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WO2001066560A2 - Nouveaux derives comprenant des phytosterols et/ou des phytostanols et des alpha-lipoiques et leur utilisation pour traiter ou prevenir les maladies cardio-vasculaires, leurs causes premieres et d'autres troubles - Google Patents

Nouveaux derives comprenant des phytosterols et/ou des phytostanols et des alpha-lipoiques et leur utilisation pour traiter ou prevenir les maladies cardio-vasculaires, leurs causes premieres et d'autres troubles Download PDF

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Publication number
WO2001066560A2
WO2001066560A2 PCT/CA2001/000285 CA0100285W WO0166560A2 WO 2001066560 A2 WO2001066560 A2 WO 2001066560A2 CA 0100285 W CA0100285 W CA 0100285W WO 0166560 A2 WO0166560 A2 WO 0166560A2
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Prior art keywords
composition
phytostanol
phytosterol
lipoic acid
phytosterols
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Ceased
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PCT/CA2001/000285
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WO2001066560A3 (fr
Inventor
Radka K. Milanova
James P. Kutney
Egon Novak
Duanjie Hou
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Forbes Medi-Tech Inc
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Forbes Medi-Tech Inc
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Priority to AU2001242130A priority Critical patent/AU2001242130A1/en
Publication of WO2001066560A2 publication Critical patent/WO2001066560A2/fr
Publication of WO2001066560A3 publication Critical patent/WO2001066560A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
    • A—HUMAN NECESSITIES
    • A21—BAKING; EDIBLE DOUGHS
    • A21D—TREATMENT OF FLOUR OR DOUGH FOR BAKING, e.g. BY ADDITION OF MATERIALS; BAKING; BAKERY PRODUCTS
    • A21D2/00—Treatment of flour or dough by adding materials thereto before or during baking
    • A21D2/08—Treatment of flour or dough by adding materials thereto before or during baking by adding organic substances
    • A21D2/14—Organic oxygen compounds
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23D—EDIBLE OILS OR FATS, e.g. MARGARINES, SHORTENINGS OR COOKING OILS
    • A23D7/00—Edible oil or fat compositions containing an aqueous phase, e.g. margarines
    • A23D7/005—Edible oil or fat compositions containing an aqueous phase, e.g. margarines characterised by ingredients other than fatty acid triglycerides
    • A23D7/0056—Spread compositions
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23D—EDIBLE OILS OR FATS, e.g. MARGARINES, SHORTENINGS OR COOKING OILS
    • A23D9/00—Other edible oils or fats, e.g. shortenings or cooking oils
    • A23D9/007—Other edible oils or fats, e.g. shortenings or cooking oils characterised by ingredients other than fatty acid triglycerides
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A23L33/11—Plant sterols or derivatives thereof, e.g. phytosterols
    • 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
    • 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
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • 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
    • A61K31/66—Phosphorus compounds
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/67—Phosphorus compounds having sulfur as a ring hetero atom
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J33/00—Normal steroids having a sulfur-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J33/002—Normal steroids having a sulfur-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed

Definitions

  • This present invention relates to the field of phytosterols and phytostanols and their use in treating and preventing cardiovascular disease and other disorders.
  • 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 a person's total serum cholesterol yields a 2% reduction in risk of a coronary artery event (3).
  • a 10% decrease in average serum cholesterol (e.g. from 6.0 mmol/L to 5.3 mmol/L) may result in the prevention of 100,000 deaths in the United States annually (4).
  • Sterols are naturally occurring compounds that perform many critical cellular functions. Phytosterols 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.
  • phytosterols Despite the obvious and well recorded advantages of phytosterols in the treatment of a number of disorders, research continues into ways in which the efficacy of phytosterols and their delivery and administration may be improved.
  • the administration of phytosterols and the incorporation thereof into foods, pharmaceuticals and other delivery vehicles has been complicated by the fact that they are highly hydrophobic (i.e. they have poor water solubility).
  • phytosterols are highly hydrophobic, they do not dissolve to any appreciable extent in the micellar phase in the digestive tract and therefore are not capable of efficiently blocking cholesterol absorption.
  • Oils and fats are capable to a limited but not satisfactory degree of dissolving free phytosterols. Since only solubilized phytosterols inhibit absorption of cholesterol, adaptations must be made.
  • composition comprising one or more of the following:
  • R is a phytosterol or phytostanol moiety
  • R2 is derived from lipoic acid and R3 is hydrogen or any metal, alkali earth metal, or alkali metal;
  • the present invention further provides for the use of the composition, defined above, for treating or preventing CVD and its underlying conditions including atherosclerosis, hypercholesterolemia, hyperlipidemia, hypertension, thrombosis, and related diseases such as Type II diabetes, as well as other diseases that include oxidative damage as part of the underlying disease process such as dementia, Alzheimer's disease, aging, and cancer.
  • the present invention further provides foods, beverages and nutraceuticals supplemented with the composition as defined above.
  • the present invention further provides a method for treating or preventing CVD and its underlying conditions including atherosclerosis, hypercholesterolemia, hyperlipidemia, hypertension, thrombosis, and related diseases such as Type II diabetes, as well as other diseases that include oxidative damage as part of the underlying disease process such as dementia, aging, and cancer by administering to a human or animal the composition as defined herein.
  • the present invention also comprises processes of preparing the novel composition as defined above.
  • composition of the present invention is based on the heretofore, uninvestigated benefit of "combining" phytosterols and/or phytostanols with lipoic acid.
  • this "combination" is achieved two ways: through the formation of a derivative (a new chemical structure) having one of the following general formulae:
  • R is a phytosterol or phytostanol moiety
  • R2 is derived from lipoic acid
  • R3 is hydrogen or any metal, alkali earth metal, or alkali metal; or through the physical mixing of the two constituent moieties, phytosterols and lipoic acid or their salts.
  • compositions of the present invention have numerous advantages over the phytosterol/stanol compositions previously known and described in the art.
  • what is primarily achieved is enhanced solubility of the phytosterol/stanol constituents in oils and fats, without the need for other structural modifications to the sterols and stanols.
  • this facilitates the incorporation of sterols and stanols into "delivery" vehicles (with the attendant cost and time savings) but this composition is more readily absorbed in bile acid micelli, thereby efficiently displacing cholesterol and. blocking its absorption.
  • Both phytosterols and phytostanols must first be dissolved in oil micelles in the intestine before interaction with cholesterol can occur.
  • compositions of the present invention can be prepared and used as such or they can be easily incorporated into foods, beverages, pharmaceuticals and nutraceuticals regardless of whether these "vehicles" are oil- based.
  • This enhanced solubility generally translates into lower administration dosages of the phytosterol/phytostanol and lipoic acid moieties in order to achieve the desired therapeutic effect.
  • a second advantage of the compositions of the present invention is that there may be an additive or synerqistic therapeutic effect, both in lowering serum cholesterol and as an anti-oxidant, between the phytosterol/stanol component and the lipoic acid.
  • Figure 1 is a schematic showing a process of preparing phytostanol-phosphate- lipoate
  • Figure 2 is a schematic showing a process of preparing phytostanol-oxalate-lipoate.
  • Figure 3 is a schematic showing a process of preparing phytostanol-lipoate.
  • R is a phytosterol or phytostanol moiety
  • R2 is derived from lipoic acid and R3 is hydrogen or any metal, alkali earth metal, or alkali metal;
  • compositions are suitable for use in human and animals for treating or preventing CVD and its underlying conditions, such as atherosclerosis, hypercholesterolemia, hyperlipidemia, hypertension, thrombosis, and related diseases such as Type II diabetes, as well as in treating and preventing other diseases that include oxidative damage as part of the underlying disease process such as dementia, Alzheimer's disease, aging, and cancer.
  • CVD cardiovascular disease
  • its underlying conditions such as atherosclerosis, hypercholesterolemia, hyperlipidemia, hypertension, thrombosis, and related diseases such as Type II diabetes
  • Other diseases that include oxidative damage as part of the underlying disease process such as dementia, Alzheimer's disease, aging, and cancer.
  • phytosterol includes all phytosterols without limitation, for example: sitosterol, campesterol, stigmasterol, brassicasterol, desmosterol, chalinosterol, poriferasterol, clionasterol and all natural or synthesized forms and derivatives thereof, including isomers.
  • phytostanol includes all saturated or hydrogenated phytosterols and all natural or synthesized forms and derivatives thereof, including isomers. It is to be understood that modifications to the phytosterols and phytostanols i.e. to include side chains also falls within the purview of this invention. It is also to be understood that, when in doubt throughout the specification, the term “phytosterol” encompasses both phytosterol and phytostanol i.e. the terms may be used interchangeably unless otherwise specified.
  • the phytosterols and phytostanols for use in forming compositions in accordance with this invention may be procured from a variety of natural sources. For example, 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
  • plant oils including aquatic plants
  • plant oils including aquatic plants
  • wheat germ oil soy extract, rice extract, rice bran, rapeseed oil, sunflower oil, sesame oil and fish (and other marine-source) oils.
  • the present invention is not to be limited to any one source of phytsterols.
  • 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
  • composition of the present invention is formed with naturally-derived or synthesized beta-sitosterol, campestanol, sitostanol and campesterol.
  • composition of the present invention is formed with naturally-derived or synthesized sitostanol or with naturally derived or synthesized campestanol or mixtures thereof.
  • Alpha-lipoic acid is chemically referred to 1 ,2-dithiolane-3-pentanoic acid, 5-(1,2- dithiolane-3-yl)-valeric acid or 5,3-(1 ,2-dithioanyl)pentanoic acid.
  • Alpha-lipoic acid possesses a chiral C atom, occurs in two enantiomeric forms and is found physiologically in plants, in bacteria and in mammals. It functions as an essential co- factor in metabolic reactions involved in energy utilization (8). Research in muscle and fat cells has demonstrated that alpha-lipoic acid stimulates glucose transport and has a positive effect on insulin-stimulated glucose up-take (9).
  • Alpha-lipoic acid and its reduced form, dihydrolipoic acid may also have effects on genes and regulatory proteins involved in normal growth and metabolism (10).
  • Alpha-lipoic acid and dihydrolipoic acid are both effective as fat and water-soluble antioxidants.
  • Alpha-lipoic acid is readily absorbed, transported and taken up by cells where it is reduced in various tissues, including the brain (11 ). It has been found to scavenge free hydroxyl radicals, singlet oxygen, hydrogen peroxide, hypochlorous acid, peroxynitrite and nitric oxide and may also exert an anti-oxidant effect through the chelation of copper, iron and other transition metals (10,12,13).
  • alpha-lipoic acid supplementation prevented symptoms of vitamin C and E deficiency indicating a synergy between alpha-lipoic acid and other anti-oxidants (14,15). Additionally, alpha-lipoic acid supplementaion has been shown to increase the intracellular levels of the anti-oxidant enzyme glutathione by 30-70% (16).
  • R2 comprises lipoic 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 phytosterol or phytostanol moiety is chemically linked to lipoic 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 phytosterol becomes possible without any further enhancements to modify its delivery.
  • novel structures comprising phytosterols and/or phytostanols and lipoic acid can be formed.
  • the selected phytosterol or stanol (or halophosphate, halocarbonate or halo-oxalate derivatives thereof) and lipoic acid are mixed together under reaction conditions to permit condensation of the "acid" moiety with the "alcohol” (phytosterol).
  • reaction 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.
  • 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 derivative comprises condensing lipoic acid with the phytosterol/phytostanol or its' halophosphate, 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 room to elevated temperatures.
  • FIG 1 is a schematic showing the formation of a chlorophosphate/stanol derivative (step a), and the condensation reaction yielding one of novel derivatives of the present invention based on formula I: phytostanol-phosphate-lipoate (noted as structure 4).
  • phytostanol chlorophosphate (structure 2) is prepared by forming a solution of phytostanol in toluene and pyridine (although other nitrogen bases such as aliphatic and aromatic amines may alternatively be used) and treating this solution with a phosphorus derivative such as phosphorus oxychloride.
  • the residue so formed after filtration and concentration of the mother liquor is phytostanol chlorophosphate (structure 3).
  • the latter is then mixed with lipoic acid and, after the addition of a suitable alcohol such as ethanol and HCI (step c), concentrated.
  • a suitable alcohol such as ethanol and HCI
  • pyridine/THF may be added and the product concentrated.
  • the resultant novel product is phytostanol-phosphate-lipoate (structure 6).
  • FIG 2 is a schematic showing the formation of the intermediary chloro- oxalate/stanol derivative (step a), and the condensation reaction (step b) yielding a novel structure 7, one of novel derivatives of the present invention based on formula ill: phytostanol-oxalate-lipoate.
  • These chloro-oxalate derivatives may be prepared by the same process outlined in detail above with respect to Figure 1 ; however, the phosphorus oxylchloride is replaced by oxalyl chloride.
  • Figure 3 is a schematic showing the formation of one of the novel derivatives of the present invention based on formula II: phytostanol-lipoate, shown as structure 8.
  • the present invention encompasses not only the parent structures comprising phytosterols or phytostanols and lipoic acid (for example, those preferred structures shown as structures 4, 7 and 8 in the Figures but also the salts thereof. These salts are even more water soluble than the corresponding parent compounds and therefore their efficacy and evaluation both in vitro and in vivo is much improved.
  • Salt formation of the derivatives of the present invention can be readily performed by treatment of the parent compound 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.
  • R3 represents either hydrogen (parent compound) or any metal, alkali earth metal, or alkali metal (the salt).
  • the phytosterol derivatives of the present invention or the constituent moieties thereof (either the phytosterol or the lipoic acid) prior to or after derivative formation may be hydrogenated or saturated.
  • the hydrogenation of heterocyclic ring systems to the partially or fully reduced analogues is a well known process.
  • the catalytic and/or chemical reduction of the ring of lipoic acid to the corresponding dihydro analogue is readily accomplished under an atmosphere of hydrogen and a metal catalyst such as platinum, palladium or Raney Nickel.
  • this reduction is performed in an organic solvent such as ethanol, ethyl acetate or similar media and either under atmospheric pressure or at a low pressure (3-5 psi) at room temperature or slightly elevated temperatures.
  • the chemical reductions of such systems involve reduction with a family of "hydride” reagents such as sodium borohydride, lithium aluminum hydride and their analogues. These reductions are generally performed in an anhydrous inert medium involving ethyl ether, tetrahydrofuran, dioxane, or benzene, toluene or similar aromatic solvents at room to reflux temperatures.
  • a family of "hydride” reagents such as sodium borohydride, lithium aluminum hydride and their analogues.
  • the present invention includes within its scope all fully or partially reduced derivatives wherein the lipoic acid is partially or fully reduced and/or wherein the phytosterol moiety is fully or partially hydrogenated.
  • the present invention comprises all derivatives comprising phytosterol and/or phytostanol and lipoic acid, including salts thereof represented by the general formulae:
  • R is a phytosterol or phytostanol moiety
  • R2 is derived from lipoic acid
  • R3 is hydrogen or any metal, alkali earth metal, or alkali metal.
  • the present invention comprises all halophosphate, halocarbonate and halo- oxalate/phytostanol/lipoate derivatives as shown in the Figures as structures 4, 7, and 8. It is to be clearly understood; however, that these structures are only a selection of the many novel derivatives which fall within the purview of formulae I, II and III. It is also to be understood that although a sodium salt is shown as structure 5 in Figure 1 , other salts are included within the scope of the invention, as described above. Potential Advantages of Novel Phytosterol Compositions
  • novel derivatives of the present invention wherein lipoic acid is attached to the phytosterol moiety affords many dietary and therapeutic advantages when compared to the use of phytosterols/phytostanols without such attachment.
  • solubility of the novel derivatives 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.
  • compositions comprising one or more phytosterols and or phytostanols in combination with lipoic acid or analogues thereof.
  • this embodiment encompasses the physical admixing of the ingredients without the necessity of forming a new chemical structure.
  • this composition there is additionally provided one or more omega-3 polyunsaturated fatty acids (“PUFA's”) admixed with the sterol/stanol component and the alpha-lipoic acid component.
  • PUFA's omega-3 polyunsaturated fatty acids
  • omega-3 PUFAs for use within the composition of the present invention are selected from alpha-linolenic acid, eicosapentaenoic acid (“EPA”) and docohexaenoic acid (“DHA”) in the form of, inter alia, fatty acids, t glycerides, phospholipids, esters or free fatty acid salts.
  • the omega-3 PUFAs may be extracted from zooplankton, fish or other marine animals using suitable bioconcentration techniques.
  • omega- 3 PUFAs may be synthesized using microalgae as the source material.
  • marine fish oil may be mixed directly with the phytosterol and/or stanol components to form the composition of the present invention.
  • the marine oil may be extracted by techniques known in the art from, inter alia: finfish such as cod, salmon, tuna, herring, halibut, shark, catfish, pollock, dogfish, anchovy, mackerel, trout, and eel; animals such as seals and whales; crustaceans such as crabs, clams and iobster; mollusks and the like.
  • plant sources of omega-3 PUFAs may be used.
  • the great advantage of plant sources is reduced odour as compared to some marine sources.
  • Plant sources include, but are not limited to, plant oils such as hemp oil, flax seed oil and corn oil as well as soy.
  • composition of phytosterols and/or phytostanols, alpha-lipoic aicd and omega-3 PUFA may be combined in any of the various conventional pharmaceutical preparations and dosage forms described below.
  • the components are combined in a capsule.
  • Preferred concentration ranges, for most dosage forms, including the capsule form are:
  • Phytosterols/Phytostanols 100-525mg (with a most preferred target dosage of
  • Omega-PUFAs 100-525 mg (with a most preferred target dosage of
  • capsule form as shown above, it is preferred that a total of three (3) capsules be administered per day with each meal for optimal therapeutic efficacy.
  • capsule fill excipients may include the following: emulsifiers/surfactants (such as lecithin, polysorbate 80, etc); suspending agents (such as beeswax, hydrogenated vegetable oils, etc); diluent (such as soybean oil, etc) and other antioxidants such as alpha-tocopherol.
  • emulsifiers/surfactants such as lecithin, polysorbate 80, etc
  • suspending agents such as beeswax, hydrogenated vegetable oils, etc
  • diluent such as soybean oil, etc
  • other antioxidants such as alpha-tocopherol.
  • the outer layer may include one or more of the following: softgel base ingredients (such as gelatin, non-bovine), plasticisers (such as glycerol), solvents for gelatin (such as water), and approved shell coloring agents (such as titanium dioxide for a white opaque capsule).
  • softgel base ingredients such as gelatin, non-bovine
  • plasticisers such as glycerol
  • solvents for gelatin such as water
  • approved shell coloring agents such as titanium dioxide for a white opaque capsule.
  • Omega-3 PUFA's although effective in lowering serum triglycerides (“TG") have the troublesome side- effect of often increasing serum levels of low density lipoprotein cholesterol (LDL-C).
  • LDL-C low density lipoprotein cholesterol
  • phytosterols while known for their beneficial LDL-C lowering effect may increase serum TG levels under some conditions. It is possible that the beneficial "synergisitic" effects of the composition described herein in lowering both serum LDL-C and TG is the result of each component "optimizing the effects of the other two.
  • omega-3 PUFA may serve to provide the lipid component needed for optimal activity of phytosterols in lowering cholesterol, may counteract the TG effect and while being at risk itself for oxidation, may benefit from the strong anti-oxidant effect of alpha-lipoic acid.
  • the derivatives may be administered to animals, particularly humans, directly and without any further modification, it is possible to take further steps to enhance delivery and ensure even distribution throughout the food, beverage, pharmaceutical, nutraceutical and the like to which they are added. It is to be understood; however, that these steps are purely optional.
  • Such enhancement may be achieved by a number of suitable means such as, for example, solubilizing or dispersing the derivatives to form emulsions, solutions and dispersions or self-emulsifying systems; lyophilizing, spray drying, controlled precipitating, or a combination thereof; forming solid dispersions, suspensions, hydrated lipid systems; forming inclusion complexations with cyclodextrins; and using hydrotopes and formulations with bile acids and their derivatives. All of these techniques are described in PCT/CA99/00512, which was published on December 16, 1999 (the contents of which are incorporated herein by reference). Methods of Use
  • compositions and derivatives of the present invention may be used directly and without further modification in cooking, baking and the like as agents to lower serum cholesterol in animals, particularly humans. They may be added to any edible oil and used for cooking, baking, and general use. Alternatively, they may be treated to enhance delivery into various other delivery media.
  • the present invention fully contemplates the formation of oleaginous gel foodstuffs such as peanut butter, mayonnaise, ice cream and margarine spreads incorporating such structures.
  • the compositions can readily be included in a variety of low fat foods such as yoghurts.
  • delivery examples There are numerous modes or "vehicles" of delivery of the composition , accordingly, this invention is not intended to be limited to the following delivery examples.
  • compositions 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, ampuls, emulsions, microemulsions, ointments, creams, suppositories, gels, and transdermal patches, 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, elixi
  • compositions of the present invention adapted into the appropriate dosage form as described above may be administered to animals, including humans, orally, by injection (intra-venously, subcutaneously, intra-peritoneally, intra-dermally or intramuscularly), topically or in other ways. Although the precise mechanism of action is unclear, the compositions of the present invention, administered intra-venously, lower serum cholesterol.
  • compositions may be used in both dietary and therapeutic capacities in order to treat and/or prevent CVD, its underlying conditions such as hypercholesterolemia, hyperlipidemia, arteriosclerosis, hypertension, thrombosis, related diseases such as Type II diabetes, as well as other diseases that include oxidative damage as part of the underlying disease process such as dementia, aging, and cancer.
  • CVD cardiovascular disease
  • its underlying conditions such as hypercholesterolemia, hyperlipidemia, arteriosclerosis, hypertension, thrombosis, related diseases such as Type II diabetes, as well as other diseases that include oxidative damage as part of the underlying disease process such as dementia, aging, and cancer.
  • diseases such as Type II diabetes
  • other diseases that include oxidative damage as part of the underlying disease process such as dementia, aging, and cancer.
  • the vehicles and foodstuffs in which they are contained be used in primary, secondary and tertiary treatment programs.
  • the doses will vary depending upon, among other factors, the mode of delivery (i.e. how and into which food or beverage or pharmaceutical the phytosterol/stanol derivatives are ultimately incorporated), the patient size and condition, the result to be achieved, as well as other factors known to those skilled in the art of food additives and medicinal agents.
  • the derivatives of the present invention be administered to humans in a form comprising up to 6 grams (based on a 70kg person) of phytosterols and/or phytostanols per day, more preferably from 1-5 grams per day and most preferably 1.5 grams per day. It will also be recognized that the provision of much larger daily doses of the derivatives are not harmful to the animal host, as excess will simply pass through normal excretory channels.
  • compositions 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;
  • Confectioneries such as chocolate, candies, chewing gum, desserts, non-dairy toppings (for example Cool WhipTM), sorbets, icings and other fillings;
  • Trie compositions of the present invention may be incorporated directly and without further modification into foods, nutraceuticals or beverages by techniques such as mixing, infusion, injection, blending, dispersing, emulsifying, immersion, spraying and kneading.
  • the compositions 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.

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Abstract

Nouveaux dérivés du phytostérol et/ou du phytostanol, et leurs sels, de formules générale (I), (II) et (III), dans lesquelles R est un fragment de phytostérol et/ou de phytostanol, R2 est un dérivé de l'acide lipoïque, et R3 est H ou tout métal, métal alcalino-terreux ou métal alcalin. Lesdits dérivés servent à traiter les maladies cardio-vasculaires ou leurs causes premières, dont l'athérosclérose et l'hyperlipidémie.
PCT/CA2001/000285 2000-03-07 2001-03-07 Nouveaux derives comprenant des phytosterols et/ou des phytostanols et des alpha-lipoiques et leur utilisation pour traiter ou prevenir les maladies cardio-vasculaires, leurs causes premieres et d'autres troubles Ceased WO2001066560A2 (fr)

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AU2001242130A AU2001242130A1 (en) 2000-03-07 2001-03-07 Novel derivatives comprising phytosterols and/or phytostanols and alpha-lipoic and use thereof in treating or preventing cardiovascular disease, its underlying conditions and other disorders

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US51927800A 2000-03-07 2000-03-07
US09/519,278 2000-03-07

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Cited By (11)

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EP1172110A3 (fr) * 2000-07-07 2003-09-17 Basf Aktiengesellschaft Utilisation de l'acide lipoique pour augmenter la biodisponibilité de sels minéraux
WO2004029068A1 (fr) * 2002-09-25 2004-04-08 Forbes Medi-Tech Inc. Derives comprenant des sterols et/ou des stanols et des classes specifiques d'agents anti-inflammatoires, et utilisation desdits derives pour le traitement ou la prevention de maladies cardiovasculaires
WO2007124598A3 (fr) * 2006-05-01 2007-12-21 Forbes Medi Tech Inc Capsules gélatineuse molle
WO2011078785A1 (fr) 2009-12-23 2011-06-30 Paresh Dutta Dérivés d'acide alpha-lipoïque à base de diacylglycérol en tant qu'antioxydants et agents pour bloquer la prise d'aliments
WO2012084416A1 (fr) * 2010-12-22 2012-06-28 Unilever Nv Émulsion d'eau dans l'huile comprenant des acides gras oméga-3 et procédé pour sa fabrication
US8865245B2 (en) 2008-12-19 2014-10-21 Conopco, Inc. Edible fat powders
US8927045B2 (en) 2005-02-17 2015-01-06 Sandra Petronella Barendse Process for the preparation of a spreadable dispersion
US8940355B2 (en) 2003-07-17 2015-01-27 Conopco, Inc. Process for the preparation of an edible dispersion comprising oil and structuring agent
US9924730B2 (en) 2010-06-22 2018-03-27 Unilever Bcs Us, Inc. Edible fat powders
US10219523B2 (en) 2010-12-17 2019-03-05 Upfield Us Inc. Process of compacting a microporous fat powder and compacted fat powder so obtained
US10456344B2 (en) 2014-12-22 2019-10-29 Conopco, Inc. Hair composition

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WO2012079957A1 (fr) 2010-12-17 2012-06-21 Unilever Nv Émulsion d'eau dans l'huile comestible
CN106810588A (zh) * 2017-01-18 2017-06-09 江南大学 一种高效合成硫辛酸甾醇酯的方法

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US5244887A (en) * 1992-02-14 1993-09-14 Straub Carl D Stanols to reduce cholesterol absorption from foods and methods of preparation and use thereof
DE4400843A1 (de) * 1994-01-13 1995-07-20 Marigen Sa Antitumorale u. Biotenside Ester der DL-alpha-Liponsäure
AU6141498A (en) * 1997-02-04 1998-08-25 John V. Kosbab Compositions and methods for prevention and treatment of vascular degenerative diseases
WO1999011144A1 (fr) * 1997-09-02 1999-03-11 The Ricex Company, Inc. Traitement de l'hypercholesterolemie, de l'hyperlipidemie, et de l'atherosclerose
WO1999057246A1 (fr) * 1998-05-01 1999-11-11 Life Technologies, Inc. Milieux de culture de cellules animales comprenant des elements nutritifs derives des vegetaux
WO2000004887A2 (fr) * 1998-07-20 2000-02-03 Forbes Medi-Tech Inc. Compositions a base de phytosterol, phytostanol ou de melange des deux, et d'acides gras φ-3 ou de certains de leurs derives, utilisation preventive ou curative de cette composition contre des affections cardio-vasculaires et autres troubles
IT1312377B1 (it) * 1999-03-05 2002-04-15 Uni Ci S R L Composizioni a base di acido tiottico, cisteina e/o n-acetil cisteinada utilizzarsi in preparazioni farmaceutiche, dietetiche e cosmetiche

Cited By (18)

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US6887894B2 (en) 2000-07-07 2005-05-03 Basf Aktiengesellschaft Use of lipoic acid for improving the bioavailability of mineral salts
EP1172110A3 (fr) * 2000-07-07 2003-09-17 Basf Aktiengesellschaft Utilisation de l'acide lipoique pour augmenter la biodisponibilité de sels minéraux
WO2004029068A1 (fr) * 2002-09-25 2004-04-08 Forbes Medi-Tech Inc. Derives comprenant des sterols et/ou des stanols et des classes specifiques d'agents anti-inflammatoires, et utilisation desdits derives pour le traitement ou la prevention de maladies cardiovasculaires
US8940355B2 (en) 2003-07-17 2015-01-27 Conopco, Inc. Process for the preparation of an edible dispersion comprising oil and structuring agent
US11278038B2 (en) 2003-07-17 2022-03-22 Upfield Europe B.V. Process for the preparation of an edible dispersion comprising oil and structuring agent
US9661864B2 (en) 2005-02-17 2017-05-30 Unilever Bcs Us, Inc. Process for the preparation of a spreadable dispersion
US8927045B2 (en) 2005-02-17 2015-01-06 Sandra Petronella Barendse Process for the preparation of a spreadable dispersion
WO2007124598A3 (fr) * 2006-05-01 2007-12-21 Forbes Medi Tech Inc Capsules gélatineuse molle
US8865245B2 (en) 2008-12-19 2014-10-21 Conopco, Inc. Edible fat powders
US8629175B2 (en) 2009-12-23 2014-01-14 Paresh Dutta Functional food additives
US9505738B2 (en) 2009-12-23 2016-11-29 Paresh Dutta Functional food additives
WO2011078785A1 (fr) 2009-12-23 2011-06-30 Paresh Dutta Dérivés d'acide alpha-lipoïque à base de diacylglycérol en tant qu'antioxydants et agents pour bloquer la prise d'aliments
US9924730B2 (en) 2010-06-22 2018-03-27 Unilever Bcs Us, Inc. Edible fat powders
US10219523B2 (en) 2010-12-17 2019-03-05 Upfield Us Inc. Process of compacting a microporous fat powder and compacted fat powder so obtained
US11071307B2 (en) 2010-12-17 2021-07-27 Upfield Europe B.V. Process of compacting a microporous fat powder and compacted powder so obtained
WO2012084416A1 (fr) * 2010-12-22 2012-06-28 Unilever Nv Émulsion d'eau dans l'huile comprenant des acides gras oméga-3 et procédé pour sa fabrication
US9119405B2 (en) 2010-12-22 2015-09-01 Conopco, Inc. Water-in-oil emulsion comprising omega-3 fatty acids and process for the manufacture of same
US10456344B2 (en) 2014-12-22 2019-10-29 Conopco, Inc. Hair composition

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WO2001066560A3 (fr) 2002-03-28

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