JPS60172920A - Gallstone dissolvent - Google Patents

Abstract

PURPOSE:A gallstone dissolvent, containing a monoterpene and a fatty acid which is a liquid at a specific temperature, capable of reducing the irritancy of the monoterpene, and increasing further the solubilizing power and rate, endoscopically usable, and capable of directly dissolving gallstones. CONSTITUTION:A gallstone dissolvent, containing (A) preferably 20-70vol% fatty acid which is a liquid at 30 deg.C, particularly linolic acid, linolenic acid, Emery type isostearic acid, 2-ethylhexanoic acid or isocaproic acid and (B) preferably 80-30vol% monoterpene, particularly limonene or menthone and preferably further (C) a nonionic surfactant, particularly sorbitan ester, polyoxyethylene sorbitan ester or glycerol ester of a fatty acid, etc. in >=0.5vol%, preferably about 1.0-3.0vol%, and capable of directly dissolving gallstones with very low irritancy to the skin.

Description

[Detailed description of the invention] The present invention relates to a novel gallstone dissolving agent.

Known gallstones include cholesterol-based gallstones, bilirubin-based gallstones, and rare stones. Due to recent changes in dietary habits, cholesterol-based gallstones have increased in Japan, accounting for approximately 85 cases of cholelithiasis.

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 if possible internally. .

There is currently no definitive medical treatment for cholesterol-based gallstones, and chenodeoxycholic acid or ursodeoxycholic acid, which are bile acids, are used, but these must be taken over a long period of time. However, it also has the disadvantage that the effectiveness rate is quite low.

Attempts have been made to use sodium cholate, heparin, and d-limonene as direct dissolving agents for residual cholesterol stones after surgery, but none of them were satisfactory. That is, sodium cholate and heparin have very low solubilizing power and their solubilizing speed is extremely slow, making it difficult to put them into practical use. Although d-limonene has a much faster solubilizing power and rate than the former, a detailed study of the clinical course during its use reveals that there are few cases in which complete dissolution within the bile duct has been confirmed. It also has drawbacks such as being irritating and requiring a catheter that is not dissolved in d-limonene.

Therefore, the present inventors aimed to improve the above-mentioned drawbacks of monoterpenes, further increase solubilizing power and solubilization rate, and provide a gallstone dissolving agent that can be used endoscopically and directly dissolves gallstones.
After many years of exploring the effects of various compounds, we discovered that when liquid fatty acids and monoterpenes are used together at 30°C, it is possible to directly dissolve gallstones, with extremely low irritation. The invention has been completed.

Therefore, the present invention relates to a first invention relating to a gallstone dissolving agent containing (a) a fatty acid that is liquid at 30°C, and (b) a monoterpene, and the above components (a) and (b) further comprising (C). A second invention relating to a gallstone dissolving agent containing a nonionic surfactant is provided.

The fatty acids that are liquid at 30°C used in the present invention include straight chain saturated fatty acids such as hexanoic acid, heptanoic acid, octanoic acid, and nonanoic acid; 2-ethylhexanoic acid, isocaproic acid, 2-methylundecanoic acid, -Methyl tocosanoic acid, 2
, 2-methyldodecanoic acid, methyltetradecanoic acid, 2-
Ethyltetradecanoic acid, 2-propyltridecanoic acid, 2
-butyldodecanoic acid, 2-pentylundecanoic acid, 2-
heptylnonanoic acid, 2,3-dimethyltetradecanoic acid,
Branched saturated fatty acids such as 2-ethylhexadecanoic acid, 2-hebutylundecanoic acid, 2-butyltetradecanoic acid, isostearic acid, and emery-type isostearic acid; 3-hexenoic acid, 4-hexenoic acid, 6-heptenoic acid, 3-octene Acid, 2-decenoic acid, 4-decenoic acid, 9-undecenoic acid, 10-undecenoic acid, 3-dodecenoic acid, cis-9-tridecenoic acid, 4-tetradecenoic acid, cis-9-hexadenoic acid, cis-7- Straight chain monoenes such as heptadecenoic acid, cis-8-heptadenoic acid, cis-9-hebutadenoic acid, cis-7-octadecenoic acid, cis-8-octadecenoic acid, cis-9-nonadecenoic acid, cis-11-eicosenoic acid, etc. Fatty acids; trans-2-methyl-2-pentenoic acid, cis-2-methyl-2-hexenoic acid, 2-methylenehexanoic acid, methacrylic acid, 2-ethylhexanoic acid, 3-methyl-2-nonenoic acid, 3- Methyl-3-nonenoic acid, L (→
Branched monoenoic fatty acids such as -2,4-dimethyl-2-dodecenoic acid; linoleic acid, trans-10, cis-12-octadecadienoic acid, cis-9, cis-11-octadecadienoic acid, lylunic acid, arachidonic acid , di-, tri- or tetraene fatty acids such as curbanodonic acid; 2-hexic acid, 2-hebutic acid, 2-octynic acid, 7-octynic acid,
2-nonynoic acid s 2-decynoic acid, 6-undecanoic acid, 6
-dobsic acid, 7-dobsic acid, 6-trypsic acid, 8
- Acetylene fatty acids such as trypsic acid and the like.

Among these, linoleic acid, lilunic acid, emery-type isostearic acid, 2-ethylhexanoic acid, and r-tukaproic acid are particularly preferred.

In addition, the monoterpenes used in the present invention include myrcene, ocimene, limonene, pinene, linalool, cheraniol, nerol, citronellol, citral, citronellal, diventine, terpineol, phelandrene, terpinene, silvestrene, terpinolene, beryaldehyde, carvone, and menthone. , piperitenone, cineole, etc., among which limonene and menthone are particularly preferred.

The fatty acid, which is the M active ingredient of the present invention, is a low-toxic one contained in natural foods, for example, and is sb, and the monoterpene, for example, dlJ monene, has an LDv of 4. st/
kg, therefore, the toxicity (LD,
. ) is, for example, d -IJ monene-linoleic acid (60:
40) is 24 f/sui, d-limonene-linoleic acid (4
0:60) is extremely low at 31 tlkg.

The gallstone dissolving agent of the present invention contains 20 to 70% of the fatty acid (hereinafter simply referred to as 迤) and 80 to 30% of the monoterpene.
It is preferable to mix them so that Furthermore, if a nonionic surfactant is used in addition to the two-sided effective ingredients, even more excellent effects can be obtained. Examples of nonionic surfactants include sorbitan monolaurate, norbitan monobalmitate, sorbitan monostearate, sorbitan sesquistearate, sorbitan tristearate, sorbitan monooleate, sorbitan sesquioleate, and sorbitan trioleate. Sorbitan fatty acid ester,
Polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxy 7
Polyoxyethylene sorbitan fatty acid esters such as ethylene sorbitan monostearate, polyoxyethylene sorbitan monooleate, coconut oil fatty acid esters,
Glycerin fatty acid esters such as glycerin monostearate and glycerin monooleate, polyoxyethylene alkyl ethers such as polyoxyethylene oleyl ether, polyoxyethylene hydrogenated castor oil derivatives, sucrose fatty acid esters, and polyethylene glycol fatty acids such as polyethylene glycol stearate. ester, polyoxyethylene sucrose fatty acid ester, etc., and in particular, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester (average number of added moles of ethylene oxide: 20), and polymexyethylene hydrogenated castor oil derivative ( The average number of added moles of ethylene oxide is preferably 60).

These nonionic surfactants account for 0.5% or more of the total composition,
Preferably 1. Excellent effects can be obtained by blending approximately 0 to 3.0 g.

Although the mechanism of action of the gallstone dissolving agent of the present invention is not necessarily clear, it is thought that the coexistence of the fatty acid and monoterpene significantly increases the solubility and dissolution rate of cholesterol-based gallstones.

The gallstone dissolving agent of the present invention can be used to dissolve stones remaining after surgery, by placing a nasobiliary drain after endoscopic papillotomy and injecting through the drain, or by injecting the stones through the nasobiliary duct. It can be used as a non-invasive therapy to directly dissolve gallstones by injecting it through a drain.

The administration time of the gallstone dissolving agent of the present invention varies depending on age, symptoms, etc., but it can be injected from the drain for 3 to 10 minutes.
/ hour, injection time 2-10 hours/day, 50-100 d/day
The administration period is preferably 3 to 14 days, usually 4 days.
~10 days is preferred.

Next, an example will be given and explained.

Example 1 The solubility of anhydrous cholesterol in a solution of linoleic acid and d-limonene mixed at various ratios was measured at 37°C. The results are shown in Figure 1. In a two-component system of linoleic acid and d-limonene, in a system where the proportion of linoleic acid is 20 to 70%, the solubility is much higher than when each is used alone. was gotten. Cholesterol was measured by a ferric chloride-sulfuric acid coloring method using Ki I 1ani reaction.Example 2 1.5 t of sorbitan monooleate was mixed with 60 m
After thoroughly mixing in a 50°C hot bath, add linoleic acid to make a total volume of 100ml. The above solution was heated at 5°C.
After being left for one day at 100°C, the product was stable for a long period of time at 5°C.

Similar effects can be obtained when nonionic surfactants such as sorbitan monolaurate, glyceryl monostearate, sorbitan monopalmitate, polyoxyethylene sorbitan monooleate, and polyoxyethylene tristearate are used in place of sorbitan monooleate. I got it.

Example 3 The solubility of anhydrous cholesterol in a solution of emery-type isostearic acid and d-limonene mixed at various ratios was measured at 37°C. The results are shown in Figure 2. In the two-component system of emery-type isostearic acid and d-limonene, the ratio of emery-type isostearic acid is 2.
In the 0-70% system, significantly higher solubility was obtained than when each was used alone. Cholesterol was measured by a ferric chloride-sulfuric acid coloring method using the Iliani reaction.

Example 4 Sorbitan monolaurate 2. d-limonene 66 in Ol
ml and mix completely in a 50°C hot bath, then add emery-type isostearic acid and bring the total amount to 100 ml.
). After the solution was left at 5°C for 1 day, the solution was stable at 5°C for a long period of time.

Similar results can be obtained when nonionic surfactants such as rubitan monooleate, glyceryl monostearate, sorbitan monopalmitate, polyoxyethylene sorbitan monooleate, and polyoxyethylene tristearate are used instead of sorbitan monolaurate. It worked.

Example 5 d-IJ monene-linoleic acid solutions having the following mixing ratios were intraperitoneally administered to SD male rats weighing approximately 250 tons. The animals were sacrificed by dislocation of the occipital vertebrae 30 minutes after administration, and the abdomen was opened to observe the condition of the inside of the first cavity, especially the small intestine.

The evaluation was based on a four-level evaluation of hyperemia and edema. The results are shown in Table 1.

Table 1 Evaluation Criteria 11 Not observed at all ±: Rarely observed +; Slightly observed +: Considerably observed As shown in Table 2, d-limonene alone causes congestion and edema within the small intestine. However, with the d-limonene-linoleic acid mixed system, hyperemia and edema rarely occur, indicating that the irritation is extremely low.

[Brief explanation of drawings]

FIG. 1 shows the cholesterol solubility curve of the linoleic acid-d-IJ monene two-component system, and FIG. 2 shows the cholesterol solubility curve of the emery-type isostearic acid-d-limonene two-component system. Above Figure 1 "9/med-limonene (%) 100 80 60 40 20
0 Reno-No Europe (%) 0 20 40 +i0 80
100 Figure 2

Claims (1)

[Claims] 1. A gallstone dissolving agent containing (a) a fatty acid that is liquid at 30°C, and (b) a monoterpene. 2. A gallstone dissolving agent containing (a) a fatty acid that is liquid at 30°C, (b) a monoterpene, and (C) a nonionic surfactant.