DE3739700A1 - Formulations containing alpha -linolenic acid (18:3, omega 3) and/or derivatives thereof, and process for their preparation and use in nutrition and medicine - Google Patents

Abstract

The unsaturated fatty acids eicosatetraenoic acid (20:4, omega 6) and eicosapentaenoic acid (20: 5, omega 3) play an extremely important role in human fat metabolism; from them are formed the metabolites prostaglandins and leucotrienes, present in every cell, which are essential for normal cell function. Eicosapentaenoic acid principally occurs in fish or fish products. A diet rich in eicosapentaenoic acid has a favourable effect on specific diseases from the prophylactic and therapeutic aspect. The supply necessary for this purpose of a considerable amount of fish or fish oil is associated with severe disadvantages such as low stability, part being in the liquid form, digestion and taste disturbance, increased supply of cholesterol and triglycerols which contain fatty acids other than eicosapentaenoic acid. alpha -Linolenic acid (18:3, omega 3) which occurs in linseed oil and other crops, is metabolised in the body to give eicosapentaenoic acid. The disadvantages of the fish diet can be avoided, retaining the same action, by using linseed oil and other alpha -linolenic acid-containing crops. The alpha -linolenic acid present in the linseed oil or in other crops can be isolated and then used itself, or better as a derivative, e.g. as the magnesium salt of alpha -linolenic acid; oral intake thus becomes significantly simpler and the taste is more pleasant. Linseed and linseed oil and the other... Original abstract incomplete.

Description

The present invention relates to alpha-linolenic acid (18: 3, Formulations containing omega 3) and / or their derivatives, and processes for their manufacture.

In addition to eicosatetraenic acid, eicosapentaic acid has re a particularly important function as another output Substance in fatty acid metabolism. The primary metabolism tion of eicosapentaenoic acid by the lipoxygenase to the corresponding leukotrienes LTA-5, LTB-5, LTC-5, LTD- 5, LTE-5, LTF-5 u. a. Is the Eikosapentaensäure primarily by When the cyclooxygenase is metabolized, the prostaglan arises dine PGD-3, PGE-3, PGF-3, PGI-3, TXA-3 and a. PGI-3 has similar properties which inhibit platelet aggregation, such as PGI-2 (prostacyclin). TXA-3 promotes platelet aggregation tion not in contrast to the TXA-2 (thromboxane). A vasodila tion is evidenced by both PGI-3 and TXA-3 called.

If there is little eicosapentaenoic acid in the food (20: 5, Omega 3), so the platelet aggregation tendency depends mainly from the metabolites of eicosatetraenoic acid (20: 4, Omega 6), the TXA-2 and PGI-2. Will the concentrate on the eicosapentaenoic acid, the platelet Inclination tendency also from the metabolites of the eikosa pentaenoic acid, the TXA-3 and PGI-3, since both fatty acids from the same enzymes are metabolized. Because the concentra tion of TXA-2 decreases and TXA-3 has no effect on the thrombus exerts cell aggregation, takes the resulting aggregation incline.  

Many diseases, e.g. B. cardiovascular diseases are through causes an increased platelet aggregation tendency or influenced. Decreases the thrombocy's tendency to aggregate from the fact that the concentration of eicosapentaenoic acid or their metabolites increase, it can be deduced from this that the risk of developing cardiovascular diseases takes.

As mentioned above, eicosatetraenoic acid can be primary can also be metabolized via lipoxygenase. Ent the leukotrienes LTA-4, LTB-4, LTC-4 u. a., the structurally different from prostaglandins the. The leukotrienes are characterized by pulmonary, cardiac, vascular u. a. Effects from. Asthma, anaphylaxis and inflammation Reaction reactions are decisively influenced by leukotrienes flows.

The eicosapentaenoic acid is also via the lipoxygenase metabolized, the leukotrienes LTA-5, LTB-5, LTC- 5 u. a. arise that are structurally and in their effect differ from the leukotrienes of eicosatetraenoic acid. It can be assumed that the leukotrienes of the eicosapentaen acid re on the development of anaphylaxis, asthma and other er diseases also have a favorable influence, in the sense of a Reduction of ongoing reactions, like the pro take staglandine of eicosapentaenoic acid in the formation of Cardiovascular disease.

Eicosatetraenic acid is only becoming moderate ingested with food. Most of the Eikosatetra Enoic acid (20: 4, omega 6) is made in the body from a precursor, the essential fatty acid linoleic acid (18: 2, omega 6). Even eicosapentaenoic acid (20: 5, omega 3) is only available in whole absorbed in small amounts with food. By far the greatest Part of the eicosapentaenoic acid is obtained from a precursor, the essential fatty acid alpha-linolenic acid (18: 3, omega 3) per  induced. Eikosatetraenic or eicosapentaenoic acid can be used then the metabolites, prostaglandins and Leukotrienes.

With the typical diet in the western industrial nations onen are almost only fatty acids of the linoleic acid type, i.e. H. in front all linoleic acid (18: 2, Omega 6) itself and Eikosatetraensäu right (20: 4, omega 6), absorbed by the body into the fat metabolism taken because alpha linolenic acid type fatty acids, i.e. H. before al lem linolenic acid (18: 3, omega 3) itself and eicosapentaenoic acid (20: 5, omega 3) hardly occur in the foods that the major industrialized countries usually for food be used. As a result, almost only the Me tabolites of eikosatetraenoic acid, but hardly that of eikosa pentaenoic acid formed. This results, for. B. a higher one Platelet tendency to aggregate compared to other other peoples.

The high ones are based on the one-sided supply of linoleic acid de The tendency towards platelet aggregation is reflected in a high rate of cardiovascular diseases in the main Chen industrialized nations; in men the heart attack is pending the top cause of death statistics. The emergence of the Cardiovascular disease has recently been fostered changed by recommending as much unsaturated fat as possible Linoleic acid such as linoleic acid and eicosatetraene to use acid.

In contrast, cardiovascular cranes are used in Eskimos and Japanese far less frequently. With these people, that is Blood fat content lower, the individual lipid fractions are in a more favorable relationship to each other (VLDL and LDL decreased, HDL increased); the tendency to aggregate Platelets are decreased. These people stand out there by the fact that, in comparison to other peoples, they are close grease not from domesticated land animals (pork, beef etc.), but mainly from sea fish (mackerel, herin gen, salmon u. a.). The fish fat or fish oil  has some peculiarities compared to the land animals on; it contains less cholesterol, more unsaturated fat acids, including small amounts of eicosatetraenoic acid especially a large amount of eicosapentaenoic acid.

As a result, there are over at the Eskimos and Japanese weighing only metabolites of the fatty acid from alpha-linolenic acid retyp, namely eicosapentaenoic acid; d. H. it will be at all namely the prostaglandins PGI-3, TXA-3 and. a. or the Leuko triene LTA-5, LTB-5, LTC-5 and a. educated.

Because of the evidence of the low rate of cardiac output running diseases in peoples, which are mainly caused by Feeding fish and thus fish fat and oil becomes prophy Lax and therapy of these diseases an increased intake recommended by fish. With a done for years special fish diet could indeed be given to others People outside of Japan or Greenland see a cut in Rate of heart disease can be achieved. (D. Kromhout et al .: The inverse relation between fish consumption and 20-year Mortality from Coronary Heart Disease. N. Engl. J. Med. 312, 1205- 1209, 1985).

For the average person in the major industrial countries however, it is hardly possible, at least 50 g daily Fish or an equivalent amount of pure fish oil as a diet to eat cum; Fish is flavored by many establish rejected. A longer term diet with fish oil is hardly possible; even the intake of fish oil in capsule form leads to digestive and taste problems. With the location The stability of the fish oil arises. In addition to the Eicosapentaenoic acid is also rich in fish oil diet Lich cholesterol and triglycerides other than fatty acids Contain eicosapentaenoic acid.

To avoid the disadvantages of fish or fish oil diet te the eicosapentaenoic acid itself or derivatives thereof such as  Salts, esters or amides can be used. The manufacture of the Eicosapentaenoic acid or its derivatives from fish or on however, the synthetic way is expensive bound.

The invention has for its object the cheap egg properties of eicosapentaenoic acid or its metabolites in Let the human body take effect under Ver Avoidance of both fish and oil intake Eicosapentaenoic acid, which can only be obtained at high cost can be.

The object is achieved in that linseed Men, linseed oil, soy flour, oil, wheat germ, oil, cod liver oil, butter and other substances containing alpha-linolenic acid or the Alpha-linolenic acid (18: 3, omega 3) itself or its deri vate or a formulation, the alpha-linolenic acid or a pharmaceutically acceptable salt, ester or amide thereof and contains a pharmaceutically acceptable carrier for Prophylaxis and therapy of diseases is used. The effect comes from the fact that the alpha linolen acid, the z. B. abundant in linseed or linseed oil, in Body is metabolized to eicosapentaenoic acid. Simultaneously The metabolism of linoleic acid to Eikosatetra is becoming more important acidic competitively inhibited because the same for this step enzymes are responsible.

As linseed oil, linseed oil, Soybean flour, oil, wheat germ, oil, cod liver oil and the like a. used so are at the same time too many calories in the form of other fatty acids ren fed. To avoid the increased calorie intake a formulation is preferably prepared which Al pha-linolenic acid, or a pharmaceutically acceptable salt Esters or amides thereof, and a pharmaceutically acceptable one Chen contains carrier, the content of alpha-linolenic acid between 50 and 95 or 100 percent by weight of the fatty acid gene should be equal to the wording.

By taking up the alpha-linolenic acid, enzyma metabolic steps the concentration of the body  own eicosapentaenoic acid increased. This goal can be also achieve by exogenous eicosapentaenoic acid itself to be led. That increasing the concentration of eikosa Pentaenoic acid is actually beneficial to the cardiovascular system has been shown in several studies in which Eicosapentaenoic acid has been detected.

D. Kromhout et al. Employee performed in the Dutch city of Zut phen has been carrying out a nutritional study since 1960. After 20 years it was found that men who regularly fish had eaten, the death rate from coronary heart crane cations (e.g. infarction) was 50% lower than in a male Chen comparison group. This success was attributed to the high content of eicosapentaenoic acid in the fish. (D. Krom hout u. Collaborator: The inverse relation between Fish Consumpti on and 20-year mortality from coronary heart disease. N. Engl. J. Med. 312, 1205-1209, 1985).

Another investigation showed that the Taking fish oil to form leukotrienes, specifically of LTB-4, in the neutrophil leukocytes and monocytes diminished by subjects. This leads to a reduction in detention ability of the white blood cells on the vascular endothelium; the ar Teriosclerosis formation is hindered. The effect is on the high concentration of eicosapentaenoic acid in fish oil returned. (T. H. Lee: Effect of dietary Enrichment with Ei kosapentanoic and doxosahexanoic acids on in vitro neutro phil and monocyte leukotrienes generation and neutrophil function, N. Engl. J. Med. 312, 1210-1216, 1985).

19 men with pathological lipid pattern and mild hyper tonie received a mackerel diet. After 14 days the trigly were zeride (VLDL) and the LDL lowered, the HDL increased. The blood pressure was back to normal. The effect was on the eikosapen taenic acid in the mackerel. (P. Singer and co-workers. Currently entire inn. Med. 41, 1986, 2).  

Europeans received egg in scientific studies a diet with saltwater fish such as mackerel and salmon. There inhibition of thromboxane formation and Platelet aggregation, as well as an extension of the Blu time. (Siese, W., B. Scherer, B. Böhlig, P. Roth, J. Kurzmann, P. C. Weber: Platelet membrane fatty acids, platelet aggregation and thromboxan formation during a mackerel diet. Lancet 1980 I, 441./Thorngren, M., A. Gustafson: Effects of 11-week increase in dietary eicosapentanenoic acid on bleeding time, lipids and platelet aggregation. Lancet 1981 / II 1190.

Animal experiments are numerous in which the inhibition of Platelet aggregation and prolongation of bleeding time has been demonstrated by the administration of eicosapentaenoic acid the. They are known to the person skilled in the art and can be extracted from the litera be removed.

Since it can be demonstrated that a diet or a diet with fish or Eicosapentaenoic acid a decrease in platelet aggregation gation and prolongation of the bleeding time and thus a ver reduction in cardiovascular disease is one of them assume that a diet or diet with alpha-linolen acid rich foods or with formulations that Al contain pha-linolenic acid and thus to an increase in lead endogenous concentration of eicosapentaenoic acid, just if a decrease in platelet aggregation and Prolongation of the bleeding time and thus a reduction which causes cardiovascular diseases.

As already explained, some Metabo are umits (PGE-2, PGI-2, LTB-4 and others) of eicosatetraenoic acid Mediator of inflammatory reactions. As in recent Time turned out to be the metabolites (PGE-3, PGI-3, LTB-5 u. a.) of eicosapentaenoic acid during inflammation - similar as with the development of arteriosclerosis - biological valuable because the inflammatory response including the Chemotaxis are not stimulated as violently by them as  through the metabolites of eicosatetraenoic acid. (Workshop Co ronary Disease: Prevention of Thrombosis Following Angio plasty, bypass, infarction, lysis. Munich, 24.-25. January 1986./ Weber, P.C., v. Schacky, C. R. Lorenz: German pharmacist newspaper, 126, 1986, 1/2 / Weber, P.C .; Omega 3 fatty acids from fish: cell function, health. German Ärztebl. 82, 49: 3688-89, 1985). As above outlines a supply of alpha-linolenic acid by Er nutrition or diet or formulations for an increase of eicosapentaenoic acid and thus to the desired Metabo liten.

There is an abnormality in autoimmune diseases Reaction of the immunocompetent tissue, whereby it becomes Mobili Defense mechanism comes, paradoxically directed against the body's own tissue and to lesions and cer disturbance of the body structures. A cause of Lu pus erythematosus, rheumatoid arthritis, dermatomyositis, pan arteritis nodosa u. a. may be the most recent one put antibodies against lipmodulin, which in this crane kungen occurs frequently. The phospholipase inhibiting effect Lipmodulin is thus canceled. (Schör, K .: Prostaglandi ne and related connections. Thieme 1986). As a consequence of this there is an increased formation of prostaglandins (PGE-2, PGD-2, PGI-2 and others) and leukotrienes such as LTA-4, LTB-4 u. a). The prostaglandins are obviously responsible for this for vasodilation, redness and pain solution, while the leukotrienes especially the leukocyte emigra tion, leukocyte enzyme secretion and vascular permeability stimu lieren, which eventually leads to tissue destruction in the long run leads.

Since the autoimmune diseases are ultimately the Consequences of an acute / chronic inflammation is to be started take that through the metabolites of eicosapentaenoic acid Inflammatory reactions are not stimulated as violently as  through the metabolites of eicosatetraenoic acid. With the gift of eicosapentaenoic acid could autoimmune diseases like PCP and IGA nephritis can be improved. (Weber, P.C .: Omega 3-fatty acids from fish: cell function, health. German Ärztebl. 82, 49: 3688-89, 1985.) A supply of alpha-linolenic acid through diet or diet or formulations leads to a Increasing the concentration of eicosapentaenoic acid or its Metabolites and thus to influence the Autoimmune diseases.

Triggers bronchial asthma and other allergic er Diseases are antigen-antibody reactions that act as immune complex irritate the mast cells. Be from the mast cell Mediator substances and metabolites of eicosatetraenoic acid (Arachidonic acid) released; these obviously have an egg significant influence on the function of the respiratory tract. At the pathophysiological events of allergic reactions are prostaglan in addition to the mediator substances such as histamine dins such as PGD-2, PGE-2, PGF-2 Alpha, TXA-2 and leukotrienes such as LTD-4, LTE-4, LTB-4 and LTC-4 involved. LTC-4, LTD-4 and LTE- 4 together are the substance that has long been known as "slow-reacting substance of anaphylaxis "is known. The fast spasmogenic asthma is obviously predominantly about preformed mediator substances mediated while the late and chronic phase due to leukotrienes, prostaglandins and maintain chemotactic factors.

As for the development of allergies in addition to the free set mediators, especially the formation of prostaglandi who is responsible for leukotrienes, can be concluded the that - similar to the inflammatory reactions - by the metabolites of eicosapentaenoic acid the asthmoid reak ions are not stimulated as violently as by meta bolites of eicosatetraenoic acid. In fact, by gift of eicosapentaenoic acid a beneficial effect on allergies  be achieved. (Weber, P. C .: Omega 3 fatty acids from fish: Cell function, health. German Ärztebl. 82, 49: 3688-89, 1985). Egg ne supply of alpha-linolenic acid through nutrition or diet or formulations causes an increase in concentration eicosapentaenoic acid or its metabolites and thus a positive influence on the allergic reactions. The etiology of EPH gestosis is not yet clear clarifies. In the past few years, the Er has become increasingly popular knows that the cause of the disease is in a miss relationship between thromboxane (TXA-2) and prostacyclin (PGI- 2) could lie. In the expert known or in the Lite studies described it could be demonstrated that the administration of prostacyclin (PGI-2) in EPH gestosis and pre- or eclampsia to an improvement or regression of the clinical symptoms.

As already explained, it comes after the administration of eikosapentaen acid to decrease thromboxane (TXA-2) formation favor the formation of TXA-3, which itself is not aggregations has promoting properties, while that of PGI-2 and PGI-3 outgoing inhibition of platelet aggregation ge is just as strong as before that of PGI-2 alone. In order to the mismatch between TXA-2 and PGI-2 is in favor shifted from PGI-2; d. H. platelet aggregation thereby more inhibited than before, the blood supply in the Placental vessels can be made easier again.

Becomes eicosapentaenoic acid in EPH gestosis and pre- or eclamp they used, it is to be expected that it will lead to a dimple tion of the increased platelet aggregation in this disease tendency to develop and thus the clinical symptoms. An intake of alpha-linolenic acid through diet or formulations leads to an increase in eikosapen taenic acid and thus to the desired metabolites, which is a Reduction in mismatch between TXA-2 and PGI-2 and thus an improvement in the clinical symptoms.  

The magnesium salt of alpha-linolenic acid can be used are used for the prophylaxis and treatment of diseases that by predominating eicosatetraenoic acid and its meta bolites compared to eicosapentaenoic acid - due to an increase in eicosatetraenoic acid and / or a deficiency of eicosapentaenoic acid - and / or a deficiency of magnesium caused or influenced. To the diseases with Metabolism disorders include eicosatetraenoic acid the above-mentioned cardiovascular crane kungen, acute and chronic inflammation, autoimmune crane cations, allergies and allergic reactions, EPH-Gestosen and Pre- or eclampsia; See above for details.

The magnesium salt can also be used if in addition to the fat metabolism disorder, a magnesium deficiency or deficiency of magnesium alone without interference in the Fat metabolism is present. With cardiovascular diseases it is not uncommon for there to be a disturbance in the fat at the same time change (mostly due to diet due to an oversupply of egg kosatetraenoic acid) and also a man related to nutrition gel of magnesium, which together contribute to the emergence of the Cardiovascular diseases are involved. A magnesium man gel alone can also increase cardiovascular disease muscle tone, paraesthesia, cramps of the extremity muscle culture, spasms of smooth muscles, vascular spasms and EPH Gestose and pre- or eclampsia.

The lack of magnesium favors myocardial insufficiency, Ar rhythmy and sudden cardiac death. In a clinical trial could be demonstrated that the magnesium infusion unmit after a heart attack occurs cheaply survival affects. In the group with magnesium acted, 4% died within 4 weeks; in the In contrast, placebo group died 19% (Rasmussen, HS, Lancet I, 234, 1986.

A balanced magnesium balance prevents arteriosclerosis table vascular changes. Through magnesium compounds can an elevated cholesterol level, the HDL / LDL-Lipopro  tein relation shifted in favor of HDL. (Ziskoven R .: Magnesium Press Forum. Medical weeks Baden-Baden, October 26 to November 3, 1985.)

Through early, continuous administration of magnesium Improved EPH stenosis and prevented pre- and eclampsia be changed. (Conradt and co-workers: Hohenheim Magnesium Sympo sium. University of Stuttgart-Hohenheim, 27-28 9.1985.)

In many more known to those skilled in the art and in the litera The studies described could prove the good effectiveness of Magnesium in the treatment of both of the above diseases as well as from paresthesia, spasms of the smooth Muscles, cramps of the limb muscles and of Vascular spasms demonstrated.

The magnesium salt of alpha-linolenic acid is one of them ideal combination for treating a deficiency in eikosapen taenic acid and / or magnesium. Please note sen that no side effects of magnesium can be expected because an overdose of magnesium is obi connection is not possible. On the other hand, there is an overdose tion of potassium or calcium salts of alpha-linolenic acid relatively easy.

The use of linseed and the above food medium with their preparations or those contained therein Alpha-linolenic acid or its derivatives is new and previously not known. This is also evident from the fact that in the mono graphic for linseed from November 1, 1984 only the following medicines The following fields of application are indicated: Habitual Obstipa tion, colon damaged by laxatives, colon irritabi le, diverticulitis. As a mucous membrane preparation for gastritis and enteritis. Externally as a cataplasm in local inflammation fertilize.

The effect of linseed on gastritis, enteritis, diverti  culitis and local inflammation was attributed to it leads to the fact that a mechani protection in the sense of a mucilaginosum for lighting te tissue was built.

About the use of wheat germ, soy flour, oil, butter and other foods containing alpha-linolenic acid The above indications have not been used either reported.

The be for the prophylactic or therapeutic effect required dose of alpha-linolenic acid will increase with the Route of administration and the type of condition to be treated to change; it becomes at least 3 g, depending on the indication up to 20 g and more. Ultimately, this has to be practical Investigations can be found. At the specified Thursday sis is the dose for an average People weighing 70 kg; the dose for other people or Animals vary according to their weight ieren.

The flaxseed can be eaten neat or as a grain special preparations such as muesli, linseed bread, multigrain bread etc. are administered; as a side effect occurs a laxative effect that also affects the men of flaxseed that can be absorbed. Flaxseed can be obtained by methods known to those skilled in the art Linseed oil are produced; Alpha linolen is in linseed oil Acid present in a concentrated amount. The linseed oil can ver are used for cooking, baking, roasting, for salad dressings and the preparation of other dishes. Like other oils with unsung Saturated fatty acids can include linseed oil along with other oils or basic materials for the production of margarine, fats and Similar substances are used, the weight percentage the alpha-linolenic acid should be between 9 to 50%. In addition to alpha-linolenic acid, linseed oil also contains others  re unsaturated fatty acids available, the less cheap Have properties and cause increased calorie intake ken. It is therefore advisable to use the above wording gene preferred, the content of alpha-linolenic acid between 50 and 90, preferably 95 or 100 percent by weight of the fatty acid content of the formulation. Li Nolic acid and arachidonic acid should each be a maximum of 1.5 up to 2.0% of the fatty acid content; the rest exist from palmitic and oleic acids and other unsaturated acid ren. The formulations of the invention should be free of saturated fatty acids and their salts, esters or amides be. The formulations should also be unsaponifiable Materials.

The alpha-linolenic acid can be known according to the person skilled in the art or methods described in the literature from linseed oil or other foods containing alpha-linolenic acid or manufactured synthetically. Alpha linolenic acid itself is also an oil. To avoid taste nuisance can include linseed oil and alpha-linolenic acid oil in capsules bottled and taken as medication.

Another way without affecting digestion large amounts of alpha-linolenic acid to feed consists of the in the linseed or linseed oil or Al contained in the above foods pha-linolenic acid and magnesium a new compound, the Mag to produce the sodium salt of alpha-linolenic acid and depict it as purely as possible. The necessary Methods are known to the person skilled in the art or in the literature described.

An additional manufacturing route for the magnesium salt of Alpha linolenic acid is that the synthetically pure Alpha linolenic acid itself is used. This will be together with a MG-II salt in a suitable, the skilled worker  organic solvent. When emerging Precipitation is the magnesium salt of the alpha Linolenic acid. The measures known to the person skilled in the art can Connection enriched and presented purely.

In order to convert the liquid alpha-linolenic acid into Other alkali ions can also bring a solid form such as B. Na, K, Cl, Ca or others can be used. Prince In particular, these ions have all that compared to magnesium Disadvantage that they have undesirable effects. in the Unlike magnesium, calcium can increase vascular tone ken and thus produce cardiovascular diseases or the best exacerbate existing diseases. For the prophylaxis or therapy of Cardiovascular diseases such as hypertension, heart attack and. a. Calcium antagonists have therefore been developed be used richly. As a natural Ca antagonist the magnesium used in the above compound alpha-linolenic acid. The magnesium salt of alpha-linolenic acid just discussed is ideally suited for prophylaxis or therapy both disorders of fat and magnesium metabolism, since neither with a magnesium normal level by adding magnesium to a normal one Fatty acid metabolism through additional administration of alpha Linolenic acid with side effects in the sense of an overdose tion is to be expected. It should be noted that the mo their diets hardly have normal fatty acid levels (see above); the magnesium levels are usually below half the norm.

Because the alpha-linolenic acid is highly unsaturated and therefore it themselves and their derivatives as well as the formulations which the Containing substances that are easily oxidized should be formulated rations containing these compounds also with An be equipped with ti-oxidants; come for example  Propyl gallate, butylated hydroxytoluene, butylated hydroxy anisole, alpha-tocopherol, vitamin C, a pharmacologically ver inert quinone u. a. in question. Maybe they can individual anti-oxidants also contribute to the effect afford the alpha-linolenic acid.

Preferably linseed, oil, wheat germ, germ oil, Soy flour, oil, butter and cod liver oil or their preparations or alpha-linolenic acid or its salts, esters or amides (ak tive compound) administered orally, as this is a suitable Represents route for routine administration; the active Compound (alpha-linolenic acid or its salts, esters or ami de) can also be done in any other way it can be successfully absorbed, e.g. B. parenteral (subcu tan, intramuscular, sublinqual or intravenous), local, rectal, can also be administered vaginally in women.

The active compound can be used as such or as a mixture individual components or as a genuine natural substance can be administered mixed. Preferably, the active ver However, bond used as a pharmaceutical formulation. The formulations according to the invention (for the human-like Ve terinary medicine) contain the active verb defined above together with one or more compatible carriers for this u. possibly with other therapeutic substances. The river Oder the carrier must be compatible with the other components the wording; they are not allowed for the patient be harmful or toxic. Unit doses of a formulation contain between 0.5 g and 2.0 g, e.g. B. 1.0 g of active verb dung. The daily dose is usually divided into three doses Splits.

Formulations include those for oral, local, rectal, vaginal or parenteral (subcutaneous, sublinqual, in tramuscular and intravenous administration are suitable.  

Alpha linolenic acid is a liquid that becomes an uncomfortable one take taste tends; therefore, it is preferably per os in a capsule e.g. B. from soft gelatin, so that you can no longer taste the alpha-linolenic acid. The size the capsules will be about 1.0 ml, so that the single dose sis can be accommodated in 2 to 3 capsules.

The unpleasant taste can also be masked by who that an oral pharmaceutical emulsion, e.g. B. oil-in-water emulsion or water-in-oil emulsion after a person known to the person skilled in the art or described in the literature ben is produced. The different emulsi on types can be used as an oral gel or as a stiff emulsion, e.g. B. as emulsion margarine, are produced and administered. Another way to mask the taste is that the alpha-linolenic acid on a, possibly meh other carriers such as calcium phosphate, starch, calcium sulphate, Chalk, kaolin, a microstalline cellulose, a me thyl or other modified cellulose is absorbed. The powder can be so or provided with flavorings buys or processed into tablets or capsules where approx. 1 g of alpha-linolenic acid for each capsule or tablet contains. The tablets can be filled with sugar or other known fabrics.

The pure representation of alpha-linolenic acid for the next processing to pharmaceutical formulations is very expensive. Formu production is becoming cheaper if the naturally occurring substances up to Contain 55% alpha-linolenic acid as the starting substance to be pulled; this primarily includes linseed oil and seeds. Not soybean flour, oil, wheat germ, oil, Butter and cod liver oil as they are far less alpha-linolenic contain acid as linseed oil or seeds. The just listed Fabrics with an oily consistency tend like the alpha linolen  acidity to an unpleasant taste. To mark the Ge The oils mentioned can be tasted in capsules or as emulsions sion processed or absorbed on the above-mentioned carrier beers.

The salts of alpha-linolenic acid, especially magnesium salt, can be used to make tablets or capsules containing approx. 1 g (between 0.5 and 2.0 g) alpha-linolenic acid formu be lated. The tablets should in turn be filled with sugar or film are covered.

The esters and amides can be formulated like the acids or salts depending on whether they are solid or liquid. A form is suitable for intramuscular injection tion in the form of an emulsion. The formulation for the intra venous injection can be according to known pharmaceutical ver drive in the form of a mixture that is injectable emulsified spontaneously.

For rectal or vaginal administration, the alpha Linolenic acid or a derivative thereof as a suppository a triglyceride base, e.g. B. Witepsol, cocoa butter formulated or in a suppository capsule made of soft gelatin to be deposited. The naturally occurring ones mentioned above Mixtures of alpha-linolenic acid can be used in the same Processed way.

The formulations can be offered as a unit dose and by any method known to those skilled in the art be filled. All procedures involve association the active connection with the carrier from one or more components. The active connection becomes the same moderately and intimately with liquid or with finely distributed solid carriers or mixed with both, and then the product is brought into a desired shape. In the present ing description and claims means the end print "carrier" one for administration to the patient  suitable substance that absorbs the active substance or / and encloses the active substance, e.g. B. the capsule or Coating a tablet.

Claims (34)

1. Formulation containing alpha-linolenic acid (18: 3, omega 3) or a pharmaceutically acceptable salt, ester or Amide thereof, and a pharmaceutically acceptable carrier where at least 50 percent by weight of the fatty acid content of the Formulation alpha-linolenic acid (18: 3, omega 3) or a Are a derivative of it. 2. Formulation according to claim 1, characterized in that at least 90 percent by weight of Fatty acid content of the formulation alpha-linolenic acid or are a derivative of it. 3. formulation according to claim 1, characterized in that at least 95 percent by weight the fatty acid content of the formulation alpha-linolenic acid (18: 3, Omega 3) or a derivative thereof. 4. formulation according to claim 1, characterized in that the total fatty acid content or essentially the total fatty acid content of alpha linolen acid (18: 3, omega 3) or a derivative thereof. 5. Formulation according to claim 1 to 3, characterized in that in the fatty acid content of For formulation about 1.5% linoleic acid and the rest arachidonic acid, Palmitic and oleic acids and other pharmaceutically acceptable are fatty acids or derivatives thereof. 6. Formulation, contain alpha-linolenic acid (18: 3, omega 3) or a pharmaceutically acceptable salt, ester or Amide thereof, and a pharmaceutically acceptable carrier, the formulation being essentially free of others unsaturated fatty acids or derivatives thereof.   7. Formulation according to one of claims 1 to 3, characterized in that they are essentially free of is their unsaturated fatty acids or derivatives thereof. 8. Formulation according to one of claims 1 to 7, characterized in that the alpha-linolenic acid in the form their calcium, sodium, potassium, preferably their magnesi salting is present. 9. Formulation according to one of claims 1 to 7, characterized in that the alpha-linolenic acid in the form of their ethyl ester is present. 10. Formulation according to one of claims 1 to 7, characterized in that the alpha-linolenic acid as sol che is used. 11. Formulation containing pharmaceutically acceptable Linseed oil and a pharmaceutically acceptable carrier, wherein at least 50% by weight of the Alpha-Lino formulation lens acid. 12. Formulation containing pharmaceutically acceptable Wheat germ oil, soybean oil or cod liver oil, and a pharmaceutical compatible carrier, at least 1 weight per of the formulation is alpha-linolenic acid. 13. Formulation according to one of claims 1 to 12, characterized in that it contains an anti-oxidant. 14. Formulation according to one of claims 1 to 13, characterized in that it ent a flavor holds. 15. Formulation according to one of claims 1 to 14, characterized in that the carrier is a solid. 16. Formulation according to one of claims 1 to 15, characterized in that the carrier is a capsule or comprises a capsule which ent the rest of the formulation holds. 17. Formulation according to one of claims 1 to 14, characterized in that the carrier is a liquid.   18. Formulation according to claim 17, characterized in that the linseed oil, wheat germ oil, soy oil, cod liver oil, alpha-linolenic acid, its salts, esters or Amide forms a disperse phase in the carrier liquid. 19. Formulation according to one of claims 17 and 18, characterized in that it is in capsule form. 20. Formulation according to one of claims 1 to 15, characterized in that it is in tablet form. 21. Formulation according to one of claims 1 to 20, characterized in that it is in a suitable form and Size for oral, parenteral, rectal, vaginal, local, intra cheal or intrapulmonary administration. 22. Formulation according to one of claims 1 to 21, characterized in that it is in the form of a unitary do sis is present. 23. Formulation according to claim 22, characterized in that they contain 0.25 to 2.0 g of alpha-lino contains lens acid. 24. Process for the preparation of a formulation according to one of claims 1 to 23, characterized in that the components together be brought into a usable preparation. 25. Formulation of a margarine, a butter, a dish oil or fat, characterized in that it contains alpha-linolenic acid (18: 3, Ome ga 3), a salt, ester or an amide thereof in one Amount contains at least 3% by weight of the formulation tion in the form of alpha-linolenic acid or a derivative of which is present. 26. Formulation of a margarine according to claim 25, characterized in that it is in the form of an emulsion mar garine is present.   27. Formulation of a bread, crispbread, pastries, snacks mountain pastries, pretzel sticks, pretzels, granules, flour, of chocolate, candy or other sweets, of a dish salt, a seasoning salt, a liquid wort, characterized in that at least 3 percent by weight of Formulation alpha-linolenic acid, a salt, ester or a Amid of it. 28. Formulation according to one of claims 1 to 27, characterized in that it is essentially free of saturated fatty acids or their salts, esters or amides is. 29. Use of alpha-linolenic acid (18: 3, omega 3) or a pharmaceutically acceptable salt, ester or amide thereof for the prophylaxis or treatment of diseases which by predominating eicosatetraenoic acid or its meta bolites compared to eicosapentaenoic acid - due to an increase in the concentration of eicosatetraenoic acid or / and a deficiency in eicosapentaenoic acid - causes or affects be flowed, especially from cardiovascular diseases, acute and chronic inflammation, allergies or allergi reactions, autoimmune diseases, EPH gestoses and Pre- or eclampsia. 30. Formulation according to one of claims 1 to 28 for use in the prophylaxis or treatment of cranes effects caused by a predominance of eicosatetraenoic acid or their metabolites compared to eicospentataenic acid - due to an increase in the concentration of Eikosatetra enoic acid and / or a lack of eicosapentaenoic acid - ver are caused or influenced, especially by the heart running diseases, acute and chronic inflammation, all allergies, autoimmune diseases, EPH gestosis and pre- or eclampsia.   31. Medicament for the prophylaxis or therapy of the heart running diseases, acute and chronic inflammation, all allergies and reactions, autoimmune diseases, EPH gestoses, pre- or eclampsia and other diseases that by predominating eicosatetraenoic acid or its Metabolites compared to eicosapentaenoic acid - conditional by increasing the concentration of eicosatetraenoic acid or / and a deficiency in eicosapentaenoic acid or be influenced characterized in that it is a formulation according to a of claims 1 to 28. 32. Use of the magnesium salt of alpha-linolenic acid (18: 3, Omega 3) for the prophylaxis and treatment of cranes effects caused by a predominance of eicosatetraenoic acid or their metabolites compared to eicosapentaenoic acid - be due to an increase in eicosatetraenic acid or / and a deficiency in eicosapentaenoic acid - and / or a deficiency of magnesium are caused or influenced, in particular of cardiovascular diseases, acute and chronic inflammation dung, allergies and allergic reactions, autoimmune disease, EPH gestosis, pre. or eclampsia, increased muscle tonus, paraesthesia, cramps of the limb muscles, spas smooth muscle and vascular spasms. 33. Formulation containing magnesium salt of the alpha-lino lens acid (18: 3, omega 3) for use in prophylaxis or treatment of diseases caused by predominance eikosatetraenic acid or its metabölites in comparison to eicosapentaenoic acid - due to an increase in the egg kosatetraenic acid and / or a lack of eikosapentaenoic acid re - or / and causes or be deficient in magnesium be influenced, especially cardiovascular diseases, acute and chronic inflammation, allergies and allergi  reactions, autoimmune diseases, EPH gestoses, pre- or eclampsia, increased muscle tone, paraesthesia, cramps of the limb muscles, spasms of the smooth muscles and vascular spasms. 34. Medicament for prophylaxis or therapy of the heart running diseases, acute and chronic inflammation, all allergies and reactions, autoimmune diseases, EPH gestosis, pre- or eclampsia, increased muscle tone, par aesthetics, cramps of the limb muscles, spasms of the smooth muscles, vascular spasms and other diseases, by a predominance of eicosatetraenoic acid or its Metabolites compared to eicosapentaenoic acid - conditional by increasing the concentration of eicosatetraenoic acid or and a lack of eicosapentaenoic acid - or / and who causes or affects a deficiency in magnesium the, characterized in that it is the magnesium salt Alpha-linolenic acid (18: 3, Omega 3).