JPH0122247B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a ready-to-use powder injection containing the cephalosporin according to the present invention. Its purpose is to stabilize the injection, and it is characterized in that glucose is incorporated for this purpose. The cephalosporin according to the present invention has the formula 7β-[D-2-(6,7-dihydroxychromone-3-carboxamide)-2 represented by
-(4-hydroxyphenyl)acetamide]-
3-(1-carboxymethyl-5-tetrazolyl)thiomethyl-3-cefem-4-carboxylic acid disodium salt. Although this cephalosporin has antibacterial activity against Pseudomonas aeruginosa and has been shown to be highly useful, it is a chemically unstable substance, and therefore it is difficult to make it into an injectable preparation. As one solution, powder injections that are dissolved before use have been provided, and although they have achieved their intended purpose, they are still not in a satisfactory state. That is, a decrease in the potency of the substance is observed not only in an aqueous solution but also in a dry powder state. In view of these circumstances, the present inventor investigated the composition of an injection that would not significantly reduce the initial potency when used as an injection that dissolves at the time of use, and as a result, it was determined that glucose is included. Therefore, the inventors realized that the intended purpose could be achieved and completed the present invention. As shown in the experimental examples below, the cephalosporin according to the present invention is unstable to light and heat, and tends to change color. According to the invention, this tendency is prevented exclusively by glucose. The minimum required amount of glucose may be at least 0.5 molar ratio to 1 molar ratio of cephalosporin according to the present invention. Cephalosporin according to the present invention is 5%
It may be used as a (W/V) aqueous solution, and in this case, the appropriate molar ratio of glucose to be added as a stabilizer and iso-enhancing agent is 3.4 molar ratio to 1 molar ratio of cephalosporin according to the present invention. The ready-to-use injection preparation of the present invention is mainly given as a lyophilized powder. That is, for example, the cephalosporin and glucose according to the present invention are dissolved in water, filtered with bacteria, a certain amount is dispensed into vials or ampoules, freeze-dried, and sealed or fused.
Alternatively, after bacterial filtration, the product may be lyophilized to form a powder, and a certain amount may be filled into a vial or ampoule. Experimental Example 1 Sample and Method Cephalosporin 10g according to the present invention and Table 1
Saccharides listed in the additive column (equivalent to 3.4 molar ratio per 1 molar ratio of cephalosporin according to the present invention) were dissolved in water to make 100 ml, passed through a membrane filter, dispensed into 10 ml vials, and lyophilized. ,
It was sealed and used as a specimen sample. A sample to which no sugars were added was separately prepared and used as a control sample. For each sample,
A storage test was conducted under storage conditions of 55°C for 1 month and 720,000 lux hours to determine changes in appearance and survival rate. The residual rate is calculated using Nucleozil C ₁₈ as the stationary phase and a mixture of water, methanol, and perchloric acid (55:
High performance liquid chromatography (OD ₂₅₄ ) was performed using 45:1) as a mobile phase, and the peak height was determined from the ratio of the peak heights of the sample and standard to the internal standard substance. Results The results are shown in Table 1. In the table, each symbol in the section of appearance change represents the following state change. : Changes in color to reddish-brown : Changes in color to brown + : Changes in color to yellow to orange-yellow - : No change in color or slightly changes in color to pale yellow

[Table] Table 1 shows that the addition of glucose is effective for stabilizing the ready-to-use powder injection containing cephalosporin according to the present invention. Experimental Example 2 Sample and Method Glucose was added to 10 g of cephalosporin according to the present invention in the molar ratio listed in the molar ratio column of Table 2, dissolved in water to make 100 ml, passed through a membrane filter, and dispensed into 10 ml vials. freeze-dried,
It was sealed and used as a specimen sample. Experimental example 1 for each sample
The same method as described was performed. Results The results are shown in Table 2. Each symbol in the table represents the one described in the section of Experimental Example 1 Results.

【table】

[Table] The present invention will be explained in more detail with the following examples. Example 1 7β-[D-2-(6,7-dihydroxychromone-3-carboxamide)-2-(4-hydroxyphenyl)acetamide]-3-(1-carboxymethyl-5-tetrazolyl)thiomethyl-
3-Cefem-4-carboxylic acid disodium salt 10
g and 4 g of glucose were dissolved in distilled water for injection to make 100 ml, and after filtering the bacteria with a membrane filter, 2.5 ml each was dispensed into 10 ml vials, freeze-dried, and sealed. Example 2 7β-[D-2-(6,7-dihydroxychromone-3-carboxamide)-2-(4-hydroxyphenyl)acetamide]-3-(1-carboxymethyl-5-tetrazolyl)thiomethyl-
3-Cefem-4-carboxylic acid disodium salt 10
g and 8 g of glucose were dissolved in distilled water for injection to make 100 ml, and after filtering the bacteria with a membrane filter, it was transferred to a shear dish so that the liquid layer was 10 mm, and freeze-dried under aseptic conditions. The obtained powder was filled into 20 ml vials in an amount of 900 mg each by aseptic operation, and the vials were tightly capped. Example 3 7β-[D-2-(6,7-dihydroxychromone-3-carboxamide)-2-(4-hydroxyphenyl)acetamide]-3-(1-carboxymethyl-5-tetrazolyl)thiomethyl-
3-Cefem-4-carboxylic acid disodium salt was dissolved in distilled water, passed through a membrane filter for bacteria, and then recrystallized in ethanol. On the other hand, glucose was also recrystallized in the same manner. 10 g of the former and 8 g of the latter were taken, mixed uniformly, and filled into 20 ml vials in an amount of 1.8 g using aseptic technique, and the vials were sealed.

Claims (1)

[Claims] 1 formula Cephalosporin, indicated by
7β-[D-2-(6,7-dihydroxychromone-3-carboxamide)-2-(4-hydroxyphenyl)acetamide]-3-(1-carboxymethyl-5-tetrazolyl)thiomethyl-3
A cephalosporin injection comprising a disodium salt of cefem-4-carboxylic acid and containing glucose. 2. The cephalosporin injection according to claim 1, wherein the molar ratio of glucose to 1 molar ratio of cephalosporin is 0.5 or more.