Lipids for use in lipid nanoparticle formulations
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Publication Number
US-12065396-B2
Publication Date
2024-08-20
Expiration Date
Abstract
Compounds are provided having the following structure (I) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R1a, R1b, R2a, R2b, R3a, R3b, R4a, R4b, R5, R6, R7, R8, L1, L2, G1, G2, G3, a, b, c and d 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 patent provides a Formula I family of amphiphilic lipid compounds, including pharmaceutically acceptable salts, tautomers, and stereoisomers. The compounds are defined by linker and heteroatom positions L, L1, and L2, structural groups G1, G2, and G3, and substituent variables Ra, R1a/R1b, R2a/R2b, R3a/R3b, R4a/R4b, R5, R6, R7, and R8, together with integers a-d and x.
The structural scope includes oxygen-containing, thio-containing, and nitrogen-containing choices for L1 and L2, selected choices for G1 and G3, and direct bond options. The variable substituents include optional carbon-carbon double bond formation when paired substituents are taken together with adjacent carbon atoms, and representative embodiments narrow these variables to defined selections such as G3 as C2-C5 alkylene, R8 as OH, and R7 as C1-C2 alkyl.
The patent also describes representative compound structures and multiple synthetic examples for related compounds, with analytical characterization and measured pKa values. It further states that the compounds are used as components of lipid nanoparticles for delivering therapeutic agents, especially nucleic acids, and that pharmaceutical compositions and lipid nanoparticle compositions are disclosed.
Claims Coverage
The consolidated claim coverage centers on a Formula I compound, including pharmaceutically acceptable salts, tautomers, and stereoisomers, defined by multiple linker, group, substituent, and integer parameters. Across the inputs, the independent claim set emphasizes 6 inventive features.
Formula I compound with defined linker and heteroatom positions
A compound having a structure of Formula I, or a pharmaceutically acceptable salt, tautomer or stereoisomer, with L1 and L2 independently selected from the listed heteroatom-containing moieties.
G1-G3 structural selection with defined alkylene and direct bond
G1 is selected from C1-C2 alkylene, carbonyl-containing linkers, a direct bond, and related heteroatom-containing groups; G2 is a direct bond; and G3 is C1-C6 alkylene, with representative narrowing to C2-C5 alkylene in one input.
Substituent-variable Ra and R1a/R1b with optional carbon-carbon double bond formation
Ra is independently H or C1-C12 alkyl; R1a and R1b are independently H or C1-C12 alkyl, with an alternative in which adjacent R1b groups form a carbon-carbon double bond with the carbon atoms to which they are bound.
Substituent-variable R2a/R2b and R3a/R3b with optional carbon-carbon double bond formation
R2a and R2b, and R3a and R3b, are independently H or C1-C12 alkyl, with an alternative in which adjacent R2b or R3b groups form a carbon-carbon double bond with the carbon atoms to which they are bound.
Substituent-variable R4a/R4b with fixed R5/R6 and defined R7/R8
R4a and R4b are independently H or C1-C12 alkyl, with an alternative carbon-carbon double bond option; R5 and R6 are each H or methyl, with one input specifying methyl; R7 is C1-C2 alkyl; and R8 is OH.
Integer indices a-d and index x for structural scope
a and d are each independently an integer from 1 to 24, b and c are each independently an integer from 2 to 12, and x is 0, 1, or 2.
The claim coverage is defined by the Formula I architecture, the L/L1/L2 and G1-G3 selections, multi-position substituent variability with optional carbon-carbon double bond formation, and constrained terminal substituents and integer ranges that delimit the compound family.
Stated Advantages
Improved nucleic-acid activity
Improved in vivo tolerability
Increased therapeutic index
Serum stability
Encapsulation/protection from degradation
Documented Applications
Lipid nanoparticles incorporating the claimed lipid compounds for delivering therapeutic agents, especially nucleic acids including mRNA, antisense oligonucleotides, siRNA, miRNA inhibitors, and plasmid DNA.
Systemic delivery and local delivery using lipid nanoparticle compositions comprising the lipid compounds with neutral/charged lipids, steroids including cholesterol, and polymer-conjugated lipids such as pegylated lipids.
Use of nucleic acid payloads to support protein expression and gene silencing, including delivery of dicer substrate RNA and complementary RNA.
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