KR102659338B1 - A pharmaceutical composition for treating dry eye syndrome - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for the treatment of dry eye syndrome containing rebamipide as an active ingredient, which maintains a stable solution formulation even after long-term storage and at the same time effectively masks the inherent bitter taste of rebamipide, thereby significantly improving patient medication compliance. A pharmaceutical composition for treating dry eye syndrome is provided.

Description

Pharmaceutical composition for treating dry eye syndrome {A PHARMACEUTICAL COMPOSITION FOR TREATING DRY EYE SYNDROME}

The present invention relates to a pharmaceutical composition for treating dry eye syndrome. Specifically, it relates to a solution formulation containing rebamipide as an active ingredient, in which rebamipide, a poorly soluble drug, is completely dissolved in an aqueous solution and maintains a stable solution formulation without forming precipitates even during long-term storage. It has the characteristic of greatly improving patient compliance with medication by masking the bitter taste felt in the body.

Rebamipide, the active ingredient of the present invention, has the compound name [2-(4-chlorobenzoylamino)-3-(2-quinolon-4-yl)propionic acid] and has a structure represented by the following formula (I) .

[Formula I]

Rebamipide is known to have anti-inflammatory and anti-ulcer effects in the digestive tract by secreting mucin, a mucin, from the gastric mucosa, and is being developed and used as the first gastric ulcer treatment. Afterwards, it was found that by increasing goblet cells in the cornea and conjunctiva of the eye, it is effective in treating dry eye by protecting or stabilizing the cornea and conjunctiva by increasing mucus and tears, and an eye drop with the product name MUCOSTA was launched in 2011. It was released.

Although rebamipide is soluble in alkaline aqueous solutions, its solubility in neutral solutions is quite poor. For this reason, Mucosta eye drops are a suspension prepared using polyvinyl alcohol, and problems such as burning sensation, severe stinging, and blurred vision when administered to the eyes and the formation of sediment when stored for a long time have been reported. Research on solution formulations that minimize these problems has continued, and in International Patent Publication No. WO 2008/050896, polyvinyl alcohol is mixed with rebamipide in an aqueous solution to maintain a stable dispersion state without agglomerating fine particles. An aqueous suspension with improved suspendability is disclosed, and International Patent Publication No. WO 2009/154304 discloses an eye drop composition with good redispersibility and improved transparency by using amino sugar and a buffering agent.

In Korean Patent No. 1718733, which is a previous study by the present inventors, rebamipide was dissolved in water with a base, and then cyclodextrin was dissolved and the pH was adjusted to a specific pH to ensure that rebamipide was completely dissolved and that the solution was stable even after long-term storage. An aqueous solution that maintains its formulation has been developed. However, research on eye drop formulations for rebamipide to date, including previous research by the present inventors, has only focused on methods for reducing eye irritation, dissolving rebamipide, and reducing precipitate generation. No attention is paid to removing the unpleasant taste felt in the mouth after administration.

International Patent Publication WO 2008/050896 International Patent Publication WO 2009/154304 Republic of Korea Patent No. 1718733

Accordingly, in the process of researching a stable solution formulation (eye drops, etc.) containing rebamipide as an active ingredient, the present inventors found that part of the solution administered to the eye passed from the lacrimal duct (tear duct) to the lacrimal sac (lacrimal sac) and into the nasolacrimal duct (nasolacrimal duct). As it transitioned to a bitter taste, it was discovered that even though it was not administered orally, a bitter taste was felt, and research was conducted to eliminate this. As a result, it was confirmed that the stabilizer unexpectedly improved the effect of the flavoring agent and masked the bitter taste of rebamipide. and completed the present invention.

The present invention aims to provide a solution formulation containing rebamipide as an active ingredient, and specifically aims to improve patients' medication compliance by removing the bitter taste felt in the mouth after administration by using a combination of a stabilizer and a flavoring agent. Make it a problem to be solved.

In order to solve the above problems, the present invention discloses the following means.

The present invention relates to rebamipide or a pharmaceutically acceptable salt thereof; mating agent; It provides a pharmaceutical composition for treating dry eye syndrome, including a stabilizer.

In one embodiment, the mating agent is L-menthol, and the concentration may be 0.001 to 0.03 w/v%.

The stabilizer is edetic acid and its alkali metal salt, and its concentration may be 0.005 to 0.05 w/v%.

In addition, the pharmaceutical composition for treating dry eye syndrome of the present invention may further include one or more additives selected from solubilizers, buffers, isotonic agents, pH adjusters, preservatives, or stabilizers.

The solubilizing agent may be cyclodextrin or a cyclodextrin derivative.

Rebamipide, the active ingredient of the present invention, is an amino acid derivative of 2-(1H)-quinolinone and has a strong bitter taste. To improve this bitter taste, the use of a binder can be considered. However, rebamipide, a drug that is poorly soluble and has the characteristic of forming precipitates due to re-agglomeration, reduces the stability of the solution formulation depending on the type and amount of the binder. There is a risk of doing so.

However, in the present invention, the bitter taste of rebamipide was masked by using a coagulant and a stabilizer.

The rebamipide can be prepared by a conventionally known manufacturing method, and the 'pharmaceutically acceptable salt' includes sodium hydroxide, potassium hydroxide, trometamol (tris(hydroxymethyl)aminomethane), monoethanolamine, diethanolamine, It may be a salt formed with triethanolamine, diisopropanolamine, meglumine, etc.

The concentration of rebamipide contained in the pharmaceutical composition of the present invention is not particularly limited, but may be 0.5 to 2.0 w/v%, preferably 2.0 w/v%.

Mating agents used in the present invention include L-menthol, DL-Camphor, sorbitol solution, sucralose, dextrose, fructose, glucose, aspartame, acesulfame salt, saccharin salt, neotime, cyclamate salt, and tau. It may be one or more selected from the group consisting of martin, Monk fruit extract, and licorice extract, and is preferably L-menthol. Additionally, the concentration of the mating agent is 0.001 to 0.03 w/v%.

The stabilizer used in the present invention may be at least one selected from the group consisting of edetic acid, citric acid, metaphosphoric acid, pyrophosphoric acid, polyphosphoric acid, malic acid, tartaric acid, phytic acid and their alkali metal salts and hydrates thereof, preferably is an alkali metal salt of edetic acid. Additionally, the concentration of the stabilizer is 0.005 to 0.05 w/v%.

The pharmaceutical composition for treating dry eye syndrome of the present invention may further include a solubilizer, buffer, solubilizer, isotonic agent, pH adjuster, thickener, preservative, or sweetener.

The solubilizing agent may be a cyclodextrin or a cyclodextrin derivative, such as α-cyclodextrin, β cyclodextrin, γ cyclodextrin, methyl-substituted cyclodextrin, ethyl-substituted cyclodextrin, hydroxyalkyl-substituted cyclodextrin, and 2-cyclodextrin. Roxypropyl-β-cyclodextrin, 2-hydroxypropyl-γ-cyclodextrin, alkyl ether cyclodextrin, branched cyclodextrin, cationic cyclodextrin, quaternary ammonium cyclodextrin, anionic cyclodextrin, amphoteric cyclodextrin, sulfo It may be one selected from the group consisting of butyl ether β-cyclodextrin, sulfoalkyl ether β-cyclodextrin or a modified form thereof, and mixtures thereof. In the present invention, the solubilizing agent forms an inclusion compound with rebamipide, thereby maintaining the medicinal efficacy of rebamipide and maintaining a transparent solution state.

The buffering agent may be a buffering agent commonly used in the field of ophthalmic preparations, for example, phosphate, citrate, acetate, bicarbonate, carbonate, gluconate, lactic acid, propionate, TRIS, basic amino acid. (arginine, lysine, histidine), borate, or borax can be used.

The solubilizing agent may be a solubilizing agent commonly used in the field of ophthalmic preparations, for example, polymers such as polyvinylpyrrolidone, macrogol (polyethylene glycol), polyvinyl alcohol, and hydroxypropylmethylcellulose; Surfactants such as polysorbate, polyoxyethylene hydrogenated castor oil, and polyoxyethylene polyoxypropylene; polyhydric alcohols such as propylene glycol; Organic acids such as benzoic acid and sorbic acid; Amino acids such as alginic acid, histidine, glycine, and lysine; And, xanthine derivatives such as caffeine can be used.

The isotonic agent may be an isotonic agent commonly used in the field of ophthalmic preparations, for example, an alkali metal halide such as sodium chloride, potassium bromide, lithium bromide, sodium iodide or sodium bromide, or a non-isotropic agent such as bromide. Chlorinated ionic compounds; Alternatively, non-ionic compounds such as urea, glycerol, glycerin, sorbitol, mannitol, propylene glycol, polyethylene glycol, or dextrose can be used.

The pH adjuster may be a pH adjuster commonly used in the field of ophthalmic preparations, for example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, hydrochloric acid, citric acid, boric acid, sodium dihydrogen phosphate, or monohydrogen phosphate. Sodium, etc. can be used.

The thickener may be a thickener commonly used in the field of ophthalmic preparations, for example, polyvinylpyrrolidone, hydroxypropylmethylcellulose, polyvinyl alcohol, or xanthan gum.

The preservative may be a preservative commonly used in the field of ophthalmic preparations, for example, benzalkonium chloride, ethylparaben, methylparaben, or propylparaben.

The sweetener can be used as a sweetener that is soluble or soluble in the oral cavity and is commonly used in the pharmaceutical field. For example, sucralose, sucrose, dextrose, fructose, glucose, liquid glucose, or maltose can be used. there is.

The pharmaceutical composition for treating dry eye syndrome of the present invention is a transparent solution in which rebamipide is dissolved, and can be used in a formulation intended to administer rebamipide in a solution state, for example, as an injection or eye drop.

In the present invention, a pharmaceutical composition containing rebamipide as an active ingredient exhibits a dry eye syndrome treatment effect. More specifically, by effectively solubilizing rebamipide, it is in an aqueous solution state in which rebamipide is completely dissolved, and not only can it maintain a stable solution formulation without forming a precipitate without changing its content even when stored for a long period of time, but at the same time. By effectively masking the inherent bitter taste of rebamipide, it can be usefully used in medical settings by greatly improving patient medication compliance.

Figure 1 shows the results of electronic tongue analysis for Group 1 of the present invention.
Figure 2 shows the results of electronic tongue analysis for Group 2 of the present invention.

Hereinafter, the present invention will be described in detail by examples. However, the following examples only illustrate the present invention, and the content of the present invention is not limited to the following examples.

Examples 1 to 3. Preparation of aqueous solutions containing mating agents and stabilizers

1) Hydroxypropyl betadex, borax, D-mannitol, L-arginine, and sodium hydroxide were dissolved in water for injection.

2) The main ingredient, rebamipide, was dissolved in the preparation solution obtained in 1) above.

3) Sodium edetate hydrate, concentrated glycerin, and L-menthol were dissolved in the preparation solution obtained in 2) above.

4) The pH of the prepared solution obtained in step 3) above was adjusted to about 7.8 using citric acid hydrate.

5) Water for injection was added to the preparation obtained in step 4) in accordance with the preparation volume.

The specific content of the aqueous solution prepared according to the above method is shown in Table 1 below.

Ingredients (mg/mL) Example 1
(F2) Example 2
(F3) Example 3
(F4) Example 4
(F5) Example 5
(F7) Example 6
(F8) rebamipide 20.00 20.00 20.00 20.0 20.00 20.00 Hydroxypropyl Betadex 61.20 61.20 61.20 61.20 61.20 61.20 borax 0.1 0.1 0.1 0.1 0.1 0.1 D-mannitol 0.1 0.1 0.1 0.1 0.1 0.1 Concentrated glycerin 14.7 14.7 14.7 14.7 14.7 14.7 Sodium edetate hydrate 0.10 0.10 0.10 0.10 0.050 0.500 L-Menthol 0.015 0.030 0.100 0.300 0.030 0.030 L-arginine 0.1 0.1 0.1 0.1 0.1 0.1 citric acid hydrate Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount sodium hydroxide 3.00 3.00 3.00 3.00 3.00 3.00 water for injection Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount

Comparative Example 1. Preparation of an aqueous solution containing no coagulant or stabilizer

1) Hydroxypropyl betadex, borax, D-mannitol, L-arginine, and sodium hydroxide were dissolved in water for injection.

2) The main ingredient, rebamipide, was dissolved in the preparation solution obtained in 1) above.

3) Concentrated glycerin was dissolved in the preparation solution obtained in 2) above.

4) The pH of the prepared solution obtained in step 3) above was adjusted to about 7.8 using citric acid hydrate.

5) Water for injection was added to the preparation obtained in step 4) in accordance with the preparation volume.

Comparative Example 2. Preparation of aqueous solution without mating agent

1) Hydroxypropyl betadex, borax, D-mannitol, L-arginine, and sodium hydroxide were dissolved in water for injection.

2) The main ingredient, rebamipide, was dissolved in the preparation solution obtained in 1) above.

3) Sodium edetate hydrate and concentrated glycerin were dissolved in the preparation solution obtained in 2) above.

4) The pH of the prepared solution obtained in step 3) above was adjusted to about 7.8 using citric acid hydrate.

5) Water for injection was added to the preparation obtained in step 4) in accordance with the preparation volume.

Comparative Example 3. Preparation of aqueous solution without stabilizer

1) Hydroxypropyl betadex, borax, D-mannitol, L-arginine, and sodium hydroxide were dissolved in water for injection.

2) The main ingredient, rebamipide, was dissolved in the preparation solution obtained in 1) above.

3) L-menthol and concentrated glycerin were dissolved in the preparation solution obtained in 2) above.

4) The pH of the prepared solution obtained in step 3) above was adjusted to about 7.8 using citric acid hydrate.

5) Water for injection was added to the preparation obtained in step 4) in accordance with the preparation volume.

The specific contents of the aqueous solutions prepared according to the methods of Comparative Examples 1 to 3 are shown in Table 2 below.

Ingredient name (mg/mL) Comparative Example 1
(C1) Comparative Example 2
(C2) Comparative Example 3
(C3) rebamipide 20.00 20.00 20.00 Hydroxypropyl Betadex 61.20 61.20 61.20 borax 0.1 0.1 0.1 D-mannitol 0.1 0.1 0.1 Concentrated glycerin 14.7 14.7 14.7 Sodium edetate hydrate - 0.10 - L-Menthol - - 0.030 L-arginine 0.1 0.1 0.1 citric acid hydrate Appropriate amount Appropriate amount Appropriate amount sodium hydroxide 3.00 3.00 3.00 water for injection Appropriate amount Appropriate amount Appropriate amount

Comparative Examples 4 to 7. Preparation of aqueous solution with adjusted contents of corrigant and stabilizer

1) Hydroxypropyl betadex, borax, D-mannitol, L-arginine, and sodium hydroxide were dissolved in water for injection.

2) The main ingredient, rebamipide, was dissolved in the preparation solution obtained in 1) above.

3) Sodium edetate hydrate, concentrated glycerin, and L-menthol were dissolved in the preparation solution obtained in 2) above.

4) The pH of the prepared solution obtained in step 3) above was adjusted to about 7.8 using citric acid hydrate.

5) Water for injection was added to the preparation obtained in step 4) in accordance with the preparation volume.

The specific content of the aqueous solution prepared according to the above method is shown in Table 3 below.

Ingredient name (mg/mL) Comparative Example 4
(F1) Comparative Example 5
(F6) Comparative Example 6
(F9) rebamipide 20.00 20.00 20.00 Hydroxypropyl Betadex 61.20 61.20 61.20 borax 0.1 0.1 0.1 D-mannitol 0.1 0.1 0.1 Concentrated glycerin 14.7 14.7 14.7 Sodium edetate hydrate 0.10 0.010 1.000 L-Menthol 0.001 0.030 0.030 L-arginine 0.1 0.1 0.1 citric acid hydrate Appropriate amount Appropriate amount Appropriate amount sodium hydroxide 3.00 3.00 3.00 water for injection Appropriate amount Appropriate amount Appropriate amount

Experimental Example 1. Confirmation of masking the bitter taste of rebamipid through electronic tongue

The eye drops prepared according to the methods and contents of the above Examples and Comparative Examples were diluted two-fold with distilled water, and then 100 mL of each diluted solution was placed in a beaker and measured for 120 seconds for each sample using an electronic tongue. The measurement was repeated 6 times, and the results for the 4 middle values were selected and indicated with dots at the bottom of the results, and the results are shown in Figures 1 and 2.

In the electronic tongue device, 7 sensors (AHS, sour taste; CTS, salty taste; NMS, savory taste; PKS, sweet taste; ANS, bitter taste; CPS; SCS) were selected and tested. In addition, in order to confirm that the combination of sodium edetate hydrate and menthol has an unexpected bitter taste masking effect, the eye drops prepared by the method and content of the above Examples and Comparative Examples were divided into two groups as follows and an electronic tongue experiment was performed. proceeded.

[Group 1] Comparative Example 1 (C1), Comparative Example 2 (C2), Comparative Example 3 (C3), Comparative Example 4 (F1), Example 1 (F2), Example 2 (F3), Example 3 ( F4), Example 4 (F5)

[Group 2] Comparative Example 1 (C1), Comparative Example 2 (C2), Comparative Example 3 (C3), Comparative Example 5 (F6), Comparative Example 6 (F9), Example 2 (F3), Example 5 ( F7), Example 6 (F8)

In the electronic tongue measurement results of Figures 1 and 2, the first main component (PC1) is an indicator that evaluates the overall taste, and the second main component (PC2) is an indicator that evaluates the auxiliary taste. As shown in Figure 1, which is the result for Group 1, in the positive direction based on PC1, Comparative Example 1 (C1), Comparative Example 2 (C2), Comparative Example 3 (C3), and Comparative Example 4 (F1), negative In the direction of Example 1 (F2), Example 2 (F3), Example 3 (F4), and Example 4 (F5), it was confirmed that the taste was clearly distinguished with a deviation of 86.595%, and based on PC2 It was confirmed that Comparative Examples 1 to 4 and Examples 1 to 4 had distinct tastes with a deviation of 12.778%. These results mean that masking the bitter taste is possible by combining menthol with sodium edetate.

In addition, as shown in Figure 2, which is the result for Group 2, in the positive direction based on PC1, Comparative Example 1 (C1), Comparative Example 2 (C2), Comparative Example 3 (C3), and Comparative Example 5 (F6) and Comparative Example 6 (F9), in the negative direction, it was confirmed that the taste was clearly distinguished with Example 2 (F3), Example 5 (F7), and Example 6 (F8) with a deviation of 84.642%, PC2 Based on , it was confirmed that Comparative Examples 1 to 3, Comparative Example 5, and Comparative Example 6 and Example 2, Example 5, and Example 6 had distinct tastes with a deviation of 14.666%. This result also means that, like Figure 1, it is possible to mask the bitter taste by combining menthol with sodium edetate.

The above results mean that in eye drops containing rebamipide as the main ingredient, sodium edetate hydrate, a stabilizer, can effectively mask the bitter taste of rebamipide by increasing the effect of menthol, a stimulant.

Since the pharmaceutical composition according to the present invention has a dry eye treatment effect, it can be used as a medicine in the pharmaceutical industry and medical fields.

Claims (5)

rebamipide; mating agent; and stabilizers,
The mating agent is L-menthol at 0.001 to 0.03 w/v%,
The stabilizer is 0.005 to 0.05 w/v% sodium edetate.
A pharmaceutical composition for treating dry eye syndrome that effectively masks the bitter taste of rebamipide. delete delete The pharmaceutical composition for treating dry eye syndrome according to claim 1, further comprising one or more additives selected from solubilizers, buffers, isotonic agents, pH adjusters, and preservatives. The method of claim 4, wherein the solubilizing agent is α-cyclodextrin, β cyclodextrin, γ cyclodextrin, methyl substituted cyclodextrin, ethyl substituted cyclodextrin, hydroxyalkyl substituted cyclodextrin, 2-hydroxypropyl-β -Cyclodextrin, 2-hydroxypropyl- γ-cyclodextrin, alkyl ether cyclodextrin, branched cyclodextrin, cationic cyclodextrin, quaternary ammonium cyclodextrin, anionic cyclodextrin, amphoteric cyclodextrin, sulfobutyl ether β A pharmaceutical composition for treating dry eye syndrome, which is selected from the group consisting of cyclodextrin, sulfoalkyl ether β-cyclodextrin or a modified form thereof, and mixtures thereof.