Carbonyl lipids and lipid nanoparticle formulations for delivery of nucleic acids
Inventors
Du, Xinyao • Ansell, Steven M.
Assignees
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Publication Number
US-11820728-B2
Publication Date
2023-11-21
Expiration Date
Abstract
Compounds are provided having one of the following structures (I) or (II): or (I) (II) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R3a, R3b, L1, L2, G1a, G1b, G2a, G2b 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 compounds having structure (I), or pharmaceutically acceptable salt or stereoisomer thereof, in which defined linker groups L1 and L2, group substituents G1a, G2a, G3, and multiple R-group substituent definitions are specified by structural rules and substitution constraints. The structure (I) includes carbonyl-containing linker options, heteroatom-containing moieties such as S(O) and S—SR, and variable alkylene, alkenylene, cycloalkylene, and cycloalkenylene segments, with additional constraints on branched C6–C24 alkyl or branched C6–C24 alkenyl for R1 and R2.
The disclosed embodiments include representative lipid nanoparticles comprising compounds of structures (I) or (II) together with a therapeutic agent, including nucleic acids such as messenger RNA or antisense RNA, and excipients including phospholipids, cholesterol, and pegylated lipids. A pegylated lipid component is defined by a general structure (III) with R8 and R9 groups and a mean w value, and the formulations include lipid excipients selected from DSPC, DPPC, DMPC, DOPC, POPC, DOPE, and SM.
The disclosure provides multiple chemical structure embodiments for a core compound framework designated structure (IA) and subsequent structures (IIB), (IIC), (IID), and (IIE). The embodiments specify explicit range and definition constraints for linkage parameters, allowed linker carbonyl and alkoxy patterns, and representative structures for structure (II), with examples listed in Table 2 as representative compounds II-1 through at least II-18.
Claims Coverage
The claim coverage centers on defined compound scaffolds and related lipid nanoparticle formulations. Across the independent claim content, the inventive features focus on the structure (I) compound scaffold with linker and substituent rules, and on a lipid nanoparticle that includes the compound.
Structure (I) compound scaffold with defined linker and substituent rules
A compound having structure (I), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein L1 and L2 are selected from defined linker patterns including carbonyl-, heteroatom-, thio-, and amino/carbonyl-linked options; G1a and G2a are each independently C2–C12 alkylene or C2–C12 alkenylene; G3 is C1–C24 alkylene, C2–C24 alkenylene, C3–C8 cycloalkylene, or C3–C8 cycloalkenylene; Ra, Rb, Rd, and Re are each independently H, C1–C12 alkyl, or C2–C12 alkenyl; Rc and Rf are each independently C1–C12 alkyl or C2–C12 alkenyl; R1 and R2 are each independently branched C6–C24 alkyl or branched C6–C24 alkenyl; R3a is —C(O)N(R4a)R5a; R4a is C1–C12 alkyl; R5a is H, C1–C8 alkyl, or C2–C8 alkenyl; and x is 0, 1, or 2.
Lipid nanoparticle containing the structure (I) compound
A lipid nanoparticle that includes the compound having structure (I) as defined.
The claim coverage is directed to a precisely defined compound scaffold with extensive linker and substituent constraints, together with formulation coverage where a lipid nanoparticle includes that structure (I) compound.
Stated Advantages
Improved in vivo activity.
Improved tolerability.
Enhanced therapeutic index.
Documented Applications
Use as a component to form lipid nanoparticles for delivering therapeutic nucleic acids, including mRNA, antisense RNA, plasmids, and miRNA/miRNA inhibitors.
Pharmaceutical compositions containing a therapeutic agent with lipid nanoparticles, where the LNPs encapsulate or associate nucleic acids.
Administration of a therapeutic agent using lipid nanoparticles with encapsulated/associated nucleic acids.
In vivo delivery evaluation using lipid nanoparticles delivering luciferase messenger RNA with measurement of liver luciferase expression.
Therapeutic agent delivery using lipid nanoparticles comprising nucleic acids, including messenger RNA and antisense RNA.
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