JP7499028B2 - Internal pharmaceutical composition - Google Patents

Description

The present invention relates to an oral pharmaceutical composition containing itopride and/or a salt thereof. More specifically, the present invention relates to an oral pharmaceutical composition in which the gastrointestinal motility stimulating effect of itopride and/or a salt thereof is enhanced.

Itopride and its salts have an antagonistic effect on dopamine receptors and activate gastrointestinal motility by releasing acetylcholine, and are therefore used to improve gastrointestinal symptoms (abdominal distension, upper abdominal pain, loss of appetite, heartburn, nausea, vomiting, etc.) in functional dyspepsia and chronic gastritis. Patent Document 1 also reports that itopride and its salts have the effect of treating and/or preventing gastrointestinal dysfunction during drug administration.

However, it is generally known that taking oral medications (especially drugs absorbed from the small intestine) when gastrointestinal motility is reduced can inhibit drug absorption, and there is a risk of weakening the gastrointestinal motility activating effect. In particular, administration of itopride and/or its salts alone has the disadvantage that it does not sufficiently activate gastrointestinal motility, and gastrointestinal motility once reduced cannot be fully restored. Therefore, there is a need for the development of a formulation that enhances the gastrointestinal motility activating effect of itopride and its salts.

On the other hand, antacids are drugs that neutralize the acid in the stomach and increase the pH level therein, and are known to have an inhibitory effect on gastrointestinal motility (e.g., Non-Patent Document 1). Conventionally, it has been thought that the combined use of a gastrointestinal motility enhancer and an antacid weakens the gastrointestinal motility activating effect.

Aryeh H et al., Gastroenterology 71; pp. 268-273, 1976

JP 2000-212091 A

The present invention aims to provide an oral pharmaceutical composition that enhances the gastrointestinal motility stimulating effect of itopride and/or its salts.

The present inventors conducted extensive research to solve the above problems and found that the gastrointestinal motility activating effect of itopride and/or its salts can be dramatically enhanced by using itopride and/or its salts in combination with an antacid in an oral pharmaceutical composition. Antacids are known to have no effect on gastrointestinal motility, but rather to have an inhibitory effect on gastrointestinal motility, so the finding that an antacid enhances the gastrointestinal motility activating effect of itopride and/or its salts is extremely unexpected. The present invention was completed based on this finding and through further research.

That is, the present invention provides the following aspects.
Item 1. A pharmaceutical composition for oral administration comprising (A) itopride and/or a salt thereof, and (B) an antacid.
Item 2. The pharmaceutical composition for internal use according to Item 1, comprising 1 to 5,000 parts by weight of the component (B) per 100 parts by weight of the component (A).
Item 3. The pharmaceutical composition for internal use according to Item 1 or 2, wherein the component (B) is sodium bicarbonate.
Item 4. A method for enhancing the gastrointestinal motility activating effect of itopride and/or a salt thereof, comprising:
A method for enhancing gastrointestinal motility activating effect, comprising blending an antacid together with itopride and/or a salt thereof in an oral pharmaceutical composition.

According to the oral pharmaceutical composition of the present invention, the gastrointestinal motility stimulating effect of itopride and/or its salt can be dramatically enhanced by combining itopride and/or its salt with an antacid.

FIG. 1 shows the results of evaluating the gastrointestinal motility activating effect in rats in which gastric motility was reduced by administration of clonidine hydrochloride in Test Example 1.

1. Oral Pharmaceutical Composition The oral pharmaceutical composition of the present invention is characterized by containing itopride and/or a salt thereof (sometimes referred to as "ingredient (A)"), and an antacid (sometimes referred to as "ingredient (B)"). The oral pharmaceutical composition of the present invention will be described in detail below.

[(A) Itopride and/or its salt]
The pharmaceutical composition for internal use of the present invention contains itopride and/or a salt thereof as component (A). Itopride is a known compound that acts on dopamine receptors to promote the release of acetylcholine and inhibits the decomposition of acetylcholine, thereby activating gastrointestinal motility.

The salts of itopride are not particularly limited as long as they are pharma- ceutically acceptable, but examples thereof include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, nitrate, and phosphate; and organic acid salts such as acetate, maleate, fumarate, malate, citrate, oxalate, lactate, and tartrate. Among these salts, inorganic acid salts are preferred, and hydrochloride is more preferred.

In the oral pharmaceutical composition of the present invention, one of itopride and its salts may be selected as component (A) and used alone, or two or more of them may be used in combination.

Among the components (A), salts of itopride are preferred, and itopride hydrochloride is more preferred.

The content of component (A) in the internal pharmaceutical composition of the present invention may be appropriately set depending on the dosage form, dosage amount, etc., but may be, for example, 0.1 to 90% by weight, preferably 1 to 30% by weight, and more preferably 2 to 10% by weight.

[(B) Antacids]
The pharmaceutical composition for internal use of the present invention contains an antacid as component (B). By using itopride and/or a salt thereof in combination with an antacid, the gastrointestinal motility stimulating effect of itopride and/or a salt thereof can be dramatically enhanced.

Antacids are drugs that neutralize gastric acid. There are no particular limitations on the type of antacid used in the present invention, but examples include sodium hydrogen carbonate, magnesium aluminometasilicate, magnesium aluminometasilicate, magnesium silicate, synthetic aluminum silicate, aluminum sucrose sulfate, dried aluminum hydroxide gel, magnesium alumina hydroxide, aluminum hydroxide gel, magnesium hydroxide, magnesium oxide, magnesium carbonate, precipitated calcium carbonate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate hydrate, squid bone, stone jelly, borei, synthetic hydrotalcite, aminobutyric acid, dihydroaluminum aminoacetate, aluminum hydroxide/sodium hydrogen carbonate co-precipitation product, aluminum hydroxide/magnesium carbonate mixed dry gel, aluminum hydroxide/magnesium carbonate/calcium carbonate co-precipitation product, glycine, dihydroxyaluminum aminoacetate, and Scolytem extract. These antacids may be used alone or in combination of two or more.

Among the (B) components, sodium bicarbonate is preferred from the viewpoint of more effectively enhancing the gastrointestinal motility stimulating effect of itopride and/or its salts.

In addition, in the oral pharmaceutical composition of the present invention, the ratio of component (A) to component (B) may be, for example, 100 to 10,000 parts by weight of the total amount of component (B) per 100 parts by weight of component (A). From the viewpoint of further enhancing the gastrointestinal motility activating effect of itopride and/or a salt thereof, the total amount of component (B) is preferably 500 to 5,000 parts by weight, more preferably 1,000 to 3,500 parts by weight, per 100 parts by weight of component (A).

The content of component (B) in the oral pharmaceutical composition of the present invention may be set appropriately according to the type, dosage form, and dosage of component (B) used within the range according to the ratio of components (A) and (B) described above, and may be, for example, 10 to 99.9% by weight, preferably 50 to 99% by weight, and more preferably 70 to 98% by weight.

[Other ingredients]
The internal pharmaceutical composition of the present invention may contain other pharmacological ingredients, if necessary, in addition to the above-mentioned ingredients. The type of such pharmacological ingredients is not particularly limited, and examples thereof include anti-inflammatory analgesics, digestive agents, antispasmodics, mucosal repair agents, astringents, antiemetics, antitussives, expectorants, anti-inflammatory enzymes, hypnotic sedatives, antihistamines, cardiac diuretics, antibacterial agents, vasoconstrictors, vasodilators, local anesthetics, proton pump inhibitors, herbal medicines, herbal extracts, caffeines, menthols, polyphenols, etc. These pharmacological ingredients may be used alone or in combination of two or more kinds. The content of these pharmacological ingredients may be appropriately set according to the type of pharmacological ingredients used and the dosage form of the internal pharmaceutical composition.

The pharmaceutical composition of the present invention may contain pharma- ceutically acceptable bases and additives, etc., as necessary, in order to prepare the pharmaceutical composition into a desired dosage form. Examples of such bases and additives include excipients, binders, disintegrants, lubricants, isotonicity agents, plasticizers, dispersants, emulsifiers, solubilizers, wetting agents, stabilizers, suspending agents, adhesives, coating agents, glossing agents, water, oils and fats, waxes, hydrocarbons, fatty acids, higher alcohols, esters, water-soluble polymers, surfactants, lower alcohols, polyhydric alcohols, pH adjusters, buffers, antioxidants, UV protection agents, preservatives, flavorings, fragrances, powders, thickeners, dyes, chelating agents, etc. These bases and additives may be used alone or in combination of two or more. The content of these bases and additives may be appropriately set according to the type of additive used and the dosage form of the pharmaceutical composition for internal use.

[Dosage form]
The dosage form of the internal pharmaceutical composition of the present invention is not particularly limited, and may be any of a solid preparation, a semi-solid preparation, or a liquid preparation.

Specific examples of solid preparations include tablets, pills, capsules (soft capsules, hard capsules), powders, and granules (including dry syrups).Specific examples of semi-solid preparations include jellies.Specific examples of liquid preparations include solutions, suspensions, and syrups.

Among these dosage forms, solid formulations are preferred.

To prepare the oral pharmaceutical composition of the present invention in the above dosage form, the composition may be formulated according to the usual formulation methods used in the pharmaceutical field using component (A), component (B), and other pharmacological ingredients, bases, and additives that are added as necessary.

[Dosage and Administration]
The pharmaceutical composition for internal use of the present invention exerts an enhanced gastrointestinal motility activating effect of itopride and/or a salt thereof, and is therefore applicable to diseases and symptoms that can be prevented or improved by activating gastrointestinal motility, specifically, gastrointestinal symptoms (abdominal distension, upper abdominal pain, loss of appetite, heartburn, nausea, vomiting, etc.) and stomach pain in functional dyspepsia or chronic gastritis.

The dosage of the oral pharmaceutical composition of the present invention may be appropriately determined depending on the intended use, the age of the recipient, etc., but may be taken, for example, 1 to 3 times a day so that the daily dosage of itopride and/or its salt is about 1 to 300 mg, preferably about 50 to 150 mg, and more preferably about 100 to 150 mg.

2. Method for enhancing gastrointestinal motility activating effect The present invention further provides a method for enhancing the gastrointestinal motility activating effect of itopride and/or a salt thereof, which comprises blending an antacid together with itopride and/or a salt thereof in an oral pharmaceutical composition.

In the method for enhancing gastrointestinal motility activation, the types of ingredients used, the amounts of ingredients used, the dosage form of the oral pharmaceutical composition, etc. are as described in the above section "1. Oral pharmaceutical composition."

The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.

Test Example 1: Evaluation of gastric emptying ability Nine-week-old male rats (Slc: Wistar strain, Japan SLC Co., Ltd.) were divided into five groups (10 to 13 rats per group): an untreated group, a control group, and a test group (Example 1 and Comparative Examples 1 and 2). The rats in each group were kept for 5 days to 1 week for acclimation, and then the test was carried out under the following conditions.

Normal group: After fasting for approximately 24 hours, physiological saline (1 ml/kg) was administered subcutaneously. 10 minutes after the administration of physiological saline, 0.1% by weight aqueous solution of carboxymethylcellulose (hereinafter referred to as CMC solution) was orally administered at a dose of 5 ml/kg (rat body weight). 20 minutes after the administration of CMC solution, 1 ml of distilled water containing 100 glass beads (diameter 750-1000 μm) was orally administered. 60 minutes after the administration of the glass beads, the stomachs of the rats were removed and the glass beads remaining in the stomach were counted to determine the gastric emptying rate.

- Control group: After fasting for about 24 hours, clonidine hydrochloride (4 μg/kg; administered volume: 1 ml/kg), which has a gastrointestinal motility inhibitory effect, was administered subcutaneously. 10 minutes after administration of clonidine hydrochloride, CMC solution was orally administered at a dose of 5 ml/kg (rat body weight). 20 minutes after administration of CMC solution, 1 ml of distilled water containing 100 glass beads (diameter 750-1000 μm) was orally administered. 60 minutes after administration of the glass beads, the stomachs of the rats were removed, and the glass beads remaining in the stomach were counted to determine the gastric emptying rate.

Test group: After fasting for about 24 hours, clonidine hydrochloride (4 μg/kg; volume of administration solution: 1 ml/kg), which has a gastrointestinal motility inhibitory effect, was administered subcutaneously. 10 minutes after administration of clonidine hydrochloride, a test solution prepared by adding the components shown in Table 1 to CMC solution to give a prescribed dose was orally administered at a dose of 5 ml/kg (rat body weight). 20 minutes after administration of the test solution, 1 ml of distilled water containing 100 glass beads (diameter 750-1000 μm) was orally administered. 60 minutes after administration of the glass beads, the stomachs of the rats were removed, the glass beads remaining in the stomach were counted, and the gastric emptying rate was calculated.

The gastric emptying rate was calculated according to the following formula.

The results are shown in Figure 1. In the control group administered with clonidine hydrochloride, the gastric emptying rate was significantly lower than in the normal group, reproducing the pathological condition of reduced gastric motility. In Comparative Example 1, in which itopride hydrochloride was administered alone after clonidine hydrochloride administration, the gastric emptying rate was significantly higher than in the control group. In Comparative Example 2, in which sodium bicarbonate was administered alone after clonidine hydrochloride administration, the gastric emptying rate was equivalent to that of the control group. On the other hand, in Example 1, in which itopride hydrochloride and sodium bicarbonate were administered after clonidine hydrochloride administration, the gastric emptying rate was significantly higher than in Comparative Examples 1 and 2, demonstrating a significantly superior effect of improving gastric emptying function.

Granules having the compositions shown in Formulation Examples Tables 2 and 3, and a liquid preparation having the composition shown in Table 4 were prepared. These preparations exhibit a significantly superior gastrointestinal motility stimulating effect due to the synergistic action of itopride hydrochloride and an antacid.

Claims (2)

A pharmaceutical composition for internal use comprising (A) itopride and/or a salt thereof, and (B) sodium bicarbonate , the total amount of said component (B) being 500 to 5,000 parts by weight per 100 parts by weight of said component (A) . A method for enhancing the gastrointestinal motility activating effect of itopride and/or a salt thereof, comprising:
A method for enhancing gastrointestinal motility activating effect, comprising compounding 500 to 5,000 parts by weight of sodium hydrogen carbonate per 100 parts by weight of itopride and/or a salt thereof in an internal pharmaceutical composition together with itopride and/or a salt thereof.

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