DD280904A5 - METHOD FOR PRODUCING HEALTH CIRCUIT ARRANGEMENTS ACTING ON THE HEART CIRCUIT SYSTEM - Google Patents

Abstract

The invention relates to a process for the preparation of medicaments which act on the cardiovascular system. The preparations prepared according to the invention contain 0.5-50% by weight of selenium-containing algae and 99.5-50% by weight of fatty acids containing 18-22 carbon atoms containing at least two unsaturated bonds, if desired together with additives and antioxidants.

Description

Field of application of the invention

The invention relates to a process for the preparation of medicament preparations acting on the cardiovascular system.

Characteristic of the known state of the art

It is known that the unsaturated ω-3 fatty acids having 18-22 carbon atoms possess advantageous biological properties. Among them, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are of outstanding importance.

Dyerberg and co-workers point to the importance and the complex biological effect of these two acids (The Lancet 15,117 (19781).

The effects associated with the major role of polyunsaturated fatty acids, among them primarily EPA and DHA, in hyperlipidemia and thrombotic disorders are reviewed by Goodnight and co-workers (Arteriosclerosis 2/2/2 /, 87 11982] Review /.

Pharmaceutical preparations containing EPA and DHA as active ingredient are described, for example, in DE-PS No. 3438630, in the first place for lowering the blood cholesterol level, and in Japanese Patent Laid-Open Nos. 5808037 and 60.49097 for preventing thrombosis in heart patients and against cerebral arteriosclerosis described.

Numerous publications are also concerned with the thrombocyte aggregation and thus the development of thrombosis-inhibiting effect of EPA and DHA, such as the articles by Spencer and Caraega (Prostagl.

Leukotrienesand Med.23, 129 (19861) and Knopp and coworkers (New Engl. Journal of Med.314, 937 (19861), The antiviral effect of EPA and DHA is described in U.S. Patent No. 4,513,008.

The active components of fish oil, such as EPA and DHA, act as precursors in the biosynthesis of the PG-3 series.

at the same time they inhibit the chain of complicated biochemical processes emanating from arachidonic acid, the formation of harmful metabolites, such as TXA ₂ and TXB ₂ , which are formed in the so-called "arachidonic acid cascade".

The polyunsaturated fatty acids, in addition to numerous favorable properties, also have the disadvantageous pathological property that they disintegrate in the human organism during the formation of active aldehydes, inter alia malonaldehyde harmful to the organism, via a spontaneous mechanism of oxidation. These aldehydes can primarily enter into a physiologically harmful reaction with the connective tissue, which can lead to the so-called "ceroid lipofuscinosis".

It is also known that the algae have been used by humanity since time immemorial versatile for food and feeding purposes. The Far Eastern peoples, for example, consume sea algae, but recently they have been consumed in dried or tablet form by large groups of developed countries.

The algae are carriers of very valuable nutrients, in dried form they contain the necessary substances for healthy life, such as vitamins, proteins, piotein-microelement complexes, saccharides, polyunsaturated fatty acids

General and detailed explanations of the algae can be found, for example, in the book by Zajic: Properties and Products of Algae (Edition Planum, New York, 1970).

In recent decades, research has begun to address the physiological effects of microelements and trace elements. So it became known that selenium is one of the most important essential substances for life. The beneficial effect of selenium is primarily due to the fact that it activates glutathione peroxidase, more specifically its prosthetic group, which is the main inhibitor of harmful peroxidation processes. Selenium itself is an effective antihypertensive substance, it improves the ischemic, hypoxic and infarctious condition of the heart and prevents ceioid lipofuscinosis of the central nervous system. It is also effective in periodontitis! Its action against cancer is significant, it certainly reduces the possibility of cancer development. In addition, it can also be used as a mutagenic inhibitor.

The selenium does not accumulate in the organism, so it must be constantly provided for replenishment. Its uptake has been mainly in the form of inorganic compounds such as SeO ₂ and Na ₂ SeO ₃ . Selenium deficiency can result in liver necrosis, muscular necrosis, destruction of the erythrocyte membrane, connective tissue damage, and may further cause ST elevation, Kwashiorkor syndrome and Sclerosia multiplex as ECG virus alteration.

A comprehensive article on the biological effects of selenium was published by Thressa and coworkers (Nutrition Review 35, 7 [1977]), Shamberger (J. of Env. Path, and Tox.4,305 (1980), and Masukawa and coworkers (Experientia 39, 405 (19831) ,

Object of the invention

The aim of the invention was to provide a medicament preparation which acts primarily on the heart and circulatory system, which completely excludes the combination of the advantageous properties of the polyunsaturated fatty acids.

Explanation of the essence of the invention

The invention has for its object to provide a method for the preparation of acting on the cardiovascular system drug preparations available.

The invention is based on the finding that the above object is fully attainable when selenium-containing algae are used together with polyunsaturated fatty acids.

Therefore, the present invention on the cardiovascular system acting drug preparations according to the invention form the 0.5-50Ma .-% selenium-containing algae and 99.5-50Ma .-% at least two unsaturated bonds containing fatty acids having 18-22 carbon atoms or derivatives thereof if desired, together with carriers and / or excipients commonly used in the manufacture of medicaments and optionally with an antioxidant.

Furthermore, the subject of the invention is a process for the preparation of these medicament preparations. According to the invention, 0.5-50% by weight, preferably 5-35% by weight, expediently 15-25% by weight, selenium-containing algae and 99.5-50% by weight, preferably 95% by weight, are used. 65% by weight, more preferably 85-75% by weight, of fatty acids containing 18-22 carbon atoms or derivatives thereof, if desired, with excipients and / or adjuvants customary in the manufacture of medicaments and optionally with antioxidants in a manner known per se formulated a drug preparation.

The production of the selenium-containing algae is described in our co-pending patent application no. (Hungarian Patent Application No. 585/88).

The preparations according to the invention contain advantageous eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) as U <-3 unsaturated fatty acids having 18-22 carbon atoms.

As the basic substance of the unsaturated ω-3 fatty acids having 18-22 carbon atoms, oils derived from various fish such as mackerel, cod, herring, sardine and cuttlefish, and liver derived from liver such as cod liver oil (cod liver oil) and Haileberöl, used.

The fish oils contain in addition to EPA and DHA in a large amount of saturated and in small amounts of unsaturated fatty acids and unsaponifiable components. The removal of these ingredients is very important because an increased dose of the pharmaceutical preparations made from the fish oils would be sensitive to the amount of calories ingested or the triglyceride level of the blood. In addition, the non-presoable ingredients may include steroids, for example cholesterol, vitamin D (its provitamin) and / or vitamin A. Vitamins D and A accumulate in the human organism. With a preparation containing these vitamins so no permanent treatment that is required to achieve the desired effect could be performed. Therefore, from the fish oil, the enumerated ingredients are isolated, such as the saturated and slightly unsaturated fatty acids and non-saponifiable components, such as cholesterol, vitamins A and D. In this way, the EPA and DHA in the fish oil to over 50% enriched.

As algae Chlorella or Scenedesmus StfeTime were preferably used, which are not only suitable for human consumption, but also 3n represent due to their very beneficial physiological effect an essential raw material of modern nutrition.

In order to inhibit the oxidation of the preparation according to the invention, it is expedient to use as active preservative a-tocopherol (vitamin E), glutathione or conventional antisoxydants, such as, for example, butylhydroxytoluene.

As a carrier, the substances commonly used in drug production, such as lactose, starch or magnesium stearate, can be used.

The pharmacological tests proved that the preparation has no harmful side effects, since even with a use of a lOOfachen amount of the usual dose in the microsomal enzyme system of the rat liver no change could be observed. By treating with the preparation according to the invention, the amount of lipofuscin accumulating in the organism was significantly reduced in comparison to the control. Because of the six-week investigations carried out on female Wistar rats with the preparation according to the invention, an inhibition of platelet aggregation could be clearly stated.

The optimal effective daily dose of fish oil and algae powder preparation (calculated on an average body weight of 75kg) is 2g with a selenium content of 240pg. The average composition of the oil component is 22% EPA and 43% DHA.

The preparation according to the invention has the following important advantages:

a) It combines the beneficial properties of EPA and DHA as well as selenium and algae.

b) It excludes the harmful effects of preparations containing fish oil, which are caused by the saturated lipid components or the content of vitamin A and D.

c) It excludes the possibility of "ceroid lipofuscinosis" occurring in the case of consumption of polyunsaturated fatty acids.

d) It contains selenium as a natural substance, enriched in algae. The selenium given together with the algae is better absorbed and its beneficial effect is better displayed.

e) It has a beneficial effect on atopic disorders, and it is also useful in the preventive treatment of eczema, asthma, allergic symptoms, allergic rhinitis, Crohn's disease, ulcerative colitis, otitis media, nephrotic syndromes and diabetes.

It is particularly suitable for the treatment of circulatory disorders, their apoplexic phenomena, thromboembolic states of the cardiovascular system, such as brain bleeding, infarction, Keshan syndrome in adolescents and for the prevention of the development of abnormal conditions.

The polyunsaturated omega-3 fatty acids used in the preparation according to the invention can, however, be prepared as described in Examples 1 and 2, whereas the algae enriched with selenium can be prepared according to Example 3. The preparation of the medicament preparations according to the invention is described in Examples 4-6.

embodiments example 1

2 kg of sodium hydroxide are dissolved in ethyl alcohol 70 liters of 95%, then 10 kg cod liver oil are added at a temperature of 50-60 ⁰ C. The Gerrisch is boiled for 2 hours in a nitrogen atmosphere, then cooled to 10 ° C. with stirring. At the same time, the sodium salt of the saturated fatty acids separates out. The crystals are filtered out and washed with a little alcohol. The alcoholic filtrate is thickened and 20 liters of boiled water are added. The unsaponifiable compounds, such as cholesterol, are completely isolated by extraction with 5 liters of hexane. The extracted aqueous phase is acidified to pH 2 with sulfuric acid, then re-extracted with 15 liters of hexane. The organic phase is washed with water, dried with solid sodium sulfate and then evaporated. So you get 3,2Kg concentrated oil. DHA content: 36.8%, EPA content: 31.8%. The oil is brown and smells of fish, so the fullerene is added to the concentrated oil, then heated under nitrogen atmosphere at 105 ⁰ C for 10 minutes and filtered hot. Is made odorless by vacuum-steam distillation for 3 hours at a pressure of 1.3 bar and a temperature of 17O ⁰ C. This gives a pale yellow, tasteless, odorless oil with virtually unchanged composition.

Example 2

24kg cod liver oil are dissolved at 60 ° C in 16 liters of methanol. At a temperature of 50-60 ⁰ C 8kg 40% sodium hydroxide solution are added dropwise with stirring, then the mixture is maintained at 60 ^c C and stirred for a further 45 minutes long. At about 60 ⁰ C of the solution 20kg of 15% hydrochloric acid are added. The phases are separated, then the organic phase is treated with 10 kg of 15% hydrochloric acid, then washed neutral with about 180 liters of hot tap water. The resulting phases are separated again. To the oily phase is added 100 liters of acetone. It is heated to about 45 ° C, then 3.8 kg in 30 liters of water dissolved LiOH · H ₂ O are added. After stirring for half an hour, the mixture is allowed to stand overnight, then it is filtered and the acetone filtrate is evaporated. It is acidified with about 8kg of 15% hydrochloric acid, shaken out with hexane three times, and finally evaporated. During the cleaning process is carried out until the end in a nitrogen atmosphere. In this way you get 6,4kg of purified fish oil. Iodine number: 285, acid number: 160.

1 kg of the thus purified cod liver oil is added dropwise at 60 ⁰ C prepared with 9 liters of methanol solution of 3 kg of urea. The mixture is stirred for 2 hours at this temperature. After cooling, it is allowed for overnight - 10 ^c are C in the freezer, then it is filtered, and the filtrate is evaporated. The evaporated substance, 2.5 liters of 1: 1 diluted hydrochloric acid are poured. Stir for 15 minutes, then shake with hexane. The hexane phase is washed neutral with water, dried with Na 2 SO 4, then evaporated. In this way one obtains 0.34 kg of unsaturated ω-3-Fettsäuron. Iodine number: 315; EPA content: 24%, DHA content: 42%.

Example 3

Into a 10-liter algae culture jar are filled 8 liter Knop-Pringöheim broth supplemented with 40 mg sodium selenite. The system is sterilized at 12O ⁰ C for 30 minutes at an overpressure of 1 bar. The sterile solution is at 25 ⁰ C with the algae pure culture Scenedesmus obtisiusculus, which is capable. Well to incorporate selenium, vaccinated. The nutrient solution at 25 ⁰ C 5 vol .-% carbon dioxide-containing air is passed under illumination through a fluorescent tube (4000lux, 440-700pm). After a breeding cycle of 14 days, the alga is isolated from the nutrient solution. The resulting algae mass is prepared by means of ultrasound, then carefully dried at a temperature below 65 ° C. This gives 6 g of algae powder with a selenium content of 1 200μg / g.

Example 4

150 g of 65% concentrated cod liver oil (EPA content: 22%, DHA content: 43%) are mixed with 100 g of Se algae powder (Se concentration: 260 pg / g). The mixture is homogenized and the homogenate is preserved with 0.1% vitamin E. The resulting active ingredient is filled into a soft gelatin-permeable capsule or soft gelatin capsule, and the capsules are packed in blister foil.

Example 5

The procedure is the same as in Example 4, except that the following starting materials are used: 400 g of 65% concentrated cod liver oil whose EPA content is 22% and the content of DHA is 43%; 70.6 g of algae powder with a selenium content of 1 200 pg / g and 0.4 g of vitamin E. The homogenate is filled into suitable for receiving 500mg of active ingredient capsules.

Example 6

Tablets of the following composition are prepared by the known pharmaceutical agents and processes:

Dorax liver oil enriched with EPA and DHA, which contains 0.1% vitamin E as preservative

(DHA content: 43%, EPA content: 22%) 200 mg

Se algae (Se concentration: 1 500 μg / g) 86 mg

Lactose 140 mg

Starch 60 mg Polyvinylpyrrolidone 3.5 mg

Magnesium stearate 3.5 mg

If desired, the tablets are coated with sugar in a coating machine.

Claims (3)

1. A process for the preparation of acting on the cardiovascular system drug preparations, characterized geken lzoichnet that one 0.5-50 Ma .-%, preferably 5-35Ma .-%, suitably 15-25Ma .-%, si lenhaltige Algae and 99.5-50Ma .-%, preferably 95-65Ma .-%, suitably 85-75Ma .-%, at least two unsaturated bonds containing fatty acids having 18-22 carbon atoms or derivatives thereof, if desired, with common in pharmaceutical drug carrier and / or excipients and optionally formulated with antioxidants in a known per se to a drug preparation. 2. The method according to claim 1, characterized in that one uses as unsaturated fatty acids extracted from the oil of marine fish extracted fatty acids. 3. The method according to claim 1 and 2, characterized in that are used as unsaturated fatty acids 5,8,11,14,17-eicosapentaenoic acid and 4,7,10,13,16,19-Dokosahexaensäure.