Lipid nanoparticle compositions and methods of formulating the same

Patent metadata

Field	Value
Publication number	US-11524023-B2
Application number	US-202117508786-A
Country	US
Kind code	B2
Filing date	Oct 22, 2021
Priority date	Feb 19, 2021
Publication date	Dec 13, 2022
Grant date	Dec 13, 2022

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 ionizable lipid comprises a tertiary amine group and can decompose into one or both of a secondary amine and a reactive aldehyde species capable of interacting with the mRNA to form an ionizable lipid-polynucleotide adduct impurity, and
wherein less than about 10% of the mRNA is in the form of the 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 less than about 5% of the mRNA is in the form of the ionizable lipid-polynucleotide adduct impurity.

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

4. The composition of claim 1 , wherein the ionizable lipid is selected from:

5. The composition of claim 4 , 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.

6. The composition of claim 4 , 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.

7. The composition of claim 4 , 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.

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

9. The composition of claim 4 , wherein the composition comprises a buffer selected from the group consisting of sodium phosphate, sodium citrate, sodium succinate, histidine histidine-HCl, sodium malate, sodium carbonate, and Tris (tris(hydroxymethyl)aminomethane).

10. The composition of claim 9 , wherein the composition comprises a cryoprotectant.

11. The composition of claim 10 , wherein the cryoprotectant is selected from the group consisting of mannitol, sucrose, trehalose, lactose, glycerol, dextrose, and combinations thereof.

12. The composition of claim 1 , wherein the ionizable lipid-polynucleotide adduct impurity comprises an aldehyde-mRNA adduct impurity.

13. The composition of claim 1 , wherein an amount of lipid aldehydes in the composition is less than about 50 ppm.

14. A composition comprising a lipid nanoparticle comprising a mRNA, a phospholipid, a cholesterol, a PEG-lipid, and an ionizable lipid comprising a tertiary amine group,
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), and
wherein an amount of the ionizable lipid-polynucleotide adduct impurity increases at an average rate of less than about 0.5% per day over a period of from 2-10 days when stored at a temperature of about 5° C.

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

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

17. The composition of claim 14 , wherein the ionizable lipid is selected from:

18. The composition of claim 17 , wherein the 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.

19. The composition of claim 17 , wherein the composition comprises a buffer selected from the group consisting of sodium phosphate, sodium citrate, sodium succinate, histidine histidine-HCl, sodium malate, sodium carbonate, and Tris (tris(hydroxymethyl)aminomethane).

20. The composition of claim 19 , wherein the composition comprises a cryoprotectant.

21. The composition of claim 20 , wherein the cryoprotectant is selected from the group consisting of mannitol, sucrose, trehalose, lactose, glycerol, dextrose, and combinations thereof.

22. The composition of claim 14 , wherein the ionizable lipid-polynucleotide adduct impurity comprises an aldehyde-mRNA adduct impurity.

23. The composition of claim 14 , wherein an amount of lipid aldehydes in the composition is less than about 50 ppm.

24. The composition of claim 21 , wherein the 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.

25. The composition of claim 4 , wherein the composition comprises a Tris buffer and sucrose.

26. The composition of claim 25 , 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.

27. The composition of claim 17 , wherein the composition comprises a Tris buffer and sucrose.

28. The composition of claim 27 , 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.

29. A composition comprising a lipid nanoparticle comprising a mRNA, a phospholipid, a cholesterol, a PEG-lipid, and an ionizable lipid,
wherein the ionizable lipid is selected from

and

wherein the composition comprises a Tris 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).

Assignees

• Modernatx Inc

Inventors

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

Classifications

• A61K9/1641

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

• A61K47/18

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

• A61K48/0041

  the non-active part being polymeric · CPC title