JPS6117596A - Freeze-dried powder of fosmidomycin or its salt and preparation thereof - Google Patents

Abstract

PURPOSE:To prepare stable freeze-dried powder of the titled compound useful as an antibacterial drug for intracutaneous injection, etc., by adding a metal halide to fosmidomycin or its salt, and freeze-drying the product. CONSTITUTION:A metal halide (e.g. sodium chloride) is added to fosmidomycin of formula [e.g. 3-(N-formyl-N-hydroxyamino)propylphosphonic acid] or its salt (e.g. forsmidomycin monosodium salt). The mixture is dissolved in distilled water and filled in a container. After freezing the content, the water is sublimed in high vacuum to effect the freeze-drying of the material. The freeze-dried powder of the objective compound can be prepared by this process.

Description

[Detailed Description of the Invention] (Object of the Invention) Industrial Application Field This invention relates to a freeze-dried powder of fosmidomycin or its salts and a method for producing the same, and is useful in the chemical industry such as pharmaceuticals and agricultural chemicals. It provides technology.

Conventional technology Fosmid mycinba general formula [3-(N-formiμ-N-hydroxyamino)propiphonufonic acid] Calcium salt, aluminum salt, ammonium salt, magnesium salt, triethylamine salt, ethano-7noamine salt, zinc chloride Hexynocyamine salt, ethylenediamine L
Salts with inorganic bases or organic bases such as N,N-dibenzylethylene diaine salts, a! Salts with basic amino acids such as reginine salt are known. (For example, JP-A-53
(Refer to Publication No. 40720) Problems to be Solved by the Invention By the way, in the production of freeze-dried powder for intradermal preparations, for example, it is difficult to obtain freeze-dried powder from an aqueous solution of fosmidomycin or its salts. If the amount of fosmidomycin or its salts is small, it will not form a water-containing lime-like solid on the wall of the vial, and even if the amount is relatively large, only a foamed solid will be obtained. It was not possible to obtain freeze-dried powder.

Therefore, the inventors of the present invention firstly aimed to obtain a whole freeze-dried powder of fosmidomycin or its salts, and further, to obtain a stable freeze-dried powder of fosmidomycin or its salts. aimed at obtaining.

(Structure of the Invention) In order to solve the above-mentioned problems, the present inventors have conducted various studies and have decided to add a metal halide to fosmidomycin or its salts when completely freeze-drying the fosmidomycin or its salts. They discovered that a good freeze-dried powder could be obtained, and as a result of further intensive research, they completed this invention.

Examples of the metal halide used here include, but are not limited to, alkaline metal halides such as sodium chloride, potassium chloride, and potassium bromide. The amount of metal halide added to fosmidomycin or its salt is usually preferably 1 part by weight or more per 1 part by weight of fosmidomycin or its salt.

To obtain the freeze-dried powder of the present invention, first, prepare a mixed aqueous solution of fosmidomycin or its salts and a metal halide, freeze-dry this by a conventional method, spray-freeze-dry, etc., and freeze. The desired lyophilized powder can be obtained by sublimating the water under high vacuum and removing the 7X.

Next, the present invention will be explained using examples.

Example 1 600 μf of fosmidomycin monosodium salt and 9 q of sodium chloride were dissolved in 0.25-ml of distilled water for injection, and the solution was filled into a 1-ml Amp) V. This filling product v-4o
After cooling and freezing to "C", water is sublimed under high vacuum to obtain an ampoule of lyophilized powder (intradermal preparation).

Example 2 Fosmidomycin monosodium m300μy and sodium chloride 300μl were added to 0.25111ml of distilled water for injection.
After cooling and freezing in a 1 pH ampoule filled with -40'' C-t, water is sublimed under high vacuum and the mixture is ampliquoted to obtain a lyophilized powder (intradermal preparation).

(Effects of the Invention) According to the present invention, a freeze-dried powder of fosmidomycin or its salts was obtained for the first time, but furthermore, the freeze-dried powder thus obtained was extremely stable. Manni)-1, which also has excellent features, is widely used as an excipient (stabilizer) in the production of lyophilized preparations.

Reference Example Fosmidomycin monosodium m300 μf was dissolved in 0.25 g of distilled water for injection, filled into a 1tttl ampoule, and freeze-dried in the same manner as in Example 1, but no freeze-dried powder was obtained. .

Furthermore, attempts were made to produce freeze-dried powders using 10% and 20% aqueous solutions of fosmidomycin monosodium salt, but collapse of the cake matrix (foaming phenomenon) occurred during the drying process, and freeze-dried powders could not be produced. There wasn't.

Comparative Example In Example 1, ampoules of lyophilized powder (preparation for internal use) were produced in the same manner as in Example 1, using mannitol 50~ in place of sodium chloride 9~. This powder and the powder obtained in the example were tested for stability by keeping them at 50'C for one month. The results are shown in the table below.

As is clear from the above table, the freeze-dried powder of this invention is
Shows excellent stability compared to the control.

Claims (4)

[Claims] (1) A freeze-dried powder of fosmidomycin or a salt thereof containing fosmidomycin or a salt thereof and a metal halide. (2) The freeze-dried powder of fosmidomycin or its salts according to claim 1, wherein the metal halide is sodium chloride. (3) The freeze-dried powder of fosmidomycin or a salt thereof according to claim 2, wherein the salt of fosmidomycin is a sodium salt. (4) A method for producing a freeze-dried powder of fosmidomycin or its salts, which comprises adding a metal halide to fosmidomycin or its salts when freeze-drying the fosmidomycin or its salts.