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WO1996019215A1 - Compositions de tocopherol et de beta-carotene - Google Patents

Compositions de tocopherol et de beta-carotene Download PDF

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Publication number
WO1996019215A1
WO1996019215A1 PCT/US1995/016769 US9516769W WO9619215A1 WO 1996019215 A1 WO1996019215 A1 WO 1996019215A1 US 9516769 W US9516769 W US 9516769W WO 9619215 A1 WO9619215 A1 WO 9619215A1
Authority
WO
WIPO (PCT)
Prior art keywords
carotene
natural
beta
tocopherol
vitamin
Prior art date
Application number
PCT/US1995/016769
Other languages
English (en)
Inventor
James P. Clark
Manfred S. Dunker
Original Assignee
Henkel Corporation
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 Henkel Corporation filed Critical Henkel Corporation
Priority to JP8520012A priority Critical patent/JPH10511355A/ja
Priority to AU47419/96A priority patent/AU702831B2/en
Priority to EP95944647A priority patent/EP0793490A4/fr
Publication of WO1996019215A1 publication Critical patent/WO1996019215A1/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
    • A61K31/01—Hydrocarbons
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to pharmaceutical compositions which exhibit a protective effect against the development of atherosclerosis.
  • These compositions comprise the combination of natural tocopherol and natural beta-carotene in a pharmaceutically acceptable carrier.
  • the present invention also includes within its scope methods of preventing the development of atherosclerosis and the resulting cardiovascular disease, e.g., coronary artery disease by administering an effective amount of the composition of the present invention to prevent atherosclerosis.
  • cardiovascular disease It is generally recognized that many factors contribute to the development of cardiovascular disease. These factors include, for example, smoking, obesity, hypertension, hyperlipidemia and hypercholesterolemia. Hyperlipidemia and hypercholesterolemia contribute to the accumulation of fatty substances on the arterial wall (atherosclerosis) resulting in narrowing of coronary blood vessels and the development of ischemic heart disease.
  • LDL low-density lipoprotein
  • Beta-carotene has also been suggested as useful in reducing vascular events in patients with chronic stable angina. See, Gaziano et al., "Beta Carotene Therapy for Chronic Stable Angina", Circulation. 82:111, Abstract No. 0796 (1990).
  • Tocopherols which occur in nature as alpha-tocopherol, beta-tocopherol, gamma-tocopherol and delta- tocopherol possess vitamin E activity. Chemically, they may be considered as having a "tocol" nucleus of the formula I:
  • R is(CH 2 ) 3 - CH(CH 2 ) 3 CH(CH 2 ) 3 CH(CH 3 ) 2
  • esters Both the free tocopherols and their esters are insoluble in water and soluble in fats and oil. Hence, they are also known as "fat-soluble vitamins. "
  • vitamin E While the precise role of vitamin E in human nutrition has not been clearly established, it has been suggested, that its deficiency may cause a variety of manifestations such as sterility, myocardial degeneration and necrosis of the liver.
  • the daily requirement is suggested to be about 30mg per day for a 70 kg adult human.
  • Carotenoids also occur in nature, mainly in plants. They are largely responsible for the yellow to red colors of many plants, particularly edible vegetables, such as carrots and squash. Chemically they are unsaturated, polyisoprene hydrocarbons. Over 500 carotenoids are known, e.g. , alpha, beta, and gamma carotene. The most widely used is beta-carotene because it is a precursor of vitamin A. The structural formula is described below (see VI). The daily requirement of vitamin A as suggested by National Research Council for maintenance of good health is 1,000 Retinol equivalents (RE) for males and 800 RE for females. (1,000 RE is equivalent to 5,000 International Unit.) The relation between carotene and vitamin A is 6 to 3.44 by weight of the respective pure compounds.
  • RE Retinol equivalents
  • compositions of polyol fatty acid polyesters such as sucrose octaoleate with vitamins, e.g., vitamin E.
  • U.S. Patent 4,005,196 discloses similar types of formulations, i.e., sucrose octacleate, with vitamins.
  • U.S. Patent 5,278,189 describes compositions of ascorbate with liprotein binders which include tocopherol and beta-carotene having the following structural formula:
  • Beta-carotene is a precursor of vitamin A. Thus, it is metabolized in the body to form vitamin A by cleavage of the double bond at the 15,15' position of compound VI.
  • vitamin A in human nutrition is known.
  • vitamin A deficiency leads to night blindness. It also plays an essential role in the growth and the formation of epithelial tissues.
  • beta-carotene acts as antioxidant in the formulation.
  • a primary object of the present invention is to provide compositions which exert a protective action against atherosclerosis and hence the prevention of the development of cardiovascular disease.
  • compositions comprise the combination of an effective antioxidant amount of natural tocopherol and a blend of natural carotene in a pharmaceutically acceptable carrier suitable for oral or parenteral administration.
  • compositions in which the protective effect of natural vitamin E has been enhanced by natural carotene blocks the oxidation of low-density lipoproteins in serum of mammals, including humans.
  • tocopherols which primarily comprise a mixture of compounds II, III and IV in the compositions are present in an effective antioxidant amount. Typically these compounds are present from about 50 to 1000
  • Natural tocotrienols and natural tocopherols are derived from vegetable oils.
  • Soy oil is the most widely used source. Sunflower, corn, peanut, rapeseed and cottonseed oils may also be used. Natural tocotrienol and natural tocopherols are very different from that produced by chemical synthesis, i.e., synthetic "vitamin E.”
  • vitamin E refers to both tocotrienols and tocopherols.
  • Synthetic vitamin E is a mixture of eight different stereoisomers, only one of which is molecularly equivalent to natural vitamin E. The other seven stereoisomers have a lower biological activity. The mammalian body prefers the natural stereoisomer.
  • Natural vitamin E is recognized as having 36 percent greater potency than synthetic vitamin E. Recent studies suggest that natural vitamin E is probably twice as effective as synthetic vitamin E.
  • Natural vitamin E also remains in the body much longer than synthetic vitamin E.
  • the seven synthetic stereoisomers are secreted into the bile and then into the intestine for removal from the body.
  • the natural vitamin E stereoisomer on the other hand, is returned to the bloodstream in the form of low density lipoproteins.
  • the natural carotene blend which will be described below is particularly preferred and is typically present from 5 to 50 mg per dosage unit.
  • the preferred naturally occurring carotene blend particularly suitable for the present invention has the following approximate composition:
  • Beta-carotene 85-90$ (approximately a 1: 1 mixture of cis- isomers and trans-isomers)
  • beta-carotene blends such as those isolated from palm oil, containing typically about 65 % all trans beta-carotene and 35 % alpha-carotene may be used in the present invention as well.
  • Lutein and zeaxanthin are naturally occurring substances from vegetable sources. Natural lycopene is found, for instance, in tomatoes. The natural enhance the biological effects of natural beta-carotene. For a fuller description of each of the foregoing compounds, please see Dictionary of Organic Compounds. Vol. 5.
  • Beta-carotene provitamin A
  • beta-carotene is readily metabolized by the body into vitamin A when required.
  • beta-carotene itself, independent of vitamin A activity.
  • the primary source of the beta-carotene is an algae named Dunaliella salina.
  • the algal cell functions just like an ordinary plant cell. It is photosynthetic, converting carbon dioxide from the atmosphere into cell material and to provide energy. This is done by the green chlorophyll in the cell which is normally not visible as it is masked by the intense orange color of the beta-carotene.
  • Natural beta-carotene from the algae comprises an approximately equal mixture of cis and trans isomers with the cis form of beta carotene being more soluble in oil than synthetic trans beta carotene.
  • Synthetic beta-carotene is derived from synthetic organic chemicals and is a crystalline form of beta-carotene, primarily the trans isomer (a molecular configuration). The synthetic form is not the focus of the present invention which is directed to natural source products because of the advantages associated with their use.
  • the synthetic crystals of beta-carotene are difficult to dissolve in organic chemical solvents, implying that the human body would have similar, or greater, difficulties in assimilating the compound.
  • the natural carotenoids are mixture of compounds. Those include beta- carotene, alpha-carotene, lutein, cryptoxanthin, zeaxanthin and lycopene.
  • the natural carotinoids are a mixture of cis and trans isomers while the synthetic carotenoids are all trans isomers.
  • Betatene natural mixed carotenoids
  • Betatene Ltd. is a registered trademark of Betatene Ltd. and is particularly useful in the practices of the present invention.
  • Betatene is a deep red suspension of natural mixed carotenoids in vegetable oil.
  • the mixed carotenoids are isolated from the sea algae Dunaliella salina.
  • Betatene, natural beta-carotene is soluble in oil to about 3.7% or about ten times the solubility of synthetic oil suspensions. This indicates a higher degree of bioavailability in the body.
  • Betatene 20% The carotenoid content of Betatene 20% is standardized to contain not less than 200 mg per gram of five naturally occurring carotenoids that are commonly found in various fruits, cruciferous, yellow, and dark green leafy vegetables.
  • the typical carotenoid distribution in Betatene 20% is as follows:
  • Beta-carotene 20% In addition to its role as an antioxidant, the beta-carotene provided by Betatene 20%, is a safe source of vitamin A, being converted to vitamin A within the body only as needed.
  • the oral compositions can be made by conventional compounding procedures known in the pharmaceutical art, that is, by mixing the active substances with edible pharmaceutically acceptable non-toxic inert, solid or liquid carriers and/or excipients suitable for systemic administration and conventionally used in oral dosage forms. Additionally, edible, non-toxic pharmaceutically acceptable stabilizers usually used as stabilizers in oral dosage forms or edible, non-toxic pharmaceutically acceptable salts thereof as well as ascorbic acid can be included in the compositions. All the above carriers, excipients and stabilizers are intended to include only those suitable for oral administration and all are conventional and known to the pharmaceutical compounding art.
  • compositions for oral administration may be in the form of tablets, including sustained release forms, lozenges, chewing gum, and capsules.
  • the soft gelatin capsule dosage form is most preferred. These dosage forms are prepared by those skilled in the art. Thus, for example, about 500 units of tocopherol and 25 mg of the beta-carotene blend as described above are blended with a sufficient amount of arachis oil to make about 450 mg. It is then dispensed into a soft gelatin capsule, the capsule is sealed by steam.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Cosmetics (AREA)

Abstract

L'invention concerne un procédé pour la prévention ou le traitement de l'athérosclérose chez un mammifère, ce procédé consistant à administrer une quantité appropriée de tocophérol naturel et de carotène naturel, pour prévenir ou traiter l'athérosclérose chez un mammifère nécessitant un tel traitement préventif ou curatif. Une composition pharmaceutique pour la prévention ou le traitement de l'athérosclérose, se présentant sous la forme de doses unitaires, contient une quantité appropriée de tocophérol naturel et de carotène naturel pour prévenir ou traiter l'athérosclérose et un excipient acceptable sur le plan pharmaceutique.
PCT/US1995/016769 1994-12-22 1995-12-22 Compositions de tocopherol et de beta-carotene WO1996019215A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP8520012A JPH10511355A (ja) 1994-12-22 1995-12-22 トコフェロールとベータ−カロチンの組成物
AU47419/96A AU702831B2 (en) 1994-12-22 1995-12-22 Compositions of tocopherol and beta-carotene
EP95944647A EP0793490A4 (fr) 1994-12-22 1995-12-22 Compositions de tocopherol et de beta-carotene

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US36161594A 1994-12-22 1994-12-22
US08/361,615 1994-12-22

Publications (1)

Publication Number Publication Date
WO1996019215A1 true WO1996019215A1 (fr) 1996-06-27

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PCT/US1995/016769 WO1996019215A1 (fr) 1994-12-22 1995-12-22 Compositions de tocopherol et de beta-carotene

Country Status (4)

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EP (1) EP0793490A4 (fr)
JP (1) JPH10511355A (fr)
AU (1) AU702831B2 (fr)
WO (1) WO1996019215A1 (fr)

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996040092A1 (fr) * 1995-06-07 1996-12-19 The Howard Foundation Carotenoides pharmaceutiquement actifs
WO1998057622A1 (fr) * 1997-06-19 1998-12-23 Lycored Natural Products Industries Ltd. Compositions synergiques pour lycopene et vitamine e permettant la prevention d'oxydation de lipoproteine de faible densite (ldl)
WO1999018814A1 (fr) * 1997-10-14 1999-04-22 Quest International B.V. Preparation permettant d'accroitre le statut antioxydant de cellules
EP0793491A4 (fr) * 1994-12-22 2000-01-12 Henkel Corp Compositions pharmaceutiques comprenant du lycopene
EP0981969A1 (fr) * 1998-08-26 2000-03-01 Basf Aktiengesellschaft Composition de caroténoides compenant un mélange de beta-caroténe, lycopene et lutéine
US6262109B1 (en) 1995-12-22 2001-07-17 Henkel Corporation Methods of preventing and/or treating high serum levels of cholesterol and/or lipids
US6329432B2 (en) 1993-06-28 2001-12-11 The Howard Foundation Mesozeaxanthin formulations for treatment of retinal disorders
US6350776B1 (en) 1999-09-20 2002-02-26 Angelo Manfredo Azzi Method of treating proliferative disease with lycopene and alpha-tocopherol
EP1140065A4 (fr) * 1998-12-17 2002-10-16 Univ Loma Linda Med Utilisation du gamma-tocopherol et de son metabolite oxydatif llu-alpha dans le traitement de maladies
US6515018B1 (en) 1997-06-19 2003-02-04 Lycored Natural Products Industries Ltd. Synergistic compositions for lycopene and Vitamin E for the prevention of LDL oxidation
WO2005075575A1 (fr) * 2004-02-10 2005-08-18 Nestec S.A. Compositions contenant des isomeres cis d'un compose carotenoide
WO2006097090A1 (fr) * 2005-03-17 2006-09-21 Schrezenmeir Juergen Retinol destine a reduire des facteurs de risque de l'atherosclerose et/ou a augmenter la sensibilite a l'insuline
WO2006112906A1 (fr) * 2005-04-13 2006-10-26 California Polytechnic State University Foundation Incorporation de lycopene dans des jaunes d'oeufs
WO2008017455A1 (fr) * 2006-08-08 2008-02-14 Nestec S.A. Compositions d'isomères de caroténoïdes stables et bio-disponibles pour la peau et les cheveux
EP3401396A1 (fr) * 2012-10-03 2018-11-14 Metabogen AB Traitement ou prevention de l'athérosclérose ou maladies associées par le bêta-carotène

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6582721B1 (en) * 1999-09-17 2003-06-24 Alcon, Inc. Stable carotene-xanthophyll beadlet compositions and methods of use

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2057463C (fr) * 1991-12-11 1998-10-27 David Rowland Composition vitaminique/minerale
FR2714292B1 (fr) * 1993-12-23 1996-02-02 Synthelabo Association d'acétylsalicylate de DL-lysine et de vitamine E.
IT1274734B (it) * 1994-08-25 1997-07-24 Prospa Bv Composizioni farmaceutiche contenenti acidi grassi poliinsaturi, loro esteri o sali, unitamente a vitamine o provitamine antiossidanti
EP0845951B1 (fr) * 1995-08-21 2002-03-27 Unilever N.V. Produits alimentaires contenant un agent antioxydant

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
See also references of EP0793490A4 *
THE LANCET, Vol. 342, issued 1993, KARDINAAL et al., "Antioxidants in Adipose Tissue and Risk of Myocardial Infarction: The Euramic Study", pages 1379-1384. *

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6329432B2 (en) 1993-06-28 2001-12-11 The Howard Foundation Mesozeaxanthin formulations for treatment of retinal disorders
US6362221B1 (en) 1994-12-22 2002-03-26 Cognis Corporation Compositions containing natural lycopene and natural tocopherol
EP0793491A4 (fr) * 1994-12-22 2000-01-12 Henkel Corp Compositions pharmaceutiques comprenant du lycopene
GB2301775B (en) * 1995-06-07 1999-08-04 Howard Foundation Treatment of age-related macular degeneration with carotenoids
WO1996040092A1 (fr) * 1995-06-07 1996-12-19 The Howard Foundation Carotenoides pharmaceutiquement actifs
US6262109B1 (en) 1995-12-22 2001-07-17 Henkel Corporation Methods of preventing and/or treating high serum levels of cholesterol and/or lipids
WO1998057622A1 (fr) * 1997-06-19 1998-12-23 Lycored Natural Products Industries Ltd. Compositions synergiques pour lycopene et vitamine e permettant la prevention d'oxydation de lipoproteine de faible densite (ldl)
US6515018B1 (en) 1997-06-19 2003-02-04 Lycored Natural Products Industries Ltd. Synergistic compositions for lycopene and Vitamin E for the prevention of LDL oxidation
WO1999018814A1 (fr) * 1997-10-14 1999-04-22 Quest International B.V. Preparation permettant d'accroitre le statut antioxydant de cellules
EP0981969A1 (fr) * 1998-08-26 2000-03-01 Basf Aktiengesellschaft Composition de caroténoides compenant un mélange de beta-caroténe, lycopene et lutéine
CN1094326C (zh) * 1998-08-26 2002-11-20 Basf公司 含有β－胡萝卜素、番茄红素和叶黄素的混合物的类胡萝卜素制剂
US6261598B1 (en) 1998-08-26 2001-07-17 Basf Aktiengesellschaft Carotenoid formulations, comprising a mixture of B-carotens, lycopene and lutein
EP1140065A4 (fr) * 1998-12-17 2002-10-16 Univ Loma Linda Med Utilisation du gamma-tocopherol et de son metabolite oxydatif llu-alpha dans le traitement de maladies
US6555575B2 (en) 1998-12-17 2003-04-29 Loma Linda University Medical Center Use of γ-tocopherol and its oxidative metabolite LLU-α in the treatment of disease
US6908943B2 (en) 1998-12-17 2005-06-21 Loma Linda University Medical Center Use of γ-tocopherol and its oxidative metabolite LLU-α in the treatment of disease
US6350776B1 (en) 1999-09-20 2002-02-26 Angelo Manfredo Azzi Method of treating proliferative disease with lycopene and alpha-tocopherol
WO2005075575A1 (fr) * 2004-02-10 2005-08-18 Nestec S.A. Compositions contenant des isomeres cis d'un compose carotenoide
AU2005210014B2 (en) * 2004-02-10 2009-12-03 Nestec S.A. Compositions containing cis-isomers of a carotenoid compound and process
WO2006097090A1 (fr) * 2005-03-17 2006-09-21 Schrezenmeir Juergen Retinol destine a reduire des facteurs de risque de l'atherosclerose et/ou a augmenter la sensibilite a l'insuline
WO2006112906A1 (fr) * 2005-04-13 2006-10-26 California Polytechnic State University Foundation Incorporation de lycopene dans des jaunes d'oeufs
WO2008017455A1 (fr) * 2006-08-08 2008-02-14 Nestec S.A. Compositions d'isomères de caroténoïdes stables et bio-disponibles pour la peau et les cheveux
US9125430B2 (en) 2006-08-08 2015-09-08 Nestec S.A. Stable and bioavailable compositions of isomers of carotenoids for skin and hair
EP3401396A1 (fr) * 2012-10-03 2018-11-14 Metabogen AB Traitement ou prevention de l'athérosclérose ou maladies associées par le bêta-carotène

Also Published As

Publication number Publication date
AU4741996A (en) 1996-07-10
EP0793490A4 (fr) 1999-12-15
EP0793490A1 (fr) 1997-09-10
JPH10511355A (ja) 1998-11-04
AU702831B2 (en) 1999-03-04

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