RNA formulations

Patent metadata

Field	Value
Publication number	US-11786607-B2
Application number	US-201816623069-A
Country	US
Kind code	B2
Filing date	Jun 15, 2018
Priority date	Jun 15, 2017
Publication date	Oct 17, 2023
Grant date	Oct 17, 2023

Abstract

This disclosure provides improved lipid-based compositions, including lipid nanoparticle compositions, and methods of use thereof for delivering agents in vivo including nucleic acids and proteins.

First claim

The invention claimed is:

1. A composition comprising an enriched population of lipid nanoparticles (LNPs), wherein the LNPs have an outer shell and an inner core and comprise an ionizable lipid, a phospholipid, a poly(ethylene glycol) (PEG) lipid, wherein at least 50% of the LNPs comprise mRNA encapsulated within the inner core and wherein the outer shell comprises at least 95% of the total PEG lipid in the LNP, and wherein the LNP's are formed by a nanoprecipitation process including a step in which additional PEG lipid was added to the LNP's after an initial nanoprecipitation reaction.

2. The composition of claim 1 , further comprising a structural lipid.

3. The composition of claim 2 , wherein at least 50% of the LNPs have a ratio of ionizable lipid:phospholipid:structural lipid of 35-50:30-40: 20-30.

4. The composition of claim 2 , wherein:
(a) the LNP is insensitive to accelerated blood clearance upon repeated administration in vivo within 10 days;
(b) at least 50% of the LNPs have 1-5 inner shells;
(c) the structural lipid is cholesterol;
(d) 10-30% of the LNP, exclusive of mRNA, is the structural lipid; and/or
(e) the outer shell is comprised of 10-30% of the structural lipid.

5. The composition of claim 1 , wherein at least 50% of the LNPs have an outer shell fluidity value of greater than a threshold polarization level.

6. The composition of claim 1 , wherein a quantitative value of the amount of mRNA encapsulated in the LNP is generated using an ion-exchange (IEX) chromatography assay.

7. The composition of claim 1 , wherein:
(a) at least about 50% of the LNPs in the population have mRNA encapsulated therein, as determined by ion-exchange chromatography (IEX); and/or
(b) the LNPs have an encapsulation efficiency of at least about 50% as determined by ion-exchange chromatography (IEX).

8. The composition of claim 1 , wherein the phospholipid is DSPC.

9. A composition comprising a population of lipid nanoparticles (LNPs), the LNPs comprise an ionizable amino lipid, a poly(ethylene glycol) (PEG) lipid, a phospholipid, wherein:
(a) at least about 50% of the LNPs in the population have mRNA encapsulated therein, as determined by ion-exchange chromatography (IEX), and wherein the LNP's are formed by a nanoprecipitation process including a step in which additional PEG lipid was added to the LNP's after an initial nanoprecipitation reaction; and/or
(b) the LNPs have an encapsulation efficiency of at least about 50% as determined by ion-exchange chromatography (IEX).

10. The composition of claim 9 , further comprising a structural lipid.

11. The composition of claim 10 , wherein the structural lipid is cholesterol or a cholesterol derivative.

12. The composition of claim 9 , wherein the composition is enriched for LNPs:
(a) lacking B1a cell-stimulating phospholipid epitopes, and/or
(b) lacking scavenger receptor ligands.

13. The composition of claim 12 , wherein at least about 50% of the LNPs:
(a) lack B1a cell-stimulating phospholipid epitopes, and/or
(b) lack scavenger receptor ligands.

14. The composition of claim 9 , wherein the composition is enriched for LNPs having a majority of the total phospholipid present in the outer LNP shell.

15. The composition of claim 14 , wherein at least about 50% of the LNPs have the majority of the total phospholipid present in the outer LNP shell.

16. The composition of claim 9 , wherein the composition is enriched for LNPs having more than 50% of the total phospholipid present on the surface.

17. The composition of claim 16 , wherein at least about 50% of the LNPs have more than 50% of the total phospholipid present on the surface.

18. The composition of claim 9 , wherein the composition is enriched for LNPs having a majority of the total PEG lipid present in the outer LNP shell.

19. The composition of claim 18 , wherein at least about 50% of the LNPs have the majority of the total PEG lipid present in the outer LNP shell.

20. The composition of claim 9 , wherein the composition is enriched for LNPs having more than 50% of the total PEG lipid present on the surface.

21. The composition of claim 20 , wherein at least about 50% of the LNPs have more than 50% of the total PEG lipid present on the surface.

22. The composition of claim 13 , wherein the phospholipid is DSPC.

Assignees

• Modernatx Inc

Inventors

• Hoge Stephen
• Schariter Joseph
• Bowerman Charles
• Smith Michael H
• Xia Yan

Classifications

• A61K47/6931 Primary

  the material constituting the nanoparticle being a polymer · CPC title

• A61K31/7105

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

• A61K47/543

  Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine · CPC title

• A61K9/5123 Primary

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

• A61K9/0019

  Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00) · CPC title