TW202320736A

TW202320736A - 用於製備脂質奈米粒子組成物之製程

用於製備脂質奈米粒子組成物之製程 Download PDF

Info

Publication number: TW202320736A
Authority: TW; Taiwan
Prior art keywords: composition; lipid; lipid nanoparticle; buffer; empty
Prior art date: 2021-07-26

Application number

TW111127849A

Other languages

English (en)

Chinese (zh)

Inventor

麥可Ｈ史密斯

尼米爾素德

田暢

丹尼爾Ｗ多爾蒂

Original Assignee

美商現代公司

Priority date

2021-07-26

Filing date

2022-07-25

Publication date

2023-06-01

2022-07-25 Application filed by 美商現代公司 filed Critical 美商現代公司

2023-06-01 Publication of TW202320736A publication Critical patent/TW202320736A/zh

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150000002632 lipids Chemical class 0.000 title claims abstract description 614
239000000203 mixture Substances 0.000 title claims abstract description 501
239000002105 nanoparticle Substances 0.000 title claims abstract description 388
238000000034 method Methods 0.000 title claims abstract description 144
230000008569 process Effects 0.000 title claims abstract description 99
108020004999 messenger RNA Proteins 0.000 claims abstract description 124
150000007523 nucleic acids Chemical class 0.000 claims abstract description 65
102000039446 nucleic acids Human genes 0.000 claims abstract description 63
108020004707 nucleic acids Proteins 0.000 claims abstract description 63
239000003795 chemical substances by application Substances 0.000 claims abstract description 44
239000000872 buffer Substances 0.000 claims description 180
239000000243 solution Substances 0.000 claims description 163
125000000217 alkyl group Chemical group 0.000 claims description 156
150000001875 compounds Chemical class 0.000 claims description 152
235000002639 sodium chloride Nutrition 0.000 claims description 110
150000003839 salts Chemical class 0.000 claims description 92
125000003342 alkenyl group Chemical group 0.000 claims description 70
150000003904 phospholipids Chemical class 0.000 claims description 69
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 68
-1 lipid amine Chemical class 0.000 claims description 66
239000002577 cryoprotective agent Substances 0.000 claims description 58
239000008351 acetate buffer Substances 0.000 claims description 54
108090000765 processed proteins & peptides Proteins 0.000 claims description 54
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 49
239000012062 aqueous buffer Substances 0.000 claims description 45
102000004196 processed proteins & peptides Human genes 0.000 claims description 39
229930006000 Sucrose Natural products 0.000 claims description 38
239000005720 sucrose Substances 0.000 claims description 38
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 37
229920001184 polypeptide Polymers 0.000 claims description 36
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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 30
239000007983 Tris buffer Substances 0.000 claims description 30
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239000007979 citrate buffer Substances 0.000 claims description 26
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LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 23
229910052739 hydrogen Inorganic materials 0.000 claims description 20
239000004094 surface-active agent Substances 0.000 claims description 20
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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 18
230000000694 effects Effects 0.000 claims description 17
238000004519 manufacturing process Methods 0.000 claims description 17
239000011780 sodium chloride Substances 0.000 claims description 17
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PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerol Substances OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 16
239000008363 phosphate buffer Substances 0.000 claims description 15
238000007865 diluting Methods 0.000 claims description 13
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 12
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LVNGJLRDBYCPGB-LDLOPFEMSA-N (R)-1,2-distearoylphosphatidylethanolamine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[NH3+])OC(=O)CCCCCCCCCCCCCCCCC LVNGJLRDBYCPGB-LDLOPFEMSA-N 0.000 claims description 4
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YCISYUZWCSTBCY-BAYLZEKJSA-N 2-aminoethyl [(2r)-2,3-bis(3,7,11,15-tetramethylhexadecoxy)propyl] hydrogen phosphate Chemical compound CC(C)CCCC(C)CCCC(C)CCCC(C)CCOC[C@H](COP(O)(=O)OCCN)OCCC(C)CCCC(C)CCCC(C)CCCC(C)C YCISYUZWCSTBCY-BAYLZEKJSA-N 0.000 claims description 3
JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 claims description 3
UKDDQGWMHWQMBI-SOFRWFQSSA-N [(2R)-2,3-bis(3,7,11,15-tetramethylhexadecanoyloxy)propyl] 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CC(C)CCCC(C)CCCC(C)CCCC(C)CC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CC(C)CCCC(C)CCCC(C)CCCC(C)C UKDDQGWMHWQMBI-SOFRWFQSSA-N 0.000 claims description 3
NMRGXROOSPKRTL-SUJDGPGCSA-N [(2r)-2,3-bis(3,7,11,15-tetramethylhexadecoxy)propyl] 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CC(C)CCCC(C)CCCC(C)CCCC(C)CCOC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OCCC(C)CCCC(C)CCCC(C)CCCC(C)C NMRGXROOSPKRTL-SUJDGPGCSA-N 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
150000008104 phosphatidylethanolamines Chemical class 0.000 claims description 3
RQOCXCFLRBRBCS-UHFFFAOYSA-N (22E)-cholesta-5,7,22-trien-3beta-ol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CCC(C)C)CCC33)C)C3=CC=C21 RQOCXCFLRBRBCS-UHFFFAOYSA-N 0.000 claims description 2
HCTYOHVVRRHDTQ-SKIDARPTSA-N (2s)-2,3-bis[(z)-octadec-9-enoxy]propan-1-ol Chemical compound CCCCCCCC\C=C/CCCCCCCCOC[C@H](CO)OCCCCCCCC\C=C/CCCCCCCC HCTYOHVVRRHDTQ-SKIDARPTSA-N 0.000 claims description 2
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 2
FVXDQWZBHIXIEJ-LNDKUQBDSA-N 1,2-di-[(9Z,12Z)-octadecadienoyl]-sn-glycero-3-phosphocholine Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC FVXDQWZBHIXIEJ-LNDKUQBDSA-N 0.000 claims description 2
GDYHKPCXCBYUMI-UUSMYCRBSA-N 1,2-diarachidonoyl-sn-glycero-3-phosphate Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(=O)OC[C@H](COP(O)(O)=O)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC GDYHKPCXCBYUMI-UUSMYCRBSA-N 0.000 claims description 2
DSNRWDQKZIEDDB-SQYFZQSCSA-N 1,2-dioleoyl-sn-glycero-3-phospho-(1'-sn-glycerol) Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@@H](O)CO)OC(=O)CCCCCCC\C=C/CCCCCCCC DSNRWDQKZIEDDB-SQYFZQSCSA-N 0.000 claims description 2
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 2
RTKYXZVOHQHXNA-JJDZEPKFSA-N 2-aminoethyl [(2R)-2,3-bis[(9Z,12Z)-octadeca-9,12-dienoxy]propyl] hydrogen phosphate Chemical compound C(CCCCCCC\C=C/C\C=C/CCCCC)OC[C@@H](OCCCCCCCC\C=C/C\C=C/CCCCC)COP(=O)(O)OCCN RTKYXZVOHQHXNA-JJDZEPKFSA-N 0.000 claims description 2
SHCCKWGIFIPGNJ-NSUCVBPYSA-N 2-aminoethyl [(2r)-2,3-bis[(z)-octadec-9-enoxy]propyl] hydrogen phosphate Chemical compound CCCCCCCC\C=C/CCCCCCCCOC[C@H](COP(O)(=O)OCCN)OCCCCCCCC\C=C/CCCCCCCC SHCCKWGIFIPGNJ-NSUCVBPYSA-N 0.000 claims description 2
SGNBVLSWZMBQTH-FGAXOLDCSA-N Campesterol Natural products O[C@@H]1CC=2[C@@](C)([C@@H]3[C@H]([C@H]4[C@@](C)([C@H]([C@H](CC[C@H](C(C)C)C)C)CC4)CC3)CC=2)CC1 SGNBVLSWZMBQTH-FGAXOLDCSA-N 0.000 claims description 2
GZDFHIJNHHMENY-UHFFFAOYSA-N Dimethyl dicarbonate Chemical compound COC(=O)OC(=O)OC GZDFHIJNHHMENY-UHFFFAOYSA-N 0.000 claims description 2
DNVPQKQSNYMLRS-NXVQYWJNSA-N Ergosterol Natural products CC(C)[C@@H](C)C=C[C@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@@H]3CC[C@]12C DNVPQKQSNYMLRS-NXVQYWJNSA-N 0.000 claims description 2
239000008777 Glycerylphosphorylcholine Substances 0.000 claims description 2
BTEISVKTSQLKST-UHFFFAOYSA-N Haliclonasterol Natural products CC(C=CC(C)C(C)(C)C)C1CCC2C3=CC=C4CC(O)CCC4(C)C3CCC12C BTEISVKTSQLKST-UHFFFAOYSA-N 0.000 claims description 2
XYNPYHXGMWJBLV-VXPJTDKGSA-N Tomatidine Chemical compound O([C@@H]1[C@@H]([C@]2(CC[C@@H]3[C@@]4(C)CC[C@H](O)C[C@@H]4CC[C@H]3[C@@H]2C1)C)[C@@H]1C)[C@@]11CC[C@H](C)CN1 XYNPYHXGMWJBLV-VXPJTDKGSA-N 0.000 claims description 2
QMGSCYSTMWRURP-UHFFFAOYSA-N Tomatine Natural products CC1CCC2(NC1)OC3CC4C5CCC6CC(CCC6(C)C5CCC4(C)C3C2C)OC7OC(CO)C(OC8OC(CO)C(O)C(OC9OCC(O)C(O)C9OC%10OC(CO)C(O)C(O)C%10O)C8O)C(O)C7O QMGSCYSTMWRURP-UHFFFAOYSA-N 0.000 claims description 2
HZYXFRGVBOPPNZ-UHFFFAOYSA-N UNPD88870 Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)=CCC(CC)C(C)C)C1(C)CC2 HZYXFRGVBOPPNZ-UHFFFAOYSA-N 0.000 claims description 2
GQVBSOVDJKCLGM-VCZQVZGSSA-N [(2R)-2,3-di(docosa-2,4,6,8,10,12-hexaenoyloxy)propyl] 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CCCCCCCCCC=CC=CC=CC=CC=CC=CC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)C=CC=CC=CC=CC=CC=CCCCCCCCCC GQVBSOVDJKCLGM-VCZQVZGSSA-N 0.000 claims description 2
UKMFPLRYBOOPKL-VHONOUADSA-N [(2R)-3-hexadecoxy-2-[(Z)-octadec-9-enoxy]propyl] 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CCCCCCCCCCCCCCCCOC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OCCCCCCCC\C=C/CCCCCCCC UKMFPLRYBOOPKL-VHONOUADSA-N 0.000 claims description 2
LGJMUZUPVCAVPU-UHFFFAOYSA-N beta-Sitostanol Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(C)CCC(CC)C(C)C)C1(C)CC2 LGJMUZUPVCAVPU-UHFFFAOYSA-N 0.000 claims description 2
SGNBVLSWZMBQTH-PODYLUTMSA-N campesterol 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)CC[C@@H](C)C(C)C)[C@@]1(C)CC2 SGNBVLSWZMBQTH-PODYLUTMSA-N 0.000 claims description 2
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OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 claims description 2
125000005265 dialkylamine group Chemical class 0.000 claims description 2
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VLBPIWYTPAXCFJ-XMMPIXPASA-N lysophosphatidylcholine O-16:0/0:0 Chemical compound CCCCCCCCCCCCCCCCOC[C@@H](O)COP([O-])(=O)OCC[N+](C)(C)C VLBPIWYTPAXCFJ-XMMPIXPASA-N 0.000 claims description 2
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