JPS626689B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a gastrointestinal ulcer therapeutic and preventive agent containing a water-soluble component derived from cinnamon (hereinafter referred to as component A) as an active ingredient. Cinnamon bark is a Chinese herbal medicine extracted from a plant in the camphorax family, and has traditionally been treated as a stomachic medicine. However, the present inventors have proceeded with screening for the pharmacological effects of component A contained in cinnamon, and have found that it has a strong effect of suppressing gastric acid secretion, increasing gastric mucosal blood flow, promoting gastric mucus secretion,
It has the effect of promoting gastric mucosal repair and suppressing gastric acid secretion, which is comparable to cimetidine, which is currently considered the most powerful anti-ulcer drug.Moreover, component A is effective against stress ulcers and serotonin ulcers. The present invention has been completed by discovering that the present invention has preventive and therapeutic effects on these diseases as well. Component A can be obtained by adding ethyl ether to a hot water extract of cinnamon, performing distribution fractionation, and collecting the aqueous fraction. Examples of cinnamon include the following: Guangnan cinnamon: Cinnamomum cassia BLUME. Dongxing cinnamon: Cinnamomum cassia BLUME. Vietnamese cinnamon: Cinnamomum obtussifolium NEES and
Cinnamomum obtussifolium NEES var
loureirii PERROT et EBERH. Ceylon cinnamon: Cinnamomum vervm JSPRESL et EBERH. Thai cinnamon: Cinnamomum iners REINW ex BLUME. Borneo cinnamon: Cinnamomum clilawan BLUME and
Cinnamomum javanicum BLUME. Cinnamomum pseudo-loureirii HAY. Japanese cinnamon: Cinnamomum sieboldii MEISN. Cinnamomum burmanni NLUME. The temperature of the hot water extract is preferably about 100℃.
The extraction time is preferably about 1 to 4 hours, particularly about 2 hours. The extract is preferably concentrated in a warm bath to about 0.1 to 0.4%, especially about 0.2%, before being subjected to partitioning using ethyl ether. The extract (concentrate) thus obtained is subjected to circulation distribution fractionation using ethyl ether, and in this case, it is preferable to use an equal amount of ethyl ether to the extract. A specific example of the method for obtaining the above component A is as follows. Grind Guangnan cinnamon (1Kg) and add 100℃ hot water10
After extraction for 1 hour with the same amount of hot water, the two solutions were combined and concentrated to 2 in a rotary evaporator in a 40°C bath. Equivalent amount (2) of ethyl ether was added to this concentrated solution, fractionated by countercurrent partitioning (transferred three times), the ethyl ether fraction (essential oil, cinnamic aldehyde, etc.) was removed, and the water-soluble fraction Collect the amount. This water-soluble fraction
Component A is obtained by concentrating to about 200 ml in a warm bath at ℃ and then freeze-drying.
This product is stable when stored refrigerated at 2-8°C.
When used, it is dissolved in physiological saline solution.
This component can be subjected to other desired known treatments that can be provided as a pharmaceutical, such as sterilization, heat treatment, etc. Next, the methods and results of experiments conducted to confirm the pharmacological actions and effects, acute toxicity tests, dosages, administration methods, etc. of the ingredients of the present invention will be shown. () Pharmacological effects The effects of ingredient A were investigated by causing (1) pylorus ligation ulcer, (2) serotonin ulcer, and (3) cold stress ulcer in experimental animals. (1) Pylorus ligation ulcer A pylorus ligation ulcer was created according to the method of Shay et al. [Gastroenterology, 5 , 43, (1945)]. In other words, male Wistar rats (weighing 160-180 g) were
After fasting for 24 hours, the pylorus was ligated under ether anesthesia. After being left without food or water for 18 hours, the stomach was removed under ether anesthesia, and the ulcer index was evaluated as the sum of the hemorrhagic erodion generated in the forestomach and the long axis of the ulcer. The samples (physiological saline containing component A shown in Table 1 and physiological saline as a control) were intraperitoneally administered 3 hours after ligation. (2) Serotonin ulcer Male Wistar rats fasted for 48 hours
30 mg/Kg of serotonin, creatinine, and sulfate are administered subcutaneously to the back of 160-180 g, and 24 hours later, the abdomen is opened and assayed. The ulcer index was expressed as the total area of hemorrhagic erodion. The specimens (physiological saline containing 100 mg/Kg of component A and physiological saline as a control) were intraperitoneally administered 30 minutes before the start of the experiment (seroton administration). (3) Cold stress ulcer SD male rat 160-180g fasted for 24 hours
was confined in a wire mesh cage and restrained at 4°±
After being left in a cold room at 1°C for 5 hours, the abdomen was opened and assayed. The ulcer index was expressed as the sum of the major axes of hemorrhagic erodions. The sample (100mg/
Kg of physiological saline containing component A and physiological saline as a control) were intraperitoneally administered 30 minutes before the start of the experiment (start of restraint). The experimental results of (1), (2), and (3) above are shown in Tables 1, 2, and 3, respectively.

【table】

【table】

[Table] As is clear from the results shown in Table 1, A
In the group administered 100mg/Kg of the ingredient, the incidence of pylorus ligation ulcer was 94% compared to the control group administered with physiological saline.
suppressed. As is clear from the results shown in Table 2, A
In the group receiving 100 mg/Kg of the ingredient, the incidence of serotonin ulcers was suppressed by 98%. As is clear from the results shown in Table 3, A
In the group administered 100mg/Kg of the ingredient, the incidence of cold stress ulcers was suppressed by 100%. () Pharmacological action The anti-ulcer action mechanism of ingredient A was investigated. (1) The inhibitory effect on gastric juice secretion was investigated. Administration was performed by intraperitoneal administration. The gastric juice secretion suppressing activity was determined by the method of Shay et al. [Gastroenterology 26 , 906,
(1954)]. Namely, male Wistar rats (body weight
The volume, total acidity, and total pepsin activity of the stored gastric fluid 18 hours after ligation of the pylorus (160 to 180 g) were measured. The total acidity was determined by titration with 1/50N NaOH using phenolphthalein as an indicator, and the total pepsin activity was determined by the Anson method using casein as a substrate [Brit.J.Pharmacol., 13 , 54, ( (1958)]. The specimens (physiological saline containing 100 mg/Kg of component A and physiological saline as a control) were intraperitoneally administered 3 hours after ligation. The results are shown in Table 4. When 100 mg/Kg of component A was administered intraperitoneally to the amount of gastric juice in the control group,
Gastric juice volume was suppressed by 46.3%. In addition, similar inhibition was observed in total acidity and total pepsin activity, which was determined to be statistically significant with a risk rate of 0.1% or less.

[Table] () Toxicity In an acute toxicity experiment using ddY male mice, Component A showed an LD ₅₀ of 4740 mg/Kg when administered intraperitoneally, ensuring high safety. () Dosage and method of administration Based on the results of the above test, Component A should be administered in doses of 1 to 1 per day.
300mg/Kg is preferred. Component A can be administered in the form of either an injection or an oral preparation. When used as an injection, for example, it is dissolved in distilled water for injection and administered intravenously or intramuscularly at the time of use. When used as an oral preparation, it is administered as a capsule, tablet, powder, or oral liquid preparation. These are made according to methods well known to those skilled in the art as described in the Japanese Pharmacopoeia. The gastrointestinal ulcer therapeutic and preventive agent consisting of component A has extremely low toxicity and exhibits remarkable pharmacological effects, making it extremely useful as a drug for treating and preventing ulcers. Example 1 (oral preparation) (1) Ingredient A 100mg (2) Fine particles for direct injection No. 209 (manufactured by Fuji Chemical) 46.6mg [Magnesium aluminate metasilicate 20% Corn starch 30% Lactose 50%] (3 ) Crystalline Cellulose 24.0mg (4) Carboxylmethylcellulose/Calcium
4.0mg (5) Magnesium stearate 0.4mg Pass all of (1), (3) and (4) through a 100 mesh sieve in advance. These (1), (3), (4), and (2) are each dried to reduce the moisture content to a certain level, and then mixed using a mixer in the above weight ratio. Add (5) to the uniformly mixed powder, mix for a short time (30 seconds), and tablet the mixed powder (punch: 6.3mmφ, 6.0mmR) to make one tablet.
It was made into an 80mg tablet. The tablets may be coated with a commonly used gastric soluble film coating agent (eg, polyvinyl acetal diethylamino acetate) or an edible coloring agent, if necessary. Example 2 (capsules) (1) Ingredient A 50g (2) Lactose 935g (3) Magnesium stearate 15g Weigh each of the above ingredients and mix them uniformly to a total of 1000g, and put the mixed powder into hard gelatin capsules.
Fill 200mg each.

Claims (1)

[Claims] 1. Preventive treatment of gastrointestinal ulcers using a cinnamon-derived water-soluble component as an active ingredient, which can be obtained by adding ethyl ether to a hot water extract of cinnamon, partitioning it, and collecting the water-soluble fraction. agent. 2. The agent for treating and preventing gastrointestinal ulcers according to claim 1, which is in the form of a powder, tablet, or capsule for oral administration. 3. The agent for treating and preventing gastrointestinal ulcers according to claim 1, which is in a liquid form for intravenous, intramuscular or oral administration.