KR19980061481A - Pharmaceutical compositions useful for the treatment of infectious diseases and preparation method thereof - Google Patents

Abstract

The present invention relates to a pharmaceutical composition useful as a therapeutic agent for infections having a synergistic effect, and a method for preparing the same. Particularly, the present invention relates to cytotaxy and (1R, 5S, 6S) -2-[(2S, 4S) -2- [ (E) -3-methanesulfonylamino-1-propenyl] pyrrolodin-4-yl-thio] -6-[(R) -1-hydroxyethyl] -1-methyl-1-carbafen-2 The present invention relates to a pharmaceutical composition having a high synergistic effect containing a compound selected from -M-3-carboxylic acid (hereinafter Compound I) or meropenem as an active ingredient, and the present invention relates to a small amount of Compound I or meropenem and Cytotaxime. In combination, the antibacterial activity of Cytotaxime against the strain of beta lactamase, which is resistant to Cytotaxime, not only shows an excellent synergistic effect, but also has an effect of improving anti-pneumoniae activity.

Description

Pharmaceutical compositions useful for the treatment of infectious diseases and preparation method thereof

The present invention relates to a pharmaceutical composition useful as a therapeutic agent for an infectious disease having a synergistic effect and a method of manufacturing the same.

In particular, the present invention relates to cephataxime and (1R, 5S, 6S) -2-[(2S, 4S) -2-[(E) -3-methanesulfonylamino-1-propenyl] pyrrolodin-4-yl Compound selected from -thio] -6-[(R) -1-hydroxyethyl] -1-methyl-1-carbafen-2-m-3-carboxylic acid (hereafter Compound I) or meropenem as an active ingredient It relates to a pharmaceutical composition having a high synergistic effect.

Beta-lactam antibiotics are bactericidal in nature, and at the same time, the bactericidal mechanism is known to be unique to bacteria to ensure safety. Currently, beta-lactam antibiotics penicillins and cephalosporins are used to combat bacterial infection. Widely used. However, due to the widespread use of beta lactam antibiotics, bacteria have acquired resistance to beta lactam antibiotics, and the most representative resistance mechanism is known to be the action of beta lactamase that hydrolyzes beta lactam antibiotics and thus loses antimicrobial activity. have. In order to treat bacterial infections obtained by the production of such beta lactamase produced by the beta lactamase, other beta lactam antibiotics or antibiotics other than beta lactam that do not act as a substrate of the beta lactamase produced by the resistant strain are used. One method is to use a method of inhibiting the activity of beta lactamase produced by a resistant strain in combination with beta lactam antibiotics to inactivate beta lactamase and to expect the action of beta lactam antibiotics. will be.

Celltaxime is a known cephalosporin-based antibiotic with beta lactam ring and is known to exhibit a wide range of strong antimicrobial activity against Gram-positive bacteria and Gram-negative bacteria, including Staphylococcus aureus (USP4,098,888). . However, like most third-generation cephalosporin-based antibiotics except ceftazidime, cytotactiles do not show antimicrobial activity against Pseudomonas aeruginosa and have the disadvantage that antimicrobial activity is greatly reduced by beta lactamase (Expert Opinion on Investgational Drugs, 4 (8): 693-704, 1995).

Compound I is a type of carbapenem antibiotic having beta lactam ring and is a well-known compound developed by the present applicant and currently pending in the patent application, and itself has strong antibacterial activity including anti-pneumoniae activity (WO95 / 14692) . On the other hand, the present inventors have a strong affinity for beta lactamase, which is the biggest cause of obtaining resistance to beta lactam antibiotics in many bacteria, in addition to its excellent antimicrobial activity, and combined with the enzyme Has been found to inhibit.

Meropenem, like Compound I, is a carbapenem-based antibiotic with a beta lactam ring and is an air compound, and itself has strong antibacterial activity including anti-pneumoniae activity (EP0126587). The present inventors found that meropenem also has a strong affinity for beta lactamase in addition to its antibacterial activity, and binds to this enzyme and inhibits its activity.

Therefore, the present inventors have conducted studies to exploit the beta lactamase inhibitory activity of the compound I and meropenem, and as a result, the beta lacta which is cytotactile resistance by the combination of a small amount of the compound I or meropenem and cytotaxime The present invention was completed by discovering the surprising fact that the antibacterial activity of Cytotaxime against the horseshoe producing strain not only shows an excellent synergistic effect but also improves the anti-pneumoniae activity. In particular, when the concentration of Compound I or meropenem was less than 1/4 of the MIC, the antibacterial activity of Cytotaxime was improved by about 30 to 200 times or more. It was confirmed that it is not affected by the antibacterial activity of.

Based on the above situation, an object of the present invention is to provide a pharmaceutical composition containing Compound I or meropenem having a novel synergistic effect capable of improving the anti-pseudomonas aeruginosa activity and beta lactamase stability of Cytotaxime, and Cytotaxime. have.

Accordingly, the pharmaceutical composition of the present invention is an excipient, a solvent, a suspending agent, a lubricant, a dissolving aid, a stabilizer, which is used alone or in a method for preparing a pharmaceutical formulation in humans or animals by known administration methods such as oral or parenteral. Gram-positive bacteria that produce beta lactamase in the form of tablets, granules, capsules, powders, syrups, ointments, suppositories, and general pharmaceutical compositions such as subcutaneous, intramuscular, intravenous or injectables, by mixing with conventional adjuvants such as antioxidants, and It can be effectively used for the prevention or treatment of bacterial infections including negative bacteria.

In the present invention, it is possible to use Compound I or meropenem and Celltaxim in various mixing ratios as confirmed in the following experimental results. For example, compound I or meropenem and cytotaxime may be used in a ratio of 1: 400 to 400: 1.

Hereinafter, although an Example demonstrates this invention, this invention is not limited to these.

Example 1

A test for selecting clinically important beta lactamase producing strains that are resistant to cytotaxy, and for determining the synergistic effect of antimicrobial activity by the combination of Compound I or meropenem with cytotaxime is the minimum According to the developmental inhibition concentration (MIC) measurement method (29 (1): 76 ~ 79, 1981) was measured as follows. 10 ml of Mueller Hinton Broth or 5% horse serum containing Mueller Hinton Broth was dispensed into sterile test tubes, and each strain was inoculated with one platinum solution and then incubated at 37 ° C. for 18 hours. Each antibiotic was weighed about 10mg, and the distilled water was dissolved to make 2mg / ml, and then diluted in 2-fold order to 0.5mg / ml in a test tube to prepare an antibiotic solution. 0.5 ml of each Compound I solution and 0.5 ml of Celltaxim solution or 0.5 ml of Meropenem solution and 0.5ml of Celltaxim solution were dispensed in a Petri dish and sterilized and cooled to 45-50 ° C. in Mueller Hinton Agar medium or 9 ml of 5% horse serum-containing Muller-Hinton agar medium was added to each well, and then hardened to prepare a flat plate for the determination of the minimum elicitation concentration. Take 0.11ml of the above culture medium and mix it into a sterile test tube containing 10ml gelatin-containing saline solution (BSG) to prepare the inoculation bacteria solution, and then inoculate the plate containing antibiotics with the inoculator using an inoculator for 18 hours at 37 ℃. After culturing, the growth of the bacteria was observed with the naked eye, and the MIC was measured and compared. As can be seen from Tables 1 to 6, the concentration of Compound I was 0.05 for 4 strains except for Pseudomonas aeruginosa among the strains of beta lactamase that had been used in this test (MIC of 50 µg / ml or more). At least 200-fold improvement in antimicrobial activity was observed in combination conditions maintained at μg / ml, and 30-fold or more antimicrobial activity was observed in the combined conditions in which the concentration of Compound I was maintained at 0.2 µg / ml against Pseudomonas aeruginosa, which produces beta lactamase. An improvement was observed. In addition, as shown in Tables 7 to 12, the same antimicrobial activity-improving effect was confirmed when the compound I and the cell taxime were used in combination with meropenem and cell taxime.

TABLE 1

Combination Effect of Compound I and Cytotaxin on Escherichia Coli EB-13

TABLE 2

Combination Effect of Compound I and Cytotaxin on Klebsiella pneumoniae EB-37

TABLE 3

Combination Effect of Compound I and Cytotaxin on Enterobacter Cloaca FP1185

TABLE 4

Combination Effect of Compound I and Cytotaxime on Proteus vulgaris FP1187

TABLE 5

Combination Effect of Compound I and Cytotaxin on Pseudomonas aeruginosa FP1190

TABLE 6

Combination Effect of Compound I and Cytotaxin on Pseudomonas aeruginosa FP1380

TABLE 7

Combination Effect of Meropenem and Cytotaxin on E. coli EB-13

TABLE 8

Combination Effect of Meropenem and Cytotaxin on Klebsiella pneumoniae EB-37

TABLE 9

Combination Effect of Meropenem and Cytotaxin on Enterobacter Cloaca FP1185

TABLE 10

Combination Effect of Meropenem and Cytotaxin on Proteus vulgaris FP1187

TABLE 11

Combination Effect of Meropenem and Cytotaxime on Pseudomonas aeruginosa FP1190

TABLE 12

Combination Effect of Meropenem and Cytotaxin on Pseudomonas aeruginosa FP1380

Claims (4)

Cefataxime and (1R, 5S, 6S) -2-[(2S, 4S) -2-[(E) -3-methanesulfonylamino-1-propenyl] pyrrolodin-4-yl-thio] -6 -[(R) -1-hydroxyethyl] -1-methyl-1-carbafen-2-m-3-carboxylic acid (hereinafter Compound I) or meropenem are mixed at a ratio of 1: 400 to 400: 1 Pharmaceutical composition useful as an agent for treating infectious diseases. The method according to claim 1, wherein the cephataxime and (1R, 5S, 6S) -2-[(2S, 4S) -2-[(E) -3-methanesulfonylamino-1-propenyl] pyrrolodin-4-yl -Thio] -6-[(R) -1-hydroxyethyl] -1-methyl-1-carbafen-2-m-3-carboxylic acid (Compound I) or meropenem: 1: 400 to 400: 1 A pharmaceutical formulation prepared by formulating in a conventional pharmaceutically acceptable method, containing in a ratio of and mixed with conventional pharmaceutically acceptable excipients. Cefataxime and (1R, 5S, 6S) -2-[(2S, 4S) -2-[(E) -3-methanesulfonylamino-1-propenyl] pyrrolodin-4-yl-thio]- 6-[(R) -1-hydroxyethyl] -1-methyl-1-carbaphen-2-em-3-carboxylic acid (compound I) or meropenem is mixed at a ratio of 1: 400 to 400: 1 A method for preparing a pharmaceutical composition useful for treating an infectious disease. The method according to claim 3, wherein the cytotaxime and (1R, 5S, 6S) -2-[(2S, 4S) -2-[(E) -3-methanesulfonylamino-1-propenyl] pyrrolodin-4-yl -Thio] -6-[(R) -1-hydroxyethyl] -1-methyl-1-carbafen-2-m-3-carboxylic acid (Compound I) or meropenem: 1: 400 to 400: 1 A method for preparing a pharmaceutical formulation prepared by mixing with a conventionally acceptable pharmaceutically acceptable excipient and formulated in a conventional pharmaceutically acceptable method.