CN105769821B - Tacrolimus self-assembly polymer nanoparticle drug delivery system and preparation method thereof - Google Patents
Tacrolimus self-assembly polymer nanoparticle drug delivery system and preparation method thereof Download PDFInfo
- Publication number
- CN105769821B CN105769821B CN201610246725.8A CN201610246725A CN105769821B CN 105769821 B CN105769821 B CN 105769821B CN 201610246725 A CN201610246725 A CN 201610246725A CN 105769821 B CN105769821 B CN 105769821B
- Authority
- CN
- China
- Prior art keywords
- tacrolimus
- self
- soluplus
- drug delivery
- delivery system
- 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.)
- Active
Links
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 title claims abstract description 65
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 title claims abstract description 65
- 229960001967 tacrolimus Drugs 0.000 title claims abstract description 63
- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- 239000002105 nanoparticle Substances 0.000 title claims abstract description 27
- 229920000642 polymer Polymers 0.000 title claims abstract description 26
- 238000012377 drug delivery Methods 0.000 title claims abstract description 21
- 238000001338 self-assembly Methods 0.000 title abstract description 4
- 239000007788 liquid Substances 0.000 claims abstract description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 34
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 19
- 239000003960 organic solvent Substances 0.000 claims description 15
- 239000002552 dosage form Substances 0.000 claims description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- 238000004108 freeze drying Methods 0.000 claims description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical group OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 7
- 229930195725 Mannitol Natural products 0.000 claims description 7
- 239000000594 mannitol Substances 0.000 claims description 7
- 235000010355 mannitol Nutrition 0.000 claims description 7
- 239000008215 water for injection Substances 0.000 claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 235000019441 ethanol Nutrition 0.000 claims description 6
- 239000003002 pH adjusting agent Substances 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 claims description 3
- 229940113088 dimethylacetamide Drugs 0.000 claims description 3
- 239000012046 mixed solvent Substances 0.000 claims description 3
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 3
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 3
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical group [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 3
- 239000008227 sterile water for injection Substances 0.000 claims description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 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 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims 1
- 235000015110 jellies Nutrition 0.000 claims 1
- 239000008274 jelly Substances 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 238000002347 injection Methods 0.000 abstract description 14
- 239000007924 injection Substances 0.000 abstract description 14
- 238000000034 method Methods 0.000 abstract description 13
- 241000700159 Rattus Species 0.000 abstract description 12
- 230000000694 effects Effects 0.000 abstract description 6
- 238000010253 intravenous injection Methods 0.000 abstract description 4
- 239000006185 dispersion Substances 0.000 abstract description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 abstract description 3
- 239000002861 polymer material Substances 0.000 abstract description 2
- BBEAQIROQSPTKN-UHFFFAOYSA-N pyrene Chemical compound C1=CC=C2C=CC3=CC=CC4=CC=C1C2=C43 BBEAQIROQSPTKN-UHFFFAOYSA-N 0.000 description 20
- GVEPBJHOBDJJJI-UHFFFAOYSA-N fluoranthrene Natural products C1=CC(C2=CC=CC=C22)=C3C2=CC=CC3=C1 GVEPBJHOBDJJJI-UHFFFAOYSA-N 0.000 description 10
- 239000012071 phase Substances 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 239000003814 drug Substances 0.000 description 8
- 229960000935 dehydrated alcohol Drugs 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000000693 micelle Substances 0.000 description 6
- 230000008961 swelling Effects 0.000 description 6
- 238000000108 ultra-filtration Methods 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
- 210000002683 foot Anatomy 0.000 description 5
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 4
- REFJWTPEDVJJIY-UHFFFAOYSA-N Quercetin Chemical compound C=1C(O)=CC(O)=C(C(C=2O)=O)C=1OC=2C1=CC=C(O)C(O)=C1 REFJWTPEDVJJIY-UHFFFAOYSA-N 0.000 description 4
- 229960004756 ethanol Drugs 0.000 description 4
- 108010036949 Cyclosporine Proteins 0.000 description 3
- 238000005538 encapsulation Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- LBGFKUUHOPIEMA-PEARBKPGSA-N sapacitabine Chemical compound O=C1N=C(NC(=O)CCCCCCCCCCCCCCC)C=CN1[C@H]1[C@@H](C#N)[C@H](O)[C@@H](CO)O1 LBGFKUUHOPIEMA-PEARBKPGSA-N 0.000 description 3
- 229920002554 vinyl polymer Polymers 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 206010012438 Dermatitis atopic Diseases 0.000 description 2
- 239000010282 Emodin Substances 0.000 description 2
- 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 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- ZVOLCUVKHLEPEV-UHFFFAOYSA-N Quercetagetin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=C(O)C(O)=C(O)C=C2O1 ZVOLCUVKHLEPEV-UHFFFAOYSA-N 0.000 description 2
- HWTZYBCRDDUBJY-UHFFFAOYSA-N Rhynchosin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=CC(O)=C(O)C=C2O1 HWTZYBCRDDUBJY-UHFFFAOYSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 201000008937 atopic dermatitis Diseases 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229960001265 ciclosporin Drugs 0.000 description 2
- 229930182912 cyclosporin Natural products 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- RHMXXJGYXNZAPX-UHFFFAOYSA-N emodin Chemical compound C1=C(O)C=C2C(=O)C3=CC(C)=CC(O)=C3C(=O)C2=C1O RHMXXJGYXNZAPX-UHFFFAOYSA-N 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 229920000578 graft copolymer Polymers 0.000 description 2
- 210000002216 heart Anatomy 0.000 description 2
- MWDZOUNAPSSOEL-UHFFFAOYSA-N kaempferol Natural products OC1=C(C(=O)c2cc(O)cc(O)c2O1)c3ccc(O)cc3 MWDZOUNAPSSOEL-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 210000003141 lower extremity Anatomy 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 239000004005 microsphere Substances 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 238000005086 pumping Methods 0.000 description 2
- 229960001285 quercetin Drugs 0.000 description 2
- 235000005875 quercetin Nutrition 0.000 description 2
- 229950006896 sapacitabine Drugs 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 238000002054 transplantation Methods 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- 229920001661 Chitosan Polymers 0.000 description 1
- 229930105110 Cyclosporin A Natural products 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 210000000544 articulatio talocruralis Anatomy 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000002146 bilateral effect Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 238000000295 emission spectrum Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 239000013505 freshwater Substances 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 238000001033 granulometry Methods 0.000 description 1
- 239000012943 hotmelt Substances 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000006070 nanosuspension Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000010494 opalescence Effects 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000013441 quality evaluation Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 239000002047 solid lipid nanoparticle Substances 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000007939 sustained release tablet Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 210000003371 toe Anatomy 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
- A61K9/48—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
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
-
- 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
- A61K31/436—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 oxygen as a ring hetero atom, e.g. rapamycin
-
- 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
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physics & Mathematics (AREA)
- Biomedical Technology (AREA)
- Nanotechnology (AREA)
- Optics & Photonics (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a tacrolimus self-assembly polymer nanoparticle drug delivery system and a preparation method thereof, wherein the tacrolimus self-assembly polymer nanoparticle drug delivery system mainly comprises tacrolimus and Soluplus in a liquid dispersion preparation form or a freeze-dried preparation form; the invention takes amphiphilic polymer material Soluplus as a carrier, adopts an injection method to prepare the tacrolimus-loaded self-assembled nanoparticles, and is administered to rats with rheumatoid arthritis by intravenous injection, so that the curative effect is obviously improved compared with the curative effect of injection.
Description
(1) technical field
The present invention relates to a kind of novel tacrolimus self-assembling polymers nanoparticle drug delivery systems and preparation method thereof.
(2) background technique
Tacrolimus (Tacrolimus also known as FK506) is a kind of neotype immunosuppressant of strength, mainly passes through suppression
The release of proleulzin (IL-2) processed inhibits T lymphocyte function comprehensively, and inhibiting effect is 100 times strong compared with cyclosporine (CsA).Face
Bed is mainly used for the organ transplantations such as liver, kidney, the heart, lung, intestines, marrow and atopic dermatitis (AD), systemic loupus erythematosus
(SLE), the autoimmune diseases such as Autoimmune ophthalmopathy.Presently commercially available dosage form mainly has capsule, injection, ointment, delays
Capsule and sustained-release tablet are released, etc..Preparation research reported in the literature have microballoon (Kojima R, Yoshida T, Tasaki H,
Umejima H,Maeda M,Higashi Y,Watanabe S,Oku N.Release mechanisms of
tacrolimus-loaded PLGA and PLA microspheres and immunosuppressive effects of
the microspheres in a rat heart transplantation model.Int J Pharm,2015,492(1-
2): 20-7), liposome (Ishii T, Asai T, Oyama D, Agato Y, Yasuda N, Fukuta T, Shimizu K,
Minamino T,Oku N.Treatment of cerebral ischemia-reperfusion injury with
1362-70.), nanoparticle PEGylated liposomes encapsulating FK506.FASEB is J.2013,27 (4):
(preparation of Wang Ruihua, Zhang Tangde, Sun Ledong tacrolimus solid lipid nano particle and physicochemical property research Nanfang Medical Univ are large
Scholar's paper, 2012), (Zhang Jingjing, Zhang Tianhong, Song Hongtao's tacrolimus body temperature are sensitive ophthalmically acceptable solidifying for beta cyclodextrin-F127 thermo-sensitive gel
The research of glue, Shenyang Pharmaceutical University's Master's thesis, 2008).But tacrolimus molecular weight is larger, water-soluble poor, commercially available injection
Agent is 20% Emulsifier EL-60 (HCO-60) and 80% dehydrated alcohol is solution (the specification 5mg/ that mixed solvent is prepared
Ml), intravenous drip after being diluted before use with 0.9%NaCl or 5% glucose, but HCO-60 may cause allergy, and dilute
Journey may cause drug precipitation.
Polyvinylcaprolactame-polyvinyl acetate-polyethyleneglycol-graft copolymer (trade name Soluplus) is N- second
Alkenyl-epsilon-caprolactams-vinyl acetate-polyethylene glycol (57:30:13) is copolymerized, molecular weight 90,000~140,
000g/mol is a kind of novel high polymer material of BASF AG's research and development listing in 2009.Have and is prepared using hot-melt extruded method
Oral cyclosporine over-saturation polymer micelle (Yu H, Xia D, Zhu Q, Zhu C, Chen D, Gan Y.Supersaturated
polymeric micelles for oral cyclosporine A delivery.Eur J Pharm Biopharm,
2013,85(3Pt B):1325-36)；Film dispersion-F127 aquation method prepares oral Quercetin and rheum emodin polymer micelle
(Dian L,Yu E,Chen X,Wen X,Zhang Z,Qin L,Wang Q,Li G,Wu C.Enhancing oral
bioavailability of quercetin using novel soluplus polymeric
micelles.Nanoscale Res Lett,2014,9(1):2406.；Allusion quotation spirit brightness, Yu Enjiang, Cheng Jilun, Guo Xianghua, Huang Zi
Honor, the preparation of Zhang Zhen's sound rheum emodin Soluplus polymer micelle and quality evaluation Chinese experimental pharmacology of traditional Chinese medical formulae magazine, 2014,20
(16): 15-18. the medicine), is can be improved into insoluble drug Sapacitabine and the Soluplus solution for being configured to solubilising
Anticancer therapeutic, but drug concentration of the medicine in Soluplus is extremely low, maximum only 49.6 μ g/ml (Obata T, Suzuki Y,
Ogawa N,Kurimoto I,Yamamoto H,Furuno T,Sasaki T,Tanaka M.Improvement of the
antitumor activity of poorly soluble sapacitabine(CS-682)by usingas a
surfactant.Biol Pharm Bull.2014；37(5):802-7.).
(3) summary of the invention
The present invention is directed to Polyvinylcaprolactame-polyvinyl acetate-polyethyleneglycol-graft copolymer (trade name
Soluplus it is) carrier, a kind of injection method is provided, novel tacrolimus self-assembling polymers nanoparticle administration system is prepared
System, for diseases such as intravenous injection or oral treatment rheumatoid joint, organ transplants.Compared with commercially available injection, this
Emulsifier EL-60 is not contained in invention drug delivery system, and the more existing injection of curative effect significantly improves.
The present invention adopts the following technical scheme:
A kind of tacrolimus self-assembling polymers nanoparticle drug delivery system mainly includes tacrolimus and Soluplus；Base
In the tacrolimus and Soluplus, the weight percent of the tacrolimus is 0.1%~35%, the Soluplus
Weight percent be 99.9%~65%；
Preferably, based on the tacrolimus and Soluplus, the weight percent of the tacrolimus is 1%~
The weight percent of 25%, the Soluplus are 99%~75%；
More preferred, based on the tacrolimus and Soluplus, the weight percent of the tacrolimus is 3%
The weight percent of~15%, the Soluplus are 97%~85%；
Tacrolimus self-assembling polymers nanoparticle drug delivery system of the present invention is liquid dispersed dosage form or is
Lyophilized preparation form.
Specifically, when the tacrolimus self-assembling polymers nanoparticle drug delivery system is liquid dispersed dosage form,
It is made of tacrolimus, Soluplus, water phase；Based on the tacrolimus and Soluplus, the weight of the tacrolimus
Percentage is 0.1%~35%, and the weight percent of the Soluplus is 99.9%~65%, and the volume of the water phase is
5~200mL/g Soluplus；
Preferably, based on the tacrolimus and Soluplus, the weight percent of the tacrolimus is 1%~
The weight percent of 25%, the Soluplus are 99%~75%；
More preferred, based on the tacrolimus and Soluplus, the weight percent of the tacrolimus is 3%
The weight percent of~15%, the Soluplus are 97%~85%；
It is preferred that the volume of the water phase is 10~100mL/g Soluplus；The volume of the more preferred water phase is
15~50mL/g Soluplus.
The water phase is formulated by pH adjusting agent is soluble in water, or is free of pH adjusting agent, is directly water；Described
Water is pure water, water for injection or sterilized water for injection, preferably sterilized water for injection；The pH value of the water phase is 3.0~9.0, excellent
Select 4.0~7.6；
The pH adjusting agent be sodium dihydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium hydroxide,
At least one of hydrochloric acid, citric acid, tartaric acid, preferably sodium dihydrogen phosphate, sodium hydroxide or hydrochloric acid.
The present invention also provides the tacrolimus self-assembling polymers nanoparticle drug delivery systems of liquid dispersed dosage form
Preparation method, there are two types of the preparation methods:
Preparation method A: during Soluplus is soluble in the aqueous phase, system I is obtained, tacrolimus is dissolved in organic solvent, is obtained
To system II, under stirring, organic solvent in system II injection system I, will be removed later, is sterile filtered to get liquid dispersed system
The tacrolimus self-assembling polymers nanoparticle drug delivery system of dosage form formula；
In preparation method A, the volumetric usage of the water phase with the quality of Soluplus be calculated as 5~200mL/g (preferably 10~
100mL/g, more preferable 15~50mL/g), the volumetric usage of the organic solvent is calculated as 0.0014 with the quality of tacrolimus~
1mL/mg (preferably 0.002~0.1mL/mg, more preferable 0.01~0.05mL/mg).
Preparation method B: tacrolimus and Soluplus are dissolved in organic solvent, obtain mixed liquor, under stirring, by gained
Mixed liquor injects in water phase, removes organic solvent later, and the tacrolimus being sterile filtered to get liquid dispersed dosage form is from group
Fill polymer nanoparticle drug delivery system；
In preparation method B, the volumetric usage of the water phase with the quality of Soluplus be calculated as 5~200mL/g (preferably 10~
100mL/g, more preferable 15~50mL/g), the volumetric usage of the organic solvent is calculated as 0.0014 with the quality of tacrolimus~
1mL/mg (preferably 0.002~0.1mL/mg, more preferable 0.01~0.05mL/mg).
System is administered in the tacrolimus self-assembling polymers nanoparticle of the liquid dispersed dosage form obtained by preparation method A or B
Freeze drying protectant is added in system and is freeze-dried and is administered to get the tacrolimus self-assembling polymers nanoparticle of lyophilized preparation form
System；
The quality dosage of the freeze drying protectant is with the tacrolimus self-assembling polymers of the liquid dispersed dosage form
The volume of nanoparticle drug delivery system is calculated as 5~250mg/ml, preferably 10~150mg/ml, more preferable 50~100mg/ml；
The freeze drying protectant is one of glucose, fructose, lactose, sucrose, chitosan, trehalose, mannitol
Or the mixture of two or more arbitrary proportions, preferred mannitol.
Preparation method A or B of the present invention is usually operated at 0~30 DEG C, described in the preparation method A or B
Organic solvent be ethyl alcohol, methanol, acetone, ethyl acetate, dimethylformamide, dimethyl acetamide, dimethyl sulfoxide, dichloro
The mixed solvent of one or more of methane, butanol, amylalcohol arbitrary proportion, preferred alcohol or acetone.
The method for removing organic solvent can be the decompression vacuum pumping method, ultrafiltration, dialysis etc. of this field routine.
In general, recommending decompression vacuum pumping method, 0~0.05MPa of vacuum degree if organic solvent is methylene chloride or ethyl acetate；If organic
Solvent is that (such as: acetone, ethyl alcohol, methanol, dimethylformamide, dimethyl acetamide, dimethyl are sub- for organic solvent miscible with water
Sulfone, butanol or amylalcohol), recommend ultrafiltration, 10~50kD of ultrafiltration membrane aperture.
It is of the present invention be sterile filtered, freeze-drying be conventional practices commonly used in the art.
Compared with prior art, the beneficial effects of the present invention are: the present invention is with amphiphilic macromolecular material Soluplus
For carrier, the self-assembled nanometer grain for carrying tacrolimus is prepared using injection method, rheumatoid arthritis in rats is given in intravenous injection,
Curative effect is significantly improved compared with injection.
(4) Detailed description of the invention
Fig. 1 is emission spectrum of the pyrene in Soluplus dispersion liquid in embodiment 1；
Fig. 2 is tacrolimus-Soluplus self-assembled nanometer grain transmission electron microscope picture in embodiment 2；
Fig. 3 is that AIA rat paw edema is write music line in embodiment 4.
(5) specific embodiment
Technical solution of the present invention is described further below by specific embodiment, but protection scope of the present invention is not
It is limited to this.
The structural identification of embodiment 1:Soluplus self-assembled nanometer grain
Pyrene is a kind of micropolar fluorescence probe of medium, belongs to condensed-nuclei aromatics class, at room temperature, when the concentration of pyrene is less than 10- 5When mol/L, after pyrene solution excites at 335nm, there are 5 fluorescent emission electricity in 373,379,384,394 and 480nm respectively
Sub- vibration peak.The ratio between the fluorescence intensity of first electronic vibration peak 373nm and third electronic vibration peak 384nm I1/I3With pyrene point
The polarity of sub- local environment is in very strong correlation.I1/I3Smaller, the polarity of corresponding environment is smaller, i.e., hydrophobicity is stronger.Usually
Think, I1/I3The turning point of ratio is critical micelle concentration.
Precision weighs pyrene 19.62mg, and dehydrated alcohol is added to dissolve, and is diluted to 10ml measuring bottle, is configured to 1.962mg/ containing pyrene
Ml solution.Precision measures liquid 0.25ml, adds ethyl alcohol to be diluted to 50ml measuring bottle, is configured to the 9.81 μ g/ml solution containing pyrene.Precision amount
100 μ l of the liquid is taken, is placed in clean and dry test tube, volatilizes.Be separately added into containing Soluplus 0,10,50,100,150,200,
300, the dispersion liquid of 500,1000,5000,10000 μ g/ml, 37 DEG C are protected from light constant temperature oscillation 12h.In F-4600 fluorescence spectrophotometry
Meter, fixed excitation wavelength 335nm, exciting slit 5nm, transmite slit 2.5nm, sweep speed 240nm/min, 350~500nm are swept
It retouches, records launching light spectrogram, and calculate I373/I384。
It can be seen from figure 1 that the fluorescence intensity of pyrene is gradually increased with the increase of Soluplus concentration, illustrate Soluplus pairs
Pyrene has solubilization, but I373/I384The ratio between do not reduce the phenomenon that.
When Soluplus concentration is 5mg/ml, that is, there is macroscopic light blue opalescence, pass through laser granulometry
Measure the range of 0.01~80mg/ml of Soluplus concentration, average grain diameter 56nm ± 5nm.Illustrate that Soluplus is self-assembly of
Particle be in nanoparticulate form, rather than the form of micella.
Embodiment 2: the preparation method of tacrolimus-Soluplus self-assembled nanometer grain compares
| Composition | Dosage |
| Tacrolimus | 300mg |
| Soluplus | 8000mg |
| Dehydrated alcohol | 10ml |
| Water for injection adds to | 100ml |
Preparation method one: tacrolimus is dissolved in dehydrated alcohol；Soluplus is dissolved in water for injection；It is stirred again in magnetic force
Mix it is lower by tacrolimus ethanol solution inject the water phase containing Soluplus in, stir evenly.
Preparation method two: tacrolimus and Soluplus are dissolved in dehydrated alcohol, under magnetic agitation, inject water for injection
In, it stirs evenly.
Partial size, encapsulation rate and the dilution stability of self-assembled nanometer grain are measured respectively.As the result is shown prepared by two methods
Self-assembled nanometer grain average grain diameter is 70nm or so, is slightly increased compared with blank nanoparticle；Encapsulation rate is 93% or more；But method
When the nanoparticle dilution of one preparation, drug leakage is easily led to, when Soluplus concentration is diluted to 0.5mg/ml from 80mg/ml,
Method one has 35% drug leakage；And method two only 21%.
Embodiment 3: the freeze-dried preparation of tacrolimus-Soluplus self-assembled nanometer grain
Preparation: tacrolimus and Soluplus are dissolved in dehydrated alcohol, under magnetic agitation, are injected in water for injection, are stirred
It mixes uniformly；Again through ultrafiltration membrane Biomax 30kD ultrafiltration, in nano suspension: fresh water for injection (1:50) ratio ultrafiltration removes
Dehydrated alcohol；Freeze drying protectant mannitol, sucrose or lactose are added, the quality dosage of freeze drying protectant is respectively water for injection
5%, 10% and the 15% of quality；It is freeze-dried freeze-dried to get tacrolimus-Soluplus self-assembled nanometer grain.
As a result: using mannitol as freeze drying protectant, complete appearance, nothing is collapsed.Other freeze drying protectant appearances exist different
The defect of degree；But redisperse and encapsulation rate are had little effect.Mannitol dosage increases, the grain after freeze-dried powder redisperse
Diameter slightly increases.Therefore freeze drying protectant is excellent with 5% mannitol.
Embodiment 4: tacrolimus-Soluplus self-assembled nanometer grain is compared with the pharmacodynamics of solution
It male SD rat 20, weight 160g or so, raises after a week, in unilateral right 100 μ L Freund of metapedes intracutaneous injection
Freund's complete adjuvant (CFA, the tubercle bacillus 5mg/mL containing inactivation) is used as the 0th day on the day of modeling.The next day measure degree of paw swelling, work as foot
Swelling > 100% is considered as rheumatoid arthritis modeling success.D7 is grouped according to the swelling of rat injection parapodum,
Every group 5, by tacrolimus dosage 10mg/kg intravenous injection give the tacrolimus self-assembled nanometer grain prepared in embodiment 2,
Solution；It is total to three times one time a day with control group blank self-assembled nanometer grain, physiological saline.
It measures the toes volume of same rat injection side and opposite side per daily drainage during administration and weighs in, give
The next day after medicine, measures.Concrete operations are as follows: using at the ankle-joint top about 1cm of rat hindleg as water-immersed online, fixation
Rat respectively immerses the left and right hind leg of rat in measuring appliance, and the weight change value of water is as big divided by the density of water in container
The water-immersed sufficient volume of mouse.Same rats with bilateral compares enough, calculates swelling, and formula is as follows:
Swelling=(Vt-Vt ')/Vt ' × 100
Vt: the t days injection parapodum volumes after modeling
Vt ': the sufficient volume of sufficient opposite side is injected within the t days after modeling
From result (Fig. 3) as it can be seen that when dosage is identical, tacrolimus self-assembled nanometer grain group is significantly dropped compared with solution group
Low the degree of paw swelling of AIA rat (p < 0.05).And blank self-assembled nanometer grain and physiological saline group are swollen almost without foot is reduced
The effect of expansibility.
Claims (4)
1. a kind of tacrolimus self-assembling polymers nanoparticle drug delivery system of liquid dispersed dosage form, which is characterized in that by
Tacrolimus, Soluplus, water phase composition；Based on the tacrolimus and Soluplus, the weight hundred of the tacrolimus
Score is 0.1%~35%, and the weight percent of the Soluplus is 99.9%~65%, and the volume of the water phase is 5
~200mL/g Soluplus；The water phase is formulated by pH adjusting agent is soluble in water, or is free of pH adjusting agent, directly
For water；The water is pure water, water for injection or sterilized water for injection；The pH value of the water phase is 3.0~9.0；
The tacrolimus self-assembling polymers nanoparticle drug delivery system of the liquid dispersed dosage form the preparation method comprises the following steps:
Tacrolimus and Soluplus are dissolved in organic solvent, mixed liquor is obtained, under stirring, gained mixed liquor is injected into water phase
In, organic solvent is removed later, is sterile filtered to get the tacrolimus self-assembling polymers nanoparticle of liquid dispersed dosage form
Drug delivery system；
The volumetric usage of the organic solvent is calculated as 0.0014~1mL/mg with the quality of tacrolimus.
2. the tacrolimus self-assembling polymers nanoparticle drug delivery system of liquid dispersed dosage form as described in claim 1,
It is characterized in that, the pH adjusting agent is sodium dihydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, hydroxide
At least one of sodium, hydrochloric acid, citric acid, tartaric acid.
3. the tacrolimus self-assembling polymers nanoparticle drug delivery system of liquid dispersed dosage form as described in claim 1,
It is characterized in that, the organic solvent be ethyl alcohol, methanol, acetone, ethyl acetate, dimethylformamide, dimethyl acetamide,
The mixed solvent of one or more of dimethyl sulfoxide, methylene chloride, butanol, amylalcohol arbitrary proportion.
4. a kind of tacrolimus self-assembling polymers nanoparticle drug delivery system of lyophilized preparation form, which is characterized in that the jelly
Tacrolimus self-assembling polymers nanoparticle drug delivery system liquid dispersed dosage form as described in claim 1 of dry preparation form
Tacrolimus self-assembling polymers nanoparticle drug delivery system be added freeze drying protectant after be freeze-dried be made；
The freeze drying protectant is mannitol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610246725.8A CN105769821B (en) | 2016-04-19 | 2016-04-19 | Tacrolimus self-assembly polymer nanoparticle drug delivery system and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610246725.8A CN105769821B (en) | 2016-04-19 | 2016-04-19 | Tacrolimus self-assembly polymer nanoparticle drug delivery system and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105769821A CN105769821A (en) | 2016-07-20 |
| CN105769821B true CN105769821B (en) | 2019-06-14 |
Family
ID=56397905
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610246725.8A Active CN105769821B (en) | 2016-04-19 | 2016-04-19 | Tacrolimus self-assembly polymer nanoparticle drug delivery system and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105769821B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110693881A (en) * | 2018-07-09 | 2020-01-17 | 安徽医科大学 | Pharmaceutical composition for treating atherosclerosis and preparation method and application thereof |
| CN112870173A (en) * | 2021-02-04 | 2021-06-01 | 南京天纵易康生物科技股份有限公司 | Freeze-dried flash-release tablet and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102198082A (en) * | 2010-05-27 | 2011-09-28 | 四川大学 | Micelle loaded with Tacrolimus or pharmaceutical salts thereof, lyophilized preparation as well as preparation methods and applications |
| CN104387592A (en) * | 2014-11-29 | 2015-03-04 | 沈阳药科大学 | Application of cyclodextrin-methyl vinyl ether/maleic anhydride copolymer and self-assembled nanoparticle of copolymer in oral medicine delivery |
| CN104387573A (en) * | 2014-11-29 | 2015-03-04 | 沈阳药科大学 | Preparation of vitamin E modified enteric polycarbonate and application of vitamin E modified enteric polycarbonate in oral medication |
-
2016
- 2016-04-19 CN CN201610246725.8A patent/CN105769821B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102198082A (en) * | 2010-05-27 | 2011-09-28 | 四川大学 | Micelle loaded with Tacrolimus or pharmaceutical salts thereof, lyophilized preparation as well as preparation methods and applications |
| CN104387592A (en) * | 2014-11-29 | 2015-03-04 | 沈阳药科大学 | Application of cyclodextrin-methyl vinyl ether/maleic anhydride copolymer and self-assembled nanoparticle of copolymer in oral medicine delivery |
| CN104387573A (en) * | 2014-11-29 | 2015-03-04 | 沈阳药科大学 | Preparation of vitamin E modified enteric polycarbonate and application of vitamin E modified enteric polycarbonate in oral medication |
Non-Patent Citations (2)
| Title |
|---|
| "高产他克莫司基因工程菌的构建及他克莫司MPEG-PLA纳米胶束治疗肝移植术后急性排斥反应的研究";徐巍;《中国博士学位论文全文数据库（电子期刊）》;20141215(第12期);E066-22 * |
| Ezequiel Bernabeu et al.."Novel Soluplus®—TPGS mixed micelles for encapsulation of paclitaxel with enhanced in vitro cytotoxicity on breast and ovarian cancer cell lines".《Colloids and Surfaces B: Biointerfaces》.2016,(第140期), * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105769821A (en) | 2016-07-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Guan et al. | N-trimethyl chitosan nanoparticle-encapsulated lactosyl-norcantharidin for liver cancer therapy with high targeting efficacy | |
| Craparo et al. | Galactosylated polymeric carriers for liver targeting of sorafenib | |
| Çırpanlı et al. | Antitumoral activity of camptothecin-loaded nanoparticles in 9L rat glioma model | |
| CN105727309B (en) | The preparation and application of sensitive amphiphilic polysaccharide-adriamycin conjugate and its pharmaceutical compositions | |
| Zhu et al. | Bioresponsive and fluorescent hyaluronic acid-iodixanol nanogels for targeted X-ray computed tomography imaging and chemotherapy of breast tumors | |
| Kang et al. | Tailoring the stealth properties of biocompatible polysaccharide nanocontainers | |
| CN106421806B (en) | A kind of response nano self-assembling dendritic prodrug and preparation method and application step by step | |
| Zhang et al. | Redox-and light-responsive alginate nanoparticles as effective drug carriers for combinational anticancer therapy | |
| CN101791411A (en) | Preparation and application of amphiphilic polysaccharide conjugate and medicinal compositions thereof | |
| Kim et al. | Low-molecular-weight methylcellulose-based thermo-reversible gel/pluronic micelle combination system for local and sustained docetaxel delivery | |
| KR20140041522A (en) | Polymeric nanoparticles for drug delivery | |
| CN103131005B (en) | Amino acid block copolymer and preparation method thereof and mixture | |
| CN101732728B (en) | Anti-inflammatory drug (polysaccharide conjugate) as well as preparation and application of drug composition thereof | |
| CN105566511B (en) | Electric charge overturns pulullan polysaccharide derivative and its preparation method and use | |
| Chen et al. | Tumor microenvironment-responsive micelles for pinpointed intracellular release of doxorubicin and enhanced anti-cancer efficiency | |
| CN102125547A (en) | Pharmaceutical composition containing gambogic acid medicament and preparation method thereof | |
| Li et al. | Photodynamic therapy-mediated remote control of chemotherapy toward synergistic anticancer treatment | |
| Lin et al. | Doxorubicin loaded silica nanoparticles with dual modification as a tumor-targeted drug delivery system for colon cancer therapy | |
| Liu et al. | Synthesis, biodistribution, and imaging of PEGylated-acetylated polyamidoamine dendrimers | |
| CN104826128A (en) | Polysaccharide modified reduction-sensitive graphene oxide carrier with organism lesion site triggered drug release and preparation and application of pharmaceutical composition thereof | |
| KR100831391B1 (en) | Chitosan complex containing pH sensitive imidazole group and preparation method thereof | |
| CN105769821B (en) | Tacrolimus self-assembly polymer nanoparticle drug delivery system and preparation method thereof | |
| EP3616726B1 (en) | Protein particle wrapped with medicine insoluble in water and preparation method therefor | |
| CN103301073B (en) | Methotrexate targeted nanoparticle sustained-release preparation and preparation method thereof | |
| Jawahar et al. | Development and characterization of PLGA-nanoparticles containing carvedilol |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |