WO2002034241A2 - Compounds comprising a phytosterol and/or phytostanol moiety and ascorbis acid and use thereof as weight regulating agents - Google Patents
Compounds comprising a phytosterol and/or phytostanol moiety and ascorbis acid and use thereof as weight regulating agents Download PDFInfo
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- WO2002034241A2 WO2002034241A2 PCT/CA2001/001483 CA0101483W WO0234241A2 WO 2002034241 A2 WO2002034241 A2 WO 2002034241A2 CA 0101483 W CA0101483 W CA 0101483W WO 0234241 A2 WO0234241 A2 WO 0234241A2
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- 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
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- 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
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- 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
- A61P3/04—Anorexiants; Antiobesity agents
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- 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
Definitions
- This present invention relates to the field of sterol and stanol derivatives and their use in decreasing weight gain and increasing weight loss in animals, including humans.
- 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 not only in the treatment of CVD and its underlying conditions such as hypercholesterolemia, hyperlipidemia, atherosclerosis, hypertension, thrombosis but in the treatment of other diseases such as Type II diabetes, dementia cancer and aging, are well recorded.
- the present invention provides novel derivatives comprising sterol and/or stanol and ascorbic acid, including salts thereof, and represented by the general 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.
- the present invention also comp ⁇ ses processes of preparing the novel derivatives having the above noted formulae.
- the present invention further comprises a composition for decreasing weight gain and/or increasing weight loss in an animal which comp ⁇ ses one or more de ⁇ vatives of sterols and/or stanols and ascorbic acid, having one or more of the above noted formulae.
- the present invention further provides foods, beverages and nutraceuticals for use in decreasing weight gain and/or increasing weight loss, supplemented with derivatives of sterols and/or stanols and ascorbic acid, having one or more of the above noted formulae.
- the present invention further provides a method of decreasing weight gain by administering to an animal derivatives of sterols and/or stanols and ascorbic acid, having one or more of the above noted formulae.
- the present invention further provides a method of increasing weight loss by administering to an animal derivatives of sterols and/or stanols and ascorbic acid, having one or more of the above noted formulae.
- the derivatives 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 water-based due to the nature of the derivatives. This enhanced solubility generally translates into lower administration dosages of the derivatives in order to achieve the desired dietary or therapeutic effect.
- Figure 1 is a schematic showing a process of preparing phytostanol-phosphate-ascorbate and its sodium salt
- Figure 2 is a schematic showing a process of preparing phytostanol-carbonate-ascorbate and its sodium salt
- Figure 3 is a schematic showing a process of preparing phytostanol-oxalate-ascorbate and its sodium salt
- derivatives of sterol and/or stanol and ascorbic acid suitable for use per se in decreasing weight gain and/or increasing weight loss in animals, including humans.
- the derivatives of the present invention are represented by one of 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.
- the components of the derivative will be described in more detail below. It should be noted that, throughout this disclosure, the terms “derivative”, “structure” and “analogue” are used interchangeably to describe the unitary compound which links both a sterol or stanol and ascorbic acid. The elements of the compounds will be described in more detail below
- sterol includes all sterols without limitation, for example: sitosterol, campesterol, stigmasterol, brassicasterol, 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 includes all saturated or hydrogenated sterols and all natural or synthesized forms and derivatives thereof, including 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. It is also to be understood that, when in doubt throughout the specification, the term “sterol” encompasses both sterol and stanol i.e. the terms may be used interchangeably unless otherwise specified.
- the sterols and stanols for use in forming derivatives 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
- 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.
- 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 sterol 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.
- L-ascorbic acid (commonly known as vitamin C) is a vital part of balanced human nutrition and plays a role as a physiological anti- oxidant.
- ascorbic acid is the least stable vitamin with which to work since it reacts extremely easily with atmospheric oxygen yielding dehydroascorbic acid which further and readily decomposes into compounds void of vitamin C efficacy. It is believed that the new structure of the present invention "protects" ascorbic acid from such decomposition.
- the weight loss function of the derivatives of the present invention may be due to the properties of the unique compounds which are formed herein. Linking ascorbic acid with sterols or stanols for the purpose of preparing a weight controlling agent has never been appreciated or explored.
- 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. Such 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 or campestanol and R3 is hydrogen or sodium.
- 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 "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/phytostanol 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.
- the reaction temperatures may vary from low (-15°C) to elevated temperatures.
- Figure 1 is a schematic showing the formation of the "protected” ascorbic acid (step a), the formation of the intermediary chlorophosphate/stanol derivative (step b), and the condensation reaction (alternatively steps c or d) yielding one of novel derivatives of the present invention based on formula I: phytostanol-phosphate-ascorbate (noted as structure 6).
- ascorbic acid is initially protected from decomposition by the formation of 5,6-isopropylidene-ascorbic acid (structure 2). 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 (refer to Example 1 below).
- Phytostanol chlorophosphate (structure 4) 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.
- phytostanol chlorophosphate structure 4
- the residue so formed after filtration and concentration of the mother liquor is phytostanol chlorophosphate (structure 4).
- the latter is then mixed with 5,6-isopropylidene-ascorbic acid and, after the addition of a suitable alcohol such as ethanol and HCI (step d), concentrated.
- a suitable alcohol such as ethanol and HCI
- pyridine/THF may be added (step c) and the product concentrated.
- step e the resultant novel product of both steps c or d is phvtostanol- phosphate-ascorbate (structure 6).
- ascorbic acid 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 phytosterols or phytostanols, derivatized as described above, using known esterification methods ultimately to produce the structures of the present invention.
- 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. Similarly, US Patent Serial No.
- FIG 2 is a schematic showing the formation of the "protected" ascorbic acid (step a), the formation of the intermediary chlorocarbonate/stanol derivative (step b), and the condensation reaction (optionally steps c or d) yielding structure 9 (10 is the same), one of novel derivatives of the present invention based on formula II: phytostanol-carbonate- ascorbate.
- These chlorocarbonate derivatives may be prepared by the same process outlined in detail above with respect to Figure 1 ; however, the phosphorus oxylchloride is replaced (as shown in step b of Figure 2) by phosgene.
- FIG 3 is a schematic showing the formation of the "protected" ascorbic acid (step a), the formation of the intermediary chloro-oxalate/stanol derivative (step b), and the condensation reaction (optionally steps c or d) yielding a novel structure 13 (same as 14), one of novel derivatives of the present invention based on formula III: phytostanol- oxalate-ascorbate (noted as structure 14).
- 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 (as shown in step b of Figure 3) by oxalyl chloride.
- the present invention encompasses not only the parent structures comprising sterols or phytostanols and ascorbic acid (for example, those preferred structures shown as structures 5 and 6 in Figure 1 , structures 9 an 10 in Figure 2 and structures 13 and 14 in Figure 3) 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 are 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 sterol derivatives of the present invention or the constituent moieties thereof (either the sterol or the ascorbic 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 ascorbic 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 ring of ascorbic acid is partially or fully reduced and/or wherein the phytosterol moiety is fully or partially hydrogenated.
- the present invention comprises all derivatives of sterol and/or stanol and ascorbic acid, including salts thereof represented by the general 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.
- the present invention comprises all halophosphate, halocarbonate and halo- oxalate/phytostanol/ascorbate derivatives as shown in Figures 1 through 3 as structures 5, 6, 7, 9, 10, 11 13 14 and 15. 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 sodium salts are shown in structures 7, 11 and 15, other salts are included within the scope of the invention, as described above.
- the derivatives of the present invention wherein ascorbic acid is attached to the sterol moiety affords many dietary and therapeutic advantages. What has been found, within the scope of the present invention, is that these derivatives are particularly useful in regulating weight, more specifically, decreasing weight gain and increasing weight loss as required.
- these derivatives are easy to use from a manufacturing and commercial perspective. They are readily soluble, both in aqueous solutions and non-aqueous media such as oils and fats.
- 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.
- 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.
- the derivatives of the present invention may be administered to animals, in particular humans, directly and without further modification or may be treated to enhance further the solubility and/or dispersability of the composition as described in detail above.
- the derivatives may be incorporated into various vehicles as described further below in order to modulate or control body weight.
- these derivatives may be combined, in therapeutically effective amounts, with customary carriers and excipients in the fields of pharmaceuticals, nutraceuticals or functional foods and administered as required.
- populations, which are considered "high-risk" for weight-related disorders or obesity it is contemplated that the derivatives of the present invention be used in primary, secondary and tertiary treatment programs.
- 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 doses of the derivatives will vary depending upon, among other factors, the mode of delivery, 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.
- an amount of the compound(s) should be administered to achieve the desired therapeutic or prophylactic result i.e. to achieve the goals of: a) preventing weight gain in an individual; and/or b) weight loss in an individual.
- the derivatives 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, micro pa rticulates, 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, micro pa rticulates, solutions (such as micellar, syrup
- 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 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;
- 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.
- Example 1 The present invention is described by the following non-limiting examples: Example 1
- phytostanol-phosphoryl- ascorbate herein referred to interchangeably as "FCP-VP4" or "FM-VP4" (at various doses) and FCP-3P4 (positive control) on weight following chronic oral administration to gerbils.
- FCP-VP4 Different concentrations of FCP-VP4 (0.25, 0.5, 1 , 2% wt/wt) and FCP-3P4 (2% wt/wt) were incorporated into standard gerbil chow by standard milling procedures (1 ). Liquid chromatography-mass spectrometry analysis was used to confirm the percentage of FCP-3P4 or -VP4 incorporated into the gerbil chow (data not shown). All gerbils used in this study were cared for in accordance with the principles promulgated by the Canadian Council on Animal Care and the University of British Columbia. Adult male Mongolian gerbils (70-80 g) were obtained from Charles River Breeders (Montreal, Quebec, Canada). All treatment groups were maintained under a 12 h light (0700- 0900)/dark cycle and supplied with a standard laboratory diet (PMI Feeds, Richmond, VA, USA) and water ad libitum.
- PMI Feeds Richmond, VA, USA
- Twenty-four pure-bred beagle dogs (12 males and 12 females) were divided into 4 groups, each consisting of 3 males and 3 females.
- Three groups received the preferred compound of the present invention, referred to as FM-VP4, administered in gelatin capsules at doses of 50, 250 or 800 mg/kg/day for 4 weeks.
- the dose was given each day as two equal subdoses with an interval of approximately 6 hours.
- the other group received empty gelatin capsules twice each day and acted as controls.
- ALT was increased during Weeks 2 and 4 for some or all males receiving 800 mg/kg/day.
- Example 6 Oral Administration to Beagle Dogs for One Week Study Two pure-bred beagle dogs (1 male and 1 female) were dosed with the preferred compound of the present invention by oral capsule twice daily for 7 days. The scheduled total daily dose of 2000 mg/kg/day was administered for 3 days.
- Both the male and female dogs showed weight loss during the dosing period of 0.3 and 0.8 kg respectively.
- Standard milling procedures (1 ) were used to incorporate different concentrations of the preferred compound of the present invention, FM-VP4 (0.25, 0.5, 1 , 2% w/w) into standard gerbil chow.
- Mongolian gerbils were used in these studies and were cared for in accordance with the Canadian Council on Animal Care and the University of British Columbia guidelines. Thirty adult male Mongolian gerbils (70-80 g) were obtained from Charles River Breeders (Montreal, Canada). The gerbils were maintained under a 12 hr light (0700-1900)/dark cycle and supplied with a standard laboratory gerbil diet (Jameison's Pet Food Distributor, Delta, B.C.) and water ad libitum.
- the gerbils were divided into fives groups of six animals matched for body weight and administered a standard gerbil diet containing either no FM-VP4 (control) or FM-VP4 at 0.25, 0.5, 1 , 2% w/w for 4 continuous weeks. Food and water was supplied ad libitum and daily intake was monitored and replaced.
- Standard milling procedures (1 ) were used to incorporate different concentrations of the preferred compound of the present invention, FM-VP4 at 2% & 4% w/w into standard gerbil chow. FM-VP4 (2% & 4% w/v) was also dissolved into drinking water. Fresh drinking water and gerbil chow was replaced on a daily basis throughout the duration of the study.
- the experimental protocol was similar to that used in example 6. Thirty adult male Mongolian gerbils (70-80 g) were obtained from Charles River Breeders (Montreal, Canada). The gerbils were maintained under a 12 hr light (0700-1900)/dark cycle and supplied with a standard laboratory gerbil diet (Jameison's Pet Food Distributor, Delta, B.C.) and water ad libitum.
- Table 3 Effect of 8-week treatment with FM-NP4 in diet and or water on average gerbil water intake (ml/day/gerbil) during each week of the study.
- Table 4 Effect of 8-week treatment with FM-NP4 in diet and or water on average gerbil food intake (grams/day/gerbil) during each week of the study.
- VP4 4% in diet d P ⁇ 0.05 vs. FM-NP4 2% in water.
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Priority Applications (11)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NZ525452A NZ525452A (en) | 2000-10-25 | 2001-10-25 | Novel structures comprising phytosterol and/or phytostanol and ascorbic acid and use thereof as weight regulating agents |
DE60125220T DE60125220T2 (en) | 2000-10-25 | 2001-10-25 | COMPOUNDS CONTAINING A PHYTOSTEROL AND / OR A PHYTOSTANOL PART AND ASCORBIC ACID AND THEIR USE AS WEIGHT REGULATORS |
AU2001295346A AU2001295346A1 (en) | 2000-10-25 | 2001-10-25 | Compounds comprising a phytosterol and/or phytostanol moiety and ascorbis acid and use thereof as weight regulating agents |
CA002426895A CA2426895A1 (en) | 2000-10-25 | 2001-10-25 | Compounds comprising a phytosterol and/or phytostanol moiety and ascorbis acid and use thereof as weight regulating agents |
DK01975935T DK1333838T3 (en) | 2000-10-25 | 2001-10-25 | Compounds comprising a phytosterol and / or phytostanol moiety and ascorbic acid, and use thereof as weight regulators |
EP01975935A EP1333838B1 (en) | 2000-10-25 | 2001-10-25 | Compounds comprising a phytosterol and/or phytostanol moiety and ascorbic acid and use thereof as weight regulating agents |
MXPA03003701A MXPA03003701A (en) | 2000-10-25 | 2001-10-25 | Novel structures comprising phytosterol and/or phytostanol and ascorbic acid and use thereof as weight regulating agents. |
SI200130669T SI1333838T1 (en) | 2000-10-25 | 2001-10-25 | Compounds comprising a phytosterol and/or phytostanol moiety and ascorbic acid and use thereof as weight regulating agents |
JP2002537295A JP2004511573A (en) | 2000-10-25 | 2001-10-25 | Novel structures comprising phytosterols and / or phytostanols and ascorbic acid and their use as weight regulators |
NO20031836A NO20031836L (en) | 2000-10-25 | 2003-04-24 | New structures comprising phytosterol and / or phytostanol and ascorbic acid and their use as weight regulators |
CY20061101870T CY1105893T1 (en) | 2000-10-25 | 2006-12-29 | CHEMICAL COMPOUNDS CONTAINING A PHYTOSTEPOL AND/OR PHYTOSTANOL PART AND ASCORBIC ACID AND THEIR USE AS WEIGHT REGULATORY AGENTS |
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Application Number | Priority Date | Filing Date | Title |
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US98574900A | 2000-10-25 | 2000-10-25 | |
US09/985,749 | 2000-10-25 |
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WO2002034241A2 true WO2002034241A2 (en) | 2002-05-02 |
WO2002034241A3 WO2002034241A3 (en) | 2003-04-10 |
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PCT/CA2001/001483 WO2002034241A2 (en) | 2000-10-25 | 2001-10-25 | Compounds comprising a phytosterol and/or phytostanol moiety and ascorbis acid and use thereof as weight regulating agents |
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EP (1) | EP1333838B1 (en) |
JP (1) | JP2004511573A (en) |
AT (1) | ATE347895T1 (en) |
AU (1) | AU2001295346A1 (en) |
CA (1) | CA2426895A1 (en) |
CY (1) | CY1105893T1 (en) |
DE (1) | DE60125220T2 (en) |
DK (1) | DK1333838T3 (en) |
ES (1) | ES2276834T3 (en) |
MX (1) | MXPA03003701A (en) |
NO (1) | NO20031836L (en) |
NZ (1) | NZ525452A (en) |
PT (1) | PT1333838E (en) |
WO (1) | WO2002034241A2 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004029068A1 (en) * | 2002-09-25 | 2004-04-08 | Forbes Medi-Tech Inc. | Derivatives comprising sterols and/or stanols and specific classes of anti-inflammatory agents and use thereof in treating or preventing cardiovascular disease |
JP2005524492A (en) * | 2002-05-06 | 2005-08-18 | ベクトン・ディキンソン・アンド・カンパニー | Methods and devices for controlling the pharmacokinetics of a drug. |
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EP0339486A2 (en) * | 1988-04-25 | 1989-11-02 | Takeda Chemical Industries, Ltd. | Ester of ascorbic acid 2-phosphate |
EP0436936A2 (en) * | 1990-01-09 | 1991-07-17 | Hoechst Aktiengesellschaft | Lipid selective anti-oxidants, their production and use |
EP0665238A1 (en) * | 1994-01-28 | 1995-08-02 | Senju Pharmaceutical Co., Ltd. | Corticoid derivatives and pharmaceutical and cosmetic compositions |
WO1997042960A1 (en) * | 1996-05-14 | 1997-11-20 | Avon Products, Inc. | Ascorbyl-phosphoryl-cholesterol |
WO2001000653A1 (en) * | 1999-06-23 | 2001-01-04 | Forbes Medi-Tech Inc. | Conjugates of phytosterol or phytostanol with ascorbic acid and use thereof in treating or preventing cardiovascular disease |
-
2001
- 2001-10-25 NZ NZ525452A patent/NZ525452A/en unknown
- 2001-10-25 PT PT01975935T patent/PT1333838E/en unknown
- 2001-10-25 ES ES01975935T patent/ES2276834T3/en not_active Expired - Lifetime
- 2001-10-25 CA CA002426895A patent/CA2426895A1/en not_active Abandoned
- 2001-10-25 EP EP01975935A patent/EP1333838B1/en not_active Expired - Lifetime
- 2001-10-25 DK DK01975935T patent/DK1333838T3/en active
- 2001-10-25 AU AU2001295346A patent/AU2001295346A1/en not_active Abandoned
- 2001-10-25 WO PCT/CA2001/001483 patent/WO2002034241A2/en active IP Right Grant
- 2001-10-25 JP JP2002537295A patent/JP2004511573A/en active Pending
- 2001-10-25 DE DE60125220T patent/DE60125220T2/en not_active Expired - Fee Related
- 2001-10-25 AT AT01975935T patent/ATE347895T1/en not_active IP Right Cessation
- 2001-10-25 MX MXPA03003701A patent/MXPA03003701A/en active IP Right Grant
-
2003
- 2003-04-24 NO NO20031836A patent/NO20031836L/en not_active Application Discontinuation
-
2006
- 2006-12-29 CY CY20061101870T patent/CY1105893T1/en unknown
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0339486A2 (en) * | 1988-04-25 | 1989-11-02 | Takeda Chemical Industries, Ltd. | Ester of ascorbic acid 2-phosphate |
EP0436936A2 (en) * | 1990-01-09 | 1991-07-17 | Hoechst Aktiengesellschaft | Lipid selective anti-oxidants, their production and use |
EP0665238A1 (en) * | 1994-01-28 | 1995-08-02 | Senju Pharmaceutical Co., Ltd. | Corticoid derivatives and pharmaceutical and cosmetic compositions |
WO1997042960A1 (en) * | 1996-05-14 | 1997-11-20 | Avon Products, Inc. | Ascorbyl-phosphoryl-cholesterol |
WO2001000653A1 (en) * | 1999-06-23 | 2001-01-04 | Forbes Medi-Tech Inc. | Conjugates of phytosterol or phytostanol with ascorbic acid and use thereof in treating or preventing cardiovascular disease |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2005524492A (en) * | 2002-05-06 | 2005-08-18 | ベクトン・ディキンソン・アンド・カンパニー | Methods and devices for controlling the pharmacokinetics of a drug. |
US9192750B2 (en) | 2002-05-06 | 2015-11-24 | Becton, Dickinson And Company | Method and device for controlling drug pharmacokinetics |
US10322272B2 (en) | 2002-05-06 | 2019-06-18 | Becton, Dickinson And Company | Method and device for controlling drug pharmacokinetics |
WO2004029068A1 (en) * | 2002-09-25 | 2004-04-08 | Forbes Medi-Tech Inc. | Derivatives comprising sterols and/or stanols and specific classes of anti-inflammatory agents and use thereof in treating or preventing cardiovascular disease |
Also Published As
Publication number | Publication date |
---|---|
NO20031836L (en) | 2003-06-19 |
EP1333838B1 (en) | 2006-12-13 |
CY1105893T1 (en) | 2011-02-02 |
DE60125220D1 (en) | 2007-01-25 |
MXPA03003701A (en) | 2005-07-01 |
NZ525452A (en) | 2007-09-28 |
EP1333838A2 (en) | 2003-08-13 |
WO2002034241A3 (en) | 2003-04-10 |
PT1333838E (en) | 2007-01-31 |
AU2001295346A1 (en) | 2002-05-06 |
ES2276834T3 (en) | 2007-07-01 |
JP2004511573A (en) | 2004-04-15 |
CA2426895A1 (en) | 2002-05-02 |
ATE347895T1 (en) | 2007-01-15 |
DK1333838T3 (en) | 2007-04-10 |
NO20031836D0 (en) | 2003-04-24 |
DE60125220T2 (en) | 2007-04-12 |
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