JPS5942653B2 - Gallstone dissolver - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a gallstone dissolving agent containing an unsaponifiable product of dog bean oil as a main component.

Treatments for patients with cholelithiasis include the duodenal probe method and the administration of anticholinergic drugs, but no drug that completely dissolves gallstones is known yet.

As a result of intensive research, the present inventors have found that unsaponifiable dog bean oil, which is obtained by esterifying the distillate obtained during the deodorization process of soybean oil and purified by molecular distillation, has a remarkable effect on inhibiting gallstone formation. We obtained this knowledge and discovered that this drug can be used as a gallstone dissolving agent.

The unsaponifiable product of dog bean oil according to the present invention is a semisolid, viscous oily substance that has a unique odor and a slightly sweet taste.

In addition, as an ingredient, plant sterols (β-sitosterol, stigmasterol, campesterol) 40
Contains ~50%, tocopherols (α-2β-2δ-tocopherol) 18-22%, and approximately 30% higher unsaturated fetal acids (lauric acid, myristic acid, palmitic acid, linoleic acid, etc.). There is.

Also, the solubility in solvent is chloroform 1.1g/m
l, ether 0.597ml, acetone 0.2X I
F297ml ethanol 0.2xlO-397ml is almost insoluble in water.

The present invention will be explained in detail below.

[Method for refining dog bean oil unsaponifiables]

Soybean crude oil is heated to approximately 230℃ using a Girdler type deodorizer for 2 to 3 hours.
When 5% steam is blown in for 1 hour under miHg vacuum,
Plant sterols (25-30%) from deodorized oil traps
A soybean oil deodorized distillate containing tocopherols (14-18%), higher unsaturated fatty acids (25-30%), etc. is obtained.

This deodorized distillate 174 (B9) was mixed with 3000 g of methanol and 34 g of concentrated sulfuric acid, and after refluxing at 68°C for 3 to 4 hours, excess methanol was distilled off under reduced pressure and the residual oil was
Wash with 5 kg of warm water while maintaining the temperature at ~100°C to remove sulfuric acid contained in the residue.

20-130 after completely distilling off the water contained in the oil
Under a vacuum of μHg and at a temperature of 170 to 190°C, the fatty acid methyl produced by molecular distillation is distilled off to obtain the target plant sterols 40 to 50, tocopherols 18 to 22,
Unsaponifiable dog bean oil containing 30% of higher unsaturated fatty acids is obtained as a pot residue method.

Actual examples under each condition are shown in Table 1.

Next, a method for quantifying the components will be briefly described.

Plant sterols: The amount of plant sterols was determined from the weight of digitonide produced by saponifying the sample with potassium hydroxide and reacting with digitonin, and the relative ratio of campesterol, stigmasterol, and β-sitosterol obtained from the gas chromatogram.

Tocopherol: Dissolve the sample in chloroform, add ferric chloride and anhydrous ethanol solution, and further add α, d-dipyridyl to form a red complex salt. Measure the absorbance at a wavelength of 520 mμ. Using α-tocopherol as a standard solution, each Determined from absorbance.

Higher fatty acid: Determined from the formula (saponification value/neutralization value) x 100 (%).

However, since the fatty acids in the sample do not always have a constant composition, the neutralization value of linoleic acid was used as a substitute for convenience.

[Acute toxicity test]

DD mice (female, male) purchased at 4 weeks of age and kept in the laboratory for 1 week, weighing 12-iB and Wista.
5 R-strain rats (female, male) weighing 60-91 each
The animals were used as a group.

Unsaponifiable dog bean oil is dissolved in sesame oil and administered to mice at 8.0g/ky orally, 4.0g/kg by subcutaneous injection, 2.0g/7kg by intraperitoneal injection, and 8.0g/ky orally for rats. .0 g/kg, 2.097 kg by subcutaneous injection, 1.07 by intraperitoneal injection.

Liveness or death was determined 72 hours after administration, and observation was continued for 10 days.

As a result, 72 hours after administration, all of the animals were found to be alive, and no deaths were observed for the next 10 days.
Calculation of D5o was not possible.

Furthermore, no differences were observed between the toxic symptoms and behavior after administration compared to the normal animal group.

[Effect on mouse cholelithiasis model]

Tepperma has shown that a cholelithiasis model in mice can be created by loading them with cholesterol and cholic acid.
First discovered by n (Amer −1can J
our own of Physiology206
628.1964), then confirmed by Frey et al. (American Journal o
fSurgery 115.75.1968).

Therefore, by this method, the effect of unsaponifiable dog bean oil on cholelithiasis was confirmed.

That is, the gallstone-forming feed was prepared by mixing 1.2% cholesterol and 0.5% cholic acid with Nippon Talea's CB-n powder feed, and the animals were fed for 8 weeks.

On the other hand, dog bean oil unsaponifiables are added to the gallstone-forming feed at 1% each.
5, 2.9%, and 5.8%, and allowed to ingest ad libitum for 8 weeks.

They were also allowed to drink water ad libitum.

At 8 weeks, each animal was fasted for one night, then sacrificed by exsanguination from the neck, and the abdomen was opened to observe the presence or absence of gallstones.

Confirm gallstones by observing with the naked eye and then using a mirror magnification (40x)
This was done by

In addition, the normal diet group was defined as one in which no gallstone-forming feed was used.

As a control drug, chenodesoxycholic
ac-id (abbreviated as CDCA) was used.

The results are shown in Table 2.

As is clear from Table 2, no gallstones were observed in the normal diet group, but gallstone formation was observed on the gold side in the gallstone formation negative group.

In the dog bean oil unsaponifiables administration group, the gallstone formation rate significantly decreased as the dose increased, and no gallstones were observed at concentrations of 5 and 8%.

[Influence on hamster cholelithiasis model] Cholelithiasis hamsters were created using the method of Dam et al.
ologicaet Microbio-1logica
5candinavica, 30,236.195
2).

That is, the group with negative gallstone formation has glucose of 71.8%, casein of 20.0%, vitamins of 0.5%, minerals of 5.0%, and CM.
The rats were fed for 6 weeks with a mixture of 5% C2 and 0.2% choline chloride.

On the other hand, the unsaponifiables of dog bean oil were added to the gallstone-forming feed at 1%, 2%, and 4%, respectively, and the CDCA was added to 0.0%, respectively.
The animals were fed with feed containing 0.001%, 0.005%, and 0.01%.

In addition, feed was provided in a feeder, and water was provided ad libitum.

Each animal was fasted overnight for 6 weeks from the start of the experiment, and the animals were killed by exsanguination from the neck, and gallstones in the gallbladder were visually observed.

The results are shown in Table 3. In the table, the gallstone formation rate in the drug administration group is expressed as a percentage when the gallstone formation negative group is taken as 100%.

As is clear from Table 3, no gallstones were observed in the normal diet group, but gallstones were observed in 20 out of 40 cases in the gallstone formation negative group.

On the other hand, among the drug administration group, in the dog bean oil unsaponifiables group, 1% was 3 out of 13 cases, 2% was 4 out of 16 cases, and 4% was 1 out of 16 cases.
Only gallstones were confirmed, and it showed a remarkable effect even in illegal cases.

Further, no significant effect was observed in the CDCA administration group.

Next, the dosage and administration method of the solution will be described.

The solution is administered orally in the form of hard or soft capsules.

When used for the treatment of adults, the effective amount is usually in the range of 15 to 1501 n9/kg body weight of dog bean oil unsaponifiables per day.

When formulating unsaponifiable dog bean oil as a hard capsule, a method is used in which high-purity silicic anhydride is used as an adsorption base and organic solvents such as chloroform, chlorocene, methylene chloride, etc. 46899), and the unsaponifiable matter of dog bean oil in one capsule is 20%.
Capsules were filled to contain 0.

To prepare soft capsules, a vegetable oil such as sesame oil, rapeseed oil, olive oil, soybean oil, etc. is dissolved in 0.20 to 0.50 ml per 1 mg of dog bean oil unsaponifiable matter, and the solution is filled into soft capsules.

For example, one capsule contains 200TnJ of dog bean oil unsaponifiables.
? 90 ml of rapeseed oil was used to achieve inclusion.

[Brief explanation of drawings]

Figure 1 shows the infrared absorption spectrum of unsaponifiable soybean oil.

Claims (1)

[Claims] 1. A gallstone dissolving agent whose main ingredient is dog bean oil unsaponifiables.