Lipid nanoparticle compositions and methods of formulating the same

Patent metadata

Field	Value
Publication number	US-11622972-B2
Application number	US-202217850702-A
Country	US
Kind code	B2
Filing date	Jun 27, 2022
Priority date	Feb 19, 2021
Publication date	Apr 11, 2023
Grant date	Apr 11, 2023

Abstract

Provided herein are compositions and methods of reducing adduct formation.

First claim

What is claimed is:

1. 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),
wherein the ionizable lipid is selected from

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 composition of claim 1 , wherein the ionizable lipid is

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

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

5. The composition 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.

6. The composition of claim 2 , wherein all uridines in the mRNA are N1-methyl-pseudouridines (m1ψ).

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

8. The composition of claim 7 , wherein an amount of lipid aldehydes in the composition is less than about 50 ppm.

9. The composition of claim 7 , wherein an amount of the ionizable lipid-polynucleotide adduct impurity increases at an average rate of less than about 2% per day when stored at a temperature of about 25° C. or below.

10. The composition of claim 7 , wherein an amount of the ionizable lipid-polynucleotide adduct impurity increases at an average rate of less than about 0.5% per day when stored at a temperature of about 5° C. or below.

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

12. The composition of claim 11 , wherein the refrigerated temperature is about 5° C.

13. The composition of claim 1 , wherein the ionizable lipid is

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

15. The composition of claim 13 , wherein less than about 1% of the mRNA is in the form of the ionizable lipid-polynucleotide adduct impurity.

16. The composition of claim 13 , 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.

17. The composition of claim 13 , wherein all uridines in the mRNA are N1-methyl-pseudouridines (m1ψ).

18. The composition of claim 13 , wherein the ionizable lipid-polynucleotide adduct impurity comprises an aldehyde-mRNA adduct impurity.

19. The composition of claim 18 , wherein an amount of lipid aldehydes in the composition is less than about 50 ppm.

20. The composition of claim 18 , wherein an amount of the ionizable lipid-polynucleotide adduct impurity increases at an average rate of less than about 2% per day when stored at a temperature of about 25° C. or below.

21. The composition of claim 18 , wherein an amount of the ionizable lipid-polynucleotide adduct impurity increases at an average rate of less than about 0.5% per day when stored at a temperature of about 5° C. or below.

22. The composition of claim 18 , wherein an amount of the ionizable lipid-polynucleotide adduct impurity increases at an average rate of less than about 0.5% per day when stored at a refrigerated temperature.

23. The composition of claim 22 , wherein the refrigerated temperature is about 5° C.

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

• A61K9/1617

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

• A61K31/7105 Primary

  Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links · CPC title