Lipid formulation
View Patent ↗The invention features a cationic lipid of formula I, an improved lipid formulation comprising a cationic lipid of formula I and corresponding methods of use. Also disclosed are targeting lipids, and specific lipid formulations comprising such targeting lipids.
1. A lipid formulation comprising:
(a) a a compound having the formula
or a salt thereof;
(b) a neutral lipid;
(c) a sterol; and
(d) a PEG-modified lipid.
2. The lipid formulation of claim 1 , comprising:
(a) 40-65% of the compound,
(b) 5-10% of the neutral lipid,
(c) 25-40% of the sterol, and
(d) 0.5-10% of the PEG-modified lipid.
3. The lipid formulation of claim 1 , wherein the neutral lipid is selected from DSPC, DPPC, DMPC, POPC, DOPE and SM.
4. The lipid formulation of claim 1 , wherein the sterol is cholesterol.
5. The lipid formulation of claim 1 , wherein the PEG lipid is PEG-C 14 to PEG-C 22 , PEG-Cer 14 to PEG-C 20 , or PEG-DSPE.
6. The lipid formulation of claim 1 , comprising:
(a) about 57.5% of the compound,
(b) about 7.5% of the neutral lipid,
(c) about 31.5% of the sterol, and
(d) about 3.5% of the PEG-modified lipid.
7. The lipid formulation of claim 1 , further comprising a therapeutic agent, which comprises a nucleic acid.
8. The lipid formulation of claim 7 , wherein the nucleic acid is an siRNA.
9. The lipid formulation of claim 8 , wherein the molar ratio of lipid : nucleic acid is about 3 to about 15.
10. The lipid formulation of claim 9 , wherein the molar ratio of lipid : nucleic acid about 5 to about 13.
11. The lipid formulation of claim 1 , comprising:
(a) about 50% of the compound,
(b) about 10% of the neutral lipid,
(c) about 38.5% of the sterol, and
(d) about 1.5% of the PEG-modified lipid.
12. The lipid formulation of claim 1 , comprising:
(a) about 50% of the compound,
(b) about 10% of the neutral lipid,
(c) about 35% of the sterol, and
(d) about 5% of the PEG-modified lipid.
13. The lipid formulation of claim 1 , comprising:
(a) about 57.2% of the compound,
(b) about 7.1% of the neutral lipid,
(c) about 34.3% of the sterol, and
(d) about 1.4% of the PEG-modified lipid.
14. A method of delivering an siRNA therapeutic agent to a cell comprising administering to a subject the lipid formulation of claim 8 .
15. The method of claim 14 , wherein the siRNA therapeutic agent is a dsRNA.
16. A method of modulating the expression of a target gene in a cell, the method comprising providing to a cell the lipid formulation of claim 8 .
17. The lipid formulation of claim 1 , comprising:
(a) 20-60% of the compound cationic lipid of formula I,
(b) 5-25% of the neutral lipid,
(c) 25-55% of the sterol, and
(d) 0.5-15% of the PEG-modified lipid.
18. The lipid formulation of claim 1 , comprising:
(a) 20-75% of the compound lipid of formula I,
(b) 5-15% of the neutral lipid,
(c) 5-50% of the sterol, and
(d) 0.5-20% of the PEG-modified lipid.
19. The lipid formulation of claim 1 , wherein the neutral lipid is DSPC, the sterol is cholesterol, the PEG-modified lipid is PEG-DMG.
20. The lipid formulation of claim 6 , wherein the neutral lipid is DSPC, the sterol is cholesterol, the PEG-modified lipid is PEG-DMG.
21. The lipid formulation of claim 11 , wherein the neutral lipid is DSPC, the sterol is cholesterol, the PEG-modified lipid is PEG-DMG.
22. The lipid formulation of claim 12 , wherein the neutral lipid is DSPC, the sterol is cholesterol, the PEG-modified lipid is PEG-DMG.
23. The lipid formulation of claim 13 , wherein the neutral lipid is DSPC, the sterol is cholesterol, the PEG-modified lipid is PEG-DMG.
24. The method of claim 14 , wherein the neutral lipid is DSPC, the sterol is cholesterol, the PEG-modified lipid is PEG-DMG.
25. The lipid formulation of claim 19 , wherein the PEG moiety of the PEG-DMG has an average molecular weight of 2,000 Da.
26. The lipid formulation of claim 20 , wherein the PEG moiety of the PEG-DMG has an average molecular weight of 2,000 Da.
27. The lipid formulation of claim 21 , wherein the PEG moiety of the PEG-DMG has an average molecular weight of 2,000 Da.
28. The lipid formulation of claim 22 , wherein the PEG moiety of the PEG-DMG has an average molecular weight of 2,000 Da.
29. The lipid formulation of claim 23 , wherein the PEG moiety of the PEG-DMG has an average molecular weight of 2,000 Da.
30. The lipid formulation of claim 24 , wherein the PEG moiety of the PEG-DMG has an average molecular weight of 2,000 Da.
31. The lipid formulation of claim 7 , wherein the formulation is prepared by a method comprising (i) extruding a liposome formed from components (a)-(d), and (ii) addition of a nucleic acid therapeutic agent to the liposome.
32. The lipid formulation of claim 7 , wherein the formulation is prepared by a method comprising mixing components (a)-(d) and a nucleic acid therapeutic agent in parallel into a mixing chamber.
33. A nucleic acid-lipid particle comprising:
(a) a lipid particle comprising:
(i) a compound having the formula
or a salt thereof,
(ii) a neutral lipid,
(iii) a sterol,
(iv) a PEG-modified lipid; and
(b) a therapeutic siRNA encapsulated in the lipid particle.
34. The nucleic acid-lipid particle of claim 33 , wherein the nucleic acid-lipid particle has a size ranging from about 70 to about 200 nm.
35. The nucleic acid-lipid particle of claim 34 , wherein the nucleic acid-lipid particle has a size ranging from about 90 to about 130 nm.