Lipids for use in lipid nanoparticle formulations
Inventors
Assignees
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Publication Number
US-11542225-B2
Publication Date
2023-01-03
Expiration Date
Abstract
Compounds are provided having the following structure (I) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein G1, G1′, G2, G2′, G3, L1, L1′, L2, L2′, X, X′, Y and Y′ 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 a compound having structure (I), or a pharmaceutically acceptable salt or stereoisomer thereof, in which X and X′ are each independently N or CR and Y and Y′ are each independently absent, O(C•O)O, (C•O)OO, or NR, with conditional rules for the presence or absence of Y and Y′ depending on whether X and X′ are N or CR. The scaffold is further defined by permitted linkage classes for L1 and L1′ and L2 and L2′, and by G1, G1′, G2, and G2′ each independently being C4–C8 alkylene or C2–C8 alkenylene, while G3 is C2–C24 heteroalkylene or C2–C24 heteroalkenylene.
The structure (I) further defines substituent constraints, including R being H or C1–C12 alkyl, and R1 and R2 each independently being branched C6–C24 alkyl or branched C6–C24 alkenyl, with z being 0, 1, or 2. Additional embodiments describe Ra, Rb, Rd, Re, and Rf as independently H, C1–C12 alkyl, or C2–C12 alkenyl, with substitution being independently substituted or unsubstituted unless otherwise specified.
The disclosed embodiments describe lipid nanoparticles comprising one or more structure (I) cationic lipid compounds together with a therapeutic agent, including nucleic acids such as antisense or messenger RNA, and excipients including neutral lipids, steroids or sterols, and pegylated lipids. The document further describes pharmaceutical compositions comprising one or more of the lipid(s) with a therapeutic agent, and LNPs containing the lipid(s).
Claims Coverage
The independent claims cover a compound having structure (I) with detailed structural substitution rules and a lipid nanoparticle comprising the compound. Across the independent claim set, the main inventive features are the constrained scaffold of the lipid compound and the LNP formulation that includes that compound.
Structure (I) compound scaffold with conditional X/Y substituent rules
A compound having structure (I) or a pharmaceutically acceptable salt or stereoisomer, wherein X and X′ are each independently N or CR; Y and Y′ are each independently absent, O(C•O)O, (C•O)OO, or NR, subject to conditions that Y is absent when X is N, Y′ is absent when X′ is N, and the allowed forms for Y and Y′ depend on whether X and X′ are N or CR.
Permitted L1/L2 linkage classes and G-chain constraints for structure (I)
In structure (I), L1 and L1′ are each independently selected from O(C•O)R1, (C•O)OR1, C(C•O)R1, OR1, S(O)zR1, SSR1, C(C•O)SR1, SC(C•O)R1, NRaC(C•O)R1, C(C•O)NRbRc, NRaC(C•O)NRbRc, OC(C•O)NRbRc, or NRaC(C•O)OR1, and L2 and L2′ are each independently selected from corresponding linkage options to R2; G1, G1′, G2, and G2′ are each independently C4–C8 alkylene or C2–C8 alkenylene; and G3 is C2–C24 heteroalkylene or C2–C24 heteroalkenylene.
Substituent-size and branching constraints including R, R1/R2 and z
The structure defines R as H or C1–C12 alkyl; R1 and R2 as branched C6–C24 alkyl or branched C6–C24 alkenyl; z as 0, 1, or 2; and, in one embodiment, Ra, Rb, Rd, and Re as independently H, C1–C12 alkyl, or C2–C12 alkenyl, with Re and Rf independently C1–C12 alkyl or C2–C12 alkenyl.
Lipid nanoparticle containing the compound
A lipid nanoparticle that includes the compound recited in structure (I).
The claim coverage centers on a structurally constrained lipid compound scaffold defined by conditional X/Y substitution, permitted linkage classes, and constrained chain and substituent ranges, and extends to a lipid nanoparticle formulation that includes the recited compound.
Stated Advantages
Serum shielding/protection of nucleic acids.
Improved in vivo activity.
Improved tolerability.
Increased therapeutic index.
Documented Applications
Use as components in lipid nanoparticle (LNP) formulations for delivering therapeutic agents in vitro and in vivo.
Delivery to a patient using LNPs containing the disclosed lipid compounds and a therapeutic agent.
Nucleic acid delivery applications including mRNA, antisense oligonucleotides, miRNA inhibitors, siRNA, plasmids, and dsRNA contaminants.
Delivery of nucleic acids, including luciferase mRNA delivery in rodents, with luciferase assay readouts and relative luciferase activity values reported for formulated lipids.
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