Classifications

• • 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
  • A61K31/56—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
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones

Definitions

• This present invention relates to methods of treating diabetes mellitus in animals, particularly humans.
• Diabetes mellitus is a heterogeneous primary disorder of carbohydrate metabolism with multiple etiologic factors that generally involve insulin deficiency or insulin resistance or both.
• Type I or juvenile onset, or insulin-dependent diabetes mellitus, is present in patients with little or no endogenous insulin secretory capacity. These patients develop extreme hyperglycemia (glucose accumulation in the bloodstream) and are entirely dependent on exogenous insulin therapy for immediate survival.
• Type 2 also called adult onset, or non-insulin-dependent diabetes mellitus (“NIDDM”), occurs in patients who retain some endogenous insulin secretory capacity, however the great majority of them are both insulin deficient and insulin resistant. Insulin resistance can be due to insufficient insulin receptor expression, reduced insulin-binding affinity, or any abnormality at any step along the insulin signaling pathway (1 )
• diabetes is probably between 2 and 4 per cent, with Type I comprising 7 to 10 per cent of all cases. Secondary complications of diabetes have serious clinical implications. Approximately 25 per cent of all new cases of end-stage renal failure occur in patients with diabetes. About 20,000 amputations (primarily of toes, feet, and legs) are carried out in patients with diabetes, representing approximately half of the non-traumatic amputations performed 5 in the United States. Furthermore, diabetes is the leading cause of new cases of blindness, with approximately 5000 new cases occurring each year.
• Carbohydrates from food are broken down in the intestine to glucose and other simple sugars. These sugars are absorbed into the bloodstream and carried (along with other nutrients) to all the cells of the body. But in order to take up glucose from the blood, the cells need insulin - a hormone made in the pancreas.
• the pancreas a large gland located behind the stomach, has multiple functions. It produces digestive enzymes - proteins that help break down food in the intestine. It also contains specialized groups of cells called "islets of Langerhans". These islet cells are of several types, each producing a different hormone. There are two main hormones that regulate blood glucose levels -- insulin and glucagon. Both are produced in the islets of Langerhans -- glucagon by alpha cells, and insulin by beta cells.
• Insulin (along with the glucose) is carried by the bloodstream to cells throughout the body.
• Various body tissues especially muscle, liver, and fat - have specialized molecules called insulin receptors on their cell surfaces. Insulin binds to these receptors, like a key in a lock - opening channels that allow glucose to enter the cells.
• glucose Once glucose is inside the cells, it can be used for energy and growth. Excess glucose is stored in the liver in the form of a complex carbohydrate called glycogen. Meanwhile, as blood glucose levels fall, insulin secretion slows down. When the blood glucose level starts to get low, it signals the alpha cells to secrete glucagon. Glucagon, in turn, signals the liver to convert glycogen back into glucose -- a process called glycogenolysis. This prevents the blood glucose level from dropping too low to ensure that the body's cells have a steady supply of glucose between meals. Glucagon also stimulates the liver to make new glucose out of other nutrients, such as amino acids (protein building blocks) by a process called gluconeogenesis thereby ensuring a backup source of glucose until the next meal.
• other nutrients such as amino acids (protein building blocks)
• insulin is the primary mode of therapy in all patients with Type I and in many with Type 2 diabetes.
• the regimen can be more or less intensive.
• the most intensive method consists of constant insulin delivery into a subcutaneous site in the abdominal wall via an open loop delivery device consisting of a small insulin pump that must be worn by the patient essentially 24 hours a day.
• Oral hypoglycemic agents such as sulfonylureas are effective in Type II patients but approximately 10 to 20 percent of patients do not respond or cease to respond 12-24 months after beginning treatment.
• Type 2 diabetes usually begins in adulthood (typically after age 40), but also can occur in younger people. Generally, in people having this condition, the pancreas produces insulin but the body's cells are unable to respond to it effectively. This is called insulin resistance. A person can have insulin resistance without diabetes, as long as there is enough insulin to overcome the resistance. But if insulin resistance continues to increase and/or insulin production falls below the amount needed to compensate, diabetes will develop.
• pancreatic beta cells may become less and less responsive thereby secreting less insulin when blood glucose levels are high. Eventually, the person may need insulin injections to help control blood glucose levels.
• diabetes mellitus may be slow-healing sores, frequent infections, or gum disease. Or the first symptoms to be noticed may be those of organ damage, such as heart disease or neuropathy. Common symptoms of diabetic neuropathy include tingling, loss of sensation, or burning pain in the feet and legs. Although the exact causes are not known, diabetes mellitus appears to result from an interaction between genes and lifestyle factors.
• the present invention provides a method for the treatment of diabetes mellitus and conditions associated with diabetes mellitus in an animal, which method comprises administering a non-toxic and therapeutically effective amount of one or more of the following compounds:
• R is a phytosterol or phytostanol moiety
• R2 is derived from ascorbic acid and R3 is hydrogen or any metal, alkali earth metal, or alkali metal; and all salts thereof.
• the present invention also provides for the use of these compounds in regulating serum glucose levels, in enhancing cellular insulin sensitivity and in enhancing glucose responsiveness and level of insulin secretions of pancreatic beta cells.
• the compounds of the present invention have been found to be surprisingly effective in improving glucose tolerance in animals. Until now, there has been no appreciation of these types of compounds having such effects.
• the compounds 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. This enhanced solubility generally translates into lower administration dosages of the compounds in order to achieve the desired therapeutic or prophylactic 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
• a method for the treatment of diabetes mellitus and conditions associated with diabetes mellitus in an animal comprises administering a non-toxic and therapeutically effective amount of one or more the following compounds: O O O 0
• R is a phytosterol or phytostanol moiety
• R2 is derived from ascorbic acid and R3 is hydrogen or any metal, alkali earth metal, or alkali metal; and all salts thereof.
• the term "therapeutically effective” is intended to qualify the amount of the compound(s) administered in order to achieve one or more of the following goals: a) treating conditions associated with diabetes such as hyperglycaemia, and insulin resistance, including acquired insulin resistance; b) treating complications of d iabetes m ellitus s uch a s insulin resistance, including hereditary insulin resistance, impaired glucose tolerance and hyperinsulinaemia; c) treating conditions associated with insulin resistance i nclude polycystic ovarian syndrome and steroid induced insulin resistance and gestational diabetes; d) treating complications associated with diabetes mellitus' includes renal diseases, especially renal disease associated with Type 2 diabetes, neuropathy and retinopathy.
• Renal diseases associated with Type 2 diabetes include nephropathy, glomerulonephritis, glomerular sclerosis, hypertensive nephrosclerosis and end stage renal disease. Additional renal diseases associated with Type 2 diabetes include nephrotic syndrome; e) improving glucose tolerance; f) regulating serum glucose levels; g) enhancing cellular insulin sensitivity; h) enhancing glucose responsiveness and level of insulin secretions of pancreatic beta cells; and i) treating pre-diabetic conditions.
• Diabetes mellitus is preferably Type 2 diabetes.
• 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 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.
• sitostanol is the phytostanol.
• the compound is any phytostanol-phosphoryl ascorbate or salts thereof.
• R2 comprises a scorbic a cid o r a ny d erivative thereof.
• W hat is a chieved 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 ascorbic acid.
• the union benefits and enhances the both parts of this new structure.
• the phytosterol moiety formerly p oorly 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.
• 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, n utraceutically o r 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.
• 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 phytostanol is sitostanol and R3 is sodium.
• phytosterols and/or phytostanols and ascorbic acid there are many processes by which structures comprising phytosterols and/or phytostanols and ascorbic acid can be formed.
• the selected phytosterol or stanol (or halophosphate, halocarbonate or halo-oxalate derivatives thereof) and ascorbic 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 "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 phytosterol/phytostanol halophospahte, halocarbonate or halo-oxalate under suitable reaction conditions.
• condensation reactions are conducted in a n o rganic solvent s uch a s 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 a lcohol such as ethanol and HCI (step d), concentrated.
• a suitable a lcohol 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 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 the 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 phytosterols 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 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 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 a nd/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 compounds for use within the methods of the present invention include 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 a method of treatment of diabetes mellitus and conditions associated with diabetes mellitus in an animal, a method of regulating serum glucose levels and enhancing cellular insulin sensitivity and a method of enhancing glucose responsiveness and level of insulin secretions of pancreatic beta cells which method comprise administering one or more of the derivatives comprising phytosterol and/or phytostanol and ascorbic acid, including salts thereof represented by the general formulae:
• R is a phytosterol or phytostanol moiety
• R2 is derived from ascorbic acid
• R3 is hydrogen or any metal, alkali earth metal, or alkali metal.
• compounds are the 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 and which may be used in accordance with the methods of the present invention. 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 amount of the compound which is required to achieve the desired effects will, of course, depend on a number of factors such as the particular compound chosen, the mode of administration and the condition of the patient.
• the compounds of the present invention can be administered to a patient either by themselves, or in pharmaceutical compositions where they are mixed with suitable carriers or excipients.
• suitable carriers or excipients Use of pharmaceutically acceptable carriers to formulate the compounds herein disclosed for the practice of the invention into dosages suitable for systemic administration is within the scope of the invention.
• the compounds of the present invention in particular, those formulated as solutions, may be administered parenterally, such as by intravenous injection.
• the compounds can be formulated readily using pharmaceutically acceptable carriers well known in the art into dosages suitable for oral administration.
• Such carriers enable the compounds of the invention to be formulated as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
• compositions comprising one or more of the compounds of the present invention, include compositions wherein the active ingredients are contained in an effective amount to achieve their intended purpose. Determination of the effective amounts is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
• compositions may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
• suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
• the preparations formulated for oral administration may be in the form of tablets, dragees, capsules, or solutions.
• compositions of the present invention may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
• compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
• compositions for oral use can be obtained by combining the active compounds with solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
• suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
• disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
• Dragee cores are provided with suitable coatings.
• suitable coatings For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
• Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
• compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
• the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
• the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
• stabilizers may be added.
• Oral liquid preparations may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
• Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p- hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents.
• suspending agents for example sorbitol, syrup, methyl cellulose
• the compounds of the present invention may be administered through 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;
• Beverages whether alcoholic or non-alcoholic and including colas and other soft drinks, juice drinks, dietary supplement and meal replacement drinks such as those sold under the trade-marks BoostTM and EnsureTM; and
• the compounds 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 compounds 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.
• Glucose was measured using the Surestep blood glucose monitoring system (Lifescan Canada). Insulin and leptin levels were measured by radioimmunoassay (RIA kits LINCO corp). Plasma cholesterol and triglyceride were measured using enzymatic kits (Sigma, St. Louis, MO) as previously described.
• FM-VP4 sitostanol-phosphate-ascorbate
• animals Prior to administration of one of the compounds of the present invention, referred to as "FM-VP4" (sitostanol-phosphate-ascorbate), animals were weighed and fasted overnight and blood samples taken for the determination of: glucose, insulin, leptin, cholesterol, and triglycerides. Animals were then treated with 250 mg/kg FM-VP4 twice daily by oral gavage for 30 days (using a 2% solution of FM-VP4 dissolved in drinking water). Every two days animals were weighed and morning blood glucose levels measured. At the end of 30 days all animals were fasted overnight and a second oral glucose tolerance test performed.
• FM-VP4 sitostanol-phosphate-ascorbate
• Intralipid ® is a sterile non-pyrogenic fat emulsion prepared for administration as a source of calories and essential fatty acids, and was used as a vehicle to solubilize and co-administer exogenous [ 3 H]-cholesterol and FM-VP4 in a palpable oral formulation. Liquid chromatography-mass spectrometry analysis revealed minimal total cholesterol and vegetable stanol content within 10% Intralipid ® prior to the addition of exogenous cholesterol (labeled and unlabeled) and FM-VP4 as previously published.
• Body weight Body weight profiles over the 30-day drug treatment period (Fig. 4) indicate no significant change in body weight in either the lean or fatty group after treatment.
• Morning blood glucose Morning blood glucose profiles over the 30-day drug treatment period (Fig. 5) indicate no significant change in morning (fed) blood glucose in either the lean or fatty group after treatment. Variability always exists in these readings as animals may vary in feeding status relative to the time of glucose measurement (8 AM). However, in these studies blood glucose levels remained relatively consistent throughout the duration of the study. Furthermore, FM-VP4 treatment did not alter lean and fatty Zucker rat daily diet and/or water consumption (data not shown).
• Plasma leptin levels Plasma leptin levels. Levels of the satiety hormone leptin did not change significantly after drug treatment in either group (Fig. 6). It should be noted that the primary defect in the fatty Zucker rat is a mutation in the central leptin receptors resulting in abnormal hypothalamic appetite regulation. As a consequence the fa/fa, fatty animals have greatly elevated leptin levels. There is a suggestion of reduced leptin levels after FM-VP4 treatment in fat animals but differences are not significant.
• OGTT Oral glucose tolerance test
• Figures 7 and 8 show OGTT glucose data in lean and fat animals respectively before and after FM-VP4 treatment. Whereas there is no alteration in glucose tolerance in the non-diabetic, normoglycemic lean group, there is a highly significant improvement in glucose tolerance in the fat group that exhibit a diabetic glucose tolerance curve (Fig. 8).
• Oral glucose tolerance test (OGTT)-lnsulin data Figures 9 and 10 show OGTT insulin data in lean and fat animals respectively before and after FM-VP4 treatment.
• the insulin response to oral glucose shows no significant change in nondiabetic lean animals (Fig 9) whereas there is a change in the insulin secretory profile in the fat group after FM-VP4 treatment (Fig. 10).
• FM-VP4 phytostanol phosphoryl ascorbate
• FM-VP4 significant improvement glucose tolerance within fatty Zucker rats without altering body weight and morning glucose, insulin, and leptin levels in both lean and fatty rats.

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• Ophthalmology & Optometry (AREA)
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• 2003
  • 2003-03-14 WO PCT/CA2003/000369 patent/WO2003075931A1/en active Application Filing
  • 2003-03-14 BR BR0308396-9A patent/BR0308396A/pt not_active IP Right Cessation
  • 2003-03-14 CN CNA038059738A patent/CN1681514A/zh active Pending
  • 2003-03-14 EP EP03711733A patent/EP1482950A1/en not_active Withdrawn
  • 2003-03-14 NZ NZ535200A patent/NZ535200A/en unknown
  • 2003-03-14 KR KR10-2004-7014408A patent/KR20040104513A/ko not_active Application Discontinuation
  • 2003-03-14 CA CA002478931A patent/CA2478931A1/en not_active Abandoned
  • 2003-03-14 AU AU2003218547A patent/AU2003218547B2/en not_active Ceased
  • 2003-03-14 JP JP2003574205A patent/JP2005528353A/ja active Pending
  • 2003-03-14 RU RU2004130463/14A patent/RU2334518C2/ru not_active IP Right Cessation
• 2004
  • 2004-10-13 NO NO20044346A patent/NO20044346L/no unknown

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