CN109364062A - 一种抗真菌的药物组合物 - Google Patents
一种抗真菌的药物组合物 Download PDFInfo
- Publication number
- CN109364062A CN109364062A CN201811173348.5A CN201811173348A CN109364062A CN 109364062 A CN109364062 A CN 109364062A CN 201811173348 A CN201811173348 A CN 201811173348A CN 109364062 A CN109364062 A CN 109364062A
- Authority
- CN
- China
- Prior art keywords
- amphotericin
- moxidectin
- component
- polyene
- composition
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 230000001857 anti-mycotic effect Effects 0.000 title claims abstract description 14
- 239000002543 antimycotic Substances 0.000 title claims abstract description 14
- 239000008194 pharmaceutical composition Substances 0.000 title abstract description 17
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 claims abstract description 45
- APKFDSVGJQXUKY-KKGHZKTASA-N Amphotericin-B Natural products O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1C=CC=CC=CC=CC=CC=CC=C[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-KKGHZKTASA-N 0.000 claims abstract description 44
- 229960003942 amphotericin b Drugs 0.000 claims abstract description 44
- 239000003429 antifungal agent Substances 0.000 claims abstract description 7
- 229960004816 moxidectin Drugs 0.000 claims description 39
- 239000000203 mixture Substances 0.000 claims description 25
- 239000003814 drug Substances 0.000 claims description 19
- 239000002459 polyene antibiotic agent Substances 0.000 claims description 15
- 239000000463 material Substances 0.000 claims description 14
- 241000233866 Fungi Species 0.000 claims description 13
- 229940079593 drug Drugs 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 201000010099 disease Diseases 0.000 claims description 6
- 229940095731 candida albicans Drugs 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 239000000651 prodrug Substances 0.000 claims description 4
- 229940002612 prodrug Drugs 0.000 claims description 4
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 claims description 4
- 241000222122 Candida albicans Species 0.000 claims description 3
- 238000009472 formulation Methods 0.000 claims description 3
- 230000002538 fungal effect Effects 0.000 claims description 3
- 150000004291 polyenes Chemical class 0.000 claims description 3
- 201000009862 superficial mycosis Diseases 0.000 claims description 3
- 230000003115 biocidal effect Effects 0.000 claims description 2
- YZBLFMPOMVTDJY-CBYMMZEQSA-N moxidectin Chemical compound O1[C@H](C(\C)=C\C(C)C)[C@@H](C)C(=N/OC)\C[C@@]11O[C@H](C\C=C(C)\C[C@@H](C)\C=C\C=C/2[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\2)O)C[C@H]4C1 YZBLFMPOMVTDJY-CBYMMZEQSA-N 0.000 claims 6
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 11
- 230000000843 anti-fungal effect Effects 0.000 abstract description 7
- 230000002401 inhibitory effect Effects 0.000 abstract description 4
- 238000002560 therapeutic procedure Methods 0.000 abstract description 4
- 231100000331 toxic Toxicity 0.000 abstract description 4
- 230000002588 toxic effect Effects 0.000 abstract description 4
- YZBLFMPOMVTDJY-LSGXYNIPSA-N Moxidectin Chemical compound O1[C@H](C(\C)=C\C(C)C)[C@@H](C)C(=N/OC)/C[C@@]11O[C@H](C\C=C(C)\C[C@@H](C)\C=C\C=C/2[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\2)O)C[C@H]4C1 YZBLFMPOMVTDJY-LSGXYNIPSA-N 0.000 description 34
- 150000001875 compounds Chemical class 0.000 description 10
- -1 sorbierite Substances 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 229920002472 Starch Polymers 0.000 description 6
- 239000012530 fluid Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 235000019698 starch Nutrition 0.000 description 6
- 239000008107 starch Substances 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 5
- 239000000825 pharmaceutical preparation Substances 0.000 description 5
- 206010017533 Fungal infection Diseases 0.000 description 4
- 208000031888 Mycoses Diseases 0.000 description 4
- 229940121375 antifungal agent Drugs 0.000 description 4
- 239000003995 emulsifying agent Substances 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 239000006187 pill Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000000080 wetting agent Substances 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000000945 filler Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- RJWUMFHQJJBBOD-UHFFFAOYSA-N 2-methylheptadecane Chemical compound CCCCCCCCCCCCCCCC(C)C RJWUMFHQJJBBOD-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 241000675278 Candida albicans SC5314 Species 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 239000001785 acacia senegal l. willd gum Substances 0.000 description 2
- 239000000853 adhesive Substances 0.000 description 2
- 230000001070 adhesive effect Effects 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
- 230000001716 anti-fugal effect Effects 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 239000000022 bacteriostatic agent Substances 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 230000000295 complement effect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 235000013399 edible fruits Nutrition 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 231100000417 nephrotoxicity Toxicity 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000007909 solid dosage form Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- DCXXMTOCNZCJGO-UHFFFAOYSA-N tristearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 1
- WBDGLSGKTWAWHK-UHFFFAOYSA-N 2,3-dibutylbenzoic acid Chemical compound CCCCC1=CC=CC(C(O)=O)=C1CCCC WBDGLSGKTWAWHK-UHFFFAOYSA-N 0.000 description 1
- AXPZIVKEZRHGAS-UHFFFAOYSA-N 3-benzyl-5-[(2-nitrophenoxy)methyl]oxolan-2-one Chemical compound [O-][N+](=O)C1=CC=CC=C1OCC1OC(=O)C(CC=2C=CC=CC=2)C1 AXPZIVKEZRHGAS-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 229930183010 Amphotericin Natural products 0.000 description 1
- QGGFZZLFKABGNL-UHFFFAOYSA-N Amphotericin A Natural products OC1C(N)C(O)C(C)OC1OC1C=CC=CC=CC=CCCC=CC=CC(C)C(O)C(C)C(C)OC(=O)CC(O)CC(O)CCC(O)C(O)CC(O)CC(O)(CC(O)C2C(O)=O)OC2C1 QGGFZZLFKABGNL-UHFFFAOYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 1
- 240000008574 Capsicum frutescens Species 0.000 description 1
- 240000004307 Citrus medica Species 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 208000003164 Diplopia Diseases 0.000 description 1
- 206010013710 Drug interaction Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 206010019851 Hepatotoxicity Diseases 0.000 description 1
- 101000991061 Homo sapiens MHC class I polypeptide-related sequence B Proteins 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 102100030300 MHC class I polypeptide-related sequence B Human genes 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 239000004909 Moisturizer Substances 0.000 description 1
- 206010029240 Neuritis Diseases 0.000 description 1
- RCEAADKTGXTDOA-UHFFFAOYSA-N OS(O)(=O)=O.CCCCCCCCCCCC[Na] Chemical compound OS(O)(=O)=O.CCCCCCCCCCCC[Na] RCEAADKTGXTDOA-UHFFFAOYSA-N 0.000 description 1
- 208000001388 Opportunistic Infections Diseases 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- 241000235342 Saccharomycetes Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000016383 Zea mays subsp huehuetenangensis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000008043 acidic salts Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 229910021502 aluminium hydroxide Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940009444 amphotericin Drugs 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 230000001032 anti-candidal effect Effects 0.000 description 1
- 230000004596 appetite loss Effects 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 210000000941 bile Anatomy 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 150000001896 cresols Chemical class 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 239000000645 desinfectant Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 238000003113 dilution method Methods 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 238000007046 ethoxylation reaction Methods 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 230000007686 hepatotoxicity Effects 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- MOYKHGMNXAOIAT-JGWLITMVSA-N isosorbide dinitrate Chemical compound [O-][N+](=O)O[C@H]1CO[C@@H]2[C@H](O[N+](=O)[O-])CO[C@@H]21 MOYKHGMNXAOIAT-JGWLITMVSA-N 0.000 description 1
- 229960000201 isosorbide dinitrate Drugs 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 208000019017 loss of appetite Diseases 0.000 description 1
- 235000021266 loss of appetite Nutrition 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 235000009973 maize Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 239000010445 mica Substances 0.000 description 1
- 229910052618 mica group Inorganic materials 0.000 description 1
- 238000005142 microbroth dilution method Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000001333 moisturizer Effects 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229940088417 precipitated calcium carbonate Drugs 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000000979 retarding effect Effects 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000011257 shell material Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 229940079827 sodium hydrogen sulfite Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 229940084106 spermaceti Drugs 0.000 description 1
- 239000012177 spermaceti Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 235000019605 sweet taste sensations Nutrition 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 206010052366 systemic mycosis Diseases 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 201000005060 thrombophlebitis Diseases 0.000 description 1
- 229940098465 tincture Drugs 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- UAEJRRZPRZCUBE-UHFFFAOYSA-N trimethoxyalumane Chemical compound [Al+3].[O-]C.[O-]C.[O-]C UAEJRRZPRZCUBE-UHFFFAOYSA-N 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种抗真菌的药物组合物，该药物组合物包括抗真菌性的A组份以及协同性的B组份。本发明能够有效减少抗真菌药物两性霉素B的最小抑菌浓度(MIC)，能够显著提高两性霉素B的抗真菌效果，从而减少治疗过程中两性霉素B的用量，进而减少其毒副作用。
Description
技术领域
本发明属于抗真菌治疗技术领域，尤其涉及一种抗真菌的药物组合物。
背景技术
真菌感染包括发病率高但危害较轻的浅部真菌感染和发病率较低但危害严重的深部真菌感染。由于近些年抗生素的滥用，器官移植的发展，以及免疫力低下患者的增多，真菌机会性感染的发病率不断上升，使真菌感染的治疗面临严峻的挑战。近年来少有具新作用机制的抗真菌药物推出，同时有关药物治疗的耐药报道也逐渐增加。因此需要发展新的抗真菌治疗方法。于是，开发新型抗真菌药物组合迫在眉睫。
以两性霉素B为代表的多烯类抗真菌药物，被广泛用于治疗表浅和深部真菌病，由于其抗真菌谱广，疗效确切，半衰期长，曾一度成为某些致命性全身真菌感染性疾病的唯一有效药物。但两性霉素B的毒性较大、不良反应较多，即便含脂两性霉素B的肾毒性降低，依旧存在即刻肝毒性、肾毒性、恶心、呕吐、食欲不振、发热、畏寒、头痛、血栓性静脉炎、白细胞下降、贫血、血压波动、周围神经炎、复视等危害，因此也逐渐退居二线。
发明内容
本发明的目的在于提供一种抗真菌的组合物，旨在解决现有技术中存在的抗真菌药物组合匮乏、抗真菌药物毒副作用大的问题。
本发明是这样实现的，一种抗真菌的药物组合物，该药物组合物包括抗真菌性的A组份以及协同性的B组份；其中，该药物组合物的真菌抑制浓度系数FICI＝(药物组合物中A组份的MIC/A组份单独使用时的MIC)+(药物组合物中B组份的MIC/B组份单独使用时的MIC)≤0.5。
其中，所述A组份包括多烯类抗生素(Polyene antimycotic)、多烯类抗生素类似物、多烯类抗生素衍生物、多烯类抗生素前药、多烯类抗生素代谢物和/或多烯类抗生素药学上可接受的盐。
其中，所述B组份包括莫西菌素(Moxidectin)、其结构类似物和/或药学上可接受的盐。
其中，所述A组份为两性霉素B(Amphotericin B)，所述B组份为莫西菌素。
其中，所述两性霉素B、莫西菌素的质量比范围为(0.25～0.5)：(1～32)。
其中，所述两性霉素B、莫西菌素的质量比0.25：(16～32)。
本发明还提供了上述组合物在制备抗真菌药物中的用途。
其中，所述药物是用于治疗由真菌所致的疾病。
其中，所述真菌包括对机体危害较轻的浅部真菌和危害严重的深部真菌。
其中，所述真菌包括白色念珠菌。
基于上述组合物的抗真菌作用，本发明还提供了两性霉素B和莫西菌素在制备抗真菌的联合用药物中的用途；两性霉素B、莫西菌素的质量比范围为(0.25～0.5)：(1～32)。
本发明组合物除了A、B两种活性成分外，还可以包括药学上可接受的辅料或辅助性成分。
本发明还提供了上述组合物的制备方法，它包括如下内容：
(1)按配比取各组份；
(2)取或不取辅料；
(3)按制剂方法制备产品。
内容(2)中的辅料，包括食品、药品、保健品、消毒剂等不同级别的辅料。
本发明所述药学上可接受的辅料，是指除活性成分以外包含在剂型中的物质，包括但不仅限于填充剂(稀释剂)、润滑剂(助流剂或抗粘着剂)、分散剂、湿润剂、粘合剂、调节剂、增溶剂、抗氧剂、抑菌剂、乳化剂、崩解剂等。粘合剂包含糖浆、阿拉伯胶、明胶、山梨醇、黄芪胶、纤维素及其衍生物(如微晶纤维素、羧甲基纤维素钠、乙基纤维素或羟丙甲基纤维素等)、明胶浆、糖浆、淀粉浆或聚乙烯吡咯烷酮等；填充剂包含乳糖、糖粉、糊精、淀粉及其衍生物、纤维素及其衍生物、无机钙盐(如硫酸钙、磷酸钙、磷酸氢钙、沉降碳酸钙等)、山梨醇或甘氨酸等；润滑剂包含微粉硅胶、硬脂酸镁、滑石粉、氢氧化铝、硼酸、氢化植物油、聚乙二醇等；崩解剂包含淀粉及其衍生物(如羧甲基淀粉钠、淀粉乙醇酸钠、预胶化淀粉、改良淀粉、羟丙基淀粉、玉米淀粉等)、聚乙烯吡咯烷酮或微晶纤维素等；湿润剂包含十二烷基硫酸钠、水或醇等；抗氧剂包含亚硫酸钠、亚硫酸氢钠、焦亚硫酸钠、二丁基苯酸等；抑菌剂包含0.5％苯酚、0.3％甲酚、0.5％三氯叔丁醇等；调节剂包含盐酸、枸橼酸、氢氧化钾(钠)、枸橼酸钠及缓冲剂(包括磷酸二氢钠和磷酸氢二钠)等；乳化剂包含聚山梨酯-80、没酸山梨坦、普流罗尼克F-68，卵磷酯、豆磷脂等；增溶剂包含吐温-80、胆汁、甘油等。
所述药学上可接受的辅助性成分，它具有一定生理活性，但该成分的加入不会改变上述化合物或衍生物在疾病治疗过程中的主导地位，而仅仅发挥辅助功效，这些辅助功效仅仅是对该成分已知活性的利用，是医药领域惯用的辅助治疗方式。若将上述辅助性成分与本发明化合物配合使用，仍然应属于本发明保护的范围。
药学上可接受的盐，包括酸式或者碱式盐，只要能够保证组份活性，均可适用。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例如，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
相比于现有技术的缺点和不足，本发明具有以下有益效果：本发明能够有效减少抗真菌药物两性霉素B的最小抑菌浓度(MIC)，能够显著提高两性霉素B的抗真菌效果，从而减少治疗过程中两性霉素B的用量，进而减少其毒副作用。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白，以下结合实施例，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅仅用以解释本发明，并不用于限定本发明。
应当明确的是，下述实施例中所使用的实验方法如无特殊说明，均为常规方法，下述实施例中所使用的材料、试剂等，如无特殊说明，均可从商业途径得到。
白色念珠菌Candida albicans SC5314购自美国标准生物品收藏中心(AmericanType Culture Collection)，保藏号为ATCC MYA-2876。
莫西菌(Moxidectin)素购自MCE公司(产品目录号HY-B0777)。
两性霉素B(Amphotericin B)购自AMRESCO公司。(产品目录号为E437)
一、莫西菌素和两性霉素B的互动抗真菌活性测试
应用棋盘法对莫西菌素和两性霉素B的互动抗真菌(白色念珠菌，CandidaalbicansSC5314)活性进行测试。
1、将白色念珠菌Candida albicans SC5314在RPMI1640培养基中，35℃，湿度为80％，5％CO2的条件下孵育。
2、将莫西菌素和两性霉素B分别溶于DMSO中，至浓度均为10mg/ml，于冰箱中贮存待用。
3、测定最小抑菌浓度(MIC)
(1)参照临床和实验室标准化协会(CLSI)M27-A3方案，即“酵母菌液体培养基稀释法抗真菌药物敏感试验方案”。用液体培养基(RPMI 1640培养基)将贮存的10mg/ml的莫西菌素和10mg/ml的两性霉素B溶液配制成一系列稀释浓度的莫西菌素和两性霉素B药液。
(2)将白色念珠菌细胞接种到96孔板中，每孔98μl(约1×104个细胞)，分别加入1μl莫西菌素和1μl两性霉素B药液，药液的组合方法如下：
第一个药物两性霉素B在96孔板上按稀释浓度从上到下纵向排布(每一横排的两性霉素B浓度相同)，每孔1μl，第二个药物莫西菌素按稀释浓度从左到右横向排布(每一纵排的莫西菌素浓度相同)，每孔1μl，记录每一个空的莫西菌素和两性霉素B的浓度，同时设单独加入梯度稀释的莫西菌素或两性霉素B药液每孔1μl的组，以及不加任何药物的空白对照组，做三个平行的96孔板，结果取平均值。
(3)将96孔板于35℃孵育20小时后600nm测试OD值。
(4)MIC值定义为能100％抑制真菌生长的最低药物浓度。各药物组合的孔通过与空白对照的OD值进行比较来确定MIC值。
此处设如下定义：通过抑制浓度系数FICI来判断两个药物A和B之间是协同、相加还是拮抗作用。
其中，FICI＝(MIC药物组合中的A/MICA单独)+(MIC药物组合中的B/MICB单独)，如果FICI值≤0.5，则表明药物A和B之间存在协同作用，若FICI值在0.5～4.0之间，则表明药物A和B的活性相加，若FICI值＞4.0，则表明药物A和B之间存在拮抗作用。
该方法为临床及实验室标准化协会(CLSI)公认有效方法，使用范围广而普遍，能够在短时间内快速实现对药物相互作用效果的检测，并可以通过对实验数据进一步分析得出可靠结论，结果稳定，可重复性高。
通过以上定义检测莫西菌素和两性霉素B的相互作用，实验所得两性霉素B的最小抑菌浓度MIC为2μg/ml，由于莫西菌素本身抗白色念珠菌活性较差，实验所进行到最高药物浓度达64μg/ml，按照微量肉汤稀释法的二倍稀释实验，实验所得莫西菌素的最小抑菌浓度MIC至少为128μg/ml，FICI计算过程中，莫西菌素无明确MIC，其MIC参考范围为[128,+∞)，各药物组合FICI范围结果如表1所示。
表1莫西菌素和两性霉素B组合后的FICI
表1表明，两性霉素B终浓度为0.5μg/ml、莫西菌素终浓度为1μg/ml；两性霉素B终浓度为0.5μg/ml、莫西菌素终浓度为2μg/ml；两性霉素B终浓度为0.5μg/ml、莫西菌素终浓度为4μg/ml；两性霉素B终浓度为0.5μg/ml、莫西菌素终浓度为8μg/ml；两性霉素B终浓度为0.25μg/ml、莫西菌素终浓度为16μg/ml；两性霉素B终浓度为0.25μg/ml、莫西菌终浓度为32μg/ml，这六组药物组合中，两性霉素B和莫西菌素存在协同抗真菌作用。
二、多烯类抗生素与大环内酯类药物的互动抗真菌
两性霉素B可使用多烯类抗生素或其类似物、衍生物、前药、代谢物和药物活性盐替代。莫西菌素可使用其类似物、衍生物、前药、代谢物和药物活性盐替代。
多烯类抗生素与莫西菌素及其结构类似物之间更具体组分的选择根据所需要抑制的真菌类型进行选择和确定，本发明药物组合物所能抑制的真菌来源广泛，包括当不限于对机体危害较轻的浅部真菌和危害严重的深部真菌，对药物组合物对真菌的最佳抑制效果还可通过上述实施方法确定两者之间的最佳混合比例来获得。
实施例1
按照两性霉素B、莫西菌素的质量比0.25：(16～32)，分别取如上两种组份。配合适当的辅料，将其制备成药物制剂。
实施例2
(1)取两性霉素B适量，配合适当的辅料，将其制备成药物制剂A；
(2)取莫西菌素适量，配合适当的辅料，将其制备成药物制剂B；
(3)将药物制剂A与药物制剂B联合使用，其中，两性霉素B、莫西菌素的质量比0.25：(16～32)。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。
Claims (10)
1.一种组合物，其特征在于，它包括A组份和B组份，其中，A组份包括多烯类抗生素Polyene antimycotic、多烯类抗生素类似物、多烯类抗生素衍生物、多烯类抗生素前药、多烯类抗生素代谢物和/或多烯类抗生素药学上可接受的盐；B组份包括莫西菌素Moxidectin、其结构类似物和/或药学上可接受的盐。
2.根据权利要求1所述的组合物，其特征在于，所述多烯类抗生素选自两性霉素BAmphotericin B。
3.根据权利要求2所述的组合物，其特征在于，所述两性霉素B、莫西菌素的质量比范围为(0.25～0.5)：(1～32)。
4.根据权利要求3所述的组合物，其特征在于，所述两性霉素B、莫西菌素的质量比0.25：(16～32)。
5.两性霉素B和莫西菌素在制备抗真菌的联合用药物中的用途；两性霉素B、莫西菌素的质量比范围为(0.25～0.5)：(1～32)。
6.权利要求1～4任意一项所述组合物在制备抗真菌药物中的用途。
7.根据权利要求6所述的用途，其特征在于，所述药物是用于治疗由真菌所致的疾病。
8.根据权利要求5～7任意一项所述的用途，其特征在于，所述真菌包括浅部真菌或/和深部真菌。
9.根据权利要求5～7任意一项所述的用途，其特征在于，所述真菌包括白色念珠菌。
10.权利要求1-4任意一项所述组合物的制备方法，其特征在于：它包括如下内容：
(1)按配比取各组份；
(2)取或不取辅料；
(3)按制剂方法制备产品。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811173348.5A CN109364062B (zh) | 2018-10-09 | 2018-10-09 | 一种抗真菌的药物组合物 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811173348.5A CN109364062B (zh) | 2018-10-09 | 2018-10-09 | 一种抗真菌的药物组合物 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109364062A true CN109364062A (zh) | 2019-02-22 |
| CN109364062B CN109364062B (zh) | 2020-12-25 |
Family
ID=65403862
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811173348.5A Expired - Fee Related CN109364062B (zh) | 2018-10-09 | 2018-10-09 | 一种抗真菌的药物组合物 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109364062B (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116236496A (zh) * | 2023-03-13 | 2023-06-09 | 新疆大学 | 一种降龙涎二醇和两性霉素b联合抗光滑念珠菌的方法 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103536613A (zh) * | 2013-10-14 | 2014-01-29 | 中国科学院微生物研究所 | 一种抗真菌的药物组合物 |
| CN107812011A (zh) * | 2017-11-13 | 2018-03-20 | 四川大学 | 一种抗真菌的药物组合物 |
-
2018
- 2018-10-09 CN CN201811173348.5A patent/CN109364062B/zh not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103536613A (zh) * | 2013-10-14 | 2014-01-29 | 中国科学院微生物研究所 | 一种抗真菌的药物组合物 |
| CN107812011A (zh) * | 2017-11-13 | 2018-03-20 | 四川大学 | 一种抗真菌的药物组合物 |
Non-Patent Citations (1)
| Title |
|---|
| YOHSUKE NAGAYOSHI等: "Unexpected effects of azole transporter inhibitors on antifungal susceptibility in Candida glabrata and other pathogenic Candida species", 《PLOS ONE》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116236496A (zh) * | 2023-03-13 | 2023-06-09 | 新疆大学 | 一种降龙涎二醇和两性霉素b联合抗光滑念珠菌的方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109364062B (zh) | 2020-12-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU675092B2 (en) | Methods of combating (pneumocystis carinii) pneumonia and compounds useful therefor | |
| US5422343A (en) | Prophylactic and therapeutic composition for MRSA infection | |
| US20100203126A1 (en) | Multilayered vitamin complex tablet containing ubidecarenone | |
| US9212201B2 (en) | Antifungal and antiparasitic polyene macrolides | |
| JP6837700B2 (ja) | ジピベフリンの使用方法 | |
| CN109364062A (zh) | 一种抗真菌的药物组合物 | |
| WO1996010405A1 (fr) | Agent antitumoral | |
| JP2020529999A (ja) | 酸性ｐＨで活性の増強を示す抗真菌剤 | |
| CN107812011A (zh) | 一种抗真菌的药物组合物 | |
| WO2023196543A2 (en) | Liquid-dispersible halopyruvate formulations and associated methods | |
| US20070199856A1 (en) | Methods of stabilizing azithromycin | |
| CN101817834B (zh) | 一类吡唑的衍生物、其制备方法和用途 | |
| RU2497521C1 (ru) | Фармацевтическая композиция, обладающая противогрибковой активностью, и способ ее получения | |
| JPH07118169A (ja) | 抗菌製剤及び抗真菌製剤 | |
| CN111991390B (zh) | 一种两性霉素b增效剂及其用途 | |
| CN108042532A (zh) | 一种抗真菌的药物组合物 | |
| WO2016086776A1 (zh) | 一种包含绿原酸的抗真菌复方制剂及其应用 | |
| EP1318800B1 (en) | 1-amino-alkylcyclohexanes as trypanocidal agents | |
| LU501676B1 (en) | Application of alkaloid compound hip in treatment of cardiac trauma | |
| US20220304989A1 (en) | Application of alkaloid compound hip in treatment of cardiac trauma | |
| US6143726A (en) | Complexes of N'-dimethylaminoacetylpartricin A dimethylaminoethylamide, or the salts thereof, and cholesterol 3-sulphate | |
| US6214381B1 (en) | Methazolamide composition and method of use | |
| US20220339175A1 (en) | Application of Stachyose in Preparation of Drug for Treating Castration-Resistant Prostate Cancer | |
| CN114159474B (zh) | 六神丸在制备治疗真菌性肺炎的药物中的应用 | |
| CN116251168A (zh) | 一种棘白素类似物的药物组合物及其制备方法 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20201225 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |