Cationic lipids for use in lipid nanoparticles
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Assignees
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Publication Number
US-12410121-B2
Publication Date
2025-09-09
Expiration Date
Abstract
Compounds are provided having the following structure: or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein a, b, c, d, G1, G2, L1, L2, R1a, R1b, R2a, R2b, R3a, R3b, R4a, R4b, R5, R6, R7, R8 and X are as defined herein. Use of the compounds as a component of lipid nanoparticle formulations for delivery of a therapeutic agent, nanoparticles comprising the compounds and methods for their use and preparation are also provided.
Core Innovation
The disclosure describes novel cationic (amino) lipid compounds having a structure of Formula (I), including pharmaceutically acceptable salt, tautomer, and stereoisomer forms, with defined substituent constraints and alternative substructures (IA) and (IB). G1 and G2 are each independently C1-C6 alkylene; L1 and L2 are each independently —O(C=O)— or —(C=O)O—; X is —(C=O)— or a direct bond; and a, b, c and d are each independently an integer from 1 to 24.
The disclosure further relates to lipid nanoparticle formulations comprising a compound having a structure of Formula (I) together with a therapeutic agent. The lipid nanoparticle is described with neutral lipids, steroids, and polymer-conjugated lipids, including PEG-DAG, PEG-PE, PEG-S-DAG, and PEG-cer, and with a compound structure (II) featuring R8 and R9 with alkyl chain lengths and a mean w value spanning about 30–60.
The document also presents example compounds of Formula (I), associated synthetic sequences for intermediates and final products, and reported characterization data. It further includes pKa determination by TNS fluorescence and in vivo luciferase expression following administration of luciferase mRNA in mice, together with formulation ratios and performance data presented in examples.
Claims Coverage
The document contains two independent claims. Independent claim 1 covers a Formula (I) compound with constrained substituent classes and integer indices a, b, c and d, including pharmaceutically acceptable salts, tautomers, and stereoisomers. Independent claim 2 covers a lipid nanoparticle comprising the Formula (I) compound together with a therapeutic agent.
Formula (I) compound structure
A compound having a structure of Formula (I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein G1 and G2 are each independently C1-C6 alkylene; L1 and L2 are each independently —O(C=O)— or —(C=O)O—; R1a/R1b, R2a/R2b, R3a/R3b, and R4a/R4b are each independently H or C1-C12 alkyl; R5 and R6 are each independently H or methyl; R7 is —O(C=O)R10, —(C=O)OR10, —NR9(C=O)R10 or —(C=O)NR9R10; R8 is OH, —N(R11)(C=O)R12, —(C=O)NR11R12, —NR11R12, —(C=O)OR12 or —O(C=O)R12; R9 is H or C1-C15 alkyl; R10 is C1-C15 alkyl; R11 is H or C1-C6 alkyl; R12 is C1-C6 alkyl; X is —(C=O)— or a direct bond; and a, b, c and d are each independently an integer from 1 to 24.
Lipid nanoparticle comprising the Formula (I) compound and a therapeutic agent
A lipid nanoparticle comprising (i) a compound having a structure Formula (I) (or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof) with the same defined substituent classes as recited and a, b, c and d each independently an integer from 1 to 24, and (ii) a therapeutic agent.
The core inventive scope is a Formula (I) cationic (amino) lipid compound with extensive substituent constraints and, separately, a lipid nanoparticle that includes that Formula (I) compound together with a therapeutic agent.
Stated Advantages
The LNPs can shield nucleic acids from serum degradation.
The LNPs improve in vivo and in vitro activity and tolerability.
Increasing therapeutic index.
Documented Applications
Intracellular delivery of therapeutic agents, especially nucleic acids (mRNA, antisense oligonucleotides, siRNA, miRNA, miRNA inhibitors, plasmids), and related nucleic-acid formats such as DNAzymes and ribozymes.
Treatment of a disease by administering the lipid nanoparticle to a patient.
Vaccination of a patient against a viral pathogen by administering a lipid nanoparticle containing a therapeutic agent that is either a viral antigen or mRNA encoding a viral antigen.
Vaccination of a patient against a viral pathogen by administering a pharmaceutical composition where the therapeutic agent is either a viral antigen or an mRNA encoding a viral antigen.
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