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(12) Patent Application Publication (10) Pub. No.: US 2010/0204195 A1 Lulla Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2010/0204195 A1 Lulla Et Al US 20100204195A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0204195 A1 Lulla et al. (43) Pub. Date: Aug. 12, 2010 (54) PHARMACEUTICAL COMPOSITIONS AND Publication Classification PROCESS FOR MAKING THEMI (51) Int. Cl. A 6LX 3L/397 (2006.01) (75) Inventors: Amar Lulla, Mumbai (IN); Geena A 6LX 3L/505 (2006.01) Malhotra, Mumbai (IN) A6II 3/448 (2006.01) A6II 3/47 (2006.01) Correspondence Address: A6II 3/44 (2006.01) CONLEY ROSE, PC. A63L/404 (2006.01) 5601 GRANITE PARKWAY, SUITE 750 A6II 3/40 (2006.01) PLANO, TX 75024 (US) A63L/366 (2006.01) A6II 3L/26 (2006.01) (73) Assignee: CIPLA LIMITED, Mumbai (IN) A6IPA63L/92 9/00 :2006.O1 OO6. 8: A6IP3/00 (2006.01) (21) Appl. No.: 12/670,717 A6IP3/10 (2006.01) A6IP 9/10 (2006.01) (22) PCT Filed: Jul. 28, 2008 (52) U.S. Cl. .................... 514/210.02: 514/275: 514/277; 514/311 514/356; 514/419:514/423: 514/460; (86). PCT No.: PCT/GB08/O2S67 514/533; 514/543; 514/571 S371 (c)(1), (57) ABSTRACT (2), (4) Date: Apr. 7, 2010 Amorphous HMG CoA reductase inhibitors, especially amorphousatorvastatin, are described. Also described are (30) Foreign Application Priority Data pharmaceutical combinations comprising amorphous HMG CoA reductase inhibitors in combination with cholesterol Jul. 27, 2007 (IN) ......................... 1446/MUM/2007 absorption inhibitors or fibrates. A method of manufacturing Jul. 31, 2007 (IN) ......................... 145OFMUMA2007 the compositions using a hot melt extrusion process are also Dec. 12, 2007 (IN) ......................... 2432AMUMA2007 described. Patent Application Publication Aug. 12, 2010 US 2010/0204195 A1 0007 US 2010/0204195 A1 Aug. 12, 2010 PHARMACEUTICAL COMPOSITIONS AND 0005. There are different types of cholesterol reducing PROCESS FOR MAKING THEMI agents that can be used. 0006. One such type is HMG-CoA reductase inhibitors, CROSS-REFERENCE TO RELATED often called “statins, which lower the level of cholesterol in APPLICATIONS the blood by reducing the production of cholesterol by the liver. Statins block the enzyme hydroxy-methylglutaryl-co 0001. This application is a filing under 35 U.S.C. 371 of enzyme A reductase (HMG-CoA reductase) in the liver. Sci International Application No. PCT/GB2008/002567 filed Jul. entifically, statins are referred to as HMG-CoA reductase 28, 2008, entitled “Pharmaceutical Compositions and Pro inhibitors. Statins are widely known for the treatment or cess for Making Them” claiming priority of Indian Patent prophylaxis of hyperlipidemia. Statins are the most effective Application Nos. 1446/MUM/2007 filed Jul. 27, 2007, 1450/ cholesterollowering agents available and in recent years have MUM/2007 filed Jul. 31, 2007, and 2432/MUM/2007 filed received increased attention for their benefits beyond helping Dec. 12, 2007, which applications are incorporated by refer patients with high cholesterol. Drugs in this group include: ence herein in their entirety. atorvastatin: cerivastatin: fluvastatin; lovastatin: pravastatin: FIELD OF THE INVENTION simvastatin; and rosuvastatin and the like. 0007 Atorvastatin calcium is R-(R*,R*)-2-(4-fluo 0002 The present invention relates to pharmaceutical rophenyl)-(beta), delta-dihydroxy-5-(1-methylethyl)-3- compositions comprising one or more cholesterol reducing phenyl-4-(phenylamino)carbonyl)-1H-pyrrole-1-heptanoic agents in an amorphous form. The invention also relates to acid, calcium salt (2:1) trihydrate. Atorvastatin calcium as a processes for the preparation of the pharmaceutical compo new chemical entity is described in U.S. Pat. No. 5.273,995. sitions. 0008 Treatment with statins results in significant lower ing of LDL cholesterol. This leads to significant reductions in BACKGROUND OF THE INVENTION cardiovascular morbidity and mortality. However, even with 0003 Cholesterol is a chemical that can both benefit and low levels of LDL cholesterol, patients with diabetes and harm the body. On the good side, cholesterol plays important metabolic syndrome continue to have a relatively high car roles in the structure of cells and in the production of hor diovascular event rate, mainly due to the presence of athero mones. Buttoo much cholesterol in the blood can lead to heart genic dyslipidemia, characterized by high triglycerides and and blood vessel disease. One type, of cholesterol called small dense LDL and low HDL. Treatment with fibrates high-density lipoprotein (HDL) cholesterol, or “good choles results in a substantial decrease in plasma triglycerides and is terol actually lowers the risk of these problems but the other usually associated with a moderate decrease in LDL choles type, low-density lipoprotein (LDL) cholesterol, or “bad cho terol and an increase in HDL cholesterol concentrations An lesterol. is the type that threatens people's health. Hyperc important clinical challenge exists in reducing residual (coro holesterolemia and hyperlipidemia, conditions of excessively nary artery disease) (CAD) risk with optimal therapies with high levels of blood cholesterol and lipids, are well recog out increasing adverse effects. nized risk factors in the onset of atherosclerosis and coronary 0009. Another class of drugs, i.e. certain hydroxy-substi heart disease. tuted azetidinones such as eZetimibe (described in U.S. Pat. 0004 For several decades, it has been known that elevated No. 5,767,115 and Re. 37721), also known as cholesterol blood cholesterol is a major risk factor for coronary heart absorption inhibitors are known to be useful as hypocholes disease (CHD), and many studies have shown that the risk of terolemic agents in the treatment and prevention of athero CHD events can be reduced by lipid-lowering therapy. Prior Sclerosis. Cholesteryl esters are a major component of ath to 1987, the lipid-lowering armamentarium was limited erosclerotic lesions and the major storage form of cholesterol essentially to a low saturated fat and cholesterol diet, the bile in arterial wall cells. Thus, inhibition of cholesteryl ester acid sequestrants (cholestyramine and colestipol), nicotinic formation and reduction of serum cholesterol is likely to acid (niacin), the fibrates and probucol. Unfortunately, all of inhibit the progression of atherosclerotic lesion formation, these treatments have limited efficacy or tolerability, or both. decrease the accumulation of cholesteryl esters in the arterial Substantial reductions in LDL (low density lipoprotein) cho wall, and block the intestinal absorption of dietary choles lesterol accompanied by increases in HDL (high density lipo terol. protein) cholesterol could beachieved by the combination of 0010 “Fibrates' are a class of drugs that lower blood a lipid-lowering diet and a bile acid sequestrant, with or triglyceride levels by reducing the liver's production of without the addition of nicotinic acid. However, this therapy VLDL (the triglyceride-carrying particle that circulates in the is not easy to administer or tolerate and was therefore often blood) and by speeding up the removal of triglycerides from unsuccessful except in specialist lipid clinics. The fibrates the blood. Fibrates are also modestly effective in increasing produce a moderate reduction in LDL cholesterol accompa blood HDL cholesterol levels; however, fibrates are not effec nied by increased HDL cholesterol and a substantial reduc tive in lowering LDL. Fibrates are widely known for the tion in triglycerides, and because they are well tolerated these treatment or prophylaxis of hyperlipidemia. drugs have been more widely used. Probucol produces only a (0011 US 2005/0171207 relates to a pharmaceutical com small reduction in LDL cholesterol and also reduces HDL position comprising a combination of R-Flurbiprofen and an cholesterol, which, because of the strong inverse relationship HMG CoA reductase inhibitor and method of treating Alzhe between HDL cholesterol level and CHD risk, is generally imer's disease. considered undesirable. With the introduction of lovastatin, (0012 WO2005/097191 relates to a pharmaceutical com the first inhibitor of HMG-CoA reductase to become avail position comprising optically pure (S)-amlodipine and a able for prescription in 1987, for the first time physicians HMG CoA reductase inhibitor. The application also discloses were able to obtain large reductions in plasma cholesterol a composition comprising optically pure (S)-amlodipine and with very few adverse effects. a cholesterol absorption inhibitor. US 2010/0204195 A1 Aug. 12, 2010 0013 WO2003/013.608 discloses to a semisolid dosage The advantage of an amorphous active Substance over a crys formulation comprising fibrates and statins. However, manu talline form is particularly evident in case of less soluble facturing process involves melting the ingredients and filling Substances such as, for example, atorvastatin calcium, and it in capsules, which is deleterious to some of the active ingre is manifested in better bioavailability of an active substance. dients. Also, the assessment of the quality of semi-solid lipid 0023 The use of a pharmaceutical formulation compris based formulations is quite difficult since the in vitro disso ing amorphous active Substance is advantageous over a phar lution test is of little help. Indeed, the in vitrofin vivo corre maceutical formulation comprising a crystalline Substance lation between dissolution and bioavailability is very poor for because the amorphous Substance dissolves faster and better the kind of formulation given in the invention. Only pharma which is an important factor for bioavailability of the active cokinetic
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