Lipid formulations for nucleic acid delivery

Patent metadata

Field	Value
Publication number	US-11141378-B2
Application number	US-202117227802-A
Country	US
Kind code	B2
Filing date	Apr 12, 2021
Priority date	Apr 15, 2008
Publication date	Oct 12, 2021
Grant date	Oct 12, 2021

Abstract

The present invention provides novel, stable lipid particles comprising one or more active agents or therapeutic agents, methods of making the lipid particles, and methods of delivering and/or administering the lipid particles. More particularly, the present invention provides stable nucleic acid-lipid particles (SNALP) comprising a nucleic acid (such as one or more interfering RNA), methods of making the SNALP, and methods of delivering and/or administering the SNALP.

First claim

What is claimed is:

1. A nucleic acid-lipid particle consisting essentially of:
(a) an RNA;
(b) a cationic lipid having a protonatable tertiary amine;
(c) a mixture of a phospholipid and cholesterol of from 30 mol % to 55 mol % of the total lipid present in the particle, wherein the phospholipid consists of from 3 mol % to 15 mol % of the total lipid present in the particle; and
(d) a polyethyleneglycol (PEG)-lipid conjugate consisting of from 0.1 mol % to 2 mol % of the total lipid present in the particle.

2. The nucleic acid-lipid particle of claim 1 , wherein the cholesterol consists of from 25 mol % to 45 mol % of the total lipid present in the particle.

3. The nucleic acid-lipid particle of claim 2 , wherein the phospholipid is distearoylphosphatidylcholine (DSPC).

4. The nucleic acid-lipid particle of claim 3 , wherein the PEG has an average molecular weight of about 2,000 daltons.

5. The nucleic acid-lipid particle of claim 4 , wherein the PEG has a terminal methoxy group.

6. The nucleic acid-lipid particle of claim 5 , wherein the PEG-lipid conjugate is a PEG-diacylglycerol (PEG-DAG) conjugate having the same saturated acyl groups.

7. The nucleic acid-lipid particle of claim 6 , wherein the cholesterol consists of from 35 mol % to 45 mol % of the total lipid present in the particle.

8. A pharmaceutical composition comprising a nucleic acid-lipid particle of claim 6 and a pharmaceutically acceptable carrier.

9. The pharmaceutical composition of claim 8 , wherein the RNA is fully encapsulated in the nucleic acid-lipid particle.

10. A pharmaceutical composition comprising a nucleic acid-lipid particle of claim 7 and a pharmaceutically acceptable carrier.

11. The pharmaceutical composition of claim 10 , wherein the RNA is fully encapsulated in the nucleic acid-lipid particle.

12. The nucleic acid-lipid particle of claim 1 , wherein the RNA is an mRNA.

13. The nucleic acid-lipid particle of claim 12 , wherein the cholesterol consists of from 25 mol % to 45 mol % of the total lipid present in the particle.

14. The nucleic acid-lipid particle of claim 13 , wherein the phospholipid is DSPC.

15. The nucleic acid-lipid particle of claim 14 , wherein the PEG has an average molecular weight of about 2,000 daltons.

16. The nucleic acid-lipid particle of claim 15 , wherein the PEG has a terminal methoxy group.

17. The nucleic acid-lipid particle of claim 16 , wherein the PEG-lipid conjugate is a PEG-DAG conjugate having the same saturated acyl groups.

18. The nucleic acid-lipid particle of claim 17 , wherein the cholesterol consists of from 35 mol % to 45 mol % of the total lipid present in the particle.

19. A pharmaceutical composition comprising a nucleic acid-lipid particle of claim 17 and a pharmaceutically acceptable carrier.

20. The pharmaceutical composition of claim 19 , wherein the mRNA is fully encapsulated in the nucleic acid-lipid particle.

21. A pharmaceutical composition comprising a nucleic acid-lipid particle of claim 18 and a pharmaceutically acceptable carrier.

22. The pharmaceutical composition of claim 21 , wherein the mRNA is fully encapsulated in the nucleic acid-lipid particle.

23. The nucleic acid-lipid particle of claim 5 , wherein the PEG-lipid conjugate comprises an amido linker moiety.

24. The nucleic acid-lipid particle of claim 3 , wherein the cholesterol consists of from 35 mol % to 45 mol % of the total lipid present in the particle.

25. The nucleic acid-lipid particle of claim 24 , wherein the PEG-lipid conjugate consists of from 0.5 mol % to 2 mol % of the total lipid present in the particle.

26. A pharmaceutical composition comprising a nucleic acid-lipid particle of claim 25 and a pharmaceutically acceptable carrier.

27. The pharmaceutical composition of claim 26 , wherein the RNA is fully encapsulated in the nucleic acid-lipid particle.

28. The nucleic acid-lipid particle of claim 16 , wherein the PEG-lipid conjugate comprises an amido linker moiety.

29. The nucleic acid-lipid particle of claim 28 , wherein the DSPC consists of from 4 mol % to 10 mol % of the total lipid present in the particle.

30. A pharmaceutical composition comprising a nucleic acid-lipid particle of claim 29 and a pharmaceutically acceptable carrier.

Assignees

• Arbutus Biopharma Corp

Inventors

• Yaworski Edward
• Lam Kieu
• Jeffs Lloyd
• Palmer Lorne
• Maclachlan Ian

Classifications

• C07J9/00

  Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane · CPC title

• C12N2310/14

  interfering nucleic acids [NA] · CPC title

• A61K9/1272 Primary

  comprising non-phosphatidyl surfactants as bilayer-forming substances, e.g. cationic lipids or non-phosphatidyl liposomes coated or grafted with polymers (lipids as modifying agents {A61K47/543}) · CPC title

• A61K31/713

  Double-stranded nucleic acids or oligonucleotides · CPC title

• C12N15/1137

  against enzymes (viral enzymes C12N15/1131; receptors C12N15/1138) · CPC title