Lipids for lipid nanoparticle delivery of active agents
Inventors
Assignees
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Publication Number
US-12583816-B2
Publication Date
2026-03-24
Expiration Date
Abstract
Compounds are provided having the following structure: (I) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein G1, R1, R2, L, and n 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 disclosure relates to cationic/amino lipid compounds having structure (I), or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof. In structure (I), G1 is either —N(R3)R4 or —OR5, R1 and R2 are selected from specified branched or unbranched, saturated or unsaturated, optionally substituted carbon-chain ranges, and R3 and R4 may together with the nitrogen form a heterocyclyl.
The structural definition further includes R5 as H or optionally substituted C1-C6 alkyl, L as —C(=O)—, C6-C12 alkylene, C6-C12 alkenylene, or C2-C6 alkynylene, and n as an integer from 1 to 12. The disclosed embodiments include multiple structural variants of the cationic lipid compound of general structure (I) within this framework.
The compounds are described for incorporation into lipid nanoparticle formulations together with lipid formulation components such as neutral lipids, cholesterol or steroids, and pegylated lipids. The disclosed lipid and lipid nanoparticle approach is used for delivering therapeutic agents to cells in vitro and in vivo, particularly nucleic acids.
Claims Coverage
The independent claim coverage centers on the compound defined by structure (I) and a lipid nanoparticle embodiment including the compound together with a therapeutic agent. The inventive features are the defined substituent pattern in structure (I) and the lipid nanoparticle composition.
Defined structure (I) with variable substituent pattern
A compound having structure (I) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein G1 is either —N(R3)R4 or —OR5; R1 is branched, saturated or unsaturated, optionally substituted C12-C36 alkyl; R2 is branched or unbranched, saturated or unsaturated, optionally substituted C12-C36 alkyl when L is —C(=O)—, or optionally substituted C4-C36 alkyl when L is C6-C12 alkylene, C6-C12 alkenylene, or C2-C6 alkynylene; R3 and R4 are each independently branched or unbranched, saturated or unsaturated, optionally substituted C1-C6 alkyl, or together with the nitrogen form a heterocyclyl; R5 is H or optionally substituted C1-C6 alkyl; L is selected from —C(=O)—, C6-C12 alkylene, C6-C12 alkenylene, or C2-C6 alkynylene; and n is an integer from 1 to 12.
Lipid nanoparticle including the compound and a therapeutic agent
A lipid nanoparticle comprising the compound of claim 1 together with a therapeutic agent.
The claim coverage centers on a compound defined by structure (I) with constrained substituent and linker options and a lipid nanoparticle embodiment that includes the compound and a therapeutic agent.
Stated Advantages
Improved serum protection.
Improved intracellular delivery.
Increased activity.
Improved in vivo tolerability.
An increased therapeutic index.
Documented Applications
Delivering therapeutic agents to cells in vitro and in vivo, particularly delivering nucleic acids including mRNA, antisense, siRNA, plasmid DNA, and miRNA inhibitors/antagomirs.
In vivo luciferase mRNA delivery using lipid nanoparticle formulations of cationic lipids of structure (I), with luciferase expression readouts reported for mouse liver/spleen.
pKa determination for cationic lipids of structure (I) using a TNS-based assay with reported pKa values.
Comparison of luciferase expression across multiple cationic lipids of structure (I) under specified luciferase mRNA dosing, reported in tables.
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