Composition for prevention or treatment of hypertriglyceridemia

Abstract: A composition for preventing or treating hypertriglyceridemia containing purple laver as an active ingredient is disclosed. Neutral fat level in blood can be reduced by ingesting the composition in a daily diet.

Description: This invention relates to preparation of a composition for prevention and treatment of hypertriglyceridemia; the composition can find use in or as medicines, additives for foods, health foods, or physiological foods. Deaths of adults from arteriosclerotic diseases such as coronary diseases and cerebral vessel diseases have been increasing. It is known that hyperlipidemia is an important risk factor of these diseases. Hyperlipidemia is a condition in which one or both of cholesterol and neutral fats (mainly triglycerides) among serum lipids increase. Primary hyperlipidemia which predominates hyperlipidemia is classified into 5 types (I to V) according to the most recent classification of WHO. Types I, IV, and V of primary hyperlipidemia are characterized by an increase in neutral fat level in the serum, and it is considered that neutral fats have greater influence than cholesterol (Beaumont, J.T. et al., Classification of Hyperlipidemia and Hyperlipoproteinemia , Bull WHO, Vol. 43, pp. 891-908 (1970)). Type I and type V are inclusively called chylomicronemia syndrome, and their relation to eruptive xanthoma, hepatosplenomegaly, pancreatitis, lipemia retinalis, etc. has been noted. Further, type IV is a main factor of endogenous hypertriglyceridemia and, according to the report of the research and investigation team (team leader: Professor Tarui Seiichiro) on primary hyperlipidemia, specified as an intractable disease by the Ministry of Health and Welfare, Japan ( Investigation Report in 1986 , p. 17, (1987)), it is present in 44.6% of male patients and 21.5% of female patients suffering from hyperlipidemia in Japan. Endogenous hypertriglyceridemia has a relatively high incidence and is said to be often accompanied by obesity, diabetes or abnormal sugar tolerance, hyperinsulinemia, insulin resistance, hyperuricemia, etc. Recently, reports supporting the theory that hypertriglyceridemia is an independent risk factor of diseases of coronary arteries have been increasing (M. Heikki Frick, et al., N. Engl. J. Med. , Vol. 317, p. 1237 (1989)). Thus, neutral fats are now attracting more attention than cholesterol as a risk factor in various deseases. It is believed that these hypertriglyceridemic conditions are related to single gene disorders or genetic predispositions combined with various environmental factors. Therefore it is effective, for preventing hypertriglyceridemia, to habitually control increase of neutral fats. More specifically, neutral fat level can be controlled by avoiding overweighing, overeating or overdrinking, reducing the body weight, using moderation in drinking, controlling sugar intake, regularly taking exercise and the like. As a dietetic treatment, it is recommended to take polyenoic fatty acids while limiting caloric intake. Known treating agents for hypertriglyceridemia include Clofibrate drugs and nicotinic acid derivatives. In particular, Bezafibrate and Gemfibrozil are known to reduce especially neutral fats (Rogers R.L., et al., Angiology , Vol. 40, No. 4, Pt. 1, pp. 260-269 (1989), etc.). In addition, various compositions effective to reduce neutral fats through daily diet have been proposed. For example, a composition for treating hypertriglyceridemia which comprises egg having a high iodine content as an active ingredient is disclosed in U.S.-A- 4,394,376). On the other hand, although purple laver is known as a highly nutritional food rich in protein, vitamins, and inorganic salts, it has been conventionally taken only as a favorite food or a taste-hitting food. There is no report of purple laver reducing blood neutral fat level. Purple laver is also known to be effective in reducing cholesterol. For instance, JP-A-58-150515 discloses a health food for reducing cholesterol level in the living body, which is prepared by molding purple laver powder mixed with binder into granules, but no suggestion is made therein as to the action of reducing blood neutral fats. As obviously implied by the above-described classification of hyperlipidemia, hypertriglyceridemia is distinguished from hypercholesterinemia. Drugs which reduce cholesterol do not always reduce neutral fats. For example, Probucol is a drug predominantly serving to reduce cholesterol, while Gemfibrozil is a drug predominantly serving to reduce neutral fats. From these facts, the composition for preventing or treating hypertriglyceridemia according to the present invention is distinguishable from the above-described health foods in range of application. An object of the present invention is to provide a composition for preventing or treating hypertriglyceridemia, not necessarily by clinical pharmacotherapy, but for example by oral ingestion through a daily diet. The inventors have investigated nutritional functions of purple laver, particularly actions on lipid metabolism. As a result, it has unexpectedly been found that purple laver has the effect of reducing neutral fats in blood plasma of rats. It has been further ascertained that purple laver has not only an effect on abnormal hypertriglyceridemia of experimental animals caused by feeding on a highly calorific diet but also an effect of reducing neutral fats in the plasma of rats fed on a general diet. The present invention permits prevention and treatment of hypertriglyceridemia through a daily diet. The term "purple laver" as used herein means a seaweed belonging to the Rhodophycophyta division, the Porphyra genus (e.g., Porphyra tenera KJELLMAN, Porphyra yezoensis VEDA), which has hitherto been eaten as food, especially in Japan, and includes unroasted sheeted purple laver, dried sheeted purple laver, and any other processed products of purple laver. A preferred composition for the present invention comprises a purple laver powder obtained by powdering dried purple laver. An example of preparing purple laver powder is described below. Preparation of Purple Laver Powder: Raw purple laver collected from sea water (grown in Ehime, Japan) is washed with water for several minutes, dehydrated at high speed for several minutes, and artificially dried at 38°C to 40°C for about 2 hours to obtain dried raw purple laver having a water content of from 12 to 13% by weight. The resulting dried raw purple laver was piled to a height of about 5 cm and dried in hot air at about 60°C for about 10 to 15 minutes. For the purpose of preventing moisture absorption, the dried laver was treated successively in a power mill in which the laver is passed through an about 5 cm mesh screen and in a sample mill in which the laver is passed through an about 1 mm mesh screen to obtain a laver powder. The resulting laver powder is packed and preserved in a polyethylene container sealed with a cap equipped with a desiccant. Purple laver powder may also be prepared by treating commercially available sun-dried raw purple laver (which powders on crumpling), or a freeze-dried product of raw purple laver, by means of the above-described power mill and sample mill. The thus obtained purple laver powder can be used as such as a composition for preventing and treating hypertriglyceridemia. If desired, the laver powder with added binder may be subjected to powdering or granulation, or laver powder with various adjuvants, such as vehicles and binders, may be formulated into tablets, capsules or the like Adjuvants which can be used in the present invention include binders, e.g., starch, gum arabic, gelatin, sorbitol, tragacanth gum, and polyvinylpyrrolidone; vehicles, e.g., lactose, sugar, corn starch, calcium phosphate, and glycine; and lubricants, e.g., magnesium stearate, talc, polyethylene glycol, and silica. According to the data furnished by National Federation of Fisheries Co-operative Association, Japan, the consumption of purple laver in Japan in 1987 amounted to about 9,600,000,000 sheets (about 30,000 tons), which corresponds to a daily intake of about 0.6 g for each Japanese. Such a low intake of purple laver, usually taken in the form of roasted purple laver sheet or seasoned and dried purple laver sheet, cannot be expected to exhibit a preventive and treating effect on hypertriglyceridemia. In general, purple laver exerts this effect when continuously ingested in an amount of from about 1 to 50 g, and preferably from about 5 to 40 g, (as a laver powder) per day for an adult. Having been conventionally used as food, purple laver has no toxicity even when ingested in such a large quantity. Such a purple laver intake reduces the neutral fat level in hypertriglyceridemia. In particular, for persons having predispositions to hypertriglyceridemia, the ingestion of purple laver reduces the neutral fat level in blood through a daily diet to prevent the onset of hypertriglyceridemia. As a matter of course, it prevents blood neutral fat level in normal persons from increasing due to overweighing, overeating, overdrinking, and the like. The purple laver in the form of powders, dusts, granules, tablets, capsules, etc. can also be used as an additive in various foods, and the resulting foods can serve as health foods for their high protein content or as physiological foods to prevent or treat hypertriglyceridemia. Where the purple laver preparation is added to various foods, the amount to be added is appropriately selected depending on the food processing method and the characteristics, taste or appearance of the food. From the viewpoint of preventive or curative effects on hypertriglyceridemia, it is desirable to add purple laver in as large a proportion as possible. Thus, the purple laver preparation to be used as a food additive is preferably ready to be added to various foods in large quantity. Foods to which the purple laver preparation may be added preferably include those which permit of incorporation of a large quantity of purple laver and those which are usually ingested in quantity. Examples of such foods include staple foods, e.g., breads, noodles, and pastes; cookies, pastries, TOFU (bean curd), pasted sea foods, MISO (a Japanese seasoning prepared from soybeans), etc. These foods incorporating purple laver, when continuously ingested in a daily diet, produce preventive or curative effects on hypertriglyceridemia. The effects of purple laver compositions for preventing or treating hypertriglyceridemia are demonstrated by the following test examples. All the percents are by weight unless otherwise indicated. TEST EXAMPLE 1 Test Animals: SD male rats (initial body weight: about 140 g) were maintained on a diet containing 20% casein as shown in Table 1 below (hereinafter referred to as 20% casein diet) for 10 days. The plasma cholesterol level of each animal was measured. After that, the rats were divided into 6 groups each of 6 animals in such a manner that each group might have the same average body weight and the Same average plasma cholesterol level, and used for the following experimentation. Test Method: The 6 test groups were fed on the respective diets shown in Table 1 for 8 days. The protein sources used in the diets and their nitrogen content were as follows. Casein ... 134 mg-nitrogen/g Egg yolk ... 122 mg-nitrogen/g Sardine ... 148 mg-nitrogen/g Isolated soybean protein ... 137 mg-nitrogen/g Purple laver (laver powder prepared as described above) ... 62.9 mg-nitrogen/g Wheat gluten ... 125 mg-nitrogen/g The amount of the protein source added to each diet was adjusted so as have the same nitrogen content as the 20% casein diet. Since purple laver has a high dietary fiber content, the diet containing the same as a protein source contained 18% of dietary fiber. In order to correct this, 18% of cellulose was added to other diets. On the final day of the experimentation (8th day), the body weight was measured, and blood was taken from the aorta abdominalis under anesthesia, and the neutral fat level was measured by using TG-EN KAINOS (a trade name of Kainos Co., Ltd.). The measured values were statistically analyzed by one-way analysis of variance (ANOVA), and significant difference of the average among groups was determined by Duncan's multiple range test. The results obtained are shown in Tables 2 and 3 below. Evaluation: As shown in Table 2, the rate of growth was not influenced by the kind of protein source except for wheat gluten. That is, no significant change in body weight was observed among the groups on the final day, except for wheat gluten. The fact that the food intake of the purple laver group was significantly lower than that of any other group appears to indicate that the low intake had no influence on growth rate because of the high nutritive qualities of purple laver. The groups fed on the isolated soybean protein diet and the purple laver diet showed significantly lower levels of neutral fats in the plasma than the group fed on the casein diet, sardine diet or egg yolk diet, as shown in Table 3. From these experimental results, it is apparent that purple laver has the effect of reducing neutral fats in the plasma without affecting the growth rate. It was also proved that this effect of purple laver is equal to or even greater than that produced by isolated soybean protein which has recently attracted attention as a protein source having a lipid reducing effect. TEST EXAMPLE 2 Test Animals: SD male rats (initial body weight: about 140 g) were maintained on a basic diet containing 25% casein shown in Table 4 below (hereinafter referred to as 25% casein basic diet) for 12 days. After that, the rats were divided into 5 groups each consisting of 6 animals in such a manner that each group had the same average body weight, and used for the following experimentation. Test Method: The 5 groups were fed respectively on the 25% casein basic diet and said basic diet plus either 20.9% of laver powder prepared as described above or 10% of agar or 10% of green asparagus or 10% of cellulose as dietary fiber source for 28 days. On the final day of experimentation (28th day), the body weight was measured. Further, blood was collected from the aorta abdominalis under anesthesia, and the neutral fat concentration in the plasma was measured. The results of experiments were statistically analyzed by one-way analysis of variance (ANOVA), and significant difference of the average among groups was determined by Duncan's multiple range test. The final body weight and the food intake for 8 days are shown in Table 5 below, and the neutral fat concentrations are shown in Table 6 below. Evaluation: In the above experiment, whether an increase in neutral fat level in the plasma induced by casein could be reduced by addition of various dietary fibers was examined over about 1 month. No significant difference in final body weight was observed among groups, indicating that the growth of the animals showed no difference depending on the kind of dietary fiber added as shown in Table 5. However, the neutral fat concentration was significantly reduced in the purple laver group as shown in Table 6. From these results, it is apparent that purple laver is superior to other various dietary fibers in reducing neutral fats. Thus, purple laver was proved to have excellent effects to reduce neutral fats as compared with either various other proteins or various other dietary fibers. As described above, a composition for preventing or treating hypertriglyceridemia containing purple laver as an active ingredient can be orally taken through a daily diet to reduce neutral fats in blood and to prevent or treat diseases associated with hypertriglyceridemia. Such compositions can be used as additives for various foods. Foods including such compositions have ensured nutritional values and increased effects to prevent or treat the above-described diseases and are therefore useful as health foods or physiological foods. The present invention is now illustrated in greater detail with reference to Examples, but it should be understood that the present invention is not deemed to be limited thereto. All the percents and parts are by weight unless otherwise specified. EXAMPLE 1 To the purple laver powder as above prepared was added an equivalent amount of a 5% aqueous solution of corn starch, and the mixture was kneaded in a kneader and granulated to obtain granules having a diameter of about 300 µm. The granules were dried in warm air to obtain raw laver granules. For prevention or treatment of hypertriglyceridemia, a preferred intake of the resulting raw laver granules is from about 5 to 30 g per day for an adult. EXAMPLE 2 Twenty parts of purple laver powder as above prepared and 80 parts of wheat flour were mixed, and to the mixed powder were added 3 parts of sugar, 2 parts of edible salt, and 3 parts of shortening. The mixture was kneaded while adding 50 parts of water. A solution of 2 parts of yeast in 6 parts of water was then added thereto, followed by thorough kneading. The resulting dough was fermented at about 28°C for 2 hours. After degassing, the fermentation was further continued, and the dough was divided into several equal masses. After proofing, the dough was shaped, put in a mold, and baked at 200 to 280°C to obtain bread containing a large amount of purple laver (about 18 dry wt.%). EXAMPLE 3 A mixture of 160 parts of wheat flour, 4 parts of edible salt, and 10 parts of purple laver powder as above prepared was kneaded with 32 parts of water. The resulting dough was rolled out by means of a rolling machine, cut to noodles by means of a noodle cutter, and dried to obtain noodles containing a large amount of purple laver (about 6 dry wt.%). EXAMPLE 4 A mixture of 100 parts of wheat flour, 5 parts of sugar, 10 parts of shortening, 20 parts of purple laver powder as above prepared, 0.4 part of saleratus (sodium bicarbonate), 0.6 part of ammonium carbonate, and 0.5 part of edible salt was kneaded with 18 parts of water. The dough was shaped and baked at 150 to 250°C to obtain crackers containing a large amount of purple laver (about 15 dry wt.%). EXAMPLE 5 A hundred parts of soybean milk, 20 parts of purple laver powder prepared from dried raw purple laver, and 0.1 part of gelatin were mixed, and 0.5 part of bittern was added thereto. The precipitate thus formed was then allowed to solidify in a mold to obtain TOFU (soybean curd) containing a large amount of purple laver (about 17 dry wt.%). EXAMPLE 6 Sixty parts of minced tuna, 40 parts of minced whale meat, and 3 parts of edible salt were mixed up, and to the mixture were added 30 parts of purple laver powder as above prepared, 1 part of sugar, and small amounts of glutamic acid, starch, flavors, antiseptics, pyroligneous acid and vitamin A. A shortening oil was further added thereto. The mixture was packed and sealed in a casing and sterilized by soaking in hot water at 85 to 88°C for 50 minutes, followed by cooling to obtain fish sausage containing a large amount of purple laver. (about 22 dry wt.%). EXAMPLE 7 Twelve parts of rice were allowed to absorb water in usual manner and smothered. After allowing to cool, the smothered rice was inoculated with koji mould to produce koji. The resulting koji was mixed with 30 parts of smothered soybean, 20 parts of purple laver as above prepared, and water were mixed up and chopped. The mixture was fermented in a fermenter at 26 to 28°C for about 75 days and finally strained to obtain MISO containing a large amount of purple laver (about 32 dry wt.%). EXAMPLE 8 Ten parts of purple laver powder as above prepared were added to a mixture of 100 parts of durum flour, a small amount of egg, and 3 to 4 parts of edible salt. Water was added thereto, and the mixture was stirred and kneaded. The resulting dough was appropriately rolled out to obtain paste having a water content of about 30%. The paste as such or stuffed with meats, cheese, vegetables, etc. was heated at about 100°C for 2 minutes and packaged to obtain a preservable paste product. The invention thus provides various foods having a high content of purple laver - e.g. from 5 to 40 dry wt.%, often about 20 or about 30 dry wt.%. There are thus crackers containing about 15 dry wt.% of purple laver; bread, tofu and sausage containing about 20 dry wt.% thereof; noodles containing over 5 wt.% thereof; miso containing about 30 dry wt.% thereof; and preservable paste containing about 10 dry wt.% thereof. While the invention has been described in detail and with reference to specific examples thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the scope thereof.

Claims: Use of purple laver for preparing a medicament for the prevention or treatment of hypertriglyceridemia.

Inventors: KIRIYAMA SHUHACHI DIA PALACE S, KIRIYAMA, SHUHACHI, DIA PALACE SHOKUBUTSUEN 803
Applicants: YAMANOUCHI PHARMA CO LTD, YAMANOUCHI PHARMACEUTICAL CO. LTD.
Application year: 1991
Main classification: A61K35
IPC codes: A61K36, A23C20, A23L1