JPH0623097B2 - Gallstone dissolving agent - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a gallstone solubilizer, and more particularly to a gallstone solubilizer containing a monoglyceride of a fatty acid having 6 to 12 carbon atoms and a monoterpene as active ingredients.

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 been improving the above-mentioned drawbacks of monoterpenes, further increasing the solubilizing power and the solubilizing speed, and providing gallstone direct solubilizing agents that can be used endoscopically, for various years with various compounds. As a result of searching for its action, it was surprisingly found that an excellent gallstone direct solubilizer can be obtained by using a monoglyceride of a fatty acid having 6 to 12 carbon atoms and a monoterpene together, and completed the present invention.

That is, the present invention relates to a gallstone dissolving agent containing 20 to 70% by volume of monoglyceride of fatty acid having 6 to 12 carbon atoms and 80 to 30% by volume of monoterpene.

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, heptanoic acid (enanthic acid) monoglyceride, octanoic acid (caprylic 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.

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.

Thus, the fatty acid monoglyceride, which is the active ingredient of the present invention, has low toxicity used as an emulsifier of foods, and the monoterpene also has an LD _{50 of} d-limonene, for example.
Is 4.5 g / Kg, and therefore the toxicity of the gallstone dissolving agent of the present invention (L
D ₅₀ ) is extremely low, for example, d-limonene-octanoic acid monoglyceride (60:40) is 25 g / Kg and d-limonene-octanoic acid monoglyceride (40:60) is 33 g / Kg.

The gallstone dissolving agent of the present invention is blended so that the monoglyceride of a fatty acid having 6 to 12 carbon atoms is 20 to 70% by volume (hereinafter simply referred to as%) and the monoterpene is 80 to 30%.

Further, by using a nonionic surfactant together with both active ingredients, the stability at low temperature can be improved. Examples of the nonionic surfactant include sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquistearate,
Sorbitan fatty acid esters such as sorbitan tristearate, sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate, polyoxy Polyoxyethylene sorbitan fatty acid ester such as ethylene sorbitan monooleate, coconut oil fatty acid ester, glycerin monostearate, glycerin fatty acid ester such as glycerin monooleate, polyoxyethylene alkyl ether such as polyoxyethylene oleyl ether, polyoxyethylene curing Polyethylene such as castor oil derivative, sucrose fatty acid ester, polyethylene glycol stearate Glycol fatty acid ester, polyoxyethylene sucrose fatty acid ester and the like can be mentioned, and sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester (average addition mole number of ethylene oxide of 20) and polyoxyethylene hydrogenated castor oil are particularly effective. 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 action mechanism of the gallstone dissolving agent of the present invention is not necessarily clear, it is considered that the coexistence of a monoglyceride of a fatty acid having 6 to 12 carbon atoms and a monoterpene remarkably increases the solubility and dissolution rate of cholesterol gallstones. To be

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 as a 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 octaglyceride monoglyceride and d-limonene were mixed at various ratios. The results are shown in FIG. 1, and in the binary system of octanoic acid monoglyceride and d-limonene, the proportion of octanoic acid monoglyceride is 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. In Example 1, decanoic acid monoglyceride was used in place of octanoic acid monoglyceride, and the solubility of anhydrous cholesterol in a solution mixed with d-limonene at various ratios was measured at 37 ° C. Results are shown in FIG.

Example 3. In Example 1, menthone was used instead of d-limonene, and the solubility of anhydrous cholesterol in a solution mixed with octanoic acid monoglyceride at various ratios was 37.
It was measured at ° C. Results are shown in FIG.

Example 4. In Example 1, α-pinene was used instead of d-limonene, and the solubility of anhydrous cholesterol in a solution mixed with octanoic acid monoglyceride at various ratios was 3%.
It was measured at 7 ° C. Results are shown in FIG.

Example 5. In Example 1, citronellal was used instead of d-limonene, and the solubility of anhydrous cholesterol in a solution mixed with octanoic acid monoglyceride at various ratios was measured at 37 ° C. Results are shown in FIG.

Example 6. In Example 1, linalool was used instead of d-limonene, and the solubility of anhydrous cholesterol in a solution mixed with octanoic acid monoglyceride at various ratios was 3%.
It was measured at 7 ° C. Results are shown in FIG.

Example 7. In Example 1, geraniol was used instead of d-limonene, and the solubility of anhydrous cholesterol in a solution mixed with octaglyceryl monoglyceride at various ratios was measured at 37 ° C. The results are shown in Fig. 7.

Example 8. In the composition shown in Table 1, sorbitan monooleate was admixed with d-limonene and thoroughly mixed in a 50 ° C. hot bath, and then octanoic acid monoglyceride was further added to bring the total amount to 100%. 3 for each solution at 5 ℃
The presence or absence of precipitation of octanoic acid monoglyceride after storage for one day was visually observed. 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 9. 1 g of artificial cholesterol calculus (tabletting at 50 kg / cm ² using a French press, diameter 10 mm, height 12 mm, cylindrical) was rotated at 37 ° C. and 25 rpm with a USP dissolution tester. At, the dissolution rate when a solvent of 50 m was used was determined. The results are shown in Table 2.

Example 10. An SD male rat weighing about 250 g was intraperitoneally d-limonene-octanoic acid monoglyceride solution in the following mixing ratios.
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 result is the third
As shown in the table.

Evaluation criteria −: Not observed ±: Almost not recognized +: Somewhat recognized: Quite observed As shown in Table 3, d-limonene alone causes hyperemia and edema in the small intestine, but is highly irritating. , D-limonene-octanoic acid monoglyceride mixed system, it is found that hyperemia and edema hardly occur, and irritation is very small.

[Brief description of drawings]

FIG. 1 shows octanoic acid monoglyceride-d-limonene 2
Cholesterol solubility curve of the component system, FIG. 2 is the cholesterol solubility curve of the decanoic acid monoglyceride-d-limonene binary system, FIG. 3 is the cholesterol solubility curve of the monoglyceride octanoate-mentone binary system, FIG.
The figure shows the cholesterol solubility curve of octanoic acid monoglyceride-α-pinene binary system, FIG. 5 shows the octanoic acid monoglyceride-citronellal binary cholesterol solubility curve, and FIG. 6 shows octanoic acid monoglyceride.
Cholesterol solubility curve of linalool binary system, No. 7
The figure is a cholesterol solubility curve of octaglyceride monoglyceride-geraniol binary system.

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

Claims (5)

[Claims] 1. A monoglyceride of a fatty acid having 6 to 12 carbon atoms.
A gallstone dissolving agent comprising 20 to 70% by volume and 80 to 30% by volume of a monoterpene. 2. The gallstone dissolving agent according to claim 1, wherein the fatty acid monoglyceride is octanoic acid monoglyceride or decanoic acid monoglyceride. 3. The gallstone dissolving agent according to claim 1, 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. 5. The nonionic surfactant is sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, glycerin fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene hydrogenated castor oil derivative, sucrose fatty acid ester, polyoxyethylene glycol. The gallstone dissolving agent according to claim 4, which is selected from the group consisting of fatty acid esters and polyoxyethylene sucrose fatty acid esters.