LU87169A1 - PHARMACEUTICAL COMPOSITIONS ACTING ON THE HEART AND THE CARDIOVASCULAR SYSTEM AND PROCESS FOR THEIR PREPARATION - Google Patents

Description

L-3222

û 7 * d 25Ί Λ GRAND-DUCHY OF LUXEMBOURG

λ Patent N ° B · I U îf

Monsieur Te Minister -> from 18 ...... Π (§, £., § ...... 1.9.88 .................... ... of Economy and Classes Meyegjj ^ E.PU * ot-ü \

Tiirp. dPÜvrP. SS Department of Intellectual Property ^ ueUe §JÇJ. \ _I ................................................ ... LUXEMBOURG \ ^ \ 9BS \

InveçgSjô Patent Application ^^^ ......................................... .................................................. .............................................. (1) I . Request Çaola ...... Kozmetikai ës ..... Hàztartàsvegyipari Vàllalat., 90 Bocskai / 2 \ ut, H-Budapest, represented by Mr Jean Waxweiler, 55 rue des Bruyères, Howald, acting as agent. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. . (3) denote (s) this ..... eighteenth of March one thousand nine hundred and eighty-eight _____________________________________ ^ to _ .. L_. hours, at the Ministry of the Economy and the Middle Classes, in Luxembourg: 1. this request for obtaining a patent for invention concerning:

Compositions ...... pharmaceuticals ...... acting health ..... on the .... heart ...... and ...... the____________ (5) system .... ..cardiovascular ...... and ...... process for their preparation ______ 2. description in French ................ language ....... .......................................... of the invention in triplicate; 3 ................................................. .................. drawing boards, in triplicate; 4. the receipt of taxes paid to the Luxembourg Registration Office on ________________; 5. the delegation of power, dated ......................................... .................................................. .. the_________________________________________________________________; 6. the successor document (authorization); declares (s) by assuming responsibility for this declaration, that the inventor (s) is (are): (6) see annex ________ claims (s) for the above patent application the priority of one (of ) request (s) for (7) .................. patent ...................... .................................................. ................................... filed in (8) ....... .... Hungary ._____________________________________________________ on (9) ..... 1..8 ....... March ....... 1.9.81 ............ .................................................. .................................................. .................................................. .................................................. ................

under N ° (10) ..... 1..1..7..3 ./. 8 ... 7 .................... .................................................. .................................................. .................................................. .................................................. .................

in the name of (he) Caola Ko zmetikai és Hàztartàsvegyipari Vàllalat elects (elect) domicile for him (her) and, if designated, for his representative, in Luxembourg ................. .................................................. .........

.5.5 ...... rue ....... des ...... Heather ........ Hawaii d .............. .................................................. .................................................. .................................................. ......................... (12) requests (s) the grant of a patent for the invention for the subject described and represented in the aforementioned annexes, with adjournment of this offense until ______________________....... 18 ................................ .................................................. .................................................. ..............month. (13)

The depositor: / agent: ............................................ .................................................. .................................................. .................................................. .. (14) Π. Deposit Minutes

The above application for a patent for invention has been filed with the Ministry of the Economy and the Middle Classes, Service de la Propriété Intellecjyells ^ Luxembourg, dated: 18.03.1988 / V .. ·· * -¾ \ A * - 4¾¾¾. \\ Pr. The Minister of Economy and the Middle Classes, at 1.5.,. 00 ..— hours / / 3 | p- d.

\ i '· »I The head of the intellectual property department, U \ WJ / im __: _ EXPLANATIONS RELATING TO THE DEPOSIT FORM.

* (X) if applicable "Request for certificate of addition to the main BST, at main patent application No ............ of ............ ”- (2) enter the surname“ first name, profession, address of the applicant, when the applicant is an individual or company name, legal form, address of head office, when the applicant is a legal person - (3) enter H \ jC the surname, first name, address of the authorized representative, industrial property attorney, with special powers, if applicable: "represented by .......... ..acting as agent "/ 'i' '- (4) date of filing in full - (5) title of invention - (6) enter the names, first names, addresses of the inventors or the indication" (see) separate designation (will follow) ”, when the designation is or will be made in a separate document, or the indication" not to mention ", when the inventor signs or signs a non-mention document to be attached to a designation / "4

List of inventors L - 3in

György BAKTAY, 10, Eötvös u., H-1153 Budapest

Dr. Péter LITERÂTI-NAGY, 38, VII u., H-1172 Budapest

Dr. Lajos György NAGY, 24, Elnök u., H-1089 Budapest

Dr. György BLASKÖ, 32-34, Zöldlomb u., H-1025 Budapest

Miklôs GROSZ, 42., Major u., H-1119 Budapest

Dr. Jànos PALINKAS, 12, Allende park, H-1119 Budapest

Dr. Mària BOROSS, 4, Pauler u., H-1013 Budapest

Dr. Miklôs FABIAN, 17, Lukâcs Gy. U., H-1039 Budapest

Erzsêbet PAKO, 16, Népezinhâz u., H-1081 Budapest

Dr. Lâszlô BOGDANY, 36, Kerëk u., H-1035 Budapest Gàbor NEMETH, 48, Zsôkavàr u., H-1157 Budapest /

V

fl Λ CLAIM OF PRIORITY Filing of the patent application and »Hungary {dd March 18, 1987 UNDER number 1173/87

DESCRIPTIVE MEMORY FILED IN SUPPORT OF A PATENT INVENTION APPLICATION IN THE GRAND DUCHY OF LUXEMBOURG

by »Caola Kozmetikai és Hàztartàsvegyipari Vàllalat 90, Bocskai ut Budapest Hungary for; Pharmaceutical compositions acting on the heart and the cardiovascular system and process for their preparation.

i!

The present invention relates to pharmaceutical compositions acting on the heart and the cardiovascular system.

According to another aspect of the invention, a process is provided for the preparation of these compositions.

5 It is known that fatty acids <o-3 unsaturated in Cjq_22 have advantageous biological properties. Eicosapentaenoic acid (EPR) and docosahexaenoic acid (DHR) are notable among these. Dyerberg et al. [The Lancet 15, 117 ¢ 1978)] emphasized the importance and the multiple biological effects of the two acids.

The effects associated with the important role of polyunsaturated fatty acids, in particular EPR and DHR in hyperlipidemia and thrombotic diseases, have been summarized by Goodnight et al. [Rrteriosclerosis 2, 87 (1982) Reviem].

Pharmaceutical compositions containing EPR and DHR as active components have been described for example in the German patent specification Ho. 3,438,630 for lowering cholesterol levels, and in Japanese patent applications published Ho. 58.08037 and 60.49097 against cerebral sclerosis and to prevent the formation of thrombi in patients suffering from cardiac diseases.

Several articles have been devoted to the effect of inhibiting platelet aggregation and therefore to the effect of inhibiting thrombus formation, exerted by EPR and DHR [Spencer and Caraega: Prostagl. Leucotrienes and Med. 23, 129 (1986); Knopp et al .: He · Engl. Daily of Red. 211, 937 (1986).

The antiviral action of EPR and DHR e and described K in U.S. Patent specification Ho, 4,513,008.

The active components of fish oil, for example EPR and DHR, are precursors of the PG-3 series biosynthesis and they inhibit the formation of harmful metabolites like THIT? and TXB ^ coming from the so-called "cascade of acid arach i don i que" which is a chain of complicated b i ο iog i ques starting from arach i don i que acid.

35 In addition to their numerous favorable effects, Λ 2 polyunsaturated fatty acids have the unfavorable pathological property of being subjected to a spontaneous oxidative decoipositon in the human organism and thus giving rise to the formation of active aldehydes, such as aalondiaidehyde which is harmful to the organist. These aldehydes are capable of reacting mainly with the connective tissues in a physiologically harmful way, which can lead to the so-called "ceroidal ipofuscinosis".

Furthermore, it is known that algae have been used since iametorial times by humanity for nutritional and nutritional purposes. Seaweed is therefore mainly consumed by the peoples of the Far East; in recent times, however, they have been widely used in dry conditions or in tablet form also in developed countries.

15 Algae are extremely interesting nutrient carriers since their dried form contains in high concentrations, substances which are essential for a healthy life, count vitamins, proteins, protein complexes with microelements, saccharides, polyunsaturated fatty acids and siai (areas.

General and detailed information about algae is described, for example, by Zajic in: Properties and Products of Rlgae (Edition Planum, Nea-Vork, 1970).

In the last decade, we began to study the biological effects of microelements and trace elements. We have thus learned that selenium is one of the most important and most essential substances in life. The beneficial action of selenium is mainly based on its activation effect directed against the enzyme glutathione peroxidase, insofar as selenium is an essential constituent of the prosthetic group of the enzyme glutathione peroxidase. This enzyme is the most important endogenous inhibitor of harmful peroxidation processes.

Selenium in itself has a hypotensive effect, it improves the ischemic, hypoxic and infarcted states of the heart and it inhibits (cereal ipofuscinosis of the central nervous system; moreover, it has a beneficial effect on periodontitis It has a notable anticancer activity and has been shown to decrease the likelihood of the development of cancer diseases] moreover, it is considered to be an agent inhibiting mutagenesis.

5 Selenium is not accumulated in the body, so it must be supplied continuously. Until now, selenium has mainly been introduced into the body in the form of inorganic compounds, for example selenium dioxide or sodium 3elenite. Numerous changes or diseases, respectively, such as liver necrosis, mgonecrosis, destruction of the erythrocyte membrane, interstitial damage, elevation of ST in the ECG, Kwashiorkor syndrome (sub- protein diet) and multiple sclerosis are induced by selenium deficiency.

A full report on the biological effects of selenium has been published by Thressa et al. [Nutrition Revies 35, 7 (1977)], Shamberger [J. of Approx. Path. and Tox. i, 305 (1980)], as well as by Hasukasa et al. [Experientia 39, 405 (1983)], 20 The present invention aims to provide a new pharmaceutical composition acting mainly on the heart and the cardiovascular system, which allows to combine the advantageous properties of DHR, EPR, algae as well as selenium and which simultaneously eliminates the disadvantageous properties of polyunsaturated fatty acids.

The invention is based on the observation that the above object can be perfectly achieved by the use of an algae containing seenium with polyunsaturated fatty acids.

The present invention therefore relates to a pharmaceutical composition acting on the heart and the cardiovascular system, which comprises 0.5 to 50) 11 by mass of algae containing seienium as well as 99.5 to 50X by mass of fatty acids in Cjg_22 containing at least two unsaturated bonds or derivatives thereof, optionally in admixture with carriers and / or h 4 additives and / or antioxidants commonly used in the industry.

In addition, the invention relates to a process for preparing the above composition, which comprises the mixture of 0.5 to 5% in 5% algae containing selenium as well as 99.5 to 50% in fatty acid bass. in £ \ q ~ 22 containing at least two unsaturated bonds or derivatives thereof, optionally with supports and / or additives and / or antioxidants commonly used in the pharmaceutical industry.

The compositions according to the invention suitably comprise eicosapentaenoic acid (EPfl) and docosahexaenoic acid (DHfl), as well as an alga containing selenium.

The selenium-containing algae is prepared according to the procedure which is described in the Applicant's patent application filed at the same time as the present application and corresponding to the Hungarian patent application No. 575/88.

Unsaturated des-3 fatty acids representing a component of the composition can be used as starting material, oils which can be obtained from various sea or freshwater fish, especially mackerel, cod, herring , sardines, squid, as well as the liver of these fish, for example cod liver oil and shark liver oil.

In addition to EPR and DHfl, fish oils contain a large amount of saturated fatty acids as well as to a small extent unsaturated fatty acids and other non-hydrolyzable components. The elimination of these constituents is very important since the administration of the therapeutic compositions prepared from fish oils would significantly increase the caloric amount introduced as well as the triglyceride level of the blood. In addition, the non-hydrolyzable constituents may contain steroids such as cholesterol, vitamin D (and its provitamin) and / or vitamin f1. Vitamins D and fl accumulate in the human body so that prolonged treatment, required for the desired effect, would be impossible with a composition containing these vitamins. The coaposants mentioned above, comprising saturated or partially unsaturated fatty acids as well as the non-hydrolysable constituents, for example cholesterol, vitamins f1 and 0, are therefore eliminated from fish oil. In this way, the total amount of EPft and DHfl in the fish oil is enriched to more than 50X.

The Chlorella or Scenedesius strains can be suitably used as acute useful for human consumption and they represent a primary ingredient Indispensable 10 for iodine orientation due to their very favorable biological effect.

It is suitable to use a-tocopherol (vita E), glutathione or traditional antioxidants coaae butylhydroxytoluene coaae active preservatives to inhibit the oxidation of the coaposition according to the present invention.

The whole couraaaent used in the pharmaceutical industry coaae lactose, aaidon or agnésiua stearate, can be eaeaployed coaae vehicle or support.

Pharaacological research has shown that coaposition is devoid of adverse health effects, in that no change was observed in the aicrosoaial enzyme system of the rat liver with a hundredfold amount of the usual amount. The amount of lipofuscin accumulated in the organism has been significantly reduced compared to that of a witness after treatment with coaposition. The studies carried out with the coaposition of the invention on Uistar rats for 6 weeks, have observed a clear effect of inhibiting the aggregation of platelets.

The effective daily dose optiaie (calculated for an average body weight of? 5 kg) of the coaposition consisting of fish oil and seaweed powder amounts to 2 g, with a selenium content of 240 pg. In the average, the oil co-component takes 22X of EPfl and 43X of DHfl.

The main advantages of the composition according to the present invention can be summarized as follows: 6 a) The preferable properties of ΓΕΡΑ and DHR as well as selenium and alga are combined.

b) The harmful effects caused by the saturated lipid components as well as by the uStaline fl and D content of the 5 known coipositions containing fish oil are eliminated.

c) The risk of the appearance of "ceroidal ipofuscinosis" by consumption of polyunsaturated fatty acids is eliminated.

d) The coiposition contains selenium as a natural substance enriched in seaweed; the selenium · administered with the alga is absorbed places and exerts its favorable effects in a more favorable way.

e) The coiposition develops an advantageous therapeutic action in the case of atopic disorders and it is useful for the preventive treatment of eczea, asthia, allergic syiptias, allergic rhinitis and / or atopic disorders, for example , tlgraine, Crohn's disease, ulcerative colitis, loyal otitis, nephrotic syndrote and diabetes.

The coiposition of the invention is particularly useful for the treatment of disorders of the cardiovascular system: for apoplectic manifestations, throibo-eibolic conditions cone an attack, an infarction and a Keshan syndrone of young adults, as well as for prevention of abnormal conditions.

The invention is illustrated in detail by the following non-limiting examples.

The polyunsaturated ω-3 fatty acids used in the coiposition of the invention can be prepared according to examples 1 and 2, while the acute enriched in selenium can be prepared according to example 3. The pharmaceutical coipositions according to the invention are described in examples 4 to 6.

Exeiole 1 2 kg of sodium hydroxide are dissolved in 70 liters of 95X ethanol and 10 kg of norue liver oil are added to a temperature of 50 to 60 ° C. The mixture is heated at reflux under nitrogen for 2 hours and then cooled to 10 ° C. with stirring. The 3eis sodium3 of saturated fatty acids are precipitated. The crystals are filtered and washed with a little ethanol. The ethanol filtrate 5 is evaporated and 20 liters of boiling water are added to the residue. Non-hydrolyzable compounds such as cholesterol are completely eliminated by extraction with 5 liters of hexane. The aqueous phase is acidified to pH 2 by addition of sulfuric acid and again extracted with 15 liters of hexane. The organic phase 10 is washed with water, dried over anhydrous sodium sulfate and evaporated to give 3.2 kg of concentrated oil having a DHR content of 36.8X and an EPR content of 31.8X. This oil is brown and smells like fish. It is therefore mixed with fuller's earth, heated 30us nitrogen at 105 ° C for 10 minutes and filtered hot. The deodorization is completed by steam distillation under vacuum at 170 ° C / 1 mm Hg for 3 hours, which provides 1.6 kg of an odorless, light yellow, flavorless oil of unchanged composition.

20 Example 2

8 kg of sodium hydroxide solution 401 at 50-60 ° C is dropped dropwise into 24 kg of cod liver oil dissolved at 60 ° C in 16 liters of methanol with stirring. The mixture is then stirred at 60 ° C for an additional 45 minutes. 20 kg of 15X hydrochloric acid are added to the solution at approximately 60 ° C. After separation, the organic phase is washed with 10 kg of 15 × hydrochloric acid and then with 180 liters of hot tap water until neutral. The phases are again separated, 100 liters of acetone are added to the oily phase which is then heated to around 45 ° C. and a solution of 3.8 kg of lithium hydroxide monohydrate in 30 liters of water is added . After 30 minutes of stirring, the mixture is left to stand overnight, then filtered and the acetone filtrate is evaporated. The residue is acidified by adding about 8 kg of 15X hydrochloric acid, extracted 3 times with hexane and evaporated.

8

A nitrogen atmosphere is used during the whole purification operation. 6.1 kg of purified fish oil are thus obtained having an iodine number of 258 and an acid number of 160.

One kg of liver oil, purified in the manner described above, is added dropwise at 60 ° C. to a solution containing 3 kg of urea in 9 liters of nethanol. The mixture is stirred at the same temperature for 2 hours and then cooled. It is left to stand at -10 ° C overnight, then filtered and the filtrate is evaporated. 2.5 liters of 1: 1 hydrochloric acid are added to the residue and the mixture is stirred for 15 minutes. After extraction with hexane, the hexane phase is washed with water until neutral, dried over anhydrous sodium sulfate and evaporated to give 0.31 kg of unsaturated m-3 fatty acid with an index of iodine of 315, containing 21X of EPR and 12 * of DHR.

15

Example 3 10 mg of sodium selenite are added to 8 liters of Knop-Pringsheim culture medium introduced into a glass vial of algae culture having a volume of 10 liters. The culture medium thus obtained is sterilized at 121 ° C under an overpressure of 1 bar for 30 minutes. Then the sterile solution is cooled and inoculated with a pure culture of Scenedesmus obtisiusculus which is capable of rapidly incorporating selenium. Sterile air containing 5 * by volume of carbon dioxide is bubbled through the culture medium at 25 ° C., while the system is illuminated with an electric discharge tube working with 1000 lux at a wavelength from 110 to 700 pm. After a culture period of 14 days, the alga is separated from the culture medium. The treble mass thus obtained is decomposed by ultrasound and dried carefully at a temperature below 65 ° C. The yield is 6 g of an algae powder having a selenium content of 1200 pg / g.

EXAMPLE 1 35 100 g of a seaweed powder containing selenium a D l 9 (selenium content; 260 pg / g) are added to 150 g of cod liver oil enriched at 65% (containing 22% d 'EPR and 431 from DHR). After homogenization, 0.1X of vitamin E is added. The active component thus obtained is introduced into soft gelatin capsules, which are packaged in blister sheets.

Example 5

The procedure of Example 4 is repeated, except that the following raw materials are used: 400 g of cod liver oil 10 enriched with 65X, containing 22% of EPR and 43X of DHR; 70.6 g of an algae powder having a selenium content of 1200 pg / g and 0.4 g of vitamin E. The homogenized product is introduced into capsules capable of receiving 500 mg of active component.

15 Example 6

Tablets having the following composition are prepared according to known procedures and with pharmaceutical devices: Cod liver oil enriched in EPR and 0HR and containing 0.1X of vitamin E (with a DHR content of 43% and a 22X EPR content) 200 mg

Seaweed powder containing selenium 25 (selenium content; 1500 Mg / g) 86 mg

Lactose 140 mg

Rmidon 60 mg

Polyvinylpyrrolidone 3.5 mg

Magnesium stearate 3.5 mg 30

The tablets can optionally be coated with sugar in an empastiiloge machine.

Claims (10)

1. Pharmaceutical composition acting on the heart and the cardiovascular system, characterized in that it comprises 0.5 to 502 by mass of algae containing selenium as well as 99.5 to 5 502 by mass of fatty acids Cjg- 22 containing at least two unsaturated bonds or derivatives thereof, optionally in admixture with carriers and / or additives and / or antioxidants commonly used in the pharmaceutical industry. 2. Composition according to claim 1, 10 characterized in that it comprises 5 to 352 by mass of algae containing selenium. 3. Composition according to claim 1, characterized in that it comprises 15 to 252 by mass of alga containing selenium. 4. Composition according to claim 1, characterized in that it comprises 95 to 652 by mass of fatty acids Cjg_22 containing at least two unsaturated bonds or derivatives i vés of these c i. 5. Composition according to claim 1, characterized in that it comprises 05 to 752 by mass of fatty acids in 8-22 containing at least two unsaturated bonds or derivatives thereof. 6. Pharmaceutical composition according to any one of claims 1 to 5, characterized in that it comprises fatty acids extracted from sea fish oil as unsaturated fatty acids. 7. Pharmaceutical composition according to any one of claims 1 to 6, characterized in that it comprises 5,6,11,14,17-eico3apentaenoic acid and 4,7,10,13,16 acid, 19-30 docosahexaenoic as unsaturated fatty acids. 8. Process for the preparation of a pharmaceutical composition acting on the heart and the cardiovascular system, characterized in that it comprises the mixture of 0.5 to 502 by mass of acute containing selenium as well as 99.5 35 to 502 by mass of fatty acids in Cjg_22 containing at least two 11 - ·. »·» * Unsaturated bonds or derivatives thereof, possibly with carriers and / or additives and / or antioxidants crown "used in the pharmaceutical industry. 9. A method according to claim 8, characterized in 5 that iélange 5 to 35X in a seaweed basket containing selenium and 95 to 65 * in a fatty acid basket Cjg_22 containing two i nsaturated sounds. 10. A method according to claim 8, characterized in that it mixes 15 to 25 * in a seaweed basket containing selenium and 10 85 to 75 * in a fatty acid basket in C] g-22 containing at least two unsaturated bonds.