WO2023217237A1 - Composé lipidique, composition, préparation et utilisation associées - Google Patents
Composé lipidique, composition, préparation et utilisation associées Download PDFInfo
- Publication number
- WO2023217237A1 WO2023217237A1 PCT/CN2023/093558 CN2023093558W WO2023217237A1 WO 2023217237 A1 WO2023217237 A1 WO 2023217237A1 CN 2023093558 W CN2023093558 W CN 2023093558W WO 2023217237 A1 WO2023217237 A1 WO 2023217237A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- acid
- lipid
- compound
- dcm
- mmol
- Prior art date
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- -1 Lipid compound Chemical class 0.000 title claims abstract description 117
- 239000000203 mixture Substances 0.000 title claims abstract description 89
- 238000002360 preparation method Methods 0.000 title claims abstract description 62
- 150000001875 compounds Chemical class 0.000 claims abstract description 99
- 239000004380 Cholic acid Substances 0.000 claims abstract description 62
- 229960002471 cholic acid Drugs 0.000 claims abstract description 62
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 claims abstract description 60
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 claims abstract description 56
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic 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)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 claims abstract description 56
- 235000019416 cholic acid Nutrition 0.000 claims abstract description 56
- 150000007523 nucleic acids Chemical class 0.000 claims abstract description 40
- 102000039446 nucleic acids Human genes 0.000 claims abstract description 38
- 108020004707 nucleic acids Proteins 0.000 claims abstract description 38
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 37
- 239000003814 drug Substances 0.000 claims abstract description 33
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 29
- 229940079593 drug Drugs 0.000 claims abstract description 27
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 25
- 102000004196 processed proteins & peptides Human genes 0.000 claims abstract description 19
- 229920001184 polypeptide Polymers 0.000 claims abstract description 17
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- 229940126586 small molecule drug Drugs 0.000 claims abstract description 13
- 229960005486 vaccine Drugs 0.000 claims abstract description 13
- 150000002632 lipids Chemical class 0.000 claims description 206
- 239000000243 solution Substances 0.000 claims description 175
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 128
- 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 description 118
- 239000002105 nanoparticle Substances 0.000 claims description 112
- 108020004999 messenger RNA Proteins 0.000 claims description 85
- 239000003020 ursodeoxycholic acid derivative Substances 0.000 claims description 81
- ZXERDUOLZKYMJM-ZWECCWDJSA-N obeticholic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)CCC(O)=O)CC[C@H]21 ZXERDUOLZKYMJM-ZWECCWDJSA-N 0.000 claims description 34
- 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 description 32
- 239000003795 chemical substances by application Substances 0.000 claims description 25
- 230000001225 therapeutic effect Effects 0.000 claims description 25
- 229960001661 ursodiol Drugs 0.000 claims description 25
- 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 24
- 238000005538 encapsulation Methods 0.000 claims description 23
- 230000003449 preventive effect Effects 0.000 claims description 23
- MWRBNPKJOOWZPW-CLFAGFIQSA-N dioleoyl phosphatidylethanolamine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(COP(O)(=O)OCCN)OC(=O)CCCCCCC\C=C/CCCCCCCC MWRBNPKJOOWZPW-CLFAGFIQSA-N 0.000 claims description 20
- 239000002245 particle Substances 0.000 claims description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 15
- 238000000502 dialysis Methods 0.000 claims description 13
- 125000005647 linker group Chemical group 0.000 claims description 13
- 229960001601 obeticholic acid Drugs 0.000 claims description 13
- 235000012000 cholesterol Nutrition 0.000 claims description 12
- 238000002347 injection Methods 0.000 claims description 12
- 239000007924 injection Substances 0.000 claims description 12
- SMEROWZSTRWXGI-HVATVPOCSA-N lithocholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 SMEROWZSTRWXGI-HVATVPOCSA-N 0.000 claims description 12
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 11
- 229920001223 polyethylene glycol Chemical class 0.000 claims description 11
- 235000015424 sodium Nutrition 0.000 claims description 11
- 239000011734 sodium Substances 0.000 claims description 11
- 229910052708 sodium Inorganic materials 0.000 claims description 11
- 239000002202 Polyethylene glycol Chemical class 0.000 claims description 10
- BHTRKEVKTKCXOH-UHFFFAOYSA-N Taurochenodesoxycholsaeure Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(=O)NCCS(O)(=O)=O)C)C1(C)CC2 BHTRKEVKTKCXOH-UHFFFAOYSA-N 0.000 claims description 10
- 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 9
- SMEROWZSTRWXGI-UHFFFAOYSA-N Lithocholsaeure Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 SMEROWZSTRWXGI-UHFFFAOYSA-N 0.000 claims description 9
- 230000002601 intratumoral effect Effects 0.000 claims description 9
- BHTRKEVKTKCXOH-LBSADWJPSA-N tauroursodeoxycholic 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)NCCS(O)(=O)=O)C)[C@@]2(C)CC1 BHTRKEVKTKCXOH-LBSADWJPSA-N 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 150000001413 amino acids Chemical class 0.000 claims description 8
- RUDATBOHQWOJDD-BSWAIDMHSA-N chenodeoxycholic 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-BSWAIDMHSA-N 0.000 claims description 7
- 229960001091 chenodeoxycholic acid Drugs 0.000 claims description 7
- DGABKXLVXPYZII-SIBKNCMHSA-N hyodeoxycholic acid Chemical compound C([C@H]1[C@@H](O)C2)[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 DGABKXLVXPYZII-SIBKNCMHSA-N 0.000 claims description 7
- 239000007927 intramuscular injection Substances 0.000 claims description 7
- 238000010255 intramuscular injection Methods 0.000 claims description 7
- 230000007935 neutral effect Effects 0.000 claims description 7
- 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 6
- YDNKGFDKKRUKPY-JHOUSYSJSA-N C16 ceramide Chemical class CCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)C=CCCCCCCCCCCCCC YDNKGFDKKRUKPY-JHOUSYSJSA-N 0.000 claims description 6
- CRJGESKKUOMBCT-VQTJNVASSA-N N-acetylsphinganine Chemical class CCCCCCCCCCCCCCC[C@@H](O)[C@H](CO)NC(C)=O CRJGESKKUOMBCT-VQTJNVASSA-N 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- 229940106189 ceramide Drugs 0.000 claims description 6
- ZVEQCJWYRWKARO-UHFFFAOYSA-N ceramide Chemical class CCCCCCCCCCCCCCC(O)C(=O)NC(CO)C(O)C=CCCC=C(C)CCCCCCCCC ZVEQCJWYRWKARO-UHFFFAOYSA-N 0.000 claims description 6
- 238000010253 intravenous injection Methods 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- VVGIYYKRAMHVLU-UHFFFAOYSA-N newbouldiamide Chemical class CCCCCCCCCCCCCCCCCCCC(O)C(O)C(O)C(CO)NC(=O)CCCCCCCCCCCCCCCCC VVGIYYKRAMHVLU-UHFFFAOYSA-N 0.000 claims description 6
- 229940045946 sodium taurodeoxycholate Drugs 0.000 claims description 6
- YXHRQQJFKOHLAP-FVCKGWAHSA-M sodium;2-[[(4r)-4-[(3r,5r,8r,9s,10s,12s,13r,14s,17r)-3,12-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]pentanoyl]amino]ethanesulfonate Chemical compound [Na+].C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 YXHRQQJFKOHLAP-FVCKGWAHSA-M 0.000 claims description 6
- SNKAWJBJQDLSFF-NVKMUCNASA-N 1,2-dioleoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC SNKAWJBJQDLSFF-NVKMUCNASA-N 0.000 claims description 5
- OHXPGWPVLFPUSM-KLRNGDHRSA-N 3,7,12-trioxo-5beta-cholanic acid Chemical compound C1CC(=O)C[C@H]2CC(=O)[C@H]3[C@@H]4CC[C@H]([C@@H](CCC(O)=O)C)[C@@]4(C)C(=O)C[C@@H]3[C@]21C OHXPGWPVLFPUSM-KLRNGDHRSA-N 0.000 claims description 5
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical group NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 claims description 5
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 claims description 5
- DGABKXLVXPYZII-UHFFFAOYSA-N Hyodeoxycholic acid Natural products C1C(O)C2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 DGABKXLVXPYZII-UHFFFAOYSA-N 0.000 claims description 5
- 125000003368 amide group Chemical group 0.000 claims description 5
- 239000000872 buffer Substances 0.000 claims description 5
- 150000001720 carbohydrates Chemical class 0.000 claims description 5
- 125000005587 carbonate group Chemical group 0.000 claims description 5
- 229960002997 dehydrocholic acid Drugs 0.000 claims description 5
- 125000004185 ester group Chemical group 0.000 claims description 5
- 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 5
- 150000008104 phosphatidylethanolamines Chemical class 0.000 claims description 5
- 229940002612 prodrug Drugs 0.000 claims description 5
- 239000000651 prodrug Substances 0.000 claims description 5
- JAJWGJBVLPIOOH-IZYKLYLVSA-M sodium taurocholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 JAJWGJBVLPIOOH-IZYKLYLVSA-M 0.000 claims description 5
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 5
- DKPMWHFRUGMUKF-UHFFFAOYSA-N (3alpha,5alpha,6alpha,7alpha)-3,6,7-Trihydroxycholan-24-oic acid Natural products OC1C(O)C2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 DKPMWHFRUGMUKF-UHFFFAOYSA-N 0.000 claims description 4
- WCGUUGGRBIKTOS-GPOJBZKASA-N (3beta)-3-hydroxyurs-12-en-28-oic acid Chemical compound C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CC[C@@H](C)[C@H](C)[C@H]5C4=CC[C@@H]3[C@]21C WCGUUGGRBIKTOS-GPOJBZKASA-N 0.000 claims description 4
- SLKDGVPOSSLUAI-PGUFJCEWSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine zwitterion Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OCCN)OC(=O)CCCCCCCCCCCCCCC SLKDGVPOSSLUAI-PGUFJCEWSA-N 0.000 claims description 4
- LVNGJLRDBYCPGB-UHFFFAOYSA-N 1,2-distearoylphosphatidylethanolamine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(COP([O-])(=O)OCC[NH3+])OC(=O)CCCCCCCCCCCCCCCCC LVNGJLRDBYCPGB-UHFFFAOYSA-N 0.000 claims description 4
- BIABMEZBCHDPBV-MPQUPPDSSA-N 1,2-palmitoyl-sn-glycero-3-phospho-(1'-sn-glycerol) Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@@H](O)CO)OC(=O)CCCCCCCCCCCCCCC BIABMEZBCHDPBV-MPQUPPDSSA-N 0.000 claims description 4
- JOYGXTIHTHBSOA-UHFFFAOYSA-N 1-(4-chlorophenyl)-3-thiophen-2-ylprop-2-en-1-one Chemical compound C1=CC(Cl)=CC=C1C(=O)C=CC1=CC=CS1 JOYGXTIHTHBSOA-UHFFFAOYSA-N 0.000 claims description 4
- NEZDNQCXEZDCBI-UHFFFAOYSA-N 2-azaniumylethyl 2,3-di(tetradecanoyloxy)propyl phosphate Chemical compound CCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCCN)OC(=O)CCCCCCCCCCCCC NEZDNQCXEZDCBI-UHFFFAOYSA-N 0.000 claims description 4
- JQKOHRZNEOQNJE-ZZEZOPTASA-N 2-azaniumylethyl [3-octadecanoyloxy-2-[(z)-octadec-9-enoyl]oxypropyl] phosphate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(COP([O-])(=O)OCC[NH3+])OC(=O)CCCCCCC\C=C/CCCCCCCC JQKOHRZNEOQNJE-ZZEZOPTASA-N 0.000 claims description 4
- 241000272517 Anseriformes Species 0.000 claims description 4
- 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 4
- 229920002307 Dextran Polymers 0.000 claims description 4
- 108010007979 Glycocholic Acid Proteins 0.000 claims description 4
- 229930195725 Mannitol Natural products 0.000 claims description 4
- RFDAIACWWDREDC-UHFFFAOYSA-N Na salt-Glycocholic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(=O)NCC(O)=O)C)C1(C)C(O)C2 RFDAIACWWDREDC-UHFFFAOYSA-N 0.000 claims description 4
- WBWWGRHZICKQGZ-UHFFFAOYSA-N Taurocholic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(=O)NCCS(O)(=O)=O)C)C1(C)C(O)C2 WBWWGRHZICKQGZ-UHFFFAOYSA-N 0.000 claims description 4
- DSNRWDQKZIEDDB-GCMPNPAFSA-N [(2r)-3-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-2-[(z)-octadec-9-enoyl]oxypropyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C/CCCCCCCC DSNRWDQKZIEDDB-GCMPNPAFSA-N 0.000 claims description 4
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 claims description 4
- 229960003964 deoxycholic acid Drugs 0.000 claims description 4
- RFDAIACWWDREDC-FRVQLJSFSA-N glycocholic 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)NCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 RFDAIACWWDREDC-FRVQLJSFSA-N 0.000 claims description 4
- 229940099347 glycocholic acid Drugs 0.000 claims description 4
- 239000000594 mannitol Substances 0.000 claims description 4
- 235000010355 mannitol Nutrition 0.000 claims description 4
- NRHMKIHPTBHXPF-TUJRSCDTSA-M sodium cholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 NRHMKIHPTBHXPF-TUJRSCDTSA-M 0.000 claims description 4
- OABYVIYXWMZFFJ-ZUHYDKSRSA-M sodium glycocholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 OABYVIYXWMZFFJ-ZUHYDKSRSA-M 0.000 claims description 4
- IYPNVUSIMGAJFC-HLEJRKHJSA-M sodium;2-[[(4r)-4-[(3r,5s,7r,8r,9s,10s,13r,14s,17r)-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]pentanoyl]amino]ethanesulfonate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS([O-])(=O)=O)C)[C@@]2(C)CC1 IYPNVUSIMGAJFC-HLEJRKHJSA-M 0.000 claims description 4
- BHTRKEVKTKCXOH-AYSJQVDDSA-N taurochenodeoxycholic acid Chemical compound C([C@H]1C[C@@H]2O)[C@H](O)CC[C@]1(C)C1C2C2CC[C@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)CC1 BHTRKEVKTKCXOH-AYSJQVDDSA-N 0.000 claims description 4
- WBWWGRHZICKQGZ-GIHLXUJPSA-N taurocholic 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)NCCS(O)(=O)=O)C)[C@@]2(C)[C@H](O)C1 WBWWGRHZICKQGZ-GIHLXUJPSA-N 0.000 claims description 4
- 229940096998 ursolic acid Drugs 0.000 claims description 4
- PLSAJKYPRJGMHO-UHFFFAOYSA-N ursolic acid Natural products CC1CCC2(CCC3(C)C(C=CC4C5(C)CCC(O)C(C)(C)C5CCC34C)C2C1C)C(=O)O PLSAJKYPRJGMHO-UHFFFAOYSA-N 0.000 claims description 4
- PORPENFLTBBHSG-MGBGTMOVSA-N 1,2-dihexadecanoyl-sn-glycerol-3-phosphate Chemical class CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(O)=O)OC(=O)CCCCCCCCCCCCCCC PORPENFLTBBHSG-MGBGTMOVSA-N 0.000 claims description 3
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 claims description 3
- 229920001661 Chitosan Chemical class 0.000 claims description 3
- 239000007995 HEPES buffer Substances 0.000 claims description 3
- 241000124008 Mammalia Species 0.000 claims description 3
- 239000002671 adjuvant Substances 0.000 claims description 3
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 claims description 3
- 229910052921 ammonium sulfate Inorganic materials 0.000 claims description 3
- 235000011130 ammonium sulphate Nutrition 0.000 claims description 3
- 239000003963 antioxidant agent Substances 0.000 claims description 3
- 239000000022 bacteriostatic agent Substances 0.000 claims description 3
- 239000002738 chelating agent Substances 0.000 claims description 3
- 150000001982 diacylglycerols Chemical class 0.000 claims description 3
- 125000005265 dialkylamine group Chemical class 0.000 claims description 3
- 150000001985 dialkylglycerols Chemical class 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 108010082974 polysarcosine Chemical class 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
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Classifications
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Definitions
- the present invention specifically relates to a type of lipid compound and its composition, preparation and use, especially its application in the preparation of nucleic acid drugs, gene vaccines, polypeptides, proteins, antibodies and small molecule drugs.
- Nucleic acid drugs refer to artificially designed DNA or RNA with disease prevention or treatment functions. They act on disease-causing target genes or target mRNA to fundamentally regulate the expression of disease-causing genes to achieve the purpose of disease prevention or treatment. Nucleic acid drugs mainly include antisense oligonucleotide (ASO), small interference RNA (siRNA), microRNA (miRNA), messenger RNA (message, mRNA), etc. As of the end of 2021, the FDA has approved more than 10 nucleic acid drugs, and multiple drug candidates are in clinical trials or preclinical trials.
- ASO antisense oligonucleotide
- siRNA small interference RNA
- miRNA microRNA
- messenger RNA messenger RNA
- RNA vaccines BNT162b2 Pfizer/BioNTech
- mRNA-1273 Moderna
- my country also has multiple new coronavirus vaccines based on mRNA technology in clinical trials or preclinical trials.
- mRNA technology has proven its unique advantages over traditional biopharmaceutical and vaccine technologies.
- Therapeutic nucleic acids have the potential to revolutionize vaccinations, gene therapies, protein replacement therapies and the treatment of other genetic diseases.
- RNA degradation determines the need for a high-quality delivery system to deliver it into the body.
- the present invention focuses on providing a new delivery carrier for RNA drugs.
- the present invention provides a new class of lipid compounds for delivering therapeutic or preventive drugs, namely lipids based on cholic acid or its derivatives, which enriches the types of lipid compounds and can be used for nucleic acid drugs, gene vaccines, polypeptides, and proteins.
- lipids based on cholic acid or its derivatives which enriches the types of lipid compounds and can be used for nucleic acid drugs, gene vaccines, polypeptides, and proteins.
- the delivery of antibodies, small molecule drugs, etc. provides more options.
- the present invention provides a lipid compound represented by the following general formula 1, general formula 2, or a pharmaceutically acceptable salt thereof, including stereoisomers, tautomers, solvates, chelates, and non-covalent compounds.
- a pharmaceutically acceptable salt thereof refers to an acid addition salt or a base addition salt.
- the acid described in the present invention includes but is not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzene
- Base addition salts refer to salts prepared by adding an inorganic base or an organic base to a free base compound.
- Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, etc.; the organic bases include, but are not limited to, ammonia, isopropylamine, trimethylamine, diethylamine, etc.
- the organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.
- the core of the lipid compound is cholic acid or a derivative thereof; wherein the linker includes one or more of an ester group, an amide group, a carbamate group, a carbonate group or a urea group. kind.
- the lipid compound, wherein cholic acid or its derivatives is optionally selected from cholic acid, obeticholic acid, ursodeoxycholic acid, ursolic acid, 3 ⁇ -hydroxy-D5-cholenoic acid, Chenodeoxycholic acid, lithocholic acid, deoxycholic acid, taurocholic acid, 5 ⁇ -cholic acid, dehydrocholic acid, hyocholic acid, cholic acid, glycinechenodeoxycholic acid, tauroursodeoxycholic acid Acid, taurochenodeoxycholic acid, glycocholic acid, hyodeoxycholic acid, hyodeoxycholic acid methyl ester, taurohodeoxycholic acid sodium, sodium dehydrocholate, sodium cholate, sodium deoxyglycholate , sodium taurodeoxycholate, sodium taurocholate, sodium taurochenodeoxycholate, glycocholic acid sodium salt, taurocholic acid-3-sulfate diso
- the lipid compound is one or more lipid compounds selected from ursodeoxycholic acid derivatives, or one or more obeticholic acid derivative lipid compounds. kind.
- the lipid compound is also selected from one or more cholic acid lipid compounds, or one or more hyodeoxycholic acid derivative lipid compounds, or chenodeoxycholic acid derivative lipids.
- One or more chemical compounds are also selected from one or more cholic acid lipid compounds, or one or more hyodeoxycholic acid derivative lipid compounds, or chenodeoxycholic acid derivative lipids.
- One or more chemical compounds are also selected from one or more cholic acid lipid compounds, or one or more hyodeoxycholic acid derivative lipid compounds, or chenodeoxycholic acid derivative lipids.
- One or more chemical compounds are also selected from one or more cholic acid lipid compounds, or one or more hyodeoxycholic acid derivative lipid compounds, or chenodeoxycholic acid derivative lipids.
- One or more chemical compounds are also selected from one or more cholic acid lipid compounds, or one or more hyodeoxycholic acid derivative lipid compounds, or
- the lipid compound may be an ionizable lipid, or a cationic lipid, or an anionic lipid, or a neutral lipid, or a polyethylene glycol derivative lipid, or a polysarcosine derivative lipid. substance, or chitosan derivative lipid, or hyaluronic acid derivative lipid.
- the lipid compound can also be a conjugate of a lipid compound, and the conjugate is mainly composed of three parts: a therapeutic or preventive drug, a linker, and a lipid compound.
- the therapeutic or preventive drugs include one or more of nucleic acids, polypeptides, proteins, antibodies, carbohydrates, polyethylene glycol and its derivatives, and small molecules.
- the nucleic acid includes any form of nucleic acid molecule.
- DNA can be non-coding DNA or coding DNA
- RNA can be selected from one or more of ASO, mRNA, siRNA, micRNA, etc.
- linker is independently selected from the group consisting of non-existent, linear compounds or containing one or more cyclic compounds, which are connected to both ends through ester groups, amide groups, carbamate groups, Carbonate group, ether group or urea group, etc. are connected.
- the linker is independently selected from linear saturated or unsaturated hydrocarbons with 2-25 C, and its two ends are one of carboxyl group, hydroxyl group, amino group, sulfate group, sulfonic acid group, and phosphate group, or Various.
- the linker is independently selected from saturated or unsaturated hydrocarbons containing 3-8 membered rings, and its two ends are one or more of carboxyl groups, hydroxyl groups, amino groups, sulfate groups, sulfonic acid groups, and phosphate groups. kind.
- the present invention also provides a lipid compound that is a lipid based on cholic acid or a derivative thereof, or a pharmaceutically acceptable salt of a lipid based on cholic acid or a derivative thereof, Prodrug or stereoisomer, the lipid compound has the structure of the following general formula 1 or general formula 2:
- the core of the lipid compound is cholic acid or a derivative thereof; wherein the linker includes one or more of an ester group, an amide group, a carbamate group, a carbonate group or a urea group. kind.
- the cholic acid or its derivative is optionally selected from the group consisting of cholic acid, obeticholic acid, ursodeoxycholic acid, ursolic acid, 3 ⁇ -hydroxy-D5-cholic acid, chenodeoxycholic acid, lithophore Cholic acid, deoxycholic acid, taurocholic acid, 5 ⁇ -cholic acid, dehydrocholic acid, hyocholic acid, cholancholic acid, glycochenodeoxycholic acid, tauroursodeoxycholic acid, taurochenodeoxycholic acid Cholic acid, glycocholic acid, hyodeoxycholic acid, methyl hyodeoxycholate, sodium taurodeoxycholate, sodium dehydrocholate, sodium cholate, sodium deoxyglycholate, sodium taurodeoxycholate , sodium taurocholate, sodium taurochenodeoxycholate, glycocholic acid sodium salt, taurocholic acid-3-sulfate disodium salt, sodium
- the lipid compound is one or more lipid compounds selected from ursodeoxycholic acid derivatives. species, or one or more obeticholic acid derivative lipid compounds, one or more cholic acid lipid compounds, one or more hyodeoxycholic acid derivative lipid compounds, chenodeoxy Cholic acid derivatives are one or more lipid compounds.
- the lipid compound may be an ionizable lipid, or a cationic lipid, or an anionic lipid, or a neutral lipid, or a polyethylene glycol derivative lipid, or a polysarcosine derivative lipid. substance, or chitosan derivative lipid, or hyaluronic acid derivative lipid.
- the lipid compound can also be a conjugate of a lipid compound, and the conjugate is mainly composed of three parts: a therapeutic or preventive drug, a linker, and a lipid compound.
- the therapeutic or preventive drugs include one or more of nucleic acids, antibodies, polypeptides, proteins, carbohydrates, polyethylene glycol and its derivatives, and small molecules.
- the nucleic acid includes any form of nucleic acid molecule.
- DNA can be non-coding DNA or coding DNA
- RNA can be selected from one or more of ASO, mRNA, siRNA, micRNA, etc.
- linker is independently selected from the group consisting of non-existent, linear compounds or containing one or more cyclic compounds, which are connected to both ends through ester groups, amide groups, carbamate groups, Carbonate group, ether group or urea group, etc. are connected.
- the linker is independently selected from linear saturated or unsaturated hydrocarbons with 2-25 C, and its two ends are one of carboxyl group, hydroxyl group, amino group, sulfate group, sulfonic acid group, and phosphate group, or Various.
- the linker is independently selected from saturated or unsaturated hydrocarbons containing 3-8 membered rings, and its two ends are one or more of carboxyl groups, hydroxyl groups, amino groups, sulfate groups, sulfonic acid groups, and phosphate groups. kind.
- a composition of lipid compounds includes a therapeutic or preventive agent and a carrier for delivering the therapeutic or preventive agent, the carrier includes one or more of the aforementioned lipid compounds.
- the composition, therapeutic or preventive agent includes one or more of nucleic acid molecules, polypeptides, proteins, antibodies and small molecule drugs.
- the mass ratio of the carrier to the therapeutic or preventive agent is 1:1 to 100:1.
- the composition is a nanoparticle preparation
- the average size of the nanoparticle preparation is 20 nm to 1000 nm
- the polydispersity coefficient of the nanoparticle preparation is ⁇ 0.5.
- the composition contains three different lipid components in the carrier, one of which Lipids are lipids based on cholic acid or its derivatives.
- the composition is characterized in that the carrier further includes a charge-assisted lipid with neutral charge, negative charge or bipolar charge.
- the composition is characterized in that the charge-auxiliary lipid is one or more of the following: distearoylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC) , dipalmitoylphosphatidylcholine (DPPC), dioleoylphosphatidylglycerol (DOPG), dipalmitoylphosphatidylglycerol (DPPG), dioleoylphosphatidylethanolamine (DOPE), palmitoyloleoylphosphatidylcholine (POPC), palmitoyloleoyl-phosphatidylethanolamine (POPE), dioleoyl-phosphatidylethanolamine 4-(N-maleimidomethyl)-cyclohexane-1-carboxylate (DOPE- mal), dipalmitoylphosphatidylethanolamine (DPPE), dimyristoylphosphatidylethanolamine (DMPE), distearoylphosphati
- the carrier further includes a structurally modified lipid.
- the structurally modified lipid includes polyethylene glycol, dextran, polylactic acid or amino acid modified phosphatidylethanolamine, phosphatidic acid, ceramide, dialkylamine, diacylglycerol, One or more dialkylglycerols.
- the composition and the carrier also include but are not limited to lipids of cholic acid or its derivatives, charge-assisted lipids, and structurally modified lipids.
- the cholic acid lipids, the charge-assisted lipids And the molar ratio of the structurally modified lipid is (30-80): (5-50): (0.5-10).
- the composition further includes one or more pharmaceutically acceptable excipients or diluents.
- the carrier also includes lipids of cholic acid or its derivatives, charge-assisted lipids, cholesterol or derivatives thereof, and structurally modified lipids.
- the cholic acid lipid, the charge-assisted lipid, the The molar ratio of cholesterol or its derivatives and the structurally modified lipid is (30-80): (0.5-10): (5-50): (0.5-2.5).
- the lipid compound or composition of the present invention can be used in the preparation of nucleic acid drugs, gene vaccines, polypeptides, proteins, antibodies and small molecule drugs.
- the lipid compound or composition of the present invention is used in the preparation of nucleic acid drugs, gene vaccines, polypeptides, proteins, antibodies and small molecule drugs, wherein the lipid nanoparticles have a concentration of 20 to 1000 nm particle size.
- compositions for preparing nucleic acid drugs, gene vaccines, polypeptides, proteins, antibodies and small molecule drugs which include nucleic acids and lipid nanoparticles encapsulating the nucleic acids, wherein each individual lipid nanoparticle contains a variety of lipids A lipid component, wherein one of the lipid components is a cholic acid-based lipid compound, including compounds thereof or pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, chelates, non- A covalent compound or prodrug, and wherein the lipid nanoparticle has a nucleic acid encapsulation ratio of at least 70%.
- the lipid nanoparticles are formed by mixing an mRNA solution and a lipid solution of any lipid compound described in this patent, wherein the medium of the mRNA solution is HEPES (hydroxyethyl ethyl alcohol). piperazine ethyl sulfate buffer), sodium phosphate, sodium acetate, ammonium sulfate, sodium bicarbonate or sodium citrate; the medium of the lipid solution is ethanol, isopropanol or dimethyl sulfoxide; wherein the lipid nanoparticles The particles are further purified by dialysis or ultrafiltration.
- HEPES hydroxyethyl ethyl alcohol
- piperazine ethyl sulfate buffer sodium phosphate, sodium acetate, ammonium sulfate, sodium bicarbonate or sodium citrate
- the medium of the lipid solution is ethanol, isopropanol or dimethyl sulfoxide
- the lipid nanoparticles The particles are further purified by
- composition described in this patent also contains one or more of buffers, carbohydrates, mannitol, proteins, polypeptides or amino acids, antioxidants, bacteriostatic agents, chelating agents, and adjuvants.
- the acid described in the present invention includes but is not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzene
- Base addition salts refer to salts prepared by adding an inorganic base or an organic base to a free base compound.
- Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, etc.
- the organic bases include, but are not limited to, ammonia, isopropylamine, trimethylamine, Diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dealcoholization, 2-dimethylaminoethanol, 2-diethylaminoethanol, lysine, arginine, histidine, caffeine, Procaine, hydrazine, choline, betaine, benethamine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, purine pyridine, piperazine, piperidine, N-ethylpiperidine, and polyamine resin.
- the present invention provides a composition comprising a therapeutic or preventive agent and a carrier for delivering the therapeutic or preventive agent, the carrier comprising a lipid based on cholic acid or a derivative thereof, or a pharmaceutically acceptable agent thereof.
- a composition comprising a therapeutic or preventive agent and a carrier for delivering the therapeutic or preventive agent, the carrier comprising a lipid based on cholic acid or a derivative thereof, or a pharmaceutically acceptable agent thereof.
- the carrier comprising a lipid based on cholic acid or a derivative thereof, or a pharmaceutically acceptable agent thereof.
- the therapeutic or preventive agent is encapsulated in or associated with a carrier.
- the therapeutic or preventive agent includes one or more of nucleic acid molecules, genetic vaccines, polypeptides, proteins, antibodies and small molecule drugs.
- the nucleic acid includes any form of nucleic acid molecule, including but not limited to single-stranded DNA, double-stranded DNA, short isomers, agomir, antagomir, antisense molecules, small interfering RNA (siRNA), asymmetric interfering RNA ( aiRNA), microRNA (miRNA), Dicer-substrate RNA (dsRNA), small hairpin RNA (shRNA), transfer RNA (tRNA), messenger RNA (mRNA) and other forms of RNA molecules known in the art, or locked nucleic acids Nucleic acid mimics such as (LNA), peptide nucleic acid (PNA) and morpholino cyclic oligonucleotides.
- LNA small interfering RNA
- aiRNA asymmetric interfering RNA
- miRNA microRNA
- dsRNA Dicer-substrate RNA
- shRNA small hairpin RNA
- tRNA transfer RNA
- mRNA messenger RNA
- the therapeutic or preventive agent comprises at least one mRNA encoding an antigen or a protein or a peptide or a fragment or epitope thereof.
- the mRNA is monocistronic or polycistronic.
- the antigen is a pathogenic antigen.
- the mRNA contains one or more functional nucleotide analogs, including but not limited to pseudouridine, 1-methyl-pseudouridine and one or more of 5-methylcytosine.
- the small molecule compounds include, but are not limited to, the active ingredients of therapeutic and/or preventive agents.
- the therapeutic and/or preventive agents are currently known drugs, such as anti-tumor drugs, anti-infective drugs, and local anesthetics. , antidepressants, anticonvulsants, antibiotics/antimicrobials, antifungals, antiparasitics, hormones, hormone antagonists, immunomodulators, neurotransmitter antagonists, antiglaucoma agents, anesthetics, or contrast media.
- the lipids comprise three different lipid components, one of which is a cholic acid or derivative thereof based lipid.
- the lipid further includes an auxiliary lipid with a neutral charge, a negative charge, or a bipolar charge.
- the lipid includes one or more of phosphatidylcholine, phosphatidylethanolamine, sphingomyelin, ceramide, sterols and derivatives thereof.
- the lipids include, but are not limited to, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine base (DPPC), 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 11,2-Dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 2-(((2,3- Bis(oleoyloxy)propyl)dimethylammonium phosphate)ethylhydrogen (DOCP), sphingomyelin (SM), ceramide and its derivatives.
- the lipids may be synthetic or derived from (isolated or modified) natural sources or compounds.
- the carrier further includes a structurally modified lipid.
- the structurally modified lipids mainly include disclosed or undisclosed lipid compounds, which can improve the stability of liposomes and reduce protein absorption of liposomes, such as polyethylene glycol, dextran, polyethylene glycol, etc.
- lipid compounds which can improve the stability of liposomes and reduce protein absorption of liposomes, such as polyethylene glycol, dextran, polyethylene glycol, etc.
- the structurally modified lipid may be PEG-c-DOMG, PEG-DMG, PEG-DLPE, PEGDMPE, PEG-DPPC, PEG-DSPE, ceramide-PEG2000, Chol-PEG2000, 1-(monomethyl Oxy-polyethylene glycol)-2,3-dimyristylglycerol (PEG-DMG), PEGylated phosphatidylethanolamine (PEG-PE), 4-O-(2',3'-bis( Tetradecanoyloxy)propyl-1-O-( ⁇ -methoxy(polyethoxy)ethyl)succinate (PEG-S-DMG), polyglycolated ceramide (PEG- cer), ⁇ -methoxy(polyethoxy)ethyl-N-(2,3-di(tetradecyloxy)propyl)carbamate, or 2,3-di(tetradecyloxy) methyl)propyl-
- the mass ratio of the carrier to the therapeutic or preventive agent is 5:1 to 50:1, more preferably 5:1 to 35:1, and more preferably 10:1 to 30:1.
- composition according to the preceding claims wherein the carrier further includes, but is not limited to, lipids of cholic acid or its derivatives, charge-assisted lipids and structurally modified lipids.
- the molar ratio of the cholic acid lipid, the charge-assisted lipid, and the structurally modified lipid is (30-80): (5-50): (0.5-10).
- lipid nanoparticles are formed by mixing an mRNA solution and a lipid solution. In some embodiments, lipid nanoparticles are further purified by tangential flow filtration.
- lipid nanoparticles are formed by mixing an mRNA solution and a lipid solution.
- the medium of the mRNA solution is HEPES, phosphate, acetate, ammonium sulfate, sodium bicarbonate or citrate.
- the medium of lipid solution is ethanol, isopropyl alcohol or dimethyl sulfoxide.
- the pharmaceutical composition is a nanoparticle preparation, and the average size of the nanoparticle preparation is 20 nm to 1000 nm, preferably 40 nm to 150 nm, further preferably 50 nm to 100 nm, and more preferably 70 nm to 100 nm.
- the polydispersity index of the nanoparticle preparation is ⁇ 0.5, further preferably ⁇ 0.3, and more preferably ⁇ 0.25.
- compositions of the present invention also typically include one or more buffers (eg neutral buffered saline or phosphate buffered water), carbohydrates (eg glucose, mannitol, sucrose, trehalose, dextrose or dextran). sugar), mannitol, proteins, peptides or amino acids (such as glycine and lysine), antioxidants (vitamin E and butylated hydroxytoluene), bacteriostatic agents, chelating agents (such as EDTA and glutathione), adjuvants (e.g. aluminum hydroxide), suspending agents/thickening agents/preservatives, etc. that make the formulation isotonic with the recipient's blood, or the composition of the invention can be formulated as a lyophilisate.
- buffers eg neutral buffered saline or phosphate buffered water
- carbohydrates eg glucose, mannitol, sucrose, trehalose, dextrose or dextran. sugar
- the administration methods of the composition include but are not limited to intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection, intratumoral injection, ocular administration, ear administration, nasal administration, and oral administration. medicine, transanal administration, transvaginal administration, etc.
- the administration objects of the composition include but are not limited to mammals such as cattle, horses, mules, donkeys, camels, pigs, sheep, dogs, foxes, rabbits, etc., and poultry such as chickens, ducks, geese, pigeons, etc., Fish, non-human primates, humans.
- the technical solution of the present invention provides a new class of lipid compounds for delivering therapeutic or preventive drugs, namely lipids based on cholic acid or its derivatives.
- the technical solution of the present invention is different from the existing patented technical solutions of foreign pharmaceutical companies. , enriches the types of lipid compounds, provides more options for the delivery of nucleic acid drugs, gene vaccines, peptides, proteins, antibodies and small molecule drugs, and can be significantly different from the technical routes of foreign companies such as Pfizer and Moderna. .
- the pharmaceutical composition of the present invention relates to the field of lipid nanoparticles (LNP).
- LNP lipid nanoparticles
- the preparation method of the nanoparticles is simple, has good repeatability, simplifies the production process and reduces costs; at the same time, it can avoid the patent blockade of the four-component LNP and is conducive to the promotion of nucleic acids. Domestic production of drugs.
- the prepared lipid nanoparticles encapsulating siRNA have better cell transfection effect; whether the nanoparticles are injected into small cells through intravenous injection Whether in mice or via intramuscular injection, LNP has a good in vivo delivery effect.
- the nanoparticles encapsulating the mRNA were injected into the tumor, and pictures were taken 6 hours after the injection. There was fluorescence expression in the tumor of the mice, indicating that the lipid nanoparticles can be administered by intratumoral injection. . Based on the in vivo and in vitro evaluation results, the nanoparticles have good delivery effects and application scenarios.
- Figure 1 is a proton nuclear magnetic resonance spectrum of ursodeoxycholic acid derivative 1 (compound 1).
- Figure 2 is a hydrogen nuclear magnetic resonance spectrum of ursodeoxycholic acid derivative 2 (compound 2).
- Figure 3 is a hydrogen nuclear magnetic resonance spectrum of ursodeoxycholic acid derivative 7 (compound 7).
- Figure 4 is a hydrogen nuclear magnetic resonance spectrum of ursodeoxycholic acid derivative 9 (compound 9).
- Figure 5 is a proton nuclear magnetic resonance spectrum of ursodeoxycholic acid derivative 10 (compound 10).
- Figure 6 is a proton nuclear magnetic resonance spectrum of ursodeoxycholic acid derivative 13 (compound 13).
- Figure 7 is a proton nuclear magnetic resonance spectrum of ursodeoxycholic acid derivative 16 (compound 16).
- Figure 8 is a proton nuclear magnetic resonance spectrum of ursodeoxycholic acid derivative 17 (compound 17).
- Figure 9 is a proton nuclear magnetic resonance spectrum of obeticholic acid derivative 18 (compound 18).
- Figure 10 is a proton nuclear magnetic resonance spectrum of ursodeoxycholic acid derivative 42 (compound 42).
- Figure 11 is a proton nuclear magnetic resonance spectrum of lithocholic acid derivative 58 (compound 58).
- Figure 12 is a hydrogen nuclear magnetic resonance spectrum of ursodeoxycholic acid derivative 62 (compound 62).
- Figure 13 is a hydrogen nuclear magnetic resonance spectrum of ursodeoxycholic acid derivative 63 (compound 63).
- Figure 14 is a hydrogen nuclear magnetic resonance spectrum of ursodeoxycholic acid derivative 66 (compound 66).
- Figure 15 is a hydrogen nuclear magnetic resonance spectrum of chenodeoxycholic acid derivative 69 (compound 69).
- Figure 16 is a hydrogen nuclear magnetic resonance spectrum of hyodeoxycholic acid derivative 72 (compound 72).
- Figure 17 is a proton nuclear magnetic resonance spectrum of ursodeoxycholic acid derivative 75 (compound 75).
- Figure 18 is a proton nuclear magnetic resonance spectrum of ursodeoxycholic acid derivative 85 (compound 85).
- Figure 19 is a proton nuclear magnetic resonance spectrum of ursodeoxycholic acid derivative 87 (compound 87).
- Figure 20 is a hydrogen nuclear magnetic resonance spectrum of ursodeoxycholic acid derivative 89 (compound 89).
- Figure 21 shows the experimental results of cells transfected with LNP-encapsulated cy3-siRNA, including a) bright field of fluorescence microscope, b) dark field of fluorescence microscope, c) cell flow cytometry.
- Figure 22 shows the experimental results of cells transfected with LNP-encapsulated EGFP mRNA, including a) bright field of fluorescence microscope, b) dark field of fluorescence microscope, c) cell flow cytometry.
- Figure 23 shows the fluorescence imaging results of LNP encapsulating Luciferase mRNA 12 hours after intravenous injection in mice.
- Figure 24 shows the fluorescence imaging results of LNP encapsulating Luciferase mRNA 12 hours after intramuscular injection in mice.
- Figure 25 is a diagram of the killing effect of tumor cells A549.
- Figure 26 shows the results of fluorescence imaging after intramuscular injection in mice.
- Figure 27 shows the results of fluorescence imaging after intravenous injection into mice.
- Figure 28 shows the results of fluorescence imaging after intratumoral injection in mice.
- Cholic acid is a naturally ubiquitous steroid molecule in humans and mammals, synthesized in the liver from cholesterol. After eating, bile acid is actively secreted by liver cells, enters the gallbladder with bile, and then enters the intestine from the gallbladder to perform its digestive function. Cholic acid enters the small intestine in the form of sodium salt to help digest and absorb lipids, and then passes through the terminal ileum. It is returned to the liver through the portal vein through active absorption or passive transport, processed and transformed in liver cells, and then secreted into the small intestine together with newly synthesized bile acids.
- This EHC (enterohepatic circulation) process of bile acids circulates 4 to 12 times a day, and about 95% of the bile acids are reabsorbed and utilized. If the EHC of bile acids is destroyed, it will not only affect the digestion and absorption of lipids in the body, but also cause the body to form cholesterol stones. Therefore, the biggest advantage of compound delivery carriers designed based on bile acid is that it has high enterohepatic circulation efficiency and participates in the enterohepatic circulation of bile acid, thereby improving drug absorption in the liver and gallbladder.
- the structural formula of cholic acid is as follows.
- the three six-membered rings and one five-membered ring on the steroid skeleton of the cholic acid molecule are on the same plane, and ring A and ring B are connected in reverse, making the molecule form a cave-like structure.
- three methyl groups are distributed on one side of the plane where the steroid ring is located, forming the hydrophobic part of the molecule.
- Three hydroxyl groups are distributed on the other side of the plane where the steroid ring is located, and together with the C24 carboxyl group, form the hydrophilic part of the molecule.
- cholic acid The special structure of the cholic acid molecule determines that it is amphiphilic, acid-base, and easy to undergo chemical modification. Therefore, this patent uses cholic acid as a building block to prepare polymers or oligomers. These cholic acid-based products Functional molecules have good technical effects in drug delivery.
- Cholic acid drugs have been on the market in China or the United States for many years, including ursodeoxycholic acid, obeticholic acid, chenodeoxycholic acid, and tauroursodeoxycholic acid.
- ursodeoxycholic acid is used to treat cholesterol gallstones and bile reflux gastritis
- obeticholic acid is used to treat primary biliary cirrhosis (PBC), and there is no adequate response to ursodeoxycholic acid or Patients who cannot tolerate it.
- PBC primary biliary cirrhosis
- Years of clinical application have shown that cholic acid compounds have good safety.
- cholic acid compounds have hydrophilic and lipophilic amphiphilic properties, and can be encapsulated or The conjugation method can improve the bioavailability of small molecule chemical drugs.
- Cholic acid compounds and cholesterol are both steroidal compounds with similar structures and more sites that can be chemically modified. Structural modification of cholic acid compounds to prepare new lipid components may potentially replace the ionizable lipids and cholesterol in the original four-component LNP to achieve similar or better mRNA delivery effects.
- This patented study constructs lipid nanoparticle carriers based on bile acid analogs and explores their application in mRNA drug delivery.
- the LNP of the present invention can simplify the production process and reduce costs; at the same time, it can avoid the patent blockade of four-component LNP, which is beneficial to promoting the localization of nucleic acid drugs.
- cholic acid or its derivatives are composed of a rigid steroid ring and an aliphatic side chain
- the steroid ring includes three six-membered rings and one five-membered ring.
- the side chain structure of cholic acid, the conformation of the steroid ring, the number of hydroxyl groups and the orientation of the steroid ring will be different.
- the common hydroxyl group of cholic acid or its derivatives and the carboxyl group of the fatty side chain are good chemical modification sites. Therefore, we believe that cholic acid or its derivatives can achieve the desired purpose through some common modifications.
- Cholic acid or its derivatives in this patent is optionally selected from the group consisting of cholic acid, obeticholic acid, ursodeoxycholic acid, ursolic acid, 3 ⁇ -hydroxy-D5-cholic acid, chenodeoxycholic acid, and stone.
- the lipid compound described in this patent is one or more compounds selected from the following structures;
- Ursodeoxycholic acid derivative lipid 1 Ursodeoxycholic acid derivative lipid:
- Ursodeoxycholic acid (393 mg, 1.0 mmol) was dissolved in DMF (8 mL), and HBTU (569 mg, 1.5 mmol), DIEA (194 mg, 1.5 mmol), and 4-pyrrole-1-butylamine (213 mg, 1.5 mmol) were added in sequence. mmol), under nitrogen protection, and stirred at room temperature overnight. TLC detection, after the reaction is completed, add Add an appropriate amount of water, extract with ethyl acetate three times, combine the organic layers, dry over anhydrous sodium sulfate, filter, and concentrate the solvent to obtain a crude product.
- Ursodeoxycholic acid (393 mg, 1.0 mmol) was dissolved in acetonitrile (10 mL), K 2 CO 3 (415 mg, 3.0 mmol), BnBr (850 mg, 5.0 mmol) were added in sequence, protected by nitrogen, and the reaction was stirred at 80°C for 5 h. TLC detection, after the reaction is completed, filter and concentrate the solvent to obtain crude product. Silica gel column chromatography, eluting with PE/EA (1:1), gave compound 6 (390 mg, 81%) as a white solid product.
- Ursodeoxycholic acid (785mg, 1.0mmol) was dissolved in DMF (20mL), K 2 CO 3 (829mg, 6.0mmol), CH 3 I (852mg, 6.0mmol) were added in sequence, under nitrogen protection, and the reaction was stirred at room temperature overnight. .
- TLC detection after the reaction is completed, add an appropriate amount of water, extract with ethyl acetate three times, combine the organic layers, dry over anhydrous sodium sulfate, filter, and concentrate the solvent to obtain a crude product.
- Silica gel column chromatography eluting with PE/EA (1:1), gave compound 8 (700 mg, 86%) as a white solid product.
- Linoleic acid (476 mg, 1.7 mmol) was dissolved in anhydrous DCM (5 mL), oxalyl chloride (0.30 mL) was added, and the mixture was stirred at room temperature for 5 h. Concentrate under vacuum to no solvent, dissolve with anhydrous DCM (2mL), and set aside. Compound 2 (240 mg, 0.34 mmol) and TEA (69 mg, 0.68 mmol) were dissolved in anhydrous DCM (5 mL). The above standby product was dropped into the reaction solution and allowed to react at room temperature overnight. Add an appropriate amount of water, extract with DCM three times, combine the organic layers, dry over anhydrous sodium sulfate, filter, and concentrate the solvent to obtain crude product.
- Example 10 The synthetic route of ursodeoxycholic acid derivative (compound 19) is as follows
- Example 11 The synthetic route of ursodeoxycholic acid derivative (compound 20) is as follows
- Example 12 The synthetic route of ursodeoxycholic acid derivative (compound 21) is as follows
- Example 13 The synthetic route of ursodeoxycholic acid derivative (compound 22) is as follows
- Example 14 The synthetic route of ursodeoxycholic acid derivative (compound 23) is as follows
- Example 15 The synthetic route of ursodeoxycholic acid derivative (compound 24) is as follows
- Example 16 The synthetic route of ursodeoxycholic acid derivative (compound 25) is as follows
- Example 17 The synthetic route of ursodeoxycholic acid derivative (compound 26) is as follows
- Example 18 The synthetic route of ursodeoxycholic acid derivative (compound 27) is as follows
- Example 19 The synthetic route of ursodeoxycholic acid derivative (compound 28) is as follows
- Example 20 The synthetic route of ursodeoxycholic acid derivative (compound 29) is as follows
- Example 21 The synthetic route of ursodeoxycholic acid derivative (compound 30) is as follows
- Example 22 The synthesis route of ursodeoxycholic acid derivative (compound 31) is as follows
- Example 23 The synthesis route of lithocholic acid derivative (compound 32) is as follows
- Example 24 The synthesis route of ursodeoxycholic acid derivative (compound 33) is as follows
- Example 25 The synthetic route of cholesterol derivative (compound 34) is as follows
- Example 26 The synthetic route of ursodeoxycholic acid derivative (compound 35) is as follows
- Example 27 The synthetic route of cholic acid derivative (compound 36) is as follows
- Example 28 The synthetic route of ursodeoxycholic acid derivative (compound 37) is as follows
- Example 29 The synthetic route of ursodeoxycholic acid derivative (compound 38) is as follows
- Example 30 The synthetic route of ursodeoxycholic acid derivative (compound 39) is as follows
- Example 31 The synthetic route of ursodeoxycholic acid derivative (compound 40) is as follows
- intermediate 40-2 Combine intermediate 40-1 (1.60g, 8.37mmol), stearic acid (5.00g, 17.57mmol), EDCI (10.00g, 52.16mmol), DMAP (0.50g, 4.09mmol) Dissolve in DCM and stir at room temperature for 16h. After TLC detection, after the reaction was completed, the reaction mixture was concentrated to obtain white viscous liquid intermediate 40-2 (5.31 g, 87%). Crude products are directly transferred to the next step.
- intermediate 40-4 Dissolve lithocholic acid (500mg, 1.33mmol), intermediate 40-3 (1.17g, 1.59mmol), HATU (0.76g, 2.00mmol), and DIPEA (0.74mL, 4.00mmol) Stir in DMF at room temperature for 20h. After TLC detection, the solvent was concentrated to obtain crude product. Silica gel column chromatography, eluting with DCM/CH 3 OH (50:1), gave off-white solid intermediate 40-4 (750 mg, 57.4%).
- Example 32 The synthesis route of ursodeoxycholic acid derivative (compound 41) is as follows
- Example 33 The synthetic route of ursodeoxycholic acid derivative (compound 42) is as follows
- Example 34 The synthesis route of ursodeoxycholic acid derivative (compound 43) is as follows
- Example 35 The synthetic route of ursodeoxycholic acid derivative (compound 44) is as follows
- Example 36 The synthetic route of ursodeoxycholic acid derivative (compound 45) is as follows
- Example 37 The synthetic route of ursodeoxycholic acid derivative (compound 46) is as follows
- Example 38 The synthetic route of ursodeoxycholic acid derivative (compound 47) is as follows
- Example 39 The synthetic route of ursodeoxycholic acid derivative (compound 48) is as follows
- Example 40 The synthetic route of ursodeoxycholic acid derivative (compound 49) is as follows
- Example 41 The synthetic route of ursodeoxycholic acid derivative (compound 50) is as follows
- Example 42 The synthetic route of obeticholic acid derivative (compound 51) is as follows
- Example 43 The synthesis route of chenodeoxycholic acid derivative (compound 52) is as follows
- Example 44 The synthetic route of ursodeoxycholic acid derivative (compound 53) is as follows
- Example 45 The synthetic route of obeticholic acid derivative (compound 54) is as follows
- Example 46 The synthetic route of obeticholic acid derivative (compound 55) is as follows
- Example 47 The synthetic route of obeticholic acid derivative (compound 56) is as follows
- Example 48 The synthetic route of ursodeoxycholic acid derivative (compound 57) is as follows
- Example 49 The synthesis route of lithocholic acid derivative (compound 58) is as follows
- Example 50 The synthetic route of ursodeoxycholic acid derivative (compound 59) is as follows
- Example 51 The synthetic route of ursodeoxycholic acid derivative (compound 60) is as follows
- intermediate 60-2 Dissolve intermediate 59-7 (200mg, 0.22mmol), intermediate 60-1 (134mg, 0.27mmol), HATU (126mg, 0.33mmol), TEA (68mg, 0.66mmol) in In DMF, stir at room temperature for 20h. After TLC detection, the solvent was concentrated to obtain crude product. Silica gel column chromatography, eluting with DCM/CH 3 OH (50:1), gave light yellow oily intermediate 60-2 (140 mg, 46.6%).
- Example 52 The synthetic route of ursodeoxycholic acid derivative (compound 61) is as follows
- Example 53 The synthetic route of ursodeoxycholic acid derivative (compound 62) is as follows
- Dissolve intermediate 59-7 (100mg, 0.115mmol) in ACN, add raw materials 62-1 (24mg, 0.138mmol), NMI (24mg, 0.288mmol), TCFH (39mg, 0.138mmol) in sequence, stir and react at room temperature for 16h . After TLC detection, the solvent was concentrated to obtain crude product. Silica gel column chromatography, eluting with DCM/CH 3 OH (10:1), gave compound 62 (55 mg, 47%) as a light yellow oil.
- Example 54 The synthetic route of ursodeoxycholic acid derivative (compound 63) is as follows
- Example 55 The synthetic route of ursodeoxycholic acid derivative (compound 64) is as follows
- 59-7 is a carboxylic acid, an intermediate in the preparation of compound 59.
- Example 56 The synthetic route of ursodeoxycholic acid derivative (compound 65) is as follows
- Example 57 The synthetic route of ursodeoxycholic acid derivative (compound 66) is as follows
- Example 58 The synthetic route of ursodeoxycholic acid derivative (compound 67) is as follows
- Example 59 The synthetic route of ursodeoxycholic acid derivative (compound 68) is as follows
- Example 60 The synthesis route of chenodeoxycholic acid derivative (compound 69) is as follows
- Example 61 The synthesis route of chenodeoxycholic acid derivative (compound 70) is as follows
- Example 62 The synthesis route of chenodeoxycholic acid derivative (compound 71) is as follows
- intermediate 71-3 Dissolve intermediate 71-1 (650 mg, 1.27 mmol) in pyridine, then add fresh acid chloride 71-2 (2.80 g, 10.18 mmol), and stir at room temperature for 3 hours. After TLC detection, the solvent was concentrated to obtain crude product. Silica gel column chromatography, eluting with PE/EA (5:1), gave colorless oil 71-3 (495 mg, 52%).
- intermediate 71-4 Dissolve intermediate 71-3 (395 mg, 0.527 mmol) in MeOH, add 10% Pd/C (59 mg, 15% wt), and stir for 16 hours under a hydrogen atmosphere. TLC detection, after the reaction is completed, filter and concentrate the solvent to obtain crude product. Silica gel column chromatography, eluted with DCM/MeOH (30:1), gave colorless oily substance 71-4 (270 mg, 78%).
- Example 63 The synthesis route of hyodeoxycholic acid derivative (compound 72) is as follows
- Example 64 The synthetic route of ursodeoxycholic acid derivative (compound 73) is as follows
- Example 65 The synthetic route of ursodeoxycholic acid derivative (compound 74) is as follows
- Example 66 The synthetic route of ursodeoxycholic acid derivative (compound 75) is as follows
- intermediate 75-2 Dissolve intermediate 75-1 (180 mg, 0.12 mmol), Pd/C (20 mg) in methanol, and stir at 25°C for 16 hours under a hydrogen atmosphere. TLC detection, after the reaction is completed, filter and concentrate the solvent to obtain crude product. Silica gel column chromatography, eluted with DCM/MeOH (20:1), gave colorless oily intermediate 75-2 (110 mg, 67.4%).
- Example 67 The synthetic route of obeticholic acid derivative (compound 76) is as follows
- Example 68 The synthetic route of obeticholic acid derivative (compound 77) is as follows
- Example 69 The synthetic route of obeticholic acid derivative (compound 78) is as follows
- Example 70 The synthetic route of obeticholic acid derivative (compound 79) is as follows
- Example 71 The synthetic route of ursodeoxycholic acid derivative (compound 80) is as follows
- Ursodeoxycholic acid (4.0g, 10.2mmol), amine (597mg, 5.1mmol), HBTU (4.63g, 12.21mmol), DIEA (2.06g, 15.9mmol) and THF were added to the reaction bottle in sequence. Stir at room temperature overnight. TLC showed that the starting material reacted completely. The reaction solution was concentrated and subjected to silica gel column chromatography, eluting with DCM/CH 3 OH (10:1) to obtain compound 80 (1.8 g, 40%) as a white solid.
- Example 72 The synthetic route of ursodeoxycholic acid derivative (compound 81) is as follows
- Example 73 The synthetic route of ursodeoxycholic acid derivative (compound 82) is as follows
- Example 74 The synthetic route of ursodeoxycholic acid derivative (compound 83) is as follows
- Example 75 The synthetic route of ursodeoxycholic acid derivative (compound 84) is as follows
- Example 76 The synthetic route of ursodeoxycholic acid derivative (compound 85) is as follows
- Example 77 The synthetic route of ursodeoxycholic acid derivative (compound 86) is as follows
- intermediate 86-3 Dissolve intermediate 86-2 (1.40g, 1.44mmol) in DCM, add TFA (1mL), and stir at room temperature for 20h. TLC detection, after the reaction is completed, the solvent is directly evaporated from the reaction solution to obtain the crude product. Silica gel column chromatography, eluting with DCM, gave colorless oily intermediate 86-3 (0.98g, 76.6%).
- Example 78 The synthetic route of ursodeoxycholic acid derivative (compound 87) is as follows
- Example 79 The synthetic route of ursodeoxycholic acid derivative (compound 88) is as follows
- Example 80 The synthesis route of the conjugate of ursodeoxycholic acid and paclitaxel (compound 89) is as follows
- Example 081 The synthesis route of the conjugate of ursodeoxycholic acid and small nucleic acid (compound 90) is as follows
- Example 082 The synthesis route of the conjugate of ursodeoxycholic acid and polypeptide (compound 91) is as follows
- Compound 91 is a solid-phase synthetic peptide with 30 amino acids, and the synthesis process adopts the Fmoc (9-fluorenylmethoxycarbonyl) solid-phase synthesis method. Connect the first alanine (Ala) at the C-terminus to the Wang resin, and then synthesize it sequentially from the C-terminus to the N-terminus according to the peptide sequence until the last Ursodeoxycholic Acid (Ursodeoxycholic Acid) is completed to obtain the compound 91 peptide resin. The compound 91 peptide resin was cleaved, precipitated with anhydrous ether, and washed to obtain the crude peptide of compound 91. The crude peptide of compound 91 is coarsely filtered, purified, salted and freeze-dried to obtain the finished product. The specific steps are as follows:
- nanoparticle compositions for delivering therapeutic and/or prophylactic agents to cells
- a series of formulations were prepared and tested. Specifically, specific ingredients and their ratios in the lipid component of the nanoparticle composition are optimized.
- Nanoparticles can be produced by mixing two fluid streams, one of which contains therapeutic and/or prophylactic agents and the other of which has a lipid component, by mixing methods such as microfluidization and T-junctions.
- phospholipids such as DOPE or DSPC, available from Avanti Polar Lipids (Alabaster, AL)
- PEG lipids such as 1,2-dimyristoyl -sn-Glycerylmethoxypolyethylene glycol, also known as PEG-DMG, available from Avanti Polar Lipids (Alabaster, AL)
- structural lipids such as cholesterol, available from Sigma-Aldrich (Tauf Wegn, Germany)
- corticosteroids such as prednisolone, dexamethasone, prednisolone and hydrocortisone
- a combination thereof to prepare a lipid composition at a concentration of about 50mM.
- corticosteroids such as prednisolone, dexamethasone, pred
- a formulation containing a therapeutic agent is prepared by combining a lipid solution with a therapeutic agent and/or prophylactic agent in a lipid component to therapeutic agent and/or prophylactic agent wt:wt ratio of between about 5:1 and about 50:1.
- Nanoparticle compositions of agents and/or prophylactic agents and lipid components are rapidly injected into the therapeutic agent and/or preventive agent solution at a flow rate between about 10 mL/min and about 18 mL/min to create a dispersion. , wherein the water to ethanol ratio is between about 2:1 and about 5:1.
- Zetasizer NanoZS (Malvern Instruments Ltd, Malvern, Worcestershire, UK) can be used to determine the particle size, polydispersity index (PDI) and ⁇ potential of the nanoparticle composition.
- the particle size is measured in 1 ⁇ PBS and ⁇ Potentials were measured in 15mM PBS.
- RNA For nanoparticle compositions containing RNA, the QUANT-ITTM RNA (Invitrogen Corporation Carlsbad, CA) assay can be used to evaluate the encapsulation of RNA by the nanoparticle composition. Samples were diluted in TE buffer solution (10mM Tris-HCl, 1mM EDTA, pH 7.5) to a concentration of approximately 5 ⁇ g/mL. Transfer 50 ⁇ L of the diluted sample to a polystyrene 96-well plate and add 50 ⁇ L of TE buffer or 50 ⁇ L of 2% Triton X-100 solution to each well. Incubate the plate at 37°C for 15 minutes.
- TE buffer solution 10mM Tris-HCl, 1mM EDTA, pH 7.5
- a fluorescent plate reader can be used ( Nivo TM Multimode Plate Readers, PerkinElmer, GER) measure fluorescence intensity at an excitation wavelength of, for example, about 480 nm and an emission wavelength of, for example, about 520 nm.
- the fluorescence value of the reagent blank was subtracted from the fluorescence value of each sample and determined by dividing the fluorescence intensity of the intact sample (without the addition of Triton X-100) by the fluorescence of the disrupted sample (caused by the addition of Triton X-100). value to determine the percentage of free RNA. See Table 1 for specific data.
- ONE-GlO+TOX Luciferase Reporter and Cell Viability Assay can be used to evaluate its transfection effect and cytotoxicity. Calculate the volume of the required nanoparticle assembly based on the RNA concentration measured in the encapsulation efficiency determination, dilute the nanoparticle assembly to 20ng/ ⁇ L, and add it according to the cell density of 2 ⁇ 10 5 cells/well in a polystyrene 96-well plate. Add 5 ⁇ L of diluent to each well for transfection. A fluorescent plate reader can be used ( Nivo TM Multimode Plate Readers, PerkinElmer, GER) were used to measure chemiluminescence intensity. See Table 2 for specific data.
- Transfection effect can provide multiples of MC3.
- Example 84 Preparation and detection of lipid nanoparticles (to verify the ability to deliver siRNA in vitro)
- Lipid nanoparticle size was determined by dynamic light scattering using a nanoparticle size and potential analyzer (NS-90Z). The encapsulation efficiency of lipid nanoparticles was determined using the Quant-it Ribogreen RNA Quantitative Assay Kit. The particle size of the lipid nanoparticles was measured to be 82nm, the PDI (polydispersity index) was 0.13, and the encapsulation rate It's 96.5%.
- Example 85 Preparation and detection of lipid nanoparticles (to verify the ability to deliver mRNA in vitro)
- the lipid nanoparticles are then filtered with a 0.22 ⁇ m sterile filter to obtain a preparation encapsulating EGFP mRNA.
- Lipid nanoparticle size was determined by dynamic light scattering using a nanoparticle size and potential analyzer (NS-90Z). Determine the encapsulation efficiency of lipid nanoparticles using the Quant-it Ribogreen RNA Quantitative Assay Kit.
- the particle size of the LNP preparation was measured to be 95nm, PDI 0.19, and the encapsulation rate was 93.1%.
- Example 86 Preparation and detection of lipid nanoparticles (to verify the in vivo delivery effect of mRNA)
- the weight ratio of total lipid to mRNA is Prepare liposomes at 20:1, remove ethanol using dialysis or tangential flow filtration, and replace with PBS solution.
- the lipid nanoparticles are then filtered with a 0.22 ⁇ m sterile filter to obtain a preparation that encapsulates mRNA.
- Lipid nanoparticle size was determined by dynamic light scattering using a nanoparticle size and potential analyzer (NS-90Z). Determine the encapsulation efficiency of lipid nanoparticles using the Quant-it Ribogreen RNA Quantitative Assay Kit. The particle size of the lipid nanoparticles was measured to be 98 nm, the PDI was 0.22, and the encapsulation rate was 88.9%.
- the synthesized lipid compound-1, DOPE and DMG-PEG2000 were dissolved in absolute ethanol at a molar ratio of 89.9:10:0.1 to prepare a lipid ethanol solution, and Luciferase mRNA (encoding luciferase mRNA) was dissolved in 50mM lemon respectively.
- Dilute the ethanol lipid solution and the mRNA solution in acid salt buffer (pH 4) using a microfluidic device to mix the ethanol lipid solution and the mRNA solution in a volume of 1:3 to prepare the lipid with a weight ratio of total lipid to mRNA of 20:1.
- the lipid nanoparticles were then filtered with a 0.22 ⁇ m sterile filter to obtain an mRNA-encapsulated preparation.
- the detected particle size was 1249nm, the PDI was 0.67, and the encapsulation rate was 31%.
- Prepare liposomes Use dialysis or tangential flow filtration to remove ethanol and replace it with PBS solution. The lipid nanoparticles were then filtered with a 0.22 ⁇ m sterile filter to obtain an mRNA-encapsulated preparation.
- the detected particle size was 467 nm, the PDI was 0.40, and the encapsulation rate was 78%.
- Use a microfluidic device to mix the ethanol lipid solution and the mRNA solution in a volume of 1:3, so that the weight ratio of total lipid to mRNA is 20: 1.
- Prepare liposomes Use dialysis or tangential flow filtration to remove ethanol and replace it with PBS solution.
- the lipid nanoparticles were then filtered with a 0.22 ⁇ m sterile filter to obtain an mRNA-encapsulated preparation.
- the detected particle size was 347nm, the PDI was 0.41, and the encapsulation rate was 81%.
- Use a microfluidic device to mix the ethanol lipid solution and the mRNA solution in a volume of 1:3, so that the weight ratio of total lipid to mRNA is 20: 1.
- Prepare liposomes Use dialysis or tangential flow filtration to remove ethanol and replace it with PBS solution.
- the lipid nanoparticles were then filtered with a 0.22 ⁇ m sterile filter to obtain an mRNA-encapsulated preparation.
- the detected particle size was 94nm, the PDI was 0.50, and the encapsulation rate was 85%.
- Use a microfluidic device to mix the ethanol lipid solution and the mRNA solution in a volume of 1:3, so that the weight ratio of total lipid to mRNA is 20: 1.
- Prepare liposomes Use dialysis or tangential flow filtration to remove ethanol and replace it with PBS solution.
- the lipid nanoparticles were then filtered with a 0.22 ⁇ m sterile filter to obtain an mRNA-encapsulated preparation.
- the detected particle size was 82nm, the PDI was 0.11, and the encapsulation rate was 96%.
- Prepare liposomes Use dialysis or tangential flow filtration to remove ethanol and replace it with PBS solution. The lipid nanoparticles were then filtered with a 0.22 ⁇ m sterile filter to obtain an mRNA-encapsulated preparation.
- the detected particle size was 145nm, the PDI was 0.23, and the encapsulation rate was 76%.
- Prepare liposomes Use dialysis or tangential flow filtration to remove ethanol and replace it with PBS solution. The lipid nanoparticles were then filtered with a 0.22 ⁇ m sterile filter to obtain an mRNA-encapsulated preparation.
- the detected particle size was 302nm, the PDI was 0.38, and the encapsulation rate was 73%.
- Prepare liposomes Use dialysis or tangential flow filtration to remove ethanol and replace it with PBS solution. The lipid nanoparticles were then filtered with a 0.22 ⁇ m sterile filter to obtain an mRNA-encapsulated preparation.
- the detected particle size was 302nm, the PDI was 0.38, and the encapsulation rate was 73%.
- the particle size (Size), polydispersity index (PDI) and electrokinetic potential (Zeta P) of the particles were determined by dynamic light scattering using the Malvern Zetasizer NanoZS (Malvern Nanoparticle Size Testing Instrument).
- the encapsulation efficiency of lipid nanoparticles was determined using QUANT-ITTM RNA (Invitrogen Corporation Carlsbad, CA). According to the characterization method of the nanoparticle assembly in Example 083, as shown in Table 3: the size of the lipid nanoparticle preparation is mostly around 100 nm, the potential is between ⁇ 20mv, the polydispersity index varies around 0.1-0.3, and the encapsulation The rate part is around 80%-99%.
- Example 96 In vitro cell transfection experiment of lipid nanoparticles
- 293T cells were seeded in a 96-well cell culture plate at a density of 3X10 ⁇ 4 cells/well and grown for 24 hours to adhere.
- Table 4 shows that the lipid nanoformulation can carry mRNA and be transfected into 293T cells and express the target fluorescent protein.
- A, B, C, and D respectively represent the compound and the commercial MC3-LNP luminous flux after normalization.
- the luminescence flux of 31 compounds was higher than that of the MC3-LNP group, indicating that the lipid nanoparticle preparation can effectively carry nucleic acids into cells.
- A, B, C, and D respectively represent the normalized results after multiplying the luminous flux of the compound and MC3-LNP.
- the magnification range is as follows:
- Example 97 Compound 46 encapsulates paclitaxel to kill cells
- Compound 46, DSPC, cholesterol, and PEG2000 were prepared according to the method in Example 83 to remove alcohol, and then 0.2, 1, 5, 10, and 20 mg/ml paclitaxel solutions were added to evaluate the killing effect of paclitaxel-loaded LNP on tumor cells A549, as follows: The results in Figure 25 show that paclitaxel-loaded lipid nanoparticles have a better tumor cell killing effect than free paclitaxel at high concentrations.
- Compound 27 was used for prescription screening, and the formula was proportioned according to the prescription composition in the following table. It was prepared by the method described in Example 83. The results are shown in Table 5. The size of the lipid nanoparticle preparation was between 70nm and 170nm, and the potential was within ⁇ Between 20mv, the polydispersity index varies between 0.1-0.3, the encapsulation rate is around 80%-90%, and the luminous flux values of the cell evaluation results are mostly higher than those of the MC3-LNP group, indicating that lipid nanoparticle preparations can Change the composition of the prescription to carry nucleic acids into cells.
- Example 99 Fluorescent protein expression experiment of lipid nanoparticle preparation in mice
- Samples were prepared according to the preparation method of the nanoparticle assembly in Example 83, using MC3-LNP as a positive reference.
- the preparations were prepared by intramuscular injection at a dose of 100 ⁇ L (0.05 ⁇ g/ ⁇ L), using the preparation method of the preparation in Example 83, and MC3-LNP was used in the control group for comparison of in vivo effects. 6 hours after administration, 200ul of D-luciferin potassium salt with a concentration of 15 mg/ml was injected intraperitoneally, and in vivo imaging was performed 5 minutes after the injection of D-luciferin potassium salt.
- A, B, C, and D respectively represent the normalized results of compound and commercial MC3-LNP fluorescence expression values after fold ratio.
- Table 6 there are compounds 27, 37, 39, 42, 43, 46, 50, 66, 69, 74, 82, 86, and 87 all reached the MC3-LNP level when administered locally, and compounds 42, 43, 50, and 69 exceeded the MC3-LNP level, indicating that lipid nanoparticle formulations can be effective Delivers mRNA and efficiently expresses the target gene protein locally.
- Table 7 and Figure 26 are the comparison results of the abdominal expression of compounds and commercial MC3-LNP, as shown in Table 7: among them, the fluorescence level of compounds 52, 67, 75, 81, 82, and 83 in the abdomen exceeds the level of MC3-LNP. , indicating that cholic acid series lipid compounds can efficiently express the target gene protein.
- a and B respectively represent the normalized results after multiplying the luminescence values of the compound and MC3-LNP.
- magnification range is as follows:
- Example 100 Fluorescent protein expression by intravenous injection of lipid nanoparticle formulations
- Compound 52, compound 67, and compound 75 were prepared using the preparation method of the preparation in Example 83, and administered intravenously according to Example 099.
- the control group used MC3-LNP for in vivo effect comparison.
- compound 52, Compound 67 and compound 75 are weaker than MC3-LNP, but both have fluorescent expression.
- Example 101 Expression of lipid nanoparticle preparation after intratumoral administration
- Compound 27 was formulated for intratumoral administration and prepared according to the method described in Example 83.
- the EG7-OVA model was established using C57 mice. The tumor was grown to 500mm3 before drug administration and intratumoral injection. Photographs were taken 6 hours after injection to observe the expression and distribution. As shown in Figure 28, there is fluorescence expression in the intratumoral site of mice, indicating that lipid nanoparticles can be administered via intratumoral injection.
- Example 102 Selecting compound 42 and compound 58 for LNP formulation screening
- Compound 42 was used for prescription screening, and the formula was proportioned according to the prescription composition in the following table. It was prepared by the method described in Example 83. The results are shown in Table 8. The size of the lipid nanoparticle preparation was between 50 nm and 200 nm, and the potential was within ⁇ 5 mv, the polydispersity index is around 0.1, the encapsulation rate is mostly above 90%, and the luminous flux values of the cell evaluation results are mostly higher than the MC3-LNP group, indicating that lipid nanoparticle preparations can change the composition of the prescription and carry nucleic acids Enter the cell.
- Example 103 Fluorescent protein expression experiment of lipid nanoparticle preparation in mice
- Example 102 The nanoparticle assembly obtained in Example 102 was used.
- the preparations were prepared by intramuscular injection at a dose of 100 ⁇ L (0.05 ⁇ g/ ⁇ L), using the preparation method of the preparation in Example 83, and MC3-LNP was used in the control group for comparison of in vivo effects. 6 hours after administration, 200ul of D-luciferin potassium salt with a concentration of 15 mg/ml was injected intraperitoneally, and in vivo imaging was performed 5 minutes after the injection of D-luciferin potassium salt.
- a and B respectively represent the normalized results of the fluorescence expression values of each group of formulas and the classic formula No. 13.
- Table 9 there are 7 formulas that have reached the level of the classic formula when administered locally in the muscle, indicating that lipid Plasma nanoparticle preparations can effectively deliver mRNA through formula changes and efficiently express the target gene protein locally in the muscle.
- the fluorescence expression levels of formulas 1, 8, and 9 in the spleen far exceeded the level of classic formulas, indicating that bile acid series lipid compounds can efficiently express gene proteins in the spleen by changing the proportion of the formula.
- Formula 3 is a three-component formula without DSPC. The results show that the local fluorescence expression value in the muscle is higher than the classic formula, indicating that the three-component formula can form nanoparticles and effectively express fluorescent proteins in the body.
- a and B respectively represent the luminescence values of each group of formulas and the classic formula No. 13 after being doubled.
- the result of normalization, the magnification range is as follows:
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Abstract
Sont divulgués un composé lipidique ayant une formule générale telle que représentée, et une composition, une préparation et une utilisation de celui-ci. Le composé lipidique est un composé à base d'acide cholique ou d'un dérivé de celui-ci, ou d'un sel pharmaceutiquement acceptable de celui-ci. Le composé lipidique et la composition de celui-ci peuvent fournir plus d'options de support pour l'administration de médicaments à base d'acide nucléique, de vaccins géniques, de polypeptides, de protéines, d'anticorps, de médicaments à petites molécules, etc.
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101798332A (zh) * | 2010-04-06 | 2010-08-11 | 四川大学 | 胆酸类偶合物、其制备方法和用途 |
CN110804082A (zh) * | 2019-11-25 | 2020-02-18 | 中国医学科学院医药生物技术研究所 | 一种胆酸类衍生物及其制备方法和应用 |
WO2021194298A1 (fr) * | 2020-03-26 | 2021-09-30 | (주) 테라베스트 | Nanoparticules comprenant des dimères de médicament et utilisation associée |
WO2021231701A1 (fr) * | 2020-05-15 | 2021-11-18 | Savage Paul B | Composés antimicrobiens stéroïdiens cationiques et procédés de fabrication de tels composés |
WO2023048453A1 (fr) * | 2021-09-27 | 2023-03-30 | (주) 테라베스트 | Nanoparticules comprenant des dimères de médicament et leur utilisation |
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US5780444A (en) * | 1991-12-13 | 1998-07-14 | Trustees Of Princeton University | Compositions and methods for cell transformation |
US5583239A (en) * | 1995-05-30 | 1996-12-10 | Lehigh University | Antimicrobial sterol conjugates |
CN101891791B (zh) * | 2009-05-22 | 2012-10-03 | 中国科学院上海应用物理研究所 | 一种标记胆汁酸衍生物及其参照化合物、制备方法和应用 |
GB201421071D0 (en) * | 2014-11-27 | 2015-01-14 | Univ Aston | Compound for treating clostridium difficile |
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Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101798332A (zh) * | 2010-04-06 | 2010-08-11 | 四川大学 | 胆酸类偶合物、其制备方法和用途 |
CN110804082A (zh) * | 2019-11-25 | 2020-02-18 | 中国医学科学院医药生物技术研究所 | 一种胆酸类衍生物及其制备方法和应用 |
WO2021194298A1 (fr) * | 2020-03-26 | 2021-09-30 | (주) 테라베스트 | Nanoparticules comprenant des dimères de médicament et utilisation associée |
WO2021231701A1 (fr) * | 2020-05-15 | 2021-11-18 | Savage Paul B | Composés antimicrobiens stéroïdiens cationiques et procédés de fabrication de tels composés |
WO2023048453A1 (fr) * | 2021-09-27 | 2023-03-30 | (주) 테라베스트 | Nanoparticules comprenant des dimères de médicament et leur utilisation |
Non-Patent Citations (2)
Title |
---|
DATABASE Registry 20 April 2022 (2022-04-20), ANONYMOUS: "Cholan-24-oic acid, 3,7,12-trihydroxy-, anhydride with methyl hydrogen carbonate, (3α,5β,7α,12α)-", XP009550506, Database accession no. 1063968-49-9 * |
POONAM SINGLAA,: "Proficiency of nanostructured lipid carriers for the formulation of amphiphilic bile acid oligomers", COLLOIDS AND SURFACESA: PHYSICOCHEMICAL AND ENGINEERING ASPECTS, vol. 611, no. 2021, 5 November 2020 (2020-11-05), XP086430558, DOI: 10.1016/j.colsurfa.2020.125841 * |
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