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WO1999039715A1 - Phytosterols facilement absorbables permettant de traiter l'hypercholesterolemie - Google Patents

Phytosterols facilement absorbables permettant de traiter l'hypercholesterolemie Download PDF

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Publication number
WO1999039715A1
WO1999039715A1 PCT/US1999/002578 US9902578W WO9939715A1 WO 1999039715 A1 WO1999039715 A1 WO 1999039715A1 US 9902578 W US9902578 W US 9902578W WO 9939715 A1 WO9939715 A1 WO 9939715A1
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WO
WIPO (PCT)
Prior art keywords
sterol
phytosterols
starch
cholesterol
phytosterol
Prior art date
Application number
PCT/US1999/002578
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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 AU26600/99A priority Critical patent/AU2660099A/en
Publication of WO1999039715A1 publication Critical patent/WO1999039715A1/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
    • A61K31/56—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

Definitions

  • Phytosterols are components of plants and grains and are contained in small amounts in their cells. About 100 different phytosterols have been isolated from plants. The most abundant by far are (in order) sitosterol, campesterol and stigmasterol. They are structurally very similar to cholesterol except they are alkylated at the 24-position in the side chain.
  • Phytosterols are natural components of the diet and are consumed in amounts of 100-500 mg/day with US consumption being generally low. (Weirauch, J.L., Gardner, J.M. 1978. Sterol content of foods of plant origin. J. Am . Diet . Assoc . 73:39-47) Reportedly, phytosterols themselves are absorbed in relatively small amounts. (Grundy, S. M. and H. Y. I. ok. 1977. Determination of cholesterol absorption in man by intestinal perfusion. Journal of Lipid Research 18:263- 271)
  • LDL low density lipoprotein
  • Sitostanol reportedly is more effective than sitosterol for cholesterol lowering in animals (Sugano, M., Morioka, H., Ikeda, I. 1977. A comparison of hypocholesterolemic activity of beta-sitosterol and beta- sitostanol in rats. J. Nutr. 107:2011-2019) and has nearly no absorption from the intestine. (Hassan, A. S . , Rampone , A.J. 1979. Intestinal absorption and lymphatic transport of cholesterol and beta-sitostanol in the rat. J". Lipid Res .
  • Sitostanol given primarily as the oleate ester in margarine reduced serum LDL cholesterol by 14% in a random population sample of 153 individuals with moderate hypercholesterolemia (mean 237 mg/dl) and moderate dietary cholesterol intake of 308-340 mg/day.
  • sitostanol oleate total plasma cholesterol declined from 235 mg/dl (at the upper end of the ⁇ CEP
  • sitostanol oleate solubilized in rapeseed oil margarine was highly effective in reducing serum cholesterol
  • 3.0 g/day of unesterified sitostanol suspended (not dissolved) in a small amount of oil was ineffective.
  • Phytosterols may be given orally as the free sterols in aqueous suspension or as dry powders. However, phytosterols are insoluble in water and poorly soluble in oil and it may take several days to achieve final equilibrium solubility when sitosterol crystals are added to aqueous bile salt micelles. (Armstrong, M. J. and M. C. Carey. 1987. Thermodynamic and molecular determinants of sterol solubilities in bile salt micelles. Journal of Lipid Research 28:1144-1155)
  • the present invention relates to sterols and hydrogenated sterols in a form that is easily absorbed through the digestive tract.
  • the invention also generally features a method of treating cholesterolemia.
  • the composition and method for treating cholesterolemia comprises of at least one phytosterol selected from a group consisting of ⁇ -sitosterol , stigmasterol and campasterol and saturated phytosterols corresponding thereto, said sterol being dissolved or dispersed in a solubilizing macromolecule .
  • Dispersion is particularly important because, surprisingly, the dispersed material is absorbed through the intestine at a substantial concentration, enhancing anti-cholesterolemic effect without the need to use substantial amounts of fatty substances as carriers.
  • Particular useful solubilizing macromolecules include phospholipids and starch, modified starch, alphalized starch, dextrin, sodium starch phosphate, glucose, lactose, monosaccharides , disaccharides, polysaccharides hydroxypropyl cellulose, methyl cellulose, and lecithin.
  • Saturated (e.g., hydrogenated sterols) or unsaturated sterols may be used.
  • Particularly useful sterols include the ⁇ -sitosterol , campasterol, and stigmasterol or the hydrogenated form thereof.
  • the therapeutic may be prepared from a solid residue remaining after removal of water or other solvents from a solution or suspension of said sterol and the carrier or diluent .
  • Dispersions of the sterols can also be obtained by milling them with solid carriers.
  • the sterol has a particle size of 1 - 100 micron.
  • These formulations are particularly useful as oral pharmaceutical compositions comprising an effective amount of the sterol and a pharmaceutically acceptable carrier or diluent.
  • Phytosterols 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 phytosterols by enhancing absorption in the intestine.
  • the invention also avoids discomfort and other problems associated with oral administration of phyosterols -- e.g,, pure phytosterols pressed into one- gram tablets can create stomach disorders. We concluded that these tablets cannot be readily digested and absorbed and therefore create a discomfort. Unmixed sitosterol powder may appear in stool samples from patients undergoing cholesterol turnover studies where sitosterol was given as a stool marker. - 5 -
  • sitostanol for example is delivered in a more soluble form without using oil or margarine as a vehicle avoiding the substantial disadvantage of administering oil to a patient in need of cholesterol reduction -- giving 3 g/day of sitostanol oleate in oil requires about 30 g oil with 270 calories.
  • Suitable sources of sterols include soybeans, wood, and apples.
  • the sterols may be obtained from these sources by known techniques, e.g., by extraction and recrystallization
  • Liposomes containing the sterols and hydrogenated sterols may be prepared by techniques generally described below.
  • Typical dosages according to the invention are from 10-500 mg/75kg patient.
  • This dosage may be formulated in a powder and dispersed in a polymer such as starch as described below. The dispersion is inserted into a standard soft gel capsule or hard capsule.
  • Phytosterols from soybeans containing sitosterol campesterol and stigmasterol (30 gram) was dissolved in 400 ml of ethylacetate and poured into a 600 ml stainless steel pressure vessel . Two grams 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 from hot ethanol two times. A sample dissolved in CDC1 3 analyzed by NMR showed the absence of double bonds .
  • the sterol is dissolved or dispersed by heating in water.
  • Water soluble or dispersible polymer or polymers are added like starch or modified starch includes natural starch obtained from corn, potato or arrowroot, alphalized starch, dextrin.
  • Water soluble starch or cellulose derivatives such as esterified starch (sodium starch phosphate) , hydroxypropyl cellulose, methyl cellulose, and the like can also be used.
  • Non-radioactive cholesterol tracer molecules may be labeled with deuterium and detected by mass spectrometry to measure cholesterol absorption directly, (Lutjohann, D., C. 0. Meese,J. R. Crouse,III, and K. von Bergmann. 1993. Evaluation of deuterated cholesterol and deuterated sitostanol (provided by Medical Isotopes, Inc.) for measurement of cholesterol absorption in humans. Journal of Lipid Research 34:1039-1046) and that technique can be used to measure the effect of the invention on absorption.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Steroid Compounds (AREA)

Abstract

L'invention concerne un procédé de préparation de stérols sous une forme facilement absorbable par le tube digestif, et des procédés de traitement de la cholestérolémie par administration d'une composition comprenant au moins un stérol choisi dans un groupe constitué de β-sitostérol, de stigmastérol et de campastérol, et des stérols saturés correspondants.
PCT/US1999/002578 1998-02-06 1999-02-05 Phytosterols facilement absorbables permettant de traiter l'hypercholesterolemie WO1999039715A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU26600/99A AU2660099A (en) 1998-02-06 1999-02-05 Readily absorbable phytosterols to treat hypercholesterrolemia

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US7398498P 1998-02-06 1998-02-06
US60/073,984 1998-02-06

Publications (1)

Publication Number Publication Date
WO1999039715A1 true WO1999039715A1 (fr) 1999-08-12

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AU (1) AU2660099A (fr)
WO (1) WO1999039715A1 (fr)

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000047213A1 (fr) * 1999-02-15 2000-08-17 Washington University Formulation de sitostanol contenant un emulsifiant utile pour reduire l'absorption du cholesterol, procede de preparation et d'utilisation de cette derniere
US6147236A (en) * 1998-08-25 2000-11-14 Mcneil-Ppc, Inc. Preparation of sterol and stanol-esters
US6184397B1 (en) 1998-08-25 2001-02-06 Mcneil-Ppc, Inc. Preparation of sterol and stanol-esters
US6410758B2 (en) 1999-05-24 2002-06-25 Mcneil-Ppc, Inc. Preparation of sterol and stanol-esters
WO2003000075A1 (fr) * 2001-06-22 2003-01-03 Archer - Daniels - Midland - Company Procede de fabrication de poudre a ecoulement libre renfermant des sterols dispersibles dans l'eau
US6623780B1 (en) 2002-03-26 2003-09-23 Cargill, Inc. Aqueous dispersible sterol product
US6677327B1 (en) 1999-11-24 2004-01-13 Archer-Daniels-Midland Company Phytosterol and phytostanol compositions
WO2005072761A1 (fr) * 2004-01-23 2005-08-11 Cargill Incorporated Compositions et methodes de diminution du cholesterol comprenant du guggul et du beta-glucan et/ou des sterols vegetaux
EP1695634A1 (fr) * 2005-02-24 2006-08-30 Cognis IP Management GmbH Dispersion solide de sterol contenant du sucre
US7182950B2 (en) 2002-06-12 2007-02-27 Nutralease Ltd. Nano-sized self-assembled liquid dilutable vehicles
US7306819B2 (en) 2002-06-12 2007-12-11 The Coca-Cola Company Beverages containing plant sterols
US7335389B2 (en) 2002-06-12 2008-02-26 The Coca-Cola Company Beverages containing plant sterols
EP1891118A1 (fr) * 2005-02-01 2008-02-27 Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. Phosphates d'amidon et procede pour les preparer
US7732000B2 (en) * 2002-06-20 2010-06-08 General Mills, Inc. Food intermediate having sequestered phytosteryl esters in a polysaccharide matrix
US7811781B2 (en) 2005-07-06 2010-10-12 Btg International Limited Core 2 β(1,6)-acetylglycosaminyltransferase as diagnostic marker for atherosclerosis
US7906493B2 (en) 2003-12-22 2011-03-15 Btg International Limited Core 2 GlcNAc-T inhibitors
US7998943B2 (en) 2005-07-06 2011-08-16 Btg International Limited Core 2 GlcNAc-T inhibitors III
US8197794B2 (en) 2003-12-22 2012-06-12 Ms Therapeutics Limited Core 2 GlcNAc-T inhibitors
US8609633B2 (en) 2005-07-06 2013-12-17 Ms Therapeutics Limited Core 2 GlcNAc-T inhibitors
CN116076640A (zh) * 2021-11-08 2023-05-09 莒南和信食品有限公司 β-谷甾醇在饮料中的应用及工艺

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE BIOSIS ON STN, No. BA71:5097, 1981:135105, TABATA T. et al., "Hypo Cholesterolemic Activity of Phyto Sterol 2.", XP002920688; & YAKUGAKU ZASSHI, 1980, Vol. 100, No. 5, pages 546-542. *

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6147236A (en) * 1998-08-25 2000-11-14 Mcneil-Ppc, Inc. Preparation of sterol and stanol-esters
US6184397B1 (en) 1998-08-25 2001-02-06 Mcneil-Ppc, Inc. Preparation of sterol and stanol-esters
WO2000047213A1 (fr) * 1999-02-15 2000-08-17 Washington University Formulation de sitostanol contenant un emulsifiant utile pour reduire l'absorption du cholesterol, procede de preparation et d'utilisation de cette derniere
US6410758B2 (en) 1999-05-24 2002-06-25 Mcneil-Ppc, Inc. Preparation of sterol and stanol-esters
US6635774B2 (en) 1999-05-24 2003-10-21 Mcneil-Ppc, Inc. Preparation of sterol and stanol-esters
US6677327B1 (en) 1999-11-24 2004-01-13 Archer-Daniels-Midland Company Phytosterol and phytostanol compositions
WO2003000075A1 (fr) * 2001-06-22 2003-01-03 Archer - Daniels - Midland - Company Procede de fabrication de poudre a ecoulement libre renfermant des sterols dispersibles dans l'eau
US6623780B1 (en) 2002-03-26 2003-09-23 Cargill, Inc. Aqueous dispersible sterol product
US7182950B2 (en) 2002-06-12 2007-02-27 Nutralease Ltd. Nano-sized self-assembled liquid dilutable vehicles
US7306819B2 (en) 2002-06-12 2007-12-11 The Coca-Cola Company Beverages containing plant sterols
US7335389B2 (en) 2002-06-12 2008-02-26 The Coca-Cola Company Beverages containing plant sterols
US8168248B2 (en) 2002-06-20 2012-05-01 General Mills, Inc. Food intermediate having sequestered phytosteryl esters in a polysaccharide matrix
US7732000B2 (en) * 2002-06-20 2010-06-08 General Mills, Inc. Food intermediate having sequestered phytosteryl esters in a polysaccharide matrix
US8197794B2 (en) 2003-12-22 2012-06-12 Ms Therapeutics Limited Core 2 GlcNAc-T inhibitors
US7906493B2 (en) 2003-12-22 2011-03-15 Btg International Limited Core 2 GlcNAc-T inhibitors
WO2005072761A1 (fr) * 2004-01-23 2005-08-11 Cargill Incorporated Compositions et methodes de diminution du cholesterol comprenant du guggul et du beta-glucan et/ou des sterols vegetaux
EP1891118A1 (fr) * 2005-02-01 2008-02-27 Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. Phosphates d'amidon et procede pour les preparer
US8029845B2 (en) 2005-02-24 2011-10-04 Cognis Ip Management Gmbh Compositions of sugar-containing sterol solids dispersions
EP1695634A1 (fr) * 2005-02-24 2006-08-30 Cognis IP Management GmbH Dispersion solide de sterol contenant du sucre
US7998943B2 (en) 2005-07-06 2011-08-16 Btg International Limited Core 2 GlcNAc-T inhibitors III
US7811781B2 (en) 2005-07-06 2010-10-12 Btg International Limited Core 2 β(1,6)-acetylglycosaminyltransferase as diagnostic marker for atherosclerosis
US8609633B2 (en) 2005-07-06 2013-12-17 Ms Therapeutics Limited Core 2 GlcNAc-T inhibitors
CN116076640A (zh) * 2021-11-08 2023-05-09 莒南和信食品有限公司 β-谷甾醇在饮料中的应用及工艺

Also Published As

Publication number Publication date
AU2660099A (en) 1999-08-23

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