Lipids and lipid nanoparticle formulations for delivery of nucleic acids
Inventors
Du, Xinyao • Ansell, Steven M.
Assignees
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Publication Number
US-10221127-B2
Publication Date
2019-03-05
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, 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 invention relates to a compound having a structure of Formula IA or IB, including pharmaceutically acceptable salts, tautomers, prodrugs, stereoisomers and related forms. The compounds are defined by specific structural elements, including L1 and L2 and the group G3 being C1-C6 alkylene, together with extensive constraints on multiple substituent positions R1a/R1b, R2a/R2b, R3a/R3b, R4a/R4b, R5/R6, R7, and R8/R9. The parameterization further includes integers a, b, c, d and x, which specify ranges and structural options within the defined structure.
The disclosure further provides lipid nanoparticle compositions that formulate the Formula (I) compounds with lipid excipients. The excipient sets include neutral lipids, cholesterol or steroid components, and pegylated lipids, where the pegylated lipid structure is provided as Formula II with variables R10/R11 and z that define the alkyl chain and mean PEG parameter. The compositions describe molar ratios for compound-to-neutral lipid, compound-to-cholesterol, and compound-to-pegylated lipid, and embodiments include therapeutic agents comprising nucleic acid.
The document also describes cationic lipid compounds and lipid nanoparticles containing a cationic lipid together with DSPC, cholesterol, and a PEG-lipid, with PEG-DMG or PEG-DMA specified. The disclosed lipid nanoparticles are associated with nucleic-acid delivery effectiveness, including luciferase mRNA delivery evaluation and pKa determination using a TNS fluorescence assay. The compounds are presented as structurally related embodiments within the same inventive concept.
Claims Coverage
The provided material includes one independent claim directed to a compound by Formula IA or IB with extensive structural constraints, and the consolidated claim coverage also includes the explicitly described lipid nanoparticle composition features. In total, the claim coverage captures one independent formula claim and the composition-related structural features explicitly described in the inputs.
Formula IA or IB compound with constrained substituent pattern
A compound having a structure of Formula IA or IB, or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof, wherein L1 and L2 are each independently selected from specified linkage patterns, G3 is C1-C6 alkylene, and multiple substituent positions follow defined H or C1-C12 alkyl choices with optional carbon-carbon double-bond-forming pairing rules. The constraints further include R5 and R6 being H or methyl, R7 being C6-C16 alkyl, R8 and R9 being C1-C12 alkyl or forming a 5, 6 or 7-membered heterocyclic ring together with nitrogen, and a, b, c and d each independently being integers from 1 to 24 with x being 0, 1 or 2.
Lipid nanoparticle compositions containing the compound of Formula (I)
Lipid nanoparticle compositions contain the compound of Formula (I) together with neutral lipids, optional cholesterol or steroid components, and pegylated lipids, including PEG-DMG or PEG-DMA. The compositions also describe molar ratios for compound-to-neutral lipid, compound-to-cholesterol, and compound-to-pegylated lipid, and include therapeutic agents comprising nucleic acid.
The consolidated claim coverage centers on the Formula IA/IB compound definition with its substitution constraints, together with the explicitly described lipid nanoparticle composition features, neutral lipids, cholesterol, pegylated lipids, and molar-ratio ranges.
Stated Advantages
A preferred pKa range of approximately 5 to 7 is correlated with nucleic-acid delivery effectiveness.
Shielding nucleic acids from serum degradation.
Improving intracellular delivery.
Improving tolerability and therapeutic index.
Documented Applications
Lipid nanoparticle formulations for delivering therapeutic nucleic acids to cells, including mRNA, antisense/siRNA, plasmid DNA, and miRNA inhibitors.
In vivo evaluation of luciferase messenger RNA delivered using lipid nanoparticles.
LNP formulations of cationic lipids are assessed for nucleic-acid delivery effectiveness correlation via pKa determination using a TNS fluorescence assay.
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