JP5753727B2 - Antacid composition - Google Patents

Description

  The present invention relates to an antacid composition comprising a magnesium-based antacid and precipitated calcium carbonate.

  The cause of symptoms such as heartburn, stomach pain, and stomach discomfort is often caused by gastric acid, and in gastrointestinal drugs, measures against gastric acid are an important issue. For this reason, most gastrointestinal drugs contain antacids that neutralize gastric acid secreted in the stomach and inactivate pepsin alone or in combination. However, when the stomach becomes alkaline due to the antacid, gastric acid secretion is increased, which is not preferable for treatment of ulcers, stomach pain and the like. For this reason, antacids that maintain gastric pH at weak acidity and have a long duration are considered to be excellent in terms of therapeutic effect. Conventionally, antacids are used in various combinations in terms of antacid power, pH, duration, and the like. Currently used as antacids are aluminum antacids such as synthetic hydrotalcite, magnesium aluminate metasilicate, magnesium aluminate silicate, dry aluminum hydroxide gel, synthetic aluminum silicate, and natural aluminum silicate. Agents, magnesium antacids such as magnesium oxide, magnesium carbonate, magnesium silicate, magnesium hydroxide, sodium antacids of sodium bicarbonate, precipitated calcium carbonate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, volley ( Calcium antacids such as powder). In addition to antacids, gastrointestinal drugs contain anti-acetylcholine agents, local anesthetics, digestive agents, digestive enzymes, gastric mucosal repair agents (mucosal protective components), herbal medicine components, and the like (non-patent literature) 1).

SIC Co., Ltd. OTC Handbook 2002-03-From Basics to Applications-Academic Information Distribution Center Co., Ltd.

  Aluminum is a metal that is not necessary for maintaining the life of the human body.In recent years, although the causal relationship between dementia and aluminum is not clear, neurotoxicity occurs when aluminum enters the brain. Is regarded as a problem. Sodium is a metal necessary for maintaining the life of the human body, but excessive intake is not preferable in terms of hypertension.

In addition, when the gastric pH becomes alkaline due to the use of an antacid, gastric acid secretion becomes active, which is not preferable for treatment of ulcers, stomach pain, and the like.
Therefore, in the present invention, an antacid composition containing no aluminum or sodium is used, and the gastric pH is kept weakly acidic and an antacid composition having a long duration is provided.

  As a result of intensive studies, the present inventors have found that an antacid composition containing a magnesium-based antacid and precipitated calcium carbonate improves the above disadvantages, has a high antacid power, and has a gastric pH. Was found to be a combination that does not lead to alkalinity.

That is, the present invention relates to the following.
(1) An antacid composition comprising 200 to 400 mg of magnesium hydroxide and 900 to 1500 mg of precipitated calcium carbonate as the amount of administration (dose) per day.
(2) The antacid composition according to (1), which does not contain an aluminum-containing antacid and a sodium-containing antacid.

  As will be apparent from the examples described later, the antacid composition containing the magnesium-based antacid and precipitated calcium carbonate of the present invention has a high antacid effect without causing the pH in the stomach to become alkaline. . Further, the pharmaceutical composition of the present invention containing a funnel extract and cetraxate hydrochloride in an antacid composition containing a magnesium-based antacid and precipitated calcium carbonate has an additively high inhibition rate in various gastric injury models. Therefore, it exhibits a significant gastric damage inhibitory action and exhibits an excellent therapeutic effect.

  A composition containing magnesium hydroxide, precipitated calcium carbonate, funnel extract, and cetraxate hydrochloride, which is a specific example of the pharmaceutical composition in the present invention, rapidly accelerates gastric acid by magnesium hydroxide and precipitated calcium carbonate in the antacid composition. Neutralizes and improves unpleasant symptoms, relieves gastric pain with anti-acetylcholine funnel extract (analgesic / antispasmodic agent), and further removes gastric mucosa damaged by gastric mucosal repair agent (mucosal protective ingredient) cetraxate hydrochloride It is to be repaired and is extremely excellent as a gastrointestinal drug.

  The antacid composition and pharmaceutical composition of the present invention do not need to worry about aluminum neurotoxicity or sodium overdose. Therefore, the antacid composition and the pharmaceutical composition of the present invention are excellent as gastrointestinal drugs that are much safer, show an antacid effect, and exhibit excellent therapeutic effects such as gastritis and gastric ulcer.

FIG. 1 shows the results of a Fuchs test for each of the magnesium-based antacid and precipitated calcium carbonate according to the present invention, and the results of a Fuchs test for the antacid composition of the present invention.

  The present invention relates to an antacid composition containing a magnesium-based antacid and precipitated calcium carbonate. The present invention will be described in detail below.

  Examples of the magnesium-based antacid according to the present invention include magnesium hydroxide, magnesium oxide, magnesium carbonate, magnesium silicate and the like. You may use these individually or in combination of 2 or more types. Magnesium hydroxide has a large antacid power to neutralize stomach acid, and 1 g of magnesium hydroxide consumes about 340 mL of 0.1N hydrochloric acid, but the maximum value of pH by Fuchs test is as high as about 9 There are too many drawbacks. 1 g of magnesium oxide is about 480 mL of consumption of 0.1N hydrochloric acid, but the maximum value of pH by the Fuchs test is about pH 9, and 1 g of magnesium carbonate is about 210 mL of consumption of 0.1N hydrochloric acid. However, the maximum value of pH by the Fuchs test is about pH 8, and 1 g of magnesium silicate is about 115 mL of consumption of 0.1N hydrochloric acid, but the maximum value of pH by the Fuchs test is about pH 7 It is.

  Further, the precipitated calcium carbonate according to the present invention has a moderate antacid power to neutralize stomach acid, and 1 g of precipitated calcium carbonate is about 200 mL of consumption of 0.1 N hydrochloric acid, and the maximum pH value by Fuchs test. Has a pH of 5.8.

  In the Fuchs test, a sample per dose was added to 50 ml of 0.1N hydrochloric acid maintained at 37 ° C. ± 2 ° C., and the pH was measured 10 minutes while stirring with a stirrer. Is added every 10 minutes and the pH is measured every 10 minutes, and the duration of the antacid effect is the time until the pH reaches 3.0 or less.

  In the antacid composition of the present invention, the blending amount of the magnesium-based antacid and precipitated calcium carbonate is such that the pH after 7.0 minutes of the test in the Fuchs test is 7.0 or less, preferably 6.0 or less. As such, it may be determined and determined as appropriate.

  In the antacid composition of the present invention, when magnesium hydroxide is used as the magnesium-based antacid, the daily dosage (dose) or compounding amount (hereinafter abbreviated as daily dose) of magnesium hydroxide. If it is less than 500 mg, the pH in the stomach does not become alkaline, which is preferable. More preferably, it is 20-400 mg, More preferably, it is 200-400 mg. The weight ratio of magnesium hydroxide to precipitated calcium carbonate is preferably 1: 1 to 1:10, more preferably 1: 2 to 1: 5. When the weight ratio of magnesium hydroxide is small and the weight ratio of precipitated calcium carbonate is large (greater than 1:10), the pH is 7 or less, but the antacid power is reduced, and further, the precipitated calcium carbonate is blended. Increasing the amount is not preferable because the formulation becomes large and difficult to take. Specifically, in the antacid composition comprising magnesium hydroxide and precipitated calcium carbonate of the present invention, it is preferable to blend 200 to 400 mg of magnesium hydroxide and 500 to 2000 mg of precipitated calcium carbonate as a daily dose. More preferably, 300 mg of magnesium hydroxide and 900-1500 mg of precipitated calcium carbonate are blended, more preferably 300 mg of magnesium hydroxide and 1200 mg of precipitated calcium carbonate.

  In the antacid composition of the present invention, when magnesium hydroxide is used as the magnesium-based antacid and the weight ratio of magnesium hydroxide to precipitated calcium carbonate is 1: 4, that is, magnesium hydroxide is used as a daily dose. When 300 mg and 1200 mg of precipitated calcium carbonate are used, the antacid power is about 350 ml / day, the pH is 6.5, and the duration of the antacid effect at pH 3.0 or more is about 40 minutes. The antacid power defined by the gastrointestinal drug manufacturing approval standards for pharmaceutical products (the antacid power of the daily preparation is 150 mL or more as a consumption of 0.1N hydrochloric acid) and the pH of the preparation (pH 3.5 or more) Satisfied. In the antacid composition of the present invention, a calcium-based antacid other than precipitated calcium carbonate such as calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, and borei (powder) is blended within the range that does not hinder the effects of the present invention. May be.

  The antacid composition of the present invention can further contain other medicinal ingredients. In the present invention, the antacid composition of the present invention further blended with other medicinal ingredients is referred to as the pharmaceutical composition of the present invention. Further, the medicinal ingredients that can be added include one or a combination of two or more selected from anti-acetylcholine agents, local anesthetics, digestive agents, digestive enzymes, gastric mucosal repair agents (mucosal protective components), herbal medicine components, etc. Can do. Examples of anti-acetylcholine agents include funnel extract, butylscopolamine bromide, methylbenactidium bromide, timepidium bromide, pirenzepine, isopropamide iodide, and local anesthetics such as ethyl aminobenzoate and oxesazein. Examples of the digestive agent (bile agent) include ursodeoxycholic acid, animal gall (bear gall, bovine gall), etc., and examples of the digestive enzyme include starch digestive enzymes (biodiastase, hawk). Diastase), fat digestive enzyme (lipase) and the like, and gastric mucosa repairing agent (mucosal protective component) includes copper chlorofin sodium, copper chlorofin potassium, aldioxa, methylmethionine sulfonium chloride, sucralfate, cetraxate hydrochloride, Sofalcon, Gefarna , Trimebutine maleate, sodium azulensulphonate, etc., and herbal ingredients include asenyaku, aniseed fruit, aloe, fennel, turmeric, ubai, oyakaku, engosaku, life-prolonging grass, oxon, oak, auren, processed oak , Gadgets, cuckoo, calamus root, citrus, licorice, pheasant, kujin, keihi, katsumeshi, gentiana, gennoshouko, kojin, koboku, goshuyu, cucumber, quintuplet, colombo, kondurango, hawthorn, salamander, yamana, peony, peony , Syougyo, Suzuzuku, Blue skin, Red bud 柏, Stone root, Centaurium grass, Sunburst, Soujyu, Souyou, Daisatsuka, Daiou, Chikutsujinjin, Clove, Chimpi, Pepper, Spruce, Nigaki, Nikuzuku, Nin Mint, mint, mint, peanut, hops, honey, rape leaves, mokko, yakchi, bay bait, ryutan, and ryokyoku, and extracts of these proofs. It is not limited to. In the present invention, among the above exemplified components, an anti-acetylcholine agent, a gastric mucosal repair agent (mucosal protective component), and a herbal medicine component are preferable as blending components. When a funnel extract is blended as an antiacetylcholine agent, the daily dose is preferably 6 to 60 mg, more preferably 6 to 30 mg, and even more preferably 30 mg. In addition, when cetraxate hydrochloride is added as a gastric mucosal repair agent (mucosal protective component), the daily dose is preferably 100 to 2000 mg, more preferably 200 to 800 mg, and even more preferably 600 mg.

  The antacid composition and pharmaceutical composition of the present invention are preferably administered orally. Although it is possible to take a simple mixture of each component according to the present invention, in consideration of ease of taking, tablets, capsules, troches, powders, granules, fine granules, suspensions It is preferable to formulate into a dosage form suitable for oral administration such as a syrup. In the present invention, capsules, pills, tablets, troches, powders, granules, and fine granules are preferred as dosage forms.

  Formulation can be performed by a known method. That is, a known formulation additive is appropriately added to the components of the antacid composition or the pharmaceutical composition of the present invention, and the capsule is prepared by, for example, the method described in the General Formulation of the 14th revised Japanese Pharmacopoeia. , Pills, tablets, troches, powders, granules, fine granules and the like can be formulated into dosage forms suitable for oral administration.

  Examples of the formulation additive include an excipient, a disintegrant, a binder, a lubricant, a coloring agent, a flavoring agent, a sweetening agent, and a corrigent. Examples of the excipient include lactose, sucrose, starch, crystalline cellulose, light anhydrous silicic acid, erythritol and the like. Examples of the disintegrant include low-substituted hydroxypropylcellulose, carmellose, carmellose calcium, and croscarmellose sodium. Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone and the like. Examples of the lubricant include magnesium stearate, calcium stearate, talc, and sucrose fatty acid ester. Examples of flavoring agents include oranges, lemons and various fragrances. Examples of the sweetening agent include aspartame, stevia, thaumatin, sodium saccharin, dipotassium glycyrrhizinate and the like. Examples of the corrigent include L-menthol, camphor, mint, sodium L-glutamate, disodium inosinate, magnesium chloride and the like. In addition, a formulation additive is not limited only to these exemplary components. What is necessary is just to add a formulation additive in a suitable process suitably in the case of formulation.

  The antacid composition and the pharmaceutical composition of the present invention are used as a gastrointestinal disease preventive or therapeutic agent, specifically, a gastrointestinal agent. Indications include: gastritis, stomach sag, stomach pain, overdose, stomach discomfort, stomach fullness, stomach weight, chest grip, heartburn, belching, rash (nausea, nausea, hangover Irritability), vomiting, hyperacidity, loss of appetite (decreased appetite), indigestion, weakness of stomach, overeating, and the like.

  Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to the examples.

Test Example 1: Fuchs test 50 ml of 0.1N hydrochloric acid is placed in a 300 ml beaker, immersed in a constant temperature bath at 37 ± 2 ° C., a pH meter electrode is inserted, each sample per dose is added, and a stirrer is used. The pH after 0.5 minutes, 1 minute, 5 minutes, and 10 minutes was measured with stirring. After 10 minutes, 2 ml of 1N hydrochloric acid was added every 10 minutes, and the pH was measured every 10 minutes.

  The results are shown in FIG. As is apparent from the upper graph of FIG. 1, in the case of magnesium hydroxide alone, if it is 400 mg / day or less, it is neutralized to 50 mL of the initial 0.1N hydrochloric acid and the pH does not increase, but 500 mg / day or more. Then, it became alkaline around pH 9. Precipitated calcium carbonate alone has a longer duration depending on the blending amount, but the pH does not depend on the blending amount and is around a slightly acidic pH of 6. As is apparent from the lower graph of FIG. 1, when magnesium hydroxide and precipitated calcium carbonate are used in combination, if the amount of magnesium hydroxide is less than 500 mg / day, the pH does not become alkaline, and 500 mg / Above the daily dose, the pH was around 9.

Test Example 2: Various types of gastric damage inhibitory action 2-1 Experimental material animals: Male Crj: CD rats (SPF) (weight 196 to 240 g) were used. Rats were fasted for approximately 22 hours or more before the start of the experiment and after grouping. In addition, water intake was free, and water was drained after grouping.
Test substances: cetraxate hydrochloride, funnel extract triple powder, precipitated calcium carbonate, magnesium hydroxide, synthetic hydrotalcite, sodium bicarbonate and funnel extract were suspended in 5% gum arabic solution. When two or more kinds of drugs were used together, they were mixed and suspended. Each drug was orally administered at a rate of 1 mL per 200 g of rat body weight. In the control group, only the solvent was orally administered in the same volume.
Indomethacin suspension: The required amount of indomethacin was weighed and then suspended in a 0.5% methylcellulose solution so as to be 6 mg / mL.
Administration formula: 8 to 10 animals were used per group, and divided into the following 5 groups. Table 1 shows the dosage of each drug per kg body weight of the rat in each dosage formulation.

Administration medium: 5% gum arabic a): 5% gum arabic, b): cetraxate hydrochloride, c): precipitated calcium carbonate, d): magnesium hydroxide, e): funnel extract tripled, f): synthetic hydrotal Site, g): sodium bicarbonate, h): funnel extract

2-2 Experimental method (1) Inhibitory effect on indomethacin gastric damage A test substance was orally administered, and 30 minutes later, an indomethacin suspension (30 mg / kg, 5 mL / kg) was subcutaneously administered to the back. Seven hours after administration of indomethacin, the rats were euthanized by cervical dislocation and the stomach was removed. The excised stomach was filled with 10 mL of physiological saline and fixed in the next day by immersing it in 10% neutral buffered formalin. After fixation, an incision was made along the large hemorrhoid, and after light washing in physiological saline, the presence or absence of ulcer occurrence was observed and the length of the ulcer was measured.

(2) Inhibitory action on ethanol gastric damage The test substance was orally administered, and ethanol (5 mg / kg) was orally administered 30 minutes later. One hour after ethanol administration, the rats were euthanized by cervical dislocation and the stomach was removed. The excised stomach was filled with 10 mL of physiological saline and fixed in the next day by immersing it in 10% neutral buffered formalin. After fixation, an incision was made along the large hemorrhoid, and after light washing in physiological saline, the presence or absence of ulcer occurrence was observed and the length of the ulcer was measured.

(3) Suppressive action against water-damaged stress gastric damage Oral administration of test substance, 30 minutes later, put into a restraining stainless steel cage (4.5 x 4.5 x 18 cm, 10 stations) in a 23 ° C water bath Soaked into the chest xiphoid process. Seven hours after water immersion, the rats were euthanized by cervical dislocation and the stomach was removed. The excised stomach was filled with 10 mL of physiological saline and fixed in the next day by immersing it in 10% neutral buffered formalin. After fixation, an incision was made along the large hemorrhoid, and after light washing in physiological saline, the presence or absence of ulcer occurrence was observed and the length of the ulcer was measured.

2-3 Statistical treatment The ulcer coefficient and the inhibition rate data were expressed as mean ± standard error and mean value of 10 animals per group, respectively. Statistical significance was examined by Bartlett's test and Dunnet's test and judged to be significant when p <0.01 and p <0.05, respectively.

2-4 Experimental results The experimental results are shown in Tables 2-4. As is clear from the results, in all gastric damage models of indomethacin gastric damage, ethanol gastric damage and water immersion restraint stress gastric damage, the antacid composition of the present invention contains an antiacetylcholine agent (roth extract; analgesic / antispasmodic agent). Or the three-drug combination administration group (pharmaceutical composition administration group of the present invention) combined with a gastric mucosal repair agent (cetraxate hydrochloride) suppressed gastric damage. In particular, ethanol gastric damage was significantly suppressed. In addition, a four-drug combination administration group (pharmaceutical composition administration group of the present invention) in which an antiacetylcholine agent (rout extract; analgesic / antispasmodic agent) and a gastric mucosal repair agent (cetraxate hydrochloride) are used in combination with the antacid composition of the present invention Significantly suppressed indomethacin gastric damage, ethanol gastric damage, and water immersion restraint stress gastric damage. On the other hand, an antacid composition (a combination of an antacid containing aluminum and sodium; an antacid composition composed of synthetic hydrotalcite and sodium hydrogen carbonate) different from the present invention and an anti-acetylcholine agent (rout extract; analgesic) -The anti-spastic agent) and the gastric mucosal repair agent (cetraxate hydrochloride) combined administration group of the four drugs was suppressed in any gastric injury model, but in the water immersion restraint stress gastric injury, the pharmaceutical composition of the present invention was administered The group was better. Therefore, the pharmaceutical composition of the present invention not only has an excellent gastric damage inhibitory action, but also does not contain aluminum and sodium, so there is no need to worry about aluminum neurotoxicity or excessive sodium intake.

Formulation Example 1 Tablet (1) 405.0 g of cetraxate hydrochloride, 112.5 g of erythritol, 265.5 g of corn starch, 94.5 g of low-substituted hydroxypropylcellulose and 20.25 g of hydroxypropylcellulose are placed in a stirring granulator, After mixing for 3 minutes, 178 mL of purified water was added and kneaded for 1.5 minutes. After kneading, the mixture was pulverized with a comil and placed in a fluidized bed granulator and dried. After drying, the obtained granulated product was sieved with a 1000 μm sieve to obtain outer layer granules A.

(2) 810.0 g of precipitated calcium carbonate, 202.5 g of magnesium hydroxide, 22.28 g of corn starch, 108.0 g of low-substituted hydroxypropylcellulose and 37.13 g of hydroxypropylcellulose are weighed and placed in a stirring granulator. After mixing for 4 minutes, 444 mL of purified water was added and kneaded for 2 minutes. After kneading, it was pulverized with a com mill, put into a fluid bed granulator, and dried. After drying, the resulting granulated product was sieved with a 1000 μm sieve to obtain outer layer granules B.

(3) Outer layer granule A 3591.0 g, outer layer granule B 4720.0 g, menthol 20 times powder (1 part by weight of L-menthol and 1 part by weight of light anhydrous silicic acid were added to 8 parts by weight of corn starch, and mixed in a V-type mixer. Thereafter, 86.4 g of the product pulverized with a sample mill) and 108.0 g of magnesium stearate were added and mixed to obtain outer layer granules.

(4) Roto extract triple powder 243.0 g, erythritol 216.0 g, corn starch 513.0 g, low-substituted hydroxypropylcellulose 121.5 g, hydroxypropylcellulose 54.0 g and aspartame 54.0 g, and stirring granulation After putting in the machine and mixing for 3 minutes, 81 mL of 99% unmodified ethanol was added and kneaded for 3 minutes. After kneading, it was put into a fluidized bed granulator and dried. After drying, the obtained granulated product was sieved with a 1000 μm sieve, 1202.0 g of this was weighed, and 13.5 g of magnesium stearate was added and mixed to obtain an inner layer granule.

(5) Using the granules obtained in (3) and (4) above, using a three-layer tableting machine, the weight of one tablet with a 9.5 mmφ 2 stage R punch, the first outer layer: 240 mg, the inner layer: 50 mg, Tableting was performed at the second outer layer: 110 mg and the total weight: 400 mg to obtain a three-layer tablet.

Formulation Example 2 Powder (1) Cetraxate hydrochloride 354.0 g, funnel extract triple powder 53.1 g, corn starch 419.98 g, erythritol 127.8 g, low-substituted hydroxypropylcellulose 35.99 g, hydroxypropylcellulose 52.86 g and 13.57 g of aspartame was weighed, put into a stirring granulator, mixed for 3 minutes, 147 mL of 99% unmodified ethanol was added and kneaded for 4 minutes. After kneading, the mixture was pulverized with a comil and placed in a fluidized bed granulator and dried. After drying, the obtained granulated material was sieved with a 500 μm sieve to obtain Powder A.

(2) Precipitated calcium carbonate 708.0 g, magnesium hydroxide 177.0 g, corn starch 89.21 g, erythritol 36.58 g, low-substituted hydroxypropylcellulose 30.68 g and hydroxypropylcellulose 20.06 g were stirred and granulated. After putting into the machine and mixing for 3 minutes, 185 mL of purified water was added and kneaded for 4 minutes. After kneading, the mixture was pulverized with a comil and placed in a fluidized bed granulator and dried. After drying, the obtained granulated material was sieved with a 500 μm sieve to obtain Powder B.

(3) Powder A4246.0g, Powder B4246.0g, and L-menthol (pulverized with a table pulverizer) 3.76g were weighed and mixed with a mixer for 15 minutes to obtain a powder.

  As is clear from the above examples, the antacid composition containing the magnesium-based antacid and precipitated calcium carbonate of the present invention has a high antacid effect without causing the pH in the stomach to become alkaline. . In addition, the pharmaceutical composition of the present invention has an additively high inhibition rate in various gastric damage models, exhibits a significant gastric damage inhibitory action, and exhibits an excellent therapeutic effect.

  The antacid composition and pharmaceutical composition of the present invention do not need to worry about aluminum neurotoxicity or sodium overdose. Therefore, the antacid composition and the pharmaceutical composition of the present invention are excellent as a gastrointestinal drug that is safer and exhibits excellent therapeutic effects such as gastritis and gastric ulcer.

Claims (2)

As daily dose (dose) amount consists magnesium hydroxide 200~400mg and precipitated calcium carbonate 900～1500Mg, characterized in that it does not contain an aluminum-containing antacids and sodium-containing antacids, antacid composition object. Administration of daily precipitated calcium carbonate (dose) amount is 1200 mg,請 Motomeko 1 antacid composition.

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