WO1996019215A1 - Compositions of tocopherol and beta-carotene - Google Patents
Compositions of tocopherol and beta-carotene Download PDFInfo
- 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
Links
- 0 C*CC(C)(CC1)Oc2c1cccc2 Chemical compound C*CC(C)(CC1)Oc2c1cccc2 0.000 description 1
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.
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP95944647A EP0793490A4 (en) | 1994-12-22 | 1995-12-22 | Compositions of tocopherol and beta-carotene |
AU47419/96A AU702831B2 (en) | 1994-12-22 | 1995-12-22 | Compositions of tocopherol and beta-carotene |
JP8520012A JPH10511355A (en) | 1994-12-22 | 1995-12-22 | Composition of tocopherol and 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 (en) | 1996-06-27 |
Family
ID=23422755
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1995/016769 WO1996019215A1 (en) | 1994-12-22 | 1995-12-22 | Compositions of tocopherol and beta-carotene |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP0793490A4 (en) |
JP (1) | JPH10511355A (en) |
AU (1) | AU702831B2 (en) |
WO (1) | WO1996019215A1 (en) |
Cited By (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996040092A1 (en) * | 1995-06-07 | 1996-12-19 | The Howard Foundation | Pharmaceutically active carotenoids |
EP0793491A1 (en) * | 1994-12-22 | 1997-09-10 | Henkel Corporation | Pharmaceutical compositions comprising lycopene |
WO1998057622A1 (en) * | 1997-06-19 | 1998-12-23 | Lycored Natural Products Industries Ltd. | Synergistic compositions for lycopene and vitamin e for the prevention of ldl oxidation |
WO1999018814A1 (en) * | 1997-10-14 | 1999-04-22 | Quest International B.V. | Preparation for the enhancement of the antioxidant status of cells |
EP0981969A1 (en) * | 1998-08-26 | 2000-03-01 | Basf Aktiengesellschaft | Carotinoid compositions comprising a mixture of beta-carotene, lycopene and lutein |
US6262109B1 (en) | 1995-12-22 | 2001-07-17 | Henkel Corporation | Methods of preventing and/or treating high serum levels of cholesterol and/or lipids |
EP1140065A1 (en) * | 1998-12-17 | 2001-10-10 | Loma Linda University Medical Center | Use of gamma-tocopherol and its oxidative metabolite llu-alpha in the treatment of disease |
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 |
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 (en) * | 2004-02-10 | 2005-08-18 | Nestec S.A. | Compositions containing cis-isomers of a carotenoid compound and process |
WO2006097090A1 (en) * | 2005-03-17 | 2006-09-21 | Schrezenmeir Juergen | Retinol for reducing risk factors of arteriosclerosis and/or increasing insulin sensitivity |
WO2006112906A1 (en) * | 2005-04-13 | 2006-10-26 | California Polytechnic State University Foundation | Lycopene incorporation into egg yolks |
WO2008017455A1 (en) * | 2006-08-08 | 2008-02-14 | Nestec S.A. | Stable and bioavailable compositions of isomers of carotenoids for skin and hair |
EP3401396A1 (en) * | 2012-10-03 | 2018-11-14 | Metabogen AB | Treating or preventing atherosclerosis or associated diseases by beta-carotene |
Families Citing this family (1)
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)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2057463C (en) * | 1991-12-11 | 1998-10-27 | David Rowland | Vitamin/mineral composition |
FR2714292B1 (en) * | 1993-12-23 | 1996-02-02 | Synthelabo | Combination of DL-lysine acetylsalicylate and vitamin E. |
IT1274734B (en) * | 1994-08-25 | 1997-07-24 | Prospa Bv | PHARMACEUTICAL COMPOSITIONS CONTAINING POLYUNSATURATED FATTY ACIDS, THEIR ESTERS OR SALTS, WITH VITAMINS OR ANTIOXIDANT PROVITAMINS |
DK0845951T3 (en) * | 1995-08-21 | 2002-05-27 | Unilever Nv | Antioxidant-containing food products |
-
1995
- 1995-12-22 AU AU47419/96A patent/AU702831B2/en not_active Ceased
- 1995-12-22 EP EP95944647A patent/EP0793490A4/en not_active Withdrawn
- 1995-12-22 JP JP8520012A patent/JPH10511355A/en active Pending
- 1995-12-22 WO PCT/US1995/016769 patent/WO1996019215A1/en not_active Application Discontinuation
Non-Patent Citations (2)
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 (25)
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 |
EP0793491A1 (en) * | 1994-12-22 | 1997-09-10 | Henkel Corporation | Pharmaceutical compositions comprising lycopene |
EP0793491A4 (en) * | 1994-12-22 | 2000-01-12 | Henkel Corp | Pharmaceutical compositions comprising lycopene |
US6362221B1 (en) | 1994-12-22 | 2002-03-26 | Cognis Corporation | Compositions containing natural lycopene and natural tocopherol |
GB2301775B (en) * | 1995-06-07 | 1999-08-04 | Howard Foundation | Treatment of age-related macular degeneration with carotenoids |
WO1996040092A1 (en) * | 1995-06-07 | 1996-12-19 | The Howard Foundation | Pharmaceutically active carotenoids |
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 (en) * | 1997-06-19 | 1998-12-23 | Lycored Natural Products Industries Ltd. | Synergistic compositions for lycopene and vitamin e for the prevention of ldl oxidation |
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 (en) * | 1997-10-14 | 1999-04-22 | Quest International B.V. | Preparation for the enhancement of the antioxidant status of cells |
EP0981969A1 (en) * | 1998-08-26 | 2000-03-01 | Basf Aktiengesellschaft | Carotinoid compositions comprising a mixture of beta-carotene, lycopene and lutein |
CN1094326C (en) * | 1998-08-26 | 2002-11-20 | Basf公司 | Carotenoid preparation having mixture of beta-carotene, lycopene and xanthophyll |
US6261598B1 (en) | 1998-08-26 | 2001-07-17 | Basf Aktiengesellschaft | Carotenoid formulations, comprising a mixture of B-carotens, lycopene and lutein |
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 |
EP1140065A4 (en) * | 1998-12-17 | 2002-10-16 | Univ Loma Linda Med | Use of gamma-tocopherol and its oxidative metabolite llu-alpha in the treatment of disease |
EP1140065A1 (en) * | 1998-12-17 | 2001-10-10 | Loma Linda University Medical Center | Use of gamma-tocopherol and its oxidative metabolite llu-alpha in the treatment of disease |
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 |
US6350776B1 (en) | 1999-09-20 | 2002-02-26 | Angelo Manfredo Azzi | Method of treating proliferative disease with lycopene and alpha-tocopherol |
WO2005075575A1 (en) * | 2004-02-10 | 2005-08-18 | Nestec S.A. | Compositions containing cis-isomers of a carotenoid compound and process |
AU2005210014B2 (en) * | 2004-02-10 | 2009-12-03 | Nestec S.A. | Compositions containing cis-isomers of a carotenoid compound and process |
WO2006097090A1 (en) * | 2005-03-17 | 2006-09-21 | Schrezenmeir Juergen | Retinol for reducing risk factors of arteriosclerosis and/or increasing insulin sensitivity |
WO2006112906A1 (en) * | 2005-04-13 | 2006-10-26 | California Polytechnic State University Foundation | Lycopene incorporation into egg yolks |
WO2008017455A1 (en) * | 2006-08-08 | 2008-02-14 | Nestec S.A. | Stable and bioavailable compositions of isomers of carotenoids for skin and hair |
US9125430B2 (en) | 2006-08-08 | 2015-09-08 | Nestec S.A. | Stable and bioavailable compositions of isomers of carotenoids for skin and hair |
EP3401396A1 (en) * | 2012-10-03 | 2018-11-14 | Metabogen AB | Treating or preventing atherosclerosis or associated diseases by beta-carotene |
Also Published As
Publication number | Publication date |
---|---|
AU702831B2 (en) | 1999-03-04 |
EP0793490A1 (en) | 1997-09-10 |
EP0793490A4 (en) | 1999-12-15 |
JPH10511355A (en) | 1998-11-04 |
AU4741996A (en) | 1996-07-10 |
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