JPS6310134B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a choleretic agent containing borneol as an active ingredient. Biliary tract, including cholangitis, cholecystitis, biliary dyskinesia (filling of the gallbladder with bile, abnormal excretory function), cholelithiasis, etc.
Gallbladder disease is unexpectedly common, and very often progresses to chronic disease. Surgery is not easy either.
Postoperative results are not always good. Therefore, it is important to use choleretic agents to ensure that bile constantly flows from the bile duct to the duodenum without stagnation. While examining the medicinal efficacy of each component of Kiōgan, the present inventor discovered that (+)-borneol has a strong and long-lasting choleretic effect, which was completely unexpected. It was revealed that the present invention has an effect, and the present invention was completed. Borneols are generally white crystalline powders or lumps with a distinctive odor. There are no known pharmacological effects, and the only exception is the naturally occurring (+)-borneol, which has an aroma and has long been used in Chinese medicine under the name ``Dragon Brain''. The pharmacological effects have been investigated, including anti-inflammatory and analgesic effects (written by Totaro Shimizu, published by Nanzando, Pharmacy's Chinese Medicine), anti-inflammatory, sedative, and palpitation effects (written by Keisetsu Otsuka et al., published by Nanzando, Practice of Chinese Herbal Medicine), and central depressant effects ( It is only said that there is a 4th edition Food Additives Official Manual (published by Hirokawa Shoten). The present invention focuses on the hitherto unknown choleretic effect of borneol, and provides a novel choleretic agent containing borneol as an active ingredient. In the present invention, borneols include the following. a (+)-borneol, (-)-borneol,
Borneol such as (±)-borneol, (+)-isoborneol, (-)-isoborneol, (±)-isoborneol and the like. (+)-, (-)-, (±)-borneol is represented by the following structural formula. Melting point is 204-208°C. (+)-, (-)-, (±)-isoborneol is represented by the following structural formula. Melting point is 212-214°C. b Esters of borneol and fatty acid (R-COOH, R is an alkyl group having 1 to 9 carbon atoms). The esterification reaction is shown by the following formula. For example, fatty acids containing the following alkyl groups are used. Acetic acid ( _CH3- ), propionic acid ( _CH3 - _CH2- )
n-Butyric acid ( _CH3- ( _CH2 ) _2- ), isovaleric acid

[Formula] n-caproic acid (CH ₃ (CH ₂ ) ₄ −), n-enantylic acid (CH ₃ (CH ₂ ) ₅ −), n-caprylic acid (CH ₃ (CH ₂ ) ₆ −), n- Pelargonic acid (CH ₃ (CH ₂ ) ₇ -), n-capric acid (CH ₃ (CH ₂ ) ₈ -) c Borneol and dicarboxylic acid (HOOC-
(CH ₂ ) _o -COOH, n is 2, 3 or 4). For example, the following dicarboxylic acids are used. Succinic acid (HOOC-(CH ₂ ) ₂ -COOH), glutaric acid (HOOC-(CH ₂ ) ₃ -COOH), adipic acid (HOOC-(CH ₂ ) ₄ -COOH) d Esters of borneol and oxycarboxylic acid kind. For example, the following oxypolybasic acids are used as the oxycarboxylic acid. malic acid

【formula】 tartaric acid

【formula】 citric acid

[Formula] e Glycoside of borneol. For example, the following glycosides are used. Glucose glycoside (bornyl glucoside) Mannose glycoside (bornyl mannoside) Galactose glycoside (bornyl galactoside) A drug efficacy test, an acute toxicity test, and a formulation example when borneols are used as a choleretic agent will be specifically explained below. Efficacy test (1) Effect on bile secretion A. Intraduodenal administration A group of 10 male Wister rats weighing 200-250 g were fasted for 6-8 hours, anesthetized with ether, fixed in the dorsal position on a fixed table, and placed in the midline. The abdomen was opened along the duct, and a polyethylene tube was inserted into the common bile duct. In this state, a period (1 hour) was allowed for the bile outflow to become stable, and the amount of bile flowing out during the subsequent 30 minutes was set as 100, which was used as a control amount for subsequent outflow. Next, the drug was administered into the duodenum, and the amount of bile dripped from the polyethylene tube was measured. The amount of bile flowing out was measured every 30 minutes until the second hour after administration of the test drug, and every hour thereafter for a total of 5 hours. As a control drug, sodium dehydrocholate, a known choleretic agent and bile acid preparation, was used. Bornyl glucoside was administered at 200 mg/Kg (rat body weight), but the doses of other borneols and sodium dehydrocholate were all 100 mg (drug)/Kg (rat body weight). Before use, the drug was suspended in a 4% aqueous gum arabic solution. Experimental results As shown in Figure 1, the kinetics of the choleretic effect of the (+)-borneol 100 mg/Kg administration group was clearly different from that of the sodium dehydrocholate administration group, which was used as a control group.
After administration for the sodium dehydrocholate administration group
While only a strong transient choleretic effect was observed at 30 minutes, the (+)-borneol administration group had a sustained and strong choleretic effect throughout the 5 hours of observation. Also, similar to (+)-borneol, (-)-borneol, (±)-
It was found that borneol, isoborneol, borneol acetate, isoborneol acetate, and bornyl glucoside also have choleretic effects and can be used for the same purpose (Figures 2 and 3). B Oral administration As in the case of duodenal administration, a polyethylene tube was placed in the common bile duct of rats, the test drug was orally administered, and the amount of bile flowing out was observed over 5 hours. Experimental Results As shown in Figure 1, as in the case of intraduodenal administration, the group administered with borneol had a stronger and longer-lasting choleretic effect, which was more evident than that of the control drug sodium dehydrocholate. Ta. It was also found that borneol succinate has a choleretic effect and can be used for the same purpose (Figure 2a). (2) Biliary properties A. Changes in the weight of solids in excreted bile The bile obtained in the bile secretion experiment (1-A) by intraduodenal administration was collected at each observation time, and a portion of it was lyophilized to determine the weight. before administering the test drug such as (+)-borneol.
The weight of bile solids for 30 minutes was taken as 100, and the changes were determined up to 5 hours. Experimental Results As shown in Figure 4, by measuring the weight of bile solids up to the 5th hour of the observation period, (+)-
The effect of continuously increasing bile parenchyma was observed in the borneol administration group compared to the control drug sodium dehydrocholate administration group. B. Changes in phospholipid and cholesterol content in bile A portion of each effluent bile obtained up to the first hour of measurement obtained in the bile secretion experiment (1-A) by intraduodenal administration was taken, and for phospholipids, phospholipid B- Test Wako (enzyme method, Wako Pure Chemical Industries), and cholesterol C-Test Wako (COD-p-
Measurement was carried out using a chlorphenol color method and a measurement kit manufactured by Wako Pure Chemical Industries. In addition, in the case of quantifying both phospholipids and cholesterol, a blank test was conducted, and quantification was performed using a calibration curve prepared in advance. The amount of phospholipids and cholesterol in bile effluent for 30 minutes before administration of the test drug was set as 100. Experimental results As shown in Figures 5 and 6, the control drug sodium dehydrocholate administration group showed a tendency for bile phospholipids and cholesterol secretion to increase, whereas borneol The administered group showed approximately the same amount of bile secretion as normal bile. C Changes in bile acid content in bile Bile acids that are important components in mammalian bile include cholic acid, chenodeoxycholic acid, deoxycholic acid, and ursodeoxycholic acid, and these exist in free form. It is generally dissolved in bile as a glycine- or taurine-conjugated form. These bile acids have the following structural formulas 3, 7, and 12.
It has an -OH group at the corresponding position below. However, if the -OH group on the steroid nucleus is on the lower side of the paper, it is marked with α, and when it is on the upper side, it is marked with β. Cholic acid: 3 (α), 7 (α), 12 (α) Chenodeoxycholic acid: 3 (α), 7 (α) Deoxycholic acid: 3 (α), 12 (α) Ursodeoxycholic acid: 3 (α) ), 7(β) The glycine-conjugated type and the taurine-conjugated type have the following structures. However, R ₂ is the part surrounded by a dashed line in the structure of the bile acid mentioned above. Glycine conjugated type Taurine conjugated type Changes in the content of these various bile acids were investigated. A portion of each effluent bile obtained up to the first hour of measurement obtained in the above-mentioned intraduodenal administration bile secretion experiment (1-A) was taken, and freshly distilled methanol was added to dilute it to 40 times the volume.
Filter using a 0.45 μ membrane filter (Toyo Roshi) and filter the filtrate to Okuyama S. et al.:
High performance liquid chromatography was performed according to the method of Chemistry Letters, p1443 (1979). Using the calibration curves of cholic acid, ursodeoxycholic acid, chenodeoxycholic acid, deoxycholic acid, and their glycine- and taurine-conjugated acids prepared in advance, the content of each bile acid in the effluent bile at each measurement time was determined. I asked for the quantity. Then, the total amount of bile acids was determined from the results. 30 days before test drug administration
The amount of each bile acid and the total amount of bile acids in the bile flowing out per minute were each set to 100. Experimental Results As shown in Figures 7 to 9, in the sodium dehydrocholate administration group, a slight tendency towards increased secretion of bile acids including deoxycholic acid was observed only 30 minutes after administration. Although it was transient, the secretion amount of various bile acids such as chenodeoxycholic acid was significantly increased in the (+)-borneol administration group. In addition, as shown in Figure 10, there was a significant increase in the amount of total bile acids in the (+)-borneol administration group compared to the non-administration group and the sodium dehydrocholate administration group, which has a hydric effect. It was bright and warm. Report of Admirand.WHet al. [(J.Clin.
Invest., 47, 1043 (1968)], cholesterol, a hydrophobic substance, is dissolved in bile by forming mixed micelles with coexisting bile salts and phospholipids. It is clear that human gallstones, especially cholesterol-based gallstones, which have been increasing rapidly in recent years, are formed by free precipitation and crystallization of cholesterol from mixed micelles due to factors such as excessive cholesterol secretion and insufficient secretion of bile salts. It is being done. On the other hand, by elucidating the mechanism of gallstone formation,
Since 1972, medical dissolution treatment of gallstones using oral bile acids such as chenodeoxycholic acid has become a reality [Danzinger RGet
al.: New Engl.J.Med., 286, 1 (1972): Isao Makino et al.: Journal of the Japanese Society of Gastroenterology, 72, 690
(1975)]. Based on these facts, bile acids in bile not only play a major role in digestion and absorption, but also have actions such as preventing the formation of gallstones, and it is preferable that the bile acids increase the secretion of bile acids. has been done. (+)-borneol has excellent properties when taking into account the remarkable and sustained effect of increasing the secretion of bile acids such as chenodeoxycholic acid, which is found in (+)-borneol, and the effect of decreasing the secretion of cholesterol and phospholipids. It is clear that it is useful as a choleretic agent. Depending on their mechanism of action, choleretic agents are classified into cholestatic agents that promote bile secretion from the liver and bile excretion promoters that promote excretion from the gallbladder. The choleretic agent of the present invention is classified as the former, that is, a choleretic agent. Furthermore, the choleretic agent of the present invention can be applied to the treatment of liver and biliary tract diseases, such as cholecystitis, cholangitis, post-cholecystectomy syndrome, hepatitis, chronic liver disease, jaundice, and cholelithiasis. Acute toxicity test: Group of 10 dd-Y male mice weighing around 20g.
After oral administration of the test drug, the LD ₅₀ value was determined from the number of deaths during the 7-day observation period. During the 7-day observation period, both food and water were provided ad libitum.
Further, the LD ₅₀ value was determined by the Litchfield-Wilcoxon method. Experimental results LD ₅₀ (mg/Kg, 95% confidence limit) (+) Borneol 10000 or more Sodium dehydrocholate 2500 (1923-3250) As is clear from the above results, borneol has traditionally been used mainly as a choleretic agent. It has a completely different chemical structure from the bile acid preparations that have been used, such as sodium dehydrocholate, and its action is long-lasting and strong. Moreover, it is presumed to have a gallstone dissolving effect, and its toxicity is extremely low. In addition, since raw materials are supplied at low cost, they are highly usable. In addition,
The administration method for borneols is generally oral;
In addition, formulations are prepared according to conventional methods, such as excipients such as starch, lubricants such as magnesium stearate,
It can be carried out using coating agents such as CAP, and the dosage forms include granules, tablets, capsules,
Any coating agent etc. may be used. When used for treatment of adults, sufficient medicinal effects can be achieved by taking tablets containing 50 to 200 mg of borneol at a time, usually two to three times a day. Examples of formulations are described below. Example 1 100 parts by weight of (+)-borneol and 90 parts by weight of potato starch
Mix the parts by weight thoroughly, add water and knead, then pass through a granulator equipped with a screen with a 1 mm ² mesh to form granules, dry, sieve through a No. 16 mesh sieve, and after grading, 10 parts by weight of steering magnesium was added and compressed to obtain 100 mg tablets. Example 2 50 mg of (+)-borneol in capsules (No. 4)
to obtain capsules.

[Brief explanation of the drawing]

Figure 1 is a graph showing the changes over time in the amount of bile secreted when (+)-borneol was administered to rats through the duodenum or orally, and Figure 2 is a graph showing (-)
- A graph showing changes over time in the amount of bile secreted when borneol, (±)-borneol, acetate ester of borneol, acetate ester of isoborneol, or isoborneol was administered to rats into the duodenum. Figure 2a shows borneol succinate. FIG. 3 is a graph showing changes over time in the amount of bile secreted when bornyl glucoside is administered orally to rats. The graphs show the changes over time in the solid weight, phospholipid content, cholesterol content, amount of each bile acid, and total amount of bile acids in secreted bile when (+)-borneol etc. were administered into the duodenum to rats. be.

Claims (1)

[Claims] 1. A choleretic agent containing borneol as an active ingredient. 2 Borneol is (+)-borneol,
(-)-borneol, (±)-borneol, (+)
-isoborneol, (-)-isoborneol,
The choleretic agent according to claim 1, which is borneol selected from (±)-isoborneol. 3. In the choleretic agent defined in claim 1, the borneols include borneol and a fatty acid (R-COOH, R is an alkyl group having 1 to 9 carbon atoms)
These are esters of 4. In the choleretic agent defined in claim 1, borneol is an ester of borneol and dicarboxylic acid (HOOC-(CH ₂ ) _o -COOH, where n is 2, 3 or 4). 5. In the choleretic agent defined in claim 1, the borneols are esters of borneol and oxycarboxylic acid. 6. In the choleretic agent defined in claim 1, the borneol is a glycoside of borneol.