JPH0623098B2 - Gallstone dissolving agent - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel gallstone solubilizers.

Known gallstones include cholesterol gallstones, bilirubin gallstones and rare stones. Due to recent changes in dietary habits, cholesterol gallstones have increased in Japan, accounting for about 85% of all cholelithiasis.

Treatment methods for cholelithiasis are roughly classified into surgical treatment by surgery and medical treatment by drugs, but it is important to try to dissolve gallstones as aggressively as medically possible considering the patient's pain.

Currently, there is no definitive medical treatment for cholesterol gallstones, and one of the bile acids, chenodeoxycholic acid or ursodeoxycholic acid, is used, but these must be taken over a long period of time. It has the drawback that it must be used, and the effective rate is considerably low.

For post-operative cholesterol-based residual stones, attempts have been made to use sodium cholate, heparin, and d-limonene as direct solubilizers, but none of them was satisfactory. That is, sodium cholate and heparin have very low solubilizing power, and their speeds are also very slow, which makes practical application difficult. d-limonene has a solubilizing power,
Although the solubilization rate is considerably faster than the former, detailed examination of the clinical course during the period of use has confirmed few cases in which complete dissolution was confirmed in the bile duct. Further, it has a drawback that it requires a catheter that is irritating and is not dissolved in d-limonene.

Therefore, the present inventors have improved the above-mentioned drawbacks of monoterpenes, further increased the solubilization power and the solubilization rate, and provided a gallstone dissolving agent that directly dissolves gallstones that can be used endoscopically. As a result of investigating the action of the compound over a long period of time, it was found that gallstones can be directly dissolved and a substance with extremely low irritation is obtained when the fatty acid triglyceride which is liquid at normal temperature and monoterpene are used together. Completed the invention.

Accordingly, the present invention provides for containing 20-70% by volume of fatty acid triglycerides and 80-30% by volume of monoterpenes which are liquid at 30 ° C.

Examples of the fatty acid triglyceride liquid at 30 ° C. used in the present invention include tributyrin (4,4,4), tricaproin (6,6,6), tricaprylin (8,
8,8), 1-caproyl-2,3-diolein (6,8)
18 ', 18'), 1-eride-2,3-dicaprylin (8,8,18 '), 1-linoleo-2,3-dicaprylin (8,8,18 "), 1-caprylyl-2,3 −
Diolein (8,18 ', 18'), Trinonanoin (9,9,9), Tricaprin (10,10,10),
1-lauro-2,3-dicaprin (10,10,1
2), 1-myristo-2,3-dicaprin (10,1
0,14), 1-oleo-2,3-dicaprin (10,
10,18 '), 1-elide-2,3-dicaprin (10,10,18'), 1-linoleo-2,3-dicaprin (10,10,18 "), 2-oleo-1,3-
Dicaprin (10,18 ', 10), 1-capryl-
2,3-diolein (10,18 ', 18'), 1-capryl-2,3-dielaidin (10,18 ', 1)
8 '), 1-oleo-2,3-dilaurin (12,1
2,18 '), 1-elaidino-2,3-dilaurin (12,12,18'), 1-linoleo-2,3-dilaurin (12,12,18 "), 2-oleo-1,3-
Dilaurin (12,18 ', 12), 1-lauro-2,
3-diolein (12,18 ', 18'), 1-lauro-2,3-dilinolein (12,18 ", 18"), 1
-Oleo-2,3-dimyristin (14,14,1
8 '), 1-linoleo-2,3-dimyristin (14,
14,18 "), 1-myristo-2,3-diolein (14,18 ', 18'), 1-myristo-2,3-dilinolein (14,18", 18 "), 1-palmito-
2,3-diolein (16,18 ', 18'), 1-palmito-2,3-dilinolein (16,18 ", 1)
8 ″), 1-stearo-2,3-diolein (18,1
8 ', 18'), 1-stearo-2,3-dilinolein (18,18 ", 18"), triolein (18 ', 1)
8 ', 18'), trilinolein (18 ", 18", 1
8 ″), 2-stearo-1,3-diolein (18 ′,
18, 18 ') and the like, but tricaprylin (caprylic acid triglyceride) and tricaprin (capric acid triglyceride) are particularly preferable.

Further, as the monoterpene used in the present invention, myrcene, ocimene, limonene, pinene, linalool, geraniol, nerol, citronellol, citral, citronellal, dipentine, terpineol, ferrandrene, terpinene, silvestrene, terpinolene, perylaldehyde, carvone, menthone. , Piperitenone,
Examples thereof include cineole, and among them, limonene, pinene, linalool, geraniol, citronellal and menthone are particularly preferable.

And Thus, fatty acid triglyceride as an active ingredient of the present invention has low toxicity, which is used as an edible oil or food additives, also LD ₅₀ for monoterpenes also e.g. d- limonene is an 4.5 g / Kg Therefore, the toxicity (LD ₅₀ ) of the gallstone dissolving agent of the present invention is, for example, 27 g / Kg for d-limonene-caprylic acid triglyceride (60:40) and 3 for d-limonene-caprylic acid triglyceride (40:60).
It is extremely low at 8 g / Kg.

The gallstone dissolving agent of the present invention is blended so that one or more of the fatty acid triglycerides may be 20 to 70% by volume (hereinafter simply referred to as%) and the monoterpene may be 80 to 30%. Further, by using a nonionic surfactant in combination with both of the above active ingredients, the stability of the gallstone dissolving agent of the present invention can be improved. Examples of the nonionic surfactant include sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquistearate, sorbitan tristearate, sorbitan monooleate, sorbitan sesquioleate, and sorbitan trioleate. Fatty acid ester, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan fatty acid ester, coconut oil fatty acid ester, glycerin monostearate Rate, such as glycerin monooleate, glycerin fatty acid ester, polyoxyethylene oleyl ether Examples thereof include oxyethylene alkyl ether, polyoxyethylene hydrogenated castor oil derivative, sucrose fatty acid ester, polyethylene glycol fatty acid ester such as polyethylene glycol stearate, polyoxyethylene sucrose fatty acid ester, and the like. Esters, polyoxyethylene sorbitan fatty acid esters (average number of moles of ethylene oxide added: 20) and polyoxyethylene hydrogenated castor oil derivatives (average number of moles of ethylene oxide added: 60) are preferred.

When these nonionic surfactants are added in an amount of 0.5% or more, preferably 1.0 to 3.0% in the total composition, more excellent effects can be obtained.

Although the mechanism of action of the gallstone dissolving agent of the present invention is not always clear, the fatty acid triglyceride and / or
It is considered that the coexistence of the fatty acid diglyceride and the monoterpene markedly increases the solubility and dissolution rate of cholesterol gallstones.

The gallstone dissolving agent of the present invention is, for postoperative residual stones, after endoscopic papillotomy, indwelling a nasal bile duct drain, and injecting from the method of dissolving the calculus, or from the nasal bile duct drain It can be used for pessimistic therapy by injecting this drug to directly dissolve gallstones.

Although the dose of the gallstone dissolving agent of the present invention varies depending on the age, symptoms, etc., the infusion rate from the drain is 3 to 10 m /
Hour, infusion time 2-10 hours / day, 50-100m a day
Administration is preferable, and the administration period is 3 to 14 days, usually 4
10 days is preferable.

Next, examples will be described.

Example 1. Solubility of anhydrous cholesterol was measured at 37 ° C in a solution in which caprylic acid triglyceride and d-limonene were mixed at various ratios. The results are shown in FIG. 1, and in the two-component system of caprylic acid triglyceride and d-limonene, the proportion of caprylic acid triglyceride was 2%.
In the 0-70% system, much higher solubilities were obtained than when used alone. Cholesterol was measured by the ferric chloride-monosulfate color development method using the Kiliani reaction.

Example 2. Solubility of anhydrous cholesterol was measured at 37 ° C. in a solution in which caprylic acid triglyceride and citronellal were mixed at various ratios. The results are shown in Fig. 2, and in the two-component system of caprylic acid triglyceride and citronellal, the solubility of caprylic acid triglyceride in the system of 20 to 70% was much higher than that when used alone. It was Cholesterol was measured by the ferric chloride monosulfate color development method using the Kiliani reaction.

Example 3. Solubility of anhydrous cholesterol was measured at 37 ° C. in a solution in which caprylic acid triglyceride and α-pinene were mixed at various ratios. The results are shown in FIG. 3, and in the binary system of caprylic triglyceride and α-pinene, the proportion of caprylic triglyceride was 20%.
In -70% systems, much higher solubilities were obtained than when used alone. Cholesterol was measured by the ferric chloride monosulfate color development method using the Kiliani reaction.

Example 4 Solubility of anhydrous cholesterol was measured at 37 ° C. in a solution in which caprylic acid triglyceride and geraniol were mixed at various ratios. The results are shown in FIG. 4, and in the two-component system of caprylic acid triglyceride and geraniol, the proportion of caprylic acid triglyceride was 2%.
In the 0-70% system, much higher solubilities were obtained than when used alone. Cholesterol was measured by the ferric chloride-monosulfuric acid color development method using the Kiliani reaction.

Example 5. Solubility of anhydrous cholesterol to 3 in a solution in which caprylic acid triglyceride and menthone were mixed in various ratios was 3
It was measured at 7 ° C. The results are shown in Figure 5,
In a two-component system of caprylic acid triglyceride and menthone, the proportion of caprylic acid triglyceride is 20 to 70.
%, Significantly higher solubilities were obtained than when used alone. Cholesterol was measured by the ferric chloride monosulfate color development method using the Kiliani reaction.

Example 6 To 1.5 g of sorbitan monooleate, 60 m of d-limonene was added and thoroughly mixed in a 50 ° C. hot bath, and then caprylic acid triglyceride was further added to bring the total amount to 100 m. After allowing the above solution to stand at 5 ° C for 1 day,
It was stable at ℃ for a long time.

When nonionic surfactants such as sorbitan monolaurate, glyceryl monostearate, sorbitan monopalmitate, polyoxyethylene sorbitan monooleate and polyoxyethylene tristearate are used in place of sorbitan monooleate, caprylic acid triglyceride Similar effects were obtained when capric acid triglyceride was used instead.

Example 7. An SD male rat having a body weight of about 250 g was intraperitoneally injected with the following mixing ratios of d-limonene-caprylic acid triglyceride solution.
2.0m was administered. 30 minutes after administration, killed by cervical dislocation,
After laparotomy, the condition of the abdominal cavity, especially the small intestine, was observed. The evaluation was based on a hyperemic state and an edema state on a 4-point scale. The results are shown in Table 1.

As can be seen from Table 1, d-limonene alone causes hyperemia and edema inside the small intestine and is highly irritating, whereas the d-limonene-caprylic acid triglyceride mixed system hardly causes hyperemia and edema and is irritating. It turns out that there are very few.

[Brief description of drawings]

FIG. 1 shows caprylic acid triglyceride-d-limonene 2
Cholesterol solubility curve of component system, FIG. 2 is a cholesterol solubility curve of caprylic acid triglyceride-citronellal binary component system, FIG. 3 is a caprylic acid triglyceride-α-pinene binary component cholesterol solubility curve, and FIG. 4 is caprylic acid triglyceride. -Geraniol binary component cholesterol solubility curve, Fig. 5 is a caprylic acid triglyceride-mentone binary component cholesterol solubility curve.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI technical display location A61K 31/23 8413-4C

Claims (4)

[Claims] 1. A fatty acid triglyceride which is liquid at 30 ° C.
A gallstone dissolving agent containing 70% by volume and 80 to 30% by volume of monoterpene. 2. The gallstone dissolving agent according to claim 1, wherein the fatty acid triglyceride is caprylic acid triglyceride or capric acid triglyceride. 3. The gallstone solubilizer according to claim 1 or 2, wherein the monoterpene is limonene, pinene, linalool, geraniol, citronellal or menthone. 4. The gallstone dissolving agent according to claim 1, further comprising 0.5% by volume or more of a nonionic surfactant.