JPS6365047B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to an aqueous solution for injection of poorly soluble pharmaceuticals, more specifically, 3[(2-
diaminomethyleneaminothiazol-4-yl)
The present invention relates to an aqueous solution for injection of methylthio]-N-sulfamoylpropionamidine (hereinafter abbreviated as "Compound A"). Compound A used in the present invention is a compound useful as a gastric acid secretion inhibitor (Japanese Patent Application Laid-open No. 56-22770),
An oral formulation has already been developed, but an injection formulation contains Compound A, which is sparingly soluble in water (solubility 0.1w/v%).
(below), its development was delayed. To use this compound A as an injection, add approximately 10 mg/ml to water.
(1w/v%), and for this purpose, a means to solubilize Compound A was required. Conventionally, it has been known that as a means to solubilize poorly soluble drugs, for example, basic drugs are made into salts with mineral acids or organic acids, and acidic drugs are made into salts with alkali salts or organic amines. Since it belongs to basic medicines, it was considered to make it into a salt with mineral acid or organic acid. However, as shown in Table 1, compound A is an unstable compound in an acidic region, so it is necessary to select an acid that not only solubilizes but also stabilizes the resulting compound. Experiments were carried out using various acids in order to find out what was the cause. The results are shown in Table 2.

【table】

【table】

[Table] As is clear from Table 2, hydrochloric acid, oxalic acid, malonic acid, succinic acid, fumaric acid, and citric acid can solubilize Compound A, but there should be almost no difference in acid strength. maleic acid, tartaric acid, and phthanolic acid cannot be solubilized;
The solubility of Compound A does not necessarily depend on the strength of the acid. Furthermore, even among the acids that could be solubilized, oxalic acid, malonic acid, succinic acid, and fumaric acid caused a large amount of crystals to precipitate within 24 hours if the solution was left at room temperature, and hydrochloric acid was kept overnight in a cool place (refrigerator). Crystals were precipitated by storage at . Although citric acid solubilized Compound A and did not form crystals, it had disadvantages such as low pH of the solution, reduced stability of Compound A, and pain when administered as an injection (intramuscular injection). Therefore, it is unsuitable for actual use. Thus, it has not been possible to provide an aqueous solution of Compound A with a common acid that can be used as an injection. Upon further research, the inventor found that it was surprisingly insoluble in water and had low acidity (PH at the time of dissolution).
It has been found that L-aspartic acid, which is a type of acidic amino acid (with a high oxidation rate), has an excellent solubilizing effect. Although this L-aspartic acid itself is poorly soluble in water (solubility: ~0.45w/v%, 20℃), by coexisting with Compound A, both become physically stable aqueous solutions, and the compound A
Even after being sufficiently solubilized and left in a cold place for 24 hours, no crystal precipitation was observed. (Actually, it is possible to solubilize up to about 4%). Incidentally, L-glutamic acid, another acidic amino acid, showed a surprisingly high solubilizing effect like L-aspartic acid, but crystals precipitated when the solution was stored in a cold place overnight. As a result of the solubilizing effect of L-aspartic acid, the aqueous solution of Compound A after solubilization has a high pH (approximately 5.3), so it was expected that good results would be obtained regarding stability.
- 1w/v of compound A with addition of aspartic acid
% reaction rate of the aqueous solution is shown in Table 3, indicating extremely excellent stability. Since the activation energy in this system is quite large (approximately 31 Kcal/mol), the rate constant of decomposition is highly dependent on temperature, but the results in Table 3 are surprising when compared with those in Table 1 at, for example, 20°C. 50～
This shows that it has been stabilized 100 times. Furthermore, L-aspartic acid does not cause any pain or harm to the human body when used as an injection, and in this respect, it is suitable for use as an injection.

[Table] From the above studies, the present inventor discovered that an aqueous solution of Compound A for injection can be provided by using L-aspartic acid, and completed the present invention. The aqueous solution for injection of the present invention can be obtained by stirring Compound A and L-aspartic acid in an amount of 1 to 2 times the molar amount in water.
Specifically, this is carried out by placing the required amounts of Compound A and L-aspartic acid in a container, adding water thereto, and stirring thoroughly until Compound A and L-aspartic acid are dissolved. The present invention will now be explained in more detail with reference to Examples. Example 1 About 1 g of compound A and 0.4 g of L-aspartic acid are mixed with water.
Add 90ml and stir well for 15-30 minutes to dissolve, then add water to make a total volume of 100ml. Example 2 About 2 g of compound A and 0.8 g of L-aspartic acid were added with water.
Add 90ml and stir well for 15-30 minutes to dissolve, then add water to make a total volume of 100ml.

Claims (1)

[Scope of Claims] 3-[(2-diaminomethyleneaminothiazole-) characterized by containing 1 L-aspartic acid
An aqueous solution of 4-yl)methylthio]-N-sulfamoylpropionamidine for injection.