Biodegradable lipids for the delivery of active agents

Patent metadata

Field	Value
Publication number	US-11400158-B2
Application number	US-202217573878-A
Country	US
Kind code	B2
Filing date	Jan 12, 2022
Priority date	Dec 7, 2011
Publication date	Aug 2, 2022
Grant date	Aug 2, 2022

Abstract

The present invention relates to a cationic lipid having one or more biodegradable groups located in a lipidic moiety (e.g., a hydrophobic chain) of the cationic lipid. These cationic lipids may be incorporated into a lipid particle for delivering an active agent, such as a nucleic acid. The invention also relates to lipid particles comprising a neutral lipid, a lipid capable of reducing aggregation, a cationic lipid of the present invention, and optionally, a sterol. The lipid particle may further include a therapeutic agent such as a nucleic acid.

First claim

What is claimed is:

1. A lipid nanoparticle comprising
(a) a small interfering RNA (siRNA),
(b) a cationic lipid, and
(c) a neutral lipid,
wherein the cationic lipid is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

2. The lipid nanoparticle of claim 1 , further comprising a PEG-modified lipid.

3. The lipid nanoparticle of claim 1 , further comprising a sterol.

4. The lipid nanoparticle of claim 1 , comprising the cationic lipid, the neutral lipid, a PEG-modified lipid, and a sterol.

5. The lipid nanoparticle of claim 4 , comprising about 25 mol % to about 75 mol % of the cationic lipid, wherein the mol % is based on 100% total moles of lipids in the lipid nanoparticle.

6. The lipid nanoparticle of claim 5 , comprising about 35 mol % to about 65 mol % of the cationic lipid.

7. The lipid nanoparticle of claim 5 , comprising about 45 mol % to about 65 mol % of the cationic lipid.

8. The lipid nanoparticle of claim 4 , comprising no more than about 15 mol % of the neutral lipid, wherein the mol % is based on 100% total moles of lipids in the lipid nanoparticle.

9. The lipid nanoparticle of claim 8 , comprising about 3 mol % to about 12 mol % of the neutral lipid.

10. The lipid nanoparticle of claim 4 , wherein the neutral lipid is dipalmitoylphosphatidylcholine (DPPC) or distearylphosphatidylcholine (DSPC).

11. The lipid nanoparticle of claim 4 , comprising about 5 mol % to about 50 mol % of the sterol, wherein the mol % is based on 100% total moles of lipids in the lipid nanoparticle.

12. The lipid nanoparticle of claim 11 , comprising about 15 mol % to about 45 mol % of the sterol.

13. The lipid nanoparticle of claim 4 , wherein the sterol is cholesterol.

14. The lipid nanoparticle of claim 4 , comprising about 0.1 mol % to about 20 mol % of the PEG-modified lipid, wherein the mol % is based on 100% total moles of lipids in the lipid nanoparticle.

15. The lipid nanoparticle of claim 14 , comprising about 0.5 mol % to about 10 mol % of the PEG-modified lipid.

16. The lipid nanoparticle of claim 4 , wherein the PEG-modified lipid is PEG-DMG or PEG-c-DMA.

17. The lipid nanoparticle of claim 4 , wherein the PEG-modified lipid comprises a PEG molecule having an average PEG molecular weight of 2000 Da.

18. The lipid nanoparticle of claim 4 , wherein the PEG-modified lipid is 1-(monomethoxy-polyethyleneglycol)-2,3-dimyristoylglycerol (PEG-DMG) comprising a PEG molecule having an average molecular weight of 2,000 Da.

19. The lipid nanoparticle of claim 4 , comprising
about 25 mol % to about 75 mol % of the cationic lipid,
about 0.5 mol % to about 15 mol % of the neutral lipid,
about 5 mol % to about 50 mol % of the sterol, and
about 0.5 mol % to about 20 mol % of the PEG-modified lipid;

wherein the mol % is based on 100% total moles of lipids in the lipid nanoparticle.

20. The lipid nanoparticle of claim 4 , comprising
about 35 mol % to about 65 mol % of the cationic lipid,
about 3 mol % to about 12 mol % of the neutral lipid,
about 15 mol % to about 45 mol % of the sterol, and
about 0.5 mol % to about 10 mol % of the PEG-modified lipid;

wherein the mol % is based on 100% total moles of lipids in the lipid nanoparticle.

21. The lipid nanoparticle of claim 4 , comprising
about 45 mol % to about 65 mol % of the cationic lipid,
about 5 mol % to about 10 mol % of the neutral lipid,
about 25 mol % to about 40 mol % of the sterol, and
about 0.5 mol % to about 5 mol % of the PEG-modified lipid;

wherein the mol % is based on 100% total moles of lipids in the lipid nanoparticle.

22. The lipid nanoparticle of claim 4 , comprising
about 50 mol % of the cationic lipid,
about 10 mol % distearoylphosphatidylcholine (DSPC),
about 38.5 mol % cholesterol, and
about 1.5 mol % of the PEG-modified lipid,

wherein the mol % is based on 100% total moles of lipids in the lipid nanoparticle.

23. A pharmaceutical composition comprising a lipid nanoparticle according to claim 4 and a pharmaceutically acceptable diluent.

24. The pharmaceutical composition of claim 23 , wherein the pharmaceutically acceptable diluent comprises phosphate buffered saline or physiological saline.

25. A method of modulating the expression of a target gene in a cell, comprising providing to the cell a lipid nanoparticle of claim 4 .

26. The method of claim 25 , wherein the cell is in a human.

27. A lipid nanoparticle comprising
(a) a small interfering RNA (siRNA),
(b) about 35 mol % to about 65 mol % of a cationic lipid,
(c) about 3 mol % to about 12 mol % distearoylphosphatidylcholine (DSPC),
(d) about 0.5 mol % to about 10 mol % 1-(monomethoxy-polyethyleneglycol)-2,3-dimyristoylglycerol (PEG-DMG), and
(e) about 15 mol % to about 45 mol % cholesterol;
wherein
the mol % is based on 100% total moles of lipids in the lipid nanoparticle; and
the cationic lipid is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

28. A pharmaceutical composition comprising a lipid nanoparticle according to claim 27 and a pharmaceutically acceptable diluent.

29. A method of modulating the expression of a target gene in a cell, comprising providing to the cell a lipid nanoparticle of claim 27 .

30. A compound having the formula:

or a pharmaceutically acceptable salt thereof.

Assignees

• Alnylam Pharmaceuticals Inc

Inventors

• Maier Martin
• Jayaraman Muthusamy
• Akinc Akin
• Matsuda Shigeo
• Kandasamy Pachamuthu
• Rajeev Kallanthottathil G
• Manoharan Muthiah

Classifications

• C07C217/08

  the oxygen atom of the etherified hydroxy group being further bound to an acyclic carbon atom · CPC title

• C07C211/09

  Diamines · CPC title

• C07C327/28

  having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms · 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

• C07D233/54

  having two double bonds between ring members or between ring members and non-ring members · CPC title