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WO2003047528A2 - Supplements contenant des extraits d'annatto et des carotenoides, et procedes d'utilisation associes - Google Patents

Supplements contenant des extraits d'annatto et des carotenoides, et procedes d'utilisation associes Download PDF

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WO2003047528A2
WO2003047528A2 PCT/US2002/038593 US0238593W WO03047528A2 WO 2003047528 A2 WO2003047528 A2 WO 2003047528A2 US 0238593 W US0238593 W US 0238593W WO 03047528 A2 WO03047528 A2 WO 03047528A2
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bixin
compound
group
human
lutein
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WO2003047528A3 (fr
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Pedro E. Levy
Luis W. Levy
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Levy Pedro E
Levy Luis W
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Priority to EP02804498A priority Critical patent/EP1461058A2/fr
Priority to AU2002365602A priority patent/AU2002365602A1/en
Publication of WO2003047528A2 publication Critical patent/WO2003047528A2/fr
Publication of WO2003047528A3 publication Critical patent/WO2003047528A3/fr

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    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/174—Vitamins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/179—Colouring agents, e.g. pigmenting or dyeing agents
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K30/00—Processes specially adapted for preservation of materials in order to produce animal feeding-stuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K50/00—Feeding-stuffs specially adapted for particular animals
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K50/00—Feeding-stuffs specially adapted for particular animals
    • A23K50/40—Feeding-stuffs specially adapted for particular animals for carnivorous animals, e.g. cats or dogs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K50/00—Feeding-stuffs specially adapted for particular animals
    • A23K50/70—Feeding-stuffs specially adapted for particular animals for birds
    • A23K50/75—Feeding-stuffs specially adapted for particular animals for birds for poultry
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/02—Algae
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/75—Rutaceae (Rue family)
    • A61K36/752—Citrus, e.g. lime, orange or lemon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/81—Solanaceae (Potato family), e.g. tobacco, nightshade, tomato, belladonna, capsicum or jimsonweed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/899—Poaceae or Gramineae (Grass family), e.g. bamboo, corn or sugar cane

Definitions

  • Annatto extracts are obtained from the seeds of the tropical tree Bixa orellana.
  • Annatto seed extracts contain bixin compounds, the isoprenoid geranylgeraniol, the vitamin E tocotrienol, and derivatives and isomers thereof.
  • the term "bixin compound” will be understood to refer to bixin per se and/or its derivatives, including salts and isomers thereof, as well as mixtures thereof including those with the other co-extractives from the amiatto seed.
  • the bixin compounds include especially compounds having the basic skeletal structure of norbixin, including its monomethyl ester (bixin), its dimethyl ester (methylbixin), and higher alkyl (e.g., C 2 -C 0 alkyl) esters, as well as optical isomers thereof and pharmaceutically and dietary acceptable salts thereof.
  • Bixin is found in nature only in the annatto seed in the form of the 9'-cis isomer. It is converted (hydro lyzed) rapidly in the mammalian body to norbixin in the form of the all-trans isomer. Bixin may be purified from the annatto seed by organic solvent extraction and is available commercially as a color additive for foods, usually as a 1.6 wt% solution in soybean oil (known as annatto color E161b). Bixin and methylbixin may also be prepared synthetically, as described in the literature.
  • Bixin and its hydrolyzed form, norbixin are used as coloring agents for human consumption, mainly in cheese (see Collins, “The role of annatto in food colouring,” Food Ingredients and Processing International, 23-27 (February 1992)).
  • methylbixin has been commercially prepared by esterification of the carboxylic ester group of the bixin molecule (Zechmelster, et al., "A stereochernical study of methylbixin,” J. Am. Chem. Soc, 66:322330 (1944); Jondiko, et al, "Terpenoids and an apocarotenoid from seeds of B.
  • bixin As a natural color additive to foods, particularly cheeses, bixin is typically added at concentrations of about 1 to 25 mg bixin per kg of food, although higher quantities may be used for some cheeses.
  • Estimates of average daily intake of bixin compounds are of the order of 0.3 to 3 mg per day per person, although some studies report higher values, through the consumption of products such as cheeses, cake decoration, breakfast cereals, ice cream, snacks, margarine, and other foods in which bixin extract is added during food manufacture to provide color.
  • the maximum ADI (acceptable daily intake) established by the Joint FAO/WHO Committee on Food Additives (JECFA, 1982) is 0.065 mg/day/kg body weight, expressed as bixin. For example, for an average human weight of 60 kg, the maximum ADI is 3.9 mg per day.
  • ingestion of bixin compounds through food coloring is highly variable and non-systematic.
  • bixin compounds are not present at all in many diets, particularly the diets of persons eating only natural foods.
  • bixin compounds and annatto seed extracts are not used in non- human animal foods, not even as coloring agents.
  • carotenoids Many important biological functions of carotenoids have been discovered in the past decade (see Krinsky, "Biological properties of carotenoids," Pure Appl. Chem., 66:1003-1010 (1994)).
  • Major research has been concentrated, however, on the more common carotenoids, such as beta-carotene, lutein, lycopene, and zeaxanthin, and only occasionally has bixin received any attention on the part of the biomedical community.
  • bixin is readily absorbed into the blood stream after human ingestion (Levy, et al, "Bixin and norbixin in human plasma: Discrimination and study of absorption of a single dose of annatto food color," Analyst, 122:977-980 (1997)), utilization of the biological importance of bixin for mammalian health has become a possibility.
  • Geranylgeraniol a 20-carbon isoprenoid alcohol formed in plant systems, was isolated from annatto seeds as such and as the formate, octadecanoate, and farnesylacetone forms by Jondiko, et al. and by Craveiro, et al. ("The presence of geranyl-geraniols in B orellana" Quim. Nova 12:297-298 (Chem. Abstr. 112:155274)). Geranylgeraniol bixinates were first reported by Mercadante et al. ("Three minor carotenoids from annatto" Phytochemisti ⁇ 52:135- 139 (1999)).
  • Geranylgeraniol is also formed in animal systems, in which it is synthesized in a complex pathway which also involves the metabolism of cholesterol.
  • the pathway starts with acetyl-coenzyme A, and after three gene-regulated steps and the synthesis of geranylphosphate, a dephosphorylation takes place to form geranylgeraniol (Edwards, et al, "Sterols and isoprenoids: signaling molecules derived from cholesterol biosynthetic pathway" Annu. Rev. Biochem. 68:157-185 (1999)).
  • Tocotrienols which are related to the family of tocopherols, were also first reported in annatto seeds by Jodinko.
  • vitamin E is now considered to be a generic name describing bioactives of both tocopherol and tocotrienol derivatives. Both consist of a common chromanol head and a side chain at the C-2 position. However, while tocopherol has a saturated phytyl tail, tocotrienol possesses an unsaturated isoprenoid side chain (Sen et al, "Molecular basis of vitamin E action” JBiol Chem 275(17):13049-13055 (2000)). Tocotrienols are minor plant constituents, especially abundant in palm oil, cereal grains, and rice bran, and can be a considerable source of vitamin E when these products are consumed.
  • annatto root extract for example, has been shown to be antisecretory, antispasmodic and hypotensive (Dunham et al, "A preliminary pharmacologic investigation of the roots of B. orellana,” J Am. Pharmac. Assoc, 49:218-219 (I960)), and the aldose reductase inhibitor isoscutellarein has been found in annatto leaf extract (Terashima et al).
  • annatto seed extract given to dogs showed the presence of a hyperglycemic principle (Morrison et al, "Extraction of an hyperglycaernic principle from the annatto, a medicinal plant in the West Indies," Tropical Geographical Medicine, 43:184-188 (1991)).
  • bixin or methylbixin shows strong antioxidant activity and lipoxidase inhibition.
  • Bixin has strong physical quenching activity of singlet molecular oxygen and thus the hypothesis has been advanced that it may exert a protective action against some types of cancer (DiMascio et al, "Carotenoids, tocopherols and thiols as biological singlet molecular oxygen quenchers," Biochem. Soc. Transact., 18:1054-1056 (1990)).
  • bixin did not prevent the formation of cancer cells in experimental carcinogenesis with methylcholantrene (Bertram et al, "Diverse carotenoids protect against chemically induced neoplastic transformation,” Carcinogenesis, 12:671-678 (1991)).
  • bixin is a potent inhibitor of lipid peroxidation at the same level of lutein and canthaxanthin and only surpassed by alpha-tocopherol (Zhang et al, "Carotenoids enhance gap junctional communication and inhibit lipid peroxidation in C3H- 1 O-T 1 -2 cells: Relationship to their cancer chemopreventive action," Carcinogenesis, 12:2109-2114 (1991)).
  • Bixin acts as a lipoxydase inhibitor and modulates lipid hydroperoxide formation (Canfield, et al, "Co-oxidations: Significance to carotenoid action in vivo, "Annals New York Academy of Science, 691:192-199 (1993)). Oral administration of bixin significantly reduced the otherwise increased level of lipid peroxides in serum and liver of rats caused by gamma-radiation and can thus be considered a candidate drag for protection against the side-effects in cancer (Thresiamma et al, "Protective effect of curcumin, ellagic acid and bixin on radiation induced lipid peroxidation," JExp. Clin.
  • Bixin does not up-regulate Com ⁇ exin-43 gene expression as some other carotenoids do, but it is active in membrane protection (Zhang et al, "Carotenoids upregulate Con ⁇ exin-43 gene expression independent of their provitamin A or antioxidant properties," Cancer Research, 52:5707-5712 (1992)). Although bixin was not specifically included in the study, it has been found that food colors in general enhance immuno globulin production by rat spleen lymphocytes (Kuramoto et al, "Effect of natural food colorings on immuno globulin production in vitro by rat spleen lymphocytes," Bioscience, Biotechnology and Biochemistiy, 60:1712-1713 (1996)).
  • vitamin E after taking up the electron, becomes a transient tocol free radical.
  • the free electron is then transferred to one after the other of the carotenoids through their conjugated double bonds.
  • the first carotenoid of this cycle regenerates the tocol to its original non-free radical state; the second carotenoid regenerates the first carotenoid, and so on.
  • the excess energy is slowly dissipated as thermal energy during the trip of the electron through the various conjugated double bond systems, and the electron is finally transferred at the lipid/water interface into the aqueous phase where ascorbic acid binds the electron and is excreted from the system, thus finally eliminating the deleterious effects of the free radical.
  • Geranylgeraniol has been shown to be a very potent inducer of apoptosis (Masuda, et al, "Geranylgeraniol potently induces caspase-3-like activity during apoptosis in human leukemia U937 cells" Biochem Biophys Res Commun 234(3):641-5 (1997); Ohizumi, "Geranylgeraniol is a potent inducer of apoptosis in tumor cells” J Biochem (Tokyo) 117(1): 11-3 (1995) and "Induction of apoptosis in various tumor cell lines by geranylgeraniol” Anticancer Res 17(2A):1051-7 (1997)).
  • geranylgeraniol selectively inhibits aberrant (oncogenic) signaling between cells without the cytotoxicity observed when lovastatin is used alone, as described in U.S. Patent No. 6,083,979 and Ownby et al. ("Farnesol and geranylgeraniol: prevention and reversion of lovastatin-induced effects in NIH3T3 cells", Lipids 37(2): 185-92 (2002)). Additionally, as disclosed in U.S. Patent No. 5,756,109, geranylgeraniol inhibits esterification of retinol into inactive retinyl esters which may be useful to improve skin desquamation and epidermal differentiation.
  • ⁇ -tocotrienol is 40 to 60 times more potent than ⁇ -tocotrienol at preventing lipid peroxidation in rat liver microsomes (Sen et al . Further, Kamat et al. ("Tocotrienols from palm oil as effective inhibitors of protein oxidation and lipid peroxidation in rat liver microsomes", Mol Cell Biochem 170(l-2):131-7 (1997)) report similar results with a tocotrienol complex in rat mitochondria.
  • U.S. Patent No. 6,187,811 describes a method to treat benign prostatic hyperplasia with tocotrienols by themselves and in combinations with a long list of herbs. Further, a method for treatment of neoplastic disease with tocotrienols in combination with limonoids and flavonoids is taught in U.S. Patent No. 6,239,114.
  • norbixin affects the glycemic levels of rats and mice in surprisingly opposite ways. Specifically, in rats, norbixin significantly induces hyperglycemia ranging from 27% at 8.5 mg dietary norbixin kg body weight to 53% at 74 mg/kg.
  • mice norbixin induces up to 22% hypoglycemia at 66 mg norbixin per kilogram body weight (Fernandes et al, "Norbixin ingestion did not induce any detectable DNA breakage in liver and kidney but caused a considerable impairment in plasma glucose levels of rats and mice" JNutr Biochem 13(7):411-420 (2002)).
  • a method for eliciting a beneficial health effect in a non-human animal is provided.
  • the method comprises adding at least one bixin compound to a feed in an amount effective to increase the bixin concentration in the blood stream of the non-human animal and feeding the feed to the non-human animal at a recommended daily dosage for a sufficient number of days.
  • a second method for eliciting a beneficial health effect in a human or non-human animal comprises adding at least one bixin compound to a nutritional supplement in an amount effective to increase the bixin concentration in the blood supply of the human or non-human animal and feeding the nutritional supplement to the human or non-human animal at a unit dosage for a sufficient number of days.
  • a method for eliciting a therapeutic health effect in a human or non-human animal comprises adding at least one bixin compound to a pharmaceutical composition in an amount effective to increase the bixin concentration in the blood stream of the human or non-human animal and feeding the composition to the human or non-human animal at a unit dosage for a sufficient number of days.
  • a nutritional supplement for a human or non-human animal comprises at least one bixin compound in an oral pharmaceutical or neutraceutical dosage for administration to the subject, wherein the dosage form provides a dosage of at least about 6 mg per day of the at least one bixin compound to the subject.
  • Bixin is one of the most powerful carotenoid antioxidants. Its conjugated double bond system is ideally suited for scavenging free radicals. It is also unique among the natural carotenoids in that it is a very polar molecule due to the presence of two carbonyl groups. As such, the bixin molecule may locate at the lipid/water interface of the cell membrane which may give it an especially important potential action in preserving health of mammals, both human and non-human.
  • Such supplementation may enhance the activity of the immune system, making these animals less prone to gastrointestinal infections and infections of the more systemic kind.
  • companion animals such as cats and dogs, this may be of great importance to the general well being of the animals (and the satisfaction of their owners).
  • the beneficial health effects are also desirable to fanned animals, such as layer hens, broiler chickens, and pigs.
  • the beneficial health effect may be elicited by adding at least one bixin compound to a food or feed product, a nutritional product or supplement, or a pharmaceutical product or supplement, in an amount effective to increase the bixin concentration in the blood supply, and feeding the feed, product or supplement to the human or non-human animal at a recommended daily dosage (unit dosage) for a sufficient number of days.
  • the bixin compound may be bixin, norbixin, methylbixin, higher alkyl esters and diesters of norbixin, isomers thereof, and/or extracts of the annatto (Bixa orellana) seed.
  • the beneficial health effect may be further enhanced by adding to the food product, feed, or nutritional supplement, in addition to the bixin compound(s), at least one carotenoid compound selected from the group consisting of lutein, zeaxanthin, beta-carotene, alpha-carotene, astaxanthin, lycopene, cryptoxanthin and the esters, diesters and isomers thereof, or an extract of marigold, corn, spinach, alfalfa, algae, bacteria, tomato, or citrus which contains at least one of these carotenoid compounds.
  • the carotenoid compound is lutein, lutein ester, lutein diester, and/or extract of marigold.
  • the recommended daily amount or unit dosage of the food product, feed, or nutritional supplement and the number of days such a product or supplement may be ingested in order to elicit the beneficial health effect are determined by a number of factors which affect the food intake of the animal. These factors include the particular species of animal, its age, body weight, and activity level, as well as the animal's particular living conditions, including the season and the outside temperature and climate. For example, an active animal will consume more than one that is passive, and an animal living on a farm will be more active than one living in a city. Further, animals living on a farm, for example, will consume different amounts of food depending on the time of year.
  • the effective amount is preferably at least about 1 mg bixin per kg of the feed, more preferably at least about 10 mg per kg, and most preferably at least about 50 g per kg.
  • the effective amount of bixin compound(s) is preferably at least about 250 micrograms ( ⁇ g) per unit dosage, more preferably at least about 1 mg per unit dosage, and most preferably at least about 10 g per unit dosage.
  • the unit dosage of the nutritional supplement may be administered parenterally or orally as a tablet, capsule, or liquid.
  • This invention also relates to a method for administering at least one bixin compound in a pharmaceutical composition to elicit a therapeutic health effect in a human or non-human animal by increasing the bixin concentration in the blood stream of the animal or human, and feeding the composition to the animal or human at a unit dosage for a sufficient number of days.
  • a method for administering at least one bixin compound in a pharmaceutical composition to elicit a therapeutic health effect in a human or non-human animal by increasing the bixin concentration in the blood stream of the animal or human, and feeding the composition to the animal or human at a unit dosage for a sufficient number of days.
  • a method may be desirable for mammals under particular stress situations in order to boost the function of their immune systems. This method is particularly suited to cats and dogs, but may be applicable to any animal or human.
  • the effective amount of the bixin compound(s), which may be any as previously described, in such a pharmaceutical composition is preferably at least about 400 ⁇ g per unit dosage, more preferably at least about 30 mg, and most preferably at least about 2 g per dosage.
  • various conditions will affect the amount of bixin that is effective, including the species of animal, its age, body weight, activity level, and living conditions.
  • the recommended daily amount or unit dosage of the pharmaceutical composition and the number of days such a product or supplement may be ingested in order to elicit the therapeutic health effect are determined by a number of factors which affect the food intake of the animal or human.
  • the therapeutic health effect may be further enhanced by the addition of at least one carotenoid compound to the pharmaceutical composition, such as lutein, zeaxanthin, beta-carotene, alpha-carotene, astaxanthin, lycopene, cryptoxanthin and the esters, diesters and isomers thereof, or at least one extract of marigold, corn, spinach, alfalfa, algae, bacteria, tomato, or citrus containing these carotenoid compounds.
  • the carotenoid compound is lutein, lutein ester, lutein diester and/or extract of marigold.
  • the therapeutic health effects which may be elicited include, but are not limited to enhancing activity of the immune system, reducing systemic infection, improving symptoms of diabetes, inhibiting cancer development, inhibiting atherosclerosis and/or heart disease, lowering LDL cholesterol, reducing inflammation of an internal organ, and protecting neuron cells from being killed due to stroke, inflammation, or neurodegenerative disease.
  • a nutritional supplement for a human or non-human animal is provided by the invention.
  • the supplement comprises at least one bixin compound, which may be any as previously described, in an oral pharmaceutical or neutraceutical dosage for administration to the subject.
  • the dosage form provides a dosage of the bixin compound(s) of at least about 3 mg per day (based on an average subject of 60 kg body weight, i.e., at least about 0.05 mg per kg body weight per day), preferably at least 6 mg per day up to about 50 mg per day, and more preferably about 10 to 30 mg per day.
  • a dosage of the bixin compound(s) of at least about 3 mg per day (based on an average subject of 60 kg body weight, i.e., at least about 0.05 mg per kg body weight per day), preferably at least 6 mg per day up to about 50 mg per day, and more preferably about 10 to 30 mg per day.
  • it is preferred to administer the bixin compound in two or more doses per day While the above amounts are preferred, it is believed that persons who do not ingest bixin compounds at all from their normal diets or do not ingest bixin compounds in significant or regular amounts may benefit by the administration of as little as one or 2 mg per day on a regular basis.
  • the bixin compound(s) in the nutritional supplement may be administered orally or parenterally in usual nutritional and/or pharmaceutical forms, such as pills, capsules, injectable solutions, and the like, containing an amount of bixin compound(s) to deliver a dosage of at least 1 mg bixin compound, preferably greater than 3 mg bixin compound, and more preferably at least 6 mg of bixin compound.
  • Preferred for convenience are oral forms, such as soybean oil solutions injected into capsules, and microbeads or compressed tablets.
  • the compositions further comprise acceptable carriers or excipients which are not critical. Such acceptable earners and excipients are well known to those skilled in the art of nutritional supplements and pharmaceutical compositions.
  • the bixin compound may also be added directly to foods, to be administered as a "fortified food.”
  • the bixin compound(s) should be present at a level of at least 50 mg per kg food, and preferably at least 80 mg per kg food.
  • beneficial health effects for the consumer may be achieved when the bixin compound level in the food is increased to 80 mg/kg or above, as it is at these levels that actual therapeutic effects of the bixin compound may be achieved.
  • Bixin is unique among the natural carotenoids, in that it is a very polar molecule from the presence of two carboxyl groups. While not wishing to be bound by any particular theory, it is believed that the bixin compound molecule may locate at the lipid/water interfaces of the cell membrane, which gives it an especially important potential action in preserving animal health, both human and non-human.
  • bixin compounds have important beneficial actions on the human body. Specifically, bixin compounds after ingestion regulate gene expression in lymphocytes and may control T-cell proliferation, differentiation, and apoptosis. This suggests that bixin and its derivatives may inhibit cancer developments as an immunological adjuvant producing large amounts of IgM antibodies and some IgG antibodies. Furthermore, preliminary results demonstrate that the oxidation of the LDL and VLDL fractions of cholesterol is effectively inhibited by bixin compounds, thus aiding in the prevention of atherosclerosis and heart disease.
  • the purified bixin compounds may be taken orally as a prescription drag by patients suffering from heart disease, atherosclerosis, or other diseases caused directly or indirectly by free-radical molecules formed in the blood stream by excessive biological oxidation reactions. They can also be used for this purpose via parenteral administration.
  • Bixin compounds may also be used as a nutritional supplement in forms such as vitamin pills or food additives by anyone who wants to reduce his or her risk of diseases caused by free radicals or to strengthen the immune system.
  • the position of bixin compounds in the metabolic cycle has not yet been clearly established. However, research results show that bixin compounds fit prominently into the scheme of protecting the animal body against the harmful effects of free radicals.
  • Bixin Free radical scavenging activity is related to the number of conjugated double bonds in the carotenoid molecule.
  • Bixin is in this group of molecules and is one of the most powerful carotenoid antioxidants. Its conjugated double bond system is ideally suited for scavenging free radicals. After consumption, it is well absorbed into the blood stream. Therefore, bixin compounds are important new nutritional supplements to improve human and non-human animal health. [0046] The invention will be further understood in conjunction with the following, non- limiting examples.
  • the serum level of bixin and norbixin was zero in the control group, while the serum levels of bixin and norbixin in the individuals of the test group reached levels of 12 and 60 micro grams/liter, respectively.
  • the oxidative stress load in the blood of the control group was high, as measured by a modified "TBAR" (thio- barbituric acid-reactive substances) test, whereas in the test group that received the bixin supplementation, the oxidative stress level of the blood remained normal. The same relation was found in the determination of free radical content of the blood.
  • EXAMPLE 2 Female BALB/c mice and the WAZ-2T(-SA) mammary tumor cell line were used to determine the efficacy of dietary bixin in inhibiting mammary tumor development. Six mice per treatment were fed a semi synthetic AIN-93M diet containing 0, 0.006 or 0.06% bixin. After 14 days, all mice were inoculated with 2500 tumor cells (a cell load which typically produces a 65% tumor incidence in untreated controls). Tumor growth was measured daily for 50 days, at which time blood, liver, spleen, and tumors were removed and evaluated. Plasma bixin and norbixin levels showed dose-dependent increases which peaked at 400 micrograms norbixin and 30 micrograms bixin/L.
  • Mammary tumor incidence and tumor growth rate were lowest in the 0.06% dietary bixin level and increased in a dose dependent manner.
  • Final tumor weight was 0.3 grams at 0.06% dietary bixin, 0.7 grams at 0.006% and 1.1 grams for the control without dietary bixin.
  • Tumor latency (number of days post inoculation when mammary tumors were first palpable) was 45 days at 0.06% dietary bixin level, 38 days at 0.006%, and 30 days for the control. Results were determined to be statistically significant at the P ⁇ 0.05 level.
  • bixin compounds and amiatto extracts exert a profound beneficial effect on the health of humans and non-human animals.
  • Bixin compounds may thus be used as nutritional supplements, food fortifiers, and pharmaceuticals in the form of tablets, capsules, liquid preparations and the like to improve the health of animals by the stimulation of immune systems, the amelioration of the symptoms associated with diabetes, the reduction of inflammatory processes of internal organs, and the protection from death of neuronal cells.
  • Such compounds may thus be used to inhibit cancer development by regulating gene expression in lymphocytes and controlling T-cell proliferation, differentiation and apoptosis, to prevent or inhibit atherosclerosis and heart disease by inhibiting the oxidation of LDL and VLDL fractions of cholesterol, and generally strengthening the immune system and reducing the risk of diseases caused directly or indirectly by excessive biological oxidation reactions by free radical molecules formed in the blood stream.
  • the nutritional supplementation of humans and non-human animals with bixin compounds and other annatto seed extractives has protective and therapeutic health effects. Although a method to separate the components of the annatto seed extract by distillation in order to use these components individually as supplements or as building blocks for chemical synthesis is described in U.S. Patent No. 6,350,453, according to the present invention the bixin compounds and other annatto seed extractives seem to cause a much more significant synergistic protective and therapeutic health effect when ingested together than when the components are administered individually.
  • the present invention provides for the dietary inclusion of these compounds which stimulates beneficial physiological functions and will allow for the manufacture of improved pet food formulae, for use in veterinary diets, which are therapeutic to address specific ailments.

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Abstract

L'invention concerne des procédés favorisant un effet bénéfique de santé chez un animal humain ou non humain consistant à ajouter au moins un composé de bixine ou un extrait de graine d'annatto (Bixa orellana) à un aliment pour animaux, à un produit alimentaire ou à un supplément nutritionnel, en une quantité effective augmentant la concentration de bixine dans la masse sanguine de l'animal lorsque l'aliment ou le supplément est consommé selon une dose journalière recommandée (dose unitaire) pendant un nombre de jours suffisant. L'invention concerne aussi un procédé favorisant un effet thérapeutique bénéfique sur la santé chez un animal humain ou non humain consistant à ajouter une quantité effective d'au moins un composé de bixine à un composé pharmaceutique. L'effet bénéfique ou thérapeutique peut être aussi amélioré par l'addition d'au moins un composé caroténoïde, ou d'un extrait contenant un caroténoïde, dans l'aliment, dans le produit alimentaire, dans le supplément nutritionnel ou dans la composition pharmaceutique. Ces procédés sont particulièrement adaptés aux animaux de compagnie, notamment aux chats et aux chiens, et aux animaux d'élevage, notamment aux poules pondeuses, aux poulets d'élevage, et aux cochons.
PCT/US2002/038593 2001-12-04 2002-12-04 Supplements contenant des extraits d'annatto et des carotenoides, et procedes d'utilisation associes WO2003047528A2 (fr)

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AU2002365602A AU2002365602A1 (en) 2001-12-04 2002-12-04 Supplements containing annatto extracts and carotenoids and methods for using the same

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004071211A1 (fr) * 2003-02-05 2004-08-26 The Iams Company Procedes et compositions utilisant de l'astaxanthine
EP1624880A4 (fr) * 2003-04-08 2009-09-23 Barrie Tan Compositions d'extrait de rocou contenant des geranylgeraniols et modes d'utilisation
WO2010112071A1 (fr) * 2009-04-01 2010-10-07 Phf S.A. Combinaison à administration orale et à effet d'écran solaire d'astaxanthine, d'antioxidants et de colorants
WO2010149942A1 (fr) 2009-06-25 2010-12-29 Institut Biophytis Composition destinee a la protection solaire
EP1617724A4 (fr) * 2003-04-10 2011-11-23 Barrie Tan Compositions d'extrait de rocou comprenant des tocotrienols et des tocopherols et procedes d'utilisation
US20130273209A1 (en) * 2012-04-13 2013-10-17 Frito-Lay North America, Inc. Bi-Colored Random Collets and Methods for Making Same
US9510617B2 (en) 2012-04-13 2016-12-06 Frito-Lay North America, Inc. Micropellets of fine particle nutrients and methods of incorporating same into snack food products
WO2016187476A3 (fr) * 2015-05-20 2017-03-16 Indiana Soybean Alliance, Inc. Procédé pour augmenter l'utilisation de protéine de soja par des salmonidés
US10220558B2 (en) 2012-05-23 2019-03-05 Frito-Lay North America, Inc. Rotor assembly with one-piece finger member
JPWO2019189088A1 (ja) * 2018-03-27 2021-03-25 国立大学法人 東京大学 アジュバントおよび該アジュバントを含むワクチン

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3920834A (en) * 1970-07-10 1975-11-18 Hoffmann La Roche Light-screening compositions and method
GB1509587A (en) * 1975-08-19 1978-05-04 Ajinomoto Kk Anti-tumour composition
US5079016A (en) * 1990-05-16 1992-01-07 Kalamazoo Holdings, Inc. Color-stabilized carotenoid pigment compositions and foods colored therewith having increased resistance to oxidative color fading
US5935581A (en) * 1996-07-24 1999-08-10 Kapadia; Govind J. Inhibitory effects of synthetic and natural colorants on carcinogenesis

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004071211A1 (fr) * 2003-02-05 2004-08-26 The Iams Company Procedes et compositions utilisant de l'astaxanthine
EP1624880A4 (fr) * 2003-04-08 2009-09-23 Barrie Tan Compositions d'extrait de rocou contenant des geranylgeraniols et modes d'utilisation
EP1617724A4 (fr) * 2003-04-10 2011-11-23 Barrie Tan Compositions d'extrait de rocou comprenant des tocotrienols et des tocopherols et procedes d'utilisation
WO2010112071A1 (fr) * 2009-04-01 2010-10-07 Phf S.A. Combinaison à administration orale et à effet d'écran solaire d'astaxanthine, d'antioxidants et de colorants
WO2010149942A1 (fr) 2009-06-25 2010-12-29 Institut Biophytis Composition destinee a la protection solaire
US20130273209A1 (en) * 2012-04-13 2013-10-17 Frito-Lay North America, Inc. Bi-Colored Random Collets and Methods for Making Same
US9510617B2 (en) 2012-04-13 2016-12-06 Frito-Lay North America, Inc. Micropellets of fine particle nutrients and methods of incorporating same into snack food products
US10220558B2 (en) 2012-05-23 2019-03-05 Frito-Lay North America, Inc. Rotor assembly with one-piece finger member
WO2016187476A3 (fr) * 2015-05-20 2017-03-16 Indiana Soybean Alliance, Inc. Procédé pour augmenter l'utilisation de protéine de soja par des salmonidés
JPWO2019189088A1 (ja) * 2018-03-27 2021-03-25 国立大学法人 東京大学 アジュバントおよび該アジュバントを含むワクチン

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AU2002365602A1 (en) 2003-06-17
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WO2003047528A3 (fr) 2003-12-18

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