KR20060122389A - Antacid complex compound comprising diomagnite - Google Patents

Abstract

An antacid composition comprising diomagnite is provided to have excellent antacid ability, and adhesive power and absorption capacity to a mucous membrane without causing any side effect such as constipation, thereby capable of inhibiting stomach ulcer development and treating gastric mucosa bleeding. The antacid composition comprises diomagnite as an effective ingredient. In the composition, at least one selected from the group consisting of methylcellulose, xanthan gum, a salt of carboxymethylcellulose, gum arabic, hydroxypropylcellulose, tragacanth, and polyvinylpyrrolidone is used as a thickening and stabilizing agent.

Description

Antacid composition containing diomagnesate as an active ingredient {ANTACID COMPLEX COMPOUND COMPRISING DIOMAGNITE}

The present invention relates to an antacid composition that serves to neutralize the acid secreted from the stomach. More specifically, the present invention relates to an antacid composition based on diomagnesate.

Antacids are widely used as the first-choice drug to prevent the worsening of diseases such as gastric ulcer and gastritis by gastric acid because it acts to neutralize the acid secreted in the stomach.

In the past, many soluble antacids mainly composed of calcium carbonate and calcium bicarbonate were used. This has a powerful effect on relieving gastrointestinal pain, but in acidic media its action is irreversible, and especially after the antacid effect, it produces more gastric acid than before taking it as a side effect of so-called secretory acid recoil. Had a problem.

In order to solve this problem, a composite component antacid of aluminum hydroxide and magnesium hydroxide, which is developed later, is disclosed in Korean Patent Laid-Open Nos. 1987-0009724 and 1999-0049931. These ingredients have been widely used worldwide because of their excellent antacid ability without inducing secretory acid recoil or metabolic alkalosis, but because the aluminum component in the formulation is combined with phosphorus in the intestine, it is excreted in the form of aluminum phosphate, an insoluble salt. The disadvantage is that the small intestine does not absorb as much phosphorus as necessary. If the phosphorus deficiency persists for a long time, it is reported that not only anorexia, anxiety, and muscle weakness occur, but also calcium metabolism is affected and diseases such as osteomalacia and osteoporosis occur.

In addition, the aluminum hydroxide formulation has a drug interaction with other drugs, such as tetracycline and cimetidine, has been pointed out that the problem of lowering the bioavailability of these other drugs when co-administered.

In addition, as the formulations developed so far, Korean Unexamined Patent Publication No. 1996-0006926, Korean Patent No. 112525, and Korean Patent No. 369874 have attempted to solve the above problems, but in case of long-term preservation, layer separation occurs, The problem that caused the change was not completely solved.

In addition, there have been reports of side effects such as constipation, although only a small amount, and there is room for improvement in antacid ability, and the application or adsorption power to the gastric mucosa is weak, so it is insufficient for the treatment of gastritis and gastroduodenal ulcer. There is a continuous demand for antacids with new compositions that can solve these problems.

The present invention for solving this problem, there is no layer separation of the formulation or changes in pH and properties, and excellent antacid power and coating power and adsorption power to the mucous membrane without causing side effects such as constipation, suppressing the occurrence of gastric ulcer and gastric mucosa An object of the present invention is to provide an antacid composition having a therapeutic effect of bleeding.

The present invention for achieving the above object, in the antacid composition, provides an antacid composition characterized in that it contains diomagnate having an antacid effect as an active ingredient.

Diomagnesate used in the present invention is a compound made by heating natural dioctahedral smectite in the presence of magnesium hydroxide, also referred to as complex silicate of magnesium hydroxide.

In addition, the present invention preferably uses at least one of the group consisting of methyl cellulose, xanthan gum, salts of carboxymethyl cellulose, gum arabic, hydroxypropyl cellulose, tragacanth, and polyvinylpyrrolidone as a thickening and stabilizing agent. Do.

Specifically, the dioctahedral smectite is a leaf silicate of aluminum and magnesium, and is formed by two-dimensional stacking of a crystalline layer composed of an intermediate layer of octahedral alumina between two outer layers of tetrahedral silica. When the headral smectite is heated in the presence of magnesium hydroxide, the magnesium hydroxide is bonded to the outer surface of the outer layer composed of tetrahedral silica, resulting in diomagnate.

At this time, the antacid action is mainly due to the magnesium hydroxide between the mineral layers, and when the diomagnate neutralizes the gastric acid, the clay mineral is restored to restore all the properties of the clay mineral-the coating force, the adsorption force, the anti-ulcer action, and the mucosa protection. Action and gradual neutralization.

Long-term use of antacids containing magnesium hydroxide can cause magnesium to be absorbed through the digestive tract and cause severe magnesium toxicity. This is because magnesium absorbed into the body is introduced into the lysosomes in the cell, which can destroy cells of the central nervous system, liver, bone tissue, heart, and the like, and is excreted in the urine through the kidneys, which may cause kidney failure.

However, since diomagnate used in the present invention is bound to the outer surface of the outer layer consisting of tetrahedral silica phosphorus magnesium hydroxide is not absorbed in the digestive tract and is excreted as it is a very safe drug even for long-term use. In addition, since magnesium hydroxide has a form bound to clay, it has very excellent stability because there is almost no change in properties, antacid and pH even during long-term distribution.

In detail, since the dioctahedral smectite, which is a substrate of diomagnate, is a natural clay and has a fine particle structure, the composition of the present invention is applied evenly and rapidly to the lesion site where gastric ulcer or inflammation has occurred, and thus it maintains gastric acid. It effectively protects the lesion from back attacks, allowing for rapid healing of gastric ulcers and gastric mucosal bleeding.

On the other hand, the content of the diomagnesate as a main component of the antacid according to the present invention is preferably 15 to 35% by weight of the total antacid. The reason is that when it is 15% by weight or less, the antacid and gastric mucosa protective action may not be sufficiently exhibited. On the contrary, when it is 35% by weight or more, there is a possibility of side effects such as constipation due to astringent action.

In addition, the antacid composition of the present invention, in addition to the main component, as an auxiliary component showing a viscosity increasing and stabilizing effect, salts of methyl cellulose, xanthan gum, carboxymethyl cellulose, gum arabic, hydroxypropyl cellulose, tragacanth, and polyvinylpi It is preferred to include at least one of the group consisting of rolidones.

Specifically, it is preferable to use a salt of xanthan gum and carboxymethyl cellulose or gum arabic, and these auxiliary components increase the compatibility of the whole composition to prevent the occurrence of sufficient amount, and the composition of the present invention maintains an appropriate viscosity to camouflage This is because the inner wall of the tube is evenly and quickly applied.

More specifically, in the present invention, the content of the increasing agent and the stabilizer is preferably 10 to 30% by weight of the total antacid. The reason is that beyond this range, the desired stability and viscosity cannot be obtained. It is preferable that the said carboxymethylcellulose salt is especially carboxymethylcellulose sodium. This is because the stability of the composition can be maximized as the antacid component of the present invention is the largest compatibility effect.

In the present invention, methyl cellulose, salts of carboxymethyl cellulose, hydroxypropyl cellulose, gum arabic, tragacanth, polyvinylpyrrolidone, and the like may be used as thickeners, and di-sorbitol and sugar may be used as sweeteners. , Glucose, mannitol, xylitol, stevioside, aspartame and the like can be further used.

According to the present invention as described above, the antacid composition exhibits excellent stability during distribution and no side effects such as constipation due to long-term administration, and excellent antacid, applicative force, and anti-ulcer action, and thus exhibits a therapeutic effect against gastric ulcers and bleeding. You can get it.

It looks at in detail through the preferred manufacturing examples of the present invention. The following preparation examples are intended to illustrate the invention and should not be understood as limiting the scope of the invention.

[Production example]

The antacid composition according to the present invention is 20 to 30% by weight of diomagnate as a main component, 2 to 3% by weight of xanthan gum and 5 to 6% by weight of sodium carboxymethylcellulose as a thickening and stabilizing agent, or instead of xanthan gum and carboxymethylcellulose sodium To achieve 7 to 9% by weight of gum arabic, 10 to 15% by weight of concentrated glycerin as a substrate was prepared.

Hereinafter, the present invention will be described in more detail with performance evaluation, for example. The following examples are intended to further clarify the technical spirit of the present invention, and are not intended to limit the scope of the technical spirit of the present invention.

Example 1

0.1 g of gum arabic was added to 6.8 g of purified water, and the temperature of the liquid was adjusted to 80 ° C., followed by stirring to dissolve. 4.6 g of di-sorbitol (70%) and 1.7 g of concentrated glycerin were added thereto, followed by stirring and mixing.

Thereafter, 3.8 g of diomagate was added thereto, and the mixture was stirred to be a suspension, and then the temperature of the liquid was cooled to 40 to 50 ° C, a flavoring agent was added thereto, followed by stirring to dissolve. The total weight of the solution thus prepared was 17 g.

Example 2

An antacid composition similar to Example 1 was prepared except that xanthan gum and carboxymethylcellulose sodium were used instead of gum arabic.

Comparative Example 1

An antacid composition having the same composition as in Example 1 was prepared in the same manner as in Example 1, except that 2.0 g of aluminum hydroxide and 1.8 g of magnesium hydroxide were used.

Performance evaluation methods of the prepared examples and comparative examples are as follows.

1. Antacid test

Take three samples of 2.0 g each from the antacids prepared according to Examples 1 and 2 and Comparative Example 1, put them in a 250 mL beaker, add 70 mL of water and 30 mL of 0.1 N hydrochloric acid, and then at 37 ± 3 ° C. Stir exactly 15 minutes and immediately titrate with 0.1 N sodium hydroxide. The end point was that the pH 3.5 is maintained for 10 to 15 seconds. Antacid here refers to the amount of 0.1 N hydrochloric acid consumed to neutralize a single dose of 17 g.

Antacid (0.1 N hydrochloric acid per dose)

Where f ₁ is: 0.1 N hydrochloric acid coefficient

f ₂ : Regulatory coefficient of 0.1 N sodium hydroxide

a: Consumption of 0.1 N sodium hydroxide (ml)

t: single dose (17 g) of subject drug

s: sample volume

The performance of this division force is shown in Table 1 below.

[Table 1] Comparison of Antacid Power

From Table 1, it can be seen that the antacid composition of Example 1 and Example 2 according to the present invention is significantly higher than the antacid of Comparative Example 1 has been conventionally used.

2. Antacid Change Test

With Example 1 and 2, the antacid power was measured for a total of 12 weeks in units of 1 week according to the following conditions to observe the degree of change. The dividing force was measured in the same manner as the 1. dividing force test.

Room temperature: 20 ~ 30 ℃, airtight container (glass)

Refrigerated: 3 ~ 5 ℃, airtight container (glass)

Acceleration: 40 ℃, Humidity: 75%, Airtight container (glass)

The degree of change of the division force is shown in Table 2 below.

[Table 2] Measurement of antacid change

As shown in Table 2, the antacid composition of Example 1 and Example 2 according to the present invention is very stable stability and is suitable for long-term distribution because the antacid capacity is almost unchanged at room temperature, refrigeration, acceleration conditions Can be.

3. pH change test

With Example 1 and 2, pH was measured for a total of 12 weeks on a weekly basis under the same conditions as the above 2. Antacid Change Test to observe the degree of change. Hanna instruments Model HI8521 pH Meter was used for pH meter calibration before measurement to minimize measurement error.

The results of this pH change test are shown in Table 3 below.

Table 3 Test Result of pH Change

As shown in Table 3, the antacid composition of Example 1 and Example 2 according to the present invention can be seen that the stability is very excellent because the pH is almost unchanged despite long-term storage.

4. Layer Separation Test

50 ml of the sample was placed in a Nessler tube having a diameter of 2.2 cm and a length of 25 cm, and left at room temperature for 90 days, and the height of the separated water layer was measured.

Whether the layers are separated is shown in Table 4 below.

Table 4 Comparison of the heights of water layers separated from Nessler tubes

Height of separated water layer (ml) Sample 1 Sample 2 Sample 3 Average Example 1 0.11 0.09 0.09 0.10 Example 2 0.10 0.11 0.09 0.10 Comparative Example 1 1.46 1.48 1.47 1.47

According to Table 4, in Examples 1 and 2, the amount of separated water was very small compared to Comparative Example 1, from which it can be seen that the antacid composition of the present invention shows much better stability than the conventional antacid. have.

5. Property change test

With Example 1 and 2, the change of the property was observed for a total of 12 weeks on a weekly basis under the same conditions as the above 2. Antacid Change Test. In both Examples 1 and 2, the initial properties were pale grey-brown suspensions, and as a result of observation for 12 weeks, there was no noticeable change in properties.

Therefore, it can be seen that the antacid composition of Example 1 and Example 2 is excellent in stability and suitable for long-term distribution because there is no change in properties at room temperature, refrigeration and acceleration conditions.

6. Coating force

Wister rats were divided into 6 groups of 10 rats and fasted 20 hours before the test. Then, Examples 1, 2 and Comparative Example 1 were administered 10 ml per kg of body weight. Animals of each group were killed as follows to observe the coating force on the gastric mucosa.

Group 1: Lethal after 10 minutes

Group 2: lethal after 30 minutes

Group 3: fatality after 60 minutes

Group 4: lethal after 2 hours

Group 5: lethal after 4 hours

Group 6: lethal after 6 hours

After cutting and dissecting the stomach of the rat (Wister rat) and lightly washed, the walking area was divided into six steps as shown below to give a value and summarized in Table 6 below.

0: not applied at all

1: very slightly applied

2: slightly applied

3: Appropriately applied

4: Applied a lot

5: very much applied

[Table 6] Comparison of application force in rat stomach

10 minutes 30 minutes 1 hours 2 hours 4 hours 6 hours Example 1 4.3 4.2 3.6 3 2.1 0.8 Example 2 4.8 4.7 4.1 3.7 3.3 1.2 Comparative Example 1 2.1 1.9 1.3 0.8 0.4 0.1

As shown in Table 6, the present invention can be seen that the coating force on the gastric mucosa is 2 to 3 times superior to that of a conventional antacid thanks to the finely divided clay particle structure of diomagnate. Example 1 shows that the first 30 minutes after administration has a high coating power, stable for 2 hours to maintain a moderate or higher coating power up to 4 hours, then gradually decreased to almost disappear 6 hours after administration Can be.

In addition, Example 2 is different in the proportion of the thickener in Example 1 shows a better coating force, it can be seen that a considerable amount remains even after 4 hours of administration.

7. Adsorption test on gastric and duodenal mucosa

Example 1, 2 and Comparative Example 1 were administered 10 mg to the oral tube in fasted rats, and then lethal after 1, 2, 6, 16 hours, and the stomach and duodenum were extracted. The amount was measured, and the results are shown in Tables 7 to 9 below.

Table 7 Example 1 Adsorbed Stomach and Duodenum

 Number of rats top Duodenum Total amount of sample (mg) Amount of sample per surface area (µg / mm2) Total amount of sample (mg) Amount of sample per surface area (µg / mm2) After 1 hour 6 3.95 10.21 1.12 3.06 2 hours later 6 2.64 4.23 0.64 1.52 6 hours later 6 1.47 1.64 0.79 1.93 After 16 hours 6 0.56 1.27 0.89 1.74

Table 8 Example 2 Adsorption to Stomach and Duodenum

 Number of rats top Duodenum Total amount of sample (mg) Amount of sample per surface area (µg / mm2)  Total amount of sample (mg) Amount of sample per surface area (µg / mm2) After 1 hour 6 4.42 11.35 1.87 4.25 2 hours later 6 3.24 5.51 1.06 2.18 6 hours later 6 2.51 3.35 1.19 2.59 After 16 hours 6 1.34 2.59 1.26 2.75

TABLE 9 Comparative Example 1 the amount adsorbed on the stomach and duodenum

 Number of rats top Duodenum Total amount of sample (mg) Amount of sample per surface area (µg / mm2) Total amount of sample (mg) Amount of sample per surface area (µg / mm2) After 1 hour 6 1.52 4.68 0.87 2.59 2 hours later 6 0.98 1.59 0.53 1.02 6 hours later 6 0.51 1.20 0.61 1.24 After 16 hours 6 0.13 0.34 0.34 1.59

From Tables 7, 8, and 9, the antacid of Comparative Example 1, which has been conventionally used, has a weak adsorption force in the stomach and duodenum, and thus, may be somewhat insufficient in ulcer treatment. On the other hand, the antacid composition of Examples 1 and 2 according to the present invention shows an adsorptive power of about 2 to 3 times higher in both the stomach and duodenum than Comparative Example 1, so it can be seen that it has an excellent effect on mucosal protection. It can also be seen that the antacid composition of Example 2 has a better adsorption capacity compared to the antacid composition of Example 1 due to the proper combination of thickeners.

8. Inhibitory effect on gastric ulcer development (pyloric ligation experiment)

The rats fasted for 24 hours were stabilized in an isolated room for 2 hours, and then the drugs of Examples 1,2 and Comparative Example 1 were orally administered. The control group received 13.5% sugar solution. In the control group, according to shay's pyloric ligation method, rats were anesthetized with ether for 30 minutes after drug administration, the abdomen was removed, the pyloric region was taken out, and the pyloric region was ligated with a suture. After 20 minutes, ulcers were induced by oral administration of 150 ml / kg of aspirin and 0.1 ml / 100 g of 0.4 N hydrochloric acid.

After 5 hours of ligation, the rats were killed by cervical dislocation, the stomach was removed, the stomach containing food or feces was removed, 10 ml of 3% formalin was injected into the lumen of the stomach, soaked in a container containing formalin and fixed for 10 minutes. Incision along the Taiwan curve above to measure the length of the ulcer (ulcer index), the results are shown in Table 10 below.

Table 10 Comparison of antacids against hydrochloric acid and aspirin-induced gastric ulcer in pyloric ligation rats

Drug dosage (ml / 100g) Number of animals Ulcer Index (mm) Control (sugar) 0.1 15 30.41 ± 5.68 Example 1 0.1 15 12.07 ± 2.48 Example 2 0.1 15 10.43 ± 3.48 Comparative Example 1 0.1 15 26.10 ± 7.27

However, each value is expressed as mean ± standard deviation. The significance of P = 0.01 compared to the control group by the Student's t-test.

As shown in Table 10, as a result of the anti-ulcer experiments according to the pyloric ligation method for the antacids of Examples 1 and 2, Comparative Example 1, Examples 1 and 2 were 60.3% and 65.7%, respectively When compared with the control group, it showed significant (P 0.01) significant ulcer suppression effect. On the other hand, in Comparative Example 1, the effect of inhibiting ulceration was only 14.2%.

9. Inhibitory effect on gastric mucosal bleeding

The stomach was removed by the same method as described above, and gastric juice was collected after completely removing blood around the stomach with saline solution. After the collected gastric juice was sonicated for 5 minutes, 25 µl was taken and placed in a test tube containing 1% ortho-toluidine dissolved in acetic acid. 0.5 ml of 1% hydrogen peroxide solution was added and 5 ml of 10% acetic acid solution was added after 20 minutes. After 10 minutes the absorbance was measured at a wavelength of 72 nm using a spectrophotometer. The standard curve was obtained by dissolving hemoglobin (Hb) by concentration, and the results are shown in Table 11 below.

Table 11 Comparison of the effects of antacids on gastric mucosal bleeding induced by hydrochloric acid aspirin in pyloric ligation rats

Drug dosage (ml / 100g) Number of animals Hemoglobin detection amount (mgHb / 5 hours) Control (sugar) 0.1 15 23.70 ± 5.20 Example 1 0.1 15 9.40 ± 1.52 Example 2 0.1 15 10.14 ± 1.20 Comparative Example 1 0.1 15 18.30 ± 5.06

However, each value is expressed as mean ± standard deviation. Compared with the control group by the Student's t-test, the significance of P = 0.005 is shown.

As shown in Table 11, the gastric mucosal bleeding inhibitory effect, the antacids of Examples 1 and 2 showed significant (P 0.005) gastric mucosal bleeding inhibitory activity of 60.3%, 57.2%, respectively, compared to the control group. On the other hand, the antacid of Comparative Example 1 did not show a significant gastric mucosal bleeding inhibitory effect.

10. Inhibition of Ulcers Induced by Anhydrous Ethanol

The rats fasted for 24 hours were stabilized in an isolated room for 2 hours, followed by oral administration of physiological saline (control) and the antacids of Examples 1, 2 and Comparative Example 1, respectively, and 1 ml of anhydrous ethanol was orally administered 30 minutes later. . After 1 hour of oral administration, rats were lethal by cervical spinal bone dissection, stomach was extracted, 10 ml of 3% formalin was injected into the gastric lumen, soaked in a container containing formalin and fixed for 10 minutes. Incision was made to measure the length of the ulcer (ulcer index), and the results are shown in Table 12 below.

Table 12.Effect of antacids on gastric ulcer induced by anhydrous ethanol in rats

Drug dosage (ml / 100g) The number of animals Ulcer Index (mm) Control group (physiological saline) 10 15 60.07 ± 6.17 Example 1 10 15 20.68 ± 6.73 Example 2 10 15 19.27 ± 2.86 Comparative Example 1 10 15 42.55 ± 4.20

However, each value is expressed as mean ± standard deviation. The significance of P = 0.01 was compared with the control group by the Student's t-test.

As shown in Table 12, the antacids of Examples 1 and 2 in anti-ulcer experiments on ulcers induced by anhydrous ethanol were 65.6% and 67.9% of significant (P = 0.01) gastric mucosa, respectively, compared to the control group. Bleeding inhibitory effect was shown. On the other hand, the antacid of Comparative Example 1 showed only 29.2% bleeding inhibitory effect compared to the control.

11. Inhibitory effect of stress ulcer by immersion restraint

Rats fasted for 24 hours were orally administered with 13.5% sugar solution and the drugs of Examples 1, 2 and Comparative Example 1, respectively. After 30 minutes, the rats were placed in a stress cage, and the rats were immersed in the water bath, which had been previously adjusted to 23 ± 1 ° C., to immerse the rats to the chest.

After 7 hours of immersion, rats were killed by cervical spinal bone dissection, stomach was extracted, 10 ml of 3% formalin was injected into the lumen of the stomach, soaked in a container containing formalin and fixed for 10 minutes. The length of the ulcer (ulcer index) was measured, and the results are shown in Table 13 below.

Table 13 Comparison of the effects of antacids on gastric ulcer induced by water restraint in rats

Drug dosage (ml / 100g)  The number of animals Ulcer Index (mm) Control (sugar) 0.1 15 48.17 ± 3.78 Example 1 0.1 15 21.00 ± 3.60 Example 2 0.1 15 21.45 ± 3.44 Comparative Example 1 0.1 15 34.83 ± 3.31

However, each value is expressed as mean ± standard deviation. Compared with the control group by the student's t-test, the significance was P = 0.05.

As a result of inhibiting stress ulcer from Table 13, the antacids of Examples 1 and 2 showed 56.4% and 55.47% of ulcer inhibition effects, respectively, compared to the control group, and the antacid of Comparative Example 2 was 27.7%. Suppressed.

The antacid composition according to the present invention can be modified and applied in various forms within the scope of the technical idea of the present invention and is not limited to the above preferred examples. The present invention described above is not limited to the above examples because various substitutions, modifications and changes are possible to those skilled in the art without departing from the spirit of the present invention. Of course, it should be determined including the claims and equivalents as well as the claims described below.

As described above, the antacid composition according to the present invention has no layer separation of the formulation, no change in pH and properties, and has excellent anti-acid and mucosal coating ability and adsorption power without causing side effects such as constipation. And gastric mucosal bleeding.

Claims (4)

In the antacid composition, An antacid composition comprising diomagnate having antacid efficacy as an active ingredient. The method of claim 1, The antacid composition, at least one of a group consisting of methyl cellulose, xanthan gum, salts of carboxymethyl cellulose, gum arabic, hydroxypropyl cellulose, tragacanth, and polyvinylpyrrolidone as an increasing and stabilizing agent An antacid composition characterized by the above. The method of claim 1, The content of the diomagnate is 15 to 35% by weight, the antacid composition, characterized in that the content of the increasing and stabilizing agent is 10 to 30% by weight. The method according to claim 1 or 2, The carboxymethyl cellulose salt is carboxymethyl cellulose sodium antacid composition, characterized in that.