KR970006083B1 - A pharmaceutical composition for treating gastrointestinal disorders - Google Patents

Abstract

The medicine comprises 1- 2 parts of ranitidine, 2- 4 parts of subcitrate and 6- 12 parts of sucralfate. Thus, 55.8 g of ranitidine hydrochloric acid, 300.0 g of sucralfate, 100.0 g of bismuth subcitrate, 14.0 g of hydroxypropyl cellulose, 17.0 g of calcium carboxymethyl cellulose, 11.0 g of magnesium stearate, 14.5 g of hydroxypropylmethyl cellulose, 5.1 g of glycerin and 0.9 g of titanium dioxide were added in 50.2 g of lactose, and mixed with ethanol solution of hydroxypropylmethyl cellulose to give the medicine.

Description

Pharmaceutical composition for treating gastrointestinal diseases

The present invention relates to a pharmaceutical composition for treating gastrointestinal diseases useful for the purpose of treating or preventing gastrointestinal diseases and a method of manufacturing the same.

Applicable examples of the pharmaceutical composition according to the present invention can be used for the purpose of treatment and prevention in gastritis, gastric ulcer, duodenitis, duodenal ulcer and the like.

The causes of such gastrointestinal diseases are known to be very diverse, but recent studies have been based on imbalances of defensive factors such as gastric acid, pepsin, helicobacter pylori, and other factors such as mucus, tissue regeneration, and blood circulation improvement. It is accepted as the most valid.

Therefore, in order to treat these diseases, first, H ₂ antagonists such as cimetidine, ranitidine, and famotidine have been developed for the purpose of treating gastric ulcers by suppressing attack factors such as gastric acid, but their effects are not sustained. Recurrence rates are known to be high [The American Journal of Medicine, Volume 91 (Suppl. 2A), August 8, 1991].

Second, bismas preparations such as bismas subcitrate and bismas subsalicylate have been developed to treat gastrointestinal diseases for the purpose of protecting gastric and duodenal ulcer sites by augmenting defense factors and killing Helicobacter pylori. Drugs 36, 132-157 (1988); Gut 28, 201-205 (1987); The American Journal of Gastroenterelogy Vol. 84 No. 3 (1989)] is known to have no antacid effect of gastric acid and suppression of pain caused by gastric acid.

Third, sucralate formulations are used for the treatment of gastritis and gastric ulcers by inactivating pepsin, which is an attacking factor, and promoting mucus secretion, antacid, stimulation of mucosal cell secretion, and stimulation of prostaglandin secretion. It is not known to be involved in inhibition.

Each of the three drugs mentioned above has excellent advantages, but there are some supplements that have been actively studied in combination administration for more complete treatment of gastrointestinal diseases.

It has been reported that co-administration with H ₂ antagonist alone or bismarth formulation alone has a higher therapeutic effect (European Patent 282132), even when the combination of H ₂ antagonist and sucral fate is administered alone. It has been reported that relapses such as gastric ulcers are more effectively inhibited than when administered [The American Journal of Medicine, Volume 79 (suppl 2c), August 30, 1985].

Therefore, in the present invention, in order to treat gastrointestinal diseases such as gastric ulcer in a short period of time and to reduce recurrence, by focusing on the balance between the factors acting as an attacking factor and the elements acting as a defensive factor, it is possible to normalize the gastrointestinal function as a whole. While researching for the development of a pharmaceutical composition for the use of the above, H ₂ antagonist, bismuth, and sucralate when combined with the complement of the disadvantages of each drug to complement the excellent therapeutic effect and pain pain The present invention has been accomplished by knowing that removal and relapse can be obtained.

The pharmaceutical composition for treating and preventing gastrointestinal diseases of the present invention contains 1 to 2 parts by weight of ranitidine in H ₂ antagonists such as ranitidine, famotidine, cimetidine, and the like which have acid secretion inhibitory function, Bismuth subsalicylate, bismuth subcitrate, bismuth subcitrate, bismas aluminate, bismas sub in bismuth preparations that suppress the recurrence rate of gastric ulcers and have a killing function of Helicobacter pylori Souk containing 2 to 4 parts by weight of one component in carbonate, bismas citrate, bismars gallate, bismars nitrate, bismas tartrate and neutralizing secreted acid and promoting regeneration of mucous cells. It is characterized by containing 6 to 12 parts by weight of a ralphate (sucralfate) preparation. The composition ratio of the preferable pharmaceutical composition of this invention is a case where the weight ratio is 1-1.5: 2: 6 of ranitidine: bismisse: sucralate agent.

Oral formulations of the present invention generally contain 50-300 mg of ranitidine and may contain, for example, 50, 75, 100, 125, 150, 175, 200, 225, 275 or 300 mg of ranitidine. It may contain 100-400 mg of bismas subcitrate and may for example contain 100, 200, 300 or 400 mg of bismas subcitrate, which may contain 300-3,000 mg of sucralate, for example 300, 600, It may contain 1200, 1500, 1800, 2100, 2400, 2700 or 3000 mg of sucralate.

From the foregoing, the preferred pharmaceutical composition of the present invention contains 50-300 mg of ranitidine, 100-400 mg of bismas subcitrate and 300 mg-1200 mg of sucralate, and within these composition ranges of ranitidine-bismas sub It can be seen that the weight ratio of citrate-sucralate is contained so as to be 1 to 1.5: 2: 6.

In addition, considering the size of the oral dosage form according to a single dose, the tablets or capsules are ideally contained in the weight of 50-75 mg of ranitidine, 100 mg of bismas subcitrate and 300 mg of sucralate in one tablet or capsule. Other liquids and powders are appropriately adjusted depending on the formulation.

The dosage of the pharmaceutical composition according to the present invention is a conventional oral dosage form for tablets (containing 50 to 75 mg of ranitidine per tablet, 100 mg of bismas subcitrate and 300 mg of sucralate), once or twice daily. It is recommended to take two tablets morning and evening.

The inventors of the present invention change the composition ratio of the pharmaceutical composition of the present invention to determine the composition ratio that can be most effectively adapted to the treatment of gastrointestinal diseases of the above-mentioned various component groups through long-term experiments to prove the superiority of the present invention. In order to confirm the therapeutic effect of gastric ulcers, an experiment was conducted using an acetic acid-induced ulcer model (Digestive Diseases, Vol. 17, No. 7, July, 1972). According to the experimental results (see Table 1), the ranitidine-bismas-sucralate combination group was treated with ranitidine, bismas, and sucralate alone, ranitidine-bismasate combination, ranitidine-sucralate combined group, and ranitidine-bismasate. -The gastric ulcer treatment effect was significantly superior to the sucralate combination group. That is, considering that the daily use of each single agent is 300-400 mg of ranitidine, 480 mg of bismuth and 3000-4000 mg of sucralate, the combination of ranitidine-bismas-sucralate according to the present invention is ranitidine 100-300 mg, bis MAS subcitrate 200-400mg and sucralate 600-1200mg proved that even if combined with less than half the normal dose of each single agent, high recovery rate for induced ulcer and rapid recovery to normal cells could be expected. In addition, the pharmaceutical composition for gastrointestinal diseases of the present invention has a significant inhibitory function compared to the control group in the effect on gastric juice and total acidity according to Shay's method (see Table 2), and inhibits gastric juice secretion and lowers the total acidity. It was found to be effective in preventing diffusion of pain and removing pain, and it is an excellent preparation that can expect immediate treatment effect and shortening of treatment period by accelerating tissue regeneration rate.

The pharmaceutical composition of the present invention may be in the form of tablets, liquids, capsules, powders, capsules containing double tablets or small tablets containing one or more pharmaceutically acceptable carriers, such as excipients, diluents, stabilizers, etc. It can be formulated through the formulation method.

The inventors of the present invention also studied the stability of the pharmaceutical composition of the present invention, such as non-compatibility of the components and changes over time (see Table 3), there was no formulation incompatibility between components and it is stable even for long-term storage Confirmed.

Hereinafter, the present invention will be described in detail with reference to Examples, and the present invention is not limited by the following Examples.

Example 1

Drug test according to composition

Acetic Acid-Induced Ulcer Model

Experimental animal: SD male rat (8 rats / group)

Experimental Method: After inducing ulcer with 30 μl of acetic acid (30% V / V), the pharmaceutical composition was administered orally once a day for 2 weeks. Distilled water was administered as a control, the dosage is mg / kg unless otherwise indicated.

Table 1 shows the results of the drug efficacy test according to the composition.

* P0.05 against group 10 by Student t-test.

According to Table 1, two co-administrations were more effective than single-component administration of ranitidine, bismas subcitrate, and sucralate, respectively. Significantly better efficacy was observed than the test group 10, which was the most effective among the eggplant co-administration.

Example 2

Gastric secretion inhibition and total acidity test

Shay's Way

Experimental animal: SD male rat (8 rats / group)

Experimental Methods: Rats fasted for 18 hours were orally administered to each group of the drugs listed in Table 1 in 0.5% CMC. After 45 minutes, the rats were opened under ether anesthesia, ligated with pyloric sutures, and sutured with open sutures. . After 4 hours, the rats were ether killed and the stomachs were removed, and the gastric juices were taken after resection to be careful of leakage of gastric juices. Gastric juice was measured and centrifuged, and the amount of gastric juice and pH were measured and shown in Table 2.

* P0.01 against group 10 by Student t-test.

In the results of Table 2, also in the gastric secretion and total acidity, the combination of the three drugs according to the present invention showed better efficacy than the combination of the two drugs.

In other words, by suppressing the secretion of gastric juice and lowering the total acidity, it is effective in preventing the expansion of ulcers and removing the pain, and also has the best effect in the recovery rate. We expect to see a drop in relapse rate.

Example 3

Formulation Example According to the Present Invention

Formulation Example 1

refine

55.8 g of ranitidine hydrochloride (50 g as ranitidine)

Sucralate 300.0g

Bismuth Subcitrate 100.0g

Lactose 50.2g

Hydroxypropylcellulose 14.0g

Carboxymethyl Cellulose Calcium 17.0g

Magnesium stearate 11.0 g

Hydroxypropyl Methyl Cellulose 14.5g

Glycerin 5.1g

Titanium oxide 0.9g

The main drug is mixed with lactose and associated by adding an ethanol solution of hydroxypropylcellulose. The union is granulated and dried according to conventional methods. The dried product is established, mixed with carboxymethyl cellulose calcium and magnesium stearate, and then compressed into 548 mg per tablet. After tableting, hydroxypropylmethylcellulose, glycerin, and titanium oxide are film-coated according to a conventional method with a film coating solution in which an organic solvent is dispersed.

Formulation Example 2

Capsule

55.8 g of ranitidine hydrochloride (50 g as ranitidine)

Sucralate 300.0g

Bismuth Subcitrate 100.0g

Lactose 80.2 g

Magnesium stearate 14.0 g

After mixing the main ingredient and the excipient, one capsule is filled with 550 mg by a conventional method.

Formulation Example 3

Liquid

5.6 g of ranitidine hydrochloride (50 g as ranitidine)

Sucralate 30.0g

Bismuth Subcitrate 10.0g

Carboxymethyl Cellulose Sodium 0.8g

Hydroxypropyl Methyl Cellulose 4.0g

0.8 g of paraoxybenzoic acid

0.2 g of paraoxybenzoate

Stevioside 2.0g

Sucrose 80.0g

Ethanol (95%) q.s.

Appropriate amount of purified water is added to the final 1000 ml.

Dissolve the main components in 600 g of purified water, add sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, stevioside, and sucrose and emulsify with a stirrer. The preservative is dissolved in ethanol (95%), added to the emulsion above, and purified water is added to make a final 1000 ml.

After sterilization, the package is packed in a volume of 20 ml.

Formulation Example 4

Tablets containing double tablets (double tablets) -1 tablet 550mg

84.0 g of ranitidine hydrochloride (75 g as ranitidine)

Sucralate 300.0g

Bismuth Subcitrate 100.0g

3.5 g of microcrystalline cellulose

Hydroxypropylcellulose 14.0g

Carboxymethyl Cellulose Calcium 17.0g

11.0 g of magnesium stearate

Hydroxypropyl Methyl Cellulose 14.5g

Glycerin 5.1g

Titanium oxide 0.9g

Ranitidine hydrochloride is blended with microcrystalline cellulose and combined by addition of an ethanol solution of hydroxypropylcellulose, and the association is granulated and dried in accordance with conventional methods. The dried product is established, mixed with calcium carboxymethyl cellulose and magnesium stearate and compressed into tablets. Hydroxypropylmethylcellulose and glycerin are film coating liquids dispersed in an organic solvent, and film-coated according to a conventional method to be used as a core tablet.

Separately sucralate, bismas subcitrate and microcrystalline cellulose are mixed and coalesced by addition of an ethanol solution of hydroxypropylcellulose and the association is granulated and dried according to conventional methods. The dried product is established, mixed with calcium carboxymethyl cellulose and magnesium stearate, and double tablets containing nuclear tablets are tableted in a conventional manner at 548 ml per tablet.

Film coating is carried out with a film coating solution in which hydroxypropyl methyl cellulose, glycerin and titanium oxide are dispersed in an organic solvent.

This preparation is taken 1-2 times a day, 1-2 tablets once.

Formulation Example 5

Campel agent-1 capsule 550mg containing small particles

84.0 g of ranitidine hydrochloride (75 g as ranitidine)

Sucralate 300.0g

Bismuth Subcitrate 100.0g

3.5 g of microcrystalline cellulose

Glycerin 5.1g

Hydroxypropylmethylcellulose 14.0g

Titanium oxide 0.9g

11.0 g of magnesium stearate

Hydroxypropylcellulose 31.5g

In a fluidized bed granulator, lanitidine hydrochloride and microcrystalline cellulose are mixed, ethanol solution of hydroxypropyl cellulose is sprayed into small particles, dried and sprayed with a film coating solution of hydroxypropyl methyl cellulose and glycerin dispersed in an organic solvent to coat the film. In a separate fluidized bed granulator, sucralate, bismuth subcitrate and microcrystalline cellulose are mixed, granulated using an aqueous solution of hydroxypropyl cellulose, dried, and mixed with lanitidine small particles and excipients. Charge according to.

This preparation is taken 1-2 times a day, 1-2 capsules once.

Example 4

Stability and Toxicity Test

1. Stability test

1) Specimen: Five formulations such as tablets, capsules, solutions, double tablets containing nuclear tablets and capsules containing small particles prepared according to Example 3 above.

2) Storage condition: Stability test for temperature and humidity

· Packing form: tablet, capsule, liquid-brown glass container and airtight with Al Cap.

Shaded airtight state with aluminum foil in double tablets and small particle-containing capsule-2.

Storage temperature: 40 ± 1 ℃, 75% RH (± 5%)

Storage period: 6 months

3) Test period: 6 months

4) Measurement time: every test start and every 2 months

5) Test item: Content test for main ingredient

6) Test method: Ranitidine hydrochloride and sucralate are tested according to the quantitative method of ranitidine hydrochloride and sucralate in the National Institutes of Health Notification No. 85-9 (October 10, 1985). It is tested according to the Assay for Potassium Bismuth Citrate, No. -43 (July 4, 1987).

7) Test Results: Table 3 below.

As a result of the above, it is understood that the compounding agent of the present invention has a tablet, a capsule, a liquid, a double tablet containing a core tablet and a capsule containing a small particle for at least three years.

In addition, in view of the appearance stability of the preparation, that is, sticking phenomenon, wetting power, color, and beauty, double tablets containing nuclear tablets are preferable to general tablets, and capsules containing small particles are more preferable than general capsules.

2. Acute Toxicity Test

1) Test substance: pharmaceutical composition consisting of ranitidine hydrochloride, bismas subcitrate, and sucralate as 1: 2: 6 and 1.5: 2: 6 parts by weight, respectively.

Test animals: male rats 6 weeks old and male mice 5 weeks old

3) Preparation of test substance: Each weight of the pharmaceutical composition was suspended in distilled water.

4) Test Method: After fasting the test animals for 6 hours, mice or rats were forcibly administered orally into the stomach of the test animals. The dose was administered at 15 ml / kg body weight based on the weight of the body immediately before administration, and the death of the administration material was observed for 14 days.

5) Test Results: The result of the acute oral toxicity test for rat and mouse negative control, 5g / kg group, 10g / in kg group died because the animal was observed LD ₅₀ of the pharmaceutical composition for the rat and mouse is 10g / kg body weight or more (see Table 4 below).

As described above, the pharmaceutical composition for the treatment of gastrointestinal diseases according to the present invention has excellent pharmacological effects on the prevention and treatment of ulcers, as well as a pharmaceutical formulation which is very stable in 1: 2: 6 or 1.5: 2: 6 using rats and mice. It can be seen that the mixed composition of all is a very safe drug even in acute toxicity test, the present invention has proved to be a very useful invention industrially.

Claims (2)

In the pharmaceutical composition for treating gastrointestinal disorders consisting of ranitidine, bismas subcitrate and sucralate, the composition ratio of 1 to 2 parts by weight of ranitidine, 2 to 4 parts by weight of bismas subcitrate, and 6 to 12 parts by weight of sucralate Constituent, ranitidine 50 ~ 150mg, bismuth subcitrate 100 ~ 200mg, sucralate 300 ~ 600mg pharmaceutical composition for the treatment of gastrointestinal disorders. Granitine 50 ~ 150mg granules are prepared as a nuclear tablet and the outer layer containing bismuth subcitrate 100 ~ 200mg, sucralate 300 ~ 600mg containing a double tablets manufacturing method of the treatment of gastrointestinal diseases.