JPS62129217A - Germicidal composition for pharmaceutical use - Google Patents

Abstract

PURPOSE:To provide a germicidal composition for pharmaceutical use obtained by compounding a cephazolin (salt) with phosphomycin (salt) or a specific compound such as cefmetazole sodium, etc., and effective especially against cephem- resistant Gram-positive bacteria by the synergistic effect. CONSTITUTION:The objective germicide can be produced by compounding cephazolin or its salt with phosphomycin or its salt or a compound of formula [R<1> is cyanomethylthioacetyl, 5-amino-5-carboxypentanoyl, etc.; R<2> is acetoxymethyl, carbamoyloxymethyl, etc.; R<3> is H or methoxy; X is S or O] or its salt. An optimum combination is cephazolin sodium and cefmetazole sodium [a compound of formula wherein R<1> is cyanomethylthioacetyl, R<2> is (1-methyl-1H-tetrazol-5-yl)thiomethyl, R<3> is methoxy and X is S]. It exhibits synergistic antibacterial activity against Staphylococcus aureus.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application: This invention relates to a novel pharmaceutical antiseptic composition, and more particularly to cefazolin or a pharmaceutically acceptable salt thereof and fosfomycin or a pharmaceutically acceptable salt thereof. salt as an active ingredient, or cefazolin or a pharmaceutically acceptable salt thereof and the following formula (1): (wherein R1 is a cyanomethylthioacetyl group, 5-amino-5-carboxypentanoylcarboxy-2-( 4-hydroxyphenyl)acetyl group, 2-phenyl-2-sulfoacetyl group or (2-chenyl)
acetyl group, R2 is acetoxymethyl group, carbamoyloxymethyl group, (4-carbamoyl-1-pyridinio)methyl group or (1-methyl-IH-tetrazol-5-yl)thiomethyl group, R3 is hydrogen atom or methoxy group, and X means a thio group or an oxy group, respectively) or a pharmaceutically acceptable salt thereof as an active ingredient.

Conventional Technique #g: In recent years, the rate of clinical isolation of cephem-resistant bacteria, especially Durham-positive bacteria such as Staphylococcus, has increased significantly, and this has become a therapeutic problem. It is known that, for example, when cephalothin and latamoxef are used together, they act synergistically against such cephem-resistant staphylococci (for example, at the 14th International Abstract of Humbres, Saibu, and Chemoterabii, Part 2
(See page 83).

Problems to be solved by the invention: As mentioned above, the isolation rate of bacteria resistant to cephem compounds is increasing, and therefore there is a desire for the emergence of more effective and safer medicines against such resistant bacteria. It is rare.

Means for solving the problem: As a result of intensive research, the inventors have found that by using cefazolin sodium in combination with fosfomycin and in combination with cefazolin sodium and the compound represented by the above formula (I),
These are various pathogenic bacteria (Durum-negative bacteria, Durum-positive bacteria,
As a result of further research, we have obtained new knowledge that it exhibits a synergistic antibacterial effect against various resistant bacteria, etc.), especially cephem-resistant Durum-positive bacteria (e.g., Staphylococcus aureus).As a result of further research, we have completed this invention. .

Cefazolin, fosfomycin, used in this invention,
The compounds represented by formula (I) and their pharmaceutically acceptable salts are already well-known antibiotics.

Pharmaceutically acceptable salts of cefazolin, fosfomycin and the compound represented by formula (I) include organic or inorganic salts such as sodium salts, potassium salts, calcium salts, ammonium salts, ethanolamine salts, triethylamine salts, dicyclohexylamine salts, etc. Organic salts such as salts with bases, acetates, trifluoroacetates, lactates, maleates, fumarates, tartrates, citrates, methanesulfonates, hydrochlorides, sulfates, nitrates, phosphates, etc. Included are the common salts of fosfomycin and cephalic compounds, such as acid addition salts with acids or non-acids.

The composition of the present invention comprises a combination of cefazolin or a pharmaceutically acceptable salt thereof and fosfomycin or a pharmaceutically acceptable salt thereof, or a combination of cefazolin or a pharmaceutically acceptable salt thereof and the above formula (I). A pharmaceutical sterilizing composition containing a combination of a compound or a pharmaceutically acceptable salt thereof as an active ingredient, and among these combinations, the most preferred combinations are, for example, as follows.

Cefazolin sodium (registered trademark: cefamedine, hereinafter sometimes abbreviated as CEZ) and cefazolin sodium formula (I>, where R1 is a cyanmethylthioacetyl group, R
A compound in which 2 is a (1-methyl-IH-tetrazol-5-yl)thiomethyl group, R3 is a methoxy group, and X is a thio group, hereinafter sometimes abbreviated as CMZ], Latamoxef sodium [formula ), R1 is a 2-carboxy-2-(4-hydroxyphenyl)acetyl group,
R2 is (1-methyl-IH-tetrazol-5-yl)
thiomethyl group, a compound in which R3 is a methoxy group and
-Carboxypentanoyl group A compound in which R2 is an acetoxymethyl group, R3 is a methoxy group, and X is a thio group, cefoxitin sodium [in formula (I), R1 is (2-
chenyl) acetyl group, R2 is a carhamoyluoquinemethyl group, R3 is a methoxy group, and X is Among them, a compound in which R1 is a 2phenyl-2-sulfoacetyl group, R2 is a (4-carbamoyl-1-pyridinio)methyl group, R3 is a hydrogen atom, and X is a thio group, hereinafter sometimes abbreviated as CFS] combination with.

The mixing ratio of cefazolin or a pharmaceutically acceptable salt thereof and fosfomycin or a pharmaceutically acceptable salt thereof, which are the active ingredients of the pharmaceutical sterilizing composition of the present invention, and the mixing ratio of cefazolin or a pharmaceutically acceptable salt thereof and the formula ( The mixing ratio of the compound represented by I) or its pharmaceutically acceptable salt varies depending on the type of combination, the type of pathogenic bacteria, the severity of the disease, etc., but usually cefazolin or its pharmaceutically acceptable salt is mixed with 1 part of cefazolin or its pharmaceutically acceptable salt. ~5(
The weight ratio (the same applies hereinafter) to fosfomycin or a pharmaceutically acceptable salt thereof, or the compound represented by formula (I) or a pharmaceutically acceptable salt thereof may be determined as appropriate within the range of 1 to 5. However, a ratio of 1:1 is generally preferred.

The pharmaceutical sterilizing compositions of the invention include, for example, solid, semisolid or liquid preparations containing the active substances of the invention in admixture with organic or inorganic carriers or excipients suitable for parenteral administration. It can be used in the form. The active ingredient is usually mixed with a non-toxic, pharmaceutically acceptable carrier and used in a suitable dosage form, such as a tablet, pellet, capsule, suppository, solution, emulsion, or suspension. The carriers here include water, glucose, lactose, gum arabic, gelatin, mannitol, starch paste, magnesium trisilicate, talc, methyl cellulose, polyethyl glycol, corn starch, keratin, colloidal silica, potato starch, base material and solids. Other carriers suitable for use in preparing solid, semi-solid or liquid preparations, which may also include adjuvants, stabilizers, thickeners and colorants and flavoring agents. . The pharmaceutical sterilizing composition may also contain preservatives or bacteriostatic agents to maintain stable activity of the active ingredients in the desired formulation. The amount of active ingredient contained in the pharmaceutical antiseptic composition is an amount sufficient to exert the desired prophylactic or therapeutic effect on disease processes and conditions.

When this pharmaceutical sterilizing composition is applied to humans, it is preferably administered by intravenous injection, subcutaneous injection, intramuscular injection, or the like. The dosage of the active ingredient of this invention varies depending on the age and severity of the disease of each individual patient to be treated, but generally the daily dosage of the active ingredient for humans is about 0.01 to 10 mg/kg is administered for prophylaxis or treatment.

effect: Next, the effects of this invention will be explained using test examples.

Test Example 1 (1) Test method: (a) Test compounds Compounds listed in the table below Note that when two compounds are used in combination, the mixing ratio is 1:1 (weight ratio). .

(b) Bacterial strain used Staphylococcus aureus In the table, P, Ml and M2 each have the following meanings.

P: Clinical isolate, β-lactamase producing, cephem-resistant strain Ml: P-derived, non-β-lactamase producing, cephem-resistant strain M2: M1-derived, non-β-lactamase producing, cephem-sensitive strain <C) MIC measurement Preculture: Mueller-Hinton broth, 37°C, 20 hours Measurement medium: Mueller-Hinton agar (Difco) Amount of inoculum: Stamp using stock solution of rrIi culture, 10-2 diluted bacterial solution or 10-3 diluted bacterial solution It was inoculated according to the law.

Cultivation: 18 hours at 30°C or 37°C (2) Test results: The following table (Tables 1 to 3) shows the MIC (N/mQ) and FIC.
Indicates the index.

Table 3 Experimental Example 2 (1) Test method: (a) Test compounds Compounds listed in the table below (b) Bacterial strain used Clinical isolate of Staphylococcus aureus (c) MI
C Measurement Same as Test Example 1 However, the amount of inoculated bacteria was inoculated using a preculture solution diluted 100 times with physiological saline using the stamp method.

(2) Test results The following table (Table 4) shows the average value of MIC (4/mu) and F
Indicates the IC index.

Examples: Next, examples of representative examples of the compositions of the present invention will be shown.

Example 1 Cefazolin sodium 125 mg Cefmetazole 125 mg The above was mixed with sterile water (2
(relatives) and used as an injection.

Example 2 Cefazolin sodium 250mg Cefmetazole 250mg” was added to water ajr&(2m
Q) to make an injection.

Claims (1)

[Scope of Claims] Contains cefazolin or a pharmaceutically acceptable salt thereof and fosfomycin or a pharmaceutically acceptable salt thereof, or cefazolin or a pharmaceutically acceptable salt thereof and the following formula: ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1 is a cyanomethylthioacetyl group, 5-amino-5-carboxypentanol group, 2-carboxy-2-(4-hydroxyphenyl)acetyl group, 2-phenyl-2-sulfoacetyl group) group or (2-thienyl)
acetyl group, R^2 is acetoxymethyl group, carbamoyloxymethyl group, (4-carbamoyl-1-pyridinio)methyl group or (1-methyl-1H-tetrazol-5-yl)thiomethyl group, R^3 is A pharmaceutical sterilizing composition comprising, as an active ingredient, a compound represented by the following formula: a hydrogen atom or a methoxy group, and X means a thio group or an oxy group, respectively, or a pharmaceutically acceptable salt thereof.