Title of Invention	NOVEL STABLE PHARMACEUTICAL COMPOSITIONS OF A BETA-ADRENORECEPTOR BLOCKER AND A CALCIUM CHANNEL BLOCKER
Abstract	A stable solid pharmaceutical composition for oral administration comprising Amlodipine besylate or maleate and Bisoprolol fumarate and pharmaceutically acceptable excipients

Full Text

FORM 2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION [See section 10, rule 13] "Novel stable pharmaceutical compositions of a beta-adrenoreceptor blocker and a calcium channel blocker" (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 this invention and the manner in which it is to be performed: Technical field of the invention This invention relates to novel stable pharmaceutical compositions comprising a dihydropyridine class calcium channel blocker drug, such as amlodipine either racemic or its enantiomer or its salts and a synthetic beta selective adrenoreceptor blocker, bisoprolol fumarate. The said salts of amlodipine are besylate or maleate and the said enantiomer is s-isomer. This invention also relates to different processes for preparing the said stable pharmaceutical composition. Further the present invention relates to stable composition useful in certain cardiovascular diseases like hypertension, chronic stable angina, vasospastic angina. Background and prior art Amlodipine besylate is chemically described as 3-ethyl-5-methyl-2-(2-aminoethoxy methyl ) - 4- (2-chloro phenyl)- 1,4- dihydro - 6 -methyl- 3,5-pyridinedicarboxylate benzenesulphonate. Its empirical formula is: C20H25CIN2O5C6H6O3S. It inhibits the transmembrane influx of calcium ions into vascular smooth muscles and cardiac muscles. Therefore, is used for the treatment of angina and hypertension. Amlodipine besylate is commercially available as Norvasc (Pfizer) in the form of oral tablets in 2.5 mg, 5 mg and 10 mg base preparations. Amlodipine is well absorbed in gastrointestinal tract. After oral administration, absorption produces peak plasma concentrations between 6 and 12 hours. Absolute bioavailability has been estimated to be between 64 and 90%. The bioavailability of amlodipine besylate is not altered by the presence of food. Plasma protein binding for Amlodipine is high in man corresponding to 97%. It is extensively converted to inactive metabolites via hepatic metabolism. Amlodipine besylate has good solubility, stability, non-hygroscopicity, processibility for tablet formulation. Due to a unique combination of good formulation properties, it is extremely suitable for the preparation of pharmaceutical formulations of Amlodipine. US patent application 2003220312 describes co-administration or sequential administration of two compounds for treating a variety of circulatory disorders including cardiovascular disorders, such as hypertension, congestive heart failure, myocardial fibrosis and cardiac hypertrophy. The first compound is characterized by a steroid-type nucleus with an epoxy moiety attached to the nucleus and having competitive aldosterone receptor binding activity. The second compound is a calcium channel blocker, preferably, amlodipine besylate. Administration may be accomplished by oral route, or by intravenous, intramuscular or subcutaneous injections. This combination has demonstrated therapeutic efficacy and safety with therapeutic benefit of the combination treatment over a mono-therapeutic regimen. Amlodipine is used in combination with statin compounds. This synergistic combination is useful for treating subjects suffering from angina pectoris, atherosclerosis, combined hypertension and hyperlipidemia and for subjects with symptoms of cardiac risk. Such pharmaceutical compositions of amlodipine and atorvastatin are described in patent CA2444554. The said patent also describes methods of preparing stable pharmaceutical compositions comprising atorvastatin and amlodipine, and a kit suitable for commercial sale. A beta blocker can also be combined with lipid lowering agent, where beta blocker can be bisoprolol, to get useful prevention of clinical events associated with the progression of atherosclerosis and/or acute vascular accidents related to atherosclerotic disease and plaque which is disclosed in patent application US 20030191177. US patent 6,670,355 discloses a novel method of treating cardiovascular disease. In accordance with this invention, rapamycin may be used as the sole active ingredient to provide the cardiovascular, cerebral, or peripheral vascular benefits. It can also be administered in combination with other agents. These other agents can be from various therapeutic classes having activity such as ACE inhibitors; angiotensin II receptor antagonists; fibric acid derivatives; HMG Co-A reductase inhibitors; beta adrenergic blocking agents; calcium channel blockers; antioxidants; anticoagulants; and agents useful in hormone replacement therapy containing estrogens. Rapamycin has been used in combination with amlodipine as well as bisoprolol, individually. Angiogenesis, the process of forming new blood vessels, plays an important role in a variety of normal processes. However, undesirable or pathological angiogenesis has been associated with a number of disease states including diabetic retinopathy, psoriasis, cancer, etc. US patent application 20030144298 describes therapeutic combinations of antihypertensive and anti angiogenic agents in which, antihypertensive agent can be from calcium channel blocker group, beta blocker etc. Thus adrenergic blocking agents and calcium channel blocking agent are used in combination with various therapeutic agents to obtain desired effect. Combination of adrenergic blocking agents and calcium channel blocking agent is also very useful. US Patent 4,794,111 (Bayer) discloses a composition comprising a synergistically effective mixture of dihydropyridine adrenergic drugs selected from the group containing Nisolidipine, Nimodipine and Nitrenidipine and a blocker drug selected from the group containing Atenolol, Sotalol, Timolol and Nadolol. AU6767198 discloses pharmaceutical combination product of a beta -blocker drug atenolol with a calcium channel blocker drug-Amlodipine besylate. It is useful in conditions like Angina pectoris, myocardial infarction, and hypertension. This patent also discloses different processes for preparing such combination product. There are various patents like US6,350,398; US6,284,803; US6,120,802; US6,001,391 which describe innovative manufacturing processes which are useful in manufacturing of different dosage forms of various drugs including amlodipine or bisoprolol, but not the combined preparation of these two drugs. None of the above mentioned prior art disclose a stable combination of the two drugs amlodipine, either racemic or its enantiomer or its salts and bisoprolol fumarate and the process for preparation and pharmaceutical composition of the said combination. Thus there exists a need to introduce a stable pharmaceutical composition comprising a combination of amlodipine and bisoprolol. Objective The main objective of this invention is to develop novel stable pharmaceutical compositions of adrenergic blocking agent, preferably bisoprolol fumarate and calcium channel blocking agent, preferably amlodipine either racemic or its enantiomer or its salts to treat various cardiovascular diseases. Amlodipine besylate and bisoprolol fumarate both being acid addition salt may react with each other leading to chemical instability thus making it difficult to use conventional tabletting methods. Hence a further objective of the present invention is to develop a method to avoid the possibility of detrimental chemical reaction between these two drugs which will provide the said stable pharmaceutical composition. SUMMARY OF THE INVENTION The present invention relates to novel stable solid pharmaceutical compositions for oral administration comprising a calcium channel blocker such as amlodipine; a synthetic betal - selective adrenoreceptor blocking agent, such as bisoprolol fumarate; and pharmaceutically acceptable excipients to the individuals suffering with certain cardiovascular ailments. The said amlodipine may be in the form of racemic mixture or S(-) isomer or its salts. The said salts are amlodipine besylate or maleate, preferably amlodipine besylate. The amount of the said amlodipine besylate is in the range of 3.0 to 15.0 mg equivalent to amlodipine free base, preferably 5 mg. The amount of the said bisoprolol fumarate is in the range of 2 to 15 mg, preferably 5 mg. The said pharmaceutical composition of amlodipine besylate and bisoprolol fumarate according to the invention is preferably in the solid dosage form, such as tablets, pills, granules, capsules or sachets, preferably tablets. The present invention further discloses different processes for preparing the said stable pharmaceutical composition of amlodipine besylate with bisoprolol fumarate. The term "amlodipine" used herein is intended to include amlodipine in racemic form or its enantiomer particularly s-enantiomer or its salts such as maleate, besylate, preferably besylate. DETAILED DESCRIPTION The present invention relates to novel stable solid pharmaceutical compositions for oral administration which comprises a dihydropyridine calcium channel blocker drug such as amlodipine and a synthetic betai-selective (cardioselective) adrenoreceptor blocking agent such as bisoprolol fumarate, along with pharmaceutically acceptable excipients. The dose range of amlodipine besylate in the said composition is 3.0 - 15.0 mg of base and dose range for bisoprolol fumarate is 2-15mg. Most preferred dose range of amlodipine besylate in the said composition is 5 mg equivalent to amlodipine and for bisoprolol fumarate is 5 mg. The present pharmaceutical composition comprises amlodipine besylate and bisoprolol fumarate in combination with pharmaceutically acceptable excipients selected from diluents, binders, flavors, preservatives, pH adjuster, alkalizing agent, disintegrating agents, film formers, plasticizers, lubricants and / or glidants. When conventional techniques of tabletting were attempted for formulating the said invention, it was noticed that there was about 5 to 10% decrease in amlodipine content during the stability study at 40°C, 75% Rh within a month. Therefore, the conventional techniques where both the drugs were mixed and blended with diluents like lactose and microcrystalline cellulose and subsequently granulated with starch paste; or when the two drugs were granulated separately such that amlodipine besylate was mixed with microcrystalline cellulose and granulated with alcoholic solution of povidone and bisoprolol fumarate was separately granulated with starch paste along with diluents lactose and microcrystalline cellulose, the dried granules of both drugs were mixed and compressed into tablets, all failed. Amlodipine besylate and bisoprolol fumarate both being acid addition salts may react with each other leading to chemical instability thus making it difficult to use conventional tabletting methods. There exists a need to provide a method to avoid the possibility of detrimental chemical reaction between these two drugs. An embodiment of the present invention provides a process for preparing a stable pharmaceutical composition comprising a bisoprolol fumarate and a amlodipine besylate. The said process comprises (i)moist granulating bisoprolol fumarate along with selected excipients; (ii) moist granulating amlodipine besylate together with selected excipients; (iii) blending granules of bisoprolol and amlodipine with selective excipients; and (iv) filling the said blend into hard gelatin capsules or compressing the said blend into tablets with or without coating. Alternatively granules can be prepared using a non¬aqueous solution of povidone. Another embodiment of the present invention provides a process for preparing the stable pharmaceutical composition comprising (i) granulating bisoprolol fumarate with excipients using a moist granulation process or dry compaction process; (ii) blending amlodipine besylate with few select excipients (iii) lubricating the said granules from (i) and blend from (ii) and compressing the said blend into tablets using standard compression tooling known in the art or filling into capsules or sachets for human oral administration. Yet another embodiment of the present invention provides a process for preparing the stable pharmaceutical composition comprising (i) granulating Bisoprolol together with carefully screened excipients using a moist granulation process or dry compaction process, (ii) granulating amlodipine together with select excipients using moist granulation process and (iii) compressing the said granules from (i) and (ii) into two layer tablets characterized by the presence of the two drug substances in two different layers, using standard compression tooling known in the art. The carefully screened pharmaceutically acceptable excipients used in the abovementioned process are selected from diluents, binders, disintegrants, lubricants, glidants, flavours, alkalizing agents, preservatives, sweeteners, film formers and plasticizers either alone or in combination thereof. The said diluents are microcrystalline cellulose, calcium phosphate, maize starch, or their modified forms. The said diluents are used in the range of 5-95% of tablet weight. The said binders are selected from the group containing maize starch, polyvinylpyrrolidone, preferably maize starch. The said maize starch is used in the range of 2-10%. The said disintegrants are selected from the group containing starch, derivative of starch., preferably sodium starch glycolate. The said sodium starch glycolate is used in the range of 1-5%. The said lubricants and glidants are selected from the group containing magnesium stearate, and colloidal silicon dioxide. The film formers are selected from the group of polymers such as hydroxypropyl methyl cellulose. The said plasticizers are selected from the group of glycols such as polyethylene glycol 6000. Other miscellaneous auxiliaries required for processing the product and maintaining its stability. The pH of the said composition is within the range of 5.0-8.0, preferably 5.5-7.0 The said stable composition may be in the dosage form of tablets, bilayered tablets, capsules and sachets. The said tablet may be film coated. The said tablet may be coated with hydroxypropylmethylcellulose, talc, titanium dioxide, polyethylene glycol 6000, iron oxide. The said composition of amlodipine besylate and bisoprolol fumarate is physically and chemically stable over its shelf life period. The following examples are merely illustrative of the present invention and should not be considered as limiting the scope of the invention in any way, as these examples and other equivalents thereof will become more apparent to those versed in the art in the light of the present invention disclosure and the accompanying claims. Each example described below contains bisoprolol fumarate 5.0mg and amlodipine besylate equivalent to amlodipine 5.0mg or the S-isomer form of amlodipine 5.0-mg. Preparation of bisoprolol fumarate granules: Bisoprolol fumarate, maize starch, dicalcium phosphate anhydrous, microcrystalline cellulose, sodium starch glycolate were mixed geometrically after sifting through mesh 40. This blend was granulated with starch paste using moist granulation. Wet granules were milled through mesh 8. Granules were dried at 40-50°C. Dried granules were sifted through mesh 20. B) Amoldipine besylate granules: Contains 5 mg of amlodipine base along with the following excipients. Preparation of amlodipine besylate granules Amlodipine besylate, maize starch, dicalcium phosphate anhydrous, microcrystalline cellulose, sodium starch glycolate were mixed geometrically after sifting through mesh 40. This blend was granulated with starch paste using moist granulation. Wet granules were milled through mesh 8. Granules were dried at 40-50°C.Dried granules were sifted through mesh 20. C) Solid dosage form I) Tablet II) Capsule Granules of bisoprolol fumarate and amlodipine besylate were mixed together and further lubricated and compressed into tablets or filled into capsules. 10 % solution of these tablets had pH in the range of 5.0-8.0. The said tablets were optionally coated with hydroxypropylmethylcellulose, talc, titanium dioxide, polyethylene glycol 6000, iron oxide till 2% weight gain was achieved. The stability data of above mentioned dosage form is as follows: Bisoprolol fumarate, maize starch, dicalcium phosphate anhydrous and microcrystalline cellulose were mixed geometrically after sifting through mesh 40. This blend was granulated with starch paste using moist granulation process. Wet granules were milled through mesh 8. Granules were dried at 40-50°C. Dried granules were sifted through mesh 20. B)Amoldipine besylate granules: Contains 5 mg of amlodipine base along with the following excipients. Preparation of amlodipine besylate dry mix Amlodipine besylate was mixed with granular dicalcium phosphate, avicel PH200, sodium starch glycolate, after sifting through mesh 40. C) Solid dosage form I) Tablet II) Capsule Bisoprolol fumarate granules and amlodipine besylate dry mix were mixed together and then lubricated with lubricant. The lubricated mixture was compressed into tablets using standard compression tooling known in the prior art. The said lubricated mixture may be filled into capsules or sachets. Bisoprolol fumarate granules and amlodipine besylate dry mix was lubricated using the following lubricants as follows: Tablets were optionally coated with hydroxypropylmethylcellulose, talc, titanium dioxide, polyethylene glycol 6000, and iron oxide till 2% weight gain was achieved. Example - III A) Bisoprolol fumarate granules: Contains 5 mg of Bisoprolol fumarate along with the following excipients Preparation of bisoprolol fumarate granules Bisoprolol fumarate, maize starch, dicalcium phosphate anhydrous, microcrystalline cellulose, sodium starch glycolate were sifted through 40mesh and were mixed geometrically. This blend was granulated with starch paste. Wet granules were milled through mesh 8. Granules were dried at 40-50°C. Dried granules were sifted through mesh 20. Sodium starch glycolate and colloidal silicone dioxide were sifted through mesh 40 and mixed with bisoprolol granules. The said blend was then lubricated with magnesium stearate. B) Amoldipine besylate granules: Contains 5 mg of amlodipine base along with the following excipients. Amlodipine besylate, maize starch, dicalcium phosphate anhydrous, microcrystalline cellulose, sodium starch glycolate, red iron oxides were sifted through mesh 40 and mixed. This blend was granulated with starch paste by moist granulation process. Wet granules were milled through mesh 8 and dried at 40-50°C. Dried granules were sifted through mesh 20. Sodium starch glycolate and colloidal silicone dioxide were sifted through mesh 40 and mixed with amlodipine besylate granules. It was then lubricated with magnesium stearate. C) Bilayered tablet Granules of each layer were fed in respective hoppers and compressed into bilayered tablets. We Claim, 1. A stable solid pharmaceutical composition for oral administration comprising Amlodipine besylate or maleate and Bisoprolol fumarate and pharmaceutically acceptable excipients. 2. The pharmaceutical composition as claimed in claim 1 wherein the said Amlodipine is in the form of racemic mixture or S (-) isomer. 3. The pharmaceutical composition as claimed in claim 1, wherein the amount of the said Amlodipine besylate is in the range of 3.0 to 15.0mg equivalent to amlodipine free base, preferably 5mg. 4. The pharmaceutical composition as claimed in claim 1, wherein the amount of the said Bisoprolol fumarate is in the range of 2 to 15 mg, preferably 5mg. 5. The pharmaceutical composition as claimed in claim 1, wherein the said pharmaceutically acceptable excipients are selected from diluents, binder, disintegrants, lubricants, glidants, flavours, alkalizing agents, preservatives, sweetners, film formers and plasticizers either alone or in combination thereof. 6. The pharmaceutical composition as claimed in claim 1 to 5, wherein the said diluents are selected from microcrystalline cellulose, calcium phosphate, maize starch, or their modified forms used in the range of 5-95% of tablet weight. 7. The pharmaceutical composition as claimed in claim land 5, wherein the said binders are selected from the group comprising maize starch, polyvinylpyrrolidone preferably maize starch used is in the range of 2-10%. 8. The pharmaceutical composition as claimed in claim land 5, wherein the said disintegrants are selected from the group comprising starch or its derivatives such as sodium starch glycolate used is in the range of 1-5%. 9. The pharmaceutical composition as claimed in claim 1 and 5, wherein the said lubricants and glidants are selected from the group comprising magnesium stearate, and colloidal silicon dioxide. 10. The pharmaceutical composition as claimed in claim land 5, wherein the film formers are selected from the group of polymers such as hydroxypropyl methyl cellulose. 11. The pharmaceutical composition as claimed in claim 1 and 5, wherein the said plasticizers are selected from the group of glycols such as polyethylene glycol 6000. 12. The pharmaceutical composition as claimed in claim 1, wherein the pH of the said composition is within the range of 5.0-8.0, preferably 5.5-7.0. 13. The pharmaceutical composition as claimed in claim 1 to 12, wherein the said stable composition is in the dosage form of tablets, bilayered tablets, capsule or sachets. 14. The pharmaceutical composition as claimed in claim 13, wherein the said tablet is optionally film coated. 15. A process for the preparation of the said pharmaceutical composition as claimed in claim 1 to 14, wherein the said process comprises granulating Bisoprolol fumarate together with selected excipients by moist granulation process or dry compaction process; blending the said Bisoprolol fumarate granules together with Amlodipine besylate and selected excipients to obtain blend; lubricating the said blend and compressing the said lubricated blend into tablets or filling into hard gelatin capsules. 16. A process for the preparation of the said pharmaceutical composition as claimed in claim 1 to 15, wherein the said process comprises granulating Bisoprolol Fumarate together with selected excipients by moist granulation process; preparing dry mix of amlodipine Besylate together with selected excipients; blending the said granules of Bisoprolol Fumarate with the said granules of amlodipine Besylate and selected lubricants and compressing the said blend into tablets or filling into hard gelatin capsules or sachets. 17. A process for the preparation of the said pharmaceutical composition as claimed in claim 1 to 15, wherein the said process comprises granulating Bisoprolol fumarate together with selected excipients by moist granulation process; blending the said granules of Bisoprolol fumarate with disintegrants, lubricants and glidants; Amlodipine besylate mixed together with selected excipients by moist granulation process; blending the said granules of Amlodipine besylate with disintegrants, lubricants and glidants and compressing the said two blends into bilayered tablet where each layer represents blend comprising single active ingredient with excipients. Dated this 5th day of August 2004 Dr. Gopakumar G. Nair Agent of the Applicant

Documents:

845-mum-2004-cancelled pages(10-07-2008).pdf

845-MUM-2004-CLAIMS(10-7-2008).pdf

845-mum-2004-claims(granted)-(05-08-2004).doc

845-mum-2004-claims(granted)-(10-07-2008).pdf

845-MUM-2004-CORRESPONDENCE(10-7-2008).pdf

845-mum-2004-correspondence(ipo)-(07-10-2008).pdf

845-mum-2004-correspondence1(28-05-2008).pdf

845-mum-2004-correspondence2(10-07-2008).pdf

845-mum-2004-form 1(05-08-2004).pdf

845-mum-2004-form 18(05-11-2006).pdf

845-mum-2004-form 2(granted)-(05-08-2004).doc

845-mum-2004-form 2(granted)-(10-07-2008).pdf

845-mum-2004-form 26(13-07-2006).pdf

845-mum-2004-form 3(05-08-2004).pdf

845-mum-2004-form 3(17-12-2007).pdf