JPS633845B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a treatment and prevention agent for gastrointestinal ulcers, the main ingredient of which is a thiamine-cobalt-chlorophyllin complex compound (hereinafter referred to as TCC) obtained by coordinating thiamine with a cobalt-chlorophyllin complex compound. This is based on the new findings that it acts directly on cells in the digestive tract, increases the activity of cells in the digestive tract, increases blood flow in local tissues of the digestive tract, and has a protective effect on the wall of the digestive tract. TCC has already been reported by the present inventors as a known compound, for example,
There are Publication No. 28687 and Special Publication No. 1972-2005. TCC specified as an active ingredient in the present invention is
It is a complex compound that has an octahedral structure by coordinating a cobalt-chlorophyllin complex compound with thiamine, which is a type of base. Contains 2 moles. That is, it is a complex compound in which 1 mol or 2 mol of vitamin B ₁ is coordinately bonded to 1 mol of a compound of 1 mol of chlorophyllin and 1 mol of cobalt. The average composition of the normally provided compound is 1.2 to 1.4 moles of thiamine per mole of the cobalt-chlorophyllin complex compound. The outline of the method for synthesizing TCC according to the present invention is as follows. Add cobalt salt to a salt-saturated acetic acid solution of chlorophyllin to precipitate cobalt chlorophyllin at pH 5-7, add this to an alkaline solution of thiamine to react, and then adjust the reaction solution to pH 4-6.
The product substance is precipitated by adjusting the temperature, and after removing impurities from the main substance, it is purified by dialysis treatment. Of course, the method for producing TCC is not limited to this synthesis method, and TCC may be produced according to other applicable methods. This TCC also includes salts as derivatives, and TCC
Water-soluble salts such as sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts,
Salts with relatively low water solubility such as barium salts and procaine salts, basic amine salts such as lysine salts, acid salts of strong acids such as hydrochlorides and sulfates, and amine salts such as triethylamine acid and dimethylamine salts. Pharmaceutically acceptable derivatives are available. Next, we will show the methods and results of experiments conducted to confirm the pharmacological effects and effects of TCC, clinical trials, acute toxicity tests, dosage and administration methods, etc. () Pharmacological actions and effects Regarding the pharmacological actions and effects of TCC, (1) gastric mucosal protective action, (2) tissue repair action, (3) mucosal component increasing action, (4) healing effect, (5) preventive effect, ( 6) Effects of increasing local gastric tissue blood flow, (7) Anti-pepsin effects, and other effects were investigated. (1) Protective effect on gastric mucosa Method: TCC was mixed with various plasma protein components and rat stomach, and the state of binding was examined by cellulose acetate membrane electrophoresis analysis. Results: TCC binds to albumin specifically and as quickly as possible. This bond is
It has a pH of 1.2 to 7 and cannot be removed easily. Combines well with rat stomach. (2) Tissue repair effect (oxygen absorption capacity and anaerobic glycolysis capacity) Method: Using rat stomachs to create experimental ulcers
I checked it with Warburg manometer. Results: Administration of TCC increased the oxygen absorption capacity and anaerobic glycolytic capacity of the gastric tissue. (3) Effect of increasing mucosal components Method: Changes in mucosal components (acidic mucopolysaccharide) were investigated using rat stomachs with experimental ulcers. Results: During the ulcer healing process, mucosal components increased in the TCC administration group. (4) Healing effect Method 1: Cauterization - Experimental gastrin ulcer method The rat's abdomen was opened, and an electric iron kept at 70°C was applied to the serosa of the stomach for 5 seconds.
Acting oil tetragastrin, 500μ
g/Kg was injected subcutaneously. This maintains the gastric PH at around 1 for more than 16 hours, and the gastric ulcer persists, making it convenient for examining the healing effect. Method 2: Clamping-cortisone experimental ulcer method (rats) Chiji Umehara, Tadashi Tadashi et al.
By the clamping-cortisone method. Bioassay of anti-ulcer agents, treatment, 47 397-408
(1965). Method 3: Indometacin experimental ulcer method (rats) This is one of the usual methods for creating drug-induced experimental ulcers. Results: For each method, the TCC administration group had more regenerated mucous membranes at the bottom of the ulcer than the control group, and tissue repair was promoted. (5) Preventive effect Method 1: Cold, -restraint experimental ulcer method (rats) This is one of the application examples of the water immersion restraint method, and 0
Ulcers are created by restraining the rats at temperatures below .degree. Method 2: Water immersion restraint experimental ulcer method (rats) Takagi, K, and Okabe, S; The
effects of drugs on the production
and recovery processes of the
stress ulcer.Jap.J.Pharmac., 18 , 9
See ~18 (1968). Method 3: Pylorus ligation (Shay rat) method Shay, H, Kamarov.SA, Fels,
S,S,Meranye.D.,Gruenstein,
M. and Siplet, H.; A simple
method for the uniform production
of gastric ulceration in the rat.
Gastroenterology, 5 , 43-61
(1949). Results: In each method, TCC probably exerts its protective effect by acting on the (mucin) production system. (6) Effect of increasing gastric local tissue blood flow Method: Hydrogen gas clearance method Results: TCC increased gastric microblood flow. (7) Anti-pepsin effect Method: In vitro results: Anti-pepsin effect was observed. (8) Suppressive effect on gastric juice secretion Method: Schild's rat method Ghosh, MNand
Schild, HO: Continuous
recording of acid gastric secretion
in the rat.Brit.J.Phar−macol., 13 ,
See 54-61 (1958). Results: TCC had no inhibitory effect on gastric acid secretion induced by histamine stimulation, tetragastrin stimulation, and carbachol stimulation. (9) Antacid action Method: in vitro and in vivo experiments (rats,
(dog) Result: Ineffective (10) Gastric motility inhibitory effect Method: Rat, dog Formation: Ineffective To summarize the anti-ulcer effect of TCC from the above experimental results, TCC promotes the regeneration and repair of gastric mucosal tissue, and in particular suppresses mucin (mucin) system and has the effect of increasing blood flow in the local tissues of the stomach. () Clinical trial A total of 38 patients: 22 patients with gastric ulcer and 16 patients with duodenal ulcer.
For example, TCC tablets (1 tablet contains 5 mg of TCC) 1
Or 2 tablets were taken 4 times a day before each meal and before bedtime for 8 weeks. As shown in Table 1, the efficacy rate was 88% when taking 4 tablets a day, and 82% when taking 8 tablets a day.

[Table] () Acute toxicity test Group of 5 mice with average weight of 20g and average weight
An acute toxicity test was conducted using 180 g of 5 rats per group. The average LD ₅₀ (mg/Kg) of each group is shown in Table 2.

【table】

[Magnesium metasilicate aluminate 20% Corn starch 30% Lactose 50%]

(3) Crystalline cellulose 24.0mg (4) Carboxymethylcellulose/calcium
4.0mg (5) Magnesium stearate 0.4mg Pass all of (1), (3) and (4) through a 100 mesh sieve in advance. After drying each of (1), (3), (4) and (2) to reduce the moisture content to a certain level, they are mixed in the above weight ratio using a mixer. Add (5) to the evenly mixed powder and mix for a short time (30 seconds).
Compress the mixed powder into tablets (punch: 6.3mmφ, 6.0mmR) to 1
The tablets were made into 80mg tablets. 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. Formulation example 2 (intravenous injection) (1) Thiamine-cobalt-chlorophyllin complex compound 50mg (2) Glucose 100mg (3) Physiological saline 10ml (3) Add (1) and (2) in the above weight ratio. Add and stir;
Dissolve completely. After this solution is filtered using a membrane filter with a pore size of 0.45 μm, sterilization filtration is performed again using a membrane filter with a pore size of 0.20 μm. Aseptically dispense 10 ml of the filtrate into vials, fill with nitrogen gas, and seal to prepare an intravenous injection. Formulation example 3 (capsules) (1) TCC 50g (2) Lactose 935g (3) Magnesium stearate 15g Weigh each of the above ingredients, mix them evenly to a total of 1000g, and put the mixed powder into hard gelatin capsules.
Fill 200mg each.

Claims (1)

[Scope of Claims] 1. A preventive agent for the treatment of gastrointestinal ulcers, the main ingredient of which is a thiamine-cobalt-chlorophyllin complex compound. 2. Treatment and prevention of gastrointestinal ulcers is possible because thiamine-cobalt-chlorophyllin complex compounds act on cells in the digestive organs, increasing tissue blood flow and increasing cell activity, thereby recovering and protecting gastrointestinal ulcer tissues. The agent for treating and preventing gastrointestinal ulcers according to claim 1. 3. The agent for treating and preventing gastrointestinal ulcers according to claim 1, wherein the thiamine-cobalt-chlorophyllin complex compound is a complex compound consisting of 1.0 mol of chlorophyllin, 1.0 mol of cobalt, and 1.0 to 2.0 mol of thiamine. 4. The agent for treating and preventing gastrointestinal ulcers according to claim 1, wherein the thiamine-cobalt-chlorophyllin complex compound has a six-coordinated octahedral structure. 5. The treatment and prevention of gastrointestinal ulcers according to any one of claims 1 to 4, wherein the average composition of the thiamine-cobalt-chlorophyllin complex compound is 1.0 mol of chlorophyllin, 1.0 mol of cobalt, and 1.2 to 1.4 mol of thiamine. agent. 6. The agent for treating and preventing gastrointestinal ulcers according to any one of claims 1 to 5, which is orally administered in the form of a tablet or capsule. 7. The agent for treating and preventing gastrointestinal ulcers according to any one of claims 1 to 5, which is administered intravenously, intramuscularly, or orally as a liquid preparation.