JPH0623099B2 - 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 as well, 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 uresodeoxycholic acid, is used, but these are taken over a long period of time. It has the disadvantage that it has to be used and the efficiency 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 drawbacks of the above-mentioned drugs, further increased the solubilizing power and the solubilization rate, and provided a gallstone solubilizing agent that directly dissolves gallstones that can be used endoscopically, and thus various compounds are provided. As a result of searching its effect over many years,
When a monoglyceride of a fatty acid having 6 to 12 carbon atoms and a fatty acid, a fatty acid triglyceride or a fatty acid diglyceride which is liquid at 30 ° C. are used in combination, it can be applied at room temperature, can directly dissolve gallstones, and has extremely low irritation. It was found that the present invention has been completed.

Therefore, the present invention is a first invention relating to a gallstone dissolving agent containing (a) a monoglyceride of a fatty acid having 6 to 12 carbon atoms, and (b) a fatty acid, a fatty acid triglyceride or a fatty acid diglyceride which is liquid at 30 ° C., A second invention relating to a gallstone dissolving agent further comprising (c) a nonionic surfactant in the above components (a) and (b) is provided.

Specific examples of the monoglyceride of fatty acid having 6 to 12 carbon atoms used in the present invention include hexanoic acid (caproic acid).
Monoglyceride, hebutanoic acid (enatonic acid) monoglyceride, octanoic acid (cabrylic acid) monoglyceride, nonanoic acid (pelargonic acid) monoglyceride, decanoic acid (capric acid) monoglyceride, undecanoic acid (undecylenic acid) monoglyceride, dodecanoic acid (lauric acid) monoglyceride, etc. Among them, octanoic acid monoglyceride and decanoic acid monoglyceride are particularly preferable.

The fatty acids which are liquid at 30 ° C. include linear saturated fatty acids such as hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid; 2-ethylhexanoic acid, isocaproic acid, 2-methylundecanoic acid, 3-methyldocosanoic acid, 2,2 -Methyldodecanoic acid, methyltetradecanoic acid, 2-ethyltetradecanoic acid, 2-propyltridecanoic acid, 2-putyldodecanoic acid, 2-pentylundecanoic acid, 2-heptylnonanoic acid, 2,3-dimethyltetradecanoic acid, 2-ethylhexadecane Branched saturated fatty acids such as acids, 2-heptylundecanoic acid, 2-butyltetradecanoic acid, isostearic acid, and emery-type isostearic acid; 3-hexenoic acid, 4-hexenoic acid, 6-heptenoic acid, 3-octenoic acid, 2-decene. Acid, 4-decenoic acid, 9-undecenoic acid, 10-undecenoic acid, 3-dodecenoic acid Cis-9-tridecenoic acid, 4
-Tetradecenoic acid, cis-9-hexadecenoic acid, cis-
7-heptadencenoic acid, cis-8-heptadecenoic acid, cis-9-heptadecenoic acid, cis-7-octadecenoic acid,
Cis-8-octadecenoic acid, cis-9-nonadecenoic acid,
Linear monoene fatty acids such as cis-11-eicosenoic acid; trans-2-methyl-2-pentenoic acid, cis-2-methyl-2-hexenoic acid, 2-methylenehexanoic acid, methacrylic acid, 2-ethylhexanoic acid, Branched monoene fatty acids such as 3-methyl-2-nonenoic acid, 3-methyl-3-nonenoic acid, L (+)-2,4-dimethyl-2-dodecenoic acid; linoleic acid, trans-10, cis-12- Octadecadienoic acid, cis-9, cis-11-octadecadienoic acid, linolenic acid, arachidonic acid, curvanodonic acid and other di, tree or tetraene fatty acids; 2-hexynoic acid, 2-heptic acid, 2-octynoic acid, Acetylene fats such as 7-octynoic acid, 2-nonic acid, 2-decynic acid, 6-undecic acid, 6-dodecic acid, 7-dodecic acid, 6-tridecic acid, 8-tridecic acid Acid and the like. Among these, linoleic acid, linolenic acid, emery isostearic acid, 2-ethylhexanoic acid, and isocaproic acid are particularly preferable.

Examples of fatty acid triglycerides that are liquid at 30 ° C. include tributyrin (4,4,4), tricaproin (6,6,6), tricaprylin (8,8,8), 1
-Caproyl-2,3-diolein (6,18 ', 1
8 '), 1-elide-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 (10,10,12), 1-
Myristo-2,3-dicaprin (10,10,14),
1-oleo-2,3-dicaprin (10,10,1
8 '), 1-elide-2,3-dicaprin (10,1
0,18 '), 1-linoleo-2,3-dicaprin (1
0,10,18 ″), 2-oleo-1,3-dicaprin (10,18 ′, 10), 1-capryl-2,3-diolein (10,18 ′, 18 ′), 1-capryl-2 ，
3-dieraidin (10,18 ', 18'), 1-oleo-2,3-dilaurin (12,12,18 '), 1-
Elaidino-2,3-dilaurin (12,12,1
8 '), 1-linoleo-2,3-dilaurin (12,1
2,18 "), 2-oleo-1,3-dilaurin (1
2,18 ', 12), 1-lauro-2,3-diolein (12,18', 18 '), 1-lauro-2,3-dilinolein (12,18', 18 "), 1-oleo- Two
3-dimyristin (14,14,18 '), 1-linoleo-2,3-dimyristin (14,14,18 "), 1
-Myristo-2,3-diolein (14,18 ', 1
8 '), 1-myristo-2,3-dilinolein (14,
18 ", 18"), 1-palmito-2,3-diolein (16,18 ', 18'), 1-palmito-2,3-dilinolein (16,18 ", 18"), 1-stearo-
2,3-diolein (18,18 ', 18'), 1-stearo-2,3-dilinolein (18,18 ", 1)
8 ″), triolein (18 ′, 18 ′, 18 ′), trilinolein (18 ″, 18 ″, 18 ″), 2-stearo-1,3-diolein (18 ′, 18,18 ′), etc. Among them, tricaprylin (octanoic acid triglyceride) and tricaprin (decanoic acid triglyceride) are particularly preferable.

Further, as the fatty acid diglyceride liquid at 30 ° C.,
1,2-Dioctanoin (octyl acid diglyceride), 1,2-dicaprine (decanoic acid diglyceride), and 1,2-dilaurin (lauric acid diglyceride) are preferred.

Thus, the fatty acid monoglyceride which is the active ingredient of the present invention is used as an emulsifier of foods, and the fatty acid, the fatty acid triglyceride and the fatty acid diglyceride all have extremely low toxicity when used for food. Therefore, the toxicity (LD ₅₀ ) of the gallstone dissolving agent of the present invention is extremely low, for example, octanoic acid monoglyceride-octanoic acid triglyceride (60:40) of 32 g / kg.

The gallstone dissolving agent of the present invention contains the component (a) in an amount of 20 to 70% by volume.
(Hereinafter, simply referred to as%), it is preferable that the component (b) is blended so as to be 80 to 30%. The component (b) fatty acid, fatty acid triglyceride and fatty acid diglyceride may be used alone or in combination of two or more kinds.

Further, by using a nonionic surfactant in combination with both of the above active ingredients, the stability at low temperatures can be improved. Examples of nonionic surfactants 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, glycerin monooleate such as glycerin monooleate, polyoxyethylene oleyl ether such as polyoxyethylene oleyl ether Carboxymethyl ethylene alkyl ethers, polyoxyethylene hardened castor oil derivatives, sucrose fatty acid esters, polyethylene glycidyl Kohli fatty acid esters such as polyethylene glycol stearate, polyoxyethylene sucrose fatty acid esters and the like,
In terms of its effect, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester (average addition mole number of ethylene oxide: 20) and polyoxyethylene hydrogenated castor oil derivative (average addition mole number of ethylenoxide 60) are preferable.

An excellent effect can be obtained by blending these nonionic surfactants in an amount of 0.5% or more, preferably 1.0 to 3.0% in the total composition.

Although the action mechanism of the gallstone dissolving agent of the present invention is not always clear, by coexisting the component (a) and the component (b),
It is considered that the dissolution rate of cholesterol gallstones is significantly increased.

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 non-invasive therapy in which this drug is infused to directly dissolve gallstones.

The dose of the gallstone dissolving agent of the present invention varies depending on the age, symptoms, etc., but the infusion rate from the drain is 3 to 10 ml / hour,
It is preferable to administer 50 to 100 ml per day at an infusion time of 2 to 10 hours / day, and the administration period is 3 to 14 days, usually 4 to 10 days.
Day is preferred.

Next, examples will be described.

Example 1. Observing the state of a solution in which octanoic acid monoglyceride and octanoic acid triglyceride were mixed at various ratios, it was found that octanoic acid monoglyceride alone solidified easily at room temperature, often solidified in the drain, and was difficult to use. 20% triglyceride octanoate
When it was more than 0.1%, it did not solidify at room temperature, and injection from the drain was easy.

Example 2. In the composition shown in Table 1, triglyceride octanoate was added to sorbitan monooleate and thoroughly mixed in a 50 ° C. hot bath, and then monoglyceride octanoate was further added to bring the total amount to 100%. For each solution, the presence or absence of octanoic acid monoglyceride was visually observed after storage at 5 ° C. for 1 month. The results are shown in Table 1.

From the results in Table 1, it is understood that the addition of sorbitan monooleate, which is a nonionic surfactant, can suppress the precipitation of octanoic acid monoglyceride at low temperatures.

When nonionic surfactants such as sorbitan monolaurate, glyceryl monostearate, sorbitan monopalmitate, polyoxyethylene sorbitan monooleate and polyoxyethylene tristearate are used instead of sorbitan monooleate, octanoic acid monoglyceride The same effect was obtained when decanoic acid monoglyceride was used instead.

Example 3. Observing the state of the solution in which octanoic acid monoglyceride and linoleic acid were mixed in various proportions, coagulation at room temperature with octanoic acid monoglyceride alone did not allow use via drain, but the proportion of linoleic acid was 25
%, It was not coagulated at room temperature, could be injected more easily than the drain, and was clinically usable.

Example 4. After adding 50 g of octanoic acid diglyceride to 1.5 g of sorbitan monolaurate and thoroughly mixing in a 50 ° C warm bath, octanoic acid monoglyceride was further added to bring the total amount to 1
Make up to 00 ml. After the solution was allowed to stand at 5 ° C. for 1 day, it was stable even after storing it at 5 ° C. for a long period of time without precipitation of octanoic acid monoglyceride.

When nonionic surfactants such as sorbitan monooleate, glycerin monostearate, sorbitan monopalmitate, polyoxyethylene sorbitan monooleate and polyoxyethylene tristearate are used instead of sorbitan monolaurate, octanoic acid monoglyceride The same effect was obtained when decanoic acid monoglyceride was used instead.

Example 5 The solubility of anhydrous cholesterol was measured at 37 ° C. in a solution obtained by mixing octanoic acid monoglyceride with emery type isostearic acid, octanoic acid triglyceride or octanoic acid diglyceride at various ratios. The results are as shown in FIGS. 1 to 3, and in the two-component system of octaglyceride monoglyceride and emery isostearic acid, octaglyceride triglyceride or octanoic acid diglyceride, the proportion of octanoic acid monoglyceride is 20 to 7.
In the 0% 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 6. 2.0 ml of octanoic acid monoglyceride-octanoic acid triglyceride solution having the following mixing ratios was intraperitoneally administered to an SD male rat having a body weight of about 250 g. Thirty minutes after administration, the animals were sacrificed by cervical dislocation, the abdomen was opened, and the state of the abdominal cavity, particularly 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 2.

As can be seen from Table 2, the monoglyceride octanoate alone causes slight hyperemia and edema inside the small intestine, but irritation is observed, but the monoglyceride octanoate-octanoic acid triglyceride mixed system causes almost no hyperemia or edema and irritation. It turns out that there is very little sex.

[Brief description of drawings]

Cholesterol solubility of octanoic acid monoglyceride-emery-type isostearic acid binary system, FIG. 2 of octanoic acid monoglyceride-octanoic acid triglyceride binary system, and FIG. 3 of octanoic acid monoglyceride-octanoic acid diglyceride binary system. It is a curve.

Claims (2)

[Claims] 1. A gallstone dissolving agent containing (a) a monoglyceride of a fatty acid having 6 to 12 carbon atoms and (b) a fatty acid, a fatty acid triglyceride or a fatty acid diglyceride which is liquid at 30 ° C. 2. A gallstone dissolving agent containing (a) a monoglyceride of a fatty acid having 6 to 12 carbon atoms, (b) a fatty acid which is liquid at 30 ° C., a fatty acid triglyceride or a fatty acid diglyceride, and (c) a nonionic surfactant.