Lipids and lipid nanoparticle formulations for delivery of nucleic acids
Inventors
Du, Xinyao • Ansell, Steven M.
Assignees
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Publication Number
US-11168051-B2
Publication Date
2021-11-09
Expiration Date
Abstract
Compounds are provided having the following structure: or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R1a, R1b, R2a, R2b, R3a, R3b, R4a, R4b, R5, R6, R7, R8, R9, L1, L2, G1, G2, G3, a, b, c and d are as defined herein. Use of the compounds as a component of lipid nanoparticle formulations for delivery of a therapeutic agent, compositions comprising the compounds and methods for their use and preparation are also provided.
Core Innovation
The invention provides compounds according to Formula (I), including pharmaceutically acceptable salts, tautomers, stereoisomers, and prodrugs. The disclosed cationic lipid compounds include multiple variable substituents and alternative sub-structures, and embodiments describe combinatorial assembly with stability considerations. The disclosure also provides a specific pegylated lipid structure (II) used in the described formulations.
The invention further provides lipid nanoparticles comprising a nucleic acid and a compound having one of the specified Formula (I) structures, with optional excipients including neutral lipids, steroids, and pegylated lipids. The lipid excipient mixture includes DSPC, DPPC, DMPC, DOPC, POPC, DOPE, SM, cholesterol, and PEGylated lipids such as PEG-DMG, PEG-PE, PEG-S-DMG, PEG-cer, and PEG dialkoxypropylcarbamate.
The disclosed cationic lipid compounds are intended to form lipid nanoparticles configured for intracellular delivery of therapeutic nucleic acids. The payloads include mRNA, miRNA inhibitors including antagomirs and antimirs, siRNA, antisense oligonucleotides, plasmid DNA, and therapeutic agents exemplified as antisense, plasmid DNA, and messenger RNA. The document also links pKa to lipid delivery effectiveness and states a preferred pKa range of approximately 5–7.
Claims Coverage
The consolidated claims coverage includes two independent claims, each grounded on structure-defined Formula (I) compounds, with one claim directed to the compound itself and another directed to lipid nanoparticles comprising nucleic acid together with the structure-defined compound. The independent claims extend to salts and stereoisomers, and the broader disclosure also includes tautomers and prodrugs.
Structure-defined cationic lipid compound
A compound having one of the following structures, or a salt or stereoisomer thereof.
Nucleic-acid lipid nanoparticle with structure-defined cationic lipid
A lipid nanoparticle comprising a nucleic acid and a compound having one of the following structures, or a salt or stereoisomer thereof.
Across the independent claims, coverage is centered on a compound defined by specific chemical structures with salt or stereoisomer embodiments, and a lipid nanoparticle that includes a nucleic acid together with the structure-defined compound, also including salt or stereoisomer embodiments.
Stated Advantages
Increased nucleic-acid activity.
Improved in vivo tolerability.
Enhanced therapeutic index.
Protection of nucleic acids from serum degradation and clearance.
Suitable systemic delivery.
Documented Applications
Lipid nanoparticle delivery evaluation for luciferase mRNA (FLuc mRNA) with a liver/luciferase readout in C57BL/6 mice.
Administration of nucleic-acid payloads, including antisense, plasmid DNA, and messenger RNA, using LNP compositions by various routes.
Intracellular delivery of therapeutic nucleic acids using lipid nanoparticles, including in vitro and in vivo contexts.
Systemic delivery of therapeutic nucleic acids using lipid nanoparticles.
Pharmaceutical compositions comprising Formula (I) compounds combined with lipid excipients and therapeutic agents in lipid-excipient mixtures.
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