Lipids and lipid nanoparticle formulations for delivery of nucleic acids
Inventors
Ansell, Steven M. • Du, Xinyao
Assignees
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Publication Number
US-11040112-B2
Publication Date
2021-06-22
Expiration Date
Abstract
Compounds are provided having the following structure: or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R1, R2, R3, L1, L2, 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 novel cationic (amino) lipid architecture used to formulate lipid nanoparticles for intracellular delivery of therapeutic nucleic acids. The lipid compounds are defined by a general structure (I) and are covered as compounds including pharmaceutically acceptable salts, stereoisomers, and related forms. The architecture includes specific structural elements such as linkers (L1/L2), spacer groups (G1/G2/G3), and substituents (R1/R2/R3), together with expandable structural options.
The structural definitions specify allowable ranges and substituent forms for multiple groups within the cationic (amino) lipid architecture, including ring-containing variants (structures IA–IJ) that incorporate a cycloalkyl/cycloalkylene ring A. Additional definitional parameters include chain-length/range parameters (n, y, z) and multiple functional options for substituent groups, including ester, amide, and heteroatom-containing functional groups. The invention further addresses the use of ionizable cationic (pH-dependent charge) behavior as part of the lipid design.
The disclosed lipids are combined with neutral lipids, charged lipids, steroids/cholesterol, and polymer or PEG-conjugated lipids to form nucleic-acid-loaded lipid nanoparticles. The formulation includes the compound of structure (I) and provides lipid nanoparticle embodiments with therapeutic nucleic acids, together with neutral lipids, cholesterol, and pegylated lipids.
Claims Coverage
The provided claim set includes one independent claim directed to the compound and dependent coverage that refines substituent selections and extends to lipid nanoparticle embodiments with therapeutic nucleic acids. Across the provided material, the inventive features center on the defined structure (I), constrained substituents, and formulation embodiments.
Defined compound structure with constrained substituents and functional-group options
A compound having the following structure (IF), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein G1 and G2 are each independently unsubstituted C4–C12 alkylene or C4–C12 alkenylene; G3 is C3–C6 alkylene; R1 and R2 are each independently branched C6–C24 alkyl; R3 is H, OR5, CN, —C(=O)OR4, —OC(=O)R4, or —NR5C(=O)R4; R4 is C1–C12 alkyl; and R5 is H or C1–C6 alkyl.
Lipid nanoparticle combining the compound with a therapeutic nucleic acid
A lipid nanoparticle that includes the compound of claim 1 and a therapeutic nucleic-acid agent.
Claim coverage centers on a compound defined by strict structural constraints for G1, G2, G3, branched C6–C24 alkyl substituents R1 and R2, and a limited set of allowed R3 functional-group forms, together with pharmaceutically acceptable salts and stereoisomers. The coverage also extends to lipid nanoparticle embodiments that combine the compound with therapeutic nucleic-acid agents.
Stated Advantages
Protects RNA in serum.
Improves tolerability.
Improves therapeutic index.
Documented Applications
Formulation of nucleic-acid-loaded lipid nanoparticles for intracellular delivery of therapeutic nucleic acids including mRNA, antisense oligonucleotides, siRNA/miRNA inhibitors/antagomirs, and plasmid DNA.
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