JPH0522688B2 - - Google Patents

Description

[Detailed description of the invention]

This invention provides a stable antibacterial freeze-dried preparation, in particular 7β-[2-(2-carbamoyl-2-fluorovinylthio)acetamide]-7α-methoxy-3-[1 -(2-Hydroxyalkyl)-1H-tetrazol-5-yl]thiomethyl-1-dethia-1-oxa-3-cephem-4-carboxylic acid alkali metal salt (). (In the formula, R represents a 2-hydroxyalkyl group and M represents an alkali metal atom.) The above compound ( ) (described in JP-A-59-62596) exhibits strong antibacterial activity against Gram-positive and Gram-negative bacteria. , useful as a medicine. When this compound is freeze-dried using a conventional method for use in medicine, a significant drop in potency is observed if left for a long time. As a result of various studies to compensate for this drawback, the inventor discovered that the above-mentioned stabilizer was effective, and completed the present invention. It is well known that sugars and the like have a stabilizing effect on freeze-dried preparations of β-lactam compounds (Japanese Unexamined Patent Application Publication No. 57-197).
-11909, etc.), but saccharides such as mannitol, which showed remarkable effects in this case, do not show the stabilizing effect of compound (). As alkali metal halides,
Particularly preferred are non-toxic sodium chloride and potassium chloride. To produce the lyophilized preparation of this invention, the compound () and the stabilizer are dissolved in an aqueous medium to form a mixed solution, and if necessary, the pH is 5 to 8, preferably 6.
After cooling and rapidly freezing at -10 to -60℃, preferably -25 to -40℃ for several minutes to 10 hours, while supplying sublimation heat if necessary, A method of sublimating and removing water by keeping it at 0.005 to 1 mb for a period of time until the specified water content is reached, filling it with an inert gas such as nitrogen or dry air if necessary, and sealing it tightly.
Preferably, conventional methods are used. Mechanical mixing of the lyophilized compound () with the stabilizer does not result in the desired stabilization. For this freeze-drying, conventional methods such as tray freeze-drying, spray freeze-drying, and vial freeze-drying can be used. The stabilizer is added in an amount of 1 to 10%, particularly 2 to 5%, based on the weight of the compound (2), to exhibit a decomposition prevention effect. In such lyophilized formulations, neither the compound () nor the stabilizer usually exhibits a crystalline structure. The formulation of this invention is highly water soluble, environmentally hygienic,
It is easy to construct aseptically and is suitable for various injection preparations. It is also suitable as a long-term storage form for bulk products. The aseptically produced preparation can be dissolved in an injectable solution at the time of use, and used for intravenous administration, intramuscular injection, etc. in a conventional manner. Examples are shown below to explain aspects of the invention. Example 1 Compound (I, M=Na, R= _-CH2CH2OH ) ₁
g Dissolve 2.5% by weight of sodium chloride (based on compound ()) in 4 ml of distilled water for injection and inject into a 10 ml vial. Place this in a freeze-drying cabinet, quickly freeze to -35°C, and then freeze at the same temperature for 3 hours. Next, the temperature of the dried material is heated to keep it at -20° C. or less, and the temperature is kept at 0.1 mb for 20 hours and 0.05 mb or less for 6 hours to sublimate the water content and obtain a stabilized freeze-dried preparation. Example 2 A stabilized lyophilized preparation is obtained even when the stabilizer in Example 1 is changed to 5% by weight of potassium chloride.

【table】

[Table] Example 3 Sodium chloride in Example 1 was reduced to 5%, distilled water for injection was reduced to 10 ml, vial was reduced to 100 ml, frozen at -40°C for 2 hours, sublimated at 0.05 mb for 10 hours and 0.005 mb for 10 hours.
to obtain a stabilized lyophilized formulation. Experimental Example If the preparations of Examples 1 to 3 are manufactured aseptically, dissolved in 4 ml of distilled water for injection, and administered to a patient with staphylococcal infection by intravenous injection or infusion three times a day,
The infection can be treated.

Claims (1)

[Claims] 1 7β-[2-(2-carbamoyl-2-fluorovinylthio)acetamide]-7α-methoxy-3-[1-(2-hydroxyalkyl)-1H- containing an alkali metal halide as a stabilizer
Freeze-dried preparation of alkali metal salt of tetrazol-5-yl]thiomethyl-1-dethia-1-oxa-3-cephem-4-carboxylic acid.