GB2167302A

GB2167302A - Stable lyophilized antibacterial preparations

Info

Publication number: GB2167302A
Application number: GB08529182A
Authority: GB
Inventors: Kazuhiro Shima; Koji Takahashi
Original assignee: Shionogi and Co Ltd
Current assignee: Shionogi and Co Ltd
Priority date: 1984-11-28
Filing date: 1985-11-27
Publication date: 1986-05-29
Also published as: JPS61130223A; GB2167302B; FR2573654B1; GB8529182D0; DE3541952A1; JPH0522688B2; FR2573654A1

Abstract

A stable preparation of a 7 beta -[2-(2-carbamoyl-2-fluorovinylthio)acetamido]-7 alpha -methoxy3-[1-(2- hydroxyalkyl)-1H-tetrazol-5-yl]thiomethyl-1-dethia-1- ox-a-3-cephem-4-carboxylic acid alkali metal salt can be prepared by forming such preparation by lyophilization in the presence of an alkali metal halide.

Description

SPECIFICATION Stable lyophilized antibacterial-preparations This invention relates to a stable lyophilized antibacterial preparation. More specifically, it relates to a lyophilized preparation of a 7fl-[2-(2-carbamoyl-24luorovinylthio)acetamido]-7a-methoxy-3 (1 - (2-hydroxyalkyl)- 1 H-tetrazol-5-yl]-thiomethyl- 1 -dethia- 1 -oxa-3-cephem-4-carboxylic acid alkali metal salt (I) containing an alkali metal halide as an agent to prevent decomposition.

(wherein R is 2-hydroxyalkyl and M is an alkali metal atom) Compound (I) (cf., British patent publication 2127825A) is a strong antibacterial agent against Gram positive and negative bacteria and is useful as a medicine. When this compound is lyophilized by usual methods (for e.g., medical use), it deteriorates remarkably upon standing for a long time.

It is known that sugars etc. can stabilize lyophilized preparations of some ss-lactam compounds (e.g., Japanese patent publication (Kokai) 11909/1982). The best stabilizing agent disclosed in this prior art, a sugar alcohol (e.g. mannitol), does not stabilize compounds (I). This invention is based upon the surprising discovery that alkali metal halides do stabilize such antibacterial salts.

Especially preferred alkali metal halides are non-toxic sodium chloride and potassium chloride.

The lyophilized preparations of this invention can, for example, be prepared as follows: A compound (I) and the stabilizing agent are dissolved in an aqueous solvent to give a mixed solution [if required the solution is adjusted to pH 5 to 8 (preferably to pH 6 to 7)], which mixed solution is poured into a vial or tray, cooled to freeze rapidly at - 10 to -600C (preferably -25 to -400C) for from several minutes to 10 hours, and the frozen material is kept at 0.005 to 1 mb for 5 to 72 hours (if required supplying any necessary heat of sublimation) to remove water by sublimation until the water content reaches a predetermined value [if required, employing filling with an inert gas (e.g., nitrogen or dry air)]. The preparation is then sealed.

Mere mechanical mixing of a lyophilized compound (I) and the said stabilizing agent does not produce the desired stabilization.

The lyophilization can be carried out by a normal methods (e.g., tray lyophilization, spray lyophilization or vial lyophilization). The amount of the stabilizing agent to be added is usually 1 to 10 (w/w) % (especially 2 to 5 %) of compound (I) to prevent decomposition. Usually, neither the stabilizing agent nor compound (I) in the lyophilized preparation shows crystalline structure.

The preparations of this invention are highly soluble in water, can be produced safely in a sterile manner and are suitable as preparations for various injection purposes and for storage of bulk product for a long time.

The present preparations produced in a sterile manner can be used in usual methods for intravenous or intramuscular injections by dissolving before use in a vehicle for injection purposes.

The following Examples illustrate the invention.

Example 1 A solution of a compound (I) (M=Na, R=CH2CH2OH.lg) and sodium chloride (2.5 (w/w)% of compound (I)) in distilled water for injection purposes (4 ml) is poured into a 10 ml vial. This is placed in a freeze-dryer, cooled rapidly to --35"C, and frozen at the same temperature for 3 hours. Then, water is sublimed from a frozen material heating to keep at lower that 20"C for 20 hours at 0.1 mb and for 6 hours at 0.05 mb or less to give a stable lyophilized preparation.

Reference is made to Table 2 which gives stability data.

Table 1 Stability of lyophilized preparation of Compound (I) (Acceleration test at 500C for 1.5 months).

Stabilizing amount 1 1.5 agent (w/w) months months none - 78.7 74.8 NaC1 X 85.4 83.1 glucose 20 X 84.3 80.4 maltose 20 X 82.6 80.3 mannitol 20 X 73.1 69.1 Na H sulfite 20 X ' 82.8 77.9 fumaric acid 20 X 80.7 78.3 Na glutamate 20 X 81.1 76.3 Example 2 Example 1 is repeated but using potassium chloride (5 (w/w)%) as the stabilising agent to give a stable lyophilized preparation.

Table 2 Stability of lyophilized preparation of Compound (i) (Acceleration test at 400C for 6 months).

Stabilizing amount 1 6 agent (V/v) months months none - 96.8 87.9 I NaC1 2. X 97.3 91.6 NaC1 5 X 95.7 maltose 20 X 93.4 88.6 mannitol 20 Z . 79.5 Example 3 Example 1 is repeated but using a different amount of sodium chloride (5% of compound (I)) and distilled water for injection purposes (10 ml), and employing a 100 ml vial, freezing for 2 hours at -40"C and sublimating at 0.05 mb for 10 hours and at 0.05 mb for 10 hours to give a stable lyophilized preparation. Reference is made to Tables 1 and 2 which give stability data.

Experiment A sterile preparation produced by any of Examples 1 to 3 is dissolved in distilled water for injection purposes (4 ml) and injected or dripped into a patient suffering from an infection caused by Staphylococcus aureus thrice a day to treat the infection.

Claims

1. A lyohphilized preparation of a 7fl-[2-(2-carbamoyl-2-fluorovinylthio)acetamidoj-7a-methoxyl 3-[1 -(2-hydroxyalkyl)- 1 H-tetrazol-5-yl]-thiomethyl-1 -dethia-1 -oxa-3-cephem-4-carboxylic acid alkali metal salt containing an alkali metal halide as a stabilising agent.

2. A preparation as claimed in claim 1, wherein the alkali metal halide is sodium chloride or potassium chloride.

3. A preparation as claimed in claim 1 or claim 2, wherein the amount of the alkali metal halide is 1 to 10 (w/w)%.

4.. A preparation as claimed in claim 3, wherein the amount of the alkali metal halide is 2 to 5 (w/w)%.

5. A preparation as claimed in any one of claims 1 to 4, wherein the preparation has been prepared by dissolving a 73-[2-(2-carbamoyl-2-fluoro-vinylthio) acetamido]-7a-methoxy-3-[1-(2-hy- droxyalkyl)- 1 H-tetrazol-5-yl]thiomethyl- 1 - 1 -dethia- 1 -oxa-3-cephem-4-carboxylic acid alkali metal salt and the stabilising agent in an aqueous solvent, pouring the solution into a vial, cooling to freeze rapidly at --10"C to -600C for from several minutes to 10 hours, keeping the frozen material at 0.005 to 1 mb for from 5 to 72 hours, and sealing the vial.

6. A preparation as claimed in claim 5, wherein the solution is adjusted to pH 5 to 8.

7. A preparation as claimed in claim 6, wherein the solution is adjusted to pH 6 to 7.

8. A preparation as claimed in any one of claims 5 to 7, wherein the cooling is carried out at -25 to -400C.

9. A lyophilized preparation as claimed in any one of claims 5 to 8, wherein the sublimation is carried out supplying heat of sublimation.

10. A lyophilized preparation as claimed in any on of claims 5 to 9, wherein the vial is filled with an inert gas.

11. A lyophilized preparation as claimed in claim 10, wherein the inert gas is nitrogen or dry air.

12. A method of preparing a stable preparation of a 7P-[2-(2-ca rba moyl-2-fl uorovinylthio)a ce- tamido]-7a-methoxyl-3-[ 1 -(2-hydroxyalkyl)- 1 H-tetrazol-5-yl]-thiomethyl- 1 -dethia- 1 -oxa-3-cephem-4carboxylic acid alkali metal salt) comprising dissolving said salt and an alkali metal halide in a solvent and freeze-drying the resulting mixed solution.

13. A method as claimed in claim 12 and further defined by the specific feature(s) of any one or more of claims 2 to 11.

14. A preparation as claimed in claim 1 and substantially as hereinbefore described.

15. A preparation as claimed in claim 1 and substantially as hereinbefore described in any one of Examples 1 to 3.

16. A method as claimed in claim 12 and substantially as hereinbefore described.

17. A method as claimed in claim 12 and substantially as hereinbefore described in any one of Examples 1 to 3.