JPH0127A - Drugs that act on the heart and cardiovascular system and methods for their production - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a drug that acts on the heart and cardiovascular system, and a method for producing the same.

[Conventional technology]

It is known that C11-22:ω-3 unsaturated fatty acids have excellent biological properties. Among these compounds, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are the main ones. Dyerberg et al. discuss the importance of both acids and their wide variety of biological effects (The Lancet 15.11).
(see page 7 (1978)).

The important role and effects of polyunsaturated fatty acids, especially EPA and DHA, in hyperlipidemia and thrombosis have been reported by Goodnight et al.
is) 2.87 pages (1982) review).

Regarding drugs containing EPA and DHA as active ingredients, for example, West German Patent No. 3,438,630 describes drugs that lower blood cholesterol levels.
Also, Japanese Patent Publication Nos. 58-08037 and 60-4
No. 9097 describes those for anti-sclerosis and for the prevention of thrombus formation in heart disease patients.

Several documents have described the platelet aggregation inhibitory effect and thrombogenicity inhibitory effect of EPA and DHA (Spencer and Caraega) Nibrostaglandin Leukotrienes and Medicine. (Prostag
l, Leu-cotrienes and Med.
) 23.129 pages (1986), and Knopp et al.
, ofMed, ) 314.937 pages (1986)
reference).

The antiviral effects of EPA and DHA are described in US Pat. No. 4,513,008.

The active ingredients of fish oil, such as EFA and DHA, are PG-
3 series of raw metal precursors;
It suppresses the production of harmful metabolic intermediates, such as TXA2 and TXB, which result from the "arachidonic acid cascade", a series of complex biosynthetic processes starting from arachidonic acid.

While polyunsaturated fatty acids have several excellent effects, they are decomposed by natural oxidation in the human body, producing active aldehydes such as malondialdehyde, which are harmful to the human body. There is a pathological defect.

Such aldehydes mostly react with connective tissue,
It causes a physiological disorder called ceroid lipofuscinosis.

As is well known, humans have been eating algae as a nutritional source since ancient times. Algae is mainly consumed in the Far East, but in recent years it has been consumed in dried or tablet form.
It is also widely used in developed countries.

Algae contain very useful nutrients. This is because dry algae contains high concentrations of substances essential for maintaining healthy life, such as vitamins, proteins, complex proteins with trace elements, carbohydrates, and polyunsaturated fatty acids. be.

For more information about algae, see
``Properties and Products of Algae (Pr.
operations and products of
Algae) J (Plenum, New York, USA)
anum) Publishing, (1970)).

It has only been about 10 years since research into the biological effects of trace elements began, and it has become clear that selenium is one of the extremely important life-sustaining substances.

The advantageous effect of selenium is primarily on the activity it exerts on glutathione peroxidase. Thus, selenium is an essential component of the prosthetic group of glutathione peroxidase. This enzyme is the most important endogenous inhibitor of harmful hyperoxidative processes.

Selenium itself has an antihypertensive effect, improves cardiac ischemic, hypoxic, and infarcted conditions, and suppresses ceroid-ribofuscinosis of the central nervous system. It is also highly effective against periodontitis. It has been demonstrated that selenium has a significant anticancer effect and suppresses the development of cancer diseases. It is also considered to be an anti-carcinogenic agent.

Selenium is not stored in the body and must be constantly replenished. Traditionally, selenium is mainly in the form of inorganic compounds, such as selenium dioxide and sodium selenite.
It has been ingested by humans.

Many modulations or diseases such as liver SW death.

Myonecrosis, destruction of red blood cell membranes, interstitial lesions, electrocardiogram (ECG)
), the ST-high state in Mulberry (Mulberr
y) Heart syndrome, Kwaziorkor syndrome (a protein malnutrition disorder), and multiple sclerosis have each been demonstrated to be caused by selenium deficiency.

Some of the published reviews regarding the biological effects of selenium include Nutrition Review (NutritionRevie%I) by Thressa et al.
), p. 35.7 (1977), by Shamberger (J, of Env, Path and T.
ox, ) p. 4.305 (1980)), Masukawa et al. (Experienia) p.
1983)).

[Object of the present invention]

The aim of the invention is to enable the combination of the superior properties of DNA, EPA, algae and selenium.

Mainly, it eliminates the disadvantages of polyunsaturated fatty acids.
The object of the present invention is to provide a new drug that acts on the heart and cardiovascular system and a method for producing the same.

[Summary of the invention]

The invention is based on the recognition that the above objectives can be fully achieved if selenium-containing algae are used together with polyunsaturated fatty acids.

According to the invention, 0.5-50% by weight of selenium-containing algae and 99.5-5% selenium containing at least two unsaturated bonds
0% by weight of Cxa~, fatty acid, or derivative thereof;
There is provided a drug that acts on the heart and cardiovascular system, comprising selectively incorporated carriers used in the conventional pharmaceutical industry and additives or antioxidants.

According to the invention, 0.5-50% by weight of selenium-containing algae and 99.5-50% by weight having at least two unsaturated bonds
50% by weight of C1, -22 fatty acids or derivatives thereof, and further selectively incorporating carriers, additives, or antioxidants used in the conventional pharmaceutical industry. is provided.

The drug according to the invention contains eicosapentaenoic acid (EPA)
, docosahexaene fi CDH^), and selenium-containing algae.

It is prepared as described in Patent Application No. 575/88).

As a raw material for Cts~22:ω-3 unsaturated fatty acid, which is a component of the drug, various marine and freshwater fish, mainly mackerel, cod, carp, sardine, squid, and oils collected from the livers of these fish, For example, cod liver oil and shark liver oil are used.

In addition to EEPA and DHA, fish oil contains large amounts of saturated fatty acids, less unsaturated fatty acids, and other non-hydrolyzable components.

Removal of these components is very important because the dosage of therapeutic agents prepared from fish oils sensitively increases the amount of calories ingested, as well as the amount of triglycerides in the blood. It also contains steroids such as cholesterol, vitamin 0 (and its propitane), or vitamin^ as non-hydrolyzable components.

Vitamins A and D accumulate in the human body, making long-term treatment with compositions containing these vitamins impossible to achieve the desired effect.

Therefore, the aforementioned components such as saturated and partially unsaturated fatty acids, as well as non-hydrolyzable components 1 such as cholesterol, vitamins A and D, are removed from the fish oil.

By doing so, the total amount of EPA and D)IA in the fish oil is increased to more than 50%.

As algae, chlorella or green algae (Scenedesm
It is preferable to use US). Their availability for human nutrition and their outstanding biological effects make them represent essential raw materials for modern nutritional methods.

To inhibit oxidation of the medicament according to the invention, preference is given to using conventional antioxidants such as alpha-tocopherol (vitamin E), glutathione or butylated hydroxytoluene as active preservative U).

As vehicles or carriers, materials commonly used in the pharmaceutical industry can be used, such as lactose, starch, or magnesium stearate.

Pharmacological studies have shown that this drug has no adverse health effects, as no changes were observed in the microsomal enzyme system of rat livers even when given at 100 times the normal dose. I can confirm that there is no such thing. The amount of lipofuscin accumulated in the human body was significantly reduced after treatment according to the main rule compared to the control.

As a result of a study using the drug according to the invention for 6 weeks in female Wistar rats, a clear anti-platelet aggregation effect was observed.

The preferred daily effective dose of the drug consisting of fish oil and powdered algae for a person with an average body weight of 75 kg is 2 g, in which the selenium content is 240 μg. The composition of the oily component is
On average, EPA 22% and DIIA 43%.

The advantages of the medicament according to the invention can be summarized as follows.

The superior properties of (a) EPA and D) IA, as well as selenium and algae, are advantageously combined.

(b) Adverse effects such as those caused by the saturated lipid components of conventional fish oil-containing compositions containing vitamins A and D are eliminated.

(c) The possibility of ceroid-ribofuscinosis, which appears when taking polyunsaturated fatty acids, is eliminated.

(d) This drug contains selenium, a natural product that is abundant in algae, and selenium administered together with algae is well absorbed and exhibits desirable and excellent effects.

(e) This drug exhibits excellent therapeutic effects on atopic diseases, including eczema, asthma, allergic symptoms, allergic rhinitis, migraine, Crohn's disease, colitis, otitis media, nephrotic syndrome, and diabetes. It is useful for the preventive treatment of atopic diseases such as.

The drug according to the invention can be used to treat cardiovascular diseases, stroke symptoms and strokes, infarctions, Keshan in young patients.
It is particularly effective in the treatment of thromboembolic syndromes, as well as in the prevention of abnormal conditions.

〔Example〕

Hereinafter, one preferred embodiment of the present invention will be explained in detail. However, the present invention is not limited to these examples.

The ω-3-position polyunsaturated fatty acid used in the composition according to the present invention was prepared according to the procedure described in Examples 1 and 2, and the selenium-rich algae was prepared according to the procedure described in Example 3.
Each is prepared separately.

Medicaments according to the invention are described in Examples 4-6.

Example 1 After dissolving 2 kg of sodium hydroxide in 70Q 95% ethanol, at a temperature of 50-60°C, ]Okg
Added cod liver oil. The mixture was refluxed for 2 hours in the presence of nitrogen and then cooled to 10° C. with stirring.

Sodium salts of saturated fatty acids precipitated. The crystals were filtered and washed with a small amount of ethanol.

The ethanolic solution was evaporated and 20Q of boiling water was added to the residue. Non-hydrolyzable compounds such as cholesterol were completely removed by extraction with 5Q hexane.

After adjusting the pH of the aqueous phase to 2 using sulfuric acid, extraction was performed using 15Q hexane. The organic phase was washed with water, then dehydrated using anhydrous sodium sulfate, and further evaporated. As a result: 1) 11^ containing 1G, 8% and 14
r'A content: 31.8% concentration i+b was obtained.

This i+b was brown in color and had a fishy odor of 1.1. This was mixed with acidic Yamagami and heated to 105℃ in the presence of nitrogen.
The mixture was heated for 10 minutes in a hot condition. n1λ degree 1
As a result of deodorization by deodorization by deodorization by distillation for 3 hours at 70°C and r (air pressure 1m1IK), a tasteless and odorless Ura with a light color of 1.61z was obtained without causing any change in the composition. It was done.

Odori! -Point 16Q To a solution of 24 kg of cod liver oil in methanol at 60°C, 8 kg of 40% sodium hydroxide solution was added dropwise at a temperature of 50-60°C. Next, the mixture was stirred at 60° C. for 45 minutes. To the solution at about 60° C., 20 kg of 15% hydrochloric acid was added.

After separation, the organic phase was washed with 15% hydrochloric acid at 18 (El) until neutral. Again, the phases were separated and the oil phase was washed with 100Q
After stirring for 630 minutes, it was heated to about 45° C. and a solution containing 3.8 kg of lithium hydroxide monohydride in 30 fl of water was added.

The mixture was left overnight. After it was filtered, acetone was used to evaporate the liquid. The residue was acidified by adding about 8 kg of 15% hydrochloric acid, extracted three times with hexane and evaporated.

A nitrogen atmosphere was used throughout the entire purification process. In this way, 6.4k of refined fish oil with an iodine value of 258 and an acid value of 160 was obtained.
g was obtained.

The above purified cod liver oil 1- was mixed with methanol and 9% at 60°C.
It was added dropwise to a solution containing 3 kg of urea in Q. The mixture was stirred at the same temperature for 2 hours and then cooled. It was left at -10°C overnight. It was then filtered and the filtrate was evaporated. To the residue was added 2.5Q of 1:1 hydrochloric acid and the mixture was stirred for 15 minutes.

After extraction with hexane, until it becomes neutral,
The hexane phase was washed with water, then dehydrated using anhydrous sodium sulfate, and evaporated, resulting in an iodine value of 3.
15, 0.34 kg of ω-3 unsaturated fatty acids containing 24% EPA and 42% DHA was obtained.

4 parts of sodium selenite was added to 8Q of Knop-Pringsheim medium in a 10Q volume algae culture glass bottle. The culture thus obtained was sterilized for 30 minutes at 121° C. under 1 bar overpressure.

The sterile solution is then cooled and sterile air containing 65% carbon dioxide by volume inoculated with a pure culture of green algae that can readily uptake selenium is bubbled through the culture medium at 25°C and is 440-700μm, illuminance is 4000
The apparatus was illuminated by a lux discharge tube. After 14 days of culture, algae were separated from the culture medium.

The algae mass thus obtained was decomposed by ultrasonication and further carefully dried at a temperature below 65°C.

The yield was 6 g as powdered algae with a selenium content of 1200 μgig.

Example 4 150 g of 65% concentrated cod liver oil (22% EPA, 4 DHA)
100g of selenium-containing powdered algae (containing 3%)
Selenium content: 260ggig> was added. After homogenization,
0.1% vitamin E was added.

The active ingredient thus obtained was filled into soft gelatin capsules and packaged in blister foil.

9 Example 5 Starting materials: 400 g of 65% concentrated cod liver oil consisting of 22% EPA and 43% DHA, selenium content 1200μ
g/g powdered algae 70.6 g%, and vitamin 20
．． The procedure was as described in Example 4, except that 4 g was used.

The homogenized product was packed into capsules containing 500 μl of the active ingredient.

A tablet consisting of the following ingredients was prepared using conventional pharmaceutical equipment and methods.

Concentrated cod liver oil with EPA and DHA (43% DHA, 22% EPA) and 0.1% vitamin E
200°Selenium-containing powdered algae (Selenium content: 1500
μg/g) 86 ■Lactose
140 ■ Starch
60 ■ Polyvinylpyrrolidone 3.5 ■ Magnesium stearate 3.5 ■ If necessary, the tablets are coated with sugar using a tablet machine.

Claims (1)

Scope of Claims: (1) 0.5 to 50% by weight of selenium-containing algae and 99.5 to 50% by weight of C_1_8 to_2_2 fatty acids or derivatives thereof having at least two unsaturated bonds;
Drugs that act on the heart and cardiovascular system, including carriers customary in the pharmaceutical industry, optionally incorporated, and additives or antioxidants. (2) Claim containing 5 to 35% by weight of selenium-containing algae (
1) Agents that act on the heart and cardiovascular system. (3) The drug acting on the heart and cardiovascular system according to claim (1), which contains 15 to 25% by weight of selenium-containing algae. (4) 95-65 having at least two unsaturated bonds
The drug acting on the heart and cardiovascular system according to claim (1), comprising % by weight of C_1_8 to_2_2 fatty acids or derivatives thereof. (6) The drug acting on the heart and cardiovascular system according to any one of claims (1) to (5), which contains a fatty acid extracted as an unsaturated fatty acid from the oil of seawater fish. (7) As unsaturated fatty acids, 5, 8, 11, 14, 17
-eicosapentaenoic acid, and 4,7,10,13,
The drug acting on the heart and cardiovascular system according to any one of claims (1) to (6), which contains 16,19-docosahexaenoic acid. (8) 0.5 to 50% by weight of selenium-containing algae and 99.5 to 50% by weight of C_1_8 to_2_2 fatty acids or derivatives thereof having at least two unsaturated bonds are mixed, and A method for producing a drug that acts on the heart and cardiovascular system, comprising the steps of selectively incorporating a carrier used in , and an additive or an antioxidant. (9) 5-35% by weight of selenium-containing algae and 95-65% by weight of C_1_ with at least two unsaturated bonds
8-_2_2 fatty acid. The method for producing a drug according to claim (8). (10) 15-25 wt% selenium-containing algae and 85-75 wt% C_ with at least two unsaturated bonds
1_8 to_2_2 fatty acids. The method for producing a drug according to claim (8).