WO2000052029A1 - Derive de sterol hydrosoluble inhibant l'absorption de cholesterol et procede d'elaboration - Google Patents

Derive de sterol hydrosoluble inhibant l'absorption de cholesterol et procede d'elaboration Download PDF

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Publication number
WO2000052029A1
WO2000052029A1 PCT/KR2000/000170 KR0000170W WO0052029A1 WO 2000052029 A1 WO2000052029 A1 WO 2000052029A1 KR 0000170 W KR0000170 W KR 0000170W WO 0052029 A1 WO0052029 A1 WO 0052029A1
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WO
WIPO (PCT)
Prior art keywords
phytosterol
compound
polyethylene glycol
group
water
Prior art date
Application number
PCT/KR2000/000170
Other languages
English (en)
Inventor
Seung-Kwon Noh
Dae-Won Chung
Original Assignee
Eugene Science 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
Priority claimed from KR1019990007121A external-priority patent/KR100292672B1/ko
Priority claimed from KR1019990007975A external-priority patent/KR100292673B1/ko
Application filed by Eugene Science Inc. filed Critical Eugene Science Inc.
Priority to AU29466/00A priority Critical patent/AU2946600A/en
Publication of WO2000052029A1 publication Critical patent/WO2000052029A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/331—Polymers modified by chemical after-treatment with organic compounds containing oxygen
    • C08G65/332—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof
    • C08G65/3322—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof acyclic
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/331—Polymers modified by chemical after-treatment with organic compounds containing oxygen
    • C08G65/332—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof
    • C08G65/3324—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof cyclic

Definitions

  • the present invention relates to water-soluble sterol derivatives for inhibiting cholesterol absorption and process for preparing the same.
  • phytosterols which originate from plants, are believed to lower serum cholesterol levels, particularly LDL-cholesterol levels, by inhibiting absorption of cholesterol in the intestine through competition with cholesterol. It is believed that phytosterols do not significantly affect the biosynthesis of cholesterol or have significant side effects.
  • Phytosterols are steroid alcohols found in higher plant and include stigmasterol, spinasterol, campesterol and sitosterol, which has , ⁇ and ⁇ -types.
  • ⁇ - sitosterol 24-ethyl-5 ⁇ -cholestene-3 ⁇ -ol
  • ⁇ -sitosterol ester compounds generated from a substitution of fatty acid have also been reported as having a cholesterol lowering effect similar to that of ⁇ - sitosterol (see: Mattson, F. H. et al . , J. Nutr . , 107:1139- 1146, 1977) .
  • ⁇ -sitosteryl oleate when 2 grams of ⁇ -sitosteryl oleate were dosed to adult humans for 5 days, cholesterol absorption was reduced by about 33% (see : Mattson, F. H. et al., Am . J. Clin . Nutr . , 35:697-700, 1982).
  • ⁇ -sitosterol is known to be the major component of Zea mays L . which is used for treating gingivitis and alveolitis.
  • phytosterols Despite their cholesterol-lowering effect, phytosterols have not been in wide use, since phytosterols are not soluble in water or in oil, their use as food additives for reducing serum cholesterol limiting levels. That is, due to their hydrophobic and lipophobic properties, phytosterols have been formulated primarily in tablet or capsule form.
  • polyoxyethylene phytostanol ether compounds have been used as an emulsifier for cosmetics ( ⁇ j ⁇ e: U.S. Patent Nos . 5,846,458, 5,593,622 and 5,676,971).
  • phytosterols are coupled to polyethylene glycols (PEGs) by relatively permanent ether bonds.
  • PEGs polyethylene glycols
  • phytosterol moieties may not become released from PEGs when administered in the body.
  • these compounds have been used primarily for cosmetic applications, particularly for skin and hair care products, but still not for food additives.
  • compositions for water-based food additives for reducing cholesterol absorption include an aqueous based micellar mix which is dried to provide a mixture of finely divided plant sterol and lecithin. Because the mixture is in micellar form, its use as food additives is believed to be significantly restricted.
  • U.S. Patent No. 5,880,131 discloses a compound having taxols coupled to polyethylene glycols with a molecular weight ranging from 20,000 to 80,000 for the purpose of making water soluble taxol derivatives. While the resulting compound is soluble in water, it is not suitable for use as cholesterol-reducing food additives. Therefore, there are strong reasons for exploring and developing water-soluble sterol derivatives for wide and convenient use as cholesterol-reducing food additives and/or supplements.
  • the present inventors have made an effort to solve the said problems, and prepared novel water-soluble sterol derivatives for inhibiting intestinal cholesterol absorption by reacting phytosterol with succinic anhydride or glutaric anhydride to obtain intermediate compounds, and coupling the intermediate compounds with hydrophilic polymer to prepare the water-soluble sterol derivatives, thereby phytosterol moieties can be released from the hydrophilic polymer in the intestine.
  • a primary object of the present invention is, therefore, to provide water-soluble sterol derivatives for inhibiting intestinal cholesterol absorption.
  • the other object of the invention is to provide a process for preparing the water-soluble sterol derivatives by reacting phytosterol with succinic anhydride or glutaric anhydride, and coupling with hydrophilic polymer.
  • Figure 1 is a reaction scheme for the intermediate compound of the present invention.
  • Figure 2 is 1 H-NMR spectrum of phytosterol derivative prepared by the present invention.
  • the present invention provides water-soluble sterol derivatives for inhibiting intestinal cholesterol absorption.
  • the sterol derivatives have phytosterols coupled to hydrophilic polymers by chemical bonds that can be hydrolyzed by enzymes in the intestine when the phytosterol derivatives are orally administered in animals.
  • the chemical bonds between the phytosterols and the hydrophilic polymers are biodegradable in the intestine by enzymes present therein such that phytosterol moieties can be released from hydrophilic polymer moieties for inhibiting intestinal absorption of cholesterol.
  • ester and/or amide bonds are preferably employed.
  • phytosterol Various types and forms of phytosterol, including phytostanols, may be used for the phytosterol derivatives of the present invention. Accordingly, in describing the water-soluble sterol derivative of the invention, the term “phytosterols” is employed to mean all types, forms and/or mixtures of phytosterols and phytostanols such as stigmasterol, spinasterol, campesterol, sitosterol, sitostanol and campestanol; and, the term “hydrophilic polymers” is employed to mean water-soluble carriers that can bond with the intermediate compounds by chemical bonds capable of being hydrolyzed (i . e .
  • hydrophilic polymers are provided for illustration purposes only and are not meant to limit the scope of the present invention. Accordingly, while any of the foregoing hydrophilic polymers can be used, PEGs having an average molecular weight ranging from 500 to 4,000, preferably from 1,000 to 3,000, and more preferably from 1,000 to 2,000 are suitable for use as hydrophilic polymers.
  • the process for preparing the phytosterol derivatives of the present invention comprises the steps of: obtaining intermediate compounds by reacting phytosterols and succinic or glutaric anhydride in a non-polar solvent in the presence of a basic catalyst; and, coupling the intermediate compounds with hydrophilic polymers in a non- polar organic solvent in the presence of a basic catalyst and a coupling agent.
  • the process for preparing the water-soluble phytosterol derivatives of the present invention is described in more detail by the following steps.
  • Phytosterol and succinic or glutaric anhydride are dissolved in a non-polar solvent in a molar ratio of 1:1.0 to 1:1.5 and more preferably 1:1.3, a basic catalyst is subsequently added, and heated to a temperature preferably ranging from 40 to 150 ° C and more preferably to the boiling temperature of the non-polar organic solvent preferably for 2 to 20 hours and more preferably for 4 to 9 hours.
  • non-polar organic solvent While toluene, methylene chloride, dichloroethane, tetrahydrofuran, benzene and diethylether are preferably employed as the non-polar organic solvent, other non-polar solvents may be used; and, 4-dimethylaminopyridine (DMAP) , pyridine and triethylamine may be used as the basic catalyst. After the starting materials disappear in TLC, the non-polar solvent is evaporated from the reaction mixture to give a solid residue.
  • DMAP 4-dimethylaminopyridine
  • the intermediate compounds (I) obtained in Step 1 and a hydrophilic polymer such as PEG, are dissolved in a non- polar organic solvent in the presence of basic catalyst in a molar ratio ranging from 1:1 to 2:1.
  • a coupling agent are added, stirred at room temperature for about 5 to 15 hours, then filtered to remove byproduct.
  • the non-polar organic solvent and basic catalyst used in Step I may be employed, and 1, 3-dicyclohexylcarbodiimide (DCC) , 1-3-diiso- propylcarbodiimide (DIPC) , 1-ethyl-3- ( 3 ' -dimethylamino- propyl) -carbodiimide, oxalyl chloride, carbonyl diimidazole, 2-chloropyridium, 2 , 2 ' -dipyridyl disulfide and 2-imidazoyl disulfide are preferably used as the coupling agent.
  • DCC 3-dicyclohexylcarbodiimide
  • DIPC 1-3-diiso- propylcarbodiimide
  • 1-ethyl-3- ( 3 ' -dimethylamino- propyl) -carbodiimide 1-ethyl-3- ( 3 ' -dimethylamino- propyl) -car
  • n is an integer ranging from 22 to 90; and, R is selected from the group consisting of -H,
  • the cholesterol lowering effect of the phytosterol derivatives of the present invention was investigated by employing experimental animals.
  • a study undertaken to investigate the solubility of the phytosterol derivatives also demonstrated that the phytosterol derivatives are soluble in water. Accordingly, the phytosterol derivatives of the present invention may be incorporated directly in water- based foodstuffs (e . g. , beverages) in any conventional manner .
  • the intermediate compound were prepared in an analogous manner as in Example 1-1 except for using ⁇ - sitosterol and succinic anhydride in a molar ratio of
  • the structure of the ⁇ -sitosterol derivatives was confirmed by X H-NMR in CDC1 3 , whose spectrum is disclosed in Figure 2.
  • the X H-NMR spectrum confirmed that ⁇ - sitosterol was coupled to PEG by an ester bond.
  • the degree of substitution (DS) of the ⁇ -sitosterol derivatives which is defined as the average molar number of sterol moieties per one molecule of phytosterol derivatives, was determined to be about 1.09, based on the X H-NMR spectrum and the following equation:
  • n is the degree of polymerization of PEG; and, a, b and c are the integrations of the peaks assigned in Figure 2.
  • the molecular weight of PEG does not have a significant effect on the degree of substitution of the phytosterol derivatives of the present invention.
  • the solubility of the phytosterol derivatives of the present invention was measured by dissolving various samples in water and leaving to stand the mixture for 2 days at different temperatures, whose results are shown in Table 2 below.
  • the phytosterol derivatives prepared with PEG having a molecular weight 1,000, 1,500, 2,000 and 4 , 000 are soluble in water. While the phytosterol derivatives of 4,000 PEG is more soluble in water than the phytosterol derivatives of 1,000, 1,500 and 2,000 PEG on the basis of weight concentration of phytosterol derivatives, the phytosterol derivatives of 1,000, 1,500 and 2,000 PEG are more soluble in water than the phytosterol derivatives of 4,000 PEG on the basis of sterol moiety.
  • Example 3-3 :
  • the solubility of Samples 4 of Table 3 above in water was measured under the temperatures indicated in Table 4 below.
  • the solubility in water at 4°C was measured to be higher than 1.0 wt% based on the amount of sterol moieties (i . e . , higher than lOmg of sterol moieties per 1 ml of water) . It was also demonstrated that temperature does not have a significant effect on the solubility of the phytosterol derivatives .
  • the amount of sterol moieties generally recommended for reducing serum cholesterol levels is about 2.7 grams per day (see : Weststrate et al . , Eur . J. Clin . Nutr . , 52:334-343, 1998; Johns et al . , Can . J. Physiol Pharmacol , 75:217-227 , 1997; Vanhanen et al . , Clin . Chim . Acta , 205:97-107, 1992; Gylling et al., J. Lip . Res .
  • Phytosterol derivatives ( III ) were prepared by using monomethyl ether-PEG (MME-PEG) , one end of which is blocked by a methyl ether group: 5g of MME-PEG having a molecular weight of 2000, 0.68g of DCC and 0.07g of DMAP were dissolved in a small amount of methylene chloride at room temperature. 1.54g(1.2 times to the moles of MME-PEG) of the intermediate compound (I) obtained in Example 1-2 was pre-dissolved in methylene chloride and was then added in a dropwise at 30°C to the MME-PEG/DCC/DMAP mixture.
  • MME-PEG monomethyl ether-PEG
  • n is an integer ranging from 22 to 90.
  • ⁇ -NMR spectrum of the phytosterol derivatives (III) demonstrated that all hydroxyl groups of MME-PEG were reacted with the intermediate compounds (I) and coupled with phytosterols.
  • the degree of substitution of the phytosterol derivatives ( III ) is one, while the solubility was measured to be substantially identical to that of Sample 2, Table 4.
  • each of the rats in Groups 3 and 4 was also administered with the amount of phytosterol derivatives equal to three and five, respectively, times the total amount of the administered cholesterol (s_e_e_: Table 5 below), while each of the rats in Groups 5 and 6 was administered with the amount of the phytosterol derivatives equivalent, in terms of sterol moiety, to three and five, respectively, times the total amount of the administered cholesterol (,se_e: Table 5) .
  • the rats were not given any rations or water for the three hour period immediately following the cholesterol/ ⁇ -sitosterol/phytosterol derivative administration. Subsequently, the rats were given free access to rations and water until 9 AM the next morning.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)

Abstract

L'invention concerne des dérivés de stérol hydrosolubles inhibant l'absorption de cholestérol, et un procédé d'élaboration correspondant. Le procédé relatif à l'élaboration des dérivés de phytostérol décrit dans l'invention comprend les étapes suivantes: élaboration de composés intermédiaires par réaction entre des phytostérols et de l'anhydride succinique ou glutarique dans un solvant non polaire, en présence d'un catalyseur basique, et couplage desdits composés avec des polymères hydrophiles dans un solvant organique non polaire, en présence d'un catalyseur basique et d'un agent de couplage. Les dérivés de phytostérol considérés peuvent être incorporés directement à des produits alimentaires à base d'eau (par exemple, boissons) selon toutes les techniques classiques.
PCT/KR2000/000170 1999-03-04 2000-03-03 Derive de sterol hydrosoluble inhibant l'absorption de cholesterol et procede d'elaboration WO2000052029A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU29466/00A AU2946600A (en) 1999-03-04 2000-03-03 Water-soluble sterol derivative for inhibiting cholesterol absorption and process for preparing the same

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
KR1019990007121A KR100292672B1 (ko) 1999-03-04 1999-03-04 콜레스테롤 저하효과를 갖는 수용성 피토스테롤 유도체의 제조방법 및 그로부터 제조되는 화합물
KR1999/0007121 1999-03-04
KR1999/0007975 1999-03-10
KR1019990007975A KR100292673B1 (ko) 1999-03-10 1999-03-10 콜레스테롤 저하효과를 갖는 수용성 피토스테롤 유도체의 제조를 위한 중간체 화합물
US43284299A 1999-11-01 1999-11-01
US09/432,842 1999-11-01

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Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20020081834A (ko) * 2001-04-20 2002-10-30 주식회사 유엘바이오텍 식물성 스테롤의 유도체를 이용한 혈중 콜레스테롤저하제의 제조방법 및 이에 의해 제조된 혈중 콜레스테롤저하제
US6677327B1 (en) 1999-11-24 2004-01-13 Archer-Daniels-Midland Company Phytosterol and phytostanol compositions
EP1382662A1 (fr) * 2001-04-27 2004-01-21 Ajinomoto Co., Inc. Compositions de sterols, compositions de matieres grasses et aliments contenant lesdites compositions de sterols
KR100440613B1 (ko) * 2001-04-20 2004-08-16 주식회사 유엘바이오텍 식물성스테롤과 생 플라보노이드의 결합체를 이용한 혈중콜레스테롤 저하제의 제조방법과 이에 의해 제조한 혈중콜레스테롤 저하제
WO2004083229A1 (fr) * 2003-03-19 2004-09-30 Cognis Ip Management Gmbh Sterol-esters ou stanol-esters d'acides ethercarboxyliques
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
WO2008032980A1 (fr) * 2006-09-12 2008-03-20 Cns Pharm Korea Co., Ltd. Nouveau dérivé de stigmastérol ou sel pharmaceutiquement acceptable correspondant, procédé de production, et composition contenant ce produit pour lutter contre l'obésité ou prévenir et traiter l'hyperlipidémie
US7368138B2 (en) 2002-03-21 2008-05-06 Archer-Daniels-Midland Company Extraction of phytosterols from corn fiber using green solvents
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
EP1985308A3 (fr) * 1999-04-02 2011-11-16 National Research Council of Canada Composition soluble dans l'eau de bioactifs lipophiles
US8197794B2 (en) 2003-12-22 2012-06-12 Ms Therapeutics Limited Core 2 GlcNAc-T inhibitors
JP2013522298A (ja) * 2010-03-12 2013-06-13 ケーアイピー バイオテック リミテッド ライアビリティ カンパニー コレステロールを低減するための水溶性フィトステロール誘導体およびその調製法
US8609633B2 (en) 2005-07-06 2013-12-17 Ms Therapeutics Limited Core 2 GlcNAc-T inhibitors
EP2755660A4 (fr) * 2011-09-16 2015-03-18 Davidson Lopez Llc Stéroïdes végétaux et leurs utilisations
TWI741660B (zh) 2020-06-29 2021-10-01 萬能學校財團法人萬能科技大學 谷甾醇型界面活性劑之製備及其應用
EP3852765A4 (fr) * 2018-09-19 2022-06-22 ModernaTX, Inc. Purification de stérol

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Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1985308A3 (fr) * 1999-04-02 2011-11-16 National Research Council of Canada Composition soluble dans l'eau de bioactifs lipophiles
US6677327B1 (en) 1999-11-24 2004-01-13 Archer-Daniels-Midland Company Phytosterol and phytostanol compositions
KR100440613B1 (ko) * 2001-04-20 2004-08-16 주식회사 유엘바이오텍 식물성스테롤과 생 플라보노이드의 결합체를 이용한 혈중콜레스테롤 저하제의 제조방법과 이에 의해 제조한 혈중콜레스테롤 저하제
KR20020081834A (ko) * 2001-04-20 2002-10-30 주식회사 유엘바이오텍 식물성 스테롤의 유도체를 이용한 혈중 콜레스테롤저하제의 제조방법 및 이에 의해 제조된 혈중 콜레스테롤저하제
EP1382662A4 (fr) * 2001-04-27 2009-12-23 Ajinomoto Kk Compositions de sterols, compositions de matieres grasses et aliments contenant lesdites compositions de sterols
EP1382662A1 (fr) * 2001-04-27 2004-01-21 Ajinomoto Co., Inc. Compositions de sterols, compositions de matieres grasses et aliments contenant lesdites compositions de sterols
US8114447B2 (en) 2002-03-21 2012-02-14 Archer Daniels Midland Company Extraction of phytosterols from corn fiber using green solvents
US7368138B2 (en) 2002-03-21 2008-05-06 Archer-Daniels-Midland Company Extraction of phytosterols from corn fiber using green solvents
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
WO2004083229A1 (fr) * 2003-03-19 2004-09-30 Cognis Ip Management Gmbh Sterol-esters ou stanol-esters d'acides ethercarboxyliques
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
US7811781B2 (en) 2005-07-06 2010-10-12 Btg International Limited Core 2 β(1,6)-acetylglycosaminyltransferase as diagnostic marker for atherosclerosis
US7998943B2 (en) 2005-07-06 2011-08-16 Btg International Limited Core 2 GlcNAc-T inhibitors III
US8609633B2 (en) 2005-07-06 2013-12-17 Ms Therapeutics Limited Core 2 GlcNAc-T inhibitors
WO2008032980A1 (fr) * 2006-09-12 2008-03-20 Cns Pharm Korea Co., Ltd. Nouveau dérivé de stigmastérol ou sel pharmaceutiquement acceptable correspondant, procédé de production, et composition contenant ce produit pour lutter contre l'obésité ou prévenir et traiter l'hyperlipidémie
KR100886466B1 (ko) * 2006-09-12 2009-03-04 (주)한국씨엔에스팜 신규한 스티그마스테롤 유도체 또는 이의 약학적으로허용가능한 염, 이의 제조방법, 및 이를 포함하는 비만억제 또는 고지혈증 예방 및 치료용 조성물
JP2013522298A (ja) * 2010-03-12 2013-06-13 ケーアイピー バイオテック リミテッド ライアビリティ カンパニー コレステロールを低減するための水溶性フィトステロール誘導体およびその調製法
EP2755660A4 (fr) * 2011-09-16 2015-03-18 Davidson Lopez Llc Stéroïdes végétaux et leurs utilisations
US10086082B2 (en) 2011-09-16 2018-10-02 Davidson Lopez Llc Plant steroids and uses thereof
EP3852765A4 (fr) * 2018-09-19 2022-06-22 ModernaTX, Inc. Purification de stérol
TWI741660B (zh) 2020-06-29 2021-10-01 萬能學校財團法人萬能科技大學 谷甾醇型界面活性劑之製備及其應用

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