Lipids for lipid nanoparticle delivery of active agents
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Publication Number
US-11453639-B2
Publication Date
2022-09-27
Expiration Date
Abstract
Compounds are provided having the following structure: or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R1, R2, R3, R4, R5, L1, L2, L3, G1, G2, and G3 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 relates to a compound having a defined chemical structure (I), including pharmaceutically acceptable salts, tautomers, and stereoisomers. The structure (I) is defined by substituent groups R1–R5, linker groups L1–L3, linkage groups G1–G3, and an integer n greater than 0. The substituent groups include optionally substituted alkyl and optionally substituted alkenyl definitions for R1, optionally substituted alkyl definitions for R2 and R3, and R4 and R5 may be optionally substituted alkyl groups or may join with the nitrogen atom to form an optionally substituted heterocyclyl ring or an optionally substituted heteroaryl ring.
The linkage groups G1–G3 and alkylene linker groups L1–L3 are constrained within the overall structure (I). G1 is defined as a direct bond, —(CH2)nO(C═O)O—, —(CH2)n(C═O)O—, or —(C═O)O—, and G2 and G3 are each independently —(C═O)O— or —O(C═O)O—. The integer n is greater than 0 and applies within the defined G1 options, limiting the allowable structural linkage patterns within the compound (I).
The disclosed compositions use the defined compound in lipid nanoparticle formulations for delivering therapeutic agents, including nucleic acids. The lipid nanoparticle formulation is used for intracellular delivery, including nucleic acid payloads such as mRNA, antisense oligonucleotides, siRNA, miRNA inhibitors, and plasmid DNA, including nucleic acids that are encapsulated or otherwise associated with the lipid nanoparticle.
Claims Coverage
The disclosed independent claim covers a specific family of ionizable cationic amino-lipid compounds defined by structure (I) with pharmaceutically acceptable salts, tautomers, and stereoisomers, featuring constrained substituents (R1–R5), linkers (L1–L3), and linkage patterns (G1–G3) with integer n>0. Dependent claims narrow substituent and linkage options and extend the compounds into compositions and lipid nanoparticle formulations with specified therapeutic-agent modalities.
Structure (I) ionizable amino lipid compounds with pharmaceutically acceptable forms
A compound having structure (I), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R1 is optionally substituted C1–C24 alkyl or optionally substituted C2–C24 alkenyl; R2 and R3 are each independently optionally substituted C1–C36 alkyl; and R4 and R5 are each independently optionally substituted C1–C6 alkyl or R4 and R5 join with the nitrogen atom to form an optionally substituted heterocyclyl ring or an optionally substituted heteroaryl ring, with L1, L2, and L3 each independently optionally substituted C1–C18 alkylene; G1 is a direct bond or one of specified G1 linkage patterns including —(CH2)nO(C═O)O—, —(CH2)n(C═O)O—, or —(C═O)O—; G2 and G3 are each independently —(C═O)O— or —O(C═O)O—; and n is an integer greater than 0.
Constrained R1 alkyl/alkenyl carbon-length options
R1 can be either optionally substituted C6–C18 alkyl or optionally substituted C14–C18 alkenyl groups.
Constrained G1 linkage via n threshold
G1 is defined as —(CH2)n(C═O)O— with n greater than 1.
R4 and R5 form an optionally substituted heterocyclyl ring with attached nitrogen
R4 and R5, together with the nitrogen atom to which they are attached, together form an optionally substituted heterocyclyl ring.
Composition comprising the defined compound and a therapeutic agent
A composition that includes the compound together with a therapeutic agent.
Lipid nanoparticle comprising messenger RNA
The lipid nanoparticle further comprises messenger RNA.
Overall, the claims coverage focuses on a structured compound family defined by the structure (I) framework (substituents, linkers, and linkage groups with n>0), then narrows key options for substituent length and G1 linkage, and extends the compounds into pharmaceutical compositions and lipid nanoparticle formulations, including lipid nanoparticles comprising messenger RNA.
Stated Advantages
Improved activity of nucleic acid delivery.
Increased in vivo tolerability.
Enhanced therapeutic index.
Serum protection and decreased nuclease degradation.
Enabling intracellular delivery.
Documented Applications
Lipid nanoparticle formulations delivering therapeutic agents to cells in vitro and in vivo.
Delivery of nucleic acids including mRNA, antisense oligonucleotides, siRNA, miRNA inhibitors (antagomirs/antimirs), and plasmid DNA.
Intracellular delivery of nucleic acids associated with the lipid nanoparticle (encapsulated/associated nucleic acids).
Systemic delivery and local delivery as defined in the document.
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