CN106821962A - Amphotericin B cubic liquid crystal gel, cubic liquid crystal nanoparticle and preparation method thereof - Google Patents
Amphotericin B cubic liquid crystal gel, cubic liquid crystal nanoparticle and preparation method thereof Download PDFInfo
- Publication number
- CN106821962A CN106821962A CN201611185282.2A CN201611185282A CN106821962A CN 106821962 A CN106821962 A CN 106821962A CN 201611185282 A CN201611185282 A CN 201611185282A CN 106821962 A CN106821962 A CN 106821962A
- Authority
- CN
- China
- Prior art keywords
- amphotericin
- liquid crystal
- cubic liquid
- cubic
- nanoparticle
- 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
- 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 title claims abstract description 235
- 229960003942 amphotericin b Drugs 0.000 title claims abstract description 235
- 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 title claims abstract description 234
- 239000004973 liquid crystal related substance Substances 0.000 title claims abstract description 180
- 239000002105 nanoparticle Substances 0.000 title claims abstract description 119
- 238000002360 preparation method Methods 0.000 title claims abstract description 36
- 239000000463 material Substances 0.000 claims abstract description 34
- 239000003381 stabilizer Substances 0.000 claims abstract description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000002994 raw material Substances 0.000 claims abstract description 16
- 239000000243 solution Substances 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 239000006185 dispersion Substances 0.000 claims description 10
- 239000012467 final product Substances 0.000 claims description 10
- 210000004027 cell Anatomy 0.000 claims description 9
- 238000000265 homogenisation Methods 0.000 claims description 8
- -1 polyoxyethylene Polymers 0.000 claims description 8
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical group CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 claims description 6
- 239000012153 distilled water Substances 0.000 claims description 6
- CGIHFIDULQUVJG-VNTMZGSJSA-N phytantriol Natural products CC(C)CCC[C@H](C)CCC[C@H](C)CCC[C@@](C)(O)[C@H](O)CO CGIHFIDULQUVJG-VNTMZGSJSA-N 0.000 claims description 6
- CGIHFIDULQUVJG-UHFFFAOYSA-N phytantriol Chemical compound CC(C)CCCC(C)CCCC(C)CCCC(C)(O)C(O)CO CGIHFIDULQUVJG-UHFFFAOYSA-N 0.000 claims description 6
- 229920001993 poloxamer 188 Polymers 0.000 claims description 6
- 229940044519 poloxamer 188 Drugs 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 208000034530 PLAA-associated neurodevelopmental disease Diseases 0.000 claims description 4
- 210000000170 cell membrane Anatomy 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 238000002844 melting Methods 0.000 claims description 4
- 230000008018 melting Effects 0.000 claims description 4
- 229920002101 Chitin Polymers 0.000 claims 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 claims description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 2
- 239000004698 Polyethylene Substances 0.000 claims description 2
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical compound ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 claims description 2
- 238000004108 freeze drying Methods 0.000 claims description 2
- 239000008055 phosphate buffer solution Substances 0.000 claims description 2
- YHHSONZFOIEMCP-UHFFFAOYSA-O phosphocholine Chemical compound C[N+](C)(C)CCOP(O)(O)=O YHHSONZFOIEMCP-UHFFFAOYSA-O 0.000 claims description 2
- 229920001308 poly(aminoacid) Polymers 0.000 claims description 2
- 229920000573 polyethylene Polymers 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- UYVVLXVBEQAATF-UHFFFAOYSA-N 4-(1,3,7,12-tetrahydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl)pentanoic acid Chemical compound OC1CC2CC(O)CC(O)C2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 UYVVLXVBEQAATF-UHFFFAOYSA-N 0.000 claims 1
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 1
- 230000004888 barrier function Effects 0.000 abstract description 15
- 230000035699 permeability Effects 0.000 abstract description 6
- 239000002245 particle Substances 0.000 description 48
- 239000003814 drug Substances 0.000 description 37
- 229940079593 drug Drugs 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 230000000052 comparative effect Effects 0.000 description 15
- 238000004090 dissolution Methods 0.000 description 15
- 230000000694 effects Effects 0.000 description 11
- 238000000034 method Methods 0.000 description 11
- 230000000968 intestinal effect Effects 0.000 description 10
- 238000010521 absorption reaction Methods 0.000 description 9
- 235000013339 cereals Nutrition 0.000 description 9
- 210000004369 blood Anatomy 0.000 description 8
- 239000008280 blood Substances 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 241000700159 Rattus Species 0.000 description 7
- 238000000338 in vitro Methods 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 102000010637 Aquaporins Human genes 0.000 description 6
- 239000012738 dissolution medium Substances 0.000 description 6
- 238000009826 distribution Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 5
- 239000012530 fluid Substances 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 210000002381 plasma Anatomy 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 239000000232 Lipid Bilayer Substances 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 230000005540 biological transmission Effects 0.000 description 4
- 239000010949 copper Substances 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 230000006378 damage Effects 0.000 description 4
- 238000009792 diffusion process Methods 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 238000003305 oral gavage Methods 0.000 description 4
- 108010063290 Aquaporins Proteins 0.000 description 3
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 229910052802 copper Inorganic materials 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 238000007710 freezing Methods 0.000 description 3
- 230000008014 freezing Effects 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 229940090044 injection Drugs 0.000 description 3
- 239000004033 plastic Substances 0.000 description 3
- 229920003023 plastic Polymers 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 238000000235 small-angle X-ray scattering Methods 0.000 description 3
- 210000002784 stomach Anatomy 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- GGYKPYDKXLHNTI-UHFFFAOYSA-N 2,6,10,14-tetramethylhexadecane Chemical compound CCC(C)CCCC(C)CCCC(C)CCCC(C)C GGYKPYDKXLHNTI-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000000604 cryogenic transmission electron microscopy Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 210000001842 enterocyte Anatomy 0.000 description 2
- 210000002919 epithelial cell Anatomy 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 210000000936 intestine Anatomy 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- ZGEGCLOFRBLKSE-UHFFFAOYSA-N methylene hexane Natural products CCCCCC=C ZGEGCLOFRBLKSE-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000003182 parenteral nutrition solution Substances 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000001568 sexual effect Effects 0.000 description 2
- 238000004088 simulation Methods 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 229910021642 ultra pure water Inorganic materials 0.000 description 2
- 239000012498 ultrapure water Substances 0.000 description 2
- DRAWQKGUORNASA-UHFFFAOYSA-N (2-hydroxy-3-octadec-9-enoyloxypropyl) octadec-9-enoate Chemical compound CCCCCCCCC=CCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCC=CCCCCCCCC DRAWQKGUORNASA-UHFFFAOYSA-N 0.000 description 1
- OILXMJHPFNGGTO-UHFFFAOYSA-N (22E)-(24xi)-24-methylcholesta-5,22-dien-3beta-ol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)C=CC(C)C(C)C)C1(C)CC2 OILXMJHPFNGGTO-UHFFFAOYSA-N 0.000 description 1
- RQOCXCFLRBRBCS-UHFFFAOYSA-N (22E)-cholesta-5,7,22-trien-3beta-ol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CCC(C)C)CCC33)C)C3=CC=C21 RQOCXCFLRBRBCS-UHFFFAOYSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- OQMZNAMGEHIHNN-UHFFFAOYSA-N 7-Dehydrostigmasterol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CC(CC)C(C)C)CCC33)C)C3=CC=C21 OQMZNAMGEHIHNN-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 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
- 241000894006 Bacteria Species 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- DNVPQKQSNYMLRS-NXVQYWJNSA-N Ergosterol Natural products CC(C)[C@@H](C)C=C[C@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@@H]3CC[C@]12C DNVPQKQSNYMLRS-NXVQYWJNSA-N 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 208000008454 Hyperhidrosis Diseases 0.000 description 1
- 206010068052 Mosaicism Diseases 0.000 description 1
- MKYBYDHXWVHEJW-UHFFFAOYSA-N N-[1-oxo-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propan-2-yl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(C(C)NC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 MKYBYDHXWVHEJW-UHFFFAOYSA-N 0.000 description 1
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- XOJVVFBFDXDTEG-UHFFFAOYSA-N Norphytane Natural products CC(C)CCCC(C)CCCC(C)CCCC(C)C XOJVVFBFDXDTEG-UHFFFAOYSA-N 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
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 206010057249 Phagocytosis Diseases 0.000 description 1
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 241000122969 Streptomyces nodosus Species 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229940009444 amphotericin Drugs 0.000 description 1
- 229940025953 amphotericin b injection Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000000227 bioadhesive Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 208000013219 diaphoresis Diseases 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000012202 endocytosis Effects 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- DNVPQKQSNYMLRS-SOWFXMKYSA-N ergosterol Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H](CC[C@]3([C@H]([C@H](C)/C=C/[C@@H](C)C(C)C)CC[C@H]33)C)C3=CC=C21 DNVPQKQSNYMLRS-SOWFXMKYSA-N 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 238000005189 flocculation Methods 0.000 description 1
- 230000016615 flocculation Effects 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 238000005374 membrane filtration Methods 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 210000004279 orbit Anatomy 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 230000008782 phagocytosis Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- UYDPQDSKEDUNKV-UHFFFAOYSA-N phosphanylidynetungsten Chemical compound [W]#P UYDPQDSKEDUNKV-UHFFFAOYSA-N 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000006920 protein precipitation Effects 0.000 description 1
- 239000010453 quartz Substances 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000003765 sex chromosome Anatomy 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- FHHPUSMSKHSNKW-SMOYURAASA-M sodium deoxycholate Chemical compound [Na+].C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 FHHPUSMSKHSNKW-SMOYURAASA-M 0.000 description 1
- JAJWGJBVLPIOOH-IZYKLYLVSA-M sodium taurocholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 JAJWGJBVLPIOOH-IZYKLYLVSA-M 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- PHYFQTYBJUILEZ-IUPFWZBJSA-N triolein Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CCCCCCCC)COC(=O)CCCCCCC\C=C/CCCCCCCC PHYFQTYBJUILEZ-IUPFWZBJSA-N 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- 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
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
-
- 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
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5015—Organic compounds, e.g. fats, sugars
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of amphotericin B cubic liquid crystal gel, cubic liquid crystal nanoparticle and preparation method thereof.The amphotericin B cubic liquid crystal gel is mainly prepared from by the raw material of following mass parts：0.1 1 parts of amphotericin B, 0.04 1.7 parts of micellar material, 16 20 parts of liquid crystal material, 0.8 3 parts of stabilizer, 15 25 parts of water；The amphotericin B is 1 with the mass ratio of micellar material:0.3‑2；The liquid crystal material is 9 with the mass ratio of stabilizer:0.4‑1.5.The amphotericin B cubic liquid crystal gel is further prepared into amphotericin B cubic liquid crystal nanoparticle, dissolving barrier and permeability barrier of the amphotericin B during oral administration can be overcome, the stability of amphotericin B is improved, the oral administration biaavailability of amphotericin B is significantly improved.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, more particularly to a kind of amphotericin B cubic liquid crystal gel, nanoparticle and its
Preparation method.
Background technology
Amphotericin B (amphotericin B, AmB) is many alkenes broad-spectrum antifungal antibiotic, tethers mould
A kind of separation product in Streptomyces nodosus nutrient solutions, this macrolide derivatives contain one in molecular structure
Individual nonpolar heptene and a polarity polyalcohol, water insoluble, ethanol, Yi Beiguang, heat and acid destruction.The antibacterial of amphotericin B
Mechanism is：Optionally combined with the ergosterol on fungal cell membrane, fenestra is formed on cell membrane, increased the logical of cell membrane
Permeability, causes various small-molecule substances such as intracellular potassium ion, nucleotides, amino acid to leak outside, and destruction eubolism causes cell
It is dead.
Clinically amphotericin B is main exists in the form of injection.Domestic and international medical personal successively successfully develops
Amphotericin B deoxycholic acid salt injection, amphotericin B lipid complex, amphotericin B colloid dispersion and anphotericin
B liposomes amount to 4 kinds of injections and supply Clinical practice.The appearance of amphotericin B lipid parenteral solution is amphotericin B injection formulation
The important breakthrough obtained in research, to the perfect of early development amphotericin B deoxycholic acid sodium injection, significantly reduces both sexes mould
The infusion reaction and renal toxicity of plain B.But, however it remains certain toxic and side effect and it is expensive the problems such as, so as to limit
Amphotericin B lipid parenteral solution is used in clinical expansion.Therefore, further screening efficiently, the newtype drug of wide spectrum, low toxicity and
It is still a very urgent task that reasonable design medicine formulation solves amphotericin B toxic and side effect
Amphotericin B is administered orally to be had many advantages, such as：Medication under without being instructed in health care professional, patient can be voluntarily
It is convenient to take at home；The problems such as oral administration avoids painful and the transfusion adverse reaction of long term injections, improves patient's
Compliance and the quality of life of raising patient；The amphotericin B research display that is administered orally can keep good anti-true of amphotericin B
Bacterium activity can significantly reduce the toxic and side effect of medicine simultaneously.However, amphotericin B oral absorption faces many technical barriers, grind
Study carefully and make slow progress.The main cause of amphotericin B oral absorption difference is as follows：Amphotericin B belongs under Biopharmaceutics Classification
4th class medicine, solubility is small, poor permeability, there is dissolving barrier and absorption barrier during oral absorption.Additionally, both sexes
Mycin B is sensitive to light and heat, and degradable, oral administration biaavailability is very low.Ground in a series of early stage amphotericin B oral formulations
Study carefully after failure, researcher show that amphotericin B should not prepare the conclusion of oral formulations.
Cubic liquid crystal nanoparticle (Cubosomes) refers to certain density amphipathic lipids material and surfactant-dispersed
Cellular or spongelike structure the nanometer of aquaporin containing co-continuous and closure lipid bilayer is self-assembled into aqueous
Particle.The system is that, with cubic lattice as construction unit, there is small pore passageway (5~10nm) in cubic lattice, contains two
The not connected co-continuous water channel of bar, wherein a water channel leads to outer continuous phase, and another water channel is then closing, doubly-linked
Continue aquaporin and closure lipid bilayer spatially three-dimensional extension, ordered stacks, with three-dimensional, cycle arrangement and minimum table
The tight structure of area feature.
The content of the invention
It is mould for oral both sexes for preparing the invention provides a kind of amphotericin B cubic liquid crystal gel based on this
Plain B cubic liquid crystals nanoparticle, to overcome amphotericin B that barrier and absorption barrier are dissolved present in oral absorption process, carries
The stability of amphotericin B high, to improve its oral administration biaavailability.
Concrete technical scheme is as follows：
A kind of amphotericin B cubic liquid crystal gel, is mainly prepared from by the raw material of following mass parts：
The amphotericin B is 1 with the mass ratio of the micellar material:0.3-2；
The liquid crystal material is 9 with the mass ratio of the stabilizer:0.4-1.5；
The micellar material is selected from NaTDC, polyoxyethylene, polyethylene glycol-chitin copolymer, PVP, imitative thin
At least one in after birth phosphocholine, polyaminoacid, PLA and Poly(D,L-lactide-co-glycolide；The liquid crystal material
It is phytantriol；The stabilizer is poloxamer188.
Wherein in some embodiments, the main raw material system by following mass parts of the amphotericin B cubic liquid crystal gel
It is standby to form：
Wherein in some embodiments, the micellar material is selected from NaTDC, PLA and poly lactic-co-glycolic acid
At least one in copolymer.
Wherein in some embodiments, the amphotericin B is 1 with the mass ratio of the micellar material:0.6-1.3.
Wherein in some embodiments, the amphotericin B is 1 with the mass ratio of the micellar material:0.7-1.0.
Wherein in some embodiments, the liquid crystal material is 9 with the mass ratio of the stabilizer:0.8-1.2.
Wherein in some embodiments, the amphotericin B cubic liquid crystal gel, mainly by the raw material system of following mass parts
It is standby to form：
The amphotericin B is 1 with the mass ratio of the NaTDC:0.7-0.9；
The phytantriol is 9 with the mass ratio of the poloxamer188:0.8-1.2.
Present invention also offers the preparation method of above-mentioned amphotericin B cubic liquid crystal gel.
Concrete technical scheme is as follows：
A kind of preparation method of above-mentioned amphotericin B cubic liquid crystal gel, comprises the following steps：
The preparation of amphotericin B micella：Amphotericin B and micellar material are added in distilled water, concentration is added dropwise is
0.08-0.12mol·L-1Sodium hydroxide solution, it is until amphotericin B is completely dissolved then molten with the phosphoric acid buffer of pH6-6.4
Liquid is diluted, then resulting solution is carried out into freeze-drying, obtains final product the amphotericin B micella；
The preparation of amphotericin B cubic liquid crystal gel：The amphotericin B micella is dissolved in claim any one of 1-6
In described water, the aqueous solution of amphotericin B is obtained；Stabilizer and liquid crystal material heating melting, whirlpool are mixed, added described
The aqueous solution of amphotericin B, whirlpool is mixed, and room temperature is placed, and obtains final product the amphotericin B cubic liquid crystal gel.
Wherein in some embodiments, the temperature of the heating melting is 40-70 DEG C.
Present invention also offers the application of above-mentioned amphotericin B cubic liquid crystal gel.
Concrete technical scheme is as follows：
Application of the above-mentioned amphotericin B cubic liquid crystal gel in amphotericin B cubic liquid crystal nanoparticle is prepared.
Present invention also offers a kind of amphotericin B cubic liquid crystal nanoparticle.
Concrete technical scheme is as follows：
A kind of amphotericin B cubic liquid crystal nanoparticle, is made by above-mentioned amphotericin B cubic liquid crystal gel dispersion in water
It is standby to form.
Present invention also offers a kind of preparation method of amphotericin B cubic liquid crystal nanoparticle.
Concrete technical scheme is as follows：
A kind of preparation method of above-mentioned amphotericin B cubic liquid crystal nanoparticle, comprises the following steps：
Amphotericin B cubic liquid crystal gel is added to the water, ultrasonic disperse is carried out with Ultrasonic cell smash, obtain both sexes
Mycin B cubic liquid crystal coarse dispersion systems；
Amphotericin B cubic liquid crystal coarse dispersion system is carried out high-pressure homogeneous, homogenization pressure is 300-1800bar, circulation
Number of times is 3-13 times, obtains final product the amphotericin B cubic liquid crystal nanoparticle.
Wherein in some embodiments, the homogenization pressure is 1100-1300bar, and cycle-index is 8-10 times.
Wherein in some embodiments, the condition of the ultrasonic disperse is that jitter time is 10-15min, and power is 150-
400w, the working time is 4-6s, and break time is 8-12s.
Amphotericin B cubic liquid crystal gel of the invention, cubic liquid crystal nanoparticle and preparation method thereof have advantages below
And beneficial effect：
The present inventor has found for amphotericin B and micellar material to be prepared into anphotericin by lot of experiments
The cubic liquid crystal gel prepared with special ratios with specific liquid crystal material and stabilizer again after B micellas, can be used to make
The standby amphotericin B cubic liquid crystal nanoparticle that entrapment efficiency is high, particle diameter is smaller and is evenly distributed.Cubic liquid crystal nanoparticle is one
Novel nano Lipid pharmaceutical carrier is planted, its huge film surface area and unique three-dimensional lattice structure have good to the medicine of indissoluble
Good solubilizing effect and sustained release performance.Thus amphotericin B cubic liquid crystal nanoparticle of the invention can overcome and be administered orally
Dissolving barrier and permeability barrier in journey, significantly improve the oral administration biaavailability of amphotericin B.
Drug concentration between the contact area of size of pharmaceutical particles, medicine and dissolution medium, and dissolution layer and medium
Difference is the key parameter for influenceing insoluble drug dissolution rate.Amphotericin B cubic liquid crystal nanoparticle of the invention is mould by both sexes
After plain B is contained into liquid crystal structure, medicine is transformed into unformed molecular state by crystal grain, is uniformly distributed in lipophilic domain,
Co-continuous aquaporin significantly increases the dissolution surface area of amphotericin B with the huge interface area of lipid bilayer.Simultaneously
Amphotericin B has larger solubility in lipophilic domain, and it is poor to form larger drug concentration between dissolution layer and medium, can enter
One step increases the dissolution rate of medicine, effectively overcomes medicine to dissolve barrier.
The unique biology in situ adhesion properties of cubic liquid crystal nanoparticle, can adsorb on intestines and stomach surface, increase medicine and stomach
Enteron aisle action time.Additionally, the lipid bilayer in cubic liquid crystal lattice element has class eucaryotic cell structure, have very strong with cell
Compatibility, gastrointestinal tract epithelial cell can be promoted to absorb the endocytosis of medicine, across small intestine gastrointestinal mucosa barrier, increase medicine
Thing absorbs.The bioadhesive of amphotericin B cubic liquid crystal nanoparticle and the class membrane structure of uniqueness can effectively overcome two
Property the permeability barrier that is administered orally of mycin B.
Amphotericin B is sensitive to light and heat, and degradable, physical and chemical stability is poor.Amphotericin B cube liquid of the invention
The lattice structure of brilliant nanoparticle has very strong protective effect to the amphotericin B for containing, and amphotericin B is contained in a cube liquid
In brilliant nanoparticle three-dimensional network lattice structure, aforementioned stable sex chromosome mosaicism can be efficiently solved.Amphotericin B is contained in liquid crystal
Inside lattice structure, it is possible to reduce medicine connects with external world sexual factor (such as light, heat, soda acid, chemistry and biology enzyme etc.)
Touch, it is to avoid amphotericin B is degraded in solvent medium or organism and loses bioactivity, isolate external world sexual factor pair
Amphotericin B structural damage, effectively keeps amphotericin B structural stability and corresponding pharmacological activity, increases both sexes mould
The stability of plain B.
In addition, amphotericin B cubic liquid crystal nanoparticle of the invention, particle diameter is smaller, and uniform particle diameter is good, is conducive to intestines
Annex in transporte to cells in epithelial cell.
Therefore, amphotericin B cubic liquid crystal nanoparticle of the invention can overcome the dissolving barrier during being administered orally
And permeability barrier, amphotericin B structure and activity are protected, increase the stability of amphotericin B, effectively improve amphotericin B
Oral administration biaavailability.
The oral Relative biological that amphotericin B cubic liquid crystal nanoparticle of the invention significantly improves amphotericin B is utilized
Degree, while amphotericin B can be made slowly to discharge, with 24 hours effects of sustained release, can delay for amphotericin B provides one kind
On The Drug Release, the amphotericin B new oral formulation that absorption is good, bioavilability is high, while nanoparticle solution is also beneficial to mouth
Clothes, it is possible to increase the compliance of patient.
The preparation method process is simple of amphotericin B cubic liquid crystal nanoparticle of the invention, envelop rate is high, makes to prepare
Amphotericin B cubic liquid crystal nanoparticle particle diameter it is small and be evenly distributed, the repeatability of technique is good, and production cost is relatively low, favorably
In industrialized production, have a good application prospect, while being conducive to advancing the industrialization development of liquid crystal nanometer.
Brief description of the drawings
Fig. 1 is amphotericin B cubic liquid crystal nanoparticle preparation flow figure in embodiment 1；
Fig. 2 is amphotericin B cubic liquid crystal nanoparticle freezing transmission electron microscope picture in embodiment 5；
Fig. 3 is amphotericin B cubic liquid crystal nanoparticle SAXS spectrograms in embodiment 5；
Fig. 4 is blank cubic liquid crystal nanoparticle SAXS spectrograms (A in embodiment 5：1200bar, homogeneous 9 times；B：1800bar,
Homogeneous 9 times)；
Fig. 5 is stability experiment result (n=of the amphotericin B cubic liquid crystal nanoparticle in simulated intestinal fluid in embodiment 6
6)；
Fig. 6 is the In-vitro release curves (n=6) of amphotericin B cubic liquid crystal nanoparticle in embodiment 8；
Fig. 7 be embodiment 9 in amphotericin B it is oral after blood concentration (n=6).
Specific embodiment
Amphotericin B cubic liquid crystal gel of the invention, cubic liquid crystal are received below by way of specific embodiment and accompanying drawing
Grain of rice and preparation method thereof is further described in detail.
Embodiment 1:The preparation of amphotericin B cubic liquid crystal nanoparticle
Referring to Fig. 1, the preparation method of the amphotericin B cubic liquid crystal nanoparticle of the present embodiment comprises the following steps：
The preparation of amphotericin B NaTDC micella：Weigh 0.5g amphotericin Bs bulk drug and 0.41g deoxycholic acids
(mass ratio is 1 to sodium：0.82), it is added in 30mL distilled water, then 0.1molL is added dropwise-1Sodium hydroxide solution, until both sexes are mould
Plain B bulk drugs are completely dissolved, then with the 0.01molL of pH 6.2-1Phosphate buffer solution is diluted to cumulative volume for 100mL.Gained
Solution places lucifuge in freeze drier, and -50 DEG C of condenser temperatures, vacuum obtains final product yellow to freeze 48h under the conditions of 0.1Mbar
Amphotericin B NaTDC micellar powder.Lucifuge, closed, 4 DEG C of Refrigerator stores.
The preparation of amphotericin B cubic liquid crystal gel：Raw material prescription weighs each raw material as shown in table 1, by F127 and phytane
In 100mL plastic centrifuge tubes, 60 DEG C of heating meltings of water-bath mix 30s to triol per 30min whirlpool suspensions device, are added after 1 hour
The aqueous solution of 60 DEG C of amphotericin B NaTDC micella is (with the amphotericin B deoxidation of recipe quantity shown in the water-soluble inducing diaphoresis 1 of 2g
Sodium taurocholate micella, now with the current), whirlpool suspension device mixes 1min, and room temperature places 48h, obtains final product amphotericin B cubic liquid crystal and coagulates
Glue.
The preparation of amphotericin B cubic liquid crystal nanoparticle：Added in gained amphotericin B cubic liquid crystal gel at room temperature
Ultra-pure water ad pond om is 20g, and Ultrasonic cell smash ultrasonic disperse 5min is used after 48h, and ultrasonic power used is 200W, is surpassed
Sound working time 5s, break time 10s obtains amphotericin B cubic liquid crystal coarse dispersion system；Again by amphotericin B cubic liquid crystal
Coarse dispersion system carries out high-pressure homogeneous (homogenization pressure is 1200bar, and homogenization cycles are 9 times) with high pressure homogenizer, obtains final product yellow fraction
The amphotericin B cubic liquid crystal nanoparticle of color.
The raw material prescription of the amphotericin B cubic liquid crystal gel of table 1
Embodiment 2:The preparation of amphotericin B cubic liquid crystal nanoparticle
The preparation method of the amphotericin B cubic liquid crystal nanoparticle of the present embodiment comprises the following steps：
The preparation of amphotericin B micella：Constituted by table 2 Suo Shi, amphotericin B bulk drug and micellar material are weighed, by reality
The method for applying example 1 prepares amphotericin B micella.
The preparation of amphotericin B cubic liquid crystal gel：Each raw material is weighed by the prescription 1-9 in embodiment 1, by embodiment 1
Method prepare.
The preparation of amphotericin B cubic liquid crystal nanoparticle：With embodiment 1
The preparing raw material of the amphotericin B micella of table 2
Comparative example 1
The raw material prescription of the amphotericin B cubic liquid crystal nanoparticle of this comparative example substantially with embodiment 1 in prescription 1-9 phases
Together, difference is that the consumption of F127 is 0.4g.Its preparation method is with embodiment 1.
Comparative example 2
The raw material prescription of the amphotericin B cubic liquid crystal nanoparticle of this comparative example substantially with embodiment 1 in prescription 1-9 phases
Together, difference is without F127.Its preparation method is with embodiment 1.
Comparative example 3
The raw material prescription of the amphotericin B cubic liquid crystal nanoparticle of this comparative example substantially with embodiment 1 in prescription 1-9 phases
Together, difference is that stabilizer used is POLOXAMER 188.Its preparation method is with embodiment 1.
Comparative example 4
The raw material prescription of the amphotericin B cubic liquid crystal nanoparticle of this comparative example substantially with embodiment 1 in prescription 1-9 phases
Together, difference is that liquid crystal material used is two oleic acid sweet acids ester (DGMO).Its preparation method is with embodiment 1.
Embodiment 3
The particle diameter of the amphotericin B cubic liquid crystal nanoparticle prepared to embodiment 1-2 and its comparative example 1-4 and encapsulating
Rate is measured.
Particle Size Determination Method is as follows:After cubic liquid crystal nanoparticle dilutes 100 times with ultra-pure water, take 1mL samples and be added to sample
Product pond, 25 DEG C of balance 1min, dispersion viscosities are 0.8872cPa, and Zetasizer Nano ZS90 determine cubic liquid crystal nanoparticle
Particle size parameters, particle size analyzer software calculates the particle size and polydispersity coefficient (PDI) of cubic liquid crystal nanoparticle.PDI is anti-
The index of particle size distribution range is reflected, the smaller expression particle sizes of PDI are more uniform, integrated distribution, the bigger expression grains of PDI
Sub- size is uneven, significant difference.
Entrapment efficiency determination method：Take 1mL amphotericin B cubic liquid crystal nanoparticle solution ultra-pure waters and be dissolved to 5mL, take
In the super filter tube of YM-100,15000r/min centrifugation 30min collect amphotericin B cubic liquid crystal nanoparticle and lower floor to 0.5mL
Liquid, after being washed with methyl alcohol, dimethyl sulfoxide (DMSO) is dissolved to 5mL, takes 0.2mL methanol constant volumes to 10mL, and high performance liquid chromatography is surveyed
Determine amphotericin B content.
Envelop rate formula：EE%=(Wtotal- Wfree)/Wtotal× 100%.
Wtotal：Amphotericin B dosage；Wfree：Free amphotericin B
High-efficient liquid phase chromatogram condition：Chromatographic column：Phenomenex luna C18 (250x4.6mm, 5 μm), mobile phase：Second
Nitrile：0.01mol pH6.20 phosphate buffer=40:60,35 DEG C of column temperature, Detection wavelength 406nm, flow velocity：1.0mLmin-1,
Sample size：20μL.
Measurement result is as shown in table 3：
The particle diameter and envelop rate of the amphotericin B cubic liquid crystal nanoparticle of table 3
The dissolution rate of amphotericin B is very slow, and dissolution rate turns into limitation amphotericin B deliquescent pass in phosphatide
Key.According to Noyes-Whitney dissolution equations：Dc/dt=DA (Cs-C)/Vh
dc/dt：Dissolution rate, D：The diffusion coefficient of medicine, A：Dissolution interfacial area, Cs：Medicine saturation solubility, C：It is molten
The concentration of medicine, V in liquid：Dissolution medium quality, h:Thickness of diffusion layer.
Understand, the dissolution rate of amphotericin B can be increased by following two aspects：1st, amphotericin B particle diameter is reduced, is increased
Plus drug-eluting surface area A, increase drug-eluting speed；2nd, reduce diameter of carrier, reduce drug diffusion layer thickness h, increase medicine
Thing dissolution rate.The present invention is prepared in the method for amphotericin B cubic liquid crystal nanoparticle, first by NaTDC solubilising both sexes
Mycin B forms micella, and particle diameter drops to nano level micella from the bulky grain of bulk drug, increases dissolution surface area.Secondly, by height
Pressure homogeneous reduces diameter of carrier, reduces drug diffusion thickness degree, accelerates the rate of dissolution of amphotericin B.
Additionally, different size of particle is different in the intake of enterocyte, cause different oral absorption effects.Particle diameter is small
Particle can be by enterocyte phagocytosis transporte to cells, and the big particle of particle diameter is difficult to be phagocytized by cells.
As seen from the results in Table 3：Content with stabilizer increases, and the particle diameter of amphotericin B cubic liquid crystal nanoparticle has one
The trend of individual obvious reduction, meet this patent reduction nanoparticle particle diameter requirement, with reference to comparative example 1-3 it is recognised that with not plus
The prescription of stabilizer is compared, and stabilizer can be substantially reduced nanoparticle particle diameter really, but too high stabiliser content is simultaneously
The rock-steady structure of liquid crystal can be destroyed, particle diameter increase is caused on the contrary, phytantriol is 9 with the optimum quality ratio of F127：1.Additionally, steady
The species for determining agent also has a certain impact, and under similarity condition, stabilizer is bigger for the prescription particle diameter of POLOXAMER 188, envelop rate
It is lower.Dosage does not have fairly obvious influence, difference dispensing to the particle diameter and envelop rate of amphotericin B cubic liquid crystal nanoparticle
The envelop rate of amount has reached 90% or so.In addition, fixed drug content, micellar material is 0.41g (medicine and micella mass ratio
1:0.82) there is the envelop rate of maximum when, when micellar material content is smaller, it is difficult to reach critical micelle concentration, therefore envelop rate is big
It is big to reduce；The micellar material of too high amount can then cause that the micella for preparing is inter-adhesive, or even can destroy the structure of micella, cause
Entrapment efficiency reduction.And the species of micellar material also has an impact to encapsulating effect, but influence, PLGA smaller than the influence of its consumption
Also there is preferable effect with PLA, obtain envelop rate higher.Different liquid crystal materials can also influence nanoparticle particle diameter and encapsulating
Rate, the envelop rate of glyceryl dioleate is relatively low, and particle diameter is larger, and effect is not so good as phytantriol.
Embodiment 4:The influence of homogenization pressure and homogenization cycles to amphotericin B cubic liquid crystal nanoparticle particle diameter
Amphotericin B cubic liquid crystal nanoparticle is prepared by the prescription 1-9 of embodiment 1, preparation method is with embodiment 1, difference
High-pressure homogeneous condition is different, is specifically shown in Table 4.
The particle diameter of amphotericin B cubic liquid crystal nanoparticle manufactured in the present embodiment is determined, assay method is surveyed with embodiment 1
Surely 4 be the results are shown in Table.
Average grain diameter result (table 4) the display amphotericin B cubic liquid crystal nanoparticle that Zetasizer Nano ZS90 are determined
Average grain diameter be not reduces with high-pressure homogeneous pressure increase, but as high-pressure homogeneous pressure increases basic holding not
Become.But PDI is shown and reduce with high-pressure homogeneous pressure increase, and the PDI of cubic liquid crystal nanoparticle is prepared from ultrasonic disperse
0.250 PDI 0.107 for being reduced to the amphotericin B cubic liquid crystal nanoparticle prepared under the conditions of high-pressure homogeneous 9 times of 1200bar.
PDI is the index for reflecting particle size distribution range, and the smaller expression particle sizes of PDI are more uniform, integrated distribution, and PDI gets over
Big expression particle size is uneven, significant difference.The Intensity figures that Zetasizer Nano ZS90 are determined show that high pressure is equal
When matter increases to 1200bar 9 times, amphotericin B cubic liquid crystal nanoparticle has no a micron sized particles, all particles size point
Cloth is in nanometer range.The Intensity figure prompting amphotericin B cubic liquid crystal nanometers that Zetasizer Nano ZS90 are determined
The particle diameter of grain reduces with high-pressure homogeneous pressure increase, when it is high-pressure homogeneous reach certain limit after, the high-pressure homogeneous pressure of increase
Power can not reduce the particle size of amphotericin B cubic liquid crystal nanoparticle.Average grain diameter is an average value of particle size,
Reflection particle fraction information, and PDI, Intensity parameter can comprehensively reflect particle size and the distribution of cubic liquid crystal nanoparticle,
It is thus determined that homogenization pressure 1200bar homogeneous is for 9 times optimal processing condition.
Influence (n=3) of the preparation technology of table 4 to the particle diameter of amphotericin B cubic liquid crystal nanoparticle
Embodiment 5:The sign (Cryo-TEM, SAXS) of amphotericin B cubic liquid crystal nanoparticle liquid crystal structure
Using two prepared in freezing transmission electron microscope (Cryo-TEM) and low-angle scattering of X-rays observation embodiment 1 prescription 1-9
The form and particle size of property mycin B cubic liquid crystal nanoparticles.
Freezing transmission electron microscope.The amphotericin B cubic liquid crystal nanoparticle solution of prescription 1-9 in 4 μ L embodiments 1 is added drop-wise to
On copper mesh, filter paper draws liquid about 3s, until cubic crystal nanoparticle is absorbed and fixed at film is formed on copper mesh completely, uses phosphorus tungsten
After sour negative staining, be put into rapidly it is quick-frozen in liquid ethane, it is quick-frozen after copper mesh be placed on cold-trap, -172 DEG C at transmission electron microscope observing stand
Square liquid crystal nano shape, CCD shoots photo.
Result is shown in Fig. 2, and amphotericin B cubic liquid crystal nanoparticle Ice mapping figure shows average grain diameter in 250nm or so, with
It is basically identical that Zetasizer Nano ZS90 measure particle size；A large amount of orderly cubic liquid crystal nanoparticles, are presented the shape of rounding
Shape, 3, upper right corner bright spot represents cubic liquid crystal internal voids passage in figure, and display nano-particle has typical cubic liquid crystal knot
Structure.
Low-angle scattering of X-rays.By the amphotericin B cube in the cubic liquid crystal nanoparticle of blank and the prescription 1-9 of embodiment 1
Liquid crystal nanoparticle solution is filled into the quartz capillary of diameter 1mm, radiation exposure 60min.Using the small angle X- of Anton Paar
Scatterometer, scattering light source is Cu, and X-ray wavelength is 0.1542nm, and angle of scattering measurement range is q=0.05~6nm-1。
The amphotericin B cubic liquid crystal nanoparticle that result is shown in after Fig. 3 and 4, Fig. 3 display 1200bar homogeneous 9 times existsThere is spectral line peak, corresponding to Miller index h k l=110,111 and 200, show the anphotericin of 60mg
Amphotericin B cubic liquid crystal nanoparticle prepared by B still has Pn3m cubic liquid crystal structures.Amphotericin B cubic liquid crystal nanoparticle
X- small-angle diffractions existThe X- that the peak width of appearance diffraction maximum is significantly greater than the blank cubic liquid crystal nanoparticle in Fig. 4 is small
Angle diffraction existsThere is the peak width of diffraction maximum, and the X- small-angle diffractions of amphotericin B cubic liquid crystal nanoparticle existDiffraction maximum disappear, display amphotericin B participate in influence cubic liquid crystal formation.
Embodiment 6:The intestinal juice stability experiment of amphotericin B cubic liquid crystal nanoparticle
Investigate stability of the amphotericin B cubic liquid crystal nanoparticle in intestinal juice.
The preparation of artificial simulation intestinal juice:Potassium dihydrogen phosphate 6.8g is taken, the 500~800mL that adds water is allowed to dissolve, with 1mol/L's
Sodium hydroxide solution adjusts pH value to 7.5, separately takes pancreatin 10g and adds water and make dissolving in right amount.After two liquid are mixed, plus distilled water is dissolved to
1000mL, obtains final product simulated intestinal fluid, standby.
The amphotericin B cubic liquid crystal nanoparticle solution of the prescription 1-9 of 0.5mL embodiments 1 preparations is accurately measured, manually mould
Intend intestinal juice be settled to 50mL, avoid light place in isothermal vibration device, 37 DEG C of water-baths, shake speed 100r/min.Exist respectively
30min, 60min, 120min, 240min take 0.5ml samples, and methanol dilution is dissolved to 5ml, 0.22 μm of membrane filtration, efficient liquid
Phase chromatographic determination amphotericin B content, method is with embodiment 3.
Amphotericin B NaTDC simulated intestinal fluid experimental comparison group：Amphotericin B NaTDC distilled water is taken to determine
It is molten to 2mgmL-1.Dilution 0.5mL is taken, artificial simulation intestinal juice is dissolved to 50mL, remaining step is ibid.
Result is shown in Fig. 5.Amphotericin B in amphotericin B cubic liquid crystal nanoparticle and amphotericin B NaTDC contains
Amount drops to 81.83 ± 2.51% and 78.56 ± 8.96%, two groups of data respectively in warm bath in simulating simulated intestinal fluid after 0.5 hour
There is no significant difference (P>0.05)；But as action time increases to 1 hour, amphotericin B cubic liquid crystal nanoparticle and two
Amphotericin B in property mycin B NaTDCs is respectively 82.40 ± 3.92% and 69.30 ± 6.70% (P<0.05), both sexes
The stability of the amphotericin B in mycin B cubic liquid crystal nanoparticles is apparently higher than control group amphotericin B NaTDC；When
Action time increases to 3 hours, and amphotericin B stability difference is more notable.These results suggest that amphotericin B of the invention
Cubic liquid crystal nanoparticle has the effect of protection amphotericin B in simulated intestinal fluid, it is to avoid the degraded of amphotericin B.
Embodiment 7:The stability of amphotericin B cubic liquid crystal nanoparticle
Prepared amphotericin B cubic liquid crystal nanoparticle in the investigation prescription 1-9 of embodiment 1 and comparative example 1,2 and 3
Stability.Place at room temperature 1 month, sampled 15 days, 30 days respectively, determine the grain of amphotericin B cubic liquid crystal nanoparticle
Footpath and envelop rate.Method is respectively with embodiment 3.
The results are shown in Table 5.Amphotericin B cubic liquid crystal nanoparticle is placed 30 days at room temperature, outward appearance yellow fraction homogeneous solution, not
See aggregation, flocculation, show good physical stability.Result show the 15th day particle diameter of amphotericin B cubic crystal nanoparticle and
Envelop rate is not changed in substantially, and the particle diameter of amphotericin B cubic liquid crystal nanoparticle has slight increase within the 30th day, while envelop rate has
Downward trend.Not plus stabilizer comparative example 2 prepare amphotericin B cubic liquid crystal nanoparticle occurred in that in 30 days it is more tight
The clustering phenomena of weight, because nanoparticle is unstable, therefore also there is obvious decline in envelop rate.The too high contrast of stabiliser content
Also there is the situation that aggregation and envelop rate decline due to cubic liquid crystal structural damage in example 1.Pool Lip river Sa is employed in comparative example 3
Nurse 188 equally can be observed the decline of stability as stabilizer.Amphotericin B cube prepared by embodiment 1-9 and comparative example
The stability result of liquid crystal nanoparticle is consistent with the particle diameter and the result of envelop rate in embodiment 3.
The particle diameter distribution of the amphotericin B cubic liquid crystal nanoparticle of table 5 and envelop rate (n=3)
Embodiment 8:Carry the release in vitro behavior of amphotericin B cubic liquid crystal nanoparticle
The release in vitro for carrying medicine cubic liquid crystal nanoparticle is investigated using Bag filter method.Both sexes in the prescription 1-9 of Example 1
Mycin B cubic liquid crystal nanoparticle 1mL and 0.25% sodium dodecyl sulfate solution 1mL be collectively disposed in bag filter (SMI companies,
Retention relative molecular mass 3500Da), it is placed on after sealing in the 50mL plastic centrifuge tubes of 15mL dissolution mediums.Both sexes are mould
Plain B is water insoluble, and the bakie bar of amphotericin B extracorporeal releasing experiment is met using 0.25% lauryl sodium sulfate dissolution medium
Part.Be subsequently placed in 37 DEG C, in the isothermal vibration device of 100rpm, respectively at 1,2,4,8,12,24,48,72,96h samplings, plastics from
Dissolution medium in heart pipe is all taken out, and adds the fresh dissolution medium of same volume simultaneously.Take the release of different time points 1mL
Medium methyl alcohol is dissolved to 5mL, the amphotericin B content in high effective liquid chromatography for measuring dissolution medium, the same embodiment of condition
3, draw release profiles.
Amphotericin B NaTDC extracorporeal releasing experiment control group：Amphotericin B NaTDC distilled water is taken to determine
It is molten to 2mgmL-1.The dilution 1mL and 0.25% sodium dodecyl sulfate solution 1mL for taking amphotericin B NaTDC are total to
With being placed in bag filter, remaining step is ibid.
Result is shown in Fig. 6.The release in vitro of result display amphotericin B cubic liquid crystal nanoparticle is slow, is within 1 hour 2.64
± 0.61%, 96h are only 12.37 ± 3.87%, and control group amphotericin B NaTDC was in the release in vitro of 1 hour
12.80 ± 2.16%, 96h release in vitro are up to 61.64 ± 3.60%.Amphotericin B cubic liquid crystal nanoparticle release in vitro is notable
Less than amphotericin B NaTDC control group, display medicine is discharged not from nanoparticle, but stomach is passed through together with carrier
The barrier of enteron aisle, be ingested absorption, it is to avoid it discharges in the gastrointestinal tract, meets with degraded or separates out crystal settling.
Embodiment 9:The pharmacokinetic of amphotericin B cubic liquid crystal nanoparticle
Investigate the pharmacokinetic characteristics of amphotericin B cubic liquid crystal nanoparticle prepared by the prescription 1-9 of embodiment 1.Take SD
Male rat, fasting 12h, free water before administration.24 rats are randomly divided into 4 groups：First group of implementation with 10mg/kg dosage
The amphotericin B cubic liquid crystal nanoparticle of the prescription 1-9 of example 1 gives rat oral gavage as experimental group 1；Second group with 20mg/kg agent
The amphotericin B cubic liquid crystal nanoparticle of the prescription 1-9 of embodiment 1 of amount gives rat oral gavage as experimental group 2；3rd group with
The amphotericin B cubic liquid crystal nanoparticle of the comparative example 4 of 10mg/kg dosage gives rat oral gavage as a control group 1；4th group with
The amphotericin B NaTDC of 10mg/kg dosage gives rat oral gavage as a control group 2.1h after administration, 2h, 4h, 8h,
12h, 24h, 48h, 72h, 96h, 120h eye socket take blood about 0.5mL, whole blood be placed in scribble heparin dry centrifuge tube,
8000rpm is centrifuged l0min separated plasmas, and -20 DEG C preserve to analysis measure.The accurate blood plasma 0.1mL that draws is in 1.5mL centrifuge tubes
In, methyl alcohol 100 μ l, vortex mixing 30s are added, the μ l of acetonitrile 100 are added, after vortex mixing 30s, 4 DEG C of refrigerator placement 5min are abundant
Protein precipitation, 16000pm centrifugation 10min, takes the μ l of supernatant 200, and 25 μ l sample introductions are determined.HPLC determines the content of amphotericin B.
HPLC conditions are as follows：Chromatographic column：Phenomenex luna C18 (250x4.6mm, 5 μm), mobile phase：Acetonitrile：
0.01mol/L pH6.2 phosphate buffers 40:60,35 DEG C of column temperature, Detection wavelength 406nm, flow velocity：1.0mLmin-1, sample introduction
Amount：25μl.Plasma drug concentration data is processed using PKSolver V2.1 pharmacokinetics software kit (China Medicine University).
According to blood concentration, calculate amphotericin B it is oral after drug plasma Cmax Cmax, peak time Tmax, eliminate half-life period
t1/2, area under the drug-time curve AUC0-120Deng kinetic parameter.
Pharmacokinetic parameters are shown in Table 6.Plasma concentration curve is shown in Fig. 7.Result shows that blood concentration result shows in SD rat bodies
After the administration of amphotericin B cubic liquid crystal nanoparticles oral compared with the amphotericin B NaTDC control group with dosage, orally
Bioavilability improves 285%.The peak time of amphotericin B is by amphotericin B NaTDC control group mouthful in blood medicine
6.3h after clothes administration brings up to the 26h after the administration of amphotericin B cubic liquid crystal nanoparticles oral.The medicine inspection of amphotericin B blood is surveyed
Time extends to amphotericin B cubic liquid crystal nanoparticle mouthful for 2 days by after amphotericin B NaTDC control group oral administration
5 days after clothes administration, display amphotericin B cubic liquid crystal nanoparticle can stick to gastrointestinal wall and play certain slow releasing function.Two
Property mycin B cubic liquid crystal nanoparticles oral dosage increases to 20mg/kg by 10mg/kg, and blood concentration increase is not obvious.Using two
As liquid crystal material compared with the phytantriol liquid crystal nanoparticle of statistic, its area under the drug-time curve is relatively for olein
Low, peak time also shifts to an earlier date.
Pharmacokinetic parameter (n=6) after the amphotericin B of table 6 is oral
Cmax：Drug plasma Cmax, Tmax：Peak time, t1/2：Eliminate half-life period, AUC0-120：Area under the drug-time curve.
Each technical characteristic of embodiment described above can be combined arbitrarily, to make description succinct, not to above-mentioned reality
Apply all possible combination of each technical characteristic in example to be all described, as long as however, the combination of these technical characteristics is not deposited
In contradiction, the scope of this specification record is all considered to be.
Embodiment described above only expresses several embodiments of the invention, and its description is more specific and detailed, but simultaneously
Can not therefore be construed as limiting the scope of the patent.It should be pointed out that coming for one of ordinary skill in the art
Say, without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to protection of the invention
Scope.Therefore, the protection domain of patent of the present invention should be determined by the appended claims.
Claims (10)
1. a kind of amphotericin B cubic liquid crystal gel, it is characterised in that be mainly prepared from by the raw material of following mass parts：
The amphotericin B is 1 with the mass ratio of the micellar material:0.3-2；
The liquid crystal material is 9 with the mass ratio of the stabilizer:0.4-1.5；
The micellar material is selected from NaTDC, polyoxyethylene, polyethylene glycol-chitin copolymer, PVP, imitative cell membrane
At least one in phosphocholine, polyaminoacid, PLA and Poly(D,L-lactide-co-glycolide；The liquid crystal material is plant
Alkane triol；The stabilizer is poloxamer188.
2. amphotericin B cubic liquid crystal gel according to claim 1, it is characterised in that main by following mass parts
Raw material is prepared from：
3. amphotericin B cubic liquid crystal gel according to claim 1, it is characterised in that the micellar material is selected from de-
At least one in oxycholic acid sodium, PLA and Poly(D,L-lactide-co-glycolide.
4. the amphotericin B cubic liquid crystal gel according to claim any one of 1-3, it is characterised in that the both sexes are mould
Plain B is 1 with the mass ratio of the micellar material:0.6-1.3.
5. the amphotericin B cubic liquid crystal gel according to claim any one of 1-3, it is characterised in that the liquid crystal material
Expect that with the mass ratio of the stabilizer be 9:0.8-1.2.
6. the amphotericin B cubic liquid crystal gel according to claim any one of 1-3, it is characterised in that main by following
The raw material of mass parts is prepared from：
The amphotericin B is 1 with the mass ratio of the NaTDC:0.7-0.9；
The phytantriol is 9 with the mass ratio of the poloxamer188:0.8-1.2.
7. the preparation method of the amphotericin B cubic liquid crystal gel described in a kind of any one of claim 1-6, it is characterised in that
Comprise the following steps：
The preparation of amphotericin B micella：Amphotericin B and micellar material are added in distilled water, dropwise addition concentration is 0.08-
0.12mol·L-1Sodium hydroxide solution, it is until amphotericin B is completely dissolved then dilute with the phosphate buffer solution of pH6-6.4
Release, then resulting solution is carried out into freeze-drying, obtain final product the amphotericin B micella；
The preparation of amphotericin B cubic liquid crystal gel：The amphotericin B micella is dissolved in described in claim any one of 1-6
Water in, obtain the aqueous solution of amphotericin B；Stabilizer and liquid crystal material heating melting, whirlpool are mixed, the both sexes are added
The aqueous solution of mycin B, whirlpool is mixed, and room temperature is placed, and obtains final product the amphotericin B cubic liquid crystal gel.
8. the amphotericin B cubic liquid crystal gel described in any one of claim 1-6 is preparing amphotericin B cubic liquid crystal nanometer
Application in grain.
9. a kind of amphotericin B cubic liquid crystal nanoparticle, it is characterised in that the both sexes as described in claim any one of 1-6 are mould
Plain B cubic liquid crystals gel dispersion is prepared from water.
10. the preparation method of the amphotericin B cubic liquid crystal nanoparticle described in a kind of claim 9, it is characterised in that including with
Lower step：
Amphotericin B cubic liquid crystal gel is added to the water, ultrasonic disperse is carried out with Ultrasonic cell smash, obtain anphotericin
B cubic liquid crystal coarse dispersion systems；
Amphotericin B cubic liquid crystal coarse dispersion system is carried out high-pressure homogeneous, homogenization pressure is 300-1800bar, cycle-index
For 3-13 times, the amphotericin B cubic liquid crystal nanoparticle is obtained final product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611185282.2A CN106821962A (en) | 2016-12-20 | 2016-12-20 | Amphotericin B cubic liquid crystal gel, cubic liquid crystal nanoparticle and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611185282.2A CN106821962A (en) | 2016-12-20 | 2016-12-20 | Amphotericin B cubic liquid crystal gel, cubic liquid crystal nanoparticle and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106821962A true CN106821962A (en) | 2017-06-13 |
Family
ID=59140787
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201611185282.2A Pending CN106821962A (en) | 2016-12-20 | 2016-12-20 | Amphotericin B cubic liquid crystal gel, cubic liquid crystal nanoparticle and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106821962A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021170841A1 (en) * | 2020-02-26 | 2021-09-02 | Biosergen As | Pharmaceutical compositions of a therapeutic polyene macrolide and methods of their use |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103505420A (en) * | 2012-06-29 | 2014-01-15 | 江西中医学院 | Liquid crystal nano-preparations as well as preparation method thereof |
| CN104622812A (en) * | 2013-11-14 | 2015-05-20 | 崔景朝 | Compound turmeric lipid cubic liquid crystalline nano-particles and preparation method thereof |
-
2016
- 2016-12-20 CN CN201611185282.2A patent/CN106821962A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103505420A (en) * | 2012-06-29 | 2014-01-15 | 江西中医学院 | Liquid crystal nano-preparations as well as preparation method thereof |
| CN104622812A (en) * | 2013-11-14 | 2015-05-20 | 崔景朝 | Compound turmeric lipid cubic liquid crystalline nano-particles and preparation method thereof |
Non-Patent Citations (4)
| Title |
|---|
| ZHIWEN YANG等: "Development of Amphotericin B-Loaded Cubosomes Through the SolEmuls Technology for Enhancing the Oral Bioavailability", 《AAPS PHARMSCITECH》 * |
| ZHIWEN YANG等: "Evaluating the potential of cubosomal nanoparticles for oral delivery of amphotericin B in treating fungal infection", 《INTERNATIONAL JOURNAL OF NANOMEDICINE》 * |
| ZHIWEN YANG等: "Optimization of the Preparation Process for an Oral Phytantriol-Based Amphotericin B Cubosomes", 《JOURNAL OF NANOMATERIALS》 * |
| 蒋智清等: "《物理化学实验指导》", 31 March 2014, 厦门大学出版社 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021170841A1 (en) * | 2020-02-26 | 2021-09-02 | Biosergen As | Pharmaceutical compositions of a therapeutic polyene macrolide and methods of their use |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2545784C2 (en) | Nanostructured sildenafil base, its pharmaceutically acceptable salts and cocrystals, their compositions method of preparing them and pharmaceutical compositions containing them | |
| Kumar et al. | Self emulsifying drug delivery system (SEDDS): Future aspects | |
| CN109125261B (en) | Edaravone dosage form | |
| CN103610649B (en) | Medicament microsphere and preparation method thereof | |
| Li et al. | Self-nanoemulsifying drug-delivery system and solidified self-nanoemulsifying drug-delivery system | |
| CN108186605B (en) | Medicine-carrying nano-particles based on tannic acid and preparation method and application thereof | |
| CN105232459B (en) | A kind of poorly water soluble drugs polymer micelle composition and preparation method thereof redissolving self assembly | |
| TW201114766A (en) | Pharmaceutical composition for a hepatitis C viral protease inhibitor | |
| CN104163915B (en) | Cholesterol-poloxamer-cholesterol triblock copolymer and its preparation method and application | |
| CN106727336B (en) | Oridonin cubic liquid crystal nanoparticles and preparation method thereof | |
| CN108578356B (en) | Artemether oral microemulsion in-situ gel and preparation method thereof | |
| CN106727309A (en) | Polymer micelle solution containing Quercetin and its preparation method and application | |
| CN106883404B (en) | Polyethylene glycol vitamin E succinate derivative and its preparation method and application | |
| Guo et al. | High oral bioavailability of 2-methoxyestradiol in PEG-PLGA micelles-microspheres for cancer therapy | |
| CN101984958A (en) | Nanoscale albendazole micropowder and preparation method thereof | |
| CN104844790A (en) | Tocopheryl polyethylene glycol succinate-cholesterol carbonate, and preparation method and application thereof | |
| US20130210794A1 (en) | Nanostructured ezetimibe compositions, process for the preparation thereof and pharmaceutical compositions containing them | |
| CN105131277A (en) | Polymer material containing cholic acid and liposome modified by same | |
| CN104367549A (en) | Psoralen-doxorubicin-loaded composite nanostructured lipid carrier preparation and preparation method thereof | |
| CN106692057A (en) | Ibuprofen cubic liquid crystal precursor solution, cubic liquid crystal nanoparticles and preparation method of cubic liquid crystal nanoparticles | |
| CN113384705A (en) | Preparation of poloxamer modified liposome and application of poloxamer modified liposome in oral drug delivery | |
| CN106821962A (en) | Amphotericin B cubic liquid crystal gel, cubic liquid crystal nanoparticle and preparation method thereof | |
| Han et al. | In vitro and in vivo evaluation of core–shell mesoporous silica as a promising water-insoluble drug delivery system: Improving the dissolution rate and bioavailability of celecoxib with needle-like crystallinity | |
| CN107233308A (en) | The preparation method of genistein VE-succinate polyethylene glycol 1000 vitamin E succinic acid ester nano-micelle | |
| Tanawade et al. | Self-emulsifying drug delivery systems: an overview |
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 | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20170613 |