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WO2003059360A1 - Nouveaux agents reduisant l'absorption de cholesterol - Google Patents

Nouveaux agents reduisant l'absorption de cholesterol Download PDF

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Publication number
WO2003059360A1
WO2003059360A1 PCT/US2003/000834 US0300834W WO03059360A1 WO 2003059360 A1 WO2003059360 A1 WO 2003059360A1 US 0300834 W US0300834 W US 0300834W WO 03059360 A1 WO03059360 A1 WO 03059360A1
Authority
WO
WIPO (PCT)
Prior art keywords
glycoside
cholesterol
sitostanol
stanol
composition
Prior art date
Application number
PCT/US2003/000834
Other languages
English (en)
Inventor
Eric Stohler
Original Assignee
Medical Isotopes, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Medical Isotopes, Inc. filed Critical Medical Isotopes, Inc.
Priority to AU2003205100A priority Critical patent/AU2003205100A1/en
Publication of WO2003059360A1 publication Critical patent/WO2003059360A1/fr

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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof

Definitions

  • This invention relates to compositions and methods for reducing cholesterol absorption and serum cholesterol content in humans.
  • Phytosterols plant sterols that are structurally similar to cholesterol
  • Bile acid sequestrants such as the ion- exchange resin cholestyramine act within the intestine but do not bind cholesterol and may actually mcrease cholesterol absorption when given repeatedly (McNamara, D. J., N.O. Davidson, P. Samuel, and E.H. Ahrens, Jr. 1980 Cholesterol absorption in man: effect of administration of clofibrate and/or cholestyramine. J. Lipid Res. 21:1058-1064).
  • neomycin is a potent, even toxic antibiotic (Samuel, P. 1979. Treatment of hypercholesterolemia with neomycin ⁇ A time for reappraisal. N. Engl. J. Med. 301:595-597).
  • phytosterols are natural products which are non-toxic and inexpensive byproducts of food processing, they may be important in the treatment of individuals with mildly increased serum cholesterol or for the general population in food products or dietary supplements.
  • the use of phytosterols could reduce the need for systemically absorbed drugs.
  • sitostanol esters dissolved in dietary fat has the disadvantage of requiring the administration of 23-50 g/day of dietary fat and of being 21% less effective at reducing cholesterol absorption in humans compared to the unesterified sterol (Mattson, F.H., S. M. Grundy, and J.R. Crouse. 1982. Optimizing the effect of plant sterols on cholesterol absorption in man. Am. J. Clin. Nutr. 35:697-700).
  • sitostanol is dissolved with an edible solubilizing agent such as triglyceride, an antioxidant such as tocopherol, and a dispersant such as lecithin, polysorbate 80, or sodium lauryl sulfate.
  • an edible solubilizing agent such as triglyceride
  • an antioxidant such as tocopherol
  • a dispersant such as lecithin, polysorbate 80, or sodium lauryl sulfate.
  • Effectiveness in reducing cholesterol abso ⁇ tion was also not determined.
  • the preferred embodiment consisted of 25% by weight stands in vegetable oil, but the solubility of sterols in oil is only 2% (Jandacek, R.J., M.R. Webb, and F.H. Mattson. 1977.
  • Cholesterol is absorbed from an intestinal micellar phase containing bile salts and phospholipids, which is in equilibrium with an oil phase inside the intestine. Delivery of phytosterol as a solid powder or aqueous suspension is not preferred because of the limited rate and extent of solubility in intestinal liquid phases. New phytosterol formulations are needed.
  • the present invention features formulations of stanol glycosides that are easily absorbed through the human digestive tract.
  • Preferred glycosides include the glucosides, galactosides, maltosides, lactosides, or cellobiosides, e.g. ⁇ -D-galactosides, ⁇ -D- maltoosides, ⁇ -D-lactosides or ⁇ -D-cellobiosides.
  • the formulation comprises sitostanol- ⁇ -D-glycoside, and campestanol- ⁇ -D-glycoside.
  • the stanol glycoside is dissolved or dispersed in a solubilizing macromolecule.
  • Preferred solubilizing macromolecules include phospholipids, starch, modified starch, alphalized starch, dextrin, sodium starch phosphate, glucose, lactose, monosaccharides, disaccharides, polysaccharides, hydroxypropyl cellulose, methylcellulose, and lecithin.
  • the stanol glycoside or stanol glycoside ester has a particle size in the range of about one to about one hundred microns.
  • the formulation may be prepared from a solid residue remaining after removal of water or other solvents from a solution or suspension of said glycosides and the carrier or diluent.
  • the stanol glycoside has a particle size of 1 - 100 micron.
  • Stanol glycoside esters may also be used. These formulations are particularly useful as oral pharmaceutical compositions comprising an effective amount of the stanol glycoside and a pharmaceutically acceptable carrier or diluent. Stands are not water-soluble and, if they are not absorbed, they may be excreted after ingestion with little or no effect to lower cholesterol.
  • the invention enhances bioavailability of stanol-glycosides by enhancing abso ⁇ tion in the intestine.
  • the invention also avoids discomfort and other problems associated with oral administration of phytosterols - e.g., pure phytosterols pressed into one-gram tablets can create stomach disorders. Unmixed sitostanol powder may appear in stool samples from patients undergoing cholesterol turnover studies where sitostanol was given as a stool marker without any cholesterol-lowering effect.
  • sitostanol glycoside is delivered in a more soluble form without using oil or margarine as a vehicle avoiding the substantial disadvantage of administering oil or fat to a patient in need of cholesterol reduction. (Giving 3 g/day of sitostanol oleate in oil requires about 30 g oil or fat with 270 calories).
  • stanol derivatives like sitostanol glycosides and glycoside esters.
  • the glycoside moiety enhances their abso ⁇ tion in the intestines and increases their bioavailability.
  • Suitable sources of sterols as raw material include soybeans, wood, and apple presscake.
  • the sterols are then converted to stanols by hydrogenation. Glycosylation of the stanols may be achieved by various techniques, e.g., by the general technique described by Vogel, Tetrahedron Ltrs. 26:1713 et. seq. (1985).
  • Reactive monosaccharide derivatives used for glycosylation may be readily prepared or can be obtained commercially.
  • Liposomes containing stanols-glycosides may be prepared by known techniques.
  • Typical dosages according to the invention are from O.lg - 10g/75kg patient. This dosage maybe formulated in a powder or liquid and dispersed in hydroxypropyl methylcellulose, phospholipids, lecithin, or also in polysaccharides such as starch, guar gum, and pectin. The dispersion is inserted into a standard soft gel capsule or hard capsule. Various techniques are known to test the dosage in animals and humans. Examples
  • Phytosterols from soybeans containing sitosterol campesterol and stigmasterol (30 gram) were dissolved in 400 ml of ethylacetate and poured into a 600 ml stainless steel pressure vessel. 2 gram of palladium on carbon (10% dispersion) was added. The pressure vessel was charged with hydrogen to a pressure of 1000 psi and magnetically stirred. After 2 hours no additional pressure drop was observed. After 24 hours the pressure was released and the content of the vessel was filtered to remove the catalyst. The solvent was evaporated on a rotary evaporator. The dry product was re-crystallized two times from hot ethanol. A sample dissolved in CDC1 3 analyzed by NMR showed the absence of double bonds.
  • sitostanol glycosides there are a number of reactive monosaccharide derivatives commercially available.
  • Acetobromo- ⁇ -D-glucopyranoside, and other conjugates can be prepared from similar derivatives, also available commercially, like the acetobromo derivatives of galactose, glucouronic acid, maltose, and fucose.
  • a sample reaction is shown in Figure 1.
  • the dissolution assay is a primary screen to investigate the general ability of the formulation, stanol glucose dispersed in Hydroxypropyl Methyl Cellulose, to dissolve or disperse the associated stanol formulation in a simulated USP gastrointestinal fluid.
  • Crystalline stanol assays at a value of 250 ug/ml (four hours) and 30 ug/ml (one hour).
  • MI-C, MI-D, and MI-E fairly linear dose response
  • MI- A, MI-B, and MI-C demonstrate the reproducibility of the screen since these are virtually the same materials.
  • the two positive controls were crystalline stanol and stanol glucoside. All formulations/controls were administered in the chow through a process of grinding the formulation directly into the chow. Since grinding the formulations/controls into the chow itself contributes to the overall activity, this screen generally provides high levels of activity with less differentiation among the formulations tested. Six hamsters were used for each dose. As you can see below we did not obtain a linear response. MI-1 is the 1 :5 ratio, MI-2 is the 1:2 ratio, and MI-3 is the 1-0.5 ratio. Dog Screen:
  • the dog study included two controls, Benecol, the positive control, and the standard diet control. Formulations were administered in capsules and the Benecol administered via syringe. Dosing coincided with the morning meal. Six dogs were used for each dose. The 5 results correlated well with the dissolution screen and unlike the hamsters, the dogs provided a nice dose response with no negative effect seen at the lowest stanol concentration formulation.
  • Hamster Potency Mean cholesterol/Mean sitostanol ratio formulation group orMean cholesterol/Mean sitostanol ratio sitostanol group

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un processus de préparation de glycosides sitostanol dans une forme qui est facilement absorbée par le système digestif, et des procédés de traitement de l'hypercholestérolémie par l'administration d'une composition qui comprend au moins un glycoside ou un ester de glycoside d'un glycoside stanol.
PCT/US2003/000834 2002-01-11 2003-01-13 Nouveaux agents reduisant l'absorption de cholesterol WO2003059360A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003205100A AU2003205100A1 (en) 2002-01-11 2003-01-13 Novel cholesterol absorption lowering agents

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US34763002P 2002-01-11 2002-01-11
US60/347,630 2002-01-11

Publications (1)

Publication Number Publication Date
WO2003059360A1 true WO2003059360A1 (fr) 2003-07-24

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2003/000834 WO2003059360A1 (fr) 2002-01-11 2003-01-13 Nouveaux agents reduisant l'absorption de cholesterol

Country Status (2)

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AU (1) AU2003205100A1 (fr)
WO (1) WO2003059360A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005042692A3 (fr) * 2003-10-31 2005-09-09 Forbes Medi Tech Inc Methode permettant d'inhiber l'expression de genes qui induisent l'influx de cholesterol cellulaire dans les cellules animales et d'inhiber la production de proteines issues de l'expression de ces genes
WO2005095436A1 (fr) * 2004-03-31 2005-10-13 Morinaga Milk Industry Co., Ltd. Glucoside comportant un squelette de 4-méthylergost-7-en-3-ol et médicament destiné à améliorer l'hyperglycémie
WO2006123464A1 (fr) * 2005-05-17 2006-11-23 Morinaga Milk Industry Co., Ltd. Médicaments, aliment ou boisson destinés à l'amélioration des fonctions pancréatiques

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005042692A3 (fr) * 2003-10-31 2005-09-09 Forbes Medi Tech Inc Methode permettant d'inhiber l'expression de genes qui induisent l'influx de cholesterol cellulaire dans les cellules animales et d'inhiber la production de proteines issues de l'expression de ces genes
WO2005095436A1 (fr) * 2004-03-31 2005-10-13 Morinaga Milk Industry Co., Ltd. Glucoside comportant un squelette de 4-méthylergost-7-en-3-ol et médicament destiné à améliorer l'hyperglycémie
KR100743852B1 (ko) * 2004-03-31 2007-08-02 모리나가 뉴교 가부시키가이샤 4-메틸에르고스트-7-엔-3-올 골격을 갖는 글리코사이드 및고혈당 개선제
RU2315770C1 (ru) * 2004-03-31 2008-01-27 Моринага Милк Индастри Ко., Лтд. Гликозидное производное, способ его получения, композиция, средство для коррекции гипергликемии, лекарственное средство, пищевые продукты, способ коррекции гипергликемии
US7534770B2 (en) 2004-03-31 2009-05-19 Morinaga Milk Industry Co., Ltd. Glycoside having 4-methylergost-7-en-3-ol skeleton and hyperglycemia improving agent
US8486462B2 (en) 2004-03-31 2013-07-16 Morinaga Milk Industry Co., Ltd. Glycoside having 4-methylergost-7-en-3-ol skeleton and hyperglycemia improving agent
WO2006123464A1 (fr) * 2005-05-17 2006-11-23 Morinaga Milk Industry Co., Ltd. Médicaments, aliment ou boisson destinés à l'amélioration des fonctions pancréatiques
US7531520B2 (en) 2005-05-17 2009-05-12 Morinaga Milk Industry Co., Ltd. Drug and food or drink for improving pancreatic functions

Also Published As

Publication number Publication date
AU2003205100A1 (en) 2003-07-30

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