Lipids and lipid nanoparticle formulations for delivery of nucleic acids
Inventors
Assignees
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Publication Number
US-10106490-B2
Publication Date
2018-10-23
Expiration Date
Abstract
Compounds are provided having the following structure: or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R1a, R1b, R2a, R2b, R3a, R3b, R4a, R4b, R5, R6, R7, R8, R9, L1, L2, a, b, c, d and e 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 structure, or a pharmaceutically acceptable salt thereof, in which X is OH or Cl. The structure further specifies each R as independently a saturated or unsaturated C1–C24 alkyl or saturated or unsaturated cycloalkyl, with m being 0 or 1 and each n being independently an integer from 5 to 24.
The disclosure further specifies example lipid-like cationic compounds with long hydrophobic chains and diamine/amide motifs, and defines variable structural options including linkers and substituents. The disclosed structural family includes variability in the hydrophobic substituent composition, including ring-containing versus branched alkyl portions, while maintaining ester functional groups and the defined parameter framework.
Lipid nanoparticles formed from the disclosed cationic lipid compounds are described for delivering nucleic acids, including mRNA, antisense oligos, miRNA inhibitors, siRNA, plasmids, and plasmid DNA. The disclosed compositions combine the compound with a cationic lipid, neutral lipids including DSPC, DPPC, DMPC, DOPC, POPC, DOPE, and SM, cholesterol, and a pegylated lipid, in the context of lipid nanoparticles.
Claims Coverage
The provided claim coverage centers on one independent structural claim directed to a compound defined by X, R, m, and n, with dependent claims narrowing those variables. The inventive features are the parameter-defined scaffold and the specific narrowing of X, R, m, and n.
Defined compound structure with X, R, m, and n variables
A compound having a defined structure, or a pharmaceutically acceptable salt thereof, wherein X is OH or Cl, each R is independently a saturated or unsaturated C1–C24 alkyl or saturated or unsaturated cycloalkyl, m is 0 or 1, and each n is independently an integer from 5 to 24.
Parameter refinement setting m to 1
The compound is defined such that the parameter m is 1.
Hydrophobic R substituent constrained to saturated C16–C24 alkyl
The compound is defined such that each R is independently a saturated C16–C24 alkyl group.
X fixed to hydroxyl
The compound is defined such that X is OH.
n fixed to 5
The compound is defined such that each n is equal to 5.
Overall, the claim coverage is anchored by a Markush-style compound definition using X, R, m, and n, with dependent claims fixing X to OH, m to 1, and n to 5, and constraining R to saturated C16–C24 alkyl.
Stated Advantages
Serum/nuclease protection.
Improved intracellular delivery.
Systemic delivery.
Favorable size range.
Documented Applications
Forming lipid nanoparticles with nucleic acids including mRNA, antisense oligonucleotides, miRNA inhibitors/antagomirs, siRNA, plasmid DNA, and plasmids.
Therapeutic agent contexts, including nucleic acid, antisense oligonucleotide, messenger RNA, and plasmid DNA.
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