Lipids and compositions for the delivery of therapeutics

Patent metadata

Field	Value
Publication number	US-12453776-B2
Application number	US-202418736363-A
Country	US
Kind code	B2
Filing date	Jun 6, 2024
Priority date	Nov 10, 2008
Publication date	Oct 28, 2025
Grant date	Oct 28, 2025

Abstract

The present invention provides lipids that are advantageously used in lipid particles for the in vivo delivery of therapeutic agents to cells. In particular, the invention provides lipids having the following structure

wherein:
R 1 and R 2 are each independently for each occurrence optionally substituted C 10 -C 30 alkyl, optionally substituted C 10 -C 30 alkenyl, optionally substituted C 10 -C 30 alkynyl, optionally substituted C 10 -C 30 acyl, or -linker-ligand; R 3 is H, optionally substituted C 1 -C 10 alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 -C 10 alkynyl, alkylhetrocycle, alkylphosphate, alkylphosphorothioate, alkylphosphorodithioate, alkylphosphonates, alkylamines, hydroxyalkyls, ω-aminoalkyls, ω-(substituted)aminoalkyls, ω-phosphoalkyls, ω-thiophosphoalkyls, optionally substituted polyethylene glycol (PEG, mw 100-40K), optionally substituted mPEG (mw 120-40K), heteroaryl, heterocycle, or linker-ligand; and E is C(O)O or OC(O).

First claim

We claim:

1. A cationic lipid having the structure

or a salt or isomer thereof,
wherein
E is C (O) O or OC (O);
R 1 and R 2 and R x are each independently for each occurrence H, optionally substituted C 1 -C 10 alkyl, or optionally substituted C 10 -C 30 acyl, provided that at least one of R 1 , R 2 and R x is not H;
R 3 is di(alkyl) aminoalkyl substituted with one or more halo, alkyl, alkenyl, alkylthio, alkoxy, alkoxycarbonyl, amino, alkylamino, and hydroxy, wherein alkoxy is optionally substituted with one or more alkyl and oxo; and
n is 0, 1, 2, or 3.

2. The cationic lipid of claim 1 , wherein at least two of R 1 , R 2 and R x are not H.

3. The cationic lipid of claim 2 , wherein R 1 and R 2 are each independently C 1 -C 10 alkyl and R x is H.

4. The cationic lipid of claim 3 , wherein n is 0.

5. A lipid particle comprising a cationic lipid of claim 1 , or a salt or isomer thereof.

6. The lipid particle of claim 5 , wherein the particle comprises about 40-60 mol % of the cationic lipid.

7. The lipid particle of claim 5 , wherein the cationic lipid has a pKa of about 4 to about 7.

8. The lipid particle of claim 5 , wherein the particle further comprises a neutral lipid and a lipid capable of reducing aggregation.

9. The lipid particle of claim 8 , wherein the neutral lipid is a phospholipid.

10. The lipid particle of claim 8 , wherein the lipid capable of reducing aggregation is a PEG-lipid.

11. The lipid particle of claim 10 , wherein the particle comprises about 40-60 mol % of the cationic lipid.

12. The lipid particle of claim 8 , wherein the particle further comprises a sterol.

13. The lipid particle of claim 12 , wherein the sterol is cholesterol.

14. The lipid particle of claim 5 , further comprising a therapeutic agent.

15. The lipid particle of claim 14 , wherein the therapeutic agent is a nucleic acid.

16. The lipid particle of claim 15 , wherein the nucleic acid is selected from the group consisting of an siRNA and an antisense oligonucleotide.

17. The lipid particle of claim 15 , wherein the nucleic acid is an siRNA.

18. The lipid particle of claim 15 , wherein the nucleic acid is an mRNA.

19. The lipid particle of claim 12 , further comprising a therapeutic agent.

20. The lipid particle of claim 19 , wherein the therapeutic agent is a nucleic acid.

21. The lipid particle of claim 20 , wherein the nucleic acid is an mRNA.

22. A lipid particle comprising a cationic lipid of claim 4 , or a salt or isomer thereof.

23. The lipid particle of claim 22 , wherein the particle comprises about 40-60 mol % of the cationic lipid.

24. The lipid particle of claim 22 , wherein the cationic lipid has a pKa of about 4 to about 7.

25. The lipid particle of claim 22 , wherein the particle further comprises a neutral lipid and a lipid capable of reducing aggregation.

26. The lipid particle of claim 25 , wherein the neutral lipid is a phospholipid.

27. The lipid particle of claim 25 , wherein the lipid capable of reducing aggregation is a PEG-lipid.

28. The lipid particle of claim 27 , wherein the particle comprises about 40-60 mol % of the cationic lipid.

29. The lipid particle of claim 25 , wherein the particle further comprises a sterol.

30. The lipid particle of claim 29 , wherein the sterol is cholesterol.

31. The lipid particle of claim 22 , further comprising a therapeutic agent.

32. The lipid particle of claim 31 , wherein the therapeutic agent is a nucleic acid.

33. The lipid particle of claim 32 , wherein the nucleic acid is selected from the group consisting of an siRNA and an antisense oligonucleotide.

34. The lipid particle of claim 32 , wherein the nucleic acid is an siRNA.

35. The lipid particle of claim 32 , wherein the nucleic acid is an mRNA.

36. The lipid particle of claim 29 , further comprising a therapeutic agent.

37. The lipid particle of claim 36 , wherein the therapeutic agent is a nucleic acid.

38. The lipid particle of claim 37 , wherein the nucleic acid is an mRNA.

39. A pharmaceutical composition comprising a lipid particle of claim 14 and a pharmaceutically acceptable excipient, carrier, or diluent.

40. A pharmaceutical composition comprising a lipid particle of claim 21 and a pharmaceutically acceptable excipient, carrier, or diluent.

41. A pharmaceutical composition comprising a lipid particle of claim 31 and a pharmaceutically acceptable excipient, carrier, or diluent.

42. A pharmaceutical composition comprising a lipid particle of claim 38 and a pharmaceutically acceptable excipient, carrier, or diluent.

43. A method of modulating the expression of a target gene in a cell, comprising providing to the cell the lipid particle of claim 14 .

44. A method of modulating the expression of a target gene in a cell, comprising providing to the cell the lipid particle of claim 21 .

45. A method of modulating the expression of a target gene in a cell, comprising providing to the cell the lipid particle of claim 31 .

46. A method of modulating the expression of a target gene in a cell, comprising providing to the cell the lipid particle of claim 38 .

Assignees

• Arbutus Biopharma Corp

Inventors

• Manoharan Muthiah
• Jayaraman Muthusamy
• Rajeev Kallanthottathil G
• Eltepu Laxman
• Ansell Steven
• Chen Jianxin

Classifications

• C07D491/113

  with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring · CPC title

• C07D491/056

  with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring · CPC title

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D317/72

  spiro-condensed with carbocyclic rings · CPC title

• C07D317/46

  condensed with one six-membered ring · CPC title