JPS5855416A - Preventive and remedy for cholelithiasis - Google Patents

Abstract

PURPOSE:A preventive and remedy for cholelithiasis that contains vitamin K as an active ingredient, thus being suitable for the use in medical treatment of cholelithiasis. CONSTITUTION:Vitamin K, which has been known as a vitamin activating the styptic mechanism and used as a styptic agent, is included as an active ingredient. Among vitamin Ks, K1 shows the strongest activity of inhibiting the formation of gallstones and its activity is stronger than that of chenodeoxycholic acid which is receiving attention as an agent for inhibiting gallstone formation. Its preparation may be in any form such as dust, capsules or injection solution and its dose is usually 10-100mg a day an adult.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a cholelithiasis treatment and prevention agent. More specifically, the present invention relates to a cholelithiasis treatment/prevention agent containing vitamin K as an active ingredient.

Gallstones include cholesterol-based gallstones2. Bilirubin-based gallstones and rare stones are known. In Japan, bilirubin-based gallstones have traditionally accounted for a high proportion, but cholesterol-based gallstones have increased in recent years.

What is the cause of lies that have become Western-style?

It is believed that the Westernization of dietary habits is a major cause.

Treatment methods for cholelithiasis can be broadly divided into surgical treatment using surgery and medical treatment using drugs, but considering the pain caused to the patient, it is important to actively attempt to dissolve the gallstones as medically possible. .

However, there is still no known drug that suppresses or prevents gallstones and is suitable from the current therapeutic point of view. The development of excellent gallstone suppression/blocking drugs is desired in this field.

There was no medical treatment for cholesterol-based gallstones other than the duodenal probe method, but in recent years, research and development of pharmaceuticals that have the effect of dissolving gallstones and even preventing their occurrence has been carried out worldwide. It is. Although there is currently no definitive answer, chenodeoxycholic acid or wolfdeoxycholic acid, which is one of the bile acids, is attracting attention.

Therefore, as a result of many years of searching for various compounds for even better gallstone formation inhibitors, the present inventors found that *<
Vitamins should be taken into consideration.

The present invention was completed after discovering that vitamin K, such as K, is excellent as a gallstone formation inhibitor.

Therefore, an object of the present invention is to provide a new and excellent gallstone dissolving agent.

The vitamins used in the present invention include K.

There are examples such as K4 t KI e KI v KY, but 2 are usually used.

Vitamins such as vitamin Kl and Ni are known as hemostatic mechanism activating vitamins, are effective against bleeding and hypothrombinism, and are used as hemostatic agents.

The present inventors have discovered that vitamin K, which is used as a hemostatic agent,
We have discovered that it is also an excellent gallstone formation inhibitor. Although the mechanism of action of the gallstone formation inhibiting effect of the present invention is not necessarily clear, it is thought that vitamin K acts on bile acid synthase in the liver and increases its activity and performance.

Next, the results of animal experiments will be shown to specifically explain the effects of the present invention.

Experimental Example 1, Experimental Method (1) Using ICR strain 4-week-old male SPF mice as experimental animals, feed (5 tons) was prepared by mixing 0.5 tons of cholesterol and 0.251 tons of cholic acid with Oriental powder feed.
a-1ndue@lng Diet). At the same time as the start of feed administration, vitamin stones (2-methyl-3-phytyl-1,4-naphthoquinone), vitamins (2-
farnesyl-3-methyl-1,4-naphthoquinone),
and vitamin did. Physiological saline was injected subcutaneously as a control. Furthermore, for the purpose of comparing and examining the effects and conditions of vitamin
A group was also created in which a diet mixed with DC (abbreviated as DC) was administered.

After 5 weeks, the gallbladder was removed at autopsy to check for the presence or absence of gallstones in the gallbladder, and the contents were collected on black paper and slide glass.
ild stereomicroscope and a Notg+arski differential interference device (Zeims).

2. Experimental results Table IK shows the results.

In Table 1, I to ■ in the column of degree of gallstone formation mean the following.

0: No gallstone formation is observed in the gallbladder 5 I: 1-20- of the gallbladder is occupied by gallstones ■: 21-40- of the gallbladder is occupied by gallstones I : 41-60% of the gallbladder is occupied by gallstones■: 61-80% of the gallbladder is occupied by gallstones■: 81-100% of the gallbladder is occupied by gallstones ■: 100% of the gallbladder is occupied by gallstones From Table 1, it is clear that vitamin IC has an excellent effect of inhibiting gallstone formation. In particular, it has the strongest effect on vitamins (stronger than CDCA and excellent as a gallstone formation inhibitor).

The form in which vitamin K is administered in the present invention is as follows.

It can be in any form such as powder, tablets, capsules, and injections. Dosage varies depending on the type of vitamin.

Although the dosage form M and the severity of symptoms cannot be limited, an adult dose of 10 to 10011I9 is administered per day.

When making a powder, use magnesium carbonate, silicic anhydride (siloid, cuplex, etc.), inorganic excipients such as synthetic aluminum silicate, calcium phosphate, and organic excipients such as lactose, corn starch, and cellulose (Avicel Nato). Adsorb and use. When preparing tablets and capsules, the above-mentioned bulk powder is made into tablets and capsules, respectively, by a conventional method.

Furthermore, K to be made into an injection is made water-soluble using a nonionic surfactant by a conventional method to prepare an injection. As a nonionic surfactant, hydrogenated castor oil ethylene oxide adduct [
For example, N1KKolHCO (product name), Emal@x
HC (product name)].

Sorbitan fatty acid ester ethylene oxide adduct [
For example, conventional nonionic surfactants such as Tw...n (trade name)], alkylphenol ethylene oxide adducts, fatty acid ethylene oxide adducts, and sorbitan fatty acid esters [for example, 5pan (trade name)] can be used.

It is also possible to add vegetable oils such as refined rice bran oil, olive oil, castor oil, sesame oil, and soybean oil, if necessary. Of course, when used as an injection, commonly used substances such as propylene glycol and glucose may be mixed.

The vitamins used in the present invention may be either naturally obtained or artificially obtained by synthesis. What can be obtained by synthesis?

Although there is a possibility that a large number of stereoisomers may occur, any of them may be used in the present invention.

The vitamins used in the present invention are already widely used as hemostatic agents, have almost no safety problems, and are ideal cholelithiasis treatment and prevention agents in that sense. Toxicity I: Q'f-
The evening was as follows.

(1) Vitamin 1 (phytonadione...
2-methyl-3-phytyl-1,4-naphthoquinone) (
b) Acute toxicity: LD50 for mice intravenously was 4,230 Wv/Y, and for oral LD50 was 53,670 η249, so the toxicity was so low that no deaths were observed.

(b) Necropsy findings after 90 days of consecutive subcutaneous injections of 2, 20 and 2001 v/kg/day to chronically toxic rats.

No abnormalities were found in blood tests or histological examination of major organs.

(2) Vitamins (Menatetrenone... Song 2-Methyl-3-All-Trans-Tetragrenyl-1,4
- Naphthoquinone) (a) Acute toxicity The maximum amount of vitamins that can be administered (5,000 mg/k
y) and a half dose thereof were administered intramuscularly and intravenously to mice and rats and observed for 10 days, but the toxicity was so low that the LD50 value could not be determined.

Furthermore, no deaths were observed when rabbits were intravenously injected with 100x249 and observed for 7 days.

(b) Subacute toxicity Subcutaneously, intraperitoneally (250 Da/yu) to rats.

It was administered intravenously (20 μ/U) to rabbits for 1 month.
In the autopsy findings, blood tests, urine, organ weights, and histological findings, no findings that could be considered to be toxic to the drug were observed except for induration at the subcutaneous administration site.

(c) Chronic toxicity rats A dose of 50 av/1 kg/day, which can be administered intraperitoneally, was administered for 6 months, and autopsy findings, blood tests, biochemical tests, and urine tests were performed. As a result, after 2 to 3 months, accumulation of ascites due to accumulation of fat-soluble substances and weakness due to this were observed.

Other than that, no abnormal findings that seemed to be in accordance with the main rules were observed.

As detailed above, vitamins are excellent as cholelithiasis treatment and prevention agents, and are safe drugs with almost no toxicity, making the present invention extremely valuable.

patent applicant Ko-zai Co., Ltd.

Claims (1)

[Claims] (1) A cholelithiasis treatment/prevention agent containing vitamin K as an active ingredient (2) A cholelithiasis treatment/prevention agent according to claim 1, wherein vitamin K is a vitamin. 3) The cholelithiasis treatment/prevention agent according to claim 1, wherein the vitamin K is a vitamin. (4) The cholelithiasis treatment/prevention agent according to claim 1, wherein the vitamin K is a vitamin.