WO2003026672A1 - Procede de reduction du transfert in vivo d'esters de cholesteryle dont la mediation est assuree par la proteine de transfert des esters de cholesterol, entre les lipoproteines de haute densite (hdl) et les lipoproteines de basse densite (ldl) - Google Patents

Procede de reduction du transfert in vivo d'esters de cholesteryle dont la mediation est assuree par la proteine de transfert des esters de cholesterol, entre les lipoproteines de haute densite (hdl) et les lipoproteines de basse densite (ldl) Download PDF

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WO2003026672A1
WO2003026672A1 PCT/CA2002/001457 CA0201457W WO03026672A1 WO 2003026672 A1 WO2003026672 A1 WO 2003026672A1 CA 0201457 W CA0201457 W CA 0201457W WO 03026672 A1 WO03026672 A1 WO 03026672A1
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Prior art keywords
hdl
ldl
stanol
density lipoproteins
group
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PCT/CA2002/001457
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English (en)
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P. Haydn Pritchard
Kishor M. Wasan
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Forbes Medi-Tech Inc.
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Priority to JP2003530307A priority Critical patent/JP2005507890A/ja
Priority to CA002461136A priority patent/CA2461136A1/fr
Priority to NZ531938A priority patent/NZ531938A/en
Priority to BR0212826-8A priority patent/BR0212826A/pt
Priority to EP02764428A priority patent/EP1432425A1/fr
Publication of WO2003026672A1 publication Critical patent/WO2003026672A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • 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
    • 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
    • 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

Definitions

  • TITLE A METHOD OF REDUCING THE IN VIVO CHOLESTEROL ESTER TRANSFER PROTEIN MEDIATED TRANSFER OF CHOLESTERYL ESTERS BETWEEN HIGH DENSITY LIPOPROTEINS (HDL) AND LOW DENSITY LIPOPROTEINS (LDL)
  • This present invention relates to methods of treating or preventing cardiovascular disease and its underlying conditions, including atherosclerosis, dyslipidemic conditions or disorders in animals, particularly humans.
  • Atherosclerosis is a degenerative process resulting from an interplay of inherited (genetic) factors and environmental factors such as diet and lifestyle.
  • CVD cardiovascular disease
  • Studies 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).
  • Overviews have indicated that a 1% reduction in an individual's total serum cholesterol yields a 2% reduction in risk of a coronary artery event (3).
  • a 10% decrease in average serum cholesterol may result in the prevention of 100,000 deaths in the United States annually (4). Accordingly, hyperlipidemic conditions associated with elevated concentrations of total cholesterol and low density lipoprotein (LDL) cholesterol are significant risk factors.
  • LDL low density lipoprotein
  • Lipoproteins are complexes of Iipids 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 Iipids consist of a core of cholesteryl esters and triglycerides, and an envelope of phospholipids, free cholesterol and apolipoproteins.
  • 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).
  • 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 Iipids 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 Iipids associated with HDL include cholesterol, cholesteryl ester, triglycerides, phospholipids and fatty acids To better understand how HDL is anti-atherogenic, a brief explanation of the atherosclerotic process is necessary. The atherosclerotic process begins when LDL becomes trapped within the vascular wall.
  • Oxidation of this LDL results in the binding of monocvtes 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 ABCAI 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
  • Esterified cholesterol is then transferred by cholesteryl ester transfer protein (CETP) from HDL to apolipoprotein-B containing lipoproteins, which are taken up by numerous receptors in the liver.
  • CTP cholesteryl ester transfer protein
  • 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 mechanism of reverse cholesterol transport may 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.
  • CETP is a plasma lipid transfer protein secreted by the liver and adipose tissues, which mediates the transfer and exchange of neutral Iipids and phospholipids (6).
  • CETP exchanges cholesteryl esters of HDL with triglycerides of VLDL, IDL, and LDL. Since these lipoproteins are catabolized faster than HDL, CETP facilitates the clearance of HDL cholesteryl esters. This process results in decreased HDL size and protein content. Thus, CETP clearly plays a central role in reverse cholesterol transport by moving cholesterol from the periphery back to the liver for disposal.
  • the present invention provides a method of reducing the in vivo cholesterol ester transfer protein mediated transfer of cholesteryl esters between high density lipoproteins (HDL) and low density lipoproteins (LDL) which comprises administering a therapeutically effective amount of one or more the following compounds:
  • R is a sterol or stanol moiety
  • R2 is derived from ascorbic acid
  • R3 is hydrogen or any metal, alkali earth metal, or alkali metal; and all salts thereof, whereby plasma HDL and LDL are controlled as a result of such administration.
  • compositions for reducing the in vivo cholesterol ester transfer protein mediated transfer of cholesteryl esters between high density lipoproteins and low density lipoproteins which comprises one or more of the compounds having the following formulae:
  • R is a sterol or stanol moiety
  • R2 is derived from ascorbic acid
  • R3 ⁇ is hydrogen or any metal, alkali earth metal, or alkali metal; and all salts of these structures; and a pharmaceutically acceptable or food grade carrier therefore.
  • the present invention further provides a method of treating or preventing cardiovascular disease and its underlying conditions, including atherosclerosis, hyperiipidemic conditions, hypoalphalipoproteinemia and hypercholesterolemia, in an animal which comprises reducing the in vivo cholesterol ester transfer protein mediated transfer of cholesteryl esters between high density lipoproteins (HDL) and low density lipoproteins (LDL), said reduction being accomplished by administering to the animal one or more sterol and/or stanol derivatives having the formulae noted above.
  • HDL high density lipoproteins
  • LDL low density lipoproteins
  • the compounds of the present invention have been found to be surprisingly effective in reducing the cholesterol ester transfer protein mediated transfer of cholesteryl esters between HDL and LDL. In particular, this results in an increase in serum HDL levels.
  • Figure 1 is the chemical structure of one of the preferred compounds of the present invention: phytostanol-phosphoryl-ascorbate (also referred to as FM-VP4) and its sodium salt;
  • a method of reducing the in vivo cholesterol ester transfer protein mediated transfer of cholesteryl esters between high density lipoproteins (HDL) and low density lipoproteins (LDL) which comprises administering a therapeutically effective amount of one or more the following compounds:
  • R is a sterol or stanol moiety
  • R2 is derived from ascorbic acid and R3 is hydrogen or any metal, alkali earth metal, or alkali metal; and all salts thereof, whereby plasma HDL and LDL are controlled as a result of such administration.
  • the term "therapeutically effective" is intended to qualify the amount of the compound(s) administered in order to achieve the goals of: a) inhibiting the CETP-mediated transfer of CE between HDL and LDL; and thereby b) increasing HDL levels; and c) preventing, reducing, eliminating or ameliorating a dyslipidemic condition or disorder; or d) preventing, reducing, eliminating or ameliorating hypercholesterolemia, hypoalphalipoproteinemia, toxic shock syndrome or the development of atherosclerotic lesions; or e) preventing, reducing, eliminating or ameliorating any condition, disease or disorder which has as its basis or which is exacerbated by a deficiency in plasma HDL, or excess of either LDL, VLDL, Lp(a), beta-VLDL, IDL or remnant lipoproteins.
  • this method further comprises the step of periodically assaying plasma LDL levels (by techniques which are known and widely applied in the art) and modifying the amount and/or concentration of the compounds to be administered, or the administration method if required.
  • the level of serum HDL is increased and the levels of atherogenic lipoproteins selected from the group consisting of LDL, VLDL, and IDL are effectively controlled.
  • Modulating or controlling plasma lipoproteins provides for the prevention, reduction, elimination or amelioration of a number of conditions and disorders, including, but not limited to: cardiovascular disease and its underlying conditions, including atherosclerosis, dyslipidemic conditions or disorders, hypercholesterolemia, and hypoalphalipoproteinemia, development of atherosclerotic lesions and toxic shock syndrome.
  • cardiovascular disease and its underlying conditions including atherosclerosis, dyslipidemic conditions or disorders, hypercholesterolemia, and hypoalphalipoproteinemia, development of atherosclerotic lesions and toxic shock syndrome.
  • Many other conditions which have as their basis or which are exacerbated by a deficiency in plasma HDL, or excess of either LDL, VLDL, or IDL will also be assisted by the method of the present invention.
  • sterol includes all sterols without limitation, for example: 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 saturated or hydrogenated sterols including all natural or synthesized forms and derivatives thereof, and isomers. It is to be understood that modifications to the sterols and stanols i.e. to include side chains also falls within the purview of this invention. For example, the purview of this invention clearly includes 24 beta-ethylchlostanol, 24-alpha-ethyl-22-dehydrocholstanol. It is also to be understood that, when in doubt throughout the specification, and unless otherwise specified, the term “sterol” encompasses both sterol and stanol.
  • the sterols and stanols for use in forming derivatives in accordance with this invention may be procured from a variety of natural sources.
  • they may be obtained from the processing of plant oils (including aquatic plants) such as corn 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.
  • plant oils including aquatic plants
  • They may also be derived from fungi, for example ergosterol, or animals, for example cholesterol.
  • 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.
  • the derivative of the present invention is formed with naturally- derived or synthesized beta-sitosterol, campestanol, sitostanol and campesterol and each of these derivatives so formed may then be admixed a composition prior to delivery in various ratios.
  • the derivative of the present invention is formed with naturally-derived or synthesized sitostanol or with naturally derived or synthesized campestanol or mixtures thereof.
  • the sterol is in its saturated form and is sitostanol.
  • R2 comprises ascorbic acid or any derivative thereof. What is achieved within the scope of the present invention is the creation of a new structure or compound wherein a sterol or stanol moiety is chemically linked to ascorbic acid. The union benefits and enhances the both parts of this new structure.
  • the phytosterol moiety formerly poorly soluble, becomes, as part of the new derivative, much more readily soluble in aqueous and non- aqueous media such as oils and fats. Accordingly, administration of the sterol becomes possible without any further enhancements to modify its delivery.
  • R3 may be hydrogen or may convert the parent compound into a salt .
  • the over-riding consideration in the selection of the appropriate salt is that they are acceptable pharmaceutically, nutraceutically or for use in foods, beverages and the like. iSuch salts must have an acceptable anion or cation.
  • suitable acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, phosphoric, metaphosphorice, nitric, sulfonic and sulfuric acids and organic acids such as acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glyconic, glycolic, isothionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, toluenesulfonic, and tartaric.
  • inorganic acids such as hydrochloric, hydrobromic, phosphoric, metaphosphorice, nitric, sulfonic and sulfuric acids
  • organic acids such as acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glyconic, glycolic, isothionic, lactic, lactobionic, maleic, malic, methanes
  • Suitable base salts include ammonium salts, or any salt of a metal, alkali earth metal or alkali metal.
  • R3 is selected from one of: calcium, magnesium, manganese, copper, zinc, sodium, potassium and lithium. Most preferably, R3 is sodium.
  • the compound is structure 1 noted above, the stanol is sitostanol and R3 is sodium.
  • esters of the present invention and their salts is described in PCT/CAOO/00730, the entirety of which is incorporated herein by reference.
  • the derivatives of the present invention may be combined, prior to administration, co-adminstered or administered separately over a time interval with one or more agents or compounds which modulate cholesterol transport.
  • the rationale for this combination is due to the fact that, as CETP increases the HDL level, there may be an increase in the amount of cholesterol being delivered from the peripheral tissues to the liver. This could result in down regulation of the LDL receptors and an increase in the production of apo B containing particles in the liver.
  • Combination of the CETP-inhibitors of the present invention with compounds that inhibit cholesterol reabsorption from the intestine address this problem by maintaining a chemical composition gradient away from the liver thereby preventing increased hepatic lipoprotein synthesis.
  • Suitable compounds which regulate cholesterol absorption include, but are not limited to: bile acid sequestrants, bile acid transporter inhibitors, phytosterols, phytostanols, modulators of ABC transporters, modulators of PPAR (alpha and gamma) and ezetimibe.
  • the combination of these cholesterol absorption inhibitors and the sterol derivatives of the present invention is synergistic and initiates and perpetuates the beneficial lipid- modulating effects.
  • the compounds of the present invention may physically block the association of CETP and lipoproteins thereby preventing CE transfer.
  • the compounds of the present invention may compete with CE for the 26 amino acid hydrophobic binding site of CETP near the -COOH terminus in a manner analogous to TP2 monoclonal antibody competitive binding. Either way, the effect is the same.
  • the desired effect of inhibiting CETP-mediated transfer of CE between HDL and LDL may be achieved in a number of different ways. These compounds may be administered by any conventional means available for use in conjunction with pharmaceuticals, nutraceuticals, foods, beverages, and the like.
  • the derivatives of the present invention may be admixed with various carriers or adjuvants to assist in direct administration or to assist in the incorporation of the composition into foods, beverages, nutraceuticals or pharmaceuticals.
  • various carriers or adjuvants to assist in direct administration or to assist in the incorporation of the composition into foods, beverages, nutraceuticals or pharmaceuticals.
  • the list below is provided.
  • the amount or dose of the compound which is required to achieve the desired CETP-inhibiting effect will, of course, depend on a number of factors such as the particular compound chosen, the mode of administration and the preventing, reducing, eliminating or ameliorating a dyslipidemic condition or disorder.
  • the compounds of the present invention may be incorporated into various conventional pharmaceutical preparations and dosage forms such as tablets (plain and coated) for use orally, bucally or lingually, capsules (hard and soft, gelatin, with or without additional coatings) powders, granules (including effervescent granules), pellets, microparticulates, solutions (such as micellar, syrups, elixirs and drops), lozenges, pastilles, ampoules, emulsions, microemulsions, ointments, creams, suppositories, gels, transdermal patches and modified release dosage forms together with customary excipients and/or diluents and stabilizers.
  • tablets plain and coated
  • bucally or lingually capsules (hard and soft, gelatin, with or without additional coatings) powders, granules (including effervescent granules), pellets, microparticulates, solutions (such as micellar, syrups, elixir
  • the derivatives of the present invention may be administered to animals, including humans, orally, by injection (intravenously, subcutaneously, intra-peritoneally, intra-dermally or intra-muscularly), topically or in other ways.
  • the compounds of the present invention are delivered in the form of phospholipid systems such as liposomes and other hydrated lipid phases, by physical inclusion.
  • This inclusion refers to the entrapment of molecules without forming a covalent bond and is widely used to improve the solubility and subsequent dissolution of active ingredients.
  • Hydrated lipid systems can be prepared using a variety of lipid and lipid mixtures, including phospholipids such as phosphatidylcholine (lecithin), phosphodiglyceride and sphingolipids, glycolipids, and the like.
  • phospholipids such as phosphatidylcholine (lecithin), phosphodiglyceride and sphingolipids, glycolipids, and the like.
  • the Iipids may preferably be used in combination with a charge bearing substances such as charge-bearing phospholipids, fatty acids, and potassium and sodium salts thereof in order to stabilize the resultant lipid systems.
  • a typical process of forming liposomes is as follows:
  • lipid or Iipids dispersion of lipid or Iipids and the compound of the present invention in an organic solvent (such as chloroform, dichloromethane, ether, ethanol or other alcohol, or a combination thereof).
  • organic solvent such as chloroform, dichloromethane, ether, ethanol or other alcohol, or a combination thereof.
  • a charged species may be added to reduce subsequent aggregation during liposome formation.
  • Antioxidants such as ascorbyl palmitate, alpha- tocopherol, butylated hydroxytoluene and butylated hydroxyanisole
  • US Patent Serial No. 4,508,703 (also incorporated herein by reference) describes a method of preparing liposomes by dissolving the amphiphillic lipidic constituent and the hydrophobic constituent to form a solution and thereafter atomizing the solution in a flow of gas to produce a pulverent mixture.
  • the compounds of the present invention can be administered as cyclodextrin complexes.
  • Cyclodextrins are a class of cyclic oligosaccharide molecules comprising glucopyranose sub-units and having a toroidal cylindrical spatial configuration. Commonly available members of this group comprise molecules containing six (alpha- cyclodextrin), seven (beta-cyclodextrin) and eight (gamma-cylcodextrin) glucopyranose molcules, with the polar (hydrophilic) hydroxyl groups oriented to the outside of the structure and the apolar (lipophilic) skeletal carbons and ethereal oxygens lining the interior cavity of the toroid. This cavity is capable of accomodating (hosting) the lipophilic moiety of an active ingredient (the guest molecule, here the derivative of the present invention ) by bonding in a non-covalent manner to form an inclusion complex.
  • the external hydroxyl substituents of the cyclodextrin molecule may be modified to form derivatives having improved solubility in aqueous media along with other desired enhancements, such as lowered toxicity, etc..
  • Examples of such derivatives are: alkylated derivatives such as 2,6-dimethyl-beta-cyclodextrin; hydroxyalkylated derivatives such as hydroxypropyl-beta-cyclodextrin; branched derivatives such as diglucosly-beta- cyclodextrin; sulfoalkyl derivatives such as sulfobutylether-beta-cyclodextrin; and carboxymethylated derivatives such as carboxymethyl-beta-cylcodextrin.
  • Other types of chemical modifications, known to those in the art, are also included within the scope of this invention.
  • the cyclodextrin complex often confers properties of improved solubility, dispersability, stability (chemical, physical and microbiological), bioavailability and decreased toxicity on the guest molecule (here, the derivative of the present invention).
  • Complexes may be produced, for example, by using the following basic methods: stirring the one or more derivatves into an aqueous or mixed aqueous-organic solution of the cyclodextrin, with or without heating; kneading, slurrying or mixing the cyclodextrin and the present composition in a suitable device with the addition of an appropriate quantity of aqueous, organic or mixed aqueous-organic liquid, with or without heating; or by physical admixture the cylcodextrin and the composition of the present invention using a suitable mixing device.
  • Isolation of the inclusion complex so formed may be achieved by co- precipitation, filtration and drying; extrusion/ spheronisation and drying; subdivision of the moist mass and drying; spray drying; lyophilization or by other suitable techniques depending on the process used to form the cyclodextrin complex.
  • a further optional step of mechanically grinding the isolated solid complex may be employed.
  • the compounds of the present invention be administered in a program combining oral and intra-venous therapy.
  • the precise modes of delivery in each case will depend upon the objectives of the administration protocol i.e. whether it be preventing, reducing, eliminating or ameliorating a dyslipidemic condition or disorder. In the case of existing conditions and disorders, it will depend upon the severity of the disorder, and as discussed above, the age, size and gender of the individual.
  • the derivatives of the present invention may be incorporated into foods, beverages and nutraceuticals, including, without limitation, the following:
  • Dairy Products such as cheeses, butter, milk and other dairy beverages, spreads and dairy mixes, ice cream and yoghurt;
  • Fat-Based Products such as margarines, spreads, mayonnaise, shortenings, cooking and frying oils and dressings
  • Cereal-Based Products-comprising grains for example, bread and pastas
  • Confectioneries such as chocolate, candies, chewing gum, desserts, non-dairy toppings (for example Cool WhipTM), sorbets, icings and other fillings;
  • the derivatives of the present invention may be incorporated directly and without further modification into the food, nutraceutical or beverage by techniques such as mixing, infusion, injection, blending, dispersing, emulsifying, immersion, spraying and kneading.
  • the derivatives may be applied directly onto a food or into a beverage by the consumer prior to ingestion. These are simple and economical modes of delivery.
  • a water-soluble phvtostanol ascorbate phvtostanol-phosphoryl-ascorbate
  • FM-VP4 modifies CETP-mediated transfer of cholesteryl esters (CE) between HDL and LDL
  • Enzyme assay kits from SigmaTM were used to determine total and lipoprotein triglyceride, cholesterol and protein concentrations
  • CETP 1-2ug protein/ml
  • TP2 4ug protein/ml
  • deoxycholate 50um
  • TP2 was use to ensure that the CE transfer measure was CETP-mediated and deoxycholate was used to demonstrate that the observed effects of phytostanol- phosphoryl-ascorbate were not a non-specific surface active phenomenon
  • Figure 2 clearly shows the efficacy of phytostanol-phosphoryl-ascorbate at both concentrations tested on the inhibition of purified CETP-mediated transfer of CE between LDL and HDL.
  • the compound reduced CE transfer to a level below that which was detectable using the assay.
  • Figure 3 corroborates these results using human plasma, as opposed to purified, CETP.
  • Figure 4 confirms that the effect of FM- VP4 is via a CETP modulating mechanism, and not by some other means.
  • the compound inhibits CETP-mediated transfer of CE between LDL to HDL.
  • Transfer of cholesteryl esters between LDL and HDL can occur only when mediated by CETP.
  • Transfer of CE the opposite way, from HDL to LDL can be CETP mediated or can occur by diffusional transfer.
  • this study only assessed the unidirectional transfer from LDL to HDL and the inhibition of CETP activity thereon, to ensure that the results truly reflect the effects of the compound on CETP i.e. the diffusional variable was removed. Nonetheless, it is also the CETP-mediated transfer of CE from HDL (the anti- atherogenic lipoproteins) to LDL (the atherogenic lipoproteins) that is favourably inhibited by administration of the compounds of the present invention.
  • TP2 is known specifically to bind CETP at the same location as the CE binding site and these results confirm blockage and inhibitions of CETP-mediated CE transfer.

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Abstract

L'invention concerne un procédé permettant de réduire le transfert in vivo d'esters de cholestéryle dont la médiation est assurée par la protéine de transfert des esters de cholestérol, entre les lipoprotéines de haute densité (HDL) et les lipoprotéines de basse densité (LDL). Ce procédé comprend l'étape consistant à administrer une dose thérapeutiquement efficace d'un ou de plusieurs des composés de formules (I), (II), ou (III), dans lesquelles R est un stérol ou une fraction de stanol, R2 est dérivé de l'acide ascorbique et R3 représente un atome d'hydrogène ou un métal quelconque, un métal alcalino-terreux ou un métal alcalin ; ainsi que tous leurs sels, la concentration plasmatique de HDL et de LDL étant vérifiée après ladite administration.
PCT/CA2002/001457 2001-09-26 2002-09-26 Procede de reduction du transfert in vivo d'esters de cholesteryle dont la mediation est assuree par la proteine de transfert des esters de cholesterol, entre les lipoproteines de haute densite (hdl) et les lipoproteines de basse densite (ldl) WO2003026672A1 (fr)

Priority Applications (5)

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JP2003530307A JP2005507890A (ja) 2001-09-26 2002-09-26 生体内のコレステロールエステル転送タンパク質介在の高密度リポタンパク質（ｈｄｌ）と低密度リポタンパク質（ｌｄｌ）の間のコレステリルエステルの転送を減少させる方法
CA002461136A CA2461136A1 (fr) 2001-09-26 2002-09-26 Procede de reduction du transfert in vivo d'esters de cholesteryl e dont la mediation est assuree par la proteine de transfert des esters de cholesterol, entre les lipoproteines de haute densite (hdl) et les lipoproteines de basse densite (ldl)
NZ531938A NZ531938A (en) 2001-09-26 2002-09-26 A method of reducing the in vivo cholesterol ester transfer protein mediated transfer of cholesteryl esters between high density lipoproteins (HDL) and low density lipoproteins (LDL)
BR0212826-8A BR0212826A (pt) 2001-09-26 2002-09-26 Método de redução da proteìna de transferência dos ésteres colesterìlicos mediada pela proteìna de transferência do éster do colesterol in vivo entre as lipoproteìnas de alta densidade (hdl) e lipoproteìnas de baixa densidade (ldl)
EP02764428A EP1432425A1 (fr) 2001-09-26 2002-09-26 Procede de reduction du transfert i in vivo /i d'esters de cholesteryle dont la mediation est assuree par la proteine de transfert des esters de cholesterol, entre les lipoproteines de haute densite (hdl) et les lipoproteines de basse densite (ldl)

Applications Claiming Priority (2)

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US96568701A 2001-09-26 2001-09-26
US09/965,687 2001-09-26

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WO2003026672A1 true WO2003026672A1 (fr) 2003-04-03

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EP (1) EP1432425A1 (fr)
JP (1) JP2005507890A (fr)
CN (1) CN1558766A (fr)
BR (1) BR0212826A (fr)
CA (1) CA2461136A1 (fr)
NZ (1) NZ531938A (fr)
RU (1) RU2004112556A (fr)
WO (1) WO2003026672A1 (fr)

Cited By (2)

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Publication number Priority date Publication date Assignee Title
WO2003104254A2 (fr) * 2002-06-06 2003-12-18 Forbes Medi-Tech Inc. Nouveaux derives d'androstane et d'androstene avec un acide ascorbique et leur utilisation dans le traitement ou la prevention de differents etats, maladies et troubles
EP2316447A1 (fr) 2003-09-26 2011-05-04 Japan Tobacco, Inc. Méthodes pour inhiber la production de lipoprotéines rémanents

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US5866147A (en) * 1995-05-15 1999-02-02 Avon Products, Inc. Ascorbyl-phosphoryl-cholesterol
WO1999015546A1 (fr) * 1997-09-09 1999-04-01 Raisio Benecol Ltd. Utilisation d'acides d'esters organiques dans les graisses alimentaires
WO2001000653A1 (fr) * 1999-06-23 2001-01-04 Forbes Medi-Tech Inc. Conjugues de phytosterol ou de phytostanol et d'acide ascorbique, et leurs utilisations dans le traitement ou la prevention des maladies cardio-vasculaires

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US5866147A (en) * 1995-05-15 1999-02-02 Avon Products, Inc. Ascorbyl-phosphoryl-cholesterol
WO1999015546A1 (fr) * 1997-09-09 1999-04-01 Raisio Benecol Ltd. Utilisation d'acides d'esters organiques dans les graisses alimentaires
WO2001000653A1 (fr) * 1999-06-23 2001-01-04 Forbes Medi-Tech Inc. Conjugues de phytosterol ou de phytostanol et d'acide ascorbique, et leurs utilisations dans le traitement ou la prevention des maladies cardio-vasculaires

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LING W H ET AL: "MINIREVIEW DIETARY PHYTOSTEROLS: A REVIEW OF METABOLISM, BENEFITS AND SIDE EFFECTS", LIFE SCIENCES, PERGAMON PRESS, OXFORD, GB, vol. 57, no. 3, 1995, pages 195 - 206, XP000995149, ISSN: 0024-3205 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003104254A2 (fr) * 2002-06-06 2003-12-18 Forbes Medi-Tech Inc. Nouveaux derives d'androstane et d'androstene avec un acide ascorbique et leur utilisation dans le traitement ou la prevention de differents etats, maladies et troubles
WO2003104254A3 (fr) * 2002-06-06 2004-05-06 Forbes Medi Tech Inc Nouveaux derives d'androstane et d'androstene avec un acide ascorbique et leur utilisation dans le traitement ou la prevention de differents etats, maladies et troubles
EP2316447A1 (fr) 2003-09-26 2011-05-04 Japan Tobacco, Inc. Méthodes pour inhiber la production de lipoprotéines rémanents
EP2319509A1 (fr) 2003-09-26 2011-05-11 Japan Tobacco, Inc. Méthodes pour inhiber la production de lipoprotéines rémanents

Also Published As

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BR0212826A (pt) 2004-08-24
CN1558766A (zh) 2004-12-29
JP2005507890A (ja) 2005-03-24
EP1432425A1 (fr) 2004-06-30
NZ531938A (en) 2006-04-28
RU2004112556A (ru) 2005-03-10
CA2461136A1 (fr) 2003-04-03

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