JPS6045531A - Cholesterol-lowering agent - Google Patents

Abstract

PURPOSE:The titled agent capable of being medicated for a long period, comprising protein polysaccharide, an extract of a mycelium obtained by cultivating Basidiomyces belonging to the genus Coriolus versicolor or its fruit body with hot water or an alkali solution, containing a specific amount of protein, as an active ingredient. CONSTITUTION:A cholesterol-lowering agent comprising protein polysaccharide (e.g., krestin), an extract of a mycelium obtained by cultivating Basidiomyces belonging to the genus Coriolus versicolor or its fruit body with hot water or an alkali solution, containing 18-38wt% protein, having 5,000-300,000mol.wt. (ultracentrifugation method) as an active ingredient. The protein polysaccharide is a substance which has extremely low toxicity, hardly causes side effects, and has extreme safety to organisms. Administration is carried out orally or parenterally, but oral administration is preferable. A dose is 10-10,000mg/kg/day, preferably 20-600mg/kg/day, and it is administered once-three times dividedly.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an antihyperlipidemic agent containing a protein polysaccharide derived from a basidiomycete belonging to the genus Corsicolor as a main component, and more specifically Krestin J, an antihyperlipidemic agent Regarding.

Krestin has already been provided to society as an antitumor agent, has extremely low toxicity, does not have to worry about disrupting the intestinal flora, and can be administered for a long period of time. = L. It has no mutagenicity or allergic reactions, so it is an extremely safe substance with no risk of teratogenicity or allergic reactions in healthy people.

The present inventors have discovered that the protein polysaccharide 1i of the present invention has pharmacological effects of antihyperlipidemia in addition to anti-liver cancer effects, and has arrived at the present invention. .

The protein polysaccharide which is the active ingredient of the antihyperlipidemic agent of the present invention is disclosed in e.g.
-36322 Publication, Special Publication No. 56-14274,
1? It is a known substance described in Publications 11ft, '+G-14276, and Japanese Patent Publication No. 56-39288, etc., and is a mycelium 198 substance (B rotll) obtained by culturing Basidiomycetes belonging to the genus Corsicolor. or a hot water or alkaline solution extract of the fruiting body, comprising about 18
Contains ~38% protein, 5,000-300,000
(ultracentrifugation measurement method).

Of the present invention, the Corsicolor mycelium [FERM-P24
12 (AV CC20547) ] As mentioned above, the protein polysaccharide derived from the protein polysaccharide is commercially available under the trade name Krestin (Recent New Drugs Vol. 28 Vol. 1).
Pages 4-16, 1977 and 29th volume 96/1
01 page, 1978, Pharmaceutical Handbook, page 1346, May 1978 6th edition, published by Yakugyo Jihosha, Medical Mulberry
Roki Pharmaceutical Collection, 7th edition, page 240.

Published by Yakugyo Jihosha in 1983, it is also called PS-, and some of its properties are as follows.

The sugar moiety of the main fraction is β-D-glucan, and the structure of this glucan moiety is a branched structure containing 1→3, 1→4, and 1→6 bonds, and the amino acids that constitute the protein include aspartic acid, glutamic acid, etc. There are many acidic amino acids and neutral amino acids such as valine and leucine, and there are few basic amino acids such as lysine and arginine. It is soluble in water, and almost insoluble in methanol, pyridine, chloroform, benzene, and niline. Gradually decomposes and covers from about 120°C.

The antihyperlipidemic effect of the drug of the present invention will be explained below.

Hyperlipidemia is known to precipitate hypercholesterolemia and is often associated with early-onset atherosclerotic disease. Therefore, treating this disease not only prevents the progression of arteriosclerosis but also slows down its improvement. Conventionally, the treatment for hyperlipidemia was to inhibit monolisterol synthesis, "Reste 1]
- Le Tatsumi fJl? ll! Some of the currently used antihyperlipidemic agents, which are used for the purpose of promoting cholesterol absorption and inhibiting cholesterol absorption, are effective due to these mechanisms of action.

However, the present invention differs from these and relates to an antihyperlipidemic agent that lowers abnormally high blood lipids through a new mechanism of action.

In other words, in recent years, hyperlipidemia is thought to be mainly caused by the deficiency and functional decline of the LDL (low-density riboprotein) receptor, and improvement of this receptor abnormality is considered to be the ideal treatment for hyperlipidemia. It became so.

The drug of the present invention is a new antihyperlipidemic agent C which is characterized by decreasing blood lipids without side effects by increasing LDL levels.

The protein polysaccharide of the present invention is known to be an extremely safe substance for living organisms, as its toxicity is extremely low and almost no noticeable side effects occur. The acute toxicity values of the protein polysaccharide of the present invention are shown in Table 1 below.

Table 1 The acute toxicity values shown in Table 1 above were determined using the following test method.

Mice are ICR-JCL strain, 4-5 weeks old, weight 21-2
4' one, rat is 6 dragon type, 4-53! iil order,
Those weighing 100 to 150 g were used. The protein polysaccharide of the present invention was administered via four routes: intravenous, subcutaneous, intraperitoneal, and oral. The protein polysaccharide of the present invention was dissolved in physiological saline and administered, and the animals were observed for general symptoms, death, and body weight for 7 days, and after the observation period, a lamellar autopsy was performed.

As shown in Table 1, no deaths were observed in both rats and mice even at the maximum dose that could be administered.
The protein polysaccharide of the present invention is extremely safe for living organisms, whereas it is virtually impossible to determine the LD value of 0 culm.

In addition, the protein polysaccharide of the present invention has an extremely low acute mfQ, is a safe drug, and has a blood cholesterol lowering effect and a lowering effect on blood β-riboprotein.

It is useful as an antihyperlipidemic agent because it exhibits LDL receptor increasing action.

When the protein polysaccharide of the present invention is used as an antihyperlipidemic agent, it can be formulated into any desired dosage form. Moreover, administration is also performed by each route. Furthermore, the drug of the present invention has a mechanism of action that is different from that of cholesterol synthesis inhibitors, cholesterol absorption inhibitors, and cholesterol excretion agents that are currently widely used as antihyperlipidemic agents. The combination of these other drugs (71), which can further enhance the efficacy (1), can be used as an effective means.

In the case of oral administration, tablets, granules,
Powders, capsules, etc. may contain additives such as binders, encapsulants, excipients, lubricants, disintegrants, and wetting agents commonly used in pharmaceutical formulations. It may also be in the form of an oral liquid preparation (if used, it may be in the form of an oral solution, a shaken mixture, a suspension, an emulsion, or a tablet). Additionally, such liquid formulations may contain any of the commonly used additives and preservatives.
:stomach.

? For single doses, the compositions may contain additives such as stabilizers, buffers, preservatives, tonicity agents, etc., and are presented in unit-dose ampoules or multi-dose containers. be done.

The above composition is an aqueous solution, ¥! Suspension, solution, oil? ! 1
or in the form of an emulsion in an aqueous vehicle, whereas the active ingredient may be redissolved in a suitable vehicle, e.g., sterile, pyrogen-free water, before use as a powder.
There may be.

The antihyperlipidemic agent of the present invention can be administered orally or parenterally to humans and animals, but oral administration is preferred. Oral administration includes oral administration. Parenteral administration includes injections such as subcutaneous, intramuscular, intravenous, infusion, and the like.

The dosage of the antihyperlipidemic agent of the present invention is determined in animals or humans.
Also, since it is influenced by age, individual differences, medical conditions, etc., there may be cases where the hanging is outside the range below.
In general, when targeting humans, the daily administration Ljm of the active substance of the present invention is 1 for body weight! 1. 10 to 1000 mg per month,
Preferably, 20 to 600 mg is administered in 1 to 3 divided doses.

Example 1 1) Hyperlipidemia faithful J3 blood lipid negative/lower effect 10 people (3 males and 7 females) with hyperlipidemia were administered Cress 1 for about 1 month. Krestin's throw L) T-Cll in front
01O3tel'01 is 293-405111 (1/
dβ.

Average 340 mo/dρ, β-riboprotein 4 +8-+
038mg/dρ, average 741m<1/dj, I
f D l−(II iQl+[) intensity l
1poproLcin) is 26. '2-96. ! 1l
ll(1/dρ.

Average 49m(]/dA+, 1'G (Trigl
yccride) is 73・~425 mg/dj
, an average of 181 m (1/dj r). All of these patients had hypercholesterolemia despite having been on various antihyperlipidemic drugs for at least 4 months, and the existing antihyperlipidemic therapy The patient did not respond to antidiabetic agents.

The dosage of Krestin was 3 times a day (1, before and after administration, 2
Blood samples were taken at week 4 and 4, and blood lipids were measured. Figure 1 (a) to (d) shows the measurement results of blood lipids on the 4th week.
Shown below.

As shown in Figure 1, Krestin is l-I D L
.

Although there was no change in TG levels, β-riboprotein and -
r-Ch(llesterol) was significantly reduced.β
- For riboproteins, the gold side showed a decrease, with an average of 150 m (]
/dp, the reduction rate was 20%.

2) Effects on LD and L receptors of human cyanoblasts Familial hyperlipidemia, which is a hereditary disease characterized by thickening of Achilles pus [Heterotype pialoblasts from patients were used. G
By modifying the h method of Oldsjein et al., 20% F et
M ['r-subculture was performed in EM containing al3ovine S crum and used between 5 and 10 generations.

Culture it in a 6cm diameter dish until it reaches a certain amount, and add 5%
L P D S (L 1poprotein def
After pre-incubation for 48 hours, 1251-1-DL was added and cultured for 6 hours.
line) After washing twice, 3odium dcx
l-1cpes buf with trenSulfate
I8 was incubated for 1 hour in a fer.

3ul-jaCCbind with active activity in liquid
ingLI) Lff1. This indicates the number of receptors. The results are expressed as a percentage, with the average value when Krestin was not added as 100, and are shown in Figure 2.

As shown in Figure 2, with the addition of Krestin, a clear 3
urfacc-3ound 1251- L D L
(7) Increase [An increase in U4 IDl-receptor was observed.

Example 2 Using a pressure-type automatic filling machine, 330 mg of Crestin was filled into a No. 0 hard caprel to produce a capsule.

[Brief explanation of drawings]

FIGS. 1(a) to (d) are graphs showing changes in blood lipids after administering the protein polysaccharide of the present invention to hyperlipidemic patients, and FIG. FIG. 2 is a graph showing the influence of the protein polysaccharide of the present invention on LDL receptors of human fibrous U cells of blood patients. Representative Patent Attorney Imamura, L Figure 1 (a) (b) V= 1398.5 TO= 3.78 V= 518
2.4 TO=6.59V=+49.3 TO=0.8
5 V=+843.6 TO=-0,33 Figure 2 clear rl (,ug/mf1)

Claims (1)

[Scope of Claims] H1) An extract of mycelia or fruiting bodies obtained by culturing Basidiomycetes belonging to the genus Corsicolor in hot water or alkaline solution, which contains about 18 to 38% protein. An antihyperlipidemic agent containing as an active ingredient a protein polysaccharide having a molecular weight of 5,000 to 300,000 (ultracentrifugation-1 measurement method). (2) The antihyperlipidemic agent according to claim 1, wherein the protein polysaccharide is Krestin.