true severity of these side effects has not been recognized until recently. For example, being a sparingly soluble substance (only 0.33 gm in 100 ml of water), the undissolved particles of aspirin will normally adhere to the gastrointestinal mucosa Such adherence can cause lesions, gastric and duodenal ulcers and bleeding. These undesirable side effects are usually persistent and cumulative and they occur in a number of patients in which aspirin is used as a ther^y.
To meet the above situation and to make good use of the activity of aspirin, delayed release aspirin pellets have been developed to reduce gastric irritation by not releasing the drug in the stomach and releasing the drug in intestine.
The corrosive effects that aspirin may display on the gastrointestinal mucosa were recognized early in the history of aspirin therapy. Consequently, attempts to produce a soluble form of this drug have been made almost continuously since then. As far as in 1903, Prior art U.S. Pat. No. 740,703 reveals efforts were made to develop the drug, exclusively on the preparation of various soluble salts, lithium, sodium, potassium, calcium and magnesium as well as with organic amines and amino acids (lysine and ornithine). The main disadvantages of these particular salt products were that, in contrast to the aspirin itself, they were not stable.
In order to make aspirin more useful as an oral dosage form for its use as preventive agent in Cardiovascular diseases such as stroke and decrease in recurrence of a heart attack and other heart problems, it is necessary to protect it against gastric juices v^ich are acidic in nature. Such a protection will enable the formulation to release aspirin in the intestine. To prevent contact of aspirin with gastric juices, the formulation is to be enteric coated.
In US patent No: 4,775,536 an enteric coated aspirin tablet and process for making is described, in v^ich the core of the tablet is coated with enteric coating layer of film forming polymers and an over coat layer of non enteric film forming polymers. The drawback of

aqueous enteric coating of aspirin tablet may lead to the hydrolysis/cleavage of parent molecule increasing the free salicylic acid content during storage period.
In US Patent No: 5,576,024 a buffered aspirin tablet composed of aqueous based polymer coated aspirin, a buffering system and a hydrophilic gel forming matrix material was described, in vAdch the buffering system and matrix material, provide a microenvironment of pH 5.0 thus increasing the solubility of the aspirin. Though the solublity may show improvement, the formulation can still cause gastric irritation.
The US Patent No: 5,582,837 alkyl -substituted cellulose based sustained release oral dosage forms are described. Sustained release oral dosage form comprise a tablet or capsule containing a plurality of particles of solid state dispersed in alkyl cellulose such as hydroxyethylcellulose or hydroxypropylcellulose. The tablet / c^sule upon ingestion disintegrates to disperse the particles into stomach vAievQ they imbibe water to cause them swell thus enhancing their retention in stomach. Imbibed water dissolves the drug entrj^ped in the particles and the resulting solution diffuses from the dispersed particles, assuring no solid drug contacts the mucosal tissue.
The US Patent No: 5,603,957 relates to a controlled release microtablets & capsules of acetyl salicylic acid coated with mixture of cellulose film formers, thus controlling release of acetyl salicylic acid throughout the length of gastrointestinal tract.
JPO 2001-139469 dated 22/05/01, a novel sustained release preparation composition consists of Aspirin with coating material, which would be used in cardiovascular diseases, primarily a process of mixing sustained release particles, excipient and homogenizing them, used for oral adminstration.
In all the above four patents the drug is released over a period of time , the drug in low doses may not provide immediate relief
In US patent No: 5,683,721 a galenic preparation of therapeutic composition containing aspirin as sublingual administration was described, in which the active ingredient is in micro

administration of aspirin may cause unpleasant taste and further keeping the large size dosage form beneath the tongue may cause discomfort to the consxmier.
In US Patent No: 5,723,453 a stabilized , sodium free, alkaline and aspirin combination compound is described, in v^ch the compoimd is readily soluble in a preselected fluid i.e.water and produces potassium acetyl salicylate. This combination compound contains aspirin (USP 60 # mesh) within a range 325 -1000 mg per unit dose and alkaline compound between 250 -3000 mg per unit dose, having a pH generally within a range of between about 8.0 and about 10.0 and being present in a molar amount which is greater than a molar amount required to neutralize aspirin granules. As the tablet is effervescent and has to be dissolved in a large amount of water before administration, some users may find inconvenience and hence non- acceptable.
In J^anese Publication Nbr 09-263538- 07/10/97 it is provided a stable pharmaceutical composition based on acetylsalicylic acid and tochoperol, for peroral administration, in treatment and prevention of cardiovascular and cancer ther^y. The pharmaceutical composition is based on capsule and is prepared by mixing with usually used additive used as excepients. The product appears to be a powder c^sule, which can cause gastric irritation.
In our continued efforts to provide valuable and effective drug for effective prevention of cardiovascular disease such as stroke and decrease in recurrence of a heart attack and other heart problems, we directed our research towards developing dosage form aspirin which will have no effect by the gastric juices
The present invention accordingly relates to a delayed release oral dosage form of aspirin which prevents gastric irritation in individuals taking it as well as a process for preparing such forms of aspirin
Delayed release composition resists the action of the acidic stomach fluids on the drug. The coating can protect the gastric mucosa from the irritating effects of aspirin. However this coating dissolves in the neutral or alkaline milieu of the intestine and active ingredients become available for absorption into blood stream.

Accordingly, the main objective of the present invention is to provide an improved stable formulation containing aspirin useful for the prevention of cardiovascular diseases such as stroke and decrease in recurrence of a heart attack and other heart problems, v^toch will be resistant to gastric juices
Another objective of the present invention is to provide an improved stable formulation containing aspirin useful for the prevention of cardiovascular diseases such as stroke and decrease in recurrence of a heart attack and other heart problems, \\4iich delays release of aspirin in the stomach and facilitate immediate release in intestine for speedy absorption as against delayed release in the prior art.
Yet another objective of the present invention is to provide a method for the preparation of an improved and stabilized formulation containing aspirin useful for the prevention of cardiovascular diseases such as stroke and decrease in recurrence of a heart attack and other heart problems, which will be resistant to gastric juices and will dissolve in neutral to alkaline media and has good stability.
We have developed this invention based on our finding that if the core containing aspirin is effectively protected its stability as well as its resistance to the action of gastric juices can be enhanced.
Accordingly, the present invention provides an improved stable pharmaceutical formulation containing aspirin wiiich is resistant to acid media in stomach and dissolves in neutral to alkaline media in intestines and having good stability and useful for the prevention of cardiovascular disease and wiiich comprises
a) an inert core comprising ofsucrose and starch.
b) a coating on the inert core with a drug layer comprising a mixture of aspirin and an alkaline agent or a mixture thereof and forming the resulting mixture into pellets or tablets.
c) the drug layer comprising aspirin and an alkaline agent , a diluent, an antiadherent compound, binder, a preservative & a hydrophilic polymer.

1
d) an intermediate layer containing a hydrophilic polymer with a diluent, an antiadherent agent and a solvent.
e) the resulting pellets / tablets having a coating of an enteric layer.
If desired the pellets /tablets thus formed can be enc^sulated by conventional methods.
The amount of sucrose & starch in the inner core may be intherangeof 2.00 to 20.00 mg per c^sule / tablet and from 1.00 to 10.00 mg per c^sule / tablet, respectively, more preferably, the amount ranges from 4.00 to 14.00 mg per capsule / tablet and 2.00 to 8.00 mg per cj^)sule / tablet respectively.
The drug layer contains Aspirin in the range of 50.00 to 400.00 mg per c^sule / tablet preferably in the range of 75.00 mg to 325.00 mg per capsule / tablet
The alkaline agent in the drug layer may be selected from magnesium oxide, magnesium carbonate, aluminum hydroxide, magnesium hydroxide, calcium carbonate, sodium carbonate, potassium carbonate and the like .The amount of alkaline agent used ranges from 5.00 to 60.00 mg per c^sule / tablet, more preferably 10.00 to 50.00 mg per capsule / tablet.
The diluent used may be selected from microcrystalline cellulose. Lactose, Mannitol, dextrose, and the like .The amount of diluent employed in the active core of drug layer, ranges from 5.00 to 60.00 mg per capsule / tablet, preferably 8.00-40.00mg per cq)sule / tablet
The drug layer may contain an anti-adherent agent selected from talc, aerosol, calcium stearate and the like. The amount ranges from 1.00 to 20.00 mg per capsule / tablet, more preferably 2.00 to 15.00 mg per c^sule / tablet
The binder when used ay be selected from Hydroxypropyl methylcellulose, Hydroxy ethyl cellulose. Polyvinylpyrrolidone and the like .The amount ranges from 2.00 to SO.OOmg per capsule / tablet, more preferably 4.00 to 25.00mg per capsule / tablet

The preservative when used may be selected from sodium benzoate, sodium metabisulfite, sodium sulfite, sodiimi bisulfite and the like. The amount ranges from 0.20 to S.OOmg per c^sule / tablet, more preferably 0.50 to 4.00 mg per capsule / tablet.
The binder \^en used may be dissolved in an organic solvent which may be selected from Isopropyl alcohol, methylene chloride, ethyl alcohol, acetone and the like or a mixture thereof.
The polymer employed in the intermediate layer may be selected from polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxy propyl cellulose, sodium carboxy methyl cellulose, carboxy methyl cellulose and the like or a mixture thereof The amount of polymer employed in the intermediate layer ranges from 2.00 to 50.00 mg per capsule / tablet , more preferably 5.00 to 40.00 mg per c^sule / tablet
The diluent when used in the Intermediate layer may be selected from microcrystalline cellulose, lactose, mannitol and the like .The amount ranges from 2.00 to 50.00mg per capsule / tablet, more preferably 3.00 to 40.00mg per c^sule / tablet.
The anti adherent agent when used may be selected from talc, aerosil, calcium carbonate and the like .The amount ranges from 1.00 to 20.00 mg per capsule / tablet more preferably 2.00 to 10.00 mg per cqjsule / tablet.
The organic solvent used in intermediate layer is selected from isopropyl alcohol, ethyl alcohol, acetone, methylene chloride and the like or mixture thereof is used to dissolve the polymer.
For the enteric coating , the polymer used may be selected from cellulose derivatives and acrylic derivatives. The cellulose derivatives are selected from Hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate and the like and the acrylic derivatives are selected from Eudragit L 100-55 and the like.
The amount of polymer used ranges from 10.00 to 100.00 mg per capsule / tablet, more preferably 20.00 to 80.00 mg per cqDsule / tablet

The plasticizer used may be selected from phthalate derivatives such as diethyl phthalate, dibutyl phthalate, dioctyl phthalate and the like and of fatty alcohol derivatives such as cetyl alcohol, stearyl alcohol and the like or mixture of phthalate & fatty alcohol. The amount of plasticizer used ranges from 3.00 to SO.OOmg per capsule / tablet, more preferably 4.00 to 24.00mg per capsule / tablet.
The antiadherent when used may be selected from talc, colloidal silicon dioxide and the like and its amount ranges from 2.00 to 16.00mg per capsule / tablet, more preferably 3.00 to 12.00mg per capsule / tablet.
The coloring agent for the enteric coating is selected from titanium dioxide, iron oxide and mixture thereof .The amount of coloring agent ranges from 0.025 to 4.00mg per capsule / tablet more preferably 0.05 to 3.00 mg per capsule / tablet.
The organic solvent used in the enteric coating used to dissolve the polymer is selected from isopropyl alcohol, ethyl alcohol, acetone, methylene chloride and the like or mixture thereof.
According to another feature of the invention, there is provided a process for the preparation of pharmaceutical formulation containing aspirin which is resistant to acid media and dissolves in neutral to alkaline media and having good stability and useful for the prevention of cardiovascular disease which comprises :
a) forming an inert core comprising of sucrose and starch.
b) Providing a coating on the inert core with a drug layer comprising a mixture of aspirin and an alkaline agent or a mixture thereof an alkaline agent , a diluent, an antiadherent compound , binder , a preservative & a hydrophilic polymer and forming the resulting mixture into pellets or tablets .
c) Providing an intermediate layer containing a hydrophilic polymer with a diluent, an antiadherent agent and a solvent.
d) Providing the resulting pellets / tablets with a coating of an enteric layer., if desired
e) encapsulating the pellets / tablets thus formed by conventional methods.

In a preferred embodiment of the present invention the amount of sucrose, starch used in the inert core range from 2.00 to 20.00 mg per c^sule / tablet and from 1.00 to 10.00 mg per c^sule /tablet, respectively, more preferably, the amount ranges from 4.00 to 14.00 mg per capsule / tablet and 2.00 to 8.00 mg per capsule / tablet respectively.
The drug layer contains aspirin in the range from 50.00 to 400.00 mg per c^sule/ tablet, preferably in the range of 75.00 mg to 325.00 mg per capsule / tablet.
In the drug layer alkaline agent is selected from magnesium oxide, magnesium carbonate, aluminum hydroxide, magnesium hydroxide, calcium carbonate, sodium carbonate, potassium carbonate. The amount of alkaline agent used ranges from 5.00 to 60.00 mg per cq)sule / tablet, more preferably 10.00 to 50.00 mg per capsule / tablet.
The diluent used is selected from microcrystalline cellulose. Lactose, Mannitol, dextrose, and the like. The amount of diluent employed in the drug layer ranges from 5.00 to 60.00 mg per c^sule / tablet preferably 8.00-40.00 mg per c^sule / tablet.
The anti-adherent agent is selected from talc, aerosol, calcium stearate and the like and its amount ranges from 1.00 to 20.00 mg per c^sule / tablet, more preferably 2.00 to 15.00 mg per capsule / tablet.
The binder used is selected from Hydroxypropyl methylcellulose. Hydroxy ethyl cellulose. Polyvinylpyrrolidone and the like and its amount ranges from 2.00 to 30.00mg per c^sule / tablet more preferably 4.00 to 25.00mg per capsule / tablet.
The preservative vAien employed is selected from sodium benzoate, sodium metabisulfite, sodium sulfite, sodium bisulfite and the like and its amount ranges from 0.20 to 5.00mg per c^sule / tablet, more preferably 0.50 to 4.00 mg per capsule / tablet
The binder is dissolved in organic solvent selected from Isopropyl alcohol, methylene chloride, ethyl alcohol, acetone and the like or a mixture thereof

The polymer employed in the Intermediate layer is selected from polj^nylpyrrolidone, hydroxypropyl methylcellulose, hydroxy propyl cellulose, sodium carboxy methyl cellulose, carboxy methyl cellulose and the like or a mixture thereof. The amount of polymer employed in intermediate layer ranges from 2.00 to 50.00 mg per c^sule / tablet, more preferably 5.00 to 40.00.mg per c^sule / tablet.
The diluent used in the Intermeidate layer is selected from microcrystalline cellulose, lactose, maimitol and the like .The s amount ranges from 2.00 to SO.OOmg per c^sule / tablet, more preferably 3.00 to 40.00mg per capsule/ tablet
The anti adherent agent is selected from talc, aerosil, calcium carbonate and the like.The amount ranges from 1.00 to 20.00 mg per c^sule / tablet more preferably 2.00 to 15.00 mg per c^sule / tablet
The organic solvent such as isopropyl alcohol, ethyl alcohol, acetone, methylene chloride and the like or mixture thereof is used to dissolved the polymer.
The enteric coating of the polymer is selected from cellulose derivatives and acrylic derivatives, v^^erein the cellulose derivatives are selected from Hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate and the like and the acrylic derivatives are selected from Eudragit L 100-55 and the like.
The amoimt of polymer used ranges from 10.00 to lOO.OOmg per capsule or tablet, more preferably 20.00 to SO.OOmg per c^sule/ tablet.
The plasticizer is selected from phthalate derivatives such as diethyl phthalate, dibutyl phthalate, dioctyl phthalate and the like and of fatty alcohol derivatives such as cetyl alcohol, stearyl alcohol and the like or mixture of phthalate & fatty alcohol. The amount of plasticizer used ranges from 3.00 to 30.00mg per capsule / tablet, more preferably 4.00 to 24.00 mg per c^sule/ tablet.

The antiadherent used is selected from talc, colloidal silicon dioxide and the like and its amount ranges from 2.00 to 16.00mg per c^sule / tablet, more preferably 3.00 to 12.00mg per capsule/ tablet.
The enteric coating contains a coloring agent such as titanium dioxide, iron oxide and mixture thereof. And its amount of coloring agent ranges from 0.025 to 4.00mg per capsule / tablet, more preferably 0.05 to 3.00 mg per capsule / tablet.
The Organic solvent used in the enteric coating is selected from isopropyl alcohol, ethyl alcohol, acetone, methylene chloride and the like or mixture thereof is used to dissolve the polymer.
The enteric coating may be applied on to intermediate layered pellets in mechanized perforated coating pan, or using any suitable coating equipment.
Enteric coated pellets may be filled into hard gelatin c^sules or compressed into tablets in a conventional maimer and may be packed into a moisture resistant primary pack. For the long term stability of formulation, water content of the pellets in formulation is kept below 2.0%
It would be observed that the active ingredient was available by using a buffered environment by enc^sulating the inert core surrounded by drug layer followed by intermediate layer and covered by enteric layer, that makes the drug stable over the entire shelf life of the product to enable it to pass from acidic layer in stomach to the alkali/neutral layer in the intestine. By doing so. Not only the stabilization of the drug is achieved but it also improve the solubility of drug, which facilitate the maximxjm bioavailability after the administration of dosage form.
Another advantage of preparing the dosage form in the form of pellets is that there are less chances of degradation of the product, as it is an individual discrete particle unlike the tablets..
The pellets are enc^sulated or compressed into tablets with a low moisture content vviiich avoids the degradation of aspirin due to moisture. The incorporation of preservatives in the

formulation makes the product free of any additional microbial burden throughout its shelf life.
The invention is described in detail in the Examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention. It should be noted that in all the Examples the pellets formed according to the invention can be enc^sulated by any conventional method.
EXAMPLE 1

Inert cores were prepared from sucrose and starch with the help of sugar syrup in a coating pan. The polymer solution was prepared by dissolving polyvinylpyrrolidone in isopropyl alcohol. Aspirin was mixed with aluminium hydroxide, sodium benzoate, microcrystaline cellulose powder, talc and is micronised. This micronized drug mixture was applied onto the inert core by dusting process employing polymer solution prepared as above as binder intermittently in conventional coating equipment

Talc 2.00
Isopropyl alcohol* 25,00
AVi.t,ui^iOii Hydroxypropyl methylcellulose was dissolved in a solvent mix of isopropyl alcohol and methylene chloride and kept for about 2 hours for complete dissolution. Microcrystaline cellulose and talc were passed through 100# and dispersed in hydroxypropyl methylcellulose solution. The dispersion was applied to drug pellets employing a perforated coating pan.
d) Composition of enteric coating mg/capsule
Hydroxypropyl methylcellulose phthalate H55S 25.00
Diethyl phthalate 5.00
Talc 3.00
Isopropyl alcohol* 650.00
Methylene chloride* 1000.00
Titanium dioxide 1.00
Diethyl phthalate was dissolved in a solvent mixture of isopropyl alcohol and methylene chloride and, Hydroxypropyl methylcellulose phthalate H55S was added slowly and dissolved until a clear solution was obtained Titanium dioxide and talc were shifted through 200# and dispersed in this polymer solution. This dispersion was ^plied on intermediate layered pellets employing a perforated coating equipment
*Used in the process but the solvents ev^ourate during the processing and in the final pellets they are only present in traces within acceptable regulatory limits.
EXAMPLE 2
a) Composition of Inert Core: mg/C^sule
Sucrose 11.00
Starch 7.00
b) Composition of drug layer mg/c^sule

Aspirin 150.00
magnesium hydroxide 35.00
Talc 10.00
Micro crystalline cellulose powder 25.00
Hydroxypropyl methylcellulose E5 10.00
Isopropyl alcohol 20.00
Methylene chloride 30.00
Inert cores were prepared from sucrose and starch with the help of sugar syrup in a coating pan. The Polymer solution was prepared by dissolving hydroxypropyl methylcellulose in a solvent mix of isopropyl alcohol and methylene chloride. Aspirin was mixed with magnesium hydroxide, sodium metabisulfite, microcrystaline cellulose powder, talc and the mixture was micronised. This micronized drug mixture was applied onto inert core by dusting process employing polymer solution prepared as above as binder intermittently in suitable coating equipment
C) Composition of Intermediate layer mg/capsule
Hydroxypropyl methylcellulose E5 32.00
Microcrystaline cellulose 10.00
Talc 4.00
Isopropyl alcohol* 50.00
Methylene chloride* 80.00
Hydroxypropyl methylcellulose E5 was dissolved in a solvent mix of isopropyl alcohol and methylene chloride and kept for about 2 hours. Microcrystaline cellulose and talc were passed through 100# and dispersed in hydroxypropyl methylcellulose solution. This dispersion was applied onto drug pellets employing a conventional coating equipment.
d) Composition of enteric coating mg/c^sule
Hydroxypropyl methylcellulose phthalate H 55 S 58.00
Diethyl phthalate 11.00

Talc 10.00
Isopropyl alcohol* 1300.00
Methylene chloride* 2500.00
Titanium dioxide 2.50
Diethyl phthalate was dissolved in a solvent mixture of isopropyl alcohol and methylene chloride and Hydroxypropyl methylcellulose phthalate H55 until a clear solution was obtained. Titanium dioxide and talc are sifted through 200# and dispersed in the polymer solution. Applied the dispersion on intermediete layered pellets employing conventional coating equipment.
*Used in the process but the solvents ev^ourate during the processing and in the final pellets they are only present in traces within acceptable regulatory limits.
EXAMPLE 3
a) Composition of Inert Core: mg/C^sule
Sucrose 6.00
Starch 4.00
b) Composition of drug layer mg/capsule
Aspirin 75.00
Calcium carbonate 15.00
Sodium sulfite 1.00
Talc 5.00
Maimitol 5.00
Hydroxypropyl methylcellulose E5 5.00
Isopropyl alcohol* 10.00
Methylene chloride 15.00
Inert cores were prepared fi-om sucrose and starch with the help of sugar syrup in a coating pan. Polymer solution was prepared by dissolving hydroxypropyl methylcellulose E5 in a solvent mix of isopropyl alcohol and methylene chloride. Aspirin was mixed with calcium carbonate, sodium sulfite, marmitol, talc and the mixture was micronized. This drug mixture was ^plied onto the inert core by dusting process employing hydroxypropyl

methylcellulose E5 solution prepared as above as binder intermitently in a conventional coating equipment
c) Composition of Intermediate layer mg/capsule
Hydroxypropyl methylcellulose E5 12.00
Microcrystaline cellulose powder 3.00
Talc 2.00
Isopropyl alcohol* 25.00
Hydroxypropyl methylcellulose E5 was dissolved in a solvent mix of isopropyl alcohol and kept for about 2 hours. Microcrystaline cellulose powder and talc were passed through 100# and dispersed in hydroxypropyl methylcellulose E5 solution. This dispersion was applied onto drug pellets employing a conventional coating equipment.
d) Composition of enteric coating mg/capsule
EudragitLlOO-55 30.00
Isopropyl alcohol* 60.00
Acetone* 90.00
Triethyl citrate 6.00
Triethyl citrate was dissolved in a solvent mix of isopropyl alcohol and acetone and Eudragit LlOO-55 was added to it until a clear solution was obtained. The solution was applied onto intermediate layered pellets employing a perforated coating pan. * *Used in the process but the solvents ev^ourate during the processing and in the final pellets they are only present in traces within acceptable regulatory limits.
EXAMPLE 4
a) Composition of Inert Core: mg/Capsule
Sucrose 12.00
Starch 8.00
b) Composition of drug layer me/caosule

Aspirin 150.00
Aluminium hydroxide 30.00
Sodium benzoate 2.00
Talc 10.00
Microcrystalline cellulose powder 20.00
Polyvinyl pyrrolidone 10.00
Isopropyl alcohol* 40.00
Inert cores were prepared from sucrose and starch with the help of sugar syrup in a coating pan. Polymer solution was prepared by dissolving polyvinylpyrrolidone in isopropyl alcohol. Aspirin was mixed with aluminium hydroxide, sodium benzoate, microcrystaline cellulose powder, talc and micronised the mixture. This micronized drug mixture was applied onto the inert core by dusting process employing polymer solution prepared as above as binder intermittently in conventional coating equipment.
c) Composition of intermediate layer mg/c^sule
Hydroxypropyl methylcellulose E5 20.00
Microcrystaline cellulose powder 6.00
Talc 4.00
Isopropyl alcohol* 50.00
Methylene chloride* 80.00
Hydroxypropyl methylcellulose E5 was dissolved in a solvent mix of isopropyl alcohol and methylene chloride and kept for about 2 hours. Microcrystaline cellulose powder and talc was passed through 100# and dispersed in hydroxypropyl methylcellulose E5 solution. This dispersion was applied onto drug pellets employing a conventional coating machine.
d) Composition of enteric coating mg/c^sule
Eudragit LlOO-55 60.00
Isopropyl alcohol* 120.00

Acetone* 180.00
Triethyl citrate 12.00
Triethyl citrate was dissolved in a solvent mix of isopropyl alcohol and acetone and Eudragit LlOO-55 was added to it until a clear solution was obtained. This solution was applied onto intermediate layered pellets employing a perforated coating pan. * *Used in the process but the solvents ev^ourate during the processing and in the final pellets they are only present in traces within acceptable regulatory limits.
The product is stable for 6 months at 30°C/ 60% RH and 25X/ 60% RH without any appreciable changes in the characteristics studied. Further studies at 30oC/ 60% RH and 25°C/ 60% RH are in progess.
ADVANTAGES OF THE INVENTION
1. It prevents gastric upset / disorder.
2. Results in immediate release of the drug after passing the stomach.
3. Enchanced and assured stability of the drug
4. The formulation can be manufactured with normally available equipments.
5. Economy and cost benefits in the production.

1. An improved pharmaceutical formulation containing aspirin which is resistant to acid media and dissolves in neutral to alkaline media and having good stability and useful for the prevention of cardiovascular disease and which comprises
a) an inert core comprising of sucrose and starch.
b) a coating on the inert core with a drug layer comprising a mixture of aspirin and an alkaline agent or a mixture thereof and forming the resulting mixture into pellets or tablets.
\c) the drug layer comprising aspirin and an alkaline agent , a diluent, an antiadherent / compound, binder, a preservative & a hydrophilic polymer.
d) an intermediate layer containing a hydrophilic polymer with a diluent, an antiadherent agent and a solvent.
the resulting pellets / tablets having a coating of an enteric layer.

2. A formulation as claimed in claim 1 wherein the amount of sucrose & starch used in the inert core range from 2.00 to 20.00 mg per capsule / tablet and from 1.00 to 10.00 mg per capsule / tablet, respectively, more preferably, the amounts range from 4.00 to 14.00 mg per capsule / tablet and 2.00 to 8.00 mg per capsule / tablet respectively.
3. A formulation as claimed in claim 2 wherein the amount of aspirin employed in the drug layer ranges from 50.00 to 400.00 mg per capsule / tablet, preferably in the range of 75.00 mg to 325.00 mg per capsule / tablet.
4.A formulation as claimed in claims 1 & 2 wherein the alkaline agent such as magnesium oxide, magnesium carbonate, aluminum hydroxide, magnesium hydroxide, calcium carbonate, sodium carbonate, potassium carbonate and the like is employed in the drug layer.
5. A formulation as claimed in claims 1 to 4 wherein the amount of alkaline agent used ranges from 5.00 to 60.00 mg per capsule / tablet, more preferably 10.00 to 50.00 mg per capsule/ tablet.
6.A formulation as claimed in claims 1 to 5 wherein the diluent used is selected from microcrystalline cellulose. Lactose, Mannitol, dextrose, and the like.

7. A formulation as claimed in claim 6 wherein the amount of diluent employed in the active core ranges from 5.00 to 60.00 mg per capsule / tablet , preferably 8.00 - 40.00 mg per capsule/tablet.
8. A formulation as claimed in claim 1 to 7 wherein the anti-adherent agent is selected from talc, aerosil, calcium stearate and the like, and its amount ranges from 1.00 to 20.00 mg per capsule / tablet, more preferably 2.00 to 15.00 mg per capsule / tablet.
9.A formulation as claimed in claim 1 to 8 wherein the binder used is selected from Hydroxypropyl methylcellulose, Hydroxy ethyl cellulose, Polyvinylpyrrolidone and the like and its amoimt ranges from 2.00 to 30.00mg per capsule / tablet, more preferably 4.00 to 25.00mg per capsule / tablet
10. A formulation as claimed in claim 1 to 9 wherein a preservative is employed which when employed is selected from sodium benzoate, sodium metabisulfite, sodium sulfite, sodium bisulfite and the like and its amount ranges from 0.20 to S.OOmg per capsule / tablet, more preferably 0.50 to 4.00 mg per capsule / tablet.
11. A formulation as claimed in claims 1 to 10 wherein the binder is dissolved in organic solvent selected from Isopropyl alcohol, methylene chloride, ethyl alcohol, acetone and the like or a mixture thereof,
12.A formulation as claimed in claims 1 to 11 wherein the polymer employed in the intermediate layer is selected from polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxy propyl cellulose, sodium carboxy methyl cellulose, carboxy methyl cellulose and the like or a mixture thereof
13. A formulation as claimed in claim 12 wiierein the amount of polymer employed in the intermediate layer ranges from 2.00 to 50.00 mg per capsule /. tablet, more preferably 5.00 to 40.00_mg per capsule/ tablet.

14. A formulation as claimed in claims 1 to 13 wherein the diluent used in the Intermediate
layer is selected from microcrystalline cellulose, lactose, mannitol and the like and its amount
ranges from 2.00 to 50.00mg per capsule / tablet, more preferably 3.00 to 40.00mg per
capsule or tablet.
15. A formulation as claimed in claims 1 to 14wherein the organic solvent such as isopropyl
alcohol, ethyl alcohol, acetone, methylene chloride and the like or mixture thereof is used to
dissolved the polymer.
16.A formulation as claimed in claims 1 to 15wherein for the enteric coating of the polymer is selected from cellulose derivatives and acrylic derivatives.
17. A formulation as claimed in claim 16wherein the cellulose derivatives are selected from Hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate and the like and the acrylic derivatives are selected from Eudragit L 100-55 and the like.
18. A formulation as claimed in claims 16& 17wherein the amount of polymer used ranges from 10.00 to lOO.OOmg per capsule /tablet, more preferably 20.00 to 80.00 mg per capsule
/tablet.
19. A formulation as claimed in claims 1 to 18 wherein the plasticizer is selected from
phthalate derivatives such as diethyl phthalate, dibutyl phthalate, dioctyl phthalate and the
like and of fatty alcohol derivatives such as cetyl alcohol, stearyl alcohol and the like or
mixture of phthalate & fatty alcohol.
20. A formulation as claimed in claim 19 wherein the amount of plasticizer used ranges from 3.00 to 30.00mg per capsule /tablet, more preferably 4.00 to 24.00mg per capsule /tablet.
21. A formulation as claimed in claims 1 to 20 wherein antiadherent used is selected from talc, colloidal silicon dioxide and the like and its amount ranges from 2.00 to 16.00mg per capsule /tablet, more preferably 3.00 to 12.00mg per capsule /tablet.

22. A formulation as claimed in claims 1 to 21 wherein the formulation contains a coloring agent such as titanium dioxide, iron oxide and mixture thereof and its amount of coloring agent ranges from 0.025 to 4.00mg per capsule / tablet more preferably 0.05 to 3.00 mg per capsule / tablet.
23. A formulation as claimed in 1 to 22 wherein the formulation contains a organic solvent used in enteric coating is selected from isopropyl alcohol, ethyl alcohol, acetone, methylene chloride and the like or mixture thereof is used to dissolve the polymer.
24. An improved process for the preparation of pharmaceutical formulation containing aspirin which is resistant to acid media and dissolves in neutral to alkaline media and having good stability and useful for the prevention of cardiovascular disease which comprises

a) forming an inert core comprising of sucrose and starch.
b) Providing a coating on the inert core with a drug layer comprising a mixture of aspirin and an alkaline agent or a mixture thereof an alkaline agent , a diluent, an antiadherent compound , binder, a preservative & a hydrophilic polymer

c) forming the resulting mixture into pellets or tablets .
d) providing an intermediate layer containing a hydrophilic polymer with a diluent, an antiadherent agent and a solvent.
e) Providing the resulting pellets / tablets with a coating of an enteric layer, t) encapsulating the pellets / tablets thus formed by conventional methods.

25. A process as claimed in claim 24 wherein the amount of sucrose & starch used in the inner core range from 2.00 to 20.00 mg per capsule / tablet and from 1.00 to 10.00 mg per capsule / tablet, respectively, more preferably, the amounts range from 4.00 to 14.00 mg per capsule / tablet and 2.00 to 8.00 mg per capsule or tablet respectively
26. A process as claimed in claims 24 and 25 wherein the amount of aspirin employed in the active core ranges from 50,00 to 400.00 mg per capsule / tablet, preferably in the range of 75.00 mg to 325.00 mg per capsule / tablet.

27. A process as claimed in claims 24 to 26 wherein the alkaline agent such as magnesium oxide, magnesium carbonate, aluminium hydroxide, magnesium hydroxide, calcium carbonate, sodium carbonate, potassium carbonate and the like is employed in the drug layer.
28. A process as claimed in claims 24 to 27 wherein the amount of alkaline agent used ranges from 5.00 to 60.00 mg per capsule / tablet, more preferably 10.00 to 50.00 mg per capsule / tablet.
29. A process as claimed in claims 24 to 28 wherein the diluent used is selected from
microcrystalline cellulose. Lactose, Mannitol, dextrose, and the like.
30. A process as claimed in claim 29 whereinjhe amount of diluent employed in the drug layer ranges from 5.00 to 60.00 mg per capsule / tablet preferably 8.00-40.00mg per capsule / tablet.
31. A process as claimed in claim 24 to 30 wherein the drug layer contains an anti-adherent agent selected from talc, aerosil, calcium stearate and the like and its amount ranges from 1.00 to 20.00 mg per capsule / tablet, more preferably 2.00 to 15.00 mg per capsule / tablet.
32. A process as claimed in claim 24 to 31 wherein the binder used is selected from
Hydroxypropyl methylcellulose, Hydroxy ethyl cellulose. Polyvinylpyrrolidone and the like
and its e amount ranges from 2.00 to 30.00mg per capsule / tablet more preferably 4.00 to
25.00mg per capsule or tablet.
33. A process as claimed in claim 24 to 32 wherein the preservative when employed is
selected from sodium benzoate, sodium metabisulfite, sodium sulfite, sodium bisulfite and
the like and its amount ranges from 0.20 to 5.00mg per capsule / tablet , more preferably
0.50 to 4.00 mg per capsule / tablet
34. A process as claimed in claims 24 to 33 wherein the binder is dissolved in organic
solvent selected from Isopropyl alcohol, methylene chloride, ethyl alcohol, acetone or a
mixture thereof

35. A process as claimed in claims 24 to 34 wherein the polymer employed in the intermediate layer is selected from polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxy propyl cellulose, sodium carboxy methyl cellulose, carboxy methyl cellulose and the like or a mixture thereof.
36. A process as claimed in claim 35 wherein the amount of polymer employed in intermediate layer ranges from 2.00 to 50.00 mg per capsule / tablet, more preferably 5.00 to 40.00,mg per capsule / tablet.

37. A process as claimed in claims 24 to 36 wherein the diluent used in the Intermediate layer is selected from microcrystalline cellulose, lactose, mannitol and the like and its amount ranges from 2.00 to 50.00mg per capsule / tablet, more preferably 3.00 to 40.00mg per capsule/ tablet.
38. A process as claimed in claims 24 to 37 wherein the anti-adherent agent is selected from talc, aerosol, calcium stearate and the like and its amount ranges from 1.00 to 20.00 mg per capsule / tablet, more preferably 2.00 to 15.00 mg per capsule or tablet.
39. A process as claimed in claims 24 to 38 wherein the organic solvent such as isopropyl alcohol, ethyl alcohol, acetone, methylene chloride and the like or mixture thereof is used to dissolved the polymer.
40. A process as claimed in claims 24 to 39 v^erein for the enteric coating of the polymer is selected from cellulose derivatives and acrylic derivatives.
41. A process as claimed in claim 40 wherein the cellulose derivatives are selected from Hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate and the like and the acrylic derivatives are selected from Eudragit L 100-55 and the like.
42. A process as claimed in claims 39 & 40 wherein the amount of polymer used ranges from 10.00 to lOO.OOmg per capsule / tablet, more preferably 20.00 to 80.00mg per capsule / tablet.

43. A process as claimed in claims 24 to 42 wherein the plasticizer is selected from
phthalate derivatives such as diethyl phthalate, dibutyl phthalate, dioctyl phthalate and
the like and of fatty alcohol derivatives such as cetyl alcohol, stearyl alcohol and the like
or mixture of phthalate & fatty alcohol.
44. A process as claimed in claim 43 wherein the amount of plasticizer used ranges from
3.00 to 30.00mg per capsule / tablet, more preferably 4.00 to 24.00 mg per capsule /
tablet.
45. A process as claimed in claims 24 to 44 wherein antiadherent used is selected from
talc, colloidal silicon dioxide and the like and its amount ranges from 2.00 to 16.00mg
per capsule / tablet, more preferably 3.00 to 12.00mg per capsule / tablet.
46. A process as claimed in claims 24 to 45 wherein enteric coating contains a coloring agent such as titanium dioxide, iron oxide and mixture thereof and its amount of coloring agent ranges from 0.025 to 3.00mg per capsule / tablet, more preferably 0.05 to 2. 50 mg per capsule / tablet.
47. A process as claimed in 24 to 46 wherein the formulation contains a organic solvent used in enteric coating is selected from isopropyl alcohol, ethyl alcohol, acetone, methylene chloride and the like or mixture thereof is used to dissolve the polymer.
48. An improved pharmaceutical formulation containing aspirin which is resistant to acid media and dissolves in neutral to alkaline media and having good stability and useful for the prevention of cardiovascular disease substantially as herein described with reference to the Examples 1 to 4.

49. A process for the preparation of an improved pharmaceutical formulation containing aspirin which is resistant to acid media and dissolves in neutral to alkaline media and having good stability and useful for the prevention of cardiovascular disease.

Documents:

165-mas-2003 abstract granted.pdf

165-mas-2003 claims granted.pdf

165-mas-2003 description (complete) granted.pdf

165-mas-2003-abstract.pdf

165-mas-2003-claims.pdf

165-mas-2003-correspondnece-others.pdf

165-mas-2003-correspondnece-po.pdf

165-mas-2003-description(complete).pdf

165-mas-2003-form 1.pdf

165-mas-2003-form 19.pdf

165-mas-2003-form 5.pdf

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Patent Number

219211

Indian Patent Application Number

165/MAS/2003

PG Journal Number

23/2008

Publication Date

06-Jun-2008

Grant Date

28-Apr-2008

Date of Filing

03-Mar-2003

Name of Patentee

NATCO PHARMA LIMITED

Applicant Address

Inventors:

#	Inventor's Name	Inventor's Address
1	RAMA RAO PENDYALA
2	KHADGAPATHI PODILI
3	VENKAIAH CHOWDARY NANNAPANENI

PCT International Classification Number

A61K31/70

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA