Lipid nanoparticle compositions and methods of formulating the same

Patent metadata

Field	Value
Publication number	US-12508278-B2
Application number	US-202318205229-A
Country	US
Kind code	B2
Filing date	Jun 2, 2023
Priority date	Feb 19, 2021
Publication date	Dec 30, 2025
Grant date	Dec 30, 2025

Abstract

Provided herein are compositions and methods of reducing adduct formation.

First claim

What is claimed is:

1 . A method of administering mRNA to a subject, comprising administering to the subject a composition comprising a lipid nanoparticle comprising a mRNA, a phospholipid, a cholesterol, a PEG-lipid, and an ionizable lipid,
wherein the mRNA comprises an N1-methyl-pseudouridine (m1ψ) nucleobase, wherein the ionizable lipid is selected from

wherein the phospholipid comprises one or more selected from 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2-dimyristoyl-sn-gly cero-phosphocholine (DMPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-diundecanoyl-sn-glycero-phosphocholine (DUPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-di-O-octadecenyl-sn-glycero-3-phosphocholine (18:0 Diether PC), 1-oleoyl-2 cholesterylhemisuccinoyl-sn-glycero-3-phosphocholine (OChemsPC), 1-hexadecyl-sn-glycero-3-phosphocholine (C16 Lyso PC), 1,2-dilinolenoyl-sn-glycero-3-phosphocholine, 1,2-diarachidonoyl-sn-glycero-3-phosphocholine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine, 1,2-diphytanoyl-sn-glycero-3-phosphoethanolamine (ME 16.0 PE), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinoleoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinolenoyl-sn-glycero-3-phosphoethanolamine, 1,2-diarachidonoyl-sn-glycero-3-phosphoethanolamine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphoethanolamine, 1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt (DOPG), and sphingomyelin,
wherein the PEG-lipid comprises one or more selected from 1,2-dimyristoyl-sn-glycerol methoxypolyethylene glycol (PEG-DMG), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)] (PEG-DSPE), PEG-disteryl glycerol (PEG-DSG), PEG-dipalmetoleyl, PEG-dioleyl, PEG-distearyl, PEG-diacylglycamide (PEG-DAG), PEG-dipalmitoyl phosphatidylethanolamine (PEG-DPPE), and PEG-1,2-dimyristyloxlpropyl-3-amine (PEG-c-DMA),
wherein the composition comprises a Tris (tris(hydroxymethyl)aminomethane) buffer and sucrose, and
wherein less than about 10% of the mRNA is in the form of an ionizable lipid-polynucleotide adduct impurity, as measured by reverse phase ion pair high performance liquid chromatography (RP-IP HPLC).

2 . The method of claim 1 , wherein the ionizable lipid is

3 . The method of claim 2 , wherein less than about 5% of the mRNA in the composition is in the form of the ionizable lipid-polynucleotide adduct impurity.

4 . The method of claim 2 , wherein less than about 1% of the mRNA in the composition is in the form of the ionizable lipid-polynucleotide adduct impurity.

5 . The method of claim 2 , wherein an amount of the ionizable lipid-polynucleotide adduct impurity in the composition increases at an average rate of less than about 2% per day when the composition is stored at a temperature of about 25° C. or below.

6 . The method of claim 2 , wherein an amount of the ionizable lipid-polynucleotide adduct impurity in the composition increases at an average rate of less than about 0.5% per day when the composition is stored at a temperature of about 5° C. or below.

7 . The method of claim 2 , wherein an amount of the ionizable lipid-polynucleotide adduct impurity in the composition increases at an average rate of less than about 0.5% per day when the composition is stored at a refrigerated temperature.

8 . The method of claim 7 , wherein the refrigerated temperature is about 5° C.

9 . The method of claim 2 , wherein the ionizable lipid-polynucleotide adduct impurity comprises an aldehyde-mRNA adduct impurity.

10 . The method of claim 2 , wherein an amount of lipid aldehydes in the composition is less than about 50 ppm.

11 . The method of claim 2 , wherein the composition comprises a molar ratio of 20-60% ionizable lipid, 5-25% phospholipid, 25-55% cholesterol, and 0.5-15% PEG lipid, based on the lipid components.

12 . The method of claim 1 , wherein the ionizable lipid is

13 . The method of claim 12 , wherein less than about 5% of the mRNA in the composition is in the form of the ionizable lipid-polynucleotide adduct impurity.

14 . The method of claim 12 , wherein less than about 1% of the mRNA in the composition is in the form of the ionizable lipid-polynucleotide adduct impurity.

15 . The method of claim 12 , wherein an amount of the ionizable lipid-polynucleotide adduct impurity in the composition increases at an average rate of less than about 2% per day when the composition is stored at a temperature of about 25° C. or below.

16 . The method of claim 12 , wherein an amount of the ionizable lipid-polynucleotide adduct impurity in the composition increases at an average rate of less than about 0.5% per day when the composition is stored at a temperature of about 5° C. or below.

17 . The method of claim 12 , wherein an amount of the ionizable lipid-polynucleotide adduct impurity in the composition increases at an average rate of less than about 0.5% per day when the composition is stored at a refrigerated temperature.

18 . The method of claim 17 , wherein the refrigerated temperature is about 5° C.

19 . The method of claim 12 , wherein the ionizable lipid-polynucleotide adduct impurity comprises an aldehyde-mRNA adduct impurity.

20 . The method of claim 12 , wherein an amount of lipid aldehydes in the composition is less than about 50 ppm.

21 . The method of claim 12 , wherein the composition comprises a molar ratio of 20-60% ionizable lipid, 5-25% phospholipid, 25-55% cholesterol, and 0.5-15% PEG lipid, based on the lipid components.

22 . The method of claim 1 , wherein the phospholipid comprises one or more selected from distearoylphosphatidylcholine (DSPC) and dipalmitoylphosphatidylcholine (DPPC), and wherein the PEG-lipid comprises one or more selected from 1,2-dimyristoyl-rac-glycerol-methoxy (polyethylene glycol)-2000 (DMG-PEG2000) and 1,2-distearoyl-sn-glycerol-methoxy (polyethylene glycol)-2000 (DSPE-PEG2000).

Assignees

• Modernatx Inc

Inventors

• Packer Meredith
• Gyawali Dipendra
• Hua Serenus
• Butora Gabor
• Mercer Gregory John

Classifications

• A61K47/26

  Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin · CPC title

• A61K47/18

  Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids · CPC title

• A61K9/5123 Primary

  Organic compounds, e.g. fats, sugars · CPC title

• A61K9/1641

  obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers · CPC title

• A61K9/1617

  Organic compounds, e.g. phospholipids, fats · CPC title