JPH0127060B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing a stable aqueous solution of an aqueous azulene derivative. Examples of azulene derivatives expressed in plant essential oils include Chamazulene (1,4-dimethyl-7) obtained from Chamazu L essential oil.
-Ethyl azulene), Guaiazulene (1,
4-dimethyl-7-isopropyl azulene) are known, and are used as anti-inflammatory agents, but they are insoluble in water, so to make them water-soluble they must be used with a sulfonic acid group introduced at the 3-position. . Water-soluble azulene derivatives are usually used as eye drops.
It is used at a concentration of 0.01-0.02%, but it is easily degraded by light, and the most stable pH range is 7.5-8.5.
Preferred stabilizers include boric acid, borax, and sodium thiosulfate. In the production of aqueous preparations such as eye drops,
Cationic surfactants (e.g. benzalkonium chloride), chlorobutanol, phenylethyl alcohol, parabens, chlorhexidine, and thimerosal are commonly used as detergents; If it is added, it becomes cloudy or forms a precipitate, so it cannot be used. In addition, the stable range of chlorobutanol deviates from the stable range of water-soluble azulene derivatives at pH 6 or below, making it unsuitable. Furthermore, parabens and phenylethyl alcohol have an eye-irritating effect when instilled into the eyes, and parabens are undesirable because they are hydrolyzed at pH 7 or higher. Since thimerosal is a mercury compound, there are not only problems with industrial wastewater, but also social problems with its administration. Therefore, in the development of eye drops containing water-soluble azulene derivatives, there is no suitable antifungal agent. On the other hand, when commercially available eye drops containing water-soluble azulene derivatives are analyzed, parabens, phenylethyl alcohol, and thimerosal are detected, but these are used out of necessity because there are no other suitable ones. it is conceivable that. Therefore, the present inventors conducted repeated research to overcome this difficulty, and found that when cationic surfactants and chlorhexidine, which were considered unusable, were added together with a small amount of nonionic surfactant, the mechanism of action was unknown. However, it was discovered that a satisfactory formulation could be obtained that did not generate precipitates or turbidity, did not impair its protective efficacy, and did not cause eye irritation when instilled.Based on this knowledge, the authors continued their research and established the present invention. I was able to do that. The present invention provides a water-soluble azulene derivative characterized in that a cationic surfactant or chlorhexidine and a nonionic surfactant are added to an aqueous solution of 1,4-dimethyl-7-lower alkyl azulene-3-sulfonate. This is a method for producing a stable aqueous solution. Examples of 1,4-dimethyl-7-lower alkyl azulene-3-sulfonic acid include 1,4-
Examples include dimethyl-7-ethyl azulene-3-sulfonic acid and 1,4-dimethyl-7-isopropylazulene-3-sulfonic acid. Examples of the salts include sodium salts and potassium salts, and any pharmaceutically acceptable water-soluble salts may be used. Examples of the cationic surfactant include benzalkonium chloride, benzethonium chloride, and pyridinium chloride. The preferred concentration of cationic surfactant in aqueous solution is usually 0.005
~0.02 (w/v)%. Chlorhexidine may be a free base or a salt form such as its gluconate salt, and the salt may be any pharmaceutically acceptable water-soluble salt. The appropriate concentration of chlorhexidine is usually 0.001-0.02
(w/v)%. As the nonionic surfactant, preferably
HLB11 or higher is used, examples of which are:
Examples include polysorbate 80, polyoxyethylene octyl phenyl ether, and polyoxyl 40. The concentration of nonionic surfactants is usually 0.001
~0.5(w/v)%, preferably 0.02-0.25(w/v)%
v)%, which is much smaller than when using this type of surfactant as a water solubilizer. The sulfonate, cationic surfactant or chlorhexidine salt and nonionic surfactant in the present invention may be dissolved in water at the same time, or may be dissolved one after the other. Further, for example, boric acid, borax, sodium chloride, etc. may be added for isotonicity. Table 1 shows that sodium 1,4-dimethyl-7-isopropylazulene-3-sulfonate (hereinafter abbreviated as IAS) is added to purified water, a cationic surfactant or chlorhexidine is added as a detergent, and a nonionic surfactant is also added. This figure shows the appearance of formulations obtained by adding polysorbate 80 at various concentrations.

[Table] Represents lorhexidine〓
Table 2 shows sodium chloride 0.4%, boric acid 1.0%,
The results obtained by examining the appearance after freezing and thawing of a preparation prepared by adding IAS, a fungicide, and a nonionic surfactant as in the previous table to a solution of 0.25% borax dissolved in purified water are shown.

【table】

[Table] Examples of the present invention are shown above. Example 1 Sodium 1,4-dimethyl-7-isopropylazulene-3-sulfonate 0.02 g Sodium chloride 0.4 Boric acid 1.0 Borax 0.25 Sodium edetate 0.02 Polysorbate 80 0.07 Benzethonium chloride 0.005 Sterile and purified Add water and dissolve to make a total volume of 100ml.
Adjust the pH to approximately 7.5, filter aseptically, and fill it into an eye drop bottle to make eye drops. Example 2 Sodium 1,4-dimethyl-7-isopropylazulene-3-sulfonate 0.01 g Aminoethylsulfonic acid 0.5 Sodium chloride 0.3 Potassium chloride 0.15 Boric acid 1.0 Borax 0.25 Sodium edetate 0.01 Polysorbate 80 0.07 〃 Sodium thiosulfate 0.01 〃 Benzalkonium chloride 0.005〃 Add sterile purified water and dissolve to make a total volume of 100ml.
Then, in the same manner as in Example 1, eye drops are obtained. Example 3 Sodium 1,4-dimethyl-7-isopropylazulene-3-sulfonate 0.01 g Boric acid 1.0 Borax 0.25 Sodium chloride 0.4 Sodium edetate 0.01 Hydroquine ethyl cellulose 0.1 Polysorbate 80 0.1 Gluconic acid Add sterile purified water to over 0.005 chlorhexidine and dissolve to make a total volume of 100ml.
Then, in the same manner as in Example 1, eye drops are obtained.

Claims (1)

[Claims] 1. A water-soluble product characterized by adding a cationic surfactant or chlorhexidine and a nonionic surfactant to an aqueous solution of 1,4-dimethyl-7-lower alkyl azulene-3-sulfonate. A method for producing a stable aqueous solution of an azulene derivative. 2. The manufacturing method according to claim 1, wherein the nonionic surfactant is added to the aqueous solution at a concentration of 0.001 (w/v)% or more, preferably 0.02 to 0.25 (w/v)%.