KR0174648B1 - Composite antacid composition - Google Patents

Abstract

The present invention relates to a complex antacid composition, and more particularly, to the gastric function regulator metoclopramide, colloidal aluminum phosphate, magnesium hydroxide and simethicone as a main component, as a thickening and stabilizing agent agar, pectin and xanthan It relates to a complex antacid composition comprising a gum.

According to the present invention, there is no side effect such as constipation due to long-term administration, and there is no side effect such as constipation during long-term preservation of distribution, and it has excellent antacid power and shows a therapeutic effect on gastric ulcer and gastric mucosal bleeding, and is caused by abnormal fermentation in gastrointestinal tract It is possible to quickly remove the bubbles, and further to obtain a complex antacid composition that can treat gastritis, dyspepsia due to lower gastric function, anorexia, nausea, vomiting and promote normalization of gastric function.

Description

Complex antacid composition containing gastric function regulator

The present invention relates to a complex antacid composition, and more particularly, to the gastric function regulator metoclopramide, colloidal aluminum phosphate, magnesium hydroxide and simethicone as a main component, as a thickening and stabilizing agent agar, pectin and xanthan It relates to a complex antacid composition comprising a point.

Antacids quickly neutralize or adsorb acid secreted in the stomach, and inactivate pepsin in gastric juice to prevent gastric mucosal damage from anorexia, thereby preventing the deterioration of diseases such as gastric ulcer and gastritis by gastric acid. It is widely used as a tea selection drug.

Conventionally, the strongest antacid is antacid. It neutralizes gastric acid and produces carbon dioxide gas, which can not be taken for a long time because the produced carbon dioxide stimulates the gastric wall to secondaryly secrete gastric acid and also cause gastric expansion.

Soluble antacids based on calcium carbonate and potassium bicarbonate are also used. This type of antacid has a powerful effect on relieving stomach pain, but when taken repeatedly, it causes hypercalcemia within a short period of time (3 days), and 90% of absorbed calcium Because of the insoluble calcium phosphate forms, there is a risk of kidney stones, hypercalcemia may increase the calcium concentration of cerebral white matter, neurological symptoms may appear. In addition, in the case of calcium salts, there is a problem in that gastric acid secretion is promoted by promoting gastrin secretion.

Antacids of aluminum salts have a weak antacid but have the advantage of protecting the gastric mucosa. However, long-term use of antacids in aluminum salts may cause constipation, and may cause intestinal obstruction because it is insoluble. Therefore, it may be used in combination with an antacid of magnesium salts.

Aluminum hydroxide in the aluminum salt antacid combines with phosphorus in the intestine to form and excrete aluminum phosphate, which is an insoluble salt, thereby inhibiting absorption of phosphorus as necessary in the small intestine. If the phosphorus deficiency persists for a long time, it is reported that not only anorexia, anxiety, and ataxia, but also calcium metabolism is affected and diseases such as osteomalacia, osteoporosis.

When the colloidal aluminum phosphate formulation developed to improve the above problems is combined with magnesium hydroxide, the phosphoric acid is administered together with the aluminum component, so the symptoms of phosphorus deficiency do not occur even after long-term administration, and there is no drug interaction. There is an advantage that does not lower the bioavailability of. In addition, since it is colloidal, it has excellent thixotropy and evenly spreads the complex wrinkles inside the gastrointestinal tract, and is known to have a very good therapeutic effect on gastric ulcer development and gastric mucosal bleeding.

On the other hand, the present inventors have excellent antacid power without side effects such as delamination or constipation of the formulation to suppress the occurrence of gastric ulcers and gastric mucosa bleeding effect, as well as to remove the colloidal phosphoric acid as a composition having a gas removal effect An antacid based on aluminum, magnesium hydroxide and simethicone was developed and filed with the Korean Intellectual Property Office. This application is disclosed in Korean Patent Publication No. 96-6926.

However, the antacids are excellent for removing gas from abnormal fermentation and improving symptoms such as gastritis and gastric ulcer due to excessive gastric acid, but can effectively treat indigestion, anorexia, nausea and vomiting symptoms due to weak mobility of the gastrointestinal tract. There are no drawbacks. In particular, in patients with chronic gastritis or gastric ulcers, complications such as indigestion and anorexia, which are caused by decreased gastric function, are not improved.

Therefore, the present invention not only shows excellent antacid effect without accompanying side effects such as constipation, treatment of nausea and vomiting caused by administration of indigestion, anorexia, migraine, anticancer drugs, or surgery, esophageal reflux and gastric stagnation Let us provide a multifunctional antacid composition exhibiting gastrointestinal function-modifying effects such as treatment.

In addition, it is an object of the present invention to ensure the stability of the gastric function regulator by manufacturing by adding agar, pectin, xanthan point and the like as a thickener and stabilizer, and does not occur in the long-term storage of the formulation does not produce excellent storage stability It is to provide the antacid composition shown.

In order to achieve this object, according to the present invention, a complex antacid comprising metoclopramide or salts thereof and colloidal aluminum phosphate, magnesium hydroxide and simethicone as main components, and agar, pectin and xanthan gum as a thickening and stabilizing agent. A composition is provided.

The present invention is described in detail as follows.

The present inventors studied to prepare an antacid composition having a function of treating gastric nausea and normalizing gastric function while adding an agent for controlling gastric function that does not affect the stability of the formulation, while maintaining an antacid effect and a gas removal effect. It has been found that the desired complex antacid can be obtained using metoclopramide or a physiologically acceptable salt thereof as a gastric function modulator.

Metoclopramide or its physiologically acceptable salts block dopamine receptors in gastrointestinal smooth muscles to normalize weakened peristalsis, promote the release of gastric contents, and relieve abdominal bloating and epigastric pressure caused by indigestion, It is used for the prevention and treatment of nausea and vomiting because it blocks the dopamine receptors in the chemoreceptors of soft water to suppress the stimulation of the vomiting center. In addition, the dopamine receptor blocking effect on the cerebral limbic system of the central nervous system is effective in relieving mental stress and anxiety, which is effective for neurological gastrointestinal diseases.It suppresses the activity of c-AMP and reduces the secretion of gastrin in the gastric mucosa. It can be used to treat ulcers.

Metoclopramide or a physiologically acceptable salt thereof used in the antacid composition of the present invention normalizes gastrointestinal function, improves nausea and vomiting, promotes gastrointestinal motility, and is associated with antacid and degassing effects. It does not affect the action of the colloidal aluminum phosphate, magnesium hydroxide and simethicone.

The content of metoclopramide or a physiologically acceptable salt thereof in the antacid according to the present invention is 0.01 to 0.1 weight. It is preferable that it is 0.1 weight If abnormal, high blood concentration may cause side effects of extrapyramidal system, 0.01 weight It is difficult to expect effective efficacy below.

Colloidal aluminum phosphate exhibits both antacid and gastrointestinal mucosa protective effects, and does not change their bioavailability even when combined with other gastric ulcer therapeutic drugs such as cimetidine. This is because colloidal aluminum phosphate binds to toxin molecules with large particle sizes but not to oral drug molecules that are nonproteinaceous. On the other hand, prolonged use of an antacid containing aluminum may cause aluminum to be absorbed through the digestive organs, resulting in severe aluminum toxicity. This is because aluminum absorbed into the body is introduced into the lysosomes in the cells to destroy the cells of the central nervous system, liver, bone tissue, heart, and the like, and is excreted in urine through the kidneys, which may cause kidney failure.

However, the colloidal aluminum phosphate used in the present invention is excreted as it is not absorbed in the digestive organs and thus is a very safe drug even for long-term administration. It also combines phosphate administration, so there is no fear of causing a deficiency.

The content of colloidal aluminum phosphate in the antacid according to the present invention is 10 to 20 weight Is preferably.

Magnesium hydroxide, which is another main component in the antacid according to the present invention, reacts rapidly with gastric hydrochloric acid to neutralize gastric acid while forming magnesium chloride and water, thereby maintaining the pH in the stomach at 4.0 or higher. Magnesium hydroxide also serves to alleviate the astringent action of colloidal aluminum phosphate, thus preventing constipation. The content of magnesium hydroxide is 1 to 10 weight Is preferred, and the content is complementary. 10 weight If abnormal, may cause diarrhea, 1 weight It is difficult to expect the effect of preventing constipation below. Instead of magnesium hydroxide, the same amount of magnesium oxide can be used.

Another main component of sime chikon of antacid of the present invention is ^{_{[(CH 3) 2 SIO -}} ] of a mixture of linear siloxane polymers containing repeating units of _n, in the bubble removal properties, given Applying the solution to lower the surface tension It stops the formation of bubbles and quickly wraps the mucous membranes to coalesce and release the bubbles from the gastrointestinal tract. Therefore, when administered orally together with the component exhibiting an antacid effect, it has a function to quickly remove the bubbles caused by abnormal fermentation in the gastrointestinal tract, so that the bubbles no longer occur. In particular, since methicone is physiologically inactive, it is not excreted in the gastrointestinal tract but is excreted as it is, and does not affect gastric acid secretion or nutrient absorption, and thus is suitable for use in the complex antacid according to the present invention. Simethicone content is 0.1 to 1 weight Is preferably. 1 weight Even if the above is used, no further effect can be expected, rather it may cause delamination of the final formulation, and 0.1 weight If the following is used, it is hard to expect sufficient gas removal effect.

The complex antacid composition of the present invention includes agar, pectin and xanthan gum as auxiliary components exhibiting viscosity increase and stabilizing effects, in addition to the above main components.

These auxiliaries increase the compatibility of the entire composition to prevent delamination and allow the composition of the present invention to maintain an appropriate viscosity to evenly and quickly apply the lining of the gastrointestinal tract. In particular, since the composition of the present invention is continuously applied to the lesion site in which the gastric ulcer or inflammation occurs, the lesion is effectively protected from an attack such as gastric acid, so that the gastric ulcer or gastric mucosal bleeding is quickly healed.

Complex antacid composition according to the present invention, in addition to the auxiliary component, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, thickeners such as gum arabic, tragacanth, polyvinylpyrrolidone, sugar , Glucose, mannitol, sorbitol, xylitol, stevioside, aspartame, isomerized sugar, honey, licorice, sweeteners such as jujubes, fragrances and the like.

The complex antacid according to the present invention is preferably prepared in suspension according to a general method for preparing a suspension formulation, and an aqueous suspension medium such as water is used as the suspension medium.

The prepared formulation is preferably administered orally 10 to 30g once or several times a day.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, the scope of the present invention is not limited thereto.

Example 1

After mixing agar 3.0g, pectin 5.0g, xanthan gum 1.0g, sorbitol 130g with each other, purified water 230 Into a solution having a viscosity of 90 ° C. or higher. Then, 4.0 g of simethicone and 124 g of colloidal aluminum phosphate were further added and mixed. The mixed solution was cooled to 25 to 30 ° C., 20 g of magnesium hydroxide and 0.28 g of metoclopramide were added, and the mixture was homogeneously mixed with purified water to make 1000 g in total, thereby obtaining a complex antacid composition.

Example 2

A composite antacid composition was prepared in the same manner as in Example 1 except that magnesium oxide was used instead of magnesium hydroxide, and metoclopramide was used instead of methoclopramide.

Example 3

A composite antacid composition was prepared in the same manner as in Example 1, except that magnesium hydroxide was excluded from the composition.

Comparative Example 1

Except for metoclopramide hydrochloride, magnesium hydroxide, simethicone in Example 1, using the same amount of the remaining components, a composite antacid composition was prepared in the same manner as in Example 1.

Comparative Example 2

Except for metoclopramide hydrochloride in Example 1, using the same amount of the remaining components, a complex antacid composition was prepared in the same manner as in Example 1.

In the following comparative test, the antacids prepared according to Examples 1, 2 and 3 and Comparative Examples 1 and 2 were denoted as antacids A, B, C, D and E, respectively.

Antacid test

Take 3 samples of 2.0 gTlr each from antacids A, B, C, D and E. 250 Placed in a beaker, about 70 purified water With 0.1N hydrochloric acid 30 After adding 37 Stir exactly 15 minutes at 3 ° C. and immediately titrate with 0.1 N sodium hydroxide. The end point was to maintain the pH of 3.5 to 10 seconds. Antacid here means the amount of 0.1 N hydrochloric acid consumed to neutralize a single dose 20 g.

Antacid (0.1 N hydrochloric acid consumption / 1 dose) = (30 × f ₁ -a × f ₂ ) ×

However, f ₁ : 0.1N coefficient of hydrochloric acid

f ₂ : Regulatory coefficient of 0.1N sodium hydroxide

a: consumption of 0.1N sodium hydroxide ( )

t: single dose of the drug (20 g)

S: Sample Collection (g)

From Table 1, it can be seen that antacid A and antacid B according to the present invention are significantly higher than the antacid D used in the past. In addition, since the antacid C exhibits a similar antacid power as the antacid D, it can be seen that the function as an antacid is inferior.

[Effect on Gastric Ulcer Development]

An antacid A and an antacid D were orally administered to male rats fasted for 24 hours. Shay's method [Harry Shay et al., A simple method for the uniform production of gastric ulceration in the rat. Gastroenterology, 4, 43-61 (1945)], 30 minutes after drug administration, rats were anesthetized with ether, opened, and aspirated (400 mg / kg body weight) dissolved in 0.4 N HCl, or 100 Ulcers were induced by oral administration of 1 ml of ethanol alone. The experimental group administered aspirin was 100 for 4 hours. The experimental group administered with ethanol was singled and fasted for 2 hours, and then lethal under an ether anesthesia. After fixing with formalin, the ulcer index was measured using a three-dimensional magnifying glass, and the results are shown in Tables 2 and 3, respectively.

However, each value is average It is expressed as standard deviation.

However, each value is average It is expressed as standard deviation.

In the aspirin-induced ulcer model of Table 2, the ulcer index of the control group was 122.50 9.01 mm ² , the ulcer index of the antacid D 4.0 g / kg administration group was 38.75 9.25mm ² showed a significant (p <0.001) decrease compared to the control. All of the antacid A-administered groups showed a significant decrease in ulceration index compared to the control group. In particular, the antacid A 8.0g / kg and 12.0g / kg-administered groups showed a significant decrease compared to the antacid D-administered group.

In the ethanol-induced ulcer model of Table 3, the ulcer index of the control group was 50.63 13.21 mm ² and the ulcer index of the antacid D 4.0 g / kg administration group was 10.38 2.31 mm ² , which showed a significant (p <0.001) decrease compared to the control. All of the antacid A-administered groups showed a significant decrease in ulcer index index compared to the control group, and the antacid A 8.0g / kg and 12.0g / kg-administered groups showed a significant decrease compared to the antacid D-administered group as in the aspirin ulcer model.

[Effects on Gastric Mucosal Hemorrhage]

To test the gastric mucosal bleeding inhibitory effect of antacids A and D on aspirin-induced ulcer model, gastric fluid was removed by completely removing gastrointestinal tract with distilled water and treating gastric mucosa in the same manner as described above. Collected. After sonication of the collected gastric solution for 15 minutes, 25 μl was taken and dissolved in acetic acid solution 1 It was placed in a test tube containing 0.5 ml of toluidine. One 0.5 ml of H ₂ O ₂ is added, and after 20 minutes, 10 After adding 5 ml of acetic acid solution, after 10 minutes, the absorbance was measured at a wavelength of 720 nm using an absorbance spectrometer to obtain hemoglobin. The results are shown in Table 2. The standard curve was obtained by dissolving hemoglobin (Hb) in distilled water by concentration.

In gastric mucosal hemorrhage induced by aspirin of Table 2, the hemoglobin value of the control group was 82.55 7.38 mgHb / 4 hour, and the hemoglobin level of the antacid D 4.0 / kg administration group was 15.56 4.98 mgHb / 4 hour showed a significant (p <0.001) decrease compared to the control. All antacid A-administered groups showed significant dose-dependent gastric mucosal bleeding reduction compared to the control group.

[Effect on Duodenal Ulcer Development]

Cysteamine (425 mg / kg) was subcutaneously injected into the female rats fasted for 24 hours, and antacid A and antacid D were administered orally three times at 7.5, 14.5, and 22.5 hours after cysteamine administration. Twenty four hours after cysteamine administration, the experimental animals were killed under esthetized anesthesia, and the duodenal sites were removed. After fixing with formalin, the degree of ulceration was measured using a three-dimensional magnifying glass, and the results are shown in Table 4. The incidence of ulceration was calculated by dividing the damage to 0-4.

However, each value is average It is expressed as standard deviation.

In the duodenal ulcer model derived from cysteamine of Table 4, the ulcer index of the control group is 3.40 Was 0.63mm ^2, ulcer index of antacids D 4.0g / kg administered group 0.20 0.20 mm ² showed a significant (p <0.001) decrease compared to the control. All of the antacid A-administered groups showed a significant decrease in ulceration index compared to the control group.

[Action on small intestinal transport ability]

10 mice fasted for 24 hours were used as a group, and antacid A and antacid D were orally administered. 0.2 ml of activated charcoal suspension was orally administered, and 40 minutes after drug administration, mice were killed and opened, and the intestines were extracted. Activated carbon migration rate was calculated according to the following equation, and the results are shown in Table 5.

However, each value is average It is expressed as standard deviation.

In Table 5, the small intestine transport rate of the control group is 64.93 2.14 The small intestine transport rate of the antacid D 4.0 g / kg administration group was 53.99 3.11 As compared with the control group, it showed a significant (p <0.01) decrease in the small intestine transport rate. However, the antacid A 8.0g / kg administration group and 12.0g / kg administration group showed a significant (p <0.001) increase in small intestine transport rate compared to the control group. Compared with the dose-dependent significant increase.

[Action on the Battlefield Transport Capacity]

Ten mice fasted for 24 hours were used as a group, and antacid A, antacid D, and antacid E were orally administered. 0.2 ml of activated carbon suspension was orally administered. Experimental animals were placed one by one in a cage with room to cover and partitioned, and the time until the activated carbon suspension was seen in feces was measured and observed for a total of 10 hours. The results are shown in Table 6.

However, each value is average It is expressed as standard deviation.

In Table 6, the total tube transport time of the control group is 360.60. 35.18 minutes and total tube transport time of antacid D 4.0 g / kg group was 455.88 29.48 minutes, 404.33 for antacid E 4.0 g / kg There was no difference from the control group at 33.72 minutes. There was no difference from the control. The antacid A-administered group showed no significant change compared to the control group, but the antacid A 1.0g / kg and 12.0g / kg-administered groups showed a significant (p <0.05) increase in total ductal transport ability compared to the antacid D 4.0g / kg-administered group. It was. However, there was no significant difference compared to antacid E.

[Effect on Degassing]

Antacids A and D were weighed 87 mg, 174 mg, 348 mg, and 522 mg, diluted in water to 0.5 ml, respectively, and then orally administered to rats fasted for 24 hours regardless of body weight. 0.5 ml of saline was administered to the control group. After 4 minutes, 0.5 ml of a foaming agent (solution of dissolving 5.34 g of sodium carbonate and 2.0 g of saponin in 100 ml of water) was administered, followed by 1.0 ml of contrast agent (solution of 49.0 g of barium sulfate and 7.2 g of citric acid in 100 ml of water). Immediately orally administered. After 2 minutes, the rats were fixed vertically and X-rays (modern X-ray M500,890 3007) were taken. The x-ray film was retaken with a camera and scanned in the Adobe Port Shop program for Macintosh. Next, using the Macintosh image program, the area occupied by the total white area shown in white and the bubbles shown in gray were obtained. The experimental results are expressed as the percentage of the area occupied by the bubble to the total gastric area.

However, each value is average It is expressed as standard deviation.

In Table 7, the gas evolution of the control induced with the gas generant reagent was 48.9 of the total gastric volume. 3.7 The gas evolution of the antacid D 174mg / rat group was 57.3 of the total gastric volume. 3.6 As compared to the control did not show a difference. However, all of the antacid A-administered groups showed a significant decrease in gas evolution in dose-dependently (p <0.001) as compared to the antacid D-administered group as well as the control group.

[Anti-vomiting Action]

Antacid D and antacid A were orally administered once per dose to hybrid commercial dogs, and physiological saline was administered to the control group, respectively. Apomorphine 0.005 mg / kg IM was injected 1 hour after drug administration. Observe for 30 minutes to find the number of vomiting, and blockage rate according to the following formula Was obtained.

However, each value is average It is expressed as standard deviation.

In Table 8, vomiting frequency of the control group induced vomiting with apomorphine is 52.83 5.36 times and vomiting frequency of antacid D 2.0g / kg group was 46.20 8.45 times did not show any difference from the control. However, in the antacid A-administered group, the vomiting effect by amorphine was suppressed, and the vomiting frequency was 2.00 in the 0.5g / kg-administered group. 2.00 times (96.2 Jersey), vomiting frequency of 0.00g / kg group was 0.00 0.00 (100.0) Jersey), 0.75 for the 2.0 g / kg dose group 0.75 times (98.58 Jersey).

According to the present invention as described above, there is no side effect such as constipation due to long-term use, there is no side separation of the preparation at the time of distribution preservation, excellent antacid power, and shows a therapeutic effect against gastric ulcer and gastric mucosal bleeding, gastrointestinal abnormality It is possible to quickly remove bubbles generated by fermentation, and to obtain a complex antacid composition which can treat gastritis, dyspepsia due to lowering of crisis, anorexia, nausea and vomiting and promote normalization of gastric function.

Claims (2)

A complex antacid composition comprising metoclopramide or a physiologically acceptable salt thereof and colloidal aluminum phosphate, magnesium hydroxide, simethicone, agar, pectin and xanthan gum. The complex antacid composition according to claim 1, wherein the content ratio of metoclopramide or a physiologically acceptable salt thereof and colloidal aluminum phosphate is 1: 100 to 2,000 by weight.