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 studies on human Subjects are reliable to assess the substance in the body. It is well known that the stability of an bioavailability of the drug. active Substance depends on the polymorphous form in which 0014 U.S. Pat. No. 6,534,088 discloses an orally admin it exists and that an amorphous form is less stable than a istered pharmaceutical composition comprising a statin and crystalline form indicating that an amorphous form compared fenofibrate in the form of microparticles of solid fenofibrate to a crystalline form is even more Susceptible to heat, light, that are stabilized by phospholipid as a surface active sub moisture and low pH. All these factors are of key importance stance. The microparticles have been prepared by a process for the stability of a pharmaceutical formulation comprising Such as homogenization, microfluidization, hot melt microf an amorphous Substance. Impurities generated at degradation luidization, and sonication so that the bioavailability of the of an active substance reduce the therapeutic effect of an drugs given in the dosage form improves. However, the for active Substance and additionally unnecessarily burden the mulation of the invention includes a range of excipients other body with unnecessary degradation products. than active ingredients. Further, the method of preparation of 0024. Atorvastatin calcium can exist in an amorphous microparticles may lead to inactivation of some ingredients. form or in different crystalline forms which are disclosed in 0015 US2007/099891 discloses a pharmaceutical com the patent applications WO 97/3958: WO 97/3959; WO position comprising a statin and/or eZetimibe and ACAT 01/36384: WO 02/41834; WO 02/43732:WO 02/.51804; and inhibitor (Acyl co-enzyme A cholesterol O acyl transferase WO 02/57229. The processes for the preparation of amor inhibitor). phousatorvastatin calcium are described in the patent appli 0016 U.S. Pat. No. 7,229,982 relates to a pharmaceutical cations WO 97/3960, WO 00/71116; WO 01/28.999; WO composition comprising eZetimibe, simvastatin, BHA and 01/42209; WO 02/57228; and WO 02/59087. citric acid in specific concentration. 0025 U.S. Pat. No. 7,151,183 relates to the preparation of 0017 Environmental influences may degrade not only the amorphousatorvastatin calcium by dissolving the crystalline active Substance(s) in a pharmaceutical dosage form, under goes degradation by environmental influences but also the form in acetone, and then recovering the amorphous form excipient(s) in a pharmaceutical dosage form may be from acetone. degraded. The degradation products of the latter may act as (0026 U.S. Pat. No. 7,230,120 relates to preparation of the reactive sites which trigger degradation reactions of the atorvastatin calcium using methanol. active Substance in a pharmaceutical dosage form. (0027 U.S. Pat. No. 6,528,660 relates to dissolving crys 0018. Among the environmental factors which have an tallineatorvastatin calcium in a nonhydroxylic solvent, then impact on an active Substance are, for example, temperature, adding a nonpolar hydrocarbon anti-solvent to precipitate out humidity, light, (e.g., UV light) and gases, present in the amorphousatorvastatin calcium. environment Such as, e.g., oxygen or carbon dioxide. An (0028 US20070066835 relates to a process of for making important factor is also the pH of the environment, that is, the the amorphous form by dissolving the salt in a mixture of presence of substances which have influence on the acidity or water and water miscible organic solvent. alkalinity of the environment (e.g., acids, alkalis, salts, metal 0029. It is known from the patent and relevant other litera oxides) and the reactivity of the ambient medium or active ture that atorvastatin calcium is an unstable Substance which Substance (free radicals, heavy metals), etc. is susceptible to heat, moisture, light and low pH at which 0019. It is well known that for prevention or reduction atorvastatin calcium is converted from the carboxylic acid degradation of active Substances from getting degraded due to form to the lactone form (U.S. Pat. No. 5,686,104). The oxidation, various approaches are used. Such as the use of problem of instability of atorvastatin calcium has been solved antioxidants which in turn reduces the formation of peroxides thus far by the addition of excipients to a pharmaceutical (formation of which causes degradation); or addition of formulation with special emphasis to stabilization of atorv chelating agents to the formulation for mitigation of metallic astatin calcium in the sense of conversion into the lactone impurities. form by the addition of a basifying or a buffering agent to the 0020. Thus, there is a need of a pharmaceutical composi pharmaceutical composition (WO 00/35425; WO94/16603). tion which stands to minimize the risks of degradation of the A procedure for stabilization of an active Substance is known active agents with incorporation of optimum excipients as when in the final phase of synthesis an alkaline Substance or pharmaceutical aids. a buffering solution is added to prepare an alkaline stabilized 0021 We have developed a pharmaceutical composition substance as described in the patent application WO which can remain stable even in the absence of wherein the O1/9386O. above additives, such as (i.e. antioxidants and, chelating 0030 US20040077708 relates to a process for preparation agents) are not incorporated, and the composition still of the stable pharmaceutical formulation comprising atorv remains stable with respect to degradation of actives. astatin calcium in an amorphous form and pharmaceutically 0022. It is well known that active substances in an amor acceptable excipients which requires stringent condition of phous form have better solubility and dissolve more rapidly storing the pharmaceutical formulation in an inert atmo than in a crystalline form and thus have better bioavailability. sphere thereby achieving the stability which is superior and/ US 2010/0204195 A1 Aug. 12, 2010 or equal to the stability of the pharmaceutical formulation preferably atorvastatin or a salt thereof, more particularly comprising the crystalline active substance. atorvastatin calcium. Most preferably, the cholesterol absorp 0031. To date, an appropriate and useful pharmaceutical tion inhibitor is eZetimibe or salt thereof. Most preferably, the compositions comprising atorvastatin calcium, EZetimibe HMG CoA reductase inhibitor is amorphous. and fenofibrate have not been described. 0041. In yet another aspect of the present invention, there 0032. Therefore, there is a need for preparing a stable is a provided pharmaceutical composition comprising com pharmaceutical composition comprising amorphous active. bination of one or more HMG CoA reductase inhibitors and Thus the present invention provides a pharmaceutical com one or more fibrates, wherein either or both the active mate position comprising an amorphous Substance, the amorphous rials are preferably formed to an amorphous form in-situ form being advantageous overa crystalline Substance form by during the manufacturing of the composition. Optionally, the better bioavailability, and which is prepared according to the composition may further include one or more excipients. The process which is simple and economically convenient. composition may beformulated for simultaneous, separate or sequential administration. Most preferably, the HMG CoA OBJECT OF THE INVENTION reductase inhibitorisatorvastatin, or a salt thereof, especially 0033. An object of the invention is to provide new phar atorvastatin calcium. Most preferably, the fibrate is fenofi maceutical formulations and methods of making them, to brate or a salt thereof. Most preferably, the HMG CoA reduc solve the problems in the prior art. The invention makes tase inhibitor is amorphous. possible the manufacture of pharmaceutical compositions 0042. In yet another aspect of the present invention, there comprising one or more cholesterol reducing agent in an is provided a method to manufacture the formulations accord amorphous form, Such as atorvastatin calcium, eZetemibe, ing to the present invention. fenofibrate and the like. 0043. The HMG CoA reductase inhibitor may be provided as the free material, or its pharmaceutically acceptable salts, SUMMARY OF THE INVENTION pharmaceutically acceptable Solvates, pharmaceutically 0034. The present invention relates to a pharmaceutical acceptable enantiomers, pharmaceutically acceptable deriva composition comprising one or more cholesterol reducing tives, pharmaceutically acceptable polymorphs or pharma agents in an amorphous form, wherein at least one agent is ceutically acceptable prodrugs thereof. This applies to any of converted in-situ from a non-amorphous form to an amor the materials used as the HMG CoA reductase inhibitor, phous form during manufacture of the composition including cerivastatin, atorvastatin, lovastatin, simvastatin, 0035. The invention further relates to a composition com rosuvastatin, pravastatin, mevastatin, fluvastatin, rivastatin, prising an extruded article containing one or more cholesterol pitavastatin. reducing agent in an amorphous form in combination with a 0044) The cholesterol absorption inhibitor may be pro polymeric carrier, and optionally at least one pharmaceuti vided as the free material, or its pharmaceutically acceptable cally acceptable excipient. salts, pharmaceutically acceptable Solvates, pharmaceuti 0036. The invention also relates to a method of making a cally acceptable enantiomers, pharmaceutically acceptable pharmaceutical composition containing one or more amor derivatives, pharmaceutically acceptable polymorphs or phous cholesterol reducing agents, comprising blending the pharmaceutically acceptable prodrugs thereof. This applies actives with a pharmaceutically acceptable polymer and to any of the materials used as the cholesterol absorption optionally one or more pharmaceutically acceptable excipi inhibitor, including ezetimibe. ents, and hot melt extruding the blend to form an extrudate. 0045. The fibrate may be provided as the free material, or its pharmaceutically acceptable salts, pharmaceutically BRIEF DESCRIPTION OF THE DRAWINGS acceptable Solvates, pharmaceutically acceptable enanti 0037 Reference is made to the accompanying drawing, in omers, pharmaceutically acceptable derivatives, pharmaceu which: tically acceptable polymorphs or pharmaceutically accept 0038 FIG. 1 indicates an X-ray powder diffractogram able prodrugs thereof. This applies to any of the materials (XRD) of crystallineatorvastatin calcium and X-ray powder used as the cholesterol absorption inhibitor, including diffractograms (XRD) of amorphousatorvastatin calcium. eZetimibe. 0046 Broadly, the invention relates to pharmaceutical DETAILED DESCRIPTION OF THE INVENTION compositions containing a cholesterol reducing agent, and to 0039. In one aspect of the present invention, there is pro methods of manufacturing the composition. The cholesterol vided a pharmaceutical composition comprising an active reducing agent is preferably one or more HMG CoA reduc substance which is an HMG CoA reductase inhibitor, prefer tase inhibitor; one or more cholesterol absorption inhibitor; ably an amorphous HMG CoA reductase, wherein the active one or more fibrate; or a combination of two or more thereof. material is formed in-situ during the manufacturing of the In particular, the invention envisages the provision of a phar composition. maceutical combination comprising one or more HMG CoA 0040. In another aspect of the present invention, there is reductase inhibitors in combination with one or more choles provided a pharmaceutical composition comprising one or terol absorption inhibitors; and the invention also envisages more HMG CoA reductase inhibitors and one or more cho the provision of a pharmaceutical combination comprising lesterol absorption inhibitors and optional pharmaceutically one or more HMG CoA reductase inhibitors in combination acceptable excipients wherein either or both the active mate with one or more fibrates. rials are preferably formed to an amorphous form in-situ 0047. The different active materials in the pharmaceutical during the manufacturing of the composition. The composi composition may be provided in a single unitary dosage form, tion may be formulated for simultaneous, separate or sequen or may be provided in separate dosage forms for separate or tial administration. The HMG CoA reductase inhibitor is sequential administration. US 2010/0204195 A1 Aug. 12, 2010

0048. Each of the cholesterol reducing agents may be pro 0058. In an embodiment, the ratio of agent to polymer is vided in an amorphous form. It is possible for one or more of from 1:1 to 1:6 on a weight basis, preferably 1:2 to 1:5 on a the cholesterol reducing agents to be provided in an amor weight basis. phous form, with other cholesterol reducing agents. 0059. In an embodiment, the composition comprises 2 to 0049. It is a feature of the invention that the amorphous 80 wt % polymer, preferably 20-80% by weight of polymer. form of the cholesterol reducing agents is formed during 0060. The extruded article may be a pharmaceutical com formation of the pharmaceutical composition. Most prefer position, perse. Alternatively, a pharmaceutical composition according to the invention may be obtained from the extruded ably, the amorphous form is formed in-situ during formation article by appropriate processing and optional mixing with at of the pharmaceutical composition. least one pharmaceutically acceptable excipient. 0050. In another aspect, the pharmaceutical composition 0061 The pharmaceutical compositions according to the may comprise an extrudate formed of at least one cholesterol invention may, for example, be formed from an extrudate reducing agent in combination with a pharmaceutically containing both actives; or from two separate extrudates, each acceptable polymer and optional pharmaceutically accept containing one active; or from an extrudate containing one or able excipients. more actives, which is Subsequently processed with one or 0051. In another aspect, the invention relates to a pharma more other actives not provided as extrudates using hot melt ceutical precursor composition comprising an extrudate technique. The active materials may be homogeneously formed of at least one cholesterol reducing agent in combi mixed in the dosage form. Alternatively, the active materials nation with a pharmaceutically acceptable polymer and along with one or more excipients may be provided in sepa optional pharmaceutically acceptable excipients. The extru rate individual layers in the tablet, such as bilayer form for date may be subsequently processed to produce a pharmaceu two actives, trilayer form for three actives, and so on. tical composition. This Subsequent processing may involve 0062. In the compositions described above, the cholesterol the addition of one or more cholesterol reducing actives (es reducing active preferably comprises at least one HMG-CoA pecially HMG CoA reductase inhibitors, cholesterol absorp inhibitor, at least one cholesterol absorption inhibitor and/or tion inhibitor and/or fibrates), which may each be in amor at least one fibrate. phous or non-amorphous form. The Subsequent processing 0063. In an especially preferred embodiment, the choles may also involve the addition of one or more pharmaceuti terol reducing agent comprises at least one HMG CoA reduc cally acceptable excipients (further to any excipients already tase inhibitor, at least one cholesterol absorption inhibitor present in the extrudate). and/or at least one fibrate. The composition may include just 0052. Thus, the invention encompasses an extruded article one active material selected from those mentioned above. containing at least one cholesterol reducing agent (especially Alternatively, there may be more than one of the same type of a HMG CoA reductase inhibitor, a cholesterol absorption active. Alternatively, there may be different types of active, or inhibitor and/or a fibrate). This extrudate typically further more than one of different types of active. comprises a pharmaceutically acceptable polymer in combi 0064. The fibrate is preferably selected from benzafibrate, nation with the actives, which are suitably homogeneously gemfibrozil, fenofibrate, simfibrate, ronifibrate, ciprofibrate, dispersed throughout the polymer. The extrudate may also etofibrate, clofibrate, clinofibrate, most preferably, the fibrate include one or more pharmaceutically acceptable excipients. is fenofibrate or its pharmaceutically acceptable salts, phar At least one of the actives, and possibly all of the actives, are maceutically acceptable solvates, pharmaceutically accept preferably present in the extrudate in amorphous form. The able enantiomers, pharmaceutically acceptable derivatives, amorphous form was preferably formed during the manufac pharmaceutically acceptable polymorphs or pharmaceuti ture of the extrudate (i.e., the starting material actives were in cally acceptable prodrugs thereof. As noted above, the fibrate form different from the amorphous form). may be in amorphous form, and it is preferably converted to 0053. The pharmaceutical composition according to the an amorphous form in situ during manufacture of the com invention may be provided in a Suitable form, including, but position. not limited to: tablet, capsule, pellet, sprinkles, powder, gran 0065. In another especially preferred embodiment, the ules; Sachet, or in the form of a liquid oral dosage Solution or cholesterol reducing agent comprises at least one HMG CoA Suspension. reductase inhibitor and/or at least one cholesterol absorption inhibitor. 0054. In accordance with one aspect of the invention, there 0066. The cholesterol absorption inhibitor is preferably is provided a pharmaceutical composition comprising one or eZetimibe or its pharmaceutically acceptable salts, pharma more cholesterol reducing agent in an amorphous form, ceutically acceptable Solvates, pharmaceutically acceptable wherein at least one active is converted in-situ to an amor enantiomers, pharmaceutically acceptable derivatives, phar phous form during the manufacture of the composition. maceutically acceptable polymorphs or pharmaceutically 0055 Preferably, the pharmaceutical composition further acceptable prodrugs thereof. As noted above, the cholesterol comprises a polymer. absorption inhibitor may be in amorphous form, and it is 0056. In accordance with another aspect of the invention preferably converted to an amorphous form in situ during there is provided a composition comprising an extruded manufacture of the composition. article containing one or more cholesterol reducing agent in 0067. In the above embodiments, the HMG CoA reductase an amorphous form in combination with a polymeric carrier, inhibitor is selected from cerivastatin, atorvastatin, lovastatin, and optionally at least one pharmaceutically acceptable simvastatin, rosuvastatin, pravastatin, mevastatin, fluvastatin, excipient. The extruded article is advantageously formed by a rivastatin, pitavastatin or its pharmaceutically acceptable hot melt extrusion process, as described below. salts, pharmaceutically acceptable Solvates, pharmaceuti 0057 Preferably, at least one amorphous agent is formed cally acceptable enantiomers, pharmaceutically acceptable in situ during the manufacture of the composition. derivatives, pharmaceutically acceptable polymorphs or US 2010/0204195 A1 Aug. 12, 2010

pharmaceutically acceptable prodrugs thereof. The preferred 0077. In an embodiment, the method further comprises HMG CoA reductase inhibitorisatorvastatin or a salt thereof, treating the extrudate to form a granulate. The granulate may most preferably atorvastatin calcium. As noted above, the be filled into a capsule or Sachet, or process into a tablet, e.g., HMG CoA reductase inhibitor may be in amorphous form, by compression. and it is preferably converted to an amorphous form in situ 0078. The compositions according to the invention may be during manufacture of the composition. used as a medicament, in particular to treat various disorders due to an increase in cholesterol. In particular, the composi 0068. In one particularly preferred embodiment of the tions may be used to treat dyslipidemia, hyperlipidemia, invention, the cholesterol reducing agent comprises atorvas hypercholesterolemia, atherosclerosis, arteriosclerosis, car tatin calcium and eZetimibe in combination. In another par diovascular disease, coronary artery disease, coronary heart ticularly preferred embodiment of the invention, the choles disease, vascular disorder and/or related disorders. The treat terol reducing active comprises atorvastatin calcium and ment may be achieved by administering a therapeutically fenofibrate. In either embodiment, the active material may be effective amount of the pharmaceutical composition of the formulated for simultaneous, sequential or separate adminis present invention to a mammal in need thereof in a Suitable tration. They are preferably formulated in a single dosage therapeutic regimen. form. They may be formed from an extrudate containing both 0079. As described above, amorphous forms have better actives; or form two separate extrudates, each containing one solubility and dissolve more rapidly than in a crystalline active; or from an extrudate containing one active, which is form. Subsequently processed with the other active not provided as 0080 We have surprisingly found that when crystalline an extrudate. The active materials may be homogeneously actives like HMG-CoA reductase inhibitors, cholesterol mixed in the dosage form. Alternatively, the active materials absorption inhibitors, fibrates are formulated by hot melt may be provided in separate individual layers in the tablet, extrusion, the resultant product is a formulation containing such as a bilayer tablet form. In either case, at least one of the the amorphous active which remains stable. actives (and possibly both) is in amorphous form, and the I0081. Thus, the present invention provides an economical amorphous form is preferably formed, in-situ during manu and easy way to formulate a stable formulation. facture. 0082. The term HMG CoA reductase inhibitors choles 0069. The compositions according the invention are pref terol absorption inhibitors, fibrates are mentioned in the erably obtainable by melt extruding at least one cholesterol description as well as the claims in a broad sense to include reducing agent along with at least one pharmaceutically not only HMG CoA reductase inhibitors cholesterol absorp acceptable polymer, and optionally one or more other phar tion inhibitors, fibrates per se, but also its pharmaceutically maceutically acceptable excipients, to form an extrudate, acceptable salts, pharmaceutically acceptable Solvates, phar optionally treating the extrudates to Suitable Solid forms and maceutically acceptable enantiomers, pharmaceutically further, optionally admixing the extrudate with one or more acceptable derivatives, pharmaceutically acceptable poly further pharmaceutically acceptable excipients. morphs or pharmaceutically acceptable prodrugs thereof. 0070 The extrudate, and optional excipient or excipients, I0083. According to the present invention, various HMG may be further treated to be filled into a suitable pharmaceu CoA reductase inhibitors can be used. These include atorv tical receptacle, Such as a Sachet or capsule, pellets, sprinkles, astatin, lovastatin, simvastatin, rosuvastatin, pravastatin, oral Suspensions. mevastatin, fluvastatin, rivastatin, pitavastatin or its pharma 0071. The extrudate, and optional excipient or excipients, ceutically acceptable salts, pharmaceutically acceptable sol may be processed, for example by compression, to form a Vates, pharmaceutically acceptable enantiomers, pharmaceu tablet. tically acceptable derivatives, pharmaceutically acceptable 0072 According to another aspect of the invention, there polymorphs or pharmaceutically acceptable prodrugs is provided a method of making a pharmaceutical composi thereof. Most preferably, the statins are amorphous. tion containing one or more cholesterol reducing actives, of I0084 Thus, to summarise, the cholesterol reducing agent which at least one and possible all are preferably in an amor may comprise at least one HMG-CoA inhibitor, at least one phous form, comprising blending the actives with a pharma cholesterol absorption inhibitor and/or at least one fibrate. ceutically acceptable polymer, and hot melt extruding the One or more of these agents may be in an amorphous form, blend to form an extrudate. and the amorphous form may beformed in-situ during manu 0073. In a preferred embodiment, at least one cholesterol facturing. Preferably, the cholesterol reducing agent com reducing agent, and possibly all of them, is blended with the prises (i) at least one HMG-CoA inhibitor and at least one polymer optionally with one or more excipients, and the cholesterol absorption inhibitor; or (ii) at least one HMG amorphous form of said active is formed in-situ during the hot CoA inhibitor and at least one fibrate. The fibrate is preferably melt extrusion. selected from benzafibrate, gemfibrozil, fenofibrate, simfi brate, ronifibrate, ciprofibrate, etofibrate, clofibrate, clinofi 0074. In the method, the cholesterol reducing active com brate, with fenofibrate being particularly preferred. The cho prises a HMG-CoA reductase inhibitor, a cholesterol absorp lesterol absorption inhibitor is preferably eZetimibe. The tion inhibitor and/or a fibrate, as described above in respect of HMG CoA reductase inhibitor is preferably selected from the compositions. cerivastatin, atorvastatin, lovastatin, simvastatin, rosuvasta 0075. In a preferred embodiment, the extrudate is pro tin, pravastatin, mevastatin, fluvastatin, rivastatin, pitavasta cessed and optionally mixed it with one or more additives to tin, with atorvastatin, especially atorvastatin calcium, being form the pharmaceutical composition. particular preferred. The combination of atorvastatin, espe 0076. In an embodiment, the method further comprises the cially atorvastatin calcium, with fenofibrate is particularly steps of cutting the extrudate to a desired shape to form a preferred. The combination of atorvastatin, especially atorv pharmaceutical composition. astatin calcium, with eZitimbe is also particularly preferred. US 2010/0204195 A1 Aug. 12, 2010

0085. The invention encompasses using a pharmaceutical 0101. In one embodiment, the cholesterol absorption acceptable salt of any of these agents. inhibitor (e.g. eZetimibe) may be manufactured using a hot 0.086 The invention encompasses using a pharmaceuti melt extrusion process as described above. This may be done cally acceptable solvate of any of these agents. in combination with the HMG CoA reductase inhibitor, or 0087. The invention encompasses using a pharmaceuti separately. cally acceptable enantiomer of any of these agents. 0102 The combination therapy of one or more HMG CoA 0088. The invention encompasses using a pharmaceuti reductase inhibitors, and one or more fibrates, preferably with cally acceptable derivative of any of these agents. one or more pharmaceutically acceptable excipients, 0089. The invention encompasses using a pharmaceuti improves the lipid profiles i.e decrease in triglycerides, mod cally acceptable polymorph of any of these agents. erate decrease in LDL cholesterol, increase in HDL choles 0090 The invention encompasses using a pharmaceuti terol that appear to be frequently necessary for high risk CAD cally acceptable prodrug of any of these agents. patients. 0103) Thus, in another aspect of the present invention, 0091. Further, it has been known that a major problem there is a provided pharmaceutical composition comprising with amorphous HMG-CoA reductase inhibitors is their sta combination of one or more HMG CoA reductase inhibitors bility when formulated perse or when combined with other and one or more fibrates, wherein either or both the active actives. materials are formed to an amorphous form in-situ during the 0092. From the prior art, it is understood that to prevent manufacturing of the composition. Optionally, the composi degradation of the actives due to oxidation, the use of addi tives like chelating agents or antioxidants are incorporated. tion may further include one or more excipients. The compo These are not needed to maintainstability in the compositions sition may be formulated for simultaneous, separate or according to the present invention. Thus, it is preferred that sequential administration. the composition according to the invention does not contain a 0104. The HMG CoA reductase inhibitors according to chelating agent. It is preferred that, if the composition accord the present invention can be selected from atorvastatin, lov ing to the invention does contain an antioxidant or chelating astatin, simvastatin, rosuvastatin, pravastatin, mevastatin, agent, the amount is not more than 0.1 to 2% by weight of the fluvastatin, rivastatin, pitavastatin. composition. 0105. The fibrate, according to the present invention, may be selected from, but is not limited to benzafibrate, gemfi 0093. We have found that a stable composition is formed brozil, fenofibrate, simfibrate, ronifibrate, ciprofibrate, etofi when such actives are formulated by hot melt extrusions. brate, clofibride and the possible pharmaceutically accept 0094 Thus, one or more cholesterol reducing agents like able salts, pharmaceutically acceptable solvates, HMG-CoA reductase inhibitors, cholesterol absorption pharmaceutically acceptable enantiomers, pharmaceutically inhibitors, fibrates can be combined together. acceptable derivatives, pharmaceutically acceptable poly 0095 Thus, in one aspect of the present invention there is morphs or pharmaceutically acceptable prodrugs thereof. provided a pharmaceutical composition comprising one or 0106. According to a preferred embodiment, the pharma more HMG CoA reductase inhibitors and one or more cho ceutical composition comprises fenofibrate or its pharmaceu lesterol absorption inhibitors and optional pharmaceutically tically acceptable salts, pharmaceutically acceptable sol acceptable excipients wherein either or both the active mate Vates, pharmaceutically acceptable enantiomers, rials are formed to an amorphous form in-situ during the pharmaceutically acceptable derivatives, pharmaceutically manufacturing of the composition. The composition may be acceptable polymorphs or pharmaceutically acceptable pro formulated for simultaneous, separate or sequential adminis drugs thereof. tration. 0107 According to present invention, the composition 0096. The HMG CoA reductase inhibitors according to comprising one or more statins preferably amorphousatorv the present invention may be selected from atorvastatin, lov astatin or its pharmaceutically acceptable salts, pharmaceu astatin, simvastatin, rosuvastatin, pravastatin, mevastatin, tically acceptable Solvates, pharmaceutically acceptable fluvastatin, rivastatin, pitavastatin. enantiomers, pharmaceutically acceptable derivatives, phar 0097. The pharmaceutical composition according to the maceutically acceptable polymorphs or pharmaceutically present invention comprises at least one cholesterol absorp acceptable prodrugs thereof; and fibrates preferably fenofi tion inhibitor, such as eZetimibe or its pharmaceutically brate or its pharmaceutically acceptable salts, pharmaceuti acceptable salts, pharmaceutically acceptable Solvates, phar cally acceptable Solvates, pharmaceutically acceptable enan maceutically acceptable enantiomers, pharmaceutically tiomers, pharmaceutically acceptable derivatives, acceptable derivatives, pharmaceutically acceptable poly pharmaceutically acceptable polymorphs or pharmaceuti morphs or pharmaceutically acceptable prodrugs thereof. cally acceptable prodrugs thereof with one or more pharma 0098. The quantity of the cholesterol absorption inhibitor ceutically acceptable excipients wherein either or both of the to be used in the formulation preferably ranges from 1% to active(s) are converted insitu to amorphous form during pro 15% by weight of the composition. cessing. 0099. The quantity of the HMG CoA reductase inhibitor to 0108. In another aspect of the present invention, the be used in the formulation is preferably from 1% to 15% by present invention relates to a method of making a pharmaceu weight of the composition. tical composition containing one or more amorphous choles 0100. The preferred formulation according to the inven terol reducing actives, comprising blending the actives with a tion comprises atorvastatin, or a salt thereof, most preferably pharmaceutically acceptable polymer with one or more phar atorvastatin calcium, in combination with eZetimibe. And maceutically acceptable excipients, and hot melt extruding most preferably the atorvastatin, oratorvastatin calcium is the blend to form an extrudate. amorphousand has preferably been produced in accordance 0109 During the hot melt extrusion process, the polymers with the methods described herein. that can be used according to the present invention, include US 2010/0204195 A1 Aug. 12, 2010 water soluble and water insoluble polymers. Examples of 0119. In addition to the drug and polymer, the blend may Suitable polymers include homopolymers and copolymers of further comprise additional excipients like plasticizers, dis N-vinyl pyrrolidone, e.g. polyvinylpyrrolidone (PVP); integrants, flow regulators, lubricants, fillers, stabilizers such copolymers of N-vinyl pyrrolidone and vinyl acetate or vinyl as antioxidants, light stabilizers, radical scavengers, stabiliz propionate; cellulose esters and cellulose ethers, in particular ers against microbial attack. The composition may contain methylcellulose and ethylcellulose; hydroxyalkylcelluloses, 0.5% to 10% alkalinizing agent by weight of the composition. in particular hydroxypropylcellulose, hydroxyalkylalkylcel I0120 Plasticizers can be incorporated depending on the luloses, in particular hydroxypropylmethylcellulose; cellu polymerand the process requirement. These, advantageously, lose phthalates or Succinates, in particular cellulose acetate when used in the hot melt extrusion process decrease the glass phthalate and hydroxypropylmethylcellulose phthalate, transition temperature of the polymer. Plasticizers also help in hydroxypropylmethylcellulose Succinate or hydroxypropyl reducing the viscosity of the polymer melt and thereby allow methylcellulose acetate Succinate; high molecular polyalky for lower processing temperature and extruder torque during lene oxides, such as polyethylene oxide and polypropylene hot melt extrusion. Examples of suitable plasticizers which oxide and copolymers of ethylene oxide and propylene oxide; can be used in the present invention, include, but are not polyacrylates and polymethacrylates such as methacrylic limited to, polysorbates Such as Sorbitan monolaurate (Span acid/ethyl acrylate copolymers, methacrylic acid/methyl 20), Sorbitan monopalmitate, Sorbitan monostearate, Sorbitan methacrylate copolymers, butyl methacrylate/2-dimethy monoisoStearate; citrate ester type plasticizers like triethyl laminoethyl methacrylate copolymers, poly(hydroxylalkyl citrate, citrate phthalate; propylene glycol, glycerin; low acrylates), poly(hydroxyalkyl methacrylates); polyacryla molecular weight polyethylene glycol; triacetin: dibutyl mides; vinyl acetate polymers such as copolymers of vinyl sebacate, tributyl sebacate; dibutyltartrate, dibutyl phthalate. acetate and crotonic acid, and partially hydrolyzed polyvinyl The plasticizer is preferably present in an amount ranging acetate (also referred to as partially saponified (“polyvinyl from 0% to 10% to the weight of polymer. alcohol) polyvinyl alcohol. I0121 Suitable flow regulators are selected from highly 0110. The water soluble polymers that can be used, dispersed silica (Aerosil), and animal or vegetable fats or according to the present invention, comprises of homopoly WaxS. mers and co-polymers of N-vinyl lactams, especially 0.122 Various other additives may be used, for example homopolymers and co-polymers of N-vinyl pyrrolidone e.g. dyes such as azo dyes, organic or inorganic pigments such as polyvinylpyrrolidone (PVP), co-polymers of PVP and vinyl aluminium oxide or titanium dioxide, or dyes of natural ori acetate, co-polymers of N-vinyl pyrrolidone and vinyl acetate gin, stabilizers such as antioxidants, light stabilizers, radical or vinyl propionate, esters and cellulose ethers, high molecu Scavengers, stabilizers against microbial attack. lar polyalkylene oxides such as polyethylene oxide and I0123. The present invention also provides a process to polypropylene oxide and co-polymers of ethylene oxide and manufacture a composition according to the present inven propylene oxide. tion. The process involves forming a powder blend, transfer 0111. The water insoluble polymer that can be used, ring the blend through a heated barrel of the extruder, according to the present invention, comprises of acrylic whereby the powder blend melts and molten solution product copolymers e.g. Eudragit E 100 or Eudragit EPO; Eudragit is collected on a conveyor whereby it is allowed to cool and L30D-55, Eudragit FS30D, Eudragit RL30D, Eudragit form an extrudate. Alternatively, the extrudate is cut into RS30D, Eudragit NE30D, Acryl-Eze (Colorcon Co.); poly pieces after solidification and can be further processed into vinylacetate, for example, Kollicoat SR 30D (BASF Co.); suitable dosage forms. More preferably the extrudates thus cellulose derivatives such as ethylcellulose, cellulose acetate finally obtained from the above process are then milled and e.g. Surelease (Colorcon Co.), Aquacoat ECD and Aquacoat ground to granules or other solid forms by the means known CPD (FMC Co.). to a person skilled in the art. 0112 Preferably, homopolymers or copolymers of N-vi 0.124. The extrudates so obtained may then be admixed nyl pyrrolidone, hydroxyalkylcelluloses, polyacrylates are with one or more other suitable pharmaceutically acceptable used. excipients. 0113 Suitably, homopolymers or copolymers of N-vinyl 0.125 Suitable bulking agents/diluents may include one or pyrrolidone include a copolymer of N-vinyl pyrrolidone & more of, but not limited to, dibasic calcium phosphate, cal vinyl acetate. A preferred polymer is a copolymer N-vinyl cium Sulfate, microcrystalline cellulose, cellulose powdered, pyrrolidone wherein about 40% by weight of the copolymer is dextrates, dextrins, maltodextrin, dextrose excipients, cros vinyl acetate. carmellose sodium, isomalt, PVA, saccharides, including 0114 Suitably, polyacrylates include cationic copolymers monosaccharides, disaccharides, polysaccharides and Sugar based on dimethylaminoethyl methacrylate and neutral meth alcohols such as arabinose, maltose, fructose, lactitol, lac acrylic esters. More preferably, the polymer can be Eudragit tose, mannitol, Sorbitol, starch, starch pregelatinized, E100. Sucrose, Sugar compressible, Sugar confectioners and mix 0115 Suitably, the hydroxyalkycellulose is hydroxypro tures thereof. The diluent may be present in a quantity from pylcellose. 30% to 85% by weight of the composition. 0116. The polymers can be present in a concentration of 2 0.126 Suitable binders may include one or more of, but not to 80% by weight of the composition, preferably 20 to 80% by limited, to methyl cellulose, hydroxypropyl cellulose, weight of the composition. hydroxypropyl methylcellulose, polyvinylpyrrolidone, gela 0117. A single polymer may be used or a combination of tin, gum arabic, polyvinyl alcohol, pullulan, Starch, pregela one or more polymers may be used. tinized Starch, agar, tragacanth, sodium alginate, propylene 0118. Different ratios of the drug: polymer may be used. glycol, alginate and other cellulose derivatives and equiva Suitably, the ratio may be of the range of 1:1 to 1:6, preferably lents thereof. Preferably the binder is present in a quantity 1:2 to 1:5. from 1% to 15% by weight of composition. US 2010/0204195 A1 Aug. 12, 2010

0127 Suitable disintegrants may include one or more of 0.136 The melt-extrusion process comprises the steps of but not limited, to starches, clays, celluloses, algins, gums or preparing a homogeneous melt of one or more drugs, the crosslinked polymers one or more of low substituted hydrox polymer and the excipients, and cooling the melt until it ypropyl cellulose, carboxymethyl cellulose, calcium car solidifies. “Melting” means a transition into a liquid or rub boxymethyl cellulose, sodium carboxymethyl cellulose, bery state in which it is possible for one component to get Sodium starch glycolate, crospovidone, croScarmellose embedded homogeneously in the other. Sodium, starch, crystalline cellulose, hydroxypropyl Starch, 0.137 Typically, one component will melt and the other and partially pregelatinized starch. The disintegrant may be components will dissolve in the melt thus forming a solution. presentina quantity ranging from 1% to 10% by weight of the Melting usually involves heating above the Softening point of composition. the polymer. The preparation of the melt can take place in a 0128 Suitable lubricants/glidants may include one or variety of ways. The mixing of the components can take place more of, but not limited to, Stearic acid, magnesium Stearate, before, during or after the formation of the melt. For example, calcium Stearate, talc, hydrogenated caster oil. Sucrose esters the components can be mixed first and then melt extruded or of fatty acid, PEG microcrystalline wax, colloidal silicon be simultaneously mixed and melt extruded. Usually, the melt dioxide and equivalents thereof. Optionally, Suitable coloring is homogenized in order to disperse the active ingredients agents may be added. The formulation may incorporate one efficiently. Also, it may be convenient first to melt the poly or more of the above lubricants or glidants. The glidant and merand then to mixin and homogenize the active ingredients. lubricant may each be present in an amount from 0.5% to 5% 0.138. Usually, the melt temperature is in the range of by weight of the composition. about 70° C. to about 200° C., preferably from about 80°C. to 0129. The composition may further comprise alkalinizing about 180° C. agents including, but not limited to, calcium carbonate, cal 0.139 Suitable extruders include single screw extruders, cium phosphate, magnesium carbonate, magnesium oxide, intermeshing screw extruders or else multiscrew extruders, potassium carbonate, potassium hydrogen carbonate, sodium preferably twin screw extruders, which can be co-rotating or carbonate, Sodium hydrogen carbonate and equivalents counter-rotating and, optionally, be equipped with kneading thereof. The formulation may incorporate one or more of the disks. It will be appreciated that the working temperatures above alkalinizing agents. will also be determined by the kind of extruder or the kind of 0130. The different active materials in the pharmaceutical configuration within the extruder that is used. composition may provided in a single unitary dosage form, or 0140. The extrudates can be in the form of beads, granu may provided in separate dosage forms for separate or lates, tube, strandor cylinder and this can be further processed sequential administration into any desired shape. 0.141. The term “extrudates' as used herein refers to solid 0131 The pharmaceutical composition according to the product solutions, Solid dispersions and glass Solutions of one invention may be provided in a Suitable form, including, but or more drugs with one or more polymers and optionally not limited to: tablet, capsule, pellet, sprinkles, powder, gran pharmaceutically acceptable excipients. ules; Sachet, or in the form of a liquid oral dosage Solution or Suspension. 0142. According to a preferred embodiment, a powder blend of the one or more active drug(s) and polymers and 0132) The pharmaceutical compositions according to the optionally pharmaceutical excipients are transferred by a invention may, for example, be formed from an extrudate rotating screw of a single screw extruder through the heated containing both actives; or from two separate extrudates, each barrel of an extruder whereby the powder blend melts and containing one active; or from an extrudate containing one or molten solution product is collected on a conveyor where it is more actives, which is Subsequently processed with one or allowed to cool to form an extrudate. Shaping of the extrudate more other actives not provided as extrudates. The active can conveniently be carried out by a calendar with two materials may be homogeneously mixed in the dosage form. counter-rotating rollers with mutually matching depressions Alternatively, the active materials may be provided in sepa on their Surface. rate individual layers in the tablet, such as bilayer form for 0.143 Abroad range of extrudated forms can be attained two actives, trilayer form for three actives, and so on. by using rollers with different forms of depressions. Alterna 0133. Further, the extrudates and the pharmaceutically tively, the extrudate is cut into pieces after solidification and acceptable excipients can be processed by techniques known can be further processed into suitable dosage forms. More to a person skilled in the art, such as direct compression, wet preferably, the extrudates thus finally obtained from the above granulation, fluidized bed granulation, extrusion, Solvent process are then milled and ground to granules by the means evaporation and are not intended to limit the scope of the known to a person skilled in the art. invention to form the desired dosage form. 0144. Further, hot melt extrusion is a fast, continuous, 0134. The present invention further provides for a method single pot manufacturing process without requirement of fur of treatment of various disorders due to increased cholesterol ther drying or discontinuous process steps; it provides short Such as dyslipidemia, hyperlipidemia, hypercholesterolemia, thermal exposure of active which allows processing of heat atherosclerosis, arteriosclerosis, cardiovascular disease, sensitive actives; process temperatures can be reduced by coronary artery disease, coronary heart disease, vascular dis addition of plasticizers; comparatively lower investment for order and related disorders by administering atherapeutically equipment as against other processes. The entire process is effective amount of the pharmaceutical composition of the anhydrous and the intense mixing and agitation of the powder present invention to a mammal in need thereof in a Suitable blend that occur during processing contribute to a very therapeutic regimen. homogenous extrudate(s). 0135) In general terms, the process of hot melt extrusion is 0145. In one aspect, the preferred embodiment in accor carried out in the conventional extruders as known to a person dance with the present invention may comprise one or more skilled in the art. statins and one or more fibrates or its pharmaceutically US 2010/0204195 A1 Aug. 12, 2010 acceptable salts, pharmaceutically acceptable Solvates, phar 0150. According to preferred embodiment, the formula maceutically acceptable enantiomers, pharmaceutically tion of the invention comprises blending of amorphousator acceptable derivatives, pharmaceutically acceptable poly vastatin or its pharmaceutically acceptable salts, pharmaceu morphs or pharmaceutically acceptable prodrugs thereof tically acceptable Solvates, pharmaceutically acceptable along with one or more water soluble polymers which are melt enantiomers, pharmaceutically acceptable derivatives, phar extruded by the process as described herein, where a powder maceutically acceptable polymorphs or pharmaceutically blend of one or more statins, preferably, amorphousatorvas acceptable prodrugs thereof and fenofibrate or its pharmaceu tatin and one or more fibrates, preferably fenofibrate or their tically acceptable salts, pharmaceutically acceptable sol pharmaceutically acceptable salts, pharmaceutically accept Vates, pharmaceutically acceptable enantiomers, pharmaceu able solvates, pharmaceutically acceptable enantiomers, tically acceptable derivatives, pharmaceutically acceptable pharmaceutically acceptable derivatives, pharmaceutically polymorphs orpharmaceutically acceptable prodrugs thereof acceptable polymorphs or pharmaceutically acceptable pro and a combination of one or more water insoluble polymer or drugs thereof along with one or more polymers and other combination of water soluble and water insoluble polymer excipients which may comprise Suitable plasticizers and/or and one or more pharmaceutically acceptable excipients bulking agents. These are processed to form a powder blend which may comprise Suitable bulking agents and plasticizers. which is transferred through the heated barrel of the extruder, 0151. These are processed to form a powder blend which whereby the powder blend melts and molten solution product is transferred through the heated barrel of the extruder, is collected on a conveyor whereby it is allowed to cool and whereby the powder blend melts and molten solution product form an extrudate. is collected on a conveyor whereby it is allowed to cool and 0146 According to preferred embodiment, the formula form an extrudate. tion of the invention comprises blending of amorphousator 0152 Alternatively, the extrudate is cut into pieces after vastatin or its pharmaceutically acceptable salts, pharmaceu solidification and can be further processed into suitable dos tically acceptable Solvates, pharmaceutically acceptable age forms. More preferably, the extrudates thus finally enantiomers, pharmaceutically acceptable derivatives, phar obtained from the above process are then milled and ground maceutically acceptable polymorphs or pharmaceutically to granules or other Solid forms by the means known to a acceptable prodrugs thereofand fenofibrate or its pharmaceu person skilled in the art. tically acceptable salts, pharmaceutically acceptable sol 0153. According to another embodiment, the present Vates, pharmaceutically acceptable enantiomers, pharmaceu invention may further involve one or more manufacturing tically acceptable derivatives, pharmaceutically acceptable process to obtain a single unitary dosage form i.e. wherein the polymorphs or pharmaceutically acceptable prodrugs thereof or each drug is processed by the techniques as discussed and one or more polymers and other excipients which may above and finally compacted to yield a single dosage form. comprise Suitable bulking agents and plasticizers. These are Preferably, statin or its pharmaceutically acceptable salts, processed to form a powder blend which is transferred pharmaceutically acceptable Solvates, pharmaceutically through the heated barrel of the extruder, whereby the powder acceptable enantiomers, pharmaceutically acceptable deriva blend melts and molten solution product is collected on a tives, pharmaceutically acceptable polymorphs or pharma conveyor whereby it is allowed to cool and forman extrudate. ceutically acceptable prodrugs in combination with one or 0147 Alternatively, the extrudate is cut into pieces after more excipients & fibrate or its pharmaceutically acceptable solidification and can be further processed into suitable dos salts, pharmaceutically acceptable Solvates, pharmaceuti age forms. More preferably, the extrudates thus finally cally acceptable enantiomers, pharmaceutically acceptable obtained from the above process are then milled and ground derivatives, pharmaceutically acceptable polymorphs or to granules by the means known to a person skilled in the art. pharmaceutically acceptable prodrugs in combination with 0148. The extrudates thus obtained as described above, one or more excipients may be processed with the techniques can be compressed as Such to form tablets or incorporated as as discussed above separately and may be combined to form granules into various pharmaceuticals compositions that single unitary dosage form. Preferably, the statin blend is include, but are not limited to, tablets, capsules, pellets mixed with fibrate blend and may be compressed into a sprinkles, oral Suspensions. single-layered tablet. Alternatively, the statin blend may be 0149. In another aspect, the preferred embodiment in compacted and compressed into a tablet and fibrate blend accordance with the present invention may comprise one or may be compacted and compressed into tablet and finally statins and a combination of one or more water insoluble each individual layer may be compressed into a bilayer tablet. polymer and one or more water soluble polymer which are According to one aspect, the tablet may be seal coated. melt extruded by the process as described herein, where a According to another aspect, the tablet may be seal coated and powder blend of one or more statins or its pharmaceutically finally film coated. The formulation can be coated with Ready acceptable salts, pharmaceutically acceptable Solvates, phar colour mix systems (such as Opadry colour mix systems). maceutically acceptable enantiomers, pharmaceutically 0154 Accordingly, the formulation of the present inven acceptable derivatives, pharmaceutically acceptable poly tion comprises blending of amorphous atorvastatin or its morphs or pharmaceutically acceptable prodrugs thereof & pharmaceutically acceptable salts, pharmaceutically accept fibrate or its pharmaceutically acceptable salts, pharmaceuti able solvates, pharmaceutically acceptable enantiomers, cally acceptable Solvates, pharmaceutically acceptable enan pharmaceutically acceptable derivatives, pharmaceutically tiomers, pharmaceutically acceptable derivatives, pharma acceptable polymorphs or pharmaceutically acceptable pro ceutically acceptable polymorphs or pharmaceutically drugs thereof with one or more pharmaceutically acceptable acceptable prodrugs thereof and a combination of water excipients, and fenofibrate or its pharmaceutically acceptable soluble polymer(s) & water insoluble polymer(s) and other salts, pharmaceutically acceptable Solvates, pharmaceuti excipients which may comprise Suitable bulking agents and cally acceptable enantiomers, pharmaceutically acceptable plasticizer. derivatives, pharmaceutically acceptable polymorphs or US 2010/0204195 A1 Aug. 12, 2010 pharmaceutically acceptable prodrugs thereof with one or pharmaceutically acceptable prodrugs and one or more more pharmaceutically acceptable excipients. Further, the excipients which includes, but are not limited to, polymers amorphousatorvastatin blend is mixed with fenofibrate blend (i.e. either water soluble or water insoluble or mixture and may be compacted and compressed into a tablet and thereof), one or more plasticizer, one or more disintegrants, finally each individual layer may be compressed into a bilayer one or more lubricants and glidants are extruded through hot tablet. According to one aspect, the tablet may be seal coated. melt extrusion technique wherein extrudates are obtained According to another aspect, the tablet may be seal coated and which can be molded into desired shapes that can be filled in finally film coated. Sachets or can be granulated. Alternatively, the granules may 0155 According to second embodiment, the present be compressed into tablets. invention may be formulated wherein the or each drug, pref 0160 More preferably, fenofibrate or its pharmaceutically erably, statin or its pharmaceutically acceptable salts, phar acceptable salts, pharmaceutically acceptable Solvates, phar maceutically acceptable solvates, pharmaceutically accept maceutically acceptable enantiomers, pharmaceutically able enantiomers, pharmaceutically acceptable derivatives, acceptable derivatives, pharmaceutically acceptable poly pharmaceutically acceptable polymorphs or pharmaceuti morphs or pharmaceutically acceptable prodrugs and one or cally acceptable prodrugs thereof and one or more pharma more excipients which includes, but are not limited to, poly ceutically acceptable excipients may be processed through mers (i.e. either water soluble or water insoluble or mixture wet granulation, direct compression and the like as mentioned thereof), one or more plasticizer, one or more disintegrants, above and fibrate or its pharmaceutically acceptable salts, one or more lubricants and glidants are extruded through hot pharmaceutically acceptable Solvates, pharmaceutically melt extrusion technique wherein extrudates are obtained acceptable enantiomers, pharmaceutically acceptable deriva which can be molded into desired shapes that can be filled in tives, pharmaceutically acceptable polymorphs or pharma Sachets or can be granulated. Alternatively, the granules may ceutically acceptable prodrugs thereof with one or more phar be compressed into tablets. maceutically acceptable excipients may be processed through 0.161 According to a preferred embodiment, the granules melt granulation, melt extrusion and the like as mentioned (comprising the individual actives) as obtained above may be above. further mixed, sieved, sifted and compressed into a single 0156 Accordingly, the formulation of present invention tablet or may be filled into capsules or Sachets or the granules comprises amorphousatorvastatin or its pharmaceutically may be administered directly. Alternatively, the tablet may be acceptable salts, pharmaceutically acceptable Solvates, phar seal coated and finally film coated. maceutically acceptable enantiomers, pharmaceutically 0162 Alternatively, the or each granules (comprising the acceptable derivatives, pharmaceutically acceptable poly individual actives) as obtained above may be individually morphs orpharmaceutically acceptable prodrugs thereof with compressed into two tablets and finally compacted and com one or more pharmaceutically acceptable excipients may be pressed into a bilayer tablet. Alternatively, the tablet may be processed through wet granulation, direct compression and seal coated and finally film coated. the like as mentioned above and fenofibrate or its pharmaceu tically acceptable salts, pharmaceutically acceptable sol EXAMPLES Vates, pharmaceutically acceptable enantiomers, pharmaceu tically acceptable derivatives, pharmaceutically acceptable 0163 The following examples are for the purpose of illus polymorphs or pharmaceutically acceptable prodrugs thereof tration of the invention only and are not intended in any way with one or more pharmaceutically acceptable excipients to limit the scope of the invention. may be processed through melt granulation, melt extrusion and the like as mentioned above. Examples 1-6 0157 Preferably, statin or its pharmaceutically acceptable salts, pharmaceutically acceptable Solvates, pharmaceuti 0164. Exemplary compositions of the present invention cally acceptable enantiomers, pharmaceutically acceptable for melt extrusion of atorvastatin calcium with one or more derivatives, pharmaceutically acceptable polymorphs or polymer (s) are shown below in table 1. pharmaceutically acceptable prodrugs are mixed with intra granular excipients which includes, but not limited to, dilu TABLE 1 ents, disintegrants and granulated with water or otheraqueous solvents, sieved, sifted and lubricated and dried. Alterna Sr. Example (ng tively, the dried granules may be compressed into tablets. No. Ingredients 1 2 3 4 5 6 0158 More preferably, amorphousatorvastatin or its phar 1 Atorvastatin Ca 8O 8O 80 80 8O 8O maceutically acceptable salts, pharmaceutically acceptable 2 Hydroxypropyl 320 — 80 – 160 Solvates, pharmaceutically acceptable enantiomers, pharma cellulose ceutically acceptable derivatives, pharmaceutically accept 3 Copolymer of N-vinyl - 320 - 80 160 able polymorphs or pharmaceutically acceptable prodrugs pyrrollidone & vinyl acetate (Kollidon are mixed with intragranular excipients which includes, but VA 64 (R) not limited to, diluents, disintegrants and granulated with 4 Dimethylaminoethyl — 320 – 160 8O water or other aqueous solvents, sieved, sifted and lubricated methacrylate ester and dried. Alternatively, the dried granules may be com (Eudragit E100 (R) pressed into tablets. 0159 Preferably, fibrate or its pharmaceutically accept 0.165. The drug and polymer(s) were passed individually able salts, pharmaceutically acceptable Solvates, pharmaceu through 20 mesh. The drug(s) and polymer(s) were mixed and tically acceptable enantiomers, pharmaceutically acceptable again passed through 20 mesh. The mixture was hot melt derivatives, pharmaceutically acceptable polymorphs or extruded at a temperature ranging from 60-160° C. Most US 2010/0204195 A1 Aug. 12, 2010 preferably, at a temperature between 90-120 C. Optionally suitable plasticizers and surfactants were added in the hot -continued melt extrusion process. Qty/Tab Example 7 S. No Ingredients (mg) 9. Talc 8.00 0166 A composition according to the invention com 10. Calcium Stearate 8.00 prised the following components: Coating 11. Opadry II 85G53348 Orange 12.O 12. Purified Water IP C.S.

Sr. Qty/Unit TOTAL 652 No. Ingredients (mg) 1 Atorvastatin Calcium 82.87 2 PVPVA 64 32O.OO (0171 1. Ezetimibe, hydroxylpropyl cellulose (HPC low 3 Span 20 32.OO Substituted), mannitol were mixed and granulated with 4 Calcium carbonate 30.00 HPMC Solution. 5 LHPC 8O.OO 6 Crosscarmellose sodium SO.OO 0172 2. The granules obtained in (1) were dried, sized and 7 Talc 16.00 blended with Atorvastatin calcium, HPC low substituted, 8 Pearlitol DC 400 (Mannitol) 369.13 calcium carbonate, talc and calcium Stearate. 9 Calcium Stearate 2O.OO 0173 3. The above blend was compressed into tablets and Total 1OOO.OO finally coated. Example 10 (0167 Atorvastatin Calcium, PVP VA-64 and Span 20 were hot melt extruded. The extrudates were sized and mixed 0.174. The formulation from example 10 was subjected to with calcium carbonate, crosscarmellose sodium and LHPC. the accelerated and long term stability studies with the result This was then diluted with Perlitol DC 400 and lubricated confirming that the formulation is stable with regards to the with talc and calcium Stearate. following quality parameters: Example 8 Long term Accelerated 0.168. It was observed that when Crystalline Atorvastatin condition after condition after was processed using hot-melt extrusion, there was a conver Condition period of 12 weeks period of 12 weeks sion of the crystalline form to amorphous form and the final Assay Atorvastatin 99.53% 100.53% formulation that was obtained contained the amorphous Ator Ezetimibe 98.98% 98.59% vastatin. Dissolution Atorvastatin 95.57% at 60 min 96.57% at 60 min 0169 FIG. 1 indicates an X-ray powder diffractogram Ezetimibe 98.07% at 60 min 95.95% at 60 min (XRD) of crystallineatorvastatin calcium and X-ray powder diffractograms (XRD) of amorphousatorvastatin calcium obtained as per the examples 1-3 of table 1 above. Example 11 Example 9 0.175. A composition according to the invention com prised the following components: 0170 A composition according to the invention com prised the following components:

QUANTITY NGREDIENTS (mg tab) Qty/Tab S. No ngredients (mg) Drug layer: Dry mix Fenofibrate 16O.OO Atorvastatin calcium 8O.OO 1. * Ezetimibe 1O.O Silicon dioxide S.OO 2. Mannitol IP 494.63 Polymer layer: 3. Low Substituted Hydroxy propyl 3O.O cellulose NF Kollidon VA64 72O.OO Binder (PVP: vinyl acetate) Sorbitan monolaurate 1S.OO 4. Hypromellose 16.00 Blending: (HPMC 6cps) 5. Purified water Calcium carbonate 2O.OO Extragranular LactOSe 16O.OO Microcrystalline 1OOOO 6.ii Atorvastatin calcium 43.37 cellulose(Avicel 102) 7. Calcium carbonate 10.00 Crospovidone 1OOOO 8. Low Substituted Hydroxy propyl 2O.OO Talc 1O.OO cellulose NF Silicon dioxide 1O.OO US 2010/0204195 A1 Aug. 12, 2010 12

-continued -continued QUANTITY QUANTITY INGREDIENTS (mg tab) NGREDIENTS (mg tab) Lubrication: Blending

Sodium stearyl fumarate 2O.OO Sodium Lauryl Sulphate 10.00 Film coating Yellow oxide of iron 1.00 Kollidon CLM 49.00 Ready colour mix system 2O.OO LactOSe 18O.OO Purified Water IP C.S. Talc 10.00 Binder Total 142O.OO Starch 35.00 Poly vinyl pyrrollidone K-30 10.00 0176 1. Atorvastatin calcium and fenofibrate with small Lubrication amounts of silicon dioxide were sieved, sifted and mixed Sodium stearyl fumarate 10.00 together in a mixer. Film coating 0177 2. Kollidon VA 64 (6:4) was mixed separately with Ready colour mix system span 20 in a granulator and the mixture was then sifted. Purified Water IP 0178. 3. The contents obtained above in (1) and (2) were mixed and was subjected to hot melt extrusion (HME) Total 142O.OO wherein the melting temperature for the extrusion process ranges from 70 to 200° C., with the molten mass thus obtained was collected on a conveyor where it was cooled 0181 1. Atorvastatin calcium with small amount of col to form extrudates and these extrudates on further milling loidal silicon dioxide was sieved, sifted and mixed together were converted into granules which was followed by addi in a mixer. tion of calcium carbonate, lactose, crospovidone and 0182 2. Kollidon VA 64 was mixed separately with microcrystalline cellulose and further lubricated with Sodium mono laurate in a granulator and the mixture was Sodium Stearyl fumarate. then sifted. 0179 4. The granules obtained were compressed to form a 0183 3. The contents obtained above in (1) and (2) were tablet which was film coated. mixed and was subjected to hot melt extrusion (HME) wherein the melting temperature for the extrusion process ranges from 70 to 200° C., with the molten mass thus Example 12 obtained was collected on a conveyor where it was cooled to form extrudates and these extrudates on further milling 0180 A composition according to the invention com were converted into granules which was followed by addi prised the following components: tion of calcium carbonate, mannitol, low Substituted hydroxylpropyl cellulose and further lubricated with cal cium Stearate. QUANTITY 0.184 4. Fenofibrate was mixed with pre-sieved and pre NGREDIENTS (mg tab) sifted amounts of lactose, starch, Kollidon CLM, sodium lauryl sulphate, yellow oxide of iron, talc. Binder Starch ATORVASTATINLAYER and polyvinylpyrrolidone K-30 were added to the drug Drug Premix premix and granulated. The granules were lubricated with Sodium Stearyl fumarate. Atorvastatin calcium 8O.OO Silicon dioxide 4.OO 0185. 5. The granules obtained in (3) and (4) were com Polymer premix pressed together to form a bilayer tablet which was then film coated. Kollidon VA-64 32O.OO (PVP: vinyl acetate) Sodium monolaurate 16.00 Example 13 Blending 0186. A composition according to the invention com Calcium carbonate 2O.OO Mannitol 16O.OO prised the following components: Low substituted 8O.OO hydroxypropyl cellulose Lubrication QUANTITY Calcium Stearate 2O.OO INGREDIENTS (mg tab) FENOFIBRATE LAYER ATORVASTATINGRANULATE Drug premix Drug premix Fenofibrate 16O.OO Starch 125.00 Atorvastatin calcium 8O.OO Kollidon CLM 11O.OO Silicon dioxide 24.00 US 2010/0204195 A1 Aug. 12, 2010 13

Example 14 -continued 0.192 A composition according to the invention com QUANTITY prised the following components: INGREDIENTS (mg tab) Polymer mix QUANTITY Kollidon VA-64 32O.OO INGREDIENTS (mg tab) (PVP: vinyl acetate) Fenofibrate Granulate Sodium monolaurate 16.00 FENOFIBRATEGRANULATE Fenofibrate 16O.OO Kollidon VA-64 48O.OO Drug premix (PVP: vinyl acetate) Silicon dioxide S.OO Atorvastatin Granulate Fenofibrate 160.00 LactOSe 18O.OO Drug premix Starch 125.00 Blending Atorvastatin calcium 8O.OO Silicon dioxide S.OO Polymer premix Kollidon CLM 60.00 Sodium lauryl Sulphate(SLS) 10.00 Kollidon VA-64 32O.OO Binder (PVP: vinyl acetate) Sodium mono laurate 16.00 Starch 35.00 Blending Polivinyl pyrrollidone K-30 10.00 Mannitol 2OO.OO EXTRAGRAULARLAYER Calcium carbonate 2O.OO Low substituted hydroxyl 8O.OO Kollidon CLM 3O.OO propyl cellulose LH11 Talc 4.OO Calcium carbonate 2O.OO Lubrication Talc 10.00 Sodium stearyl fumarate 10.00 Calcium Stearate 30.00 Lactose 110.00 Film coating Film coating Opadry II 2O.O Purified Water IP Qs Ready colour mix system 2O.O Purified Water IP qS Total 142O.OO

Total 1220.00 0193 1. Fenofibrate was mixed with silicon dioxide and Kollidon VA 64 and the extrudates were prepared by hot 0187 l. Atorvastatin calcium and silicon dioxide were melt extrusion method (HME). These extrudates on further sifted & mixed together in a mixer. milling were converted in the form of granules. 0188 2. Kollidon VA 64 was mixed separately with 0194 2. Atorvastatin calcium with small amount of silicon Sodium mono laurate in a granulator and the mixture was dioxide was sieved, sifted and mixed together in a mixer. then sifted. (0195 3. Kollidon VA 64 was mixed separately with 0189 3. The contents obtained in (1) and (2) were mixed Sodium mono laurate in a granulator and the mixture was and subjected to hot melt extrusion (HME) wherein the then sifted. melting temperature for the extrusion process ranges from 0.196 4. The contents obtained above in (2) and (3) were 70 to 200° C., with the molten mass thus obtained was mixed and was subjected to hot melt extrusion (HME) collected on a conveyor where it was cooled to form extru wherein the melting temperature for the extrusion process dates and these extrudates on further milling were con ranges from 70 to 200° C., with the molten mass thus verted in the form of granules. obtained was collected on a conveyor where it was cooled 0190. 4. Fenofibrate granules were prepared by mixing to form extrudates and these extrudates on further milling lactose, starch, kollidon CLM, Sodium lauryl Sulphate, were converted into granules which was followed by addi polyvinyl pyrrolidone. tion of calcium carbonate, mannitol, low Substituted 0191 5. Amorphous Atorvastatin granules and fenofibrate hydroxylpropyl cellulose, talc and further lubricated with granules were mixed with extragranular components such calcium Stearate. as kollidon CLM, calcium carbonate, talc, Sodium Stearyl 0.197 5. The granules obtained in (1) and (4) were mixed fumarate, lactose were mixed and compressed together to and compressed together to form tablet which was then form a tablet which was then film coated. film coated. US 2010/0204195 A1 Aug. 12, 2010

Example 15 0203 5. The granules obtained in (3) and (4) were com pressed together to form a bilayer tablet which was then 0198 film coated. 0204. It is to be understood that the phraseology and ter minology used herein is for the purpose of description and should not be regarded as limiting. The use of “including.” QUANTITY “comprising,” or “having and variations thereof herein is NGREDIENTS (mg tab) meant to encompass the items listed thereafter and equiva EZETIMIBELAYER lents thereofas well as additional items. 0205. It must be noted that, as used in this specification Dry mix and the appended claims, the singular forms “a” “an and Ezetimibe 10.00 “the include plural references unless the context clearly Mannitol 25 118.00 dictates otherwise. Thus, for example, reference to “a poly Hydroxypropyl cellulose (Low Substituted) S.OO mer' includes a single polymeras well as two or more differ Yellow iron oxide ent polymers, reference to a "plasticizer” refers to a single Binder plasticizer or to combinations of two or more plasticizer, and HPMC 6 cps 4.OO the like. Purified water C.S. 0206. It will be readily apparent to one skilled in the art Lubrication that varying Substitutions and modifications may be made to Prosolve SMCC 90 SO.OO the invention disclosed herein without departing from the Microcrystalline cellulose 109.8 scope and spirit of the invention. Thus, it should be under Calcium Stearate 3.00 stood that although the present invention has been specifically Total Weight 3OO.OO disclosed by preferred embodiments and optional features, ATORVASTATINLAYER modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such Drug premix modifications and variations are considered to be falling Atorvastatin calcium 43.37 within the scope of the invention. Kollidon VA 64 160.00 1. A pharmaceutical composition comprising one or more Aerosil 200 2.50 Span 20 8.00 cholesterol reducing agents inanamorphous form, whereinat Blending & Lubrication least one agent is converted in-situ to an amorphous form during the manufacture of the composition. Calcium carbonate 25.00 2. The pharmaceutical composition according to claim 1, Ac-Di-Sol 90.00 Hydroxypropyl cellulose (Low Substituted) 100.00 further comprising a polymer. Aerosi 20 6.OO 3. A composition comprising an extruded article contain Prosolve SMCC 90 155.13 ing one or more cholesterol reducing agents in an amorphous Calcium Stearate 10.00 form in combination with a polymeric carrier, and optionally at least one pharmaceutically acceptable excipient. Total Weight 600.00 4. The composition according to claim 3, wherein at least one amorphousagentis formed in situ during the manufacture of the composition. Procedure: 5. The composition according to claim 2, wherein the ratio of agent to polymer is from 1:1 to 1:6 on a weight basis. 0199. 1. Ezetimibe, mannitol and small amount of 6. The composition according to claim 2, comprising 2 to Hydroxypropyl cellulose (Low substituted) and yellow 80 wt % polymer. iron oxide were sieved, sifted and mixed together in a 7-8. (canceled) mixer. 9. A pharmaceutical composition obtainable from a com 0200 2. A separate solution of HPMC 6 cps was prepared position according to claim3, optionally in combination with in sufficient purified water. at least one pharmaceutically acceptable excipient. 0201 3. The contents obtained above in (1) and (2) were 10. The composition according to claim 1, wherein the mixed and was subjected to hot melt extrusion (HME) cholesterol reducing agent comprises at least one HMG-CoA wherein the melting temperature for the extrusion process inhibitor, at least one cholesterol absorption inhibitor and/or ranges from 70 to 200° C., with the molten mass thus at least one fibrate or its pharmaceutically acceptable salts, obtained was collected on a conveyor where it was cooled pharmaceutically acceptable Solvates, pharmaceutically to form extrudates and these extrudates on further milling acceptable enantiomers, pharmaceutically acceptable deriva were converted into granules which was followed by addi tives, pharmaceutically acceptable polymorphs or pharma tion of prosolve SMCC 90, microcrystalline cellulose and ceutically acceptable prodrugs thereof. further lubricated with calcium stearate. 11. The composition according to claim 1, wherein the 0202) 4. Atorvastatin calcium was mixed with pre-sieved cholesterol reducing additive comprises at least one HMG and pre-sifted amounts of Kollidon VA 64, Aerosil 200 and CoA reductase inhibitor and/or at least one fibrate or its span 20. Blending agents such as calcium carbonate. Ac pharmaceutically acceptable salts, pharmaceutically accept Di-sol, Hydroxypropyl cellulose (Low substituted), Aero able solvates, pharmaceutically acceptable enantiomers, sil 200 and prosolve SMCC 90 were added to the drug pharmaceutically acceptable derivatives, pharmaceutically premix and granulated. The granules were lubricated with acceptable polymorphs or pharmaceutically acceptable pro calcium Stearate. drugs thereof. US 2010/0204195 A1 Aug. 12, 2010

12. The composition according to claim 10, wherein the maceutically acceptable solvates, pharmaceutically accept fibrate is selected from benzafibrate, gemfibrozil, fenofibrate, able enantiomers, pharmaceutically acceptable derivatives, simfibrate, ronifibrate, ciprofibrate, etofibrate, clofibrate, cli pharmaceutically acceptable polymorphs or pharmaceuti nofibrate or its pharmaceutically acceptable salts, pharma cally acceptable prodrugs thereof. ceutically acceptable Solvates, pharmaceutically acceptable 19. The composition according to claim 1, wherein the enantiomers, pharmaceutically acceptable derivatives, phar cholesterol reducing active comprises atorvastatin calcium maceutically acceptable polymorphs or pharmaceutically and fenofibrate or its pharmaceutically acceptable salts, phar acceptable prodrugs thereof. maceutically acceptable solvates, pharmaceutically accept 13. The composition according to claim 10, wherein the able enantiomers, pharmaceutically acceptable derivatives, fibrate is fenofibrate or its pharmaceutically acceptable salts, pharmaceutically acceptable polymorphs or pharmaceuti pharmaceutically acceptable Solvates, pharmaceutically cally acceptable prodrugs thereof. acceptable enantiomers, pharmaceutically acceptable deriva 20. The composition according to claim 1, obtainable by tives, pharmaceutically acceptable polymorphs or pharma melt extruding at least one cholesterol reducing agent along ceutically acceptable prodrugs thereof. with at least one pharmaceutically acceptable polymer, and 14. The composition according to claim 1, wherein the optionally one or more other pharmaceutically acceptable cholesterol reducing agent comprises at least one HMG CoA excipients, to form an extrudate, and optionally admixing the reductase inhibitor and/or at least one cholesterol absorption extrudate with one or more further pharmaceutically accept inhibitor or its pharmaceutically acceptable salts, pharmaceu able excipients. tically acceptable Solvates, pharmaceutically acceptable 21-22. (canceled) enantiomers, pharmaceutically acceptable derivatives, phar 23. The composition according to claim 1, effective for use maceutically acceptable polymorphs or pharmaceutically in treating dyslipidemia, hyperlipidemia, hypercholester acceptable prodrugs thereof. olemia, atherosclerosis, arteriosclerosis, cardiovascular dis 15. The composition according to claim 10, wherein the ease, coronary artery disease, coronary heart disease, vascu cholesterol absorption inhibitor is eZetimibe or its pharma lar disorder and/or a related disorder. ceutically acceptable salts, pharmaceutically acceptable sol 24. The method of making a pharmaceutical composition Vates, pharmaceutically acceptable enantiomers, pharmaceu as defined in claim 1, containing one or more amorphous tically acceptable derivatives, pharmaceutically acceptable cholesterol reducing agents, comprising blending the agents polymorphs or pharmaceutically acceptable prodrugs with a pharmaceutically acceptable polymer, and hot melt thereof. extruding the blend to form an extrudate. 16. The composition according to claim 10, wherein the 25. The method according to claim 24, wherein at least one HMG CoA reductase inhibitor is selected from cerivastatin, cholesterol reducing agent is blended with the polymer, and atorvastatin, lovastatin, simvastatin, rosuvastatin, pravasta the amorphous form of said active is formed in-situ during the tin, mevastatin, fluvastatin, rivastatin, pitavastatin or its phar hot melt extrusion. maceutically acceptable salts, pharmaceutically acceptable 26-35. (canceled) Solvates, pharmaceutically acceptable enantiomers, pharma 36. The method according to claim 24, comprising pro ceutically acceptable derivatives, pharmaceutically accept cessing the extrudate and optionally mixing it with one or able polymorphs or pharmaceutically acceptable prodrugs more additives to form the pharmaceutical composition. thereof. 37. The method according to claim 24, comprising cutting 17. The composition according to claim 10, wherein the the extrudate to a desired shape to form the pharmaceutical HMG CoA reductase inhibitor is atorvastatin or its pharma composition. ceutically acceptable salts, pharmaceutically acceptable sol 38. The method according to claim 24, comprising treating Vates, pharmaceutically acceptable enantiomers, pharmaceu the extrudate to form a granulate. tically acceptable derivatives, pharmaceutically acceptable 39. The method according to claim 38, comprising filling polymorphs or pharmaceutically acceptable prodrugs the granulate into a capsule, or compressing the granulate to thereof. form a tablet. 18. The composition according to claim 1, wherein the 40. (canceled) cholesterol reducing agent comprises atorvastatin calcium and eZetimibe or its pharmaceutically acceptable salts, phar