Pharmaceutical composition

Abstract

To provide a technology that suppresses the strong bitter taste of rebamipide in various dosage forms of formulations. [Solution] A pharmaceutical composition containing rebamipide, an organic acid (excluding amino acids), and an amino acid.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition containing levamiside.

Background Art

[0002] Levamiside, as an oral preparation, increases the endogenous prostaglandin of the gastric mucosa and is used for the treatment of gastritis and gastric ulcer. Also, as an eye drop, it promotes the production of mucin which is a component of tears, stabilizes the state of tears, improves corneal epithelial disorders, and is used for the treatment of dry eye. Since levamiside has a particularly strong bitter taste, in oral preparations, mainly film-coated tablets are commonly used, and granules are used in film-coated preparations that mask the bitter taste of the active ingredient. OD tablets are also commercially available, but because they dissolve easily in the oral cavity, they are said to be difficult to drink due to a strong bitter taste. Also, tablets are a representative example of drugs that are not desirable to be crushed because they have a very strong bitter taste when crushed and dispensed. In eye drops, taste disorders are often seen. This is caused by levamiside migrating from the eye to the mouth through the nasolacrimal duct, and some people experience loss of appetite and nausea due to the bitter taste, which has become a major problem.

[0003] Various attempts have been devised to mask the particularly strong bitter taste of levamiside. Those obtained by coating levamiside granules with a higher fatty acid or a higher alcohol and a saccharide or a saccharide alcohol (Patent Document 1). Powders, fine granules or granules coated with a gastric-soluble polymer-containing composition and granulated (Patent Document 2). Those containing levamiside, L-arginine, and a sweetening agent (somatine, stevia, lacanca extract) and suppressing the bitter taste of levamiside (Patent Document 3).

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

[0005] However, these methods were devised for solid dosage forms and could not solve the problem of bitterness in liquid or eye drops. Therefore, there was a great need for the development of a technology to suppress the strong bitterness of rebamipide that could be applied not only to solid dosage forms but also to liquid and eye drops.

[0006] Therefore, the object of the present invention is to provide a technology for suppressing the strong bitter taste of rebamipide in various dosage forms of formulations. [Means for solving the problem]

[0007] Therefore, the inventors conducted diligent research and discovered that adding organic acids (excluding amino acids) and amino acids to rebamipide can suppress bitterness, thus completing the present invention.

[0008] In other words, the present invention provides the following inventions [1] to [6]. [1] A pharmaceutical composition containing rebamipide, organic acids (excluding amino acids), and amino acids. [2] The pharmaceutical composition according to [1], comprising 1-3 w / v% of rebamipide. [3] The pharmaceutical composition according to [1] or [2], wherein the organic acid is succinic acid and contains 0.1 to 3 w / v% succinic acid. [4] A pharmaceutical composition according to any one of [1] to [3], wherein the amino acid is glutamic acid and contains 0.01 to 0.5 w / v% of glutamic acid. [5] A pharmaceutical composition according to any one of [1] to [4], which is in liquid form. [6] A method for suppressing the bitter taste of rebamipide in a pharmaceutical composition, characterized by including an organic acid (except for amino acids) and an amino acid in the pharmaceutical composition containing rebamipide. [Effects of the Invention]

[0009] The present invention provides pharmaceuticals in which the bitterness of rebamipide is suppressed in various dosage forms. In particular, it can be applied to liquid formulations, where suppressing bitterness was previously difficult, and it is possible to provide pharmaceuticals that can prevent taste disturbances, a common side effect of eye drops. [Modes for carrying out the invention]

[0010] The pharmaceutical composition of the present invention comprises rebamipide, an organic acid (excluding amino acids), and an amino acid.

[0011] The rebamipide used in the pharmaceutical composition of the present invention has the molecular formula: C 19 H 15 ClN2O4 is a quinolinone derivative with a molecular weight of 370.79. As an oral medication, it increases endogenous prostaglandins in the gastric mucosa and is used to treat gastritis and gastric ulcers. Furthermore, as eye drops, it promotes the production of mucin, a component of tears, and stabilizes tear film, thereby improving corneal epithelial damage and thus being used to treat "dry eye."

[0012] The concentration of rebamipide in the pharmaceutical composition of the present invention is not particularly limited as it varies depending on the dosage form. However, for example, in the case of a liquid dosage form such as eye drops, it is preferably 1 to 3 w / v%, more preferably 1.5 to 2.5 w / v%, and particularly preferably 2 w / v%. In this specification, 1 w / v% means that 1 g of the component is contained per 100 ml.

[0013] The organic acids used in the pharmaceutical composition of the present invention are not particularly limited as long as they can be used in pharmaceutical compositions, but examples include monocarboxylic acid salts (e.g., acetic acid, trifluoroacetic acid, butyric acid, palmitic acid, stearic acid, etc.), polycarboxylic acids (e.g., fumaric acid, maleic acid, succinic acid, malonic acid, etc.), oxycarboxylic acids (lactic acid, tartaric acid, citric acid, etc.), and organic sulfonic acids (methanesulfonic acid, toluenesulfonic acid, tosylic acid, etc.). One or more of these organic acids can be used. Among these, in the pharmaceutical composition of the present invention, it is preferable to use polycarboxylic acids such as fumaric acid, maleic acid, succinic acid, and malonic acid, and succinic acid is particularly optimal in terms of its bitterness suppression effect. Note that the organic acids used in the present invention do not contain amino acids.

[0014] The concentration of the organic acid in the pharmaceutical composition of the present invention is not particularly limited as it varies depending on the dosage form. However, for example, in the case of a liquid dosage form such as eye drops, it is preferably 0.1 to 3 w / v%, and particularly preferably 0.5 to 2.5 w / v%.

[0015] The amino acids used in the pharmaceutical composition of the present invention are not particularly limited as long as they can be used in a pharmaceutical composition, but examples include alanine, aspartic acid, glutamic acid, and arginine. One or more of these amino acids can be used. Among these, glutamic acid and arginine are preferred, and glutamic acid is particularly preferred.

[0016] The concentration of amino acids in the pharmaceutical composition of the present invention is not particularly limited as it varies depending on the dosage form. However, for example, in the case of a liquid dosage form such as eye drops, it is preferably 0.01 to 0.5 w / v%, and particularly preferably 0.05 to 0.4 w / v%.

[0017] The mass ratio of organic acid to amino acid (organic acid / amino acid) in the pharmaceutical composition of the present invention is not particularly limited, but is preferably 1 to 40, more preferably 2 to 30, and particularly preferably 3 to 20.

[0018] In addition to the above levamiside, organic acid, and amino acid, the pharmaceutical composition of the present invention may also contain one or more pharmaceutical additives that can usually be used in pharmaceuticals, as long as they do not affect the bitter taste suppressing effect. Specific examples of these additives are described in the Pharmaceutical Additive Dictionary 2021 (edited by the Japan Pharmaceutical Additive Association, Yakujutsu Shimbunsha), Yakushokuhatsu 1204 No. 1 (Pharmaceutical Affairs Administrative Law), and the website of the Japan Pharmaceutical Additive Association (http: / / www.jpec.gr.jp / ).

[0019] Specific examples of the above pharmaceutical additives include, for example, in the case of a liquid eye drop, solubilizing agents such as povidone, buffering agents such as boric acid and tromethamine, amino sugars such as meglumine, and water.

[0020] The pharmaceutical composition of the present invention can be produced in various dosage forms by a usual method by adding other components to the above components as necessary. The production method is not limited.

[0021] The dosage form of the pharmaceutical composition of the present invention is not particularly limited as long as it can be taken by eye drops or orally to feel the bitterness of levamiside. For example, liquid forms such as eye drops and solutions, and solid forms such as tablets, capsules, and chewable tablets can be mentioned. Among these dosage forms, liquid forms such as eye drops and solutions are preferred, and eye drops are more preferred because they can prevent side effects of taste disorders.

[0022] The pharmaceutical composition of the present invention can be used for the pharmaceutical use of levamiside, for example, for the treatment of dry eye, gastritis, and gastric ulcer.

[0023] Preferred embodiments of the present invention include those containing the following components. (a) Levamiside, 1 to 3 w / v%, preferably 1.5 to 2.5 w / v%, more preferably 2 w / v% (b) Organic acid (excluding amino acids), 0.1 to 3 w / v%, preferably 0.5 to 2.5 w / v% (c) Amino acid, 0.01 to 0.5 w / v%, preferably 0.05 to 0.4 w / v%

[0024] A more preferred embodiment of the present invention includes the following components: (a) Rebamipide, 1-3 w / v%, preferably 1.5-2.5 w / v%, more preferably 2 w / v% (d) Succinic acid, 0.1-3 w / v%, preferably 0.5-2.5 w / v% (e) Glutamic acid, 0.01-0.5 w / v%, preferably 0.05-0.4 w / v%

[0025] The above preferred and more preferred embodiments are preferably in liquid form, and more preferably as eye drops.

[0026] The pharmaceutical composition of the present invention described above can suppress the bitter taste of rebamipide in the pharmaceutical composition by including organic acids (except amino acids) and amino acids in the pharmaceutical composition containing rebamipide.

[0027] Here, suppression of bitterness means, for example, that the bitterness of rebamipide felt when the liquid is taken as eye drops or orally is suppressed compared to when rebamipide is used alone, or that the bitterness output value of a taste recognition device, such as the one used in the examples, is reduced compared to when rebamipide is used alone. [Examples]

[0028] The present invention will now be described in more detail with reference to examples, but the present invention is not limited thereto.

[0029] Test Example 1 (Investigation of the effect of additives on suppressing bitterness) Eye drops with the compositions shown in Table 1 were prepared by mixing each component. These eye drops were used to measure the bitterness index using a taste recognition device (TS-5000Z, manufactured by Intelligent Sensor Technology Co., Ltd.). The results are shown in Table 1.

[0030] Using the values ​​obtained from the taste recognition device, the difference between Examples 1 and 2 and Comparative Example 1 was calculated based on the following formula.

number

[0031] [Table 1]

[0032] It was found that the bitterness of rebamipide was suppressed by combining it with succinic acid, an organic acid, and glutamic acid, an amino acid.

[0033] Examples 3-6 Eye drops with the compositions shown in Table 2 were prepared by mixing each component.

[0034] [Table 2]

[0035] These eye drops, like the eye drops in Examples 1 and 2, suppressed the bitter taste of rebamipide. [Industrial applicability]

[0036] This invention can be used in pharmaceuticals in which the bitter taste of rebamipide is suppressed.

Claims

1. A pharmaceutical composition containing rebamipide, organic acids (excluding amino acids), and amino acids.

2. The pharmaceutical composition according to claim 1, comprising 1 to 3 w / v% of rebamipide.

3. The pharmaceutical composition according to claim 1, wherein the organic acid is succinic acid, and the composition contains 0.1 to 3 w / v% succinic acid.

4. The pharmaceutical composition according to claim 1, wherein the amino acid is glutamic acid, and the composition contains 0.01 to 0.5 w / v% of glutamic acid.

5. A pharmaceutical composition according to any one of claims 1 to 4, wherein the composition is in liquid form.

6. A method for suppressing the bitter taste of rebamipide in a pharmaceutical composition, characterized by including an organic acid (excluding amino acids) and an amino acid in the pharmaceutical composition containing rebamipide.

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