CN102755628A - Antifungal pharmaceutical composition - Google Patents
Antifungal pharmaceutical composition Download PDFInfo
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- CN102755628A CN102755628A CN201210245954XA CN201210245954A CN102755628A CN 102755628 A CN102755628 A CN 102755628A CN 201210245954X A CN201210245954X A CN 201210245954XA CN 201210245954 A CN201210245954 A CN 201210245954A CN 102755628 A CN102755628 A CN 102755628A
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Abstract
本发明公开了一种抗真菌药物组合物。该药物组合物由A和B组成；其中，所述A选自下述至少一种：喹喔啉类抗生素及其类似物、衍生物、前药、代谢物和药物活性盐；所述B选自下述至少一种：三唑类化合物及其类似物、衍生物、前药、代谢物和药物活性盐。体外抗菌试验证明，将泊沙康唑和棘霉素联合应用，表现出很强的协同活性。使双方的用药剂量均降低32-64倍，体外实验中仍能保证受试真菌被100％清除。这样的组合物将提供联合治疗，对于具有难治性，侵入性的真菌感染是有效的。并且可以因此降低泊沙康唑的用药剂量，减轻患者的经济负担，减轻泊沙康唑的毒性反应，有效降低真菌耐药性的发展。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
Technical field
The present invention relates to a kind of antifungal medicament compositions.
Background technology
Fungal infection, the especially sickness rate of hypoimmunity patient opportunistic fungal infection constantly rise treatment of fungal infections are faced with formidable challenges.Though there are some fungi-medicines to come out one after another, treatment has brought new favourable turn to fungal infection, and the simultaneously relevant drug-fast report of Drug therapy also increases gradually.Therefore need the new antifungal therapy method of development.
Posaconazole generally is used for intractable and invasive infections with fungi or other medicines drug resistance cause fungal infection.This kind infection generally occurs on one's body the patient of immunity infringement, for example organ transplantation or carry out the patient of chemotherapy.Compare with itraconazole with the control drug fluconazol of anti-fungal infection, posaconazole more can effectively prevent the aggressive aspergillin infection and can reduce the relevant mortality rate of invasive infections with fungi.But posaconazole costs an arm and a leg, and often follows some serious adverse reactions such as hyperbilirubinemia in the therapeutic process, and liver enzyme raises, symptoms such as hepatocellular damage and nausea and vomiting.
Summary of the invention
The purpose of this invention is to provide a kind of antifungal medicine composition with synergistic function.
Antifungal medicine composition provided by the present invention is made up of A and B; Wherein, Said A is selected from following at least a: quinoxaline antibiotic and analog thereof, derivant, prodrug, metabolite and pharmaceutically active salt, said B is selected from following at least a: triazole class compounds and analog thereof, derivant, prodrug, metabolite and pharmaceutically active salt.
In some embodiments, said A is selected from following any one material: Quinomycin A. and analog thereof, derivant, prodrug, metabolite and pharmaceutically active salt.
In some embodiments, said B is selected from following any one material: posaconazole and analog thereof, derivant, prodrug, metabolite and pharmaceutically active salt.
In the preferred embodiment, said A is a Quinomycin A., and said B is a posaconazole, and both mass ratioes are (12.5-1600): 1, and preferred mass is than being (200-1600): 1.
Antibiotic of quinoxaline described in the present invention and analog thereof, derivant, prodrug, metabolite and pharmaceutically active salt can obtain through microbial fermentation, chemical improvement, chemosynthesis or commercial sources.
Triazole class compounds described in the present invention and analog thereof, derivant, prodrug, metabolite and pharmaceutically active salt can obtain through chemosynthesis or commercial sources.
Another object of the present invention provides the application of above-mentioned antifungal medicine composition.
To be it be used for treating the application of the medicine of fungal infection in preparation in application provided by the present invention.
In some embodiments, the fungus that is infected can be selected from but be not limited to by aspergillosis, Fusarium spp., Candida albicans (being saccharomyces albicans).
The present invention also protects a kind of medicine that is used to treat fungal infection.
The medicine that the present invention protected, its active component are antifungal medicine composition of the present invention.
But the method for said medicine administered through oral, external, injection, infiltration, absorption, physics or chemistry mediation imports body such as muscle, Intradermal, subcutaneous, vein or mucosal tissue; Or by other material mixing or parcel back importing body.
When needing, in said medicine, can also add one or more pharmaceutically acceptable carriers.Said carrier comprises diluent, excipient, filler, binding agent, wetting agent, disintegrating agent, absorption enhancer, surfactant, absorption carrier and the lubricant etc. that pharmaceutical field is conventional.
The said medicine that is used to treat fungal infection can be processed various ways such as injection, tablet, powder, granule, capsule, unguentum, cream.The medicine of above-mentioned various dosage forms all can be according to the conventional method preparation of pharmaceutical field.
The in-vitro antibacterial evidence with posaconazole and Quinomycin A. Combined application, shows very strong synergistic activity.Make both sides' dosage all reduce 32-64 doubly, still can guarantee to be tried fungus in the experiment in vitro and removed by 100%.Such compositions will provide therapeutic alliance, and will be intractable for having, and invasive fungal infection is effective.And can therefore reduce the dosage of posaconazole, alleviate patient's financial burden, alleviate the toxic reaction of posaconazole, effectively reduce the chemical sproof development of fungus.
Description of drawings
Fig. 1 is the collaborative antifungal activity result (composition of medicine MIC value during 100% inhibition conk) of posaconazole and Quinomycin A.
The specific embodiment
The present invention will be described through specific embodiment below, but the present invention is not limited thereto.
Experimental technique described in the following embodiment like no specified otherwise, is conventional method; Said reagent and biomaterial like no specified otherwise, all can obtain from commercial sources.
Used Candida albicans (Candida albicans SC5314/ATCC MYA-2876) is available from the biological article collecting center (American Type Culture Collection) of Unite States Standard among the following embodiment.
The interactive antifungal activity test of embodiment 1, Quinomycin A. and posaconazole
Using chessboard method tests interactive antifungal (the Candida albicans SC5314) activity of Quinomycin A. and posaconazole.Concrete grammar is:
Candida albicans SC5314 in the RPMI1640 culture medium, 35 ℃, humidity 80%, 5%CO
2Condition under hatch.Quinomycin A. and posaconazole are dissolved in respectively among the DMSO, to concentration be 1mg/mL, stored for future use in refrigerator.In order to measure minimal inhibitory concentration (MIC), adopt doubling dilution during sample test.Specifically with reference to the M-27A of standardization committee of American National clinical laboratory (NCCLS) scheme, i.e. " yeast liquid media dilution method antifungal drug STT scheme ".Adopt 2 times of dilution methods to prepare the medicinal liquid of a series of diluted concentrations with fluid medium (RPMI1640), then with Candida albicans SC5314 cell (78 μ l ,～1 * 10
4Individual) be inoculated in 96 orifice plates, the back adds 2 μ l drug solutions.First medicine posaconazole is vertically arranged by diluted concentration on 96 orifice plates, and second medicine Quinomycin A. laterally arranged by diluted concentration.Hatch test OD value after 18 hours for 35 ℃.Compare to confirm the MIC value through OD value with blank.The MIC value defined is the lowest drug concentration that ability 100% suppresses conk here.
For confirm to work in coordination with between two medicine A and the B, addition or antagonism, we judge through inhibition concentration coefficient FICI.FICI=(A/MICA in the MIC drug regimen is independent)+(B/MICB in the MIC drug regimen is independent) is if FICI value＜0.50 then shows to have interactive activity; If the FICI value is between 0.5-4.0; Then for showing active addition, if FICI value＞4.0 then show to have antagonism between the two.
Table 1. is worked in coordination with the antifungal activity test result
The result shows that posaconazole concentration is 0.002ug/ml, and Quinomycin A. concentration is 0.025ug/ml; Posaconazole concentration is 0.001ug/ml, and Quinomycin A. concentration is 0.05ug/ml; Posaconazole concentration is 0.0005ug/ml, and Quinomycin A. concentration is 0.1ug/ml; Posaconazole concentration is 0.00025ug/ml, and Quinomycin A. concentration is 0.1ug/ml; Posaconazole concentration is 0.000125ug/ml, and all there was collaborative antifungic action in two chemical compounds when Quinomycin A. concentration was 0.2ug/ml.Wherein posaconazole concentration is 0.00025ug/ml, and when Quinomycin A. concentration was 0.1ug/ml, collaborative antifungal activity was the strongest.
Claims (8)
1. an antifungal medicine composition is made up of A and B; Wherein, said A is selected from following at least a: quinoxaline antibiotic and analog thereof, derivant, prodrug, metabolite and pharmaceutically active salt; Said B is selected from following at least a: triazole class compounds and analog thereof, derivant, prodrug, metabolite and pharmaceutically active salt.
2. antifungal medicine composition according to claim 1 is characterized in that: said A is selected from following any one material: Quinomycin A. and analog thereof, derivant, prodrug, metabolite and pharmaceutically active salt.
3. antifungal medicine composition according to claim 1 and 2 is characterized in that: said B is selected from following any one material: posaconazole and analog thereof, derivant, prodrug, metabolite and pharmaceutically active salt.
4. according to each described antifungal medicine composition among the claim 1-3, it is characterized in that: said A is a Quinomycin A., and said B is a posaconazole, and the mass ratio of said Quinomycin A. and posaconazole is (12.5-1600): 1.
5. each described antifungal medicine composition is used for treating the application of the medicine of fungal infection among the claim 1-4 in preparation.
6. application according to claim 5 is characterized in that: said fungal infection is caused by following at least a fungus: aspergillosis, Fusarium spp. and Candida albicans.
7. medicine that is used to treat fungal infection, its active component is each described antifungal medicine composition among the claim 1-4.
8. medicine according to claim 7 is characterized in that: said fungal infection is caused by following at least a fungus: aspergillosis, Fusarium spp. and Candida albicans.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201210245954 CN102755628B (en) | 2012-07-16 | 2012-07-16 | Antifungal pharmaceutical composition |
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| Application Number | Priority Date | Filing Date | Title |
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| CN 201210245954 CN102755628B (en) | 2012-07-16 | 2012-07-16 | Antifungal pharmaceutical composition |
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| CN102755628A true CN102755628A (en) | 2012-10-31 |
| CN102755628B CN102755628B (en) | 2013-10-23 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1688306A (en) * | 2002-09-23 | 2005-10-26 | 先灵公司 | Use of posaconazole for the treatment of fungal infections |
| CN1988887A (en) * | 2004-05-28 | 2007-06-27 | 先灵公司 | Pharmaceutical suspension for injection containing posaconazole |
| CN102391968A (en) * | 2011-11-17 | 2012-03-28 | 中国科学院微生物研究所 | Streptomyces and its application in echinomycin production |
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2012
- 2012-07-16 CN CN 201210245954 patent/CN102755628B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1688306A (en) * | 2002-09-23 | 2005-10-26 | 先灵公司 | Use of posaconazole for the treatment of fungal infections |
| CN1988887A (en) * | 2004-05-28 | 2007-06-27 | 先灵公司 | Pharmaceutical suspension for injection containing posaconazole |
| CN102391968A (en) * | 2011-11-17 | 2012-03-28 | 中国科学院微生物研究所 | Streptomyces and its application in echinomycin production |
Non-Patent Citations (2)
| Title |
|---|
| 陈念等: "喹喔啉类抗肿瘤抗生素研究进展", 《实用医学杂志》, vol. 22, no. 21, 30 November 2006 (2006-11-30), pages 2569 - 2570 * |
| 陈敏等: "泊沙康唑治疗侵袭性真菌病研究进展", 《中国实用内科杂志》, vol. 32, no. 2, 29 February 2012 (2012-02-29), pages 154 - 157 * |
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| CN102755628B (en) | 2013-10-23 |
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