WO2001010424A2 - Reducing cholesterol oxides using n-3-pufa and vitamin e - Google Patents

Reducing cholesterol oxides using n-3-pufa and vitamin e Download PDF

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Publication number
WO2001010424A2
WO2001010424A2 PCT/EP2000/007604 EP0007604W WO0110424A2 WO 2001010424 A2 WO2001010424 A2 WO 2001010424A2 EP 0007604 W EP0007604 W EP 0007604W WO 0110424 A2 WO0110424 A2 WO 0110424A2
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Prior art keywords
pufa
vitamin
use according
acid
oil
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PCT/EP2000/007604
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German (de)
French (fr)
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WO2001010424A3 (en
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Klaus Krämer
Tilmann Grune
Werner G. Siems
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Basf Aktiengesellschaft
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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
    • A61K31/33—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
    • 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
    • A23K20/158—Fatty acids; Fats; Products containing oils or fats
    • 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
    • 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 COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • 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
    • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
    • A23L33/12—Fatty acids or derivatives thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/40—Complete food formulations for specific consumer groups or specific purposes, e.g. infant formula
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the invention relates to the use of polyunsaturated 5 fatty acids (PUFA) of the type n-3-PUFA (or ⁇ -3-PUFA) and / or vitamin E to reduce cholesterol oxide formation in the human or animal body.
  • PUFA polyunsaturated 5 fatty acids
  • Unsaturated fatty acids are divided into 3 families (n-9, n-6 and n-3) 10, which is based on the position of the first double bond from the methyl end. Fatty acids with more than one double bond are referred to as polyunsaturated fatty acids (PUFA). The fatty acid families mentioned cannot be converted into one another.
  • PUFA polyunsaturated fatty acids
  • Cholesterol oxides are increasingly found in atherosclerotic lesions in the human body.
  • both in vitro and in vivo studies have shown their high angiotoxicity and
  • this object was achieved by the finding according to the invention that when certain polyunsaturated fatty acids are administered, namely n-3-PUFA ( ⁇ -3-PUFA) and / or vitamin E, cholesterol oxide can be significantly reduced.
  • a first subject of the invention therefore relates to the use of n-3-PUFA and / or vitamin E for the production of an agent for reducing cholesterol oxide formation and / or for preventing cholesterol oxide-mediated disease states in the human or animal body.
  • a “reduction in cholesterol oxide formation” means the reduction in the formation of at least one atherogenic cholesterol oxide.
  • Atherogenic cholesterol oxides include: 7 ⁇ -0H-cholesterol (Colest-5-en-3ß, 7ß-diol), 7-keto-cholesterol (Colest-5-en-3ß-ol-7-one) and 5, 6 ⁇ -epoxy 5 ⁇ -cholestan-3ß-ol (cholesterol-5 ⁇ , 6 ⁇ -epoxide), 5 ⁇ -cholestan-3ß, 5,6ß-triol (cholestanetriol) and 5,6ß-epoxy-5ß-cholestan-3ß-ol (choleste- rin-5ß, 6ß-epoxy).
  • a first preferred subject of the invention relates to the use of n-3-PUFA and / or vitamin E for the production of a veterinary medicament or a feed for reducing the cholesterol oxide formation in the animal body or in foods of animal origin, such as eggs and egg products .
  • specially prepared feed or medication can be administered to the animal, such as pigs, rabbits, fish, such as, for example, trout, salmon, and in particular poultry, such as ducks, geese and especially chickens.
  • These preparations are formulated in such a way that they take up n-3-PUFA in a dose in the range from about 0.1 to 10000 mg / kg of body weight, such as. B.
  • Suitable veterinary medicines contain n-3-PUFA in a proportion of approximately 10 to 1000 mg per dose unit and / or vitamin E in a proportion of approximately 5 to 1500 mg per dose unit. 5
  • Suitable feed contains n-3-PUFA in a proportion of about 0.1 to 10 wt .-%, such as. B. 1 to 5 wt .-%, and / or vitamin E in a proportion of about 5 to 2000 mg / kg of feed, such as. B. 10 to 500 mg / kg of feed.
  • Another preferred object of the invention relates to the use of n-3-PUFA and / or vitamin E for the manufacture of a medicament or a food supplement, supplements or fortified food, for reducing the cholesterol
  • n-3 PUFA 15 rinoxide formation in the human body.
  • These preparations are formulated to take n-3 PUFA in a dose in the range of greater than about 1 mg / kg body weight, e.g. about 1 to 200 or about 10 to 2000, e.g. 10 to 200 mg / kg body weight, and / or the intake of vitamin E in one dose
  • Range greater than about 0.5 mg / kg body weight e.g. about 0.5 to 50 or about 5 to 2000, e.g. 5 to 100 mg / kg body weight, guaranteed by the human body.
  • Suitable drugs contain n-3-PUFA in a proportion of about 25 20 to 10000 mg, such as. B. about 100 to 2000 mg, per dose unit and / or vitamin E in a proportion of about 20 to 20,000 mg, such as. B. about 50 to 2000 mg, per unit dose.
  • Suitable food supplements contain n-3-PUFA in a proportion of about 10 to 1000 mg / kg, such as. B. 100 to 500 mg / kg, and / or vitamin E in a proportion of about 5 to 1000, such as about 10 to 400 mg / kg.
  • Suitable fortified foods contain n-3-PUFA in a portion of about 10 to 500 mg per ready-to-eat portion and / or vitamin E in an amount of about 5 to 1000 mg, such as. B. about 10 to 100 mg, per ready-to-eat portion.
  • Examples of foods that are suitable for fortification with 40 n-3 PUFA and / or vitamin E are baked products, such as, in particular, bread, cereals, milk, milk products, such as, in particular, yoghurt, chocolate, chocolate bars and the like.
  • the invention particularly relates to the use of 45 n-3 PUFA and / or vitamin E for the manufacture of a medicament, a food supplement / supplement or fortified food as defined above for the prevention of cholesterol oxide-mediated atherosclerotic lesions or cholesterol-oxide-mediated angiotoxic or atherogenic effects in humans.
  • n-3 PUFAs can be used as pure substances on their own or in a mixture with other n-3 or n-6 PUFAs. There is also the possibility of using mixed preparations or extracts of plant or animal origin which have a high n-3-PUFA content.
  • n-3-PUFAs can be used as free acid or as a physiologically acceptable salt or in particular also as biodegradable esters or as phospholipids.
  • Preferred esters include alkyl esters, the alkyl part having one to six carbon atoms, or mono-, di- or triglycerides.
  • suitable salts are salts with inorganic bases, for example metal hydroxides or carbonates of alkali metals, alkaline earth metals or transition metals, or with organic bases, for example basic amino acids, such as arginine and lysine, mono- or di-C ⁇ -C -Alkyl- or -CC-hydroxyalkylamines, such as.
  • B. mono- or diethylamine, mono- and diethanolamine,
  • C 2 -C 6 -alkylenediamines such as ethylenediamine or hexamethylenetetraamine
  • saturated cyclic amines with 4 to 6 ring carbon atoms such as piperidine, piperazine, pyrrolidine and morpholine, as well as other organic bases, for example N-methylglucamine, creatine and tromethamine.
  • salts with inorganic bases for. B. Na, K, Mg, Ca, Zn, Cr and Fe salts.
  • n-3 PUFA a polyunsaturated n-3 fatty acid is used according to the invention as the n-3 PUFA
  • the polyunsaturated n-3 fatty acid is particularly preferably selected from ⁇ -linolenic acid (C18: 3n-3) ( ⁇ -LNA), eicosapentaenoic acid (C20: 5n-3) (EPA); docosahexaenoic
  • N-3-PUFA mixtures which can be administered particularly preferably include EPA and DHA; ⁇ -LNA and EPA; or ⁇ -LNA and DHA. In these n-3-PUFA mixtures preferably have the following mixing ratios:
  • DHA 5:95% to 95: 5% by weight; such as. 15:85 wt% to 60:40 wt%;
  • the vitamin E used in the context of the invention comprises the tocopherols ⁇ , ⁇ , ⁇ , and ⁇ and the tocotrienols ⁇ , ⁇ , ⁇ and ⁇ individually or in a mixture, such as e.g. a mixture of tocopherol ⁇ and ⁇ .
  • the invention relates to the use of a combination of n-3-PUFA or a biodegradable ester thereof and vitamin E for the purposes mentioned above.
  • one or more n-3 PUFA or one or more biodegradable esters thereof are used without the addition of vitamin E.
  • n-3-PUFA and / or vitamin E can be administered in the form of suitable human or veterinary medicinal drugs. They are present as mixtures of the active ingredients with suitable pharmaceutical carriers or diluents.
  • suitable pharmaceutical formulations are solid pharmaceutical forms, such as powders, powders, granules, tablets, in particular film-coated tablets, pastilles, sachets, cachets, dragees, capsules such as hard and soft gelatin capsules, semi-solid pharmaceutical forms, such as ointments, creams, hydrogels, pastes or plasters, and also liquid pharmaceutical forms, such as solutions, emulsions, in particular oil-in-water emulsions, suspensions, for example lotions, injection and infusion preparations, eye and ear drops.
  • Implanted delivery devices can also be used for the administration of active substances according to the invention. Liposomes or microspheres can also be used.
  • the formulations can be administered, for example, by the oral, transdermal, subcutaneous, intravenous, intramuscular or intranasal route. Oral administration is preferred.
  • the active ingredients are usually mixed or diluted with a suitable excipient or excipient.
  • Excipients can be solid, semi-solid or liquid materials that serve as vehicles, carriers or media for the active ingredient. If necessary, further auxiliaries are added in a manner known per se. Shaping steps, possibly in connection with mixing processes, can be carried out, for example granulation, compression and the like.
  • the active ingredient components can be formulated together.
  • they can also be processed separately first and then in a compartmented, e.g. multilayer drug form can be merged.
  • possible drug incompatibilities and different drug properties such as bioavailability, stability, solubility and the like can be taken into account.
  • Oral agents can be present, for example, as tablets or capsules and can contain conventional excipients, such as binders (e.g. syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone), fillers (e.g. lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine), lubricants (e.g. magnesium stearate, talc, polyethylene glycol or silicon dioxide), disintegrating agents (e.g. starch) or wetting agents (e.g. sodium lauryl sulfate).
  • binders e.g. syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone
  • fillers e.g. lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine
  • lubricants e.g. magnesium stearate, talc,
  • Oral liquid preparations can be in the form of aqueous or oily suspensions, solutions, emulsions, syrups, elixirs or sprays etc. or can be in the form of dry powder for reconstitution with water or another suitable carrier.
  • Such liquid preparations can contain conventional additives, for example suspending agents, flavoring agents, diluents or emulsifiers. Solutions or suspensions with conventional pharmaceutical carriers can be used for parenteral administration.
  • the agents according to the invention can be administered to a human or an animal in a daily dose of about 0.1 to about 10000 mg / kg body weight, such as. B. up to about 2000 mg / kg body weight, administered. They can be administered in a single dose or in multiple doses.
  • n-3-PUFA and / or vitamin E can also be administered in the form of suitable supplements / food supplements.
  • suitable supplements / food supplements examples include fat emulsions enriched with n-3-PUFA and / or vitamin E.
  • n-3-PUFA and / or vitamin E can also be formulated as specially fortified foods, which, like the supplements or dietary supplements mentioned, can be used as part of enteral nutritional therapy.
  • suitable foods e.g. dietary foods such as nutrient-defined drinking food, sports food, diabetic food or baby or premature food, breakfast preparations, especially in the form of muesli or bars.
  • n-3-PUFA and / or vitamin E can, if desired, be combined with other active ingredients.
  • Suitable active ingredients are e.g. B. vitamins, cofactors, trace elements, minerals, amino acids or pharmaceutical substances. The combination with essential nutrients is particularly preferred.
  • the essential nutrients include in particular vitamins, provitamins, trace elements, amino acids and fatty acids.
  • Isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine are mentioned as essential amino acids.
  • This also includes semi-essential amino acids that have to be added, for example, during growth phases or deficiency states, such as glutamine, arginine, histidine, cysteine and tyrosine.
  • trace elements essential minerals and trace elements, the necessity of which has been proven for humans and the lack of which leads to the manifestation of clinical symptoms: iron, copper, zinc, chromium, selenium, calcium, magnesium, potassium, cobalt, molybdenum, iodine, silicon, Fluorine, manganese.
  • elements whose function is not yet sufficiently assured for humans tin, nickel, vanadium, arsenic.
  • essential fatty acids for humans linoleic acid and linolenic acid and under certain circumstances also arachidonic acid, eicosapentaenoic acid and docosahexaenoic acid.
  • a comprehensive list of vitamins can be found in "Reference Values for Nutrient Supply", 1st edition, Umschau Braus Verlag, Frankfurt am Main, 2000, published by the German Nutrition Society.
  • the active compounds according to the invention are combined with conventional nutritional components.
  • These include vegetable but also animal products, especially sugar if necessary in the form of syrups, fruit preparations, such as fruit juices, nectar, fruit pulps, purees or dried fruits, for example apple juice, grapefruit juice, orange juice, applesauce, tomato sauce, tomato juice, tomato puree;
  • Cereal products such as wheat flour, rye flour, oat flour, corn flour, barley flour, spelled flour, corn syrup, and starches of the cereals mentioned; Dairy products such as milk protein, whey, yogurt, lecithin and milk sugar.
  • n-3-PUFA and / or vitamin E are administered individually or in combination in feed
  • the active compounds are administered as pure substance or mixtures of substances or liquid or solid extracts together with conventional feed ingredients.
  • common feed ingredients are: maize, barley, wheat, oats, rye, tritale, sorghum, rice and bran, semolina and flours of these cereals, soybeans, soy products such as soy extraction meal, rapeseed, rapeseed extraction meal, cottonseed and extraction meal, sunflower, sunflower extract, sunflower extract , Flax extraction meal, oil seed expeller, field beans, peas, gluten, gelatin, tapioca, yeast, single cell protein, meat bone meal, meat meal, blood meal,
  • Figure 1 shows the concentration curve of various cholesterol oxides in fresh egg yolk (black symbols) or after 4 weeks of storage of the egg at room temperature (light
  • Example 1 Examination of cholesterol oxide formation in egg yolk when n-3-PUFA and various amounts of vitamin E were fed
  • the basic feed had the following nutrient, vitamin and trace element content (Table 2):
  • Table 2 calculated nutrient, vitamin and trace element content
  • the analysis of the total cholesterol and the cholesterol oxidation products was carried out according to the method of Sevianian A., et al. in Free Radic. Biol. Med. (1994); 17: 397-409. The analyzes were carried out on both fresh and stored eggs (four weeks at room temperature). Vitamin E was analyzed by HPLC, as described, for example, by Wahl, et al., J. Sei. Food Agric (1993), 61, 463; the analysis of n-3-PUFA was carried out by gas chromatography (Simopoulos et al., loc. cit.).
  • n-3-PUFA in egg yolk rose to values of about 10 mg / g, mainly in the form of DHA.
  • Vitcimin E content in the feed, the vitamin E content also increased from 5.33 +/- 1.54 nmol / g to 11.63 +/- 2.96 nmol / g, determined by HPLC.
  • a muesli bar containing 250 mg fish oil and 100 mg vitamin E per bar (60 g) is produced in a known manner according to the following recipe: Fish oil 250 mg (corresponding to approx. 85 mg n-3-PUFA)
  • a muesli containing 200 mg fish oil and 60 mg vitamin E per 100 g muesli is produced according to the following recipe in a manner known per se:
  • Soft gelatin capsules containing 500 mg fish oil and 60 mg vitamin E per capsule, are manufactured according to the following recipe in a manner known per se:

Abstract

The invention relates to the use of n-3-PUFA and/or vitamin E for reducing the formation of cholesterol oxides.

Description

Verringerung von Cholesterinoxiden durch n-3-PUFA und Vitamin E Reduction of cholesterol oxides by n-3-PUFA and vitamin E
Die Erfindung betrifft die Verwendung von mehrfach ungesättigten 5 Fettsäuren (PUFA) des Typs n-3-PUFA (oder ω-3-PUFA) und/oder Vitamin E zur Verringerung der Cholesterinoxid-Bildung im menschlichen oder tierischen Körper.The invention relates to the use of polyunsaturated 5 fatty acids (PUFA) of the type n-3-PUFA (or ω-3-PUFA) and / or vitamin E to reduce cholesterol oxide formation in the human or animal body.
Ungesättigte Fettsäuren werden in 3 Familien (n-9, n-6 und n-3) 10 eingeteilt, wobei sich diese Einteilung an der Position der ersten Doppelbindung vom Methylende her orientiert. Fettsäuren mit mehr als einer Doppelbindung werden als mehrfach ungesättigte Fettsäuren (poly-unsaturated fatty acids, PUFA) bezeichnet. Die genannten Fettsäurefamilien können nicht ineinander überführt 15 werden.Unsaturated fatty acids are divided into 3 families (n-9, n-6 and n-3) 10, which is based on the position of the first double bond from the methyl end. Fatty acids with more than one double bond are referred to as polyunsaturated fatty acids (PUFA). The fatty acid families mentioned cannot be converted into one another.
Cholesterinoxide findet man im menschlichen Körper vermehrt in atherosklerotischen Läsionen. Außerdem wurde sowohl in in vitro- als auch in in vivo-Untersuchungen deren hohe Angiotoxizität undCholesterol oxides are increasingly found in atherosclerotic lesions in the human body. In addition, both in vitro and in vivo studies have shown their high angiotoxicity and
20 atherogene Aktivität festgestellt (Peng, S.K., et. al., J. Clin. Lab. Anal. (1991); 5: 144-152; Imai, H., Science (1980); 207: 651-653). Quelle endogener Cholesterinoxide ist die Cholesterino- xidation in vivo. Außerdem werden Cholesterinoxide über die Nahrung, insbesondere durch den Verzehr von Eiprodukten, aufgenommen 5 (Jacobson, M.S., The Lancet (1987); 8560:656-658).20 atherogenic activity noted (Peng, S.K., et. Al., J. Clin. Lab. Anal. (1991); 5: 144-152; Imai, H., Science (1980); 207: 651-653). Cholesterol oxidation in vivo is the source of endogenous cholesterol oxides. In addition, cholesterol oxides are ingested through food, particularly through the consumption of egg products 5 (Jacobson, M.S., The Lancet (1987); 8560: 656-658).
Aufgrund des oben beschriebenen atherogenen Effektes empfiehlt die American Health Association gesunden Erwachsenen den Verzehr von Eiern auf 3 - 4 Mahlzeiten pro Woche zu beschränken.Because of the atherogenic effect described above, the American Health Association recommends healthy adults to limit their egg consumption to 3-4 meals a week.
3030
Von Simopoulos, A.P., et al. (Am. J. Clin. Nutr. (1992); 55: 411-414) wurde bereits vorgeschlagen, langkettige, mehrfach ungesättigte Fettsäuren in Eidotter anzureichern und in dieser Form Kindernahrung, wie z.B. Säuglingsmilchnahrungen, zuzusetzen. Die-Simopoulos, A.P., et al. (Am. J. Clin. Nutr. (1992); 55: 411-414) has already been proposed to accumulate long-chain, polyunsaturated fatty acids in egg yolk and in this form baby food, e.g. Infant formula, to add. The-
35 ser Vorschlag ist jedoch insofern bedenklich, als aufgrund der allgemein bekannten, leichten Oxidierbarkeit mehrfach ungesättigter Fettsäuren (PUFA) eine verstärkte Bildung von Cholesterin- Oxidationsprodukten in Hühnerei zu erwarten ist. So berichten Marshall, A.C., et al., in Journal of Food Science (1994), 59, 3:However, this proposal is questionable insofar as, due to the well-known, easy oxidizability of polyunsaturated fatty acids (PUFA), an increased formation of cholesterol oxidation products in chicken eggs is to be expected. For example, Marshall, A.C., et al., In Journal of Food Science (1994), 59, 3 report:
40 561-563, daß nach Fütterung von mehrfach ungesättigte Fettsäuren enthaltendem Fischöl an Hühner vermehrt Lipid-Oxidationsprodukte in Eidotter nachzuweisen waren. Eine erfolgreiche Verwendung von PUFA zur gezielten Verringerung von Cholesterinoxiden konnte daher nicht erwartet werden.40 561-563 that, after feeding fish oil containing polyunsaturated fatty acids to chickens, lipid oxidation products in egg yolk were increasingly to be detected. A successful use of PUFA for the targeted reduction of cholesterol oxides could therefore not be expected.
45 Es war deshalb Aufgabe der vorliegenden Erfindung einen Weg zu finden, um den Gehalt an atherogenen Cholesterinoxiden im menschlichen oder tierischen Körper oder in Nahrungsmitteln tierischen Ursprungs zu verringern. Damit sollte eine Präventionsmöglich- keit für Cholesterinoxid-vermittelte atherosklerotische Läsionen oder Cholesterinoxid-vermittelte angiotoxische oder atherogene Effekte geschaffen werden.45 It was therefore an object of the present invention to find a way to reduce the content of atherogenic cholesterol oxides in the human or animal body or in foods of animal origin. This was intended to create a possibility of preventing cholesterol oxide-mediated atherosclerotic lesions or cholesterol oxide-mediated angiotoxic or atherogenic effects.
Überraschenderweise wurde diese Aufgabe gelöst durch den erfin- dungsgemäßem Befund, daß bei Verabreichung bestimmter mehrfach ungesättigter Fettsäuren, nämlich von n-3-PUFA (ω-3-PUFA) und/ oder Vitamin E Cholesterinoxid signifikant verringerbar ist.Surprisingly, this object was achieved by the finding according to the invention that when certain polyunsaturated fatty acids are administered, namely n-3-PUFA (ω-3-PUFA) and / or vitamin E, cholesterol oxide can be significantly reduced.
Ein erster Gegenstand der Erfindung betrifft daher die Verwendung von n-3-PUFA und/oder Vitamin E zur Herstellung eines Mittels zur Verringerung der Cholesterinoxidbildung und/oder zur Prävention Cholesterinoxid-vermittelter Krankheitszustände im menschlichen oder tierischen Körper.A first subject of the invention therefore relates to the use of n-3-PUFA and / or vitamin E for the production of an agent for reducing cholesterol oxide formation and / or for preventing cholesterol oxide-mediated disease states in the human or animal body.
Eine "Verringerung der Cholesterinoxidbildung" bedeutet im Rahmen der vorliegenden Erfindung die Verringerung der Bildung wenigstens eines atherogenen Cholesterinoxids . Atherogene Cholesterinoxide umfassen: 7ß-0H-Cholesterin (Colest-5-en-3ß,7ß-diol) , 7-Ke- tocholesterin (Colest-5-en-3ß-ol-7-on) und 5 , 6α-Epoxy-5α-chole- stan-3ß-ol (Cholesterin-5α,6α-epoxid) , 5α-Cholestan-3ß,5,6ß-triol (Cholestantriol) und 5,6ß-Epoxy-5ß-cholestan-3ß-ol (Choleste- rin-5ß,6ß-epoxid) .In the context of the present invention, a “reduction in cholesterol oxide formation” means the reduction in the formation of at least one atherogenic cholesterol oxide. Atherogenic cholesterol oxides include: 7β-0H-cholesterol (Colest-5-en-3ß, 7ß-diol), 7-keto-cholesterol (Colest-5-en-3ß-ol-7-one) and 5, 6α-epoxy 5α-cholestan-3ß-ol (cholesterol-5α, 6α-epoxide), 5α-cholestan-3ß, 5,6ß-triol (cholestanetriol) and 5,6ß-epoxy-5ß-cholestan-3ß-ol (choleste- rin-5ß, 6ß-epoxy).
Ein erster bevorzugter Gegenstand der Erfindung betrifft die Ver- wendung von n-3-PUFA und/oder Vitamin E zur Herstellung eines veterinärmedizinischen Medikaments oder eines Futtermittels zur Verringerung des Cholesterinoxidbildung im tierischen Körper oder in Nahrungsmitteln tierischer Herkunft, wie z.B. Eiern und Eipro- dukten. Zu diesem Zweck können dem Tier, wie Schweinen, Kanin- chen, Fischen, wie z.B. Forellen, Lachsen, und insbesondere Geflügel, wie Enten, Gänsen und vor allem Hühnern, speziell zubereitete Futtermittel oder Medikamente verabreicht werden. Diese Präparate sind so formuliert, daß sie eine Aufnahme von n-3-PUFA in einer Dosis im Bereich von etwa 0,1 bis 10000 mg/kg Körperge- wicht, wie z. B. 0,1 bis 5000 oder 0,1 bis 2000 mg/kg Körpergewicht, und/oder die Aufnahme von Vitamin E in einer Dosis im Bereich von etwa 0,1 bis 2000 mg/kg Körpergewicht, wie z. B. 0,1 bis 1000 oder 0,1 bis 500 mg/kg Körpergewicht, durch den tierischen Körper gewährleisten. Geeignete veterinärmedizinische Medikamente enthalten n-3-PUFA in einem Anteil von etwa 10 bis 1000 mg pro Dosiseinheit und/oder Vitamin E in einem Anteil von etwa 5 bis 1500 mg pro Dosiseinheit. 5A first preferred subject of the invention relates to the use of n-3-PUFA and / or vitamin E for the production of a veterinary medicament or a feed for reducing the cholesterol oxide formation in the animal body or in foods of animal origin, such as eggs and egg products , For this purpose, specially prepared feed or medication can be administered to the animal, such as pigs, rabbits, fish, such as, for example, trout, salmon, and in particular poultry, such as ducks, geese and especially chickens. These preparations are formulated in such a way that they take up n-3-PUFA in a dose in the range from about 0.1 to 10000 mg / kg of body weight, such as. B. 0.1 to 5000 or 0.1 to 2000 mg / kg body weight, and / or the intake of vitamin E in a dose in the range of about 0.1 to 2000 mg / kg body weight, such as. B. 0.1 to 1000 or 0.1 to 500 mg / kg body weight, by the animal body. Suitable veterinary medicines contain n-3-PUFA in a proportion of approximately 10 to 1000 mg per dose unit and / or vitamin E in a proportion of approximately 5 to 1500 mg per dose unit. 5
Geeignete Futtermittel enthalten n-3-PUFA in einem Anteil von etwa 0,1 bis 10 Gew.-%, wie z. B. 1 bis 5 Gew.-%, und/oder Vitamin E in einem Anteil von etwa 5 bis 2000 mg/kg Futter, wie z. B. 10 bis 500 mg/kg Futter.Suitable feed contains n-3-PUFA in a proportion of about 0.1 to 10 wt .-%, such as. B. 1 to 5 wt .-%, and / or vitamin E in a proportion of about 5 to 2000 mg / kg of feed, such as. B. 10 to 500 mg / kg of feed.
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Ein weiterer bevorzugter Gegenstand der Erfindung betrifft die Verwendung von n-3-PUFA und/oder Vitamin E zur Herstellung eines Medikaments oder eines Nahrungsergänzungsmittels, Supplements oder angereicherten Lebensmittels, zur Verringerung der Choleste-Another preferred object of the invention relates to the use of n-3-PUFA and / or vitamin E for the manufacture of a medicament or a food supplement, supplements or fortified food, for reducing the cholesterol
15 rinoxidbildung im menschlichen Körper. Diese Präparate sind so formuliert, daß sie eine Aufnahme von n-3-PUFA in einer Dosis im Bereich von mehr als etwa 1 mg/kg Körpergewicht, wie z.B. etwa 1 bis 200 oder etwa 10 bis 2000, wie z.B. 10 bis 200 mg/kg Körpergewicht, und/oder die Aufnahme von Vitamin E in einer Dosis im15 rinoxide formation in the human body. These preparations are formulated to take n-3 PUFA in a dose in the range of greater than about 1 mg / kg body weight, e.g. about 1 to 200 or about 10 to 2000, e.g. 10 to 200 mg / kg body weight, and / or the intake of vitamin E in one dose
20 Bereich von mehr als etwa 0,5 mg/kg Körpergewicht, wie z.B. etwa 0,5 bis 50 oder etwa 5 bis 2000, wie z.B. 5 bis 100 mg/kg Körpergewicht, durch den menschlichen Körper gewährleisten.Range greater than about 0.5 mg / kg body weight, e.g. about 0.5 to 50 or about 5 to 2000, e.g. 5 to 100 mg / kg body weight, guaranteed by the human body.
Geeignete Medikamente enthalten n-3-PUFA in einem Anteil von etwa 25 20 bis 10000 mg, wie z. B. etwa 100 bis 2000 mg, pro Dosiseinheit und/oder Vitamin E in einem Anteil von etwa 20 bis 20000 mg, wie z. B. etwa 50 bis 2000 mg, pro Dosiseinheit.Suitable drugs contain n-3-PUFA in a proportion of about 25 20 to 10000 mg, such as. B. about 100 to 2000 mg, per dose unit and / or vitamin E in a proportion of about 20 to 20,000 mg, such as. B. about 50 to 2000 mg, per unit dose.
Geeignete Nahrungsergänzungsmittel enthalten n-3-PUFA in einem 30 Anteil von etwa 10 bis 1000 mg/kg, wie z. B. 100 bis 500 mg/kg, und/oder Vitamin E in einem Anteil von etwa 5 bis 1000, wie z.B. etwa 10 bis 400 mg/kg.Suitable food supplements contain n-3-PUFA in a proportion of about 10 to 1000 mg / kg, such as. B. 100 to 500 mg / kg, and / or vitamin E in a proportion of about 5 to 1000, such as about 10 to 400 mg / kg.
Geeignete angereicherte Lebensmittel enthalten n-3-PUFA in einem 35 Anteil von etwa 10 bis 500 mg pro verzehrfertige Portion und/oder Vitamin E in einem Anteil von etwa 5 bis 1000 mg, wie z. B. etwa 10 bis 100 mg, pro verzehrfertige Portion.Suitable fortified foods contain n-3-PUFA in a portion of about 10 to 500 mg per ready-to-eat portion and / or vitamin E in an amount of about 5 to 1000 mg, such as. B. about 10 to 100 mg, per ready-to-eat portion.
Beispiele für Lebensmittel, die sich zur Anreicherung mit 40 n-3-PUFA und/oder Vitamin E eignen, sind Backprodukte, wie insbesondere Brot, Zerealien, Milch, Milchprodukte, wie insbesondere Joghurt, Schokolade, Schokoriegel und dergleichen.Examples of foods that are suitable for fortification with 40 n-3 PUFA and / or vitamin E are baked products, such as, in particular, bread, cereals, milk, milk products, such as, in particular, yoghurt, chocolate, chocolate bars and the like.
Gegenstand der Erfindung ist insbesondere auch die Verwendung von 45 n-3-PUFA und/oder Vitamin E zur Herstellung eines Medikaments, eines Nahrungsergänzungsmittels /Supplements oder angereicherten Lebensmittels gemäß obiger Definition zur Prävention Cholesteri- noxid-vermittelter atherosklerotischer Läsionen oder Cholesteri- noxid-vermittelter angiotoxischer oder atherogener Effekte beim Menschen.The invention particularly relates to the use of 45 n-3 PUFA and / or vitamin E for the manufacture of a medicament, a food supplement / supplement or fortified food as defined above for the prevention of cholesterol oxide-mediated atherosclerotic lesions or cholesterol-oxide-mediated angiotoxic or atherogenic effects in humans.
5 Im Rahmen der vorliegenden Erfindung können einzelne n-3-PUFA als Reinsubstanz alleine oder im Stoffgemisch mit anderen n-3- oder n-6-PUFA eingesetzt werden. Ebenso besteht die Möglichkeit, Mischpräparate oder Extrakte pflanzlichen oder tierischen Ursprungs zu verwenden, welche einen hohen n-3-PUFA Gehalt aufwei- 10 sen.5 In the context of the present invention, individual n-3 PUFAs can be used as pure substances on their own or in a mixture with other n-3 or n-6 PUFAs. There is also the possibility of using mixed preparations or extracts of plant or animal origin which have a high n-3-PUFA content.
Als Beispiele können hierzu genannt werden: Stoffgemische, ausgewählt unter Extrakten, Trockenpräparaten oder Homogenaten mariner Einzeller, Fischextrakten oder -ölen und Pflanzenextrakten oder 15 -ölen, und insbesondere Fischöl, Leinöl, Hanföl, Rapsöl und Soja- bohnenöl und aus marinen Einzellern, wie Phytoplankton und Algen, gewonnenen Ölen.Examples can be given here: mixtures of substances selected from extracts, dry preparations or homogenates of marine unicellular organisms, fish extracts or oils and plant extracts or 15 oils, and in particular fish oil, linseed oil, hemp oil, rapeseed oil and soybean oil and from marine unicellular organisms, such as phytoplankton and algae, extracted oils.
Im Rahmen der Erfindung sind n-3-PUFAs als freie Säure oder als 0 physiologisch verträgliches Salz oder insbesondere auch als biologisch abbaubare Ester oder als Phospholipide einsetzbar. Bevorzugte Ester umfassen Alkylester, wobei der Alkylteil ein bis sechs Kohlenstoffatome unfasst, oder Mono-, Di- oder Triglyce- ride. Beispiele für geeignete Salze sind Salze mit anorganischen 5 Basen, beispielsweise Metallhydroxiden bzw. -carbonaten von Alkali-, Erdalkali- oder Übergangsmetallen, oder mit organischen Basen, beispielsweise basischen Aminosäuren, wie Arginin und Ly- sin, Mono- oder Di-Cχ-C-Alkyl- oder Cι-C-Hydroxyalkylaminen, wie z. B. Mono- oder Diethylamin, Mono- und Diethanolamin,In the context of the invention, n-3-PUFAs can be used as free acid or as a physiologically acceptable salt or in particular also as biodegradable esters or as phospholipids. Preferred esters include alkyl esters, the alkyl part having one to six carbon atoms, or mono-, di- or triglycerides. Examples of suitable salts are salts with inorganic bases, for example metal hydroxides or carbonates of alkali metals, alkaline earth metals or transition metals, or with organic bases, for example basic amino acids, such as arginine and lysine, mono- or di-Cχ-C -Alkyl- or -CC-hydroxyalkylamines, such as. B. mono- or diethylamine, mono- and diethanolamine,
30 l-Amino-2-propanol oder 3-Amino-l-propanol, C2-C6-Alkylendiamine, wie Ethylendiamin oder Hexamethylentetraamin, gesättigte cycli- sche Amine mit 4 bis 6 Ringkohlenstoffatomen, wie Piperidin, Piperazin, Pyrrolidin und Morpholin, sowie weitere organische Basen, beispielsweise N-Methylglucamin, Kreatin und Tromethamin.30 l-amino-2-propanol or 3-amino-l-propanol, C 2 -C 6 -alkylenediamines, such as ethylenediamine or hexamethylenetetraamine, saturated cyclic amines with 4 to 6 ring carbon atoms, such as piperidine, piperazine, pyrrolidine and morpholine, as well as other organic bases, for example N-methylglucamine, creatine and tromethamine.
35 Bevorzugt werden Salze mit anorganischen Basen, z. B. Na-, K-, Mg-, Ca-, Zn-, Cr- und Fe-Salze.35 Preferred are salts with inorganic bases, for. B. Na, K, Mg, Ca, Zn, Cr and Fe salts.
Gemäß einer bevorzugten Ausführungsform verwendet man erfindungsgemäß als n-3-PUFA eine mehrfach ungesättigte n-3-Fettsäure mitAccording to a preferred embodiment, a polyunsaturated n-3 fatty acid is used according to the invention as the n-3 PUFA
40 18 bis 22 Kohlenstoffatomen oder ein wenigstens eine mehrfach ungesättigte n-3-Fettsäure mit 18 bis 22 Kohlenstoffatomen enthaltendes Stoffgemisch. Besonders bevorzugt ist dabei die mehrfach ungesättigte n-3-Fettsäure ausgewählt unter α-Linolensäure (C18:3n-3) (α-LNA), Eicosapentaensäure (C20:5n-3) (EPA); Docosa-40 18 to 22 carbon atoms or a mixture containing at least one polyunsaturated n-3 fatty acid with 18 to 22 carbon atoms. The polyunsaturated n-3 fatty acid is particularly preferably selected from α-linolenic acid (C18: 3n-3) (α-LNA), eicosapentaenoic acid (C20: 5n-3) (EPA); docosahexaenoic
45 pentaensäure (C22:5n-3) (DPA) und Docosahexaensäure (C22:6n-3) (DHA) . Besonders bevorzugt verabreichbare n-3-PUFA-Gemische umfassen EPA und DHA; α-LNA und EPA; oder α-LNA und DHA. In diesen n-3-PUFA Gemischen liegen vorzugsweise folgenden Mischungsverhältnisse vor:45 pentaenoic acid (C22: 5n-3) (DPA) and docosahexaenoic acid (C22: 6n-3) (DHA). N-3-PUFA mixtures which can be administered particularly preferably include EPA and DHA; α-LNA and EPA; or α-LNA and DHA. In these n-3-PUFA mixtures preferably have the following mixing ratios:
EPA : DHA = 5:95 Gew.-% bis 95:5 Gew.-%; wie z.B. 15:85 Gew.-% bis 60:40 Gew.-%;EPA: DHA = 5:95% to 95: 5% by weight; such as. 15:85 wt% to 60:40 wt%;
α-LNA : EPA = 5:95 Gew.-% bis 95:5 Gew.-%;α-LNA: EPA = 5:95% by weight to 95: 5% by weight;
α-LNA : DHA = 5:95 Gew.-% bis 95:5 Gew.-%;α-LNA: DHA = 5:95% by weight to 95: 5% by weight;
Das im Rahmen der Erfindung verwendete Vitamin E umfasst die To- copherole α, ß, γ, und δ und die Tocotrienole α, ß, γ un δ einzeln oder im Gemisch, wie z.B. ein Gemisch von Tocopherol α und γ.The vitamin E used in the context of the invention comprises the tocopherols α, β, γ, and δ and the tocotrienols α, β, γ and δ individually or in a mixture, such as e.g. a mixture of tocopherol α and γ.
In einer weiteren bevorzugten Ausfuhrungsform betrifft die Erfindung die Verwendung einer Kombination von n-3-PUFA oder eines biologisch abbaubaren Esters davon und Vitamin E zu den oben genannten Zwecken.In a further preferred embodiment, the invention relates to the use of a combination of n-3-PUFA or a biodegradable ester thereof and vitamin E for the purposes mentioned above.
Gemäß einer weiteren bevorzugten Ausfuhrungsform werden eine oder mehrere n-3-PUFA oder ein oder mehrere biologisch abbaubarer Ester davon ohne Zusatz von Vitamin E verwendet.According to a further preferred embodiment, one or more n-3 PUFA or one or more biodegradable esters thereof are used without the addition of vitamin E.
Zur erfindungsgemäßen Verwendung können n-3-PUFA und/oder Vitamin E, entweder als einzelne Wirkstoffe oder als Mischungen mit anderen therapeutischen Wirkstoffen, in Form geeigneter human- oder veterinärmedizischer Medikamente verabreicht werden. Darin liegen sie als Mischungen der Wirkstoffe mit geeigneten pharmazeutischen Trägern oder Verdünnungsmitteln vor.For the use according to the invention, n-3-PUFA and / or vitamin E, either as individual active substances or as mixtures with other therapeutic active substances, can be administered in the form of suitable human or veterinary medicinal drugs. They are present as mixtures of the active ingredients with suitable pharmaceutical carriers or diluents.
Beispiele geeigneter pharmazeutischer Formulierungen sind feste Arzneiformen, wie Pulver, Puder, Granulate, Tabletten, insbesondere Filmtabletten, Pastillen, Sachets, Cachets, Dragees, Kapseln wie Hart- und Weichgelatinekapseln, halbfeste Arzneiformen, wie Salben, Cremes, Hydrogele, Pasten oder Pflaster, sowie flüssige Arzneiformen, wie Lösungen, Emulsionen, insbesondere Öl-in-Was- ser-Emulsionen, Suspensionen, beispielsweise Lotionen, Injek- tions- und Infusionszubereitungen, Augen- und Ohrentropfen. Auch implantierte Abgabevorrichtungen können zur Verabreichung erfin- dungsgemäßer Wirkstoffe verwendet werden. Ferner können auch Li- posomen oder Mikrosphären zur Anwendung kommen.Examples of suitable pharmaceutical formulations are solid pharmaceutical forms, such as powders, powders, granules, tablets, in particular film-coated tablets, pastilles, sachets, cachets, dragees, capsules such as hard and soft gelatin capsules, semi-solid pharmaceutical forms, such as ointments, creams, hydrogels, pastes or plasters, and also liquid pharmaceutical forms, such as solutions, emulsions, in particular oil-in-water emulsions, suspensions, for example lotions, injection and infusion preparations, eye and ear drops. Implanted delivery devices can also be used for the administration of active substances according to the invention. Liposomes or microspheres can also be used.
Die Formulierungen können beispielsweise auf oralem, transdermalem, subkutanem, intravenösem, intramuskulärem oder intranasalem Weg verabreicht werden. Bevorzugt ist die orale Verabreichung. Bei der Herstellung der Zusammensetzungen werden die Wirkstoffe gewöhnlich mit einem geeigneten Hilfsstoff oder Exzipienten vermischt oder verdünnt. Exzipienten können feste, halbfeste oder flüssige Materialien sein, die als Vehikel, Träger oder Medium für den Wirkstoff dienen. Die Zumischung weiterer Hilfsstoffe erfolgt erforderlichenfalls in an sich bekannter Weise. Es können Formgebungsschritte, gegebenenfalls in Verbindung mit Mischvör- gangen, durchgeführt werden, z.B. eine Granulierung, Komprimierung und ähnliches .The formulations can be administered, for example, by the oral, transdermal, subcutaneous, intravenous, intramuscular or intranasal route. Oral administration is preferred. When preparing the compositions, the active ingredients are usually mixed or diluted with a suitable excipient or excipient. Excipients can be solid, semi-solid or liquid materials that serve as vehicles, carriers or media for the active ingredient. If necessary, further auxiliaries are added in a manner known per se. Shaping steps, possibly in connection with mixing processes, can be carried out, for example granulation, compression and the like.
Insbesondere können die Wirkstoffkomponenten gemeinsam formuliert werden. Sie können aber auch zunächst getrennt verarbeitet und anschließend in einer kompartimentierten, z.B. mehrschichtigen Arzneiform zusammengeführt werden. Dadurch kann möglichen Wirk- stoffinkompatibilitäten und unterschiedlichen Wirkstoffeigenschaften, wie Bioverfügbarkeit, Stabilität, Löslichkeit und ähnlichem, Rechnung getragen werden.In particular, the active ingredient components can be formulated together. However, they can also be processed separately first and then in a compartmented, e.g. multilayer drug form can be merged. In this way, possible drug incompatibilities and different drug properties such as bioavailability, stability, solubility and the like can be taken into account.
Die Art des pharmazeutischen Mittels und des pharmazeutischen Trägers bzw. Verdünnungsmittels hängt von der gewünschten Verabreichungsart ab. Orale Mittel können beispielsweise als Tabletten oder Kapseln vorliegen und können übliche Exzipienzien enthalten, wie Bindemittel (z. B. Sirup, Akazia, Gelatine, Sorbit, Tragant oder Polyvinylpyrrolidon) , Füllstoffe (z. B. Lactose, Zucker, Maisstärke, Calciumphosphat, Sorbit oder Glycin), Gleitmittel (z. B. Magnesiumstearat, Talcum, Polyethylenglykol oder Siliciumdio- xid), disintegrierende Mittel (z. B. Stärke) oder Netzmittel (z. B. Natriumlaurylsulfat) . Orale flüssige Präparate können in Form wässriger oder öliger Suspensionen, Lösungen, Emulsionen, Siru- pen, Elixieren oder Sprays usw. vorliegen oder können als Trok- kenpulver zur Rekonstitution mit Wasser oder einem anderen geeigneten Träger vorliegen. Derartige flüssige Präparate können übliche Additive, beispielsweise Suspendiermittel, Geschmacksstoffe, Verdünnungsmittel oder Emulgatoren, enthalten. Für die parenterale Verabreichung kann man Lösungen oder Suspensionen mit üblichen pharmazeutischen Trägern einsetzen.The type of pharmaceutical agent and the pharmaceutical carrier or diluent depends on the desired mode of administration. Oral agents can be present, for example, as tablets or capsules and can contain conventional excipients, such as binders (e.g. syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone), fillers (e.g. lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine), lubricants (e.g. magnesium stearate, talc, polyethylene glycol or silicon dioxide), disintegrating agents (e.g. starch) or wetting agents (e.g. sodium lauryl sulfate). Oral liquid preparations can be in the form of aqueous or oily suspensions, solutions, emulsions, syrups, elixirs or sprays etc. or can be in the form of dry powder for reconstitution with water or another suitable carrier. Such liquid preparations can contain conventional additives, for example suspending agents, flavoring agents, diluents or emulsifiers. Solutions or suspensions with conventional pharmaceutical carriers can be used for parenteral administration.
Die erfindungsgemäßen Mittel können an einen Menschen oder ein Tier in einer täglichen Dosis von etwa 0,1 bis etwa 10000 mg/kg Körpergewicht, wie z. B. bis etwa 2000 mg/kg Körpergewicht, verabreicht werden. Sie können in einer Einzeldosis oder in mehreren Dosen verabreicht werden.The agents according to the invention can be administered to a human or an animal in a daily dose of about 0.1 to about 10000 mg / kg body weight, such as. B. up to about 2000 mg / kg body weight, administered. They can be administered in a single dose or in multiple doses.
Zur erfindungsgemäßen Verwendung können n-3-PUFA und/oder Vitamin E auch in Form geeigneter Supplemente/ Nahrungsergänzungsmittel verabreicht werden. Als Beispiele können genannt werden mit n-3-PUFA und/oder Vitamin E angereicherte Fettemulsionen, welche man z.B. in herkömmlicher Weise aus Sojabohnenöl oder Fischöl mit Eilecithin als Emulgator herstellt. Vorteilhafterweise verwendet man dazu Eilecithin, das aus Ei von Legehennen gewonnen wurde, welche mit n-3-PUFA- und/oder Vitamin E-reichem Futter längere Zeit, wie z.B. 3 bis 6 Wochen, gefüttert wurden.For the use according to the invention, n-3-PUFA and / or vitamin E can also be administered in the form of suitable supplements / food supplements. Examples include fat emulsions enriched with n-3-PUFA and / or vitamin E. one produces in a conventional manner, for example, from soybean oil or fish oil with egg lecithin as the emulsifier. Egg lecithin, which was obtained from egg from laying hens, which were fed with n-3-PUFA and / or vitamin E-rich feed for a long time, such as, for example, 3 to 6 weeks, is advantageously used for this purpose.
n-3-PUFA und/oder Vitamin E können weiterhin als speziell angereicherte Lebensmittel formuliert werden, welche ebenso wie die genannten Supplemente oder Nahrungsergänzungsmittel im Rahmen ei- ner enteralen Ernährungstherapie einsetzbar sind. Als Beispiele für geeignete Lebensmittel können z.B. diätetische Lebensmittel, wie z.B. nährstoffdefinierte Trinknahrung, Sportlernahrung, Diabetikernahrung oder Säuglings- oder Frühgeborenennahrung, Frühstückszubereitungen, vor allem in Form von Müslis oder Riegeln, genannt werden.n-3-PUFA and / or vitamin E can also be formulated as specially fortified foods, which, like the supplements or dietary supplements mentioned, can be used as part of enteral nutritional therapy. As examples of suitable foods e.g. dietary foods such as nutrient-defined drinking food, sports food, diabetic food or baby or premature food, breakfast preparations, especially in the form of muesli or bars.
In den erfindungsgemäß eingesetzten Mitteln können n-3-PUFA und/ oder Vitamin E gewünschtenfalls mit weiteren Wirkstoffen kombiniert werden. Geeignete Wirkstoffe sind z. B. Vitamine, Cofakto- ren, Spurenelemente, Mineralstoffe, Aminosäuren oder pharmazeutische Substanzen. Besonders bevorzugt ist die Kombination mit essentiellen Nährstoffen.In the agents used according to the invention, n-3-PUFA and / or vitamin E can, if desired, be combined with other active ingredients. Suitable active ingredients are e.g. B. vitamins, cofactors, trace elements, minerals, amino acids or pharmaceutical substances. The combination with essential nutrients is particularly preferred.
Zu den essentiellen Nährstoffen zählen insbesondere Vitamine, Provitamine, Spurenelemente, Aminosäuren und Fettsäuren. Als essentielle Aminosäuren seien genannt Isoleucin, Leucin, Lysin, Me- thionin, Phenylalanin, Threonin, Tryptophan und Valin. Dazu gehören auch semi-essentielle Aminosäuren, die beispielsweise in Wachstumsphasen oder Mangelzuständen zugeführt werden müssen, wie Glutamin, Arginin, Histidin, Cystein und Tyrosin. Als Spurenelemente seien genannt: essentielle Mineralstoffe und Spurenelemente, deren Notwendigkeit für den Menschen erwiesen ist und deren Mangel zur Manifestation klinischer Symptome führt: Eisen, Kupfer, Zink, Chrom, Selen, Calcium, Magnesium, Kalium, Cobalt, Molybdän, Iod, Silicium, Fluor, Mangan. Ebenso Elemente, deren Funktion für den Menschen noch nicht genügend gesichert ist: Zinn, Nickel, Vanadium, Arsen. Als für den Menschen essentielle Fettsäuren seien genannt: Linolsäure und Linolensäure und unter bestimmten Umständen auch Arachidonsäure, Eicosapentaensäure und Docosahexaensäure. Eine umfassende Aufzählung von Vitaminen findet sich in "Referenzwerte für die Nährstoffzufuhr", 1. Auflage, Umschau Braus Verlag, Frankfurt am Main, 2000, herausgegeben von der Deutschen Gesellschaft für Ernährung.The essential nutrients include in particular vitamins, provitamins, trace elements, amino acids and fatty acids. Isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine are mentioned as essential amino acids. This also includes semi-essential amino acids that have to be added, for example, during growth phases or deficiency states, such as glutamine, arginine, histidine, cysteine and tyrosine. The following may be mentioned as trace elements: essential minerals and trace elements, the necessity of which has been proven for humans and the lack of which leads to the manifestation of clinical symptoms: iron, copper, zinc, chromium, selenium, calcium, magnesium, potassium, cobalt, molybdenum, iodine, silicon, Fluorine, manganese. Likewise, elements whose function is not yet sufficiently assured for humans: tin, nickel, vanadium, arsenic. The following are mentioned as essential fatty acids for humans: linoleic acid and linolenic acid and under certain circumstances also arachidonic acid, eicosapentaenoic acid and docosahexaenoic acid. A comprehensive list of vitamins can be found in "Reference Values for Nutrient Supply", 1st edition, Umschau Braus Verlag, Frankfurt am Main, 2000, published by the German Nutrition Society.
in Lebensmitteln werden die erfindungsgemäßen Wirkstoffe mit üblichen Nahrungskomponenten kombiniert. Diese umfassen pflanzliche aber auch tierische Produkte, insbesondere Zucker gegebenenfalls in Form von Sirups, FruchtZubereitungen, wie Fruchtsäfte, Nektar, Fruchtpulpen, Pürees oder getrocknete Früchte, beispielsweise Apfelsaft, Grapefruitsaft, Orangensaft, Apfelmus, Tomatensauce, Tomatensaft, Tomatenpüree; Getreideprodukte, wie Weizenmehl, Rog- genmehl, Hafermehl, Maismehl, Gerstenmehl, Dinkelmehl, Maissirup, sowie Stärken der genannten Getreide; Milchprodukte, wie Milcheiweiß, Molke, Joghurt, Lecithin und Milchzucker.in foods, the active compounds according to the invention are combined with conventional nutritional components. These include vegetable but also animal products, especially sugar if necessary in the form of syrups, fruit preparations, such as fruit juices, nectar, fruit pulps, purees or dried fruits, for example apple juice, grapefruit juice, orange juice, applesauce, tomato sauce, tomato juice, tomato puree; Cereal products, such as wheat flour, rye flour, oat flour, corn flour, barley flour, spelled flour, corn syrup, and starches of the cereals mentioned; Dairy products such as milk protein, whey, yogurt, lecithin and milk sugar.
Werden n-3-PUFA und/oder Vitamin E einzeln oder in Kombination in Futtermittel verabreicht, so werden die aktiven Verbindungen als Reinsubstanz oder Stoffgemische oder flüssige oder feste Extrakte zusammen mit üblichen Futtermittelbestandteilen verabreicht. Beispiele üblicher Futtermittelbestandteile sind: Mais, Gerste, Weizen, Hafer, Roggen, Tritikale, Sorghum, Reis und Kleien, Gries- kleien sowie Mehle dieser Getreidearten, Sojabohnen, Sojaprodukte wie Sojaextraktionsschrot, Raps, Rapsextraktionsschrot, Baumwollsaat und Extraktionsschrot, Sonnenblumen, Sonnenblumenextraktionsschrot, Leinsaat, Leinextraktionsschrot, Expeller von Ölsaa- ten, Ackerbohnen, Erbsen, Gluten, Gelatine, Tapioka, Hefen, Sin- gle Cell Protein, Fleischknochenmehl, Fleischmehl, Blutmehl,If n-3-PUFA and / or vitamin E are administered individually or in combination in feed, the active compounds are administered as pure substance or mixtures of substances or liquid or solid extracts together with conventional feed ingredients. Examples of common feed ingredients are: maize, barley, wheat, oats, rye, tritale, sorghum, rice and bran, semolina and flours of these cereals, soybeans, soy products such as soy extraction meal, rapeseed, rapeseed extraction meal, cottonseed and extraction meal, sunflower, sunflower extract, sunflower extract , Flax extraction meal, oil seed expeller, field beans, peas, gluten, gelatin, tapioca, yeast, single cell protein, meat bone meal, meat meal, blood meal,
Fischmehl, Salze, Mineralstoffe, Spurenelemente, Vitamine, Aminosäuren, Futterfett und dergleichen .Fish meal, salts, minerals, trace elements, vitamins, amino acids, feed fat and the like.
Die vorliegende Erfindung wird nun durch folgendes Ausführungs- beispiel und unter Bezugnahme auf die beiliegende Figur 1 näher erläutert.The present invention is now explained in more detail by the following exemplary embodiment and with reference to the accompanying FIG. 1.
Figur 1 zeigt den Konzentrationsverlauf verschiedener Cholesterinoxide in frischem Eidotter (schwarze Symbole) bzw. nach 4-wöchiger Lagerung des Eis bei Raumtemperatur (helleFigure 1 shows the concentration curve of various cholesterol oxides in fresh egg yolk (black symbols) or after 4 weeks of storage of the egg at room temperature (light
Symbole), jeweils nach 4-wöchiger Verfütterung eines 1,5 Gew.-% Fischöl und verschiedene Mengen (mg/kg) Vitamin E enthaltenden Futters an Legehennen.Symbols), each after 4 weeks of feeding 1.5% by weight of fish oil and various amounts (mg / kg) of vitamin E to laying hens.
Beispiel 1: Untersuchung der Cholesterinoxid-Bildung in Eidotter bei Verfütterung von n-3-PUFA und verschiedener Mengen Vitamin EExample 1: Examination of cholesterol oxide formation in egg yolk when n-3-PUFA and various amounts of vitamin E were fed
a) Folgende Grundmischung (Tabelle 1) für ein Legehennen-Allein- futter wurde hergestellt: Tabelle 1: Futtergrundmischunga) The following basic mixture (Table 1) for a layer hen feed was produced: Table 1: Basic feed mix
Figure imgf000010_0001
Figure imgf000010_0001
1) Zusammensetzung siehe Tabelle 21) For composition, see table 2
2) ohne Vitamin E; Zusammensetzung siehe Tabelle 22) without vitamin E; For composition, see table 2
3) C30-Ester (gelb)3) C 30 -Ester (yellow)
Das Grundfutter wies folgenden Nährstoff-, Vitamin- und Spurenelementgehalt (Tabelle 2) auf: The basic feed had the following nutrient, vitamin and trace element content (Table 2):
Tabelle 2: kalkulierter Nährstoff-, Vitamin- und SpurenelementgehaltTable 2: calculated nutrient, vitamin and trace element content
Figure imgf000011_0001
χ) metabolisierbare Energie
Figure imgf000011_0001
χ ) metabolizable energy
b) Diese Grundfuttermischung wurde mit 1,5 Gewichtsprozent Fischöl (enthaltend 11,5 Gew.-% Eicosapentaensäure (EPA) und 8 Gew.-% Docosahexanensaure (DHA)) versetzt. Außerdem wurden dem Futter die in Figur 1 angegebenen Vitamin E-Mengen (0, 5, 10, 20, 160 mg/kg Futter) zugesetzt. Weiße Legehennen (Alter 35 Wochen) wurden in verschiedene Versuchsgruppen zu je 12 Tieren (Kontrollgruppe 36 Tiere) aufgeteilt und mit den unterschiedlich supple- mentierten Futterzusammensetzungen ad libitum gefüttert. Eine Kontrollgruppe erhielt unsupplementiertes Futter. Die Fütterungs- phase betrug vier Wochen. In der fünften Woche wurden die Eier gesammelt und analysiert. Die Analyse des Gesamt-Cholesterols sowie der Cholesterol-Oxidationsprodukte erfolgte nach dem von Se- vanian A., et al. in Free Radic. Biol. Med. (1994); 17: 397-409 beschriebenen Verfahren. Die Analysen wurden sowohl an frischen als auch an gelagerten (vier Wochen bei Raumtemperatur) Eiern durchgeführt. Die Analyse von Vitamin E erfolgte durch HPLC, wie z.B. beschrieben von Wähle, et al., J. Sei. Food Agric (1993), 61, 463; die Analyse von n-3-PUFA erfolgte durch Gaschromatographie (Simopoulos et al., a.a.O.).b) 1.5% by weight of fish oil (containing 11.5% by weight of eicosapentaenoic acid (EPA) and 8% by weight of docosahexane acid (DHA)) was added to this basic feed mixture. In addition, the amounts of vitamin E given in FIG. 1 (0, 5, 10, 20, 160 mg / kg feed) were added to the feed. White laying hens (age 35 weeks) were divided into different test groups of 12 animals each (control group 36 animals) and fed ad libitum with the differently supplemented feed compositions. A control group received unsupplemented feed. The feeding phase was four weeks. In the fifth week, the eggs were collected and analyzed. The analysis of the total cholesterol and the cholesterol oxidation products was carried out according to the method of Sevianian A., et al. in Free Radic. Biol. Med. (1994); 17: 397-409. The analyzes were carried out on both fresh and stored eggs (four weeks at room temperature). Vitamin E was analyzed by HPLC, as described, for example, by Wahl, et al., J. Sei. Food Agric (1993), 61, 463; the analysis of n-3-PUFA was carried out by gas chromatography (Simopoulos et al., loc. cit.).
c) Der Gehalt an n-3-PUFA in Eidotter stieg auf Werte von etwa 10 mg/g und zwar überwiegend in Form von DHA. Mit zunehmendem Vitcimin E-Gehalt im Futter nahm auch der Vitamin E-Gehalt von 5,33 +/- 1,54 nmol/g auf 11,63 +/- 2,96 nmol/g, bestimmt durch HPLC, zu.c) The content of n-3-PUFA in egg yolk rose to values of about 10 mg / g, mainly in the form of DHA. With increasing Vitcimin E content in the feed, the vitamin E content also increased from 5.33 +/- 1.54 nmol / g to 11.63 +/- 2.96 nmol / g, determined by HPLC.
Während der Cholesteringehalt in Dotter im Verlauf der Verfütterung von Vitamin E oder bei der Lagerung konstant blieb, wurde überraschenderweise beobachtet, daß mit vermehrter Gabe von n-3-PUFA und/oder Vitamin E weniger Cholesterin-Oxidationspro- dukte akkumulierten (vgl. Figur 1). Die Summe der nachweisbaren Cholesterin-Oxidationsprodukte im Eidotter (d.h. Summe aus Cho- lest-5-en-3ß,7ß-diol, Cholest-5-en-3ß-ol-7-on und Cho- lest-5-en-3ß,25-diol) betrug in der Kontrollgruppe 266 +/- 49 nmol/mg Eidotter und wurde durch Verfütterung von n-3-PUFA um 20 % und durch Verfütterung von Vitcimin E (20 mg/kg Futter) um ein weiteres Drittel gesenkt.While the cholesterol content in yolk remained constant during the course of feeding vitamin E or during storage, it was surprisingly observed that with increased administration of n-3-PUFA and / or vitamin E less cholesterol oxidation products accumulated (cf. FIG. 1 ). The total of the detectable cholesterol oxidation products in the egg yolk (ie the sum of cholest-5-en-3ß, 7ß-diol, cholest-5-en-3ß-ol-7-one and cholest-5-en-3ß , 25-diol) was 266 +/- 49 nmol / mg egg yolk in the control group and was reduced by 20% by feeding n-3-PUFA and by feeding Vitcimin E (20 mg / kg feed) by a further third.
Zusammenfassend ist somit festzustellen, daß eine Anreicherung von Hühnerei mit n-3-PUFA und Vitamin E den Gehalt an Cholesterinoxiden im Eidotter verringert und somit die Produktion von Hühe- rei mit geringeren atherogenen Eigenschaften ermöglicht.In summary, it can thus be stated that an enrichment of chicken egg with n-3-PUFA and vitamin E reduces the content of cholesterol oxides in the egg yolk and thus enables the production of chicken egg with lower atherogenic properties.
Beispiel 2: Funktionale NahrungsmittelExample 2: Functional foods
a) Müsliriegela) Granola bars
Ein Müsliriegel, enthaltend 250 mg Fischöl und 100 mg Vitamin E pro Riegel (60 g) wird nach folgender Rezeptur in an sich bekann- ter Weise hergestellt: Fischöl 250 mg (entspr. ca. 85 mg n-3-PUFA)A muesli bar containing 250 mg fish oil and 100 mg vitamin E per bar (60 g) is produced in a known manner according to the following recipe: Fish oil 250 mg (corresponding to approx. 85 mg n-3-PUFA)
D/L-α-Tocopherol 100 mgD / L-α-tocopherol 100 mg
Sirup aus Fructose 4,2 gFructose syrup 4.2 g
Glucose 12 gGlucose 12 g
Gebräuntem Zucker 3 gBrowned sugar 3 g
Glycerin 3 gGlycerin 3 g
Leeithin 125 mgCurrently 125 mg
Gehärtetes Pflanzenöl 1,2 gHardened vegetable oil 1.2 g
Geröstete Haferflocken 17,975 gRoasted oatmeal 17.975 g
Puffreis 7 gPuffed rice 7 g
Geröstete und gehackte Mandeln 5,6 gRoasted and chopped almonds 5.6 g
Kokosflocken 4 gCoconut flakes 4 g
b) Ein Müsli, enthaltend 200 mg Fischöl und 60 mg Vitamin E pro 100 g Müsli wird nach folgender Rezeptur in an sich bekannter weise hergestellt:b) A muesli containing 200 mg fish oil and 60 mg vitamin E per 100 g muesli is produced according to the following recipe in a manner known per se:
Haferflocken 35 g Weizenflocken 27 gOat flakes 35 g wheat flakes 27 g
Rosinen 13 gRaisins 13 g
Getrocknete Apfelscheiben 6 gDried apple slices 6 g
Getrocknete Aprikosen 3 gDried apricots 3 g
Weizenkeime 3 g Geröstete und gemahleneWheat germ 3 g Roasted and ground
Haselnüsse 6 gHazelnuts 6 g
Angereichertes Milchpulver, 7 g enthaltendEnriched milk powder, containing 7 g
Fischöl 200 mg (entsp. ca 70 mg n-3-PUFA)Fish oil 200 mg (approx. 70 mg n-3-PUFA)
D/L-α-Tocopherol 60 mgD / L-α-tocopherol 60 mg
Lecithin 200 mgLecithin 200 mg
Beispiel 3: Weichgelatine-KapselnExample 3: Soft gelatin capsules
Weichgelatine-Kapseln, enthaltend 500 mg Fischöl und 60 mg Vitamin E pro Kapsel, werden nach folgender Rezeptur in an sich bekannter Weise hergestellt:Soft gelatin capsules, containing 500 mg fish oil and 60 mg vitamin E per capsule, are manufactured according to the following recipe in a manner known per se:
Fischöl 500 mg (entsp. ca. 170 mg n-3-PUFA) D/L-α-Tocopherol 60 mg Fish oil 500 mg (approx. Approx. 170 mg n-3-PUFA) D / L-α-tocopherol 60 mg

Claims

Patentansprüche claims
1. Verwendung von n-3-PUFA und/oder Vitamin E zur Herstellung eines Mittels zur Verringerung der Cholesterinoxidbildung und/oder zur Prävention Cholesterinoxid-vermittelter Krank- heitszustände im menschlichen oder tierischen Körper.1. Use of n-3-PUFA and / or vitamin E for the production of an agent for reducing cholesterol oxide formation and / or for preventing cholesterol oxide-mediated disease states in the human or animal body.
2. Verwendung nach Anspruch 1 zur Herstellung eines veterinärme- dizinischen Medikaments oder eines Futtermittels zur Verringerung der Cholesterinoxidbildung im tierischen Körper oder in Nahrungsmitteln tierischer Herkunft.2. Use according to claim 1 for the manufacture of a veterinary medicinal medicament or a feed for reducing cholesterol oxide formation in the animal body or in foods of animal origin.
3. Verwendung nach Anspruch 1 zur Herstellung eines Medikaments , eines Nahrungsergänzungsmittels/Supplements oder angereicherten Lebensmittels zur Verringerung der Cholesterinoxidbildung im menschlichen Körper.3. Use according to claim 1 for the manufacture of a medicament, a food supplement / supplement or fortified food for reducing cholesterol oxide formation in the human body.
4. Verwendung nach Anspruch 1 zur Herstellung eines Medikaments, eines Nahrungsergänzungsmittels/ Supplements oder angereicherten Lebensmittels zur Prävention Cholesterinoxid-vermittelter atherosklerotischer Läsionen oder Cholesterinoxid-vermittelter angiotoxischer oder atherogener Effekte beim Menschen.4. Use according to claim 1 for the manufacture of a medicament, a food supplement / supplement or fortified food for the prevention of cholesterol oxide-mediated atherosclerotic lesions or cholesterol oxide-mediated angiotoxic or atherogenic effects in humans.
5. Verwendung nach einem der vorhergehenden Ansprüche, wobei n-3-PUFA oder ein biologisch abbaubarer Ester davon und Vitamin E in Kombination eingesetzt werden.5. Use according to one of the preceding claims, wherein n-3-PUFA or a biodegradable ester thereof and vitamin E are used in combination.
6. Verwendung nach einem der vorhergehenden Ansprüche, wobei als n-3-PUFA wenigstens eine mehrfach ungesättigte n-3-Fettsäure mit 18 bis 22 Kohlenstoffatomen oder ein wenigstens eine mehrfach ungesättigte n-3-Fettsäure mit 18 bis 22 Kohlenstoffatomen enthaltendes Stoffgemisch eingesetzt wird.6. Use according to one of the preceding claims, wherein at least one polyunsaturated n-3 fatty acid with 18 to 22 carbon atoms or at least one polyunsaturated n-3 fatty acid with 18 to 22 carbon atoms is used as the n-3-PUFA ,
7 . Verwendung nach Anspruch 6 , wobei die mehrfach ungesättigte n-3-Fettsäure ausgewählt ist unter α-Linolensäure (Cιβ : 3n-3 ) , Eicosapentaensäure (C2ü : 5n-3 ) ; Docosapentaensäure (C22 :5n-3 ) und Docosahexaensäure (C22 : 6n-3 ) .7. Use according to claim 6, wherein the polyunsaturated n-3 fatty acid is selected from α-linolenic acid (Cιβ: 3n-3), eicosapentaenoic acid (C 2ü : 5n-3); Docosapentaenoic acid (C 22 : 5n-3) and Docosahexaenoic acid (C 22 : 6n-3).
8. Verwendung nach Anspruch 6, wobei das Stoffgemisch ausgewählt ist unter Extrakten, Trockenpräparaten oder Homogenaten mariner Einzeller, Fischextrakten oder -ölen und Pflanzenextrakten oder -ölen. Verwendung nach Anspruch 8, worin das Stoffgemisch ausgewählt ist unter Fischöl, Leinöl, Hanföl, Rapsöl und Sojabohnenöl und aus marinen Einzellern gewonnenen Ölen. 8. Use according to claim 6, wherein the mixture of substances is selected from extracts, dry preparations or homogenates of marine unicellular organisms, fish extracts or oils and plant extracts or oils. Use according to claim 8, wherein the mixture of substances is selected from fish oil, linseed oil, hemp oil, rapeseed oil and soybean oil and oils obtained from marine unicellular organisms.
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