JPS6299323A - Agent for hyperlipemia - Google Patents

Abstract

PURPOSE:An agent for hyperlipemia useful for various diseases caused by lipid metabolism disorder, having no toxicity, capable of being administered for a long period, showing improved cholesterol lowering action, containing hexacosanol of a higher fatty alcohol as an active ingredient. CONSTITUTION:An agent for hyperlipemia containing hexacosanol as an active ingredient. Hexacosanol shows improved cholesterol lower action on serum cholesterol, liver cholesterol and no side effect such as gastrointestinal disorder, etc. Addition of another anti-lepemia component such as beta-sitosterol may show synergistic effects. This agent is useful for preventing and remedying diseases related to lipid metabolism disorder such as hypertension, arteriosclerosis, cerebral infarct, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is useful for the prevention and treatment of hyperlipidemia, which is an adult disease associated with arteriosclerosis, diabetes, hypertension, heart disease, obesity, and other lipid metabolic disorders. For more details regarding useful hyperlipidemic agents, hexacosanol (hexae
A hyperlipidemic agent characterized by containing Osano I) as an active ingredient.

Hexaphthalate is cerylfurfur (cerylfurfur).
Naturally occurring C2g known aliphatic higher alcohols, also called col + ol), are available on the market and include carnauba wax, cochineal wax, beeswax,
It is also known to exist in wool wax, germ, hemlock, apple skin, buckwheat, green leaves of plants, etc., forming ester bonds with fatty acids.

In recent years, there has been increasing interest in drugs useful for the prevention and treatment of hyperlipidemia symptoms.
A number of proposals are known that attempt to provide hyperlipidemic agents that reduce or suppress the increase in DL cholesterol. However, most of these drugs are of the type that are used only after symptoms become difficult to control with dietary therapy, which is the basic treatment for hyperlipidemia, and they are associated with various side effects.
For example, there are problems in that the drug is unsuitable for administration to patients with liver disorders or pregnant women, and it is difficult to administer it for a long period of time, so it is desired to develop a hyperlipidemia drug that does not have such inconveniences or troubles. .

In order to meet these demands, attempts have been made to develop a hyperlipidemic agent that has the effect of controlling exogenous cholesterol like a dietary therapy and does not have serious side effects. There are some unsaponifiable substances such as soybean oil, such as soysterol, which are in practical use, but the reality is that they still cause problems in terms of gastrointestinal disorders.

For example, soysterol contains 40 to 50 plant sterols.
%, natural tocopherol 18-22%, and other higher unsaturated fatty acids such as linoleic acid.
Gastrointestinal disorders such as loss of appetite, diarrhea, loose stools, constipation, abdominal pain,
Difficulties that are easily accompanied by nausea, nausea, etc., hypersensitivity, rash, pain
It is known to have disadvantages such as itching and sores. Furthermore, β-sitosterol, which belongs to plant sterols, is also known to have a cholesterol-lowering effect, but it has not been put to practical use.

The present inventors have conducted research in order to provide a hyperlipidemic agent that is free from side effects, can be safely administered over a long period of time, and exhibits a practical cholesterol-lowering effect.

As a result, hexacosanol, which belongs to a higher aliphatic alcohol that has not been known to have antilipidemic effects, has surprisingly shown excellent cholesterol-lowering effects on serum cholesterol and liver cholesterol. I discovered that it shows.

Further, the hexacosanol is LD. (rat, oral)
A unique compound that has an extremely low toxicity of 10 g/kg or more, which can be said to be virtually non-toxic, has no trouble with side effects, can be administered for a long period of time, and substantially exhibits an excellent cholesterol-lowering effect. It turned out to be. Furthermore, the compound has the advantage of being an easily available compound, and can be used advantageously in foods and drinks,
It has been found that there is also the benefit of being able to incorporate it into luxury foods and use it in the form of dietary foods.

Therefore, an object of the present invention is to provide a new type of hyperlipidemic agent that is safe and effective.

The above objects and other objects and advantages of the present invention will become more apparent from the following description.

According to the present invention, there is provided a hyperlipidemia agent characterized by containing hexafsanol, a known aliphatic higher alcohol, as an active ingredient. The hexacosanol used is commercially available and can be used in the present invention, but it may be extracted and separated from a natural product or a synthetic product. Normal n-hex: 2”F/-/l/[CHl(CH
2) 24C1120H] Salesaluca may contain other diabetic aliphatic alcohols with similar carbon numbers.

The hyperlipidemia agent of the present invention exhibits an effect of lowering or suppressing increase in cholesterol, and is useful for prevention and treatment of various symptoms associated with lipid metabolic disorders. Examples of such symptoms include the following symptoms. The hyperlipidemic agent of the present invention can be used to treat hypertension, arteriosclerosis, peripheral circulation disorders associated with open arteriosclerosis, cerebral arteriosclerosis, stroke, cerebral infarction, myocardial infarction, thrombosis, etc. The dosage form may be: Techniques for preparing oral dosage forms are well known per se and can be used to prepare the agents of the present invention. Examples of such oral preparations include powders, fine granules, granules, tablets, troches,
Examples include capsules, tablets, liquids, and syrups. Furthermore. The active ingredient of the present invention can also be used in the form of diet foods mixed with various foods and drinks M (including luxury items). When preparing the hyperlipidemia agent of the present invention,
Carriers and diluents known per se can be used. As examples of such pharmaceutical ingredients, liquid or solid pharmaceutical ingredients such as those described in Figure 1 can be used. For example, thiamin, riboflavin, pyridoxine hydrochloride, sia7cobalamin, ascorbic acid, biotin, calcium pantothenate, niacin, choline chloride, ascorbic acid, carotene, vitamin A1 vitamin D2, vitamin E
1 Nutrients such as linole oil, amino acids, free salts, lecithin, benzoic acid, paraoxybenzoate esters, preservatives such as sodium benzoate, gum arabic, tragacanth, sodium alginate, methylcellulose, hydroxypropylcellulose, carboxymethylcellulose, Additives include magnesium stearate, aluminum silicate, calcium silicate, light anhydrous silicic acid, lactose, starch, glucose, sucrose, honey, mannitol, sorbitol, polysorbate 80, and sucrose aliphatic esters.

The hyperlipidemia agent of the present invention is usually administered orally as described above, and the dosage can be changed as appropriate depending on the type and degree of symptoms. For example, about 5 mg/kg/day to about 50 v
ag/kg/day preferably about 10 to about 3011
An example of a dosage is 1 g/kg/day. Furthermore,
The active ingredient of the present invention is L Ds. (rat, oral) is 10
g/kg or more, it is an extremely low toxicity compound that can be said to be virtually non-toxic, and no side effects such as gastrointestinal disorders have been observed, making it useful as a highly stable shavings.

The hyperlipidemic agent of the present invention can be administered in combination with other antilipidemic ingredients that exhibit cholesterol-lowering effects,
Alternatively, it can also be co-administered in the form of a complex with such other anti-i% lipidemia components. An example of such other components is β-sitosterol, which belongs to the plant sterol family known to have a cholesterol-lowering effect, and may exhibit a synergistic effect.

Examples of other known ingredients that can be used in combination include, in addition to β-sitosterol, stigmasterol, toco7dylol, pyridoxine, nicotinamide, campesterol, and the like.

Tests and results regarding the cholesterol-lowering effect and toxicity of the useful ingredients of the present invention will be shown below.

[11 Cholesterol suppression test.

After raising Wistar male rats (4 weeks old) for one week with normal breeding feed, rats weighing around 100 g are selected and used as test animals. Both the control group and the drug-administered group had 6 animals per group.The control group was given only the HCD feed shown in Table 1 below, and the drug-administered group was given the HCD feed with the drug added at regular intervals. Then, serum cholesterol or liver cholesterol was assayed.

Assay of Serum Cholesterol Knee rats were fixed in a dorsal position without anesthesia, and about 0.6 ml of blood was collected from the jugular vein according to the method of Kaneana et al. After coagulating the collected blood sample, centrifugation #I (3+000 r, p, m, 1
Serum cholesterol was measured using the Wako Jun fiSWJl clinical test kit for these 12 serum samples. Liver cholesterol assay: Breeding on HCl) feed or drug-added HCD feed
The liver was removed, 1 g of it was accurately weighed as a sample, and 20 times the amount of ethanol was added to the sample for homogenization, followed by the method of Abell et al. [L, L].

Abell+B, B, Levy+B,
B, Brodie, F”, E.

Kendall ;J, )3io1. Chem,
+195t357 (1952)], the total cholesterol amount was measured using a clinical test kit manufactured by Wako Junkuwa.

Table 1 (Composition of HCD sample) Cholesterol 1% by weight Furic acid
1〃Casein
25 Sucrose
50 〃Hydrogenated fat 10 〃Cellulose 5 〃Vitamin, mineral M4 tt Dried fishmeal 4 〃The control group (6 animals per group) was given only the HCD feed shown in Table 1 above, and the drug administration group (6 animals per group) was given the following table. The animals were fed a feed in which 1 weight ff1s of the drug shown in 2 was added to 100 parts by weight of the HCD feed shown in NJ Table 1 above.

Serum cholesterol was measured every third day according to the serum cholesterol assay described above, and the results were as shown in Table 21 below. In addition, liver cholesterol at the 68th day of feeding was measured according to the liver cholesterol assay described above. Liver weight (
(approximately 7.5 g), no difference was observed. The results were as shown in Table 3 below.

-3 cholesterol (feed WE16B) Total cholesterol (sag/liver g) Significant difference p<o, os [11] Acute toxicity test.

LDso (rat, oral) test result is 108/k
It was found to be substantially non-toxic at concentrations of more than 100 g.

Below are some examples of preparations.

Preparation example 1 (granules) (in 14.5 g of ff per day) Hexacosa/-le 1200 mg β-sitosterol 600B lactose
1300B Ballet Denbun
1150mg hydroxypropyl cellulose 2
50B 500mg The above was produced according to the Japanese Pharmacopoeia, granule manufacturing method to obtain an orally administered preparation (granule).

Preparation example 2 (tablets) (6 tablets per day, 1800mg) Hexacosanol 1200mg lactose
180mg potato starch 120B hydroxypropylcellulose 100B magnesium stearate
30m800B The above product was made into tablets according to the Japanese Pharmacopoeia, tablet manufacturing method.

SII formulation example; 3 (emulsion) (10ml/day J11) Hexacosanol 10g Sucrose fatty acid ester 1g Polysorbate 80
1g 50% Sorbitol 50
11 Purified water -1-1 The above was made into an emulsion according to the emulsion manufacturing method of the Japanese Pharmacopoeia.

Preparation example 4 (soft capsules) (daily dose of 6 capsules, 1800 mg) Hexacosa/-
Le 900a+g linole oil
350mg wheat germ oil
300n+g soy lecithin
601I1g tocopherol acetate
60a+g dispersion grinding - once once Once the above was made into soft capsules according to the method for manufacturing soft capsules according to the Japanese Pharmacopoeia.

Claims (1)

[Scope of Claims] 1. A hyperlipidemia agent characterized by containing hexacosanol as an active ingredient. 2. Claim 1 characterized in that it contains hexacosanol and β-sitosterol as active ingredients.
Hyperlipidemic agents as described in Section 1.