CN102755628B - Antifungal pharmaceutical composition - Google Patents

Abstract

The invention discloses an antifungal pharmaceutical composition. The pharmaceutical composition is composed of A and B; wherein, said A is selected from at least one of the following: quinoxaline antibiotics and their analogs, derivatives, prodrugs, metabolites and pharmaceutically active salts; said B is selected from At least one of the following: triazole compounds and their analogs, derivatives, prodrugs, metabolites and pharmaceutically active salts. Antibacterial tests in vitro proved that the combined application of posaconazole and echinomycin showed strong synergistic activity. The dosages of both parties are reduced by 32-64 times, and the tested fungus can still be guaranteed to be 100% eliminated in the in vitro experiment. Such compositions would provide combination therapy effective for refractory, invasive fungal infections. In addition, the dose of posaconazole can be reduced, the economic burden of patients can be reduced, the toxicity of posaconazole can be reduced, and the development of fungal drug resistance can be effectively reduced.

Description

A kind of antifungal pharmaceutical composition

technical field

The invention relates to an antifungal pharmaceutical composition.

Background technique

The increasing incidence of fungal infections, especially opportunistic fungal infections in immunocompromised patients, poses a serious challenge to the treatment of fungal infections. Although some fungal drugs have come out one after another, which has brought a new opportunity to the treatment of fungal infections, but at the same time, reports on drug resistance to drug treatment have gradually increased. Therefore, there is a need to develop new antifungal treatments.

Posaconazole is generally used for refractory and invasive fungal infections or other drug-resistant fungal infections. Such infections typically occur in immunocompromised patients, such as those undergoing organ transplants or chemotherapy. Posaconazole was more effective in preventing invasive Aspergillus infection and reduced invasive fungal infection-related mortality compared with antifungal comparators fluconazole and itraconazole. However, posaconazole is expensive, and the treatment process is often accompanied by some serious adverse reactions such as bilirubinemia, elevated liver enzymes, liver cell damage, nausea and vomiting and other symptoms.

Contents of the invention

The object of the present invention is to provide an antifungal pharmaceutical composition with synergistic effect.

The antifungal pharmaceutical composition provided by the present invention consists of A and B; wherein, said A is selected from at least one of the following: quinoxaline antibiotics and their analogs, derivatives, prodrugs, metabolites and pharmaceutical activity Salt, said B is at least one selected from the following: triazole compounds and their analogs, derivatives, prodrugs, metabolites and pharmaceutically active salts.

In some embodiments, the A is selected from any one of the following substances: echinomycin and its analogs, derivatives, prodrugs, metabolites and pharmaceutically active salts.

In certain embodiments, the B is selected from any one of the following substances: posaconazole and its analogs, derivatives, prodrugs, metabolites and pharmaceutically active salts.

In a more preferred embodiment, the A is echinomycin, and the B is posaconazole, and the mass ratio of the two is (12.5-1600):1, preferably (200-1600):1.

The quinoxaline antibiotics and their analogs, derivatives, prodrugs, metabolites and pharmaceutically active salts described in the present invention can be obtained through microbial fermentation, chemical transformation, chemical synthesis or commercial means.

The triazole compounds and their analogs, derivatives, prodrugs, metabolites and pharmaceutically active salts described in the present invention can be obtained by chemical synthesis or commercially.

Another object of the present invention is to provide the application of the above antifungal pharmaceutical composition.

The application provided by the present invention is its application in the preparation of medicines for treating fungal infections.

In some embodiments, the infected fungus may be selected from, but not limited to, Aspergillus, Fusarium, and Candida albicans (ie, Candida albicans).

The invention also protects a medicine for treating fungal infection.

The active ingredient of the medicine protected by the invention is the antifungal pharmaceutical composition of the invention.

The above-mentioned drugs can be introduced into the body through oral administration, external application, injection, penetration, absorption, physical or chemical mediated methods such as muscle, intradermal, subcutaneous, vein or mucosal tissue; or introduced into the body after being mixed or encapsulated by other substances.

When necessary, one or more pharmaceutically acceptable carriers can also be added to the above drugs. The carrier includes conventional diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers and lubricants in the pharmaceutical field.

The medicine for treating fungal infection can be made into various forms such as injection, tablet, powder, granule, capsule, ointment, cream and the like. The above-mentioned medicines in various dosage forms can be prepared according to conventional methods in the field of pharmacy.

Antibacterial tests in vitro proved that the combined application of posaconazole and echinomycin showed strong synergistic activity. The dosages of both parties are reduced by 32-64 times, and the tested fungus can still be guaranteed to be 100% eliminated in the in vitro experiment. Such compositions would provide combination therapy effective for refractory, invasive fungal infections. In addition, the dose of posaconazole can be reduced, the economic burden of patients can be reduced, the toxicity of posaconazole can be reduced, and the development of fungal drug resistance can be effectively reduced.

Description of drawings

Figure 1 is the result of the synergistic antifungal activity of posaconazole and echinomycin (the MIC value of the combined drug when 100% inhibits fungal growth)

Detailed ways

The present invention will be described below through specific examples, but the present invention is not limited thereto.

The experimental methods described in the following examples, unless otherwise specified, are conventional methods; the reagents and biological materials, unless otherwise specified, can be obtained from commercial sources.

Candida albicans (Candida albicans SC5314/ATCC MYA-2876) used in the following examples was purchased from American Type Culture Collection.

Embodiment 1, the interactive antifungal activity test of echinomycin and posaconazole

The interactive antifungal activity of echinomycin and posaconazole (Candida albicans SC5314) was tested by the checkerboard method. The specific method is:

Candida albicans SC5314 were incubated in RPMI1640 medium at 35°C, humidity 80%, and 5% CO ₂ . Dissolve echinomycin and posaconazole in DMSO to a concentration of 1 mg/mL, and store in a refrigerator until use. To determine the minimum inhibitory concentration (MIC), samples were tested using the two-fold dilution method. Specifically, refer to the National Committee for Clinical Laboratory Standards (NCCLS) M-27A protocol, that is, "Yeast Liquid Medium Dilution Antifungal Drug Susceptibility Test Protocol". Liquid medium (RPMI1640) was used to prepare a series of diluted drug solutions by 2-fold dilution method, and then Candida albicans SC5314 cells (78 μl, ~1×10 ⁴ cells) were inoculated into 96-well plates, and then 2 μl of drug solution was added. The first drug, posaconazole, is arranged vertically according to the diluted concentration on the 96-well plate, and the second drug, echinomycin, is arranged horizontally according to the diluted concentration. The OD value was measured after incubation at 35°C for 18 hours. The MIC value was determined by comparison with the OD value of the blank control. Here MIC value is defined as the lowest drug concentration that can 100% inhibit fungal growth.

In order to determine whether the two drugs A and B are synergistic, additive or antagonistic, we use the inhibitory concentration coefficient FICI to judge. FICI=(A/MICA alone in the MIC drug combination)+(B/MICB alone in the MIC drug combination), if the FICI value is <0.50, it indicates that there is interaction activity, if the FICI value is between 0.5-4.0, it is It indicates that the activities are additive, and if the FICI value>4.0, it indicates that there is antagonism between the two.

Table 1. Synergistic antifungal activity test results

The results showed that the posaconazole concentration was 0.002ug/ml, and the echinomycin concentration was 0.025ug/ml; the posaconazole concentration was 0.001ug/ml, and the echinomycin concentration was 0.05ug/ml; the posaconazole concentration is 0.0005ug/ml, echinomycin concentration is 0.1ug/ml; posaconazole concentration is 0.00025ug/ml, echinomycin concentration is 0.1ug/ml; posaconazole concentration is 0.000125ug/ml, echinomycin Both compounds have synergistic antifungal effects when the concentration of 0.2ug/ml is 0.2ug/ml. Among them, when the concentration of posaconazole is 0.00025ug/ml and the concentration of echinomycin is 0.1ug/ml, the synergistic antifungal activity is the strongest.

Claims (5)

1. an antifungal medicine composition is comprised of Quinomycin A. and posaconazole, and the mass ratio of described Quinomycin A. and posaconazole is (12.5-1600): 1.

Antifungal medicine composition claimed in claim 1 for the preparation of the treatment fungal infection medicine in application.

3. application according to claim 2 is characterized in that, described fungal infection is caused by following at least a fungus: aspergillosis, Fusarium spp. and Candida albicans.

4. medicine that is used for the treatment of fungal infection, its active component is antifungal medicine composition claimed in claim 1.

5. medicine according to claim 4 is characterized in that, described fungal infection is caused by following at least a fungus: aspergillosis, Fusarium spp. and Candida albicans.

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