CN117582408A - Nanometer liposome for aerosol inhalation and preparation method and application thereof - Google Patents
Nanometer liposome for aerosol inhalation and preparation method and application thereof Download PDFInfo
- Publication number
- CN117582408A CN117582408A CN202311538781.5A CN202311538781A CN117582408A CN 117582408 A CN117582408 A CN 117582408A CN 202311538781 A CN202311538781 A CN 202311538781A CN 117582408 A CN117582408 A CN 117582408A
- Authority
- CN
- China
- Prior art keywords
- hydrogenated
- liposome
- soybean
- phosphatidylcholine
- acid
- 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
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- 239000002502 liposome Substances 0.000 title claims abstract description 63
- 239000000443 aerosol Substances 0.000 title claims abstract description 36
- 238000002360 preparation method Methods 0.000 title abstract description 22
- RUDATBOHQWOJDD-UHFFFAOYSA-N (3beta,5beta,7alpha)-3,7-Dihydroxycholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 RUDATBOHQWOJDD-UHFFFAOYSA-N 0.000 claims abstract description 61
- RUDATBOHQWOJDD-UZVSRGJWSA-N ursodeoxycholic acid Chemical compound 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)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-UZVSRGJWSA-N 0.000 claims abstract description 61
- 229960001661 ursodiol Drugs 0.000 claims abstract description 61
- 239000003814 drug Substances 0.000 claims abstract description 16
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 36
- 235000010469 Glycine max Nutrition 0.000 claims description 20
- 244000068988 Glycine max Species 0.000 claims description 20
- 239000012528 membrane Substances 0.000 claims description 19
- KILNVBDSWZSGLL-KXQOOQHDSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCC KILNVBDSWZSGLL-KXQOOQHDSA-N 0.000 claims description 18
- 235000012000 cholesterol Nutrition 0.000 claims description 18
- 150000002632 lipids Chemical class 0.000 claims description 17
- 239000002245 particle Substances 0.000 claims description 16
- 150000003904 phospholipids Chemical class 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- 239000000725 suspension Substances 0.000 claims description 13
- ATBOMIWRCZXYSZ-XZBBILGWSA-N [1-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-3-hexadecanoyloxypropan-2-yl] (9e,12e)-octadeca-9,12-dienoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C\C\C=C\CCCCC ATBOMIWRCZXYSZ-XZBBILGWSA-N 0.000 claims description 11
- 229920001223 polyethylene glycol Polymers 0.000 claims description 11
- 239000002202 Polyethylene glycol Substances 0.000 claims description 10
- 230000002401 inhibitory effect Effects 0.000 claims description 10
- 150000003905 phosphatidylinositols Chemical class 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 claims description 9
- 208000001528 Coronaviridae Infections Diseases 0.000 claims description 9
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 claims description 9
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- 150000008104 phosphatidylethanolamines Chemical class 0.000 claims description 9
- PORPENFLTBBHSG-MGBGTMOVSA-N 1,2-dihexadecanoyl-sn-glycerol-3-phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(O)=O)OC(=O)CCCCCCCCCCCCCCC PORPENFLTBBHSG-MGBGTMOVSA-N 0.000 claims description 7
- -1 dimyristoyl ethyl phosphorylcholine Chemical compound 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 7
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 claims description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 6
- JLPULHDHAOZNQI-JLOPVYAASA-N [(2r)-3-hexadecanoyloxy-2-[(9e,12e)-octadeca-9,12-dienoyl]oxypropyl] 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C\C\C=C\CCCCC JLPULHDHAOZNQI-JLOPVYAASA-N 0.000 claims description 6
- 239000003963 antioxidant agent Substances 0.000 claims description 6
- 230000003078 antioxidant effect Effects 0.000 claims description 6
- 235000006708 antioxidants Nutrition 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
- 239000003381 stabilizer Substances 0.000 claims description 6
- 238000009210 therapy by ultrasound Methods 0.000 claims description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 5
- 238000000889 atomisation Methods 0.000 claims description 5
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- FVJZSBGHRPJMMA-IOLBBIBUSA-N PG(18:0/18:0) Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@@H](O)CO)OC(=O)CCCCCCCCCCCCCCCCC FVJZSBGHRPJMMA-IOLBBIBUSA-N 0.000 claims description 4
- 239000012736 aqueous medium Substances 0.000 claims description 4
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 claims description 4
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 4
- WKJDWDLHIOUPPL-JSOSNVBQSA-N (2s)-2-amino-3-({[(2r)-2,3-bis(tetradecanoyloxy)propoxy](hydroxy)phosphoryl}oxy)propanoic acid Chemical compound CCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCC WKJDWDLHIOUPPL-JSOSNVBQSA-N 0.000 claims description 3
- IBUKXRINTKQBRQ-KCKFLZCVSA-N 1,2-dihexadecanoyl-sn-glycero-3-phospho-D-myo-inositol Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCCCCCCCCCC)COP(O)(=O)O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](O)[C@H]1O IBUKXRINTKQBRQ-KCKFLZCVSA-N 0.000 claims description 3
- YFWHNAWEOZTIPI-DIPNUNPCSA-N 1,2-dioctadecanoyl-sn-glycerol-3-phosphate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(O)=O)OC(=O)CCCCCCCCCCCCCCCCC YFWHNAWEOZTIPI-DIPNUNPCSA-N 0.000 claims description 3
- OZSITQMWYBNPMW-GDLZYMKVSA-N 1,2-ditetradecanoyl-sn-glycerol-3-phosphate Chemical compound CCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(O)=O)OC(=O)CCCCCCCCCCCCC OZSITQMWYBNPMW-GDLZYMKVSA-N 0.000 claims description 3
- QCDSEQXIYMEZMJ-UHFFFAOYSA-O CCP(=O)=C(O)C[N+](C)(C)C Chemical compound CCP(=O)=C(O)C[N+](C)(C)C QCDSEQXIYMEZMJ-UHFFFAOYSA-O 0.000 claims description 3
- KLFKZIQAIPDJCW-HTIIIDOHSA-N Dipalmitoylphosphatidylserine Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCC KLFKZIQAIPDJCW-HTIIIDOHSA-N 0.000 claims description 3
- FQZQXPXKJFOAGE-KICCZPNWSA-N [(2r)-3-[hydroxy-[(5r)-2,3,4,5,6-pentahydroxycyclohexyl]oxyphosphoryl]oxy-2-octadecanoyloxypropyl] octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCCCCCCCCCCCC)COP(O)(=O)OC1C(O)C(O)C(O)[C@@H](O)C1O FQZQXPXKJFOAGE-KICCZPNWSA-N 0.000 claims description 3
- LYBDVVBIMGTZMB-HVIJGSDCSA-N [3-[hydroxy-[(2s,3r,5s,6s)-2,3,4,5,6-pentahydroxycyclohexyl]oxyphosphoryl]oxy-2-tetradecanoyloxypropyl] tetradecanoate Chemical compound CCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCC)COP(O)(=O)OC1[C@@H](O)[C@@H](O)C(O)[C@@H](O)[C@@H]1O LYBDVVBIMGTZMB-HVIJGSDCSA-N 0.000 claims description 3
- 239000008350 hydrogenated phosphatidyl choline Substances 0.000 claims description 3
- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 claims description 3
- 125000003696 stearoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 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 claims description 2
- IHNKQIMGVNPMTC-UHFFFAOYSA-N (2-hydroxy-3-octadecanoyloxypropyl) 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COP([O-])(=O)OCC[N+](C)(C)C IHNKQIMGVNPMTC-UHFFFAOYSA-N 0.000 claims description 2
- VXUOFDJKYGDUJI-UHFFFAOYSA-N (2-hydroxy-3-tetradecanoyloxypropyl) 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CCCCCCCCCCCCCC(=O)OCC(O)COP([O-])(=O)OCC[N+](C)(C)C VXUOFDJKYGDUJI-UHFFFAOYSA-N 0.000 claims description 2
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims description 2
- NRJAVPSFFCBXDT-HUESYALOSA-N 1,2-distearoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCCCC NRJAVPSFFCBXDT-HUESYALOSA-N 0.000 claims description 2
- PYVRVRFVLRNJLY-KTKRTIGZSA-N 1-oleoyl phosphatidylethanolamine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(O)COP(O)(=O)OCCN PYVRVRFVLRNJLY-KTKRTIGZSA-N 0.000 claims description 2
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 claims description 2
- PWKSKIMOESPYIA-UHFFFAOYSA-N 2-acetamido-3-sulfanylpropanoic acid Chemical compound CC(=O)NC(CS)C(O)=O PWKSKIMOESPYIA-UHFFFAOYSA-N 0.000 claims description 2
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims description 2
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- 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 claims description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- 229930091371 Fructose Natural products 0.000 claims description 2
- 239000005715 Fructose Substances 0.000 claims description 2
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 claims 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 claims 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 claims description 2
- 239000005639 Lauric acid Substances 0.000 claims description 2
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- 239000005642 Oleic acid Substances 0.000 claims description 2
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- 235000021314 Palmitic acid Nutrition 0.000 claims description 2
- MUPFEKGTMRGPLJ-RMMQSMQOSA-N Raffinose Natural products O(C[C@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O[C@@]2(CO)[C@H](O)[C@@H](O)[C@@H](CO)O2)O1)[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 MUPFEKGTMRGPLJ-RMMQSMQOSA-N 0.000 claims description 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 2
- 235000021355 Stearic acid Nutrition 0.000 claims description 2
- 229930006000 Sucrose Natural products 0.000 claims 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 claims description 2
- 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 claims description 2
- MUPFEKGTMRGPLJ-UHFFFAOYSA-N UNPD196149 Natural products OC1C(O)C(CO)OC1(CO)OC1C(O)C(O)C(O)C(COC2C(C(O)C(O)C(CO)O2)O)O1 MUPFEKGTMRGPLJ-UHFFFAOYSA-N 0.000 claims description 2
- 229930003268 Vitamin C Natural products 0.000 claims description 2
- 229930003427 Vitamin E Natural products 0.000 claims description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- 150000003863 ammonium salts Chemical class 0.000 claims description 2
- 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 claims description 2
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 claims description 2
- 235000015165 citric acid Nutrition 0.000 claims description 2
- 238000001704 evaporation Methods 0.000 claims description 2
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- 230000000887 hydrating effect Effects 0.000 claims description 2
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 239000002609 medium Substances 0.000 claims description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 2
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 claims description 2
- 229940042880 natural phospholipid Drugs 0.000 claims description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 235000021317 phosphate Nutrition 0.000 claims description 2
- 150000008103 phosphatidic acids Chemical class 0.000 claims description 2
- 150000008105 phosphatidylcholines Chemical class 0.000 claims description 2
- 150000008106 phosphatidylserines Chemical class 0.000 claims description 2
- MUPFEKGTMRGPLJ-ZQSKZDJDSA-N raffinose 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[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)O)O1 MUPFEKGTMRGPLJ-ZQSKZDJDSA-N 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- 235000002639 sodium chloride Nutrition 0.000 claims description 2
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 2
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 2
- 229940001584 sodium metabisulfite Drugs 0.000 claims description 2
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Classifications
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- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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- 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
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
-
- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1277—Processes for preparing; Proliposomes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
Abstract
The invention belongs to the field of biological medicine, and in particular relates to a nano liposome for aerosol inhalation, and a preparation method and application thereof. The invention uses liposome to load ursodeoxycholic acid and then aerosol inhalation for administration, so that the invention has the double advantages of liposome nano preparation and lung administration: the liposome can integrate poorly soluble ursodeoxycholic acid into lipid bilayer, greatly increase its solubility in aqueous phase, and improve in vivo and in vitro stability. The ursodeoxycholic acid is directly concentrated in the respiratory tract by the inhalation administration mode, and the concentration and the retention of the ursodeoxycholic acid in the lung are increased, so that the effects of reducing the adhesion of novel coronaviruses and infecting the respiratory tract and lung cells are achieved; and has the effects of slow release and long-time action.
Description
Technical Field
The invention belongs to the field of biological medicine, and in particular relates to a nano liposome for aerosol inhalation, and a preparation method and application thereof.
Background
Angiotensin converting enzyme 2 (ACE 2) is a membrane-bound receptor of novel coronaviruses, present in nasal mucosa cells and pulmonary alveolar cells, and involved in the fusion and invasion processes of viruses and host cells during the infection of the novel coronaviruses. Blocking the combination of virus and ACE2 is expected to play a role in protecting virus infection. Ursodeoxycholic acid is a drug clinically used for treating gall stones and is also an inhibitor of the Farnesol X Receptor (FXR). Related researches show that ursodeoxycholic acid can reduce the expression of ACE2 in tissues and organs such as respiratory tract, intestinal tract and the like by inhibiting FXR, and has the effects of reducing novel coronavirus infection and preventing further deterioration of the disease. However, ursodeoxycholic acid has poor water solubility, is mainly metabolized through liver and intestine after oral administration, lacks enrichment at respiratory tract and lung parts, and is difficult to continuously play a role in inhibiting novel coronavirus pulmonary infection. There is therefore a need to develop new formulations or new routes of administration of ursodeoxycholic acid to continue to function effectively in inhibiting novel coronavirus infections.
The novel coronavirus is mainly transmitted through air, so that the adhesion and invasion of the novel coronavirus on respiratory tract mucosa cells are blocked, and the infection probability can be reduced. The receptor protein of the novel coronavirus is angiotensin converting enzyme 2 (ACE 2). ACE2 is involved in the fusion and invasion processes of viruses and host cells during the new coronavirus infection process. Blocking the binding of virus and ACE2 receptor is expected to protect virus infection. ACE2 receptors are present in nasal mucosa cells and pulmonary alveolar cells. Ursodeoxycholic acid is a drug clinically used for treating gall stones and is also an inhibitor of the Farnesol X Receptor (FXR). Related researches show that ursodeoxycholic acid (UDCA) can reduce the expression of ACE2 in tissues and organs such as respiratory tract, intestinal tract and the like by inhibiting FXR, and has the effect of reducing novel coronavirus infection (Nature. 2023, 615:134-142).
Disclosure of Invention
Ursodeoxycholic acid has poor water solubility, is mainly metabolized by liver and intestine after oral administration (Scand J Gastroenterol suppl 1994; 204:1-15), lacks enrichment at respiratory tract and lung parts, and is difficult to continuously and effectively play a role in inhibiting infection caused by novel coronaviruses through respiratory action.
In order to solve the technical problems, the application provides the following technical scheme:
aiming at the defects of poor pharmacokinetic property and lack of enrichment in respiratory tract and lung of ursodeoxycholic acid after oral administration, the invention provides a ursodeoxycholic acid liposome preparation for aerosol inhalation and a preparation method thereof. Aerosol inhalation is an effective delivery means for delivering drugs directly to the respiratory tract and focal sites of the lungs, while liposomes are a good carrier for inhalation. The liposome preparation provided by the invention can effectively load ursodeoxycholic acid, and can deliver the ursodeoxycholic acid to the lung of a mouse after aerosol inhalation administration, so that the liposome preparation has the effect of inhibiting novel coronavirus infection in a long time.
The invention provides a nano liposome for atomization inhalation, which comprises the following components in parts by weight:
2-35% ursodeoxycholic acid, 50-95% phospholipid, 0-40% lipid membrane stabilizer, 0-5% antioxidant and the balance of aqueous medium;
the aqueous medium is selected from one or more of water, glucose, trehalose, lactose, sucrose, maltose, raffinose, fructose, xylitol, sorbitol, mannitol, sodium chloride, phosphate, acetate, organic and buffered pairs with buffer capacity.
Preferably, the concentration of the total lipid in the nano-liposome for aerosol inhalation is 1.2-30mg/mL.
Preferably, the phospholipid is selected from one or more of natural phospholipid, hydrogenated phospholipid, synthetic phospholipid and polyethylene glycol modified derivatives thereof.
Further, the phospholipid is selected from the group consisting of phosphatidylcholine (EPC), phosphatidylglycerol (EPG), phosphatidylinositol (EPI), phosphatidylserine (EPS), phosphatidylethanolamine (EPE), phosphatidic acid (EPA), soybean Phosphatidylcholine (SPC), soybean Phosphatidylglycerol (SPG), soybean Phosphatidylserine (SPS), soybean Phosphatidylinositol (SPI), soybean Phosphatidylethanolamine (SPE), soybean Phosphatidic Acid (SPA), hydrogenated phosphatidylcholine (HEPC), hydrogenated phosphatidylglycerol (HEPG), hydrogenated phosphatidylinositol (HEPI), hydrogenated phosphatidylserine (HEPS), hydrogenated phosphatidylethanolamine (HEPE), hydrogenated phosphatidic acid (HEPA), hydrogenated Soybean Phosphatidylcholine (HSPC), hydrogenated Soybean Phosphatidylglycerol (HSPG), hydrogenated Soybean Phosphatidylserine (HSPS), hydrogenated Soybean Phosphatidylinositol (HSPC), hydrogenated Soybean Phosphatidylethanolamine (SPS), hydrogenated Soybean Phosphatidylinositol (HSPA), hydrogenated soybean phosphatidylinositol (DPPC), ditolyphosphatidylcholine (DMPC), distearoyl phosphatidylcholine (dsphosphatidylcholine (dspe), stearoyl phosphatidylcholine (dspe), palmitoyl Stearoyl Phosphatidylglycerol (PSPG), mono-oleoyl phosphatidylethanolamine (mop), ammonium salts of phospholipids, dilauroyl ethyl phosphorylcholine (DLEP), dimyristoyl ethyl phosphorylcholine (DMEP), dipalmitoyl ethyl phosphorylcholine (DPEP), and distearoyl ethyl phosphorylcholine (DSEP), distearoyl phosphatidylglycerol (DSPG), dimyristoyl phosphatidic acid (DMPA), dipalmitoyl phosphatidic acid (DPPA), distearoyl phosphatidic acid (DSPA), dimyristoyl phosphatidylinositol (DMPI), dipalmitoyl phosphatidylinositol (DPPI), distearoyl phosphatidylinositol (DSPI), dimyristoyl phosphatidylserine (DMPS), dipalmitoyl phosphatidylserine (DPPS), distearoyl phosphatidylserine (DSPS), palmitoyl lysolecithin (P-LysoPC), myristoyl lysolecithin (M-LysoPC), stearoyl lysolecithin (S-LysoPC), phosphatidylcholine-polyethylene glycol (PC-PEG), phosphatidylethanolamine-polyethylene glycol (PE-PEG), or distearoyl phosphatidylethanolamine-PEG (DSPE-PEG).
Preferably, the lipid membrane stabilizer is selected from one or more of cholesterol, oleic acid, lauric acid, palmitic acid and stearic acid.
Preferably, the antioxidant is selected from one or more of fat-soluble vitamin E, water-soluble vitamin C, L-cysteine, sodium sulfite, sodium bisulfite, sodium metabisulfite, sodium thiosulfate and citric acid.
Preferably, the particle size of the nano liposome for aerosol inhalation is 50-1000nm.
Further, the particle size of the nano liposome for aerosol inhalation is 90-250 nm.
The invention also provides a preparation method of the nano liposome for aerosol inhalation, which comprises the following steps:
(1) Dissolving 2-35% ursodeoxycholic acid, 50-95% phospholipid, 0-40% lipid film stabilizer and 0-5% antioxidant in organic solvent according to weight fraction, and evaporating under reduced pressure to obtain lipid film;
(2) Hydrating the lipid film with a water phase medium, and heating or performing ultrasonic treatment to obtain liposome suspension;
(3) And extruding or homogenizing the liposome suspension filter membrane to obtain the nano liposome for atomization inhalation.
Preferably, the organic solvent is selected from ethanol, isopropanol or propylene glycol.
Preferably, in the step (1), the dissolution method is shaking, ultrasonic or heating.
Preferably, the filter is selected from the group consisting of 1000nm, 400 nm, 200 nm, 100 nm, or 80 nm.
The invention also provides application of the nano liposome for aerosol inhalation in preparing a medicament for inhibiting novel coronavirus infection, wherein the administration mode of the medicament for inhibiting novel coronavirus infection is aerosol inhalation.
The invention uses liposome to load ursodeoxycholic acid and then aerosol inhalation for administration, so that the invention has the double advantages of liposome nano preparation and lung administration: the liposome can integrate poorly soluble ursodeoxycholic acid into lipid bilayer, greatly increase its solubility in aqueous phase, and improve in vivo and in vitro stability. The ursodeoxycholic acid is directly concentrated in the respiratory tract by the inhalation administration mode, and the concentration and the retention of the ursodeoxycholic acid in the lung are increased, so that the effects of reducing the adhesion of novel coronaviruses and infecting the respiratory tract and lung cells are achieved; and has the effects of slow release and long-time action.
Compared with the prior art, the technical scheme of the invention has the following advantages:
the ursodeoxycholic acid liposome preparation can effectively load ursodeoxycholic acid, has good inhalability of respiratory tract and lung, and can be deposited in the respiratory tract and the lung in a large amount to exert pharmacodynamic treatment effect.
The ursodeoxycholic acid liposome for aerosol inhalation prepared by the invention can be directly used in respiratory tract and lung. Compared with ursodeoxycholic acid oral medicine, the medicine has greatly raised medicine effect and efficiency, reduced medicine dosage and long lasting effect.
The invention solves the problem of poor solubility of ursodeoxycholic acid, and adopts liposome loading technology to prepare liposome suspension with almost quantitative encapsulation efficiency. The medicine concentration can reach 1 mg/mL, the administration volume is small, the medicine compliance is good, and the administration requirement of aerosol inhalation can be well met.
The auxiliary materials adopted by the liposome preparation technology are lipid materials with good biocompatibility, are not easy to generate irritation and inflammation after spray inhalation administration, and have good safety.
By adopting liposome technology, the medicine can effectively adhere to and permeate the lung cells of the respiratory tract, the acting time of ursodeoxycholic acid is prolonged, and the long-time effectiveness is maintained.
Drawings
FIG. 1 is a fluorescent image of a living animal optical imaging system.
Detailed Description
The present invention will be further described with reference to the accompanying drawings and specific examples, which are not intended to be limiting, so that those skilled in the art will better understand the invention and practice it.
Example 1
Ursodeoxycholic acid liposome for aerosol inhalation comprises the following components in percentage by mass of lipid raw materials:
table 1 example 1 raw material ratio in ursodeoxycholic acid liposome for aerosol inhalation
| Dipalmitoyl phosphatidylcholine (DPPC) | 150 mg | 81.4% |
| Ursodeoxycholic acid (UDCA) | 23 mg | 12.5% |
| Cholesterol (CH) | 11.3 mg | 6.1% |
The preparation method comprises the following steps: weighing prescription amount ursodeoxycholic acid (UDCA), dipalmitoyl phosphatidylcholine (DPPC) and Cholesterol (CH) in eggplant-shaped glass bottle, adding 30 mL absolute ethyl alcohol, heating at 50 ℃ and performing ultrasonic treatment to dissolve the reagent, distilling under reduced pressure to remove the solvent, adding 20mL physiological saline for hydration, and performing ultrasonic oscillation under the condition of 65 ℃ hot water bath to obtain dispersed large-particle-size liposome suspension. The liposome suspension is extruded through polycarbonate nuclear pore membranes of 1000nm, 400 nm, 200 nm, 100 nm and 80 nm in sequence under the pressurized condition (each pore diameter is respectively extruded for more than 6 times) to obtain liposome preparations with different particle diameters, and the particle diameters of the liposome extruded through the nuclear pore membranes of 400 nm, 200 nm, 100 nm and 80 nm are respectively measured by a dynamic light scattering method, and the result is as follows:
table 2 example 1 characterization of ursodeoxycholic acid liposome performance parameters for aerosol inhalation
| Nuclear pore membrane aperture (nm) | Average particle diameter (nm) | Polymer polydispersity index (PDI) |
| 400 | 341±7.1 | 0.28 |
| 200 | 185.3±1.6 | 0.175 |
| 100 | 159.1±3.0 | 0.083 |
| 80 | 109.1±2.2 | 0.103 |
Example 2
Ursodeoxycholic acid liposome for aerosol inhalation comprises the following components in percentage by mass of lipid raw materials:
TABLE 3 example 2 raw material ratios in ursodeoxycholic acid liposome for aerosol inhalation
| Dipalmitoyl phosphatidylcholine (DPPC) | 150 mg | 81.4% |
| Ursodeoxycholic acid (UDCA) | 17.2mg | 9.3% |
| Cholesterol (CH) | 17mg | 9.2% |
The preparation method comprises the following steps: weighing prescription amount ursodeoxycholic acid (UDCA), dipalmitoyl phosphatidylcholine (DPPC) and Cholesterol (CH) in eggplant-shaped glass bottle, adding 30 mL absolute ethyl alcohol, heating at 50 ℃ and performing ultrasonic treatment to dissolve the reagent, distilling under reduced pressure to remove the solvent, adding 20mL physiological saline for hydration, and performing ultrasonic oscillation under the condition of 65 ℃ hot water bath to obtain dispersed large-particle-size liposome suspension. The liposome suspension is extruded through polycarbonate nuclear pore membranes of 400 nm, 200 nm and 100 nm in sequence under the condition of pressurization (each pore diameter is repeatedly extruded for more than 6 times respectively), so that liposome preparations with different particle diameters are obtained, and the particle diameters of the liposome extruded through the nuclear pore membranes of 400 nm, 200 nm and 100 nm are respectively measured by a dynamic light scattering method, and the result is as follows:
table 4 example 2 characterization of ursodeoxycholic acid liposome performance parameters for aerosol inhalation
| Nuclear pore membrane aperture (nm) | Average particle diameter (nm) | Polymer polydispersity index (PDI) |
| 400 | 381.2±22.9 | 0.25 |
| 200 | 233.5±7.1 | 0.03 |
| 100 | 155.6±8.2 | 0.065 |
Example 3
Ursodeoxycholic acid liposome for aerosol inhalation comprises the following components in percentage by mass of lipid raw materials:
TABLE 5 example 3 raw material ratios in ursodeoxycholic acid liposome for aerosol inhalation
| Dipalmitoyl phosphatidylcholine (DPPC) | 150 mg | 69.8% |
| Ursodeoxycholic acid (UDCA) | 17.2 mg | 8% |
| Cholesterol (CH) | 17 mg | 7.9% |
| Distearoyl phosphatidylethanolamine-polyethylene glycol 2000 (DSPE-PEG 2 k) | 30.8 mg | 14.3% |
The preparation method comprises the following steps: weighing prescription amount ursodeoxycholic acid (UDCA), dipalmitoyl phosphatidylcholine (DPPC), cholesterol (CH) and distearoyl phosphatidylethanolamine-polyethylene glycol 2000 (DSPE-PEG 2 k) in a eggplant-shaped glass bottle, adding 30 mL absolute ethyl alcohol, heating at 50 ℃ and performing ultrasonic treatment to dissolve the reagent, distilling under reduced pressure to remove the solvent, adding 20mL physiological saline for hydration, and performing ultrasonic oscillation under the condition of 65 ℃ hot water bath to obtain dispersed large-particle-size liposome suspension. The liposome suspension was sequentially extruded through 400 nm, 200 nm, 100 nm and 80 nm polycarbonate nuclear pore membranes under pressurized conditions (each pore diameter was repeatedly extruded more than 6 times, respectively) to obtain liposome preparations with different particle diameters, and the particle diameters of the liposomes extruded through 400 nm, 200 nm, 100 nm and 80 nm nuclear pore membranes were respectively measured by a dynamic light scattering method, and the results were as follows:
TABLE 6 example 3 characterization of ursodeoxycholic acid liposome Performance parameters for aerosolized inhalation
| Nuclear pore membrane aperture (nm) | Average particle diameter (nm) | Polymer polydispersity index (PDI) |
| 400 | 249.4±16.7 | 0.2 |
| 200 | 175.8±5.4 | 0.06 |
| 100 | 151.4±3.4 | 0.1 |
| 80 | 136.9±2.1 | 0.11 |
Example 4
Imaging investigation of mice after aerosol inhalation of near infrared fluorescent dye-labeled ursodeoxycholic acid liposomes
A fluorescent-labeled ursodeoxycholic acid liposome for atomization inhalation comprises the following components in percentage by mass of lipid raw materials:
TABLE 7 example 4 raw material ratios in ursodeoxycholic acid liposome for aerosol inhalation
| Dipalmitoyl phosphatidylcholine (DPPC) | 150 mg | 81.4% |
| Ursodeoxycholic acid (UDCA) | 17.2 mg | 9.3% |
| Cholesterol (CH) | 17 mg | 9.3% |
| DiR dyes | 0.38 mg | 0.2% |
The preparation method comprises the following steps: the preparation method comprises the steps of weighing prescription amounts of ursodeoxycholic acid (UDCA), dipalmitoyl phosphatidylcholine (DPPC), cholesterol (CH) and distearoyl phosphatidylethanolamine-polyethylene glycol 2000 (DSPE-PEG 2 k) in a eggplant-shaped glass bottle, adding 1 mL ethanol solution containing 0.38 mg DiR, adding 30 mL absolute ethanol, heating at 50 ℃ and carrying out ultrasonic treatment to dissolve a reagent, distilling under reduced pressure to remove a solvent, adding 20mL normal saline for hydration, and carrying out ultrasonic oscillation under the condition of 65 ℃ hot water bath to obtain dispersed large-particle-size liposome suspension. The liposome suspension is extruded through polycarbonate nuclear pore membranes of 400 nm, 200 nm and 80 nm in sequence under the condition of pressurization (each pore diameter is repeatedly extruded for more than 6 times respectively), so that liposome preparations with different particle diameters are obtained, and the particle diameters of the liposome extruded through the nuclear pore membranes of 200 nm and 80 nm pore diameters are respectively measured by a dynamic light scattering method, and the result is as follows:
TABLE 8 example 4 raw material ratios in ursodeoxycholic acid liposome for aerosol inhalation
| Nuclear pore membrane aperture (nm) | Average particle diameter (nm) | Polymer polydispersity index (PDI) |
| 200 | 130.7±1.4 | 0.079 |
| 80 | 91.8±0.8 | 0.093 |
Babl/c mice were selected as experimental animals and the liposomes labeled with the above-mentioned near infrared fluorescent dye with particle size of 91.8.+ -. 0.8 nm were administered as ursodeoxycholic acid 5 mg/kg by tracheal injection. Fluorescence imaging was performed with an IVIS Spectrum small animal in vivo optical imaging system after administration of 1 h, 4 h, 8 h, 24 h, respectively. Excitation wavelength: 780 nm, emission wavelength: > 810 nm. Representative near infrared fluorescence images as shown in fig. 1, ursodeoxycholic acid liposome-supported dye can be rapidly distributed to the lungs and cleared slowly, with retention in the lungs of up to about 8 h.
It is apparent that the above examples are given by way of illustration only and are not limiting of the embodiments. Other variations and modifications of the present invention will be apparent to those of ordinary skill in the art in light of the foregoing description. It is not necessary here nor is it exhaustive of all embodiments. And obvious variations or modifications thereof are contemplated as falling within the scope of the present invention.
Claims (10)
1. The nano liposome for aerosol inhalation is characterized by comprising the following components in parts by weight:
2-35% ursodeoxycholic acid, 50-95% phospholipid, 0-40% lipid membrane stabilizer, 0-5% antioxidant and the balance of aqueous medium;
the aqueous medium is selected from one or more of water, glucose, trehalose, lactose, sucrose, maltose, raffinose, fructose, xylitol, sorbitol, mannitol, sodium chloride, phosphate, acetate, organic and buffered pairs with buffer capacity.
2. The nanoliposome for aerosol inhalation according to claim 1, wherein the concentration of total lipid in the nanoliposome for aerosol inhalation is 1.2 to 30mg/mL.
3. The nanoliposome for aerosol inhalation according to claim 1, wherein the phospholipid is selected from one or more of natural phospholipid, hydrogenated phospholipid, synthetic phospholipid and polyethylene glycol modified derivatives thereof.
4. The nanoliposome for inhalation according to claim 3, the phospholipid is selected from the group consisting of phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, phosphatidylethanolamine, phosphatidic acid, soybean phosphatidylcholine, soybean phosphatidylglycerol, soybean phosphatidylserine, soybean phosphatidylinositol, soybean phosphatidylethanolamine, soybean phosphatidic acid, hydrogenated phosphatidylcholine, hydrogenated phosphatidylglycerol, hydrogenated phosphatidylinositol, hydrogenated phosphatidylserine, hydrogenated phosphatidylethanolamine, hydrogenated phosphatidic acid, hydrogenated soybean phosphatidylcholine, hydrogenated soybean phosphatidylglycerol, hydrogenated soybean phosphatidylserine, hydrogenated soybean phosphatidylinositol, hydrogenated soybean phosphatidylethanolamine, hydrogenated soybean phosphatidylcholine, dipalmitoyl phosphatidylcholine, dimyristoyl phosphatidylglycerol, dipalmitoyl phosphatidylglycerol distearoyl phosphatidylcholine, distearoyl phosphatidylglycerol, dioleyl phosphatidylethanolamine, palmitoyl stearoyl phosphatidylcholine, palmitoyl stearoyl phosphatidylglycerol, monooleoyl phosphatidylethanolamine, ammonium salts of phospholipids, dilauroyl ethyl phosphorylcholine, dimyristoyl ethyl phosphorylcholine, dipalmitoyl ethyl phosphorylcholine, distearoyl phosphatidylglycerol, dimyristoyl phosphatidic acid, dipalmitoyl phosphatidic acid, distearoyl phosphatidic acid, dimyristoyl phosphatidylinositol, dipalmitoyl phosphatidylinositol, distearoyl phosphatidylinositol, dimyristoyl phosphatidylserine, dipalmitoyl phosphatidylserine, distearoyl phosphatidylserine, palmitoyl lysolecithin, myristoyl lysolecithin, stearoyl lysolecithin, phosphatidylcholine-polyethylene glycol, phosphatidylethanolamine-polyethylene glycol or distearoyl phosphatidylethanolamine-polyethylene glycol.
5. The nanoliposome for aerosol inhalation according to claim 1, wherein the lipid membrane stabilizer is selected from one or more of cholesterol, oleic acid, lauric acid, palmitic acid and stearic acid.
6. The nanoliposome for aerosol inhalation according to claim 1, wherein the antioxidant is selected from one or more of fat-soluble vitamin E, water-soluble vitamin C, L-cysteine, sodium sulfite, sodium bisulfite, sodium metabisulfite, sodium thiosulfate and citric acid.
7. The nanoliposome for inhalation according to claim 1, wherein the particle size of the nanoliposome for inhalation is 50 to 1000nm.
8. A method for preparing nanoliposomes for inhalation by atomization as claimed in any one of claims 1 to 7, comprising the steps of:
(1) Dissolving 2-35% ursodeoxycholic acid, 50-95% phospholipid, 0-40% lipid film stabilizer and 0-5% antioxidant in organic solvent according to weight fraction, and evaporating under reduced pressure to obtain lipid film;
(2) Hydrating the lipid film with a water phase medium, and heating or performing ultrasonic treatment to obtain liposome suspension;
(3) And extruding or homogenizing the liposome suspension filter membrane to obtain the nano liposome for atomization inhalation.
9. The method of claim 8, wherein the organic solvent is selected from ethanol, isopropanol, and propylene glycol.
10. Use of nanoliposomes for aerosol inhalation according to any one of claims 1 to 7 for the manufacture of a medicament for inhibiting novel coronavirus infection, characterized in that the administration of the medicament for inhibiting novel coronavirus infection is aerosol inhalation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311538781.5A CN117582408A (en) | 2023-11-17 | 2023-11-17 | Nanometer liposome for aerosol inhalation and preparation method and application thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311538781.5A CN117582408A (en) | 2023-11-17 | 2023-11-17 | Nanometer liposome for aerosol inhalation and preparation method and application thereof |
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| Publication Number | Publication Date |
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| CN117582408A true CN117582408A (en) | 2024-02-23 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN202311538781.5A Pending CN117582408A (en) | 2023-11-17 | 2023-11-17 | Nanometer liposome for aerosol inhalation and preparation method and application thereof |
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| Country | Link |
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| CN (1) | CN117582408A (en) |
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2023
- 2023-11-17 CN CN202311538781.5A patent/CN117582408A/en active Pending
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