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Pharmaceutical formulationRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Preparations Characterized By Special Physical Form, Tablets, Lozenges, Or PillsPharmaceutical formulation description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070160666, Pharmaceutical formulation. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Application No. 60/398,691 filed Jul. 26, 2002, the disclosure of which is hereby incorporated by reference in its entirety. BACKGROUND OF THE INVENTION [0002] The instant invention involves a pharmaceutical formulation for bulk composition and oral dosage units comprised of the combination of a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, particularly simvastatin, with a cholesterol absorption inhibitor, particularly ezetimibe, or pharmaceutically acceptable salts, solvates or esters of these compounds, which is useful for lipid management and for preventing and treating atherosclerotic diseases and related conditions and disease events. [0003] It has been clear for several decades that elevated blood cholesterol is a major risk factor for coronary heart disease (CHD), and many studies have shown that the risk of CHD events can be reduced by lipid-lowering therapy. Prior to 1987, the lipid-lowering armamentarium was limited essentially to a low saturated fat and cholesterol diet, the bile acid sequestrants (cholestyramine and colestipol), nicotinic acid (niacin), the fibrates and probucol. Unfortunately, all of these treatments have limited efficacy or tolerability, or both. Substantial reductions in LDL (low density lipoprotein) cholesterol accompanied by increases in HDL (high density lipoprotein) cholesterol could be achieved by the combination of a lipid-lowering diet and a bile acid sequestrant, with or without the addition of nicotinic acid. However, this therapy is not easy to administer or tolerate and was therefore often unsuccessful except in specialist lipid clinics. The fibrates produce a moderate reduction in LDL cholesterol accompanied by increased HDL cholesterol and a substantial reduction in triglycerides, and because they are well tolerated these drugs have been more widely used. Probucol produces only a small reduction in LDL cholesterol and also reduces HDL cholesterol, which, because of the strong inverse relationship between HDL cholesterol level and CHD risk, is generally considered undesirable. With the introduction of lovastatin, the first inhibitor of HMG-CoA reductase to become available for prescription in 1987, for the first time physicians were able to obtain large reductions in plasma cholesterol with very few adverse effects. [0004] Recent studies have unequivocally demonstrated that lovastatin, simvastatin and pravastatin, all members of the HMG-CoA reductase inhibitor class, slow the progression of atherosclerotic lesions in the coronary and carotid arteries. Simvastatin and pravastatin have also been shown to reduce the risk of coronary heart disease events, and in the case of simvastatin a highly significant reduction in the risk of coronary death and total mortality has been shown by the Scandinavian Simvastatin Survival Study. This study also provided some evidence for a reduction in cerebrovascular events. [0005] Despite the substantial reduction in the risk of coronary morbidity and mortality achieved by simvastatin, the risk is still substantial in the treated patients. For example, in the Scandinavian Simvastatin Survival Study, the 42% reduction in the risk of coronary death still left 5% of the treated patients to die of their disease over the course of this 5 year study. Further reduction of risk is clearly needed. [0006] Certain hydroxy-substituted azetidinones such as ezetimibe (described in U.S. Pat. Nos. 5,767,115 and Re. 37721) are now known to be useful as hypocholesterolemic agents in the treatment and prevention of atherosclerosis. Cholesteryl esters are a major component of atherosclerotic lesions and the major storage form of cholesterol in arterial wall cells. Formation of cholesteryl esters is also a key step in the intestinal absorption of dietary cholesterol. Thus, inhibition of cholesteryl ester formation and reduction of serum cholesterol is likely to inhibit the progression of atherosclerotic lesion formation, decrease the accumulation of cholesteryl esters in the arterial wall, and block the intestinal absorption of dietary cholesterol. [0007] Further risk reduction can be achieved with a combination therapy comprised of an HMG-CoA reductase inhibitor such as simvastatin with a cholesterol absorption inhibitor such as ezetimibe to provide lipid management, and to treat or reduce the risk of atherosclerotic disease; the combined use of these two active agents is described in U.S. Pat. No. 5,846,966. Since ezetimibe can be given orally once daily, like HMG-CoA reductase inhibitors such as simvastatin, it would be beneficial to combine the two active agents into a single orally administerable pharmaceutical dosage unit such as a tablet using a formulation that is stable and minimizes the degradation of the active agents. [0008] The instant invention addresses this need by providing a novel formulation for bulk pharmaceutical composition and for oral pharmaceutical dosage units comprised of simvastatin and ezetimibe that can be produced in a robust process that provides a high quality finished product with minimal unwanted degradation by-products and desirable shelf-life stability. SUMMARY OF THE INVENTION [0009] The instant invention provides a novel pharmaceutical formulation comprised of a cholesterol absorption inhibitor and an HMG-CoA reductase inhibitor having desirable stability but which does not require the presence of ascorbic acid, nor does it require the presence of pre-gelatinized starch. [0010] More particularly, the instant invention provides a pharmaceutical composition comprised of from 1% to 20% by weight of a cholesterol absorption inhibitor such as ezetimibe; from 1% to 80% by weight of an HMG-CoA reductase inhibitor such as simvastatin; and from 0.01% to 2% by weight of a stabilizing agent such as BHA. It further comprises from 1% to 80% by weight of microcrystalline cellulose; from 0.5% to 10% by weight of hydroxypropyl methylcellulose; from 0.1% to 4% by weight of magnesium stearate; and from 25% to 70% by weight of lactose. The composition may also optionally be comprised of one or more of croscarmellose sodium, citric acid, ascorbic acid and propyl gallate. Although the composition can include ascorbic acid, it is not necessary to include ascorbic acid in order to obtain desirable results. Similarly, although the composition could include pre-gelatinized starch, the composition need not include pre-gelatinized starch to obtain desirable results. The composition can be prepared in bulk form and is suitable for forming into individual oral dosage units, such as tablets, which are useful for treating vascular conditions such as hyperlipidemia including hypercholesterolemia and treating and preventing atherosclerotic disease and events such as myocardial infarction. [0011] Another aspect of the present invention is a pharmaceutical composition comprising from 1 to 20% by weight of a cholesterol absorption inhibitor such as ezetimibe; from 1 to 80% by weight of at least one HMG-CoA reductase inhibitor; and from 0.005 to 10% by weight of at least one stabilizing agent. Additional aspects will be evident from the following detailed description. DETAILED DESCRIPTION OF THE INVENTION [0012] The instant invention is directed to formulations of HMG-CoA reductase inhibitors and cholesterol absorption inhibitors. More particularly the HMG-COA reductase inhibitor is a statin, including, for example, simvastatin, lovastatin, atorvastatin, fluvastatin, pravastatin, cerivastatin, pitavastatin and rosuvastatin. The cholesterol absorption inhibitor may be selected from any of those disclosed in U.S. Pat. Nos. RE 37,721; 5,688,990; 5,656,624; 5,624,920; 5,698,548; 5,627,176; 5,633,246; 5,688,785; 5,688,787; 5,744,467; 5,756,470; 5,767,115 and U.S. patent application Ser. No. 10/166,942 filed Jun. 11, 2002, which are incorporated herein by reference. Methods of making such compounds are also disclosed in those patents. Specifically, the instant invention is directed to formulations of simvastatin and ezetimibe. [0013] Simvastatin is marketed worldwide, and sold in the U.S. under the tradename ZOCOR.RTM.. Methods for making it are described in U.S. Pat. Nos. 4,444,784; 4,916,239; 4,820,850; among other patent and literature publications. Simvastatin is shown below as structural formula I: [0014] Ezetimibe is now marketed in the U.S. under the tradename ZETIA.RTM.. The ZETIA.RTM. formulation contains ezetimibe as the only active ingredient. Methods for making ezetimibe are described in U.S. Pat. Nos. 5,631,365; Re. 37721; 5,846,966; 5,767,115, 6,207,822; U.S. application Ser. No. 10/105,710 filed Mar. 25, 2002 and PCT No. 93/02048. Ezetimibe is shown below as structural formula II, and can be in an anhydrous or hydrated form: [0015] In addition to the HMG-CoA reductase inhibitor and cholesterol absorption inhibitor active agents, particularly simvastatin and ezetimibe, the instant oral pharmaceutical composition may contain one or more of microcrystalline cellulose, hydroxypropyl methylcellulose (HPMC), magnesium stearate, lactose and povidone (PVP). The composition is also comprised of one or more stabilizing agents including antioxidant agents such as, for example, butylated hydroxyanisole (BHA), 2,6-di-tert-butyl-4-methylphenol (BHT), propyl gallate, ascorbic acid, citric acid, edetate disodium and calcium metabisulphite, with BHA, propyl gallate and combinations thereof being preferred, and a combination of BHA with propyl gallate being most preferred. Optionally, one or more of croscarmellose sodium (CCNa), citric acid, lactic acid, malic acid, succinic acid, tartaric acid and ethylenediaminetetraacetic acid (EDTA) and salts thereof may also be included in the composition. In particular, although ascorbic acid could be included in the composition, the composition does not require the presence of ascorbic acid as a component to achieve good results. Similarly, the composition does not require the presence of pregelatinized starch as a component to achieve good results, although pregelatinized starch could be included in the composition if desired. When the term "ascorbic acid" is used herein, it is intended to include the free acid as well as salt forms thereof, such as sodium ascorbate. [0016] It is known that ascorbic acid tends to discolor compositions, pharmaceutical and otherwise, when it is a component. When used in pharmaceutical tablets, this discoloring effect may necessitate the use of a coating over the tablet to mask the discoloration. Since the composition of this invention can be formulated without ascorbic acid, such tablets formed without ascorbic acid can be prepared without the extra step of adding a film coating. Of course, a film coating could be added if desired, for example for aesthetic purposes, but the need to add a coating to mask the discoloration caused by ascorbic acid is removed. [0017] As used herein, the terms "pharmaceutical composition" and "composition" encompass both the bulk composition and individual oral dosage units (tablets, pills and the like) comprised of the two pharmaceutically active agents, e.g. simvastatin and ezetimibe, with the pharmaceutically inactive excipients described herein (the active agents and the excipients are collectively referred to herein as the "components" of the composition). The bulk composition is material that has not yet been formed into individual oral dosage units. The oral dosage unit form of the pharmaceutical composition is preferably a tablet. [0018] Other than in the operating examples, or where otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about." [0019] As intended herein, the total weight of a single oral dosage unit, e.g. the weight of one tablet, is determined by adding the weights of all the components (i.e., the two active agents and the excipients) in the dosage unit, and does not include the weight of any coatings which may optionally be externally applied to the dosage unit after it has been formed from the bulk composition. It also does not include any solvents used during the granulation process which are subsequently removed during drying. The total weight of a single oral dosage unit as defined above is used as the basis for calculating the weight percentage of each of the components that comprise the dosage unit. However, dosage units comprised of the components described herein that are uncoated as well as those that are coated with waxes, colorants, and the like are included within the scope of this invention. [0020] The total weight of the bulk composition comprised of the components described herein will necessarily vary according to the amount of bulk composition that is desired to be produced. For the purpose of calculating the weight percentage of each of the components that comprise any given amount of bulk composition, the weights of all the components (i.e., the two active agents and the excipients) in a given amount of bulk composition are added together to determine the total weight of the bulk composition. As would be understood in the art, the bulk composition would not contain either solvents used in the granulation process, nor coating materials as components, and therefore such coating materials and solvents would not be included in the total weight calculation of the bulk composition. Continue reading about Pharmaceutical formulation... 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