CN112336868A - 聚乙基亚胺苦参碱脂微球抗真菌制剂及其应用 - Google Patents
聚乙基亚胺苦参碱脂微球抗真菌制剂及其应用 Download PDFInfo
- Publication number
- CN112336868A CN112336868A CN202011168666.XA CN202011168666A CN112336868A CN 112336868 A CN112336868 A CN 112336868A CN 202011168666 A CN202011168666 A CN 202011168666A CN 112336868 A CN112336868 A CN 112336868A
- Authority
- CN
- China
- Prior art keywords
- medicine
- oil
- injection
- lipid microsphere
- percent
- 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.)
- Pending
Links
- 239000004005 microsphere Substances 0.000 title claims abstract description 59
- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- 229920002873 Polyethylenimine Polymers 0.000 title claims abstract description 23
- 230000000843 anti-fungal effect Effects 0.000 title claims abstract description 18
- ZSBXGIUJOOQZMP-UHFFFAOYSA-N Isomatrine Natural products C1CCC2CN3C(=O)CCCC3C3C2N1CCC3 ZSBXGIUJOOQZMP-UHFFFAOYSA-N 0.000 title claims description 18
- 229930014456 matrine Natural products 0.000 title claims description 18
- 229940121375 antifungal agent Drugs 0.000 title claims description 13
- -1 matrine lipid Chemical class 0.000 title claims description 6
- 239000003814 drug Substances 0.000 claims abstract description 58
- 150000002632 lipids Chemical class 0.000 claims abstract description 54
- 239000007924 injection Substances 0.000 claims abstract description 18
- 238000002347 injection Methods 0.000 claims abstract description 18
- 150000003904 phospholipids Chemical class 0.000 claims abstract description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000000203 mixture Substances 0.000 claims abstract description 17
- 230000001954 sterilising effect Effects 0.000 claims abstract description 12
- 239000000284 extract Substances 0.000 claims abstract description 8
- 235000015112 vegetable and seed oil Nutrition 0.000 claims abstract description 8
- 239000008158 vegetable oil Substances 0.000 claims abstract description 8
- 239000007951 isotonicity adjuster Substances 0.000 claims abstract description 7
- 239000003429 antifungal agent Substances 0.000 claims abstract description 6
- 239000002553 antibacterial enhancer Substances 0.000 claims abstract description 4
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 4
- 230000003078 antioxidant effect Effects 0.000 claims abstract description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerol group Chemical group OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 33
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 28
- ZSBXGIUJOOQZMP-JLNYLFASSA-N Matrine Chemical compound C1CC[C@H]2CN3C(=O)CCC[C@@H]3[C@@H]3[C@H]2N1CCC3 ZSBXGIUJOOQZMP-JLNYLFASSA-N 0.000 claims description 17
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 16
- 238000002156 mixing Methods 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- 230000000844 anti-bacterial effect Effects 0.000 claims description 13
- 239000003921 oil Substances 0.000 claims description 13
- 235000019198 oils Nutrition 0.000 claims description 13
- 238000004806 packaging method and process Methods 0.000 claims description 13
- 239000000243 solution Substances 0.000 claims description 11
- 238000009472 formulation Methods 0.000 claims description 10
- 239000002245 particle Substances 0.000 claims description 10
- 229930003427 Vitamin E Natural products 0.000 claims description 8
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims description 8
- 229940046009 vitamin E Drugs 0.000 claims description 8
- 239000011709 vitamin E Substances 0.000 claims description 8
- 235000019165 vitamin E Nutrition 0.000 claims description 8
- MCCACAIVAXEFAL-UHFFFAOYSA-N 1-[2-(2,4-dichlorophenyl)-2-[(2,4-dichlorophenyl)methoxy]ethyl]imidazole;nitric acid Chemical compound O[N+]([O-])=O.ClC1=CC(Cl)=CC=C1COC(C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 MCCACAIVAXEFAL-UHFFFAOYSA-N 0.000 claims description 7
- 210000002969 egg yolk Anatomy 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 7
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 claims description 7
- 229960004884 fluconazole Drugs 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 7
- 229960005040 miconazole nitrate Drugs 0.000 claims description 7
- 238000007789 sealing Methods 0.000 claims description 7
- 235000012424 soybean oil Nutrition 0.000 claims description 7
- 239000003549 soybean oil Substances 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- 239000008215 water for injection Substances 0.000 claims description 7
- 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 claims description 5
- FRPZMMHWLSIFAZ-UHFFFAOYSA-N 10-undecenoic acid Chemical compound OC(=O)CCCCCCCCC=C FRPZMMHWLSIFAZ-UHFFFAOYSA-N 0.000 claims description 5
- 239000000787 lecithin Substances 0.000 claims description 5
- 229940067606 lecithin Drugs 0.000 claims description 5
- 235000010445 lecithin Nutrition 0.000 claims description 5
- GAAKLDANOSASAM-UHFFFAOYSA-N undec-10-enoic acid;zinc Chemical compound [Zn].OC(=O)CCCCCCCCC=C GAAKLDANOSASAM-UHFFFAOYSA-N 0.000 claims description 5
- 229940118257 zinc undecylenate Drugs 0.000 claims description 5
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 claims description 4
- KHAVLLBUVKBTBG-UHFFFAOYSA-N caproleic acid Natural products OC(=O)CCCCCCCC=C KHAVLLBUVKBTBG-UHFFFAOYSA-N 0.000 claims description 4
- 229960002703 undecylenic acid Drugs 0.000 claims description 4
- 235000019485 Safflower oil Nutrition 0.000 claims description 3
- 235000006708 antioxidants Nutrition 0.000 claims description 3
- 229960003913 econazole Drugs 0.000 claims description 3
- 239000002674 ointment Substances 0.000 claims description 3
- 239000004006 olive oil Substances 0.000 claims description 3
- 235000008390 olive oil Nutrition 0.000 claims description 3
- 239000012744 reinforcing agent Substances 0.000 claims description 3
- 235000005713 safflower oil Nutrition 0.000 claims description 3
- 239000003813 safflower oil Substances 0.000 claims description 3
- LEZWWPYKPKIXLL-UHFFFAOYSA-N 1-{2-(4-chlorobenzyloxy)-2-(2,4-dichlorophenyl)ethyl}imidazole Chemical compound C1=CC(Cl)=CC=C1COC(C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 LEZWWPYKPKIXLL-UHFFFAOYSA-N 0.000 claims description 2
- 241000402754 Erythranthe moschata Species 0.000 claims description 2
- 239000006071 cream Substances 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- 239000000839 emulsion Substances 0.000 claims description 2
- 239000001525 mentha piperita l. herb oil Substances 0.000 claims description 2
- 235000019477 peppermint oil Nutrition 0.000 claims description 2
- 239000008347 soybean phospholipid Substances 0.000 claims description 2
- 239000007921 spray Substances 0.000 claims description 2
- 239000010642 eucalyptus oil Substances 0.000 claims 1
- 229940044949 eucalyptus oil Drugs 0.000 claims 1
- 239000010666 rose oil Substances 0.000 claims 1
- 235000019719 rose oil Nutrition 0.000 claims 1
- 210000003491 skin Anatomy 0.000 abstract description 35
- 230000000694 effects Effects 0.000 abstract description 25
- 229940079593 drug Drugs 0.000 abstract description 19
- 239000002502 liposome Substances 0.000 abstract description 10
- 238000004659 sterilization and disinfection Methods 0.000 abstract description 5
- 230000017531 blood circulation Effects 0.000 abstract description 4
- 239000006184 cosolvent Substances 0.000 abstract description 4
- 210000004207 dermis Anatomy 0.000 abstract description 4
- 239000003623 enhancer Substances 0.000 abstract description 4
- 238000010521 absorption reaction Methods 0.000 abstract description 3
- 239000011248 coating agent Substances 0.000 abstract description 3
- 238000000576 coating method Methods 0.000 abstract description 3
- 230000000638 stimulation Effects 0.000 abstract description 2
- 229940126678 chinese medicines Drugs 0.000 abstract 1
- 230000000295 complement effect Effects 0.000 abstract 1
- 229940126673 western medicines Drugs 0.000 abstract 1
- 238000012360 testing method Methods 0.000 description 19
- 241000222122 Candida albicans Species 0.000 description 11
- 229940095731 candida albicans Drugs 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 8
- 229960001727 tretinoin Drugs 0.000 description 8
- 230000003385 bacteriostatic effect Effects 0.000 description 7
- 238000000338 in vitro Methods 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 6
- XMAYWYJOQHXEEK-OZXSUGGESA-N (2R,4S)-ketoconazole Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 XMAYWYJOQHXEEK-OZXSUGGESA-N 0.000 description 5
- SODWJACROGQSMM-UHFFFAOYSA-N 5,6,7,8-tetrahydronaphthalen-1-amine Chemical compound C1CCCC2=C1C=CC=C2N SODWJACROGQSMM-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 241001045770 Trichophyton mentagrophytes Species 0.000 description 5
- 241000223229 Trichophyton rubrum Species 0.000 description 5
- 230000001580 bacterial effect Effects 0.000 description 5
- 229960003645 econazole nitrate Drugs 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 229960004125 ketoconazole Drugs 0.000 description 5
- 239000012528 membrane Substances 0.000 description 5
- 230000035515 penetration Effects 0.000 description 5
- 210000000434 stratum corneum Anatomy 0.000 description 5
- 241001225321 Aspergillus fumigatus Species 0.000 description 4
- 241000193830 Bacillus <bacterium> Species 0.000 description 4
- 241000233866 Fungi Species 0.000 description 4
- 239000003242 anti bacterial agent Substances 0.000 description 4
- 229940091771 aspergillus fumigatus Drugs 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 230000000699 topical effect Effects 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 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 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229940088710 antibiotic agent Drugs 0.000 description 3
- 230000003115 biocidal effect Effects 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 230000004927 fusion Effects 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 230000001575 pathological effect Effects 0.000 description 3
- 208000017520 skin disease Diseases 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 230000002195 synergetic effect Effects 0.000 description 3
- JQWAHKMIYCERGA-UHFFFAOYSA-N (2-nonanoyloxy-3-octadeca-9,12-dienoyloxypropoxy)-[2-(trimethylazaniumyl)ethyl]phosphinate Chemical compound CCCCCCCCC(=O)OC(COP([O-])(=O)CC[N+](C)(C)C)COC(=O)CCCCCCCC=CCC=CCCCCC JQWAHKMIYCERGA-UHFFFAOYSA-N 0.000 description 2
- AXTGDCSMTYGJND-UHFFFAOYSA-N 1-dodecylazepan-2-one Chemical compound CCCCCCCCCCCCN1CCCCCC1=O AXTGDCSMTYGJND-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 102000011724 DNA Repair Enzymes Human genes 0.000 description 2
- 108010076525 DNA Repair Enzymes Proteins 0.000 description 2
- 239000000232 Lipid Bilayer Substances 0.000 description 2
- 108010040201 Polymyxins Proteins 0.000 description 2
- 241000191967 Staphylococcus aureus Species 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 229930013930 alkaloid Natural products 0.000 description 2
- 230000003796 beauty Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 239000002537 cosmetic Substances 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 210000002615 epidermis Anatomy 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 210000003780 hair follicle Anatomy 0.000 description 2
- 230000036571 hydration Effects 0.000 description 2
- 238000006703 hydration reaction Methods 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 210000002510 keratinocyte Anatomy 0.000 description 2
- 230000003902 lesion Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- OQQOAWVKVDAJOI-UHFFFAOYSA-N (2-dodecanoyloxy-3-hydroxypropyl) dodecanoate Chemical compound CCCCCCCCCCCC(=O)OCC(CO)OC(=O)CCCCCCCCCCC OQQOAWVKVDAJOI-UHFFFAOYSA-N 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 238000012935 Averaging Methods 0.000 description 1
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 1
- 244000037364 Cinnamomum aromaticum Species 0.000 description 1
- 235000014489 Cinnamomum aromaticum Nutrition 0.000 description 1
- 241000186427 Cutibacterium acnes Species 0.000 description 1
- 230000033616 DNA repair Effects 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 241000220485 Fabaceae Species 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 244000153234 Hibiscus abelmoschus Species 0.000 description 1
- 206010020112 Hirsutism Diseases 0.000 description 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
- 206010024229 Leprosy Diseases 0.000 description 1
- 241000589902 Leptospira Species 0.000 description 1
- 241000219745 Lupinus Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241001480037 Microsporum Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Natural products C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 1
- 241000588769 Proteus <enterobacteria> Species 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 206010040880 Skin irritation Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 241000246044 Sophora flavescens Species 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- 241000607626 Vibrio cholerae Species 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 206010047601 Vitamin B1 deficiency Diseases 0.000 description 1
- 208000000260 Warts Diseases 0.000 description 1
- 230000037374 absorbed through the skin Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 150000001412 amines Chemical group 0.000 description 1
- 229940126575 aminoglycoside Drugs 0.000 description 1
- 229940124350 antibacterial drug Drugs 0.000 description 1
- 239000007640 basal medium Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 208000002894 beriberi Diseases 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 229920006317 cationic polymer Polymers 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 230000004734 cutaneous carcinogenesis Effects 0.000 description 1
- 230000002951 depilatory effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000012470 diluted sample Substances 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 208000001848 dysentery Diseases 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 210000001723 extracellular space Anatomy 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 244000053095 fungal pathogen Species 0.000 description 1
- 201000004946 genital herpes Diseases 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 229920006008 lipopolysaccharide Polymers 0.000 description 1
- 238000009630 liquid culture Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 239000002353 niosome Substances 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 238000001225 nuclear magnetic resonance method Methods 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 206010033675 panniculitis Diseases 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 230000000379 polymerizing effect Effects 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- CMDGQTVYVAKDNA-UHFFFAOYSA-N propane-1,2,3-triol;hydrate Chemical compound O.OCC(O)CO CMDGQTVYVAKDNA-UHFFFAOYSA-N 0.000 description 1
- 229940055019 propionibacterium acne Drugs 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- LJPZHJUSICYOIX-UHFFFAOYSA-N quinolizidine Chemical class C1CCCC2CCCCN21 LJPZHJUSICYOIX-UHFFFAOYSA-N 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 210000001732 sebaceous gland Anatomy 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000036556 skin irritation Effects 0.000 description 1
- 231100000475 skin irritation Toxicity 0.000 description 1
- 201000010153 skin papilloma Diseases 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 210000004304 subcutaneous tissue Anatomy 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000013271 transdermal drug delivery Methods 0.000 description 1
- 229940075466 undecylenate Drugs 0.000 description 1
- 229940033063 undecylenic acid / zinc undecylenate Drugs 0.000 description 1
- 229940118696 vibrio cholerae Drugs 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
-
- 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
- A61K31/74—Synthetic polymeric materials
- A61K31/785—Polymers containing nitrogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- 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)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Dermatology (AREA)
- Communicable Diseases (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Oncology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
本发明属于药物领域，涉及一种具有抗真菌作用的脂微球制剂。该脂微球制剂，主要由以下成分组成：(1)中药提取物，(2)抗真菌药物，(3)植物油，(4)抗菌增强剂，(5)注射用磷脂，(6)等渗剂，(7)抗氧化剂VE。本发明制备的脂微球制剂发挥了中西药物的互补作用，通过脂质体包裹可以很好的解决药物的水溶性，采用聚乙亚胺的增强药物杀菌作用，利用透皮增强剂提高药物的透皮吸收并将药物送入真皮层提高药效，避免有副作用的传统助溶剂的使用，可以减少药物以及助溶剂进入全身血液循环系统，可以减少对皮肤的刺激。
Description
技术领域
本发明属于药物领域，涉及一种具有抗真菌作用的脂微球制剂。
背景技术
脂微球是将药物包封于磷脂双分子层，或者包裹在内核的植物油中。脂微球 结构类似细胞结构，具有一定的生物膜的特性和功能，它可以包裹水溶性和脂溶 性两种类型的药物，已广泛用于药物制剂领域，该类药物载体具有提高生物利用 度、降低药物毒副作用、长效缓释等作用。
皮肤疾病大多位于毛囊、皮脂腺等活的表皮组织，如疱疹、皮炎、粉刺等， 药物局部治疗成功的关键是药物必须透过角质层而达到病变部位，并维持一定时 间。使用具有生物膜相似结构的脂微球作为局部用药载体，与传统外用制剂膏剂 等相比，皮肤角质层药物透过量更多，减少药物进入血液循环，同时可避免处方 中使用氮酮等促透药需要乙醇、甲醇等溶剂促渗透，刺激病变部位皮肤。研究表 明氮酮对水溶性药物的促渗作用强于脂溶性药物，而脂微球制剂则可根据药物性 质调节膜材比例提高包水、油溶性两种药物载药量。采用磷脂制备的脂微球本身 具有护肤、美容功效，采用脂微球制剂对局部创伤或病变皮肤、粘膜进行治疗， 不仅利于药物在局部发挥药效，同时，脂微球本身可生物降解，无毒性，不产生 皮肤刺激性，兼具化妆品美容产品功效。
脂微球对皮肤有以下几种作用机制：(1)水合机制脂微球提供了外源性脂 质双层膜，使角质细胞间结构改变，脂质双层中疏水性尾部排列紊乱，脂溶性药 物可通过扩散和毛细管作用进入细胞间隙，使角质层湿化和水合作用加强，有人 作过比较，用亲水性的磷脂与直径200nm左右的多室脂质体结合能力比较，发 现后者为前者的5倍。(2)穿透机制作为转运药物的载体，完整的脂微球可以 穿过角质细胞、角质细胞之间的间隙和皮肤附属管道开口进入皮肤，因脂微球大 小组成不同，穿透皮肤浓度亦不一样，同时把药物带入的深度不一样[1]。
等[7]将不同浓度的脂微球涂布于猪背部脱毛皮肤上，分离研究表明，在皮肤中 各层磷脂含量随脂微球浓度增高而增高，但当磷脂浓度大于1.0mg·cm-2时不再增高，其中分布于角质层中磷脂含量占99.5％。Egbaria[3]通过类似实验证明,皮 肤脂质所组成的脂微球作用优于磷脂脂质体。利用此特点我们可进行合理的处方 设计。(3)融合机制提供必须脂肪酸和类脂双层膜，脂微球磷脂与角质层脂质融 合使角质层组成和结构改变，形成一种扁平的颗粒结构，通过脂质颗粒间隙，脂 微球包封的药物便于进入皮肤，经由脂质交换、融合作用，维护皮肤生理功能[4]。 Blume等[5]用核磁共振方法研究不同组分脂微球与皮肤角质层模拟物的相互作 用，表明当加热到37℃放置2～24h，可观察到脂质互相混合，可能由于脂质分子 单体通过水相交换，但也不排斥颗粒间的融合。Gulaskharan[6]于1979年，首 次报道以脂微球包封药物用于透皮吸收，可使更多药物留在表皮到真皮之间，而 使透皮吸收进入血液系统的药量减少，从而有效的避免了全身性不良反应。Masini等[8]在研究维A酸脂微球应用时发现，0.01％维A酸脂微球经皮肤局部给 药后生物利用度高于0.05％维A酸凝胶剂，且前者在靶组织中蓄积和贮存量增加 而进入血液循环的药量减少，表明脂微球能增进维A酸的疗效，减少其毒副作用。
Artisan等[9]用市售大豆磷脂作实验证实，分子量在2万～5万的单克隆抗体 脂微球能很快进入皮肤深层，但不能穿透皮肤，而这种抗体的水溶液不能渗透皮 肤。同时Jorosh等有关DNA修复酶脂微球应用于皮肤的研究也证实了这一点。 说明水溶性药物脂微球也能很快地进入皮肤深层，高分子量物质可以以脂微球为 载体透皮吸收。这对于生物大分子药物防治皮肤病具有重要意义。如生物蛋白 T4N5的脂微球定位于皮肤DNA修复，从而降低紫外线引起皮肤癌发生的可能性 [10]。使用α-干扰素可治疗疱疹、生殖器疣等病毒性感染皮肤病，Hu等以甘油 二月桂酸酯、胆固醇和聚氧乙烯-10-硬脂酸酯制备其脂微球，该脂微球能促进 α-干扰素局部转运进入无毛小鼠皮肤活的表皮组织。
Row等[11]以黄体酮脂微球治疗多毛症时发现，真皮层及皮下组织(毛囊处) 中药物浓度较高，以益康唑脂微球进行体外试验，证明与传统制剂相比，表皮中 有较高的药物浓度。Siciliao[12]强调指出，脂微球在皮肤病学和化妆品方面的良 好前景。
聚乙基亚胺是由亚乙基亚胺聚合而成的高分子化合。与普通的直链高分子不 同，聚乙基亚胺有伯胺、叔胺、和季胺，以1:2:1的比列组成。聚乙基亚胺有一 定的抗菌作用，与很多抗菌药物有很强的协同性，可以增强这些药物的杀菌作用。
聚乙基亚胺(PEI)是一种弱碱性、脂肪族高分子聚合物，根据研究[12][13]发 现，聚乙基亚胺对各种抗生素具有协同作用，可以对抗白色念珠菌等引起的疾病。 聚乙烯亚胺增强了部分亲水性和疏水性抗生素的杀菌效果。聚乙烯亚胺可能通过 竞争细菌脂多糖的阳离子结合位点来减少多粘菌素类的聚阳离子抗生素和氨基 糖苷类的摄取，破坏了整个细菌组织，促进了抗生素的渗透。
苦参碱[14]体外具有抗真菌活性，能抑制和杀灭羊毛状小孢子菌、白色念珠 菌等多种真菌。苦参碱是由豆科植物苦参的根、茎、果实经乙醇等有机溶剂提取 的一种生物碱，属于喹诺里西啶类的衍生物羽扇豆生物碱类。0.3％～1％苦参碱 溶液对乙型链球菌、痢疾杆菌、变形杆菌、大肠杆菌、金黄色葡葡球菌、绿脓杆 菌均有较强的抑制作用。有报道苦参总碱对结核杆菌、霍乱弧菌、麻风杆菌、皮 肤致病性真菌及钩端螺旋体等病原体也都有一定抑制杀灭作用。苦参碱溶于冷水、 乙醇、乙醚、氯仿和苯，难溶于石油醚，在热水中溶解度比在冷水中小。苦参碱 的高脂溶性非常适合制备成脂微球制剂。
本发明利用聚乙基亚胺与脂微球粗渗透作用、保护皮肤等功效，通过包裹可 以抗真菌的苦参碱，以及其它常用抗真菌药物，协同作用，达到增强抗菌杀菌作 用，同时对病变皮肤起到修复作用。
发明内容
本发明的目的在于提供一种具有抗真菌作用的脂微球制剂。
本发明制备的脂微球制剂采用中药提取物与现代制剂技术制备，通过脂微球 包裹可以很好的解决药物的水溶性，采用透皮增强剂聚乙亚胺提高药物的透皮吸 收并将药物送入真皮层提高药效，避免有副作用的传统助溶剂的使用，增强药物 杀菌作用，利用可以减少药物以及助溶剂进入全身血液循环系统，减少对皮肤的 刺激。
本发明通过下述技术方案实现：
本发明提供一种抗真菌组合药物，其特征在于，组成如下：
(1)中药提取物，用量为0.1％-20％(2)抗真菌药物，用量为0.1％-10％(3) 植物油，用量为5％-30％，(4)抗菌增强剂，用量为0.02％-8％(5)注射用磷脂 0.3％-3％，(6)等渗剂，用量为0.5％-5％(7)抗氧化剂VE，用量为1％
上述中药提取物选自：苦参碱、以及土荆皮、白鲜皮、花椒、百部、地肤子、 黄柏中的一种或一种以上，优选为苦参碱。
上述抗真菌药物选自：硝酸咪康唑、益康唑、曲康唑、氟康唑、十一烯酸、 十一烯酸锌中的一种或一种以上，
上述植物油选自：市售注射用大豆油、注射用中链油、红花油、橄榄油、桉 树油、薄荷油、玫瑰油、麝香油中的一种或一种以上。
上述抗菌增强剂选用分子量为2-50ku的聚乙基亚胺。
上述注射用磷脂选自：市售注射用大豆磷脂、注射用蛋黄卵磷脂、氢化大豆 磷脂、氢化蛋黄磷脂中的一种或多种。
等渗剂为甘油。
本发明所述的脂微球制剂，可以制备成任何可药用剂型，优选为外用制剂， 包括：喷雾剂、乳剂、膏剂、霜剂、贴剂。
本发明所述的脂微球制剂优选配方如下：
本发明提供的抗真菌药物制剂制备方法如下：
取注射用磷脂，抗菌增强剂加入植物油中搅拌加热至45℃约30分钟混匀， 然后加入中药提取物，抗真菌药物，维生素E，溶解混匀。另取注射用水，加入 等渗剂。在氮气保护的条件下，将上述混合油溶液加入混合水溶液中。经高压均 质机均质7-8次，压力为100MPa，至粒径范围在180-300nm，调节pH 7.0-8.0， 过滤，分装，通入氮气，密封。115℃灭菌30分钟，灯检合格后，包装。在25℃ 以下贮藏。
本发明与现有技术相比，具有如下优点：
1.透皮性能好，作用持久，减少复发：脂微球独特的结构以及采用聚乙烯亚 胺组成的多元促透剂可以达到单一促透剂无法比拟的效果，使该产品具有很强的 透皮性，能将药物快速送达并蓄积于皮肤深层，彻底治愈，有效减少复发
2.疗程短：由于聚乙烯亚胺与被包裹抗真菌药物具有协同作用，抗真菌效果 提高，所以使用该制剂可缩短疗程；
3.护肤作用：脂微球中的磷脂具有护肤作用，维生素E的抗氧化剂和皮肤 营养作用也对皮肤起到保护作用，在治疗的同时，促进病变皮肤复原。
具体实施方式：
为使本发明的目的、技术方案和优点更加清楚明白，下面结合实施例，对本 发明作进一步的详细说明，本发明的示意性实施方式及其说明仅用于解释本发明， 并不作为对本发明的限定。
实施例1：
将上述处方量注射用蛋黄卵磷脂，聚乙烯亚胺加入大豆油、麝香油中搅拌 加热至45℃约30分钟混匀，然后加入苦参碱，硝酸咪康唑，维生素E，溶解混 匀。另取注射用水，加入甘油。在氮气保护的条件下，将上述混合油溶液加入甘 油水溶液中。经高压均质机均质7-8次，压力为100MPa，至粒径范围在180-300nm， 调节pH 7.0-8.0，过滤，分装，通入氮气，密封。115℃灭菌30分钟，灯检合格 后，包装。在25℃以下贮藏。
实施例2：
将上述处方量注射用蛋黄卵磷脂，聚乙烯亚胺加入注射用大豆油、薄荷油 中搅拌加热至45℃约30分钟混匀，然后加入苦参碱，硝酸益康唑，维生素E， 溶解混匀。另取注射用水，加入甘油。在氮气保护的条件下，将上述混合油溶液 加入甘油水溶液中。经高压均质机均质7-8次，压力为100MPa，至粒径范围在 180-300nm，调节pH 7.0-8.0，过滤，分装，通入氮气，密封。115℃灭菌30分 钟，灯检合格后，包装。在25℃以下贮藏。
实施例3：
将上述处方量注射用蛋黄卵磷脂，聚乙烯亚胺加入注射用大豆油、红花油 中搅拌加热至45℃约30分钟混匀，然后加入苦参碱，酮康唑，维生素E，溶解 混匀。另取注射用水，加入甘油。在氮气保护的条件下，将上述混合油溶液加入 甘油水溶液中。经高压均质机均质7-8次，压力为100MPa，至粒径范围在 180-300nm，调节pH 7.0-8.0，过滤，分装，通入氮气，密封。115℃灭菌30分 钟，灯检合格后，包装。在25℃以下贮藏。
实施例4：
将上述处方量注射用蛋黄卵磷脂，聚乙烯亚胺加入大豆油、中链油橄榄油 中搅拌加热至45℃约30分钟混匀，然后加入苦参碱，维生素E，溶解混匀。另 取注射用水，加入氟康唑，加入甘油。在氮气保护的条件下，将上述混合油溶液 加入甘油水溶液中。经高压均质机均质7-8次，压力为100MPa，至粒径范围在 180-300nm，调节pH 7.0-8.0，过滤，分装，通入氮气，密封。115℃灭菌30分 钟，灯检合格后，包装。在25℃以下贮藏。
实施例5：
将上述处方量注射用蛋黄卵磷脂，聚乙烯亚胺加入大豆油、中链油橄榄油 中搅拌加热至45℃约30分钟混匀，然后加入苦参碱，十一烯酸，十一烯酸锌， 维生素E，溶解混匀。另取注射用水，加入甘油。在氮气保护的条件下，将上述 混合油溶液加入甘油水溶液中。经高压均质机均质7-8次，压力为100MPa，至 粒径范围在180-300nm，调节pH 7.0-8.0，过滤，分装，通入氮气，密封。115℃ 灭菌30分钟，灯检合格后，包装。在25℃以下贮藏。
使用效果测试 随机选取30名长期脚气患者作为试用者，分为三组，每组10名，清洁皮肤后， 取实施例1-3适量涂抹于患病部位，每天早晚各一次，连续使用至症状消失。试用效果如下所示：
抗菌效果测试
实验材料菌株：金黄葡萄球菌、白色念珠菌、痤疮丙酸杆菌
实验方法：1、按照QB/T2738-2012《日化产品抗菌抑菌效果的评价方法》7.2抑 菌型日化产品的抗菌效果检验方法(悬液定量法)
2、按照1:1(V/V)比例用无菌水稀释试验样品，然后取稀释后样品对试验菌作 用5min，试验在20±1℃条件下重复3次，取平均值。
效果评价：杀菌率≥90％，产品有杀菌作用；杀菌率≥50％-90％的产品有抑菌作用。
试验结果：
实施例1：
实施例2：
实施例3：
抑菌体外实验
对实施例1-5组合物和单个抗真菌药物硝酸咪康唑、硝酸益康唑、酮康唑、 氟康唑、十一烯酸/十一烯酸锌进行体外抗真菌试验。试验所用细胞株均为卫生 部医学微生物菌(毒)种保藏管理中心真菌中心提供ATCC标准菌株，其中包括:
熏颜色曲霉:菌号ATCC3626
白念珠菌：菌号ATCC90028
红色毛癣菌：菌号ATCC4438
须癣毛癣菌：菌号ATCC4439
参照美国临床和实验室标准化研究所颁布的酵母菌M-27A3和丝状真菌 M-38P的标准方法进行实验：
菌液制备：实验前，将实验菌活化后，酵母菌在沙保弱琼脂培养基上，30℃ 培养48小时，丝状真菌在马铃薯葡萄糖琼脂培养基上，26℃培养7-10天，用无 菌生理盐水配成悬液，经血球计数板计数，用倍量含2％葡萄糖RMPI-1640液体 培养基稀释成白念球菌1.0×103cfu/mL，其它三株丝状真菌配成2.5×104cfu/mL, 分别取菌液0.1ml，加入含有实施例1-5制备得到的制剂和相同剂量的硝酸咪康 唑、硝酸益康唑、酮康唑、氟康唑、十一烯酸/十一烯酸锌的培养基到各孔中， 溶媒对照孔中加入0.1ml稀释后的溶媒，对照孔中加入0.1ml的蒸馏水。加样完 毕后，放在摇板机上，转速100r/minx10min，使得药物与菌液充分接触。以不含 任何抗生素的2％葡萄糖RMPI-1640液体培养基作为基础培养基。下表为90％最 低抑菌浓度(90％MIC)测定结果：
| 熏颜色曲霉 | 白念珠菌 | 红色毛癣菌 | 须癣毛癣菌 | |
| 实施例1制剂 | 2.5 | 1.4 | 3.3 | 4.6 |
| 硝酸咪康唑 | 3.8 | 1.6 | 4.5 | 5.1 |
上述实验结果表明，实施例1制剂抑菌效果优于硝酸咪康唑单独使用。
| 熏颜色曲霉 | 白念珠菌 | 红色毛癣菌 | 须癣毛癣菌 | |
| 实施例2制剂 | 7.5 | 2.2 | 5.9 | 4.3 |
| 硝酸益康唑 | 8.9 | 2.4 | 7.8 | 5.5 |
上述实验结果表明，实施例2制剂抑菌效果优于硝酸益康唑单独使用。
| 熏颜色曲霉 | 白念珠菌 | 红色毛癣菌 | 须癣毛癣菌 | |
| 实施例3制剂 | 2.5 | 1.9 | 6.3 | 6.6 |
| 酮康唑 | 4.7 | 3.6 | 6.8 | 7.3 |
上述实验结果表明，实施例3制剂抑菌效果优于酮康唑单独使用。
| 熏颜色曲霉 | 白念珠菌 | 红色毛癣菌 | 须癣毛癣菌 | |
| 实施例4制剂 | 4.1 | 3.2 | 5.6 | 6.2 |
| 氟康唑 | 4.6 | 3.9 | 8.3 | 5.1 |
上述实验结果表明，实施例4制剂抑菌效果优于氟康唑单独使用。
上述实验结果表明，实施例5制剂抑菌效果优于使用十一烯酸、十一烯酸锌组合物的抑菌效果。
参考文献
1、Messy M,Gulasekuaram V.liposomes–a selective drug delivery systemfor the topical route of administration:gel dosage from.J Pham Pharmacol,1982,34: 473
2、
J,Artmann C.The fate of liposome in animal skin.In:Braun-Falcon O, Korting HC,Maibach HI ends.Liposome Dermatics.Berlin:Springer-Verlag 1992: 185～194
3、Egbaria K,Wiener N.Topical delivery of liposomally encapsulatedingredients evaluated by in vito diffusion studies.In:Braun–Falcon O,KortingHC,Maibach HI ends Liposome Dermatics,Berlin:Sprinkle-Verlag,1992:172～181
4、
J,Ghyczy M.Control of skin humidity with liposomes.
1991,10: 372
5、Blume G,Jansen M,Ghyczy M,et al.Interaction of phospholipidliposome with lipid model mixtures for startum corneum lipid.Int J Pharm,1993,99:219
6、Gulasekharan Vertal.J.Pham Pharmacol.1982:34,473
7、Brouwstra JA,Hofland HE J,Spies F,et al.Changes in the structure ofthe human stratum coreum induced by liposomes
8、Masini V,Bonte F,Meykeck A,et al.J Pham Sci,1993,82(1):17
9、Schhreier H,Bouwstra J.Liposomes and niosomes as topical drugarrivers: dermal and transdermal drug delivery.J Controlled Release,1994,30(1):1
10、Yarosh D,Klein J.Adv Drug Delivery Rev,1996:18(3):325
11、Row TC et al.The Prostate,1984,5:346
12、陈涛等，聚乙烯亚胺阳离子高聚物对白色念珠菌的体外抗真菌活性.第 四军医大学学报，10.3321/j.issn:1000-2790.2006.15.012
13、陈涛等，聚乙烯亚胺单独及与三种抗菌药物联用对白念珠菌的体外抗菌 活性.中国抗生素杂志，2007(032)008
14、桂属华等，苦参碱体外抗真菌活性研究，中药新药与临床药理，2011， 4：382
Claims (7)
1.一种抗真菌的脂微球制剂，其特征在于，主要由以下成分组成：
(1)中药提取物，用量为0.1％-20％，(2)抗真菌药物，用量为0.1％-10％，(3)植物油，用量为5％-30％，(4)抗菌增强剂，用量为0.02％-8％，(5)注射用磷脂0.3％-3％，(6)等渗剂，用量为0.5％-5％(7)抗氧化剂VE，用量为1％。
2.根据权利要求1所述的脂微球制剂，其特征在于，
中药提取物选自：苦参碱、以及土荆皮、白鲜皮、花椒、百部、地肤子、黄柏中的一种或一种以上，
抗真菌药物选自：硝酸咪康唑、益康唑、曲康唑、氟康唑、十一烯酸、十一烯酸锌中的一种或一种以上，
植物油选自：市售注射用大豆油、注射用中链油、红花油、橄榄油、桉树油、薄荷油、玫瑰油、麝香油中的一种或一种以上，
抗菌增强剂选用分子量为2-50ku的聚乙基亚胺，
注射用磷脂选自：市售注射用大豆磷脂、注射用蛋黄卵磷脂、氢化大豆磷脂、氢化蛋黄磷脂中的一种或多种，
等渗剂为甘油。
3.根据权利要求1所述的脂微球制剂，其特征在于，主要由以下成分组成：
4.根据权利要求1所述的脂微球制剂，其特征在于，主要由以下成分组成：
5.根据权利要求1所述的脂微球制剂，其特征在于，制备成任何可药用剂型。
6.根据权利要求1所述的脂微球制剂，其特征在于，制备成外用制剂，包括：
喷雾剂、乳剂、膏剂、霜剂、贴剂。
7.权利要求1所述的脂微球制剂，其特征在于，包括以下步骤：
取注射用磷脂，抗菌增强剂加入植物油中搅拌加热至45℃约30分钟混匀，然后加入中药提取物，抗真菌药物，维生素E，溶解混匀，另取注射用水，加入等渗剂，在氮气保护的条件下，将上述混合油溶液加入混合水溶液中，经高压均质机均质7-8次，压力为100MPa，至粒径范围在180-300nm，调节pH 7.0-8.0，过滤，分装，通入氮气，密封，115℃灭菌30分钟，灯检合格后，包装。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011168666.XA CN112336868A (zh) | 2020-10-28 | 2020-10-28 | 聚乙基亚胺苦参碱脂微球抗真菌制剂及其应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011168666.XA CN112336868A (zh) | 2020-10-28 | 2020-10-28 | 聚乙基亚胺苦参碱脂微球抗真菌制剂及其应用 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN112336868A true CN112336868A (zh) | 2021-02-09 |
Family
ID=74359167
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011168666.XA Pending CN112336868A (zh) | 2020-10-28 | 2020-10-28 | 聚乙基亚胺苦参碱脂微球抗真菌制剂及其应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112336868A (zh) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101032486A (zh) * | 2006-03-08 | 2007-09-12 | 张宏 | 逆转唑类药物抗真菌活性多药耐药性的药用植物增效剂 |
| CN101700229A (zh) * | 2009-11-20 | 2010-05-05 | 西安力邦制药有限公司 | 静脉注射用前列地尔长循环脂微球制剂及其制备方法 |
| CN101966150A (zh) * | 2010-09-25 | 2011-02-09 | 西安力邦制药有限公司 | 鱼腥草素衍生物脂微球制剂及其制备方法 |
| CN102526065A (zh) * | 2011-12-26 | 2012-07-04 | 西安力邦制药有限公司 | 一种治疗心脑血管疾病的复方注射制剂及其制备方法 |
| CN102525921A (zh) * | 2012-02-06 | 2012-07-04 | 西安力邦制药有限公司 | 2,2’,6,6’-四异丙基-4,4’-二联苯酚脂微球制剂及其制备方法 |
| CN104146957A (zh) * | 2014-07-24 | 2014-11-19 | 西安力邦肇新生物科技有限公司 | 亚微乳抗真菌药物喷雾剂制剂 |
-
2020
- 2020-10-28 CN CN202011168666.XA patent/CN112336868A/zh active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101032486A (zh) * | 2006-03-08 | 2007-09-12 | 张宏 | 逆转唑类药物抗真菌活性多药耐药性的药用植物增效剂 |
| CN101700229A (zh) * | 2009-11-20 | 2010-05-05 | 西安力邦制药有限公司 | 静脉注射用前列地尔长循环脂微球制剂及其制备方法 |
| CN101966150A (zh) * | 2010-09-25 | 2011-02-09 | 西安力邦制药有限公司 | 鱼腥草素衍生物脂微球制剂及其制备方法 |
| CN102526065A (zh) * | 2011-12-26 | 2012-07-04 | 西安力邦制药有限公司 | 一种治疗心脑血管疾病的复方注射制剂及其制备方法 |
| CN102525921A (zh) * | 2012-02-06 | 2012-07-04 | 西安力邦制药有限公司 | 2,2’,6,6’-四异丙基-4,4’-二联苯酚脂微球制剂及其制备方法 |
| CN104146957A (zh) * | 2014-07-24 | 2014-11-19 | 西安力邦肇新生物科技有限公司 | 亚微乳抗真菌药物喷雾剂制剂 |
Non-Patent Citations (1)
| Title |
|---|
| 陈涛等: "聚乙烯亚胺单独及与三种抗菌药物联用对白念珠菌的体外抗菌活性", 《中国抗生素杂志》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Bseiso et al. | Novel nail penetration enhancer containing vesicles “nPEVs” for treatment of onychomycosis | |
| JP5694665B2 (ja) | 局所製剤とその用法 | |
| CN110585114B (zh) | 一种调节皮肤微生物菌群的杀菌组合物及其应用 | |
| KR20070072482A (ko) | 치료적 응용을 위한 유기겔 제제형 | |
| UA89500C2 (uk) | Органогель для терапевтичного застосування | |
| US9775789B2 (en) | Topical liposome compositions containing phenolic anti-inflammatory agents and their methods of preparation | |
| CN102552147B (zh) | 一种布拉他辛醇质体凝胶剂及其制备方法 | |
| US20210244684A1 (en) | Cannabinoid and menthol transdermal delivery systems and methods | |
| CN104983675B (zh) | 一种维a酸醇质体凝胶剂及其制备方法 | |
| Vanić | Phospholipid vesicles for enhanced drug delivery in dermatology | |
| CN112587593A (zh) | 一种治疗痤疮的组合物及其制备方法 | |
| Ansari et al. | Ethosomes-based gel formulation of karanjin for treatment of acne vulgaris: in vitro investigations and preclinical assessment | |
| CN112263544B (zh) | 一种盐酸利多卡因凝胶及其制备方法 | |
| CN110974861B (zh) | 一种艾纳香油脂质体 | |
| CN107921137A (zh) | 组合物和治疗方法 | |
| CN111840148B (zh) | 一种具有抗敏和防腐功效的护肤组合物及其制备方法 | |
| CN112336868A (zh) | 聚乙基亚胺苦参碱脂微球抗真菌制剂及其应用 | |
| Waghmare et al. | Novasome: advance in liposome and niosome | |
| GÜNAYDIN et al. | Recent approaches in topical acne treatment and drug delivery. | |
| Faheem et al. | Niosome-based gels: a smart nano-carrier for effective and advanced transdermal drug delivery | |
| CN101744799B (zh) | 一种兽用沃尼妙林及其盐的脂质体新剂型及其制备方法 | |
| Gupta et al. | Transfersomes for Escalating Effectiveness of Drugs via Transdermal and Topical Administration: A Review | |
| CN116602959B (zh) | 一种具有抗炎镇痛功效的含茶活性成分的组合物脂质体及其应用 | |
| CN113713000B (zh) | 用于治疗疮痈、烧烫伤和痤疮的主药成分组合物、缓控释药物制剂及其制备方法和应用 | |
| KR20040076092A (ko) | Ａｌａ 및 양이온성 리포좀을 포함하는 여드름 치료용외용 제제 |
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 | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20210209 |
|
| RJ01 | Rejection of invention patent application after publication |