Lipid nanoparticle formulations
Inventors
Hope, Michael J. • Mui, Barbara • Lin, Paulo Jia Ching • Barbosa, Christopher J. • Madden, Thomas D. • Ansell, Steven M. • Du, Xinyao
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11712481-B2
Publication Date
2023-08-01
Expiration Date
Abstract
Improved formulations of lipid nanoparticles are provided. Use of the lipid nanoparticles for delivery of a therapeutic agent and methods for their preparation are also provided.
Core Innovation
The invention relates to lipid nanoparticles comprising a cationic lipid, a neutral lipid, a steroid, a polymer conjugated lipid, and a nucleic acid encapsulated within or associated with the lipid nanoparticle. The lipid nanoparticle includes from 47 to 48 mol percent of the cationic lipid, and the cationic lipid is defined by Formula II or by the specified alternative structures, including pharmaceutically acceptable salt, tautomer, or stereoisomer forms.
The described compositions further define the cationic lipid through detailed linker group, connectivity, and substituent limitations, including L1 and L2 options, G1, G2, and G3 definitions, and variables such as Ra, R1a/R1b, R2a/R2b, R3a/R3b, R4a/R4b, R5, R6, R7, and R8/R9. The disclosure also includes alternative forms such as Formula I and Formula III and related sub-forms, representative compounds in tables, pKa values for selected entries, and quantitative component constraints.
The nucleic acid payload includes therapeutic nucleic acids such as antisense RNA, mRNA, oligonucleotides, miRNA inhibitors, antagomirs, antimirs, siRNA-related modalities, and plasmid DNA. The document also states lipid nanoparticle performance and characterization concepts including effective pKa, serum stability, mean diameter, polydispersity, encapsulation, and activity.
Claims Coverage
Three independent claim formulations are identifiable across the provided items. Each centers on a lipid nanoparticle composition with 47 to 48 mol percent cationic lipid together with a neutral lipid, a steroid, a polymer conjugated lipid, and a nucleic acid encapsulated within or associated with the nanoparticle, while the inventive distinction lies in the structural definition of the cationic lipid.
Lipid nanoparticle composition with 47 to 48 mol percent cationic lipid
A lipid nanoparticle comprising from 47 to 48 mol percent of a cationic lipid, a neutral lipid, a steroid, a polymer conjugated lipid, and a nucleic acid, or a pharmaceutically acceptable salt thereof, encapsulated within or associated with the lipid nanoparticle.
Cationic lipid structure as Formula II with defined linkers and substituents
The cationic lipid has a structure of Formula II, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, where L1 and L2 are selected from the stated linkage options, G1, G2, and G3 are defined by the stated structural constraints, and substituents Ra, R1a/R1b, R2a/R2b, R3a/R3b, R4a/R4b, R5, R6, R7, and R8/R9 are defined by the stated rules and ranges.
Cationic lipid structure as one of the following structures
A lipid nanoparticle comprising from 47 to 48 mol percent of a cationic lipid, a neutral lipid, a steroid, a polymer conjugated lipid, and a nucleic acid, or a pharmaceutically acceptable salt thereof, encapsulated within or associated with the lipid nanoparticle, wherein the cationic lipid has one of the following structures.
Composition and quality constraints
Dependent claims refine the composition with additional molar percentage and molar ratio constraints, selected neutral lipid species, polydispersity thresholds, nucleic acid types, and disease-treatment use.
The claim coverage is anchored on the same lipid nanoparticle composition: 47 to 48 mol percent cationic lipid together with a neutral lipid, a steroid, a polymer conjugated lipid, and nucleic acid encapsulated within or associated with the nanoparticle. The inventive features are the defined cationic lipid structures, including Formula II with explicit linker and substituent constraints and alternative specified structure embodiments.
Stated Advantages
Increased stability of the lipid nanoparticle.
Enhanced delivery.
Increased encapsulation efficiency and/or in vivo activity.
Improved therapeutic index.
Increased LNP activity when mixtures of cationic lipids are used even when one cationic lipid has pKa outside an ideal range.
Activity and encapsulation depend on addition of anionic phospholipids (DOPG or DSPG).
LNP activity is correlated with mRNA-to-lipid N/P ratio and can be characterized using luciferase readout and encapsulation characterization.
Documented Applications
Intracellular delivery of therapeutic nucleic acids, including mRNA and oligonucleotides such as antisense and miRNA inhibitors/antagomirs/antimirs, and siRNA-related modalities, as well as plasmid DNA.
Treating a disease in a patient by administering the lipid nanoparticle as a therapeutic agent effective against the disease.
Interested in licensing this patent?