EP1644399A2 - Nouveaux composes et compositions comprenant des sterols et/ou des stanols et des inhibiteurs de biosynthese du cholesterol et utilisation associees pour le traitement et la prevention de maladies et d'etats divers - Google Patents

Nouveaux composes et compositions comprenant des sterols et/ou des stanols et des inhibiteurs de biosynthese du cholesterol et utilisation associees pour le traitement et la prevention de maladies et d'etats divers

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Publication number
EP1644399A2
EP1644399A2 EP04737936A EP04737936A EP1644399A2 EP 1644399 A2 EP1644399 A2 EP 1644399A2 EP 04737936 A EP04737936 A EP 04737936A EP 04737936 A EP04737936 A EP 04737936A EP 1644399 A2 EP1644399 A2 EP 1644399A2
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European Patent Office
Prior art keywords
preventing
treating
alleviating
cholesterol
compound
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EP04737936A
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German (de)
English (en)
Inventor
James P. Kutney
Haydn P. Pritchard
Tatjana Lukic
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Forbes Medi-Tech Inc
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Forbes Medi-Tech Inc
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Publication of EP1644399A2 publication Critical patent/EP1644399A2/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • This present invention relates to the field of sterols and stanols and novel derivatives thereof and their use in treating and preventing cardiovascular disease and other disorders.
  • CVD cardiovascular disease
  • the primary cause of CVD is atherosclerosis, a disease characterized by the deposition of lipids, including cholesterol, in the arterial vessel wall resulting in a narrowing of the vessel passages and ultimately a hardening of the vascular system.
  • Atherosclerosis is a degenerative process resulting from aninterplay of inherited (genetic) factors and environmental factors such as diet and lifestyle.
  • Research to date suggest that cholesterol may play a role in atherosclerosis by forming atherosclerotic plaques in blood vessels, ultimately cutting off blood supply to the heart muscle or alternatively to the brain or limbs, depending on the location of the plaque in the arterial tree 1 2 .
  • a total cholesterol in excess of 225-250 mg/dl is associated with significantly elevated risk of CVD, includinpj vascular disease.
  • 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 step in the intestinal absorption of dietary cholesterol through homeostatic control mechanisms. These control mechanisms involve the inter-related regulation of dietary cholesterol, cholesterol biosynthesis and catabolism of cholesterol-containing plasma lipoproteins. Cholesterol biosynthesis and catabolism occur primarily in the liver and hence, it is a prime determinant of plasma cholesterol levels.
  • Lipoproteins are complexes of lipids and proteins held together by non-covalent bonds. Each type of lipoprotein class has a characteristic mass, chemical composition, density and physiological role. Irrespective of density or particle size, circulating lipids consist of a core of cholesteryl esters and triglycerides, and an envelope of phospholipids, free cholesterol and apolipoproteins. The apolipoproteins are involved in the assembly and secretion of the lipoprotein, provide structural integrity, activate lipoprotein-modifying enzymes, and are the ligand for a large assortment of receptors and membrane proteins. Lipoprotein classes found in plasma include HDL, LDL, intermediate density lipoproteins (IDL) and very low density lipoproteins (VLDL).
  • HDL high density lipoproteins
  • IDL intermediate density lipoproteins
  • VLDL very low density lipoproteins
  • Each type of lipoprotein has a characteristic apolipoprotein composition or ratio.
  • the most prominent apolipoprotein in HDL is apolipoprotein-AI (apo-AI), which accounts for approximately 70% of the protein mass, with apo-AII accounting for another 20%.
  • the ratio of apoA-l to apoA-ll may determine HDL functional and anti-atherogenic properties.
  • Circulating HDL particles consist of a heterogeneous mixture of discoidal and spherical particles with a mass of 200 to 400 kilo-daltons and a diameter of 7 to 10) nm.
  • HDL is one of the major classes of lipoproteins that function in the transport of lipids in plasma, and has multiple functions within the body, including reverse cholesterol transport, providing the cholesterol molecule substrate for bile acid synthesis, transport of clusterin, transport of paraoxanase, prevention of lipoprotein oxidation and selective uptake of cholesterol by adrenal cells.
  • the major lipids associated with HDL includes cholesterol, cholesteryl ester, triglycerides, phospholipids and fatty acids.
  • the atherosclerotic process begins when LDL becomes trapped within the vascular wall. Oxidation of this LDL results in the binding of monocytes to the endothelial cells lining the vessel wall. These monocytes are activated and migrate into the endothelial space where they are transformed into macrophages, leading to further oxidation of the LDL. The oxidized LDL is taken up through the scavenger receptor on the macrophage, leading to the formation of foam cells. A. fibrous cap is generated through the proliferation and migration of arterial smooth muscle cells, thus creating an atherosclerotic plaque.
  • HDL is essential for the transport of cholesterol from extra-hepatic tissues to the liver, where it is excreted into bile as free cholesterol or as bile acids that are formed from cholesterol.
  • the process requires several steps. The first is the formation of nascent or pre-beta HDL particles in the liver and intestine. Excess cholesterol moves across cell membranes into the nascent HDL through the action of the ABC A1 transporter. Lecithin cholesterol acyl transferase (LCAT) converts the cholesterol to cholesteryl ester and the subsequent conversion of nascent HDL to mature HDL.
  • LCAT Lecithin cholesterol acyl transferase
  • Esterifie cholesterol is then transferred by cholesteryl ester transfer protein (CETP) from HDL to apolipoprotein-B containing lipoproteins, which are taken up by numerous receptors i ⁇ * the liver.
  • CTP cholesteryl ester transfer protein
  • 1 Nascent HDL is regenerated via. hepatic triglyceride lipase and phospholipid transfer protein and the cycle continues.
  • HDL accepts cholesterol from LDL and erythrocyte membranes.
  • Another m echanism of reverse cholesterol transport m ay involve passive diffusion of cholesterol between cholesterol-poor membranes and HDL or other acceptor molecules.
  • HDL protects against the development of atherosclerosis both through its role in reverse cholesterol transport and possibly by impeding LDL oxidation.
  • Several HDL- associated enzymes are involved in the process. Paroxonase (PON1 ), LCAT, and platelet activating factor acetylhydrolase (PAFAH) all participate by hydrolyzing phospholipid hydroperoxides generated during LDL oxidation and act in tandem to prevent the accumulation of oxidized lipid in LDL. These enzymes are responsible for the anti-oxidative and anti-inflammatory properties of HDL. Studies have shown that a low plasma concentration of HDL cholesterol is a significant risk factor for the development of atherosclerosis 6 and that high levels are protective.
  • the liver is the major organ responsible for synthesis and secretion of VLDLs, which, as noted above, are metabolized to LDL in circulation.
  • LDLs are the predominant cholesterol carrying lipoproteins in plasma and hence an increase in their concentration is directly correlated with atherosclerosis. Simply put, when intestinal cholesterol absorption is reduced, by any means, less cholesterol is d elivered to t he l iver. As a result, VLDL production is reduced and there is a concomitant increase in hepatic clearance of plasma cholesterol, mostly in the form of LDL.
  • cholesterol acts on three different levels to regulate its own synthesis. Firstly, it suppresses endogenous cholesterol synthesis by inhibiting the enzyme HMG CoA reductase. Secondly, it activates LCAT. Thirdly, it regulates the synthesis of the LDL- receptor ensuring that a cell already having a sufficient amount of cholesterol will not take up additional cholesterol.
  • Sterols are naturally occurring compounds that perform many critical cellular functions. Sterols such as campesterol, stigmasterol and beta-sitosterol in plants, ergosterol in fungi and cholesterol in animals are each primary components of cellular and sub-cellular membranes in their respective cell types.
  • the dietary source of phytosterols in humans comes from plant materials i.e. vegetables and plant oils.
  • the estimated daily phytosterol content in the conventional western-type diet is approximately 60-80 milligrams in contrast to a vegetarian diet which would provide about 500 milligrams per day.
  • Phytosterols have received a great deal of attention due to their ability to decrease serum cholesterol levels when fed to a number of mammalian species, including humans. While the precise mechanism of action remains largely unknown, the relationship between cholesterol and phytosterols is apparently due in part to the similarities between the respective chemical structures (the differences occurring in the side chains of the molecules). It is assumed that phytosterols displace cholesterol from the micellar phase and thereby reduce its absorption or possibly compete with receptor and/or carrier sites in the cholesterol absorption process.
  • the present invention provides, in one aspect, novel compounds having one or more of the following formulae: a) o R 2 — (CH 2 ) n — C -O-R
  • R is a sterol or stanol moiety
  • R 2 is a cholesterol biosynthesis inhibitor with at least one free and reactive carboxyl group
  • R 3 is a cholesterol biosynthesis inhibitor with at least one free and reactive hydroxyl group
  • R 4 is derived from ascorbic acid
  • composition comprising: a) at least one cholesterol absorption inhibitor selected from compounds having the general formulae:
  • R is a sterol or stanol moiety
  • the present invention provides, in another aspect, a method of achieving one or more of the following therapeutic goals: a) preventing, treating or alleviating one or more conditions associated with CVD generally and including arteriosclerosis, atherosclerosis, arteriolosclerosis, angina pectoris, and thrombosis; b) reducing and/or eliminating one or more of the risk factors associated with CVD; c) preventing, treating or alleviating atherosclerosis; d) preventing, treating or alleviating hyperchoiesterolemia; e) preventing, treating or alleviating a hyperiipidic condition; f) preventing, treating or alleviating dislipidemia; g) preventing, treating or alleviating hypertension; h) preventing, treating or alleviating coronary artery disease; i) preventing, treating or alleviating coronary plaque development; j) preventing, treating or alleviating coronary plaque inflammation; k) lowering serum LDL cholesterol; I) increasing serum HDL cholesterol; m) decreasing serum triglycerides levels; n) decreasing cholesterol
  • the present invention provides, in yet another aspect, a method for treating or preventing cardiovascular disease and its underlying conditions including, without limitation, atherosclerosis, hypercholesterolemia, hyperlipidemia, dislipidemia, hypertension, thrombosis, coronary artery disease, and for treating and reducing inflammation including coronary plaque inflammation, which comprises administering to an animal, a non-toxic and therapeutically effective amount of one or more of the compounds, as shown above.
  • a method for treating or preventing cardiovascular disease and its underlying conditions including, without limitation, atherosclerosis, hypercholesterolemia, hyperlipidemia, dislipidemia, hypertension, thrombosis, coronary artery disease, and for treating and reducing inflammation including coronary plaque inflammation, which comprises administering to an animal, a non-toxic and therapeutically effective amount of the composition, as described in summary above.
  • the present invention relates to a pharmaceutical composition comprising an effective or therapeutic amount of one or more of the novel compounds described herein and a pharmaceutically acceptable carrier.
  • the present invention relates to a pharmaceutical composition comprising an effective or therapeutic amount of at least one cholesterol absorption inhibitor having one of formulae i)-iv) together with an effective or therapeutic amount at least one cholesterol biosynthesis inhibitor and a pharmaceutically acceptable carrier.
  • the present invention provides a kit comprising, in one container, an effective amount at least one cholesterol absorption inhibitor having one of formulae i)-iv and a pharmaceutically acceptable carrier and in another separate container, an effective amount at least one cholesterol biosynthesis inhibitor and a pharmaceutically acceptable carrier.
  • the crux of the present invention is the provision and co-administration of sterols and/or stanois with cholesterol biosynthesis inhibitors, for example and preferably, statins.
  • This can be accomplished in two ways: 1 ) via the formation of novel compounds wherein sterols and/or stanois are chemically joined to the selected cholesterol biosynthesis inhibitor in a unified structure; and 2) via the formation of novel compositions, wherein selected cholesterol absorption inhibitors (in the form of sterol and/or stanol esters or derivatives) are admixed with the selected cholesterol biosynthesis inhibitor.
  • the cholesterol biosynthesis inhibitors are either derivatized with the sterol/stanol component as described herein, or merely co-adminstered with sterols/stanols in composition, a lower d osage of the selected cholesterol biosynthesis inhibitor may be required to a chieve the d esired effects.
  • T his i important due to the documented adverse side-effects of some cholesterol biosynthesis inhibitors, including some statins. The reduction of potential side-effects is also considered important from the perspective of patient compliance.
  • Some of the compounds of the present invention (those depicted in formulae (e) and (f) and in i) through iv) above) comprise an ascorbyl moiety. These particular compounds have numerous advantages. In particular, solubility in aqueous solutions such as water is improved by the ascorbyl moiety thereby allowing oral administration perse. Likewise, other modes of administration are facilitated. Accordingly, these selected compounds of the present invention can be prepared and used as such or they can be easily incorporated into pharmaceutical preparations regardless of whether such preparations are water-based. This enhanced solubility generally translates into lower administration dosages of the compounds in order to achieve the desired therapeutic effect.
  • Figure 1 is a schematic showing a process of preparing ascorbyl sitostanyl or campestanyl atorvastatin phosphate ester and its sodium salt;
  • Figure 2 is a schematic showing a process of preparing ascorbyl sitostanyl or campestanyl simavastatin phosphate ester and its sodium salt;
  • Figure 3 is a schematic showing a process of preparing sitostanyl or campestanyl simavastatin phosphate ester.
  • Figure 4 is a schematic showing a process of preparing sitostanyl or campestanyl atorvastatin carboxylic ester.
  • animal means any member of the animal kingdom, including all mammals and most preferably humans.
  • prodrug refers to compounds that are drug precursors, which, following administration to a patient, release the drug in vivo via some chemical or physiological process (for example, a prodrug, on being brought to physiological pH or through enzyme action is converted to the desired drug form).
  • solvate refers to a molecular or ionic complex of molecules or ions of solvent with those of solute (for example the compounds of formulae a) to f) or prodrugs of compounds a) to f)).
  • useful solvents include polar, protic solvents such as water and/or alcohols (for example methanol).
  • the terms "effective” or “therapeutically effective”, are intended to qualify the amount of the compound(s) or composition administered to an animal, in particular a human, in order to elicit a biological or medical response of a tissue, system, animal or mammal that is being sought by the person administering the compound(s) or composition and which amount achieves one or more of the following goals: a) preventing, treating or alleviating one or more conditions associated with CVD generally and including arteriosclerosis, atherosclerosis, arteriolosclerosis, angina pectoris, and thrombosis; b) reducing and/or eliminating one or more of the risk factors associated with CVD c) preventing, treating or alleviating atherosclerosis; d) preventing, treating or alleviating hypercholesterolemia; e) preventing, treating or alleviating a hyperlipidic condition; f) preventing, treating or alleviating dislipidemia; g) preventing, treating or alleviating hypertension; h) preventing, treating or alleviating coronary artery disease;
  • statin includes any naturally occurring or synthetic compound that inhibits 3-hydroxy-3-methylglutaryl coenzyme A reductase by competing with 3- hydroxy-3-methylglutaric acid for the substrate binding site on HMG CoA reductase.
  • sterol includes all sterols without limitation, for example: (from any source and in any form: ⁇ , ⁇ and y) sitosterol, campesterol, stigmasterol, brassicasterol (including dihydrobrassicasterol), desmosterol, chalinosterol, poriferasterol, clionasterol, ergosterol, coprosterol, codisterol, isofucosterol, fucosterol, clerosterol, nervisterol, lathosterol, stellasterol, spinasterol, chondrillasterol, peposterol, avenasterol, isoavenasterol. fecosterol, pollinastasterol, cholesterol and all natural or synthesized forms and derivatives thereof, including isomers.
  • stanol refers to, for example: (from any source and in any form: ⁇ , ⁇ and y) saturated or hydrogenated sterols including all natural or synthesized forms and derivatives thereof, and isomers, including sitostanol, campestanol, stigmastanol, brassicastanol (including dihydrobrassicastanol), desmostanol, chalinostanol, poriferastanol, clionastanol, ergostanol, coprostanol, codistanol, isofucostanol, fucostanol, clerostanol, nervistanol, lathostanol, stellastanol, spinastanol, chondrillastanol, pepostanol, avenastanol, isoavenastanol, fecostanol, and pollinastastanol.
  • the sterols and stanois for use in forming derivatives in accordance with this invention may be procured from a variety of natural sources or they may be artificially synthesized. For example, they may be obtained from the processing of plant oils (including aquatic plants) such as com oil and other vegetable oils, wheat germ oil, soy extract, rice extract, rice bran, rapeseed oil, sunflower oil, sesame oil and fish (and other marine-source) oils. They may also be derived from yeasts and fungi, for example ergosterol. Accordingly, the present invention is not to be limited to any one source of sterols.
  • US Patent Serial No. 4,420,427 teaches the preparation of sterols from vegetable oil sludge using solvents such as methanol.
  • phytosterols and phytostanols may be obtained from tall oil pitch or soap, by-products of forestry practises as described in US Patent Serial No.5,770, 749, incorporated herein by reference.
  • a further method of extracting sterols and stanois from tall oil pitch is described in Canadian Patent Application Serial No. 2,230,373 which was filed on February 20, 1998 (corresponding to PCT/CA99/00150 which was filed on February 19, 1999) and US Patent Application Serial No 10/060,022 which was filed on January 28, 2002 the contents of all of which are incorporated herein by reference.
  • sterol and "stanol” as used herein, including, but not limited to: free sterols and stanois, esterified sterols and stanois with aliphatic or aromatic acids (thereby forming aliphatic or aromatic esters, respectively), phenolic acid esters, cinnamate esters, ferulate esters, phytosterol and phytostanol glycosides and acylated glycosides or acylglycosides.
  • sterols and “stanois” encompasses all analogues, whichi may further h ave a d ouble bond at the 5 -position i n t he cyclic u nit as in most natural sterols, or one or more double bonds at other positions in the rings (for example, 6, 7, 8(9), 8(14), 14 5/7) or no double bonds in the cyclic unit as in stanois. Further, there may be additional methyl groups as, for example, in ⁇ Vsitosterol.
  • cholesterol biosynthesis inhibitor refers to any compound having a negative effect on systemic cholesterol production by whatever mechanism.
  • Non-limiting examples of such compounds include: competitive inhibitors of 1) 3-hydroxy-3-methylglutaryl coenzyme A reductase " HMG CoA reductase", 2) 3-hydroxy-3-methylglutaryl coenzyme A synthase "HMG CoA synthase”, 3) squalene synthase, and 4) squalene epoxidase.
  • HMG CoA reductase inhibitors are more commonly known as "statins". These agents have been used for primary and secondary prevention of coronary artery disease. HMG CoA reductase is a key enzyme in the cholesterol biosynthetic pathway. Statins decrease liver cholesterol biosynthesis (approximately 50% of circulating cholesterol is endogenously synthesized, principally as LDL cholesterol), which in turn increases the production of LDL receptors thereby decreasing plasma total and LDL cholesterol 10 . Depending on the agent and dose used, statins may also decrease serum triglycerides levels and increase serum HDL. Statins have become the standard therapy for LDL cholesterol lowering.
  • Dyspepsia, abdominal pain and flatulence are among the most common side effects of statin administration.
  • the most severe adverse effects of statins are elevations of the serum transaminase levels and development of myositis.
  • Myotoxicity is a common effect of all statins at high doses 11
  • the mechanism appears to be oxidative damage to mitochondria.
  • Statins cause a drop in the lactate/pyruvate level 12 .
  • the lactate/pyruvate ratio is a sensitive measure of mitochondrial dysfunction and oxidative status 13 . It has been shown in clinical studies that statins deplete an essential cofactor required for energy production, coenzyme Q 14 .
  • the depletion of coenzyme Q is dose dependent 15 .
  • Coenzyme Q is an essential part of the mitochondrial electron transport process which provides energy derived from oxidative processes.
  • Statins work by blocking cholesterol synthesis at the HMG CoA reductase catalyzed step.
  • Mevalonate through a series of enzymatic steps, is used to synthesize cholesterol. Mevalonate is also a precursor to coenzyme Q. The inhibition of cholesterol synthesis thereby inhibits the synthesis of coenzyme Q.
  • muscle cells which have high energy requirements are the most susceptible to damage by statins
  • liver cells are also subject to injury. The latter is probably the result of the relatively hypoxic condition of the centrilobular liver cells in which the primary blood supply is from the hepatic portal system. The most serious form of muscle damage occurs when the muscle cell contents are released into the systemic circulation (rhabdomyolysis). Major complications include acute renal failure and cardiac abnormalities.
  • the cardiac toxicity may be a direct effect of the statins on the heart muscle coenzyme Q levels.
  • statins are used in combination with other medications that inhibit the cytochrome P450 system, such as azole antifungal agents, cimetadine and methotrexate.
  • azole antifungal agents such as azole antifungal agents, cimetadine and methotrexate.
  • statin-related myositis increases in patients taking gemfibrozil, nicotinic acid or macrolides. References describing reported statin indications are widespread 16,17,18
  • statins Even without the possibility of drug interactions, the primary side effect of statins on muscle is a considerable disincentive to patients to remain on such medication. Since muscle toxicity is dose dependent, any safe adjunct therapy that will allow use of a lower statin dose and still achieve the target LDL cholesterol level is highly desirable. Accordingly, there is a niche for compounds and compositions as provided within the scope of the present invention that can work additively with a statin to provide an additional lowering of LDL cholesterol without, at the same time, increasing the risk of an adverse reaction.
  • lovastatin [1S[1 a(R) 3 alpha, 7 beta, 8 beta (2S, 4S), 8a beta]]-1 , 2,3,7, 8,8a- hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1- naphthalenyl-2-methylbutanoate.
  • pravastatin sodium 1-naphthalene-heptanoic acid, 1 ,2,6,7,8a-hexahydro-beta, delta, 6-trihydroxy-2-methyl-8-(2-ethyl-1-oxybutoxy)-1-monosodium salt
  • statins Naturally occurring statins are derivatives of fungi metabolites (ML- 236B/compactin/monocalin K) isolated from Pythium ultimum, Monacus ruber, Penicillium citrinum, Pencillium brevicompactum and Aspergillus terreus, though as shown above, they can be prepared synthetically as well.
  • Statin derivatives are well known in the literature and can be prepared by methods as disclosed in US Patent 4,397,786. Other methods are well known in the art today. Structures of the most preferred statins for use in accordance with the present invention are as follows:
  • Atorvastatin Lovastatin
  • Squalene synthase inhibitors decrease the activity of squalene synthase, thus inhibiting the conversion of farnesyl pyrophosphate into squalene.
  • Squalene synthase inhibitors can act on squalene synthase directly or indirectly by: 1 ) decreasing the activity of one or more enzymes or cofactors involved in the activation or squalene synthase; 2) increasing the activity of one or more enzymes or cofactors involved in the down regulation of squalene synthase
  • Suitable squalene synthase inhibitors include, but are not limited to ⁇ -phosphono- sulfonates disclosed in US Patent No 5,712,396 including isoprenoid (phosphinyl- methyl)phosphonates as well as other known squalene synthetase inhibitors, for example as disclosed in US Patent No. 4,871 ,721 , terpenoid pyrophosphates, farnesyl diphosphate analog A and presqualene pyrophosphate analogs.
  • the cholesterol biosynthesis inhibitor is selected is from the group consisting of: a HMG Co A reductase inhibitor selected from the group consisting of lovastatin (for example MEVACOR® which is available from Merck & Co.), pravastatin (for example PRAVACHOL® which is available from Bristol Meyers Squibb), fluvastatin, simvastatin (for example ZOCOR® which is available from Merck & Co.), atorvastatin, cerivastatin, CI-981 and pitavastatin (such as NK-104 of Negma Kowa of Japan); HMG CoA synthetase inhibitors, for example L- 659,699 ((E,E)-1 1 -[3'R-(hydroxyl-methyl)-4'-oxo-2'R-oxetanyl]-3,5,7R-trimethyl-2,4- undecadienoic acid); squalene synthesis inhibitors, for example s
  • the compounds of the present invention comprise a sterol or stanol moiety and a. cholesterol biosynthesis inhibitor moiety represented by one or more of the following formulae:
  • R is the sterol or stanol moiety
  • R 2 is a cholesterol biosynthesis inhibitor with a least one free and reactive carboxyl group
  • R 3 is a cholesterol biosynthesis inhibitor witri at least one free and reactive hydroxyl group
  • F ⁇ is derived from ascorbic acid
  • the compounds within the scope of the present invention include all biologically acceptable salts or solvates o prodrugs of at least one such compound or of the salts or of the solvates thereof.
  • the cholesterol biosynthesis inhibitors, R 2 and R 3> are selected from the group consisting of competitive inhibitors of HMG CoA reductase, HMG CoA synthase, squalene synthase, and squalene epoxidase.
  • R 2 is either atorvastatin or pravastatin sodium.
  • R 3 is either simvastatin or lovastatin.
  • compounds a), b), c) and e) can only be achieved by selecting a cholesterol biosynthesis inhibitor with at least one free and reactive carboxyl group.
  • compounds d) and f) can only be achieved by selecting a cholesterol biosynthesis inhibitor with at least one free and reactive hydroxyl group. While, appropriate cholesterol biosynthesis inhibitors must be selected on this basis, it is entirely within the purview of even a student of chemistry to do so.
  • the compound formed between the sterol and/or stanol moiety and selected cholesterol biosynthesis inhibitor is selected from the group consisting of:
  • the compounds of the present invention are formed of naturally-derived or artificially synthesized beta-sitosterol, campestanol, sitostanol, and campesterol and each of these compounds so formed is then admixed in a pharmaceutical composition prior to delivery in various ratios.
  • the compound of the present invention comprises a chemical linkage between one or more disodium ascorbyl phytostanyl phosphates (referred to herein as "FM-VP4") which comprises two major components: disodium ascorbyl campestanyl phosphate (“DACP”) and disodium ascorbyl sitostanyl phosphate (“DASP").
  • biologically acceptable salts refers any salts that retain the desired biological and/or physiological activity of the compounds as described herein and exhibit minimal undesired toxicological effects. Accordingly, reference to compounds of formulae a) through f) thereby includes reference to acidic and/or base salts thereof, formed with inorganic and/or organic acids and bases.
  • Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example trifluroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclpentanepropionates, digluconates, dodecylsulfates, heptanoates, hexanoates, hydrochlorideshyrobromides, hydroiodides, 2- hydroethanesulfonates, lactates, maleates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfonates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates
  • the present invention encompasses not only the parent compounds comprising the selected sterol and/or stanol and cholesterol biosynthesis inhibitor bu also, where possible (i.e. where the parent contains a free hydroxyl group), the presen invention encompasses the biologically acceptable metal, alkali earth metal, or alkali metal salts of the disclosed compounds.
  • the salts, as described herein, are even more water soluble than the corresponding parent compounds and therefore their efficacy and evaluation both in vitro and in vivo may be enhanced.
  • Salt formation of the compounds of the present invention can be readily performed, fo example, by treatment of any parent compound containing a free OH group with a series of bases (for example, sodium methoxide or other metal alkoxides) to produce the corresponding alkali metal salts.
  • bases for example, sodium methoxide or other metal alkoxides
  • Other metal salts of calcium, magnesium, manganese, copper, zinc, and the like can be generated by reacting the parent with suitable metal alkoxides.
  • novel compounds comprising sterols and/or stanois and the selected cholesterol biosynthesis inhibitors can be formed.
  • the selected sterol or stanol (or halophosphate, halocarbonate or halo-oxalate derivatives thereof) and the cholesterol biosynthesis inhibitor are mixed together under reaction conditions to permit condensation of the "acid" moiety with the "alcohol” (phytosterol).
  • the process to form the ester derivative comprises; "protecting" the hydroxyl groups of the cholesterol biosynthesis inhibitor as esters (for example, as acetate esters) or ethers (for example, methyl ethers) and then condensing the protected cholesterol biosynthesis inhibitor with the reactive sterol/stanol (or its halophosphate, halocarbonate or halo-oxalate) under suitable reaction conditions.
  • the reactive sterol/stanol or its halophosphate, halocarbonate or halo-oxalate
  • condensation reactions are conducted in an organic solvent such as diethyl ether, tetrahydrofuran, or benzene, toluene or similar aromatic solvents.
  • the reaction temperatures may vary from low (- 15°C) to elevated temperatures.
  • Figure 1 is a schematic showing the formation of ascorbyl sitostanyl or campestanyl atorvastatin phosphate esters and their sodium salts.
  • the starting material prepared by a previously developed method , is condensed with atorvastatin in the presence of sulfuric acid as catalyst, in a classical esterification process, to form the coupled product.
  • the latter is then treated with sodium methoxide to obtain the sodium salt as the final product.
  • All stereoisomers of the compounds of the present invention are contemplated within the scope of the present invention.
  • Individual stereoisomers of the compounds of the present invention may, for example, be admixed as racemates or with all other, or other selected sterioisomers.
  • the chiral centres of the compounds can have the S or R configuration as defined by the IUPAC 1974 Recommendations.
  • compositions comprising at least one sterol/stanol based cholesterol absorption inhibitor, as described herein, admixed with at least one cholesterol biosynthesis inhibitor, which compositions are suitable for use in treating or preventing CVD and its underlying conditions including, without limitation, atherosclerosis, hypercholesterolemia, hyperlipidemia, dislipidemia, hypertension, thrombosis, coronary artery disease, and inflammation including coronary plaque inflammation.
  • composition comprises: a) at least one cholesterol absorption inhibitor selected from compounds having the general formulae:
  • R is a sterol or stanol moiety
  • the compounds of formulae i) to iv) can be prepared by known methods, for example those described below and in PCT/CA00/00730, which was filed on June 20, 2000 and claims priority back to US Patent Application 09/339,903 filed on June 23, 1999, the entire contents of which are incorporated herein by reference..
  • compounds of formulae i) to iv) can be prepared as follows: the selected sterol 0 r s tanol ( or h alophosphate, h alocarbonate or halo-oxalate derivatives thereof) and ascorbic acid are mixed together under reaction conditions " to permit condensation of the "acid" moiety with the "alcohol” (sterol). These conditions are the same as those used in other common esterification reactions such as the Fisher esterification process in which the acid component and the alcohol component are allowed to react directly or in the presence of a suitable acid catalyst such as mineral acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid.
  • a suitable acid catalyst such as mineral acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid.
  • the organic solvents generally employed in such esterification reactions are ethers such as diethyl ether, tetrahydrofuran, or benzene, toluene or similar aromatic solvents and the temperatures can vary from room to elevated temperatures depending on the reactivity of the reactants undergoing the reaction.
  • the process to form the ester comprises "protecting" the hydroxyl groups of the ascorbic acid or derivatives thereof as esters (for example, as. acetate esters) or ethers (for example, methyl ethers) and then condensing the protected ascorbic acid with the sterol/stanol halophospahte, halocarbonate or halo-oxalate under suitable reaction conditions.
  • condensation reactions are conducted in an organic solvent such as diethyl ether, tetrahydrofuran, or benzene, toluene or similar aromatic solvents.
  • organic solvent such as diethyl ether, tetrahydrofuran, or benzene, toluene or similar aromatic solvents.
  • the reaction temperatures may vary from low (-15°C) to elevated temperatures.
  • ascorbic acid is initially protected from decomposition by the formation of 5,6-isopropylidene-ascorbic acid. This can be achieved by mixing acetone with ascorbic acid and an acidic catalyst such as sulfuric acid or hydrochloric acid under suitable reaction conditions.
  • Phytostanol chlorophosphate is prepared by forming a solution of phytostanol in toluene and pyridine (although other nitrogen b ases s uch a s a liphatic a nd a romatic a mines m ay a Itematively be used) and treating this solution with a phosphorus derivative such as phosphorus oxychloride.
  • a phosphorus derivative such as phosphorus oxychloride.
  • the latter is then mixed with 5,6-isopropylidene-ascorbic acid and, after the addition of a suitable alcohol such as ethanol and HCI, concentrated.
  • a suitable alcohol such as ethanol and HCI
  • pyridine/THF may be added and the product concentrated. After final washing and drying, the resultant novel product a stanol
  • ascorbic a cid is protected at the hydroxyl sites not as 5,6-isopropylidene-ascorbic acid but as esters (for example as acetates, phosphates and the like..).
  • esters for example as acetates, phosphates and the like..
  • the latter may then be condensed with sterols or stanois, derivatized as described above, using known esterification methods ultimately to produce the compounds.
  • the formation of mono and diphosphates of ascorbic acid is described thoroughly in the literature. For example, US Patent Serial No. 4,939,128 to Kato et al., the contents of which are incorporated herein by reference, teaches the formation of phosphoric acid esters of ascorbic acid.
  • the composition of the present invention comprises one or more disodium ascorbyl phytostanyl phosphates (referred to as "FM-VP4") which comprises two major components: disodium ascorbyl campestanyl phosphate (“DACP”) and disodium ascorbyl sitostanyl phosphate (“DASP”) together with at least one statin.
  • FM-VP4 disodium ascorbyl phytostanyl phosphates
  • DASP disodium ascorbyl sitostanyl phosphate
  • the sterol and/or stanol moiety may be incorporated into a micelle prior to or after combining with the selected cholesterol biosynthesis inhibitor.
  • T his m icelle can b e p roduced u sing l ecithin o r a ny other suitable emulsifying agent and using techniques known and applied widely in the art.
  • compositions of the present invention allow for a "combination therapy" wherein the cholesterol absorption inhibitor and the cholesterol biosynthesis inhibitor are either co- administered in a substantially simultaneous manner, for example, in a single tablet or capsule having a fixed ratio of active ingredients or in multiple, separate administrations for each therapeutic agent.
  • This separate administration includes sequential dosage forms.
  • the present invention provides a method of achieving one or more of the following therapeutic goals: a) preventing, treating or alleviating one or more conditions associated with CVD generally and including arteriosclerosis, atherosclerosis, arteriolosclerosis, angina pectoris, and thrombosis; b) reducing a nd/or e liminating o ne o r more of the risk factors associated with CVD; c) preventing, treating or alleviating atherosclerosis; d) preventing, treating or alleviating hypercholesterolemia; e) preventing, treating or alleviating a hyperlipidic condition; f) preventing, treating or alleviating dislipidemia; g) preventing, treating or alleviating hypertension; h) preventing, treating or alleviating coronary artery disease; i) preventing, treating or alleviating coronary plaque development; j) preventing, treating or alleviating coronary plaque inflammation; k) lowering serum LDL cholesterol; I) increasing serum HDL cholesterol; m) decreasing serum triglycerides
  • the compounds and compositions of the present invention have been found to be especially useful in addressing at least two significant factors contributing to the multi-factorial presentation of cardiovascular disease: intestinal cholesterol absorption and systemic cholesterol biosynthesis.
  • Serum cholesterol levels are controlled primarily by two organs: the liver, which produces cholesterol and bile acids (which are used in digestion), and the intestine, which absorbs cholesterol both from food and from the bile (produced by the liver).
  • Sterols lower LDL serum cholesterol levels through a unique mechanism of action by inhibiting cholesterol absorption in the intestine. This mechanism of action makes sterols complementary to cholesterol biosynthesis inhibitors, such as statins, which work in the liver. Therefore, patients who take sterols with statins can achieve additional reductions in LDL and total cholesterol.
  • one moiety which simultaneously lowers cholesterol absorption for example: sterols/stanols
  • another moiety which decreases cholesterol biosynthesis for example: statins.
  • This can be achieved either through the administration of at least one of the compounds of formulae a) through f) or through the administration of a composition comprising a cholesterol absorption inhibitor (having one of the formulae i) through iv)) and a cholesterol biosynthesis inhibitor.
  • the most important benefits derived from use of the compounds and compositions described herein are a decrease in serum LDL cholesterol and a decrease in total serum cholesterol, with additional beneficial effects being achieved via an increase in serum HDL cholesterol and a decrease in serum triglycerides. These benefits are achieved without the adverse effects associated with statin administration.
  • the compounds of the present invention there is a significant biological consequence (and benefit) of changing the overall hydophobicity of the cholesterol biosynthesis inhibitors (such as the statins) by covalently modifying them with the sterol-based cholesterol absorption inhibitors as described herein.
  • the compounds of the present invention have a higher overall hydrophobicity than the native statins. This is important on at least two fronts.
  • statins there may be an enhancement of the pleotropic effects of the statins.
  • the compounds are absorbed in tact, it is likely that the ADME properties of the statins might be different, thereby decreasing their potential toxicities, among other benefits.
  • statin While not intending to be bound by any one theory as to mechanism of action, it is possible that since the structural changes in the compound as compared to free statins will result in a higher proportional distribution into the plasma lipoprotein pool, the active components will be delivered in greater proportion to peripheral tissues, especially if the drug is carried by HDL. This may significantly enhance the potential effect of the compounds of the present invention on many reported "statin" indications, including Alzheimer's disease and osteoporosis.
  • some of the compounds of the present invention comprise an ascorbyl moiety.
  • solubility of the compounds is greatly enhanced, both in aqueous solutions and non-aqueous media such as oils and fats. With this greater solubility, effective dietary and therapeutic dosages and concomitantly costs, can be reduced.
  • the formation of these compounds allows the full potential of ascorbic acid to be realized while eliminating decomposition.
  • these derivatives are heat stable (stable to oxidation and hydrolysis) which is essential for some processing mechanisms.
  • the compounds and compositions of the present invention may be administered by any conventional means available for use in conjunction with pharmaceuticals. Accordingly, the present invention relates, on aspect, to a pharmaceutical composition comprising one or more of the compounds of formulae a) to f) and a pharmaceutically acceptable carrier.
  • the present invention relates, in another- respect, to a pharmaceutical composition comprising an effective or therapeutic amount of at least one cholesterol absorption inhibitor having one of formulae i)-iv) together with an effective or therapeutic amount at least one cholesterol biosynthesis inhibitor and a pharmaceutically acceptable carrier.
  • compositions can be administered in any conventional dosage form, preferably an oral dosage form such as a tablet, capsule, powder, cachet, suspension or solution.
  • the pharmaceutical compositions can comprise from about 1% to 99% of the "active" components (cholesterol absorption inhibitors and cholesterol biosynthesis inhibitors) and preferably from about 5% to 95% of the active components.
  • compositions and pharmaceutical compositions can be prepared using conventional, pharmaceutically available excipients, and additives and by conventional techniques.
  • pharmaceutically acceptable excipients and additives include non-toxic compatible fillers, binders, disintegrants, buffers, preservatives, anti-oxidants, lubricants, flavourings, thickeners, colouring agents, emulsifiers and the like.
  • the exact amount or dose of the compound or composition which is required to achieve the desired effects will, of course, depend on a number of factors such as the particular compound or composition chosen, the potency of the compound or composition administered, the mode of administration and the age, weight, condition and response of the patient. All of these factors, among others, will be considered by the attending clinician with respect to each individual or patient.
  • the typical daily dose of the cholesterol biosynthesis inhibitor can range from about 0.1 mg to 160mg/kg and preferably from 2mg to 80mg of mammalian body weight per day administered in single or divided doses, u sually o nce o r twice a d ay.
  • about 0.25mg to 40mg per dose is given one to two times per day, giving a total daily dose of from about 0.5mg to 80mg.
  • about 1 mg to about 1000mg per dose is given one or two times per day, giving a total daily dose of 1 mg to about 2000mg per day.
  • a total daily dose the cholesterol absorption inhibitor having one of formulae i)-iv) and comprising sterols and/or stanois may be administered in a daily dosage range of from 10mg to about 20 g, more preferably 10mg to 1.5g, per day in single or multiple divided doses.
  • the number of doses and the amount of such dosage of each component given per day may not necessarily be the same.
  • the cholesterol absorption inhibitor may require either a greater number of administrations per day than the cholesterol biosynthesis inhibitor and/or may require a larger dosage.
  • compositions and compounds can be administered to an individual in a single dose or in multiple doses, as required. Sustained release dosages can be used.
  • compositions of the present invention may be administered parenterally, such as by intravenous injection.
  • pharmaceutically acceptable carriers well known in the art into dosages suitable for oral administration.
  • Such carriers enable the compounds and compositions of the invention to be formulated as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • compositions comprising one or more of the compounds of the present invention, include compositions wherein the active ingredients are contained in an effective amount to achieve their intended purpose. Determination of the effective amounts is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
  • compositions may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
  • suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
  • the preparations formulated for oral administration may be in the form of tablets, dragees, capsules, or solutions.
  • compositions of the present invention may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • compositions for oral use can be obtained by combining the active compounds with solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • suitable excipients include lactose, sucrose, mannitol, sorbitol, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added.
  • Oral liquid preparations may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non- aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propy! p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, syrup, methyl cellulose
  • kits for such purpose.
  • a kit is contemplated wherein two separate units are combined: a pharmaceutical composition comprising at last one cholesterol biosynthesis inhibitor, as described herein, and a separate pharmaceutical composition comprising at least one cholesterol absorption inhibitor, as described herein.
  • the kit will preferably include directions for the administration of the separate components. This type of kit arrangement is particularly useful when separate components must be administered in different dosage forms (for example, oral and parenteral) or are administered at different dosage intervals.
  • Brinton EA Lipid abnormalities in the metabolic syndrome. Carl T. Hayden VA Medical Center, Section of Metabolism, Endocrinology, & Nutrition, Department of Internal Medicine, 111 E, 650 East Indian School Road, Phoenix, AZ 85012, USA. Curr Diab Rep. 2003 Feb;3(1 ):65-72.

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Abstract

Selon un aspect, l'invention concerne des nouveaux composés comprenant des stérols et/ou des stanols et des inhibiteurs de biosynthèse du cholestérol, notamment des sels, des solvates et des promédicaments de ces composés et/ou des sels. Selon un autre aspect, l'invention concerne des compositions comprenant au moins un ester de stérol et/ou de stanol et au moins un inhibiteur de biosynthèse du cholestérol. L'invention concerne également des méthodes de traitement ou de prévention de maladies, d'états et de troubles divers par administration des composés ou compositions de l'invention.
EP04737936A 2003-07-09 2004-07-09 Nouveaux composes et compositions comprenant des sterols et/ou des stanols et des inhibiteurs de biosynthese du cholesterol et utilisation associees pour le traitement et la prevention de maladies et d'etats divers Withdrawn EP1644399A2 (fr)

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JP2007525470A (ja) 2007-09-06
NO20060632L (no) 2006-04-06
CN1832957A (zh) 2006-09-13
RU2006103797A (ru) 2006-07-27
NZ545087A (en) 2009-10-30
MXPA06000326A (es) 2006-03-30
WO2005005453A3 (fr) 2005-06-09
CA2531836A1 (fr) 2005-01-20
WO2005005453A2 (fr) 2005-01-20
KR20060052792A (ko) 2006-05-19

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