Biodegradable lipids for the delivery of active agents
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.
1. A pharmaceutical composition comprising a lipid particle and a pharmaceutically acceptable diluent, wherein the lipid particle comprises:
(i) a nucleic acid,
(ii) 35-65 mol % of a cationic lipid compound,
(iii) 3-12 mol % distearoylphosphatidylcholine (DSPC),
(iv) 15-45 mol % cholesterol, and
(v) 0.5-10 mol % of a PEG-modified lipid,
wherein the mol % is based on 100% total moles of lipids in the lipid particle,
wherein the lipid compound comprises a head group, hydrophobic tails, and a central moiety to which the head group and the hydrophobic tails are directly bonded, wherein:
the central moiety is a nitrogen atom;
the hydrophobic tails consist of two hydrophobic tails;
each of the two hydrophobic tails has the formula —R 12 -M 1 -R 13 , wherein:
R 12 is a C 4 -C 14 alkyl group,
M 1 is an ester group, and
R 13 is a C 10 -C 20 alkyl group that is branched at the α-position relative to M 1 ;
the chain length of formula —R 12 -M 1 -R 13 is from 17 to 24 atoms; and
the total carbon atom content of each hydrophobic tail is 21 to 26 carbon atoms.
2. The pharmaceutical composition of claim 1 , wherein the lipid compound is protonatable.
3. The pharmaceutical composition of claim 1 , wherein the nucleic acid comprises RNA.
4. The pharmaceutical composition of claim 3 , wherein the ester group in each hydrophobic tail is —OC(O)—.
5. The pharmaceutical composition of claim 4 , wherein the two hydrophobic tails are identical.
6. The pharmaceutical composition of claim 5 , wherein the pharmaceutical composition is a vaccine.
7. The pharmaceutical composition of claim 6 , further comprising sodium chloride.
8. The pharmaceutical composition of claim 7 , further comprising potassium chloride.
9. The pharmaceutical composition of claim 8 , wherein the lipid particle comprises 45-65 mol % of the lipid compound, 5-10 mol % of DSPC, 15-45 mol % of cholesterol, and 0.5-5 mol % of the PEG-modified lipid.
10. The pharmaceutical composition of claim 9 , wherein the lipid particle comprises about 50 mol % of the lipid compound, about 10 mol % of DSPC, about 38.5% of cholesterol, and about 1.5 mol % of the PEG-modified lipid.
11. The pharmaceutical composition of claim 10 , wherein, in each hydrophobic tail, R 12 is n-hexyl.
12. The pharmaceutical composition of claim 11 , wherein the chain length of formula —R 12 -M 1 -R 13 is 17 atoms.
13. The pharmaceutical composition of claim 12 , wherein the head group consists of a saturated aliphatic group and a hydroxyl group.
14. The pharmaceutical composition of claim 13 , wherein the PEG-modified lipid comprises a PEG molecule having an average molecular weight of 2,000 Da.
15. A pharmaceutical composition comprising a lipid particle and a pharmaceutically acceptable diluent, wherein the lipid particle comprises:
(i) a nucleic acid,
(ii) about 45-65 mol % of a protonatable lipid compound,
(iii) about 5-10 mol % distearoylphosphatidylcholine (DSPC),
(iv) about 25-40 mol % of cholesterol,
(v) 0.5-5 mol % of a PEG-modified lipid,
wherein the mol % is based on 100% total moles of lipids in the lipid particle;
wherein the nucleic acid comprises an RNA;
wherein the protonatable lipid compound comprises a head group, hydrophobic tails, and a central moiety to which the head group and the two hydrophobic tails are directly bonded, wherein:
the central moiety is a nitrogen atom;
the hydrophobic tails consist of two identical hydrophobic tails; and
each hydrophobic tail has the formula —R 12 -M 1 -R 13 , wherein:
R 12 is a C 4 -C 14 alkyl group;
M 1 is —OC(O)—;
R 13 is a C 10 -C 20 alkyl group that is branched at the α-position relative to M 1 ;
the chain length of formula —R 12 -M 1 -R 13 is from 17 to 24 atoms; and
the total carbon atom content of each hydrophobic tail is 21 to 26 carbon atoms.
16. The pharmaceutical composition of claim 15 , wherein the chain length of formula —R 12 -M 1 -R 13 is 17 atoms.
17. The pharmaceutical composition of claim 16 , wherein R 12 is a straight-chain C 4 -C 14 alkyl group.
18. The pharmaceutical composition of claim 17 , wherein R 12 is n-hexyl.
19. The pharmaceutical composition of claim 18 , wherein the head group consists of a saturated aliphatic group and a hydroxyl group.
20. The pharmaceutical composition of claim 19 , further comprising potassium chloride and sodium chloride.
21. The pharmaceutical composition of claim 20 , wherein the PEG-modified lipid comprises a PEG molecule having an average molecular weight of 2,000 Da.
22. A pharmaceutical composition comprising a lipid particle, a pharmaceutically acceptable diluent, potassium chloride, and sodium chloride,
wherein the lipid particle comprises:
(i) a nucleic acid,
(ii) about 45-65 mol % of a protonatable lipid compound,
(iii) about 5-10 mol % distearoylphosphatidylcholine (DSPC),
(iv) about 25-40 mol % of cholesterol,
(v) 0.5-5 mol % of a PEG-modified lipid,
wherein the mol % is based on 100% total moles of lipids in the lipid particle;
wherein the nucleic acid comprises an RNA;
wherein the protonatable lipid compound comprises a head group, hydrophobic tails, and a central moiety to which the head group and the two hydrophobic tails are directly bonded, wherein:
the central moiety is a nitrogen atom;
the hydrophobic tails consist of two identical hydrophobic tails; and
each hydrophobic tail has the formula —R 12 -M 1 -R 13 , wherein:
R 12 is n-hexyl;
M 1 is —OC(O)—;
R 13 is a C 10 -C 20 alkyl group that is branched at the α-position relative to M 1 ;
the chain length of formula —R 12 -M 1 -R 13 is 17 atoms; and
the total carbon atom content of each hydrophobic tail is 21 to 26 carbon atoms.
23. The pharmaceutical composition of claim 22 , wherein the head group consists of a saturated aliphatic group and a hydroxyl group.
24. The pharmaceutical composition of claim 23 , wherein the PEG-modified lipid comprises a PEG molecule having an average molecular weight of 2,000 Da.
25. A method for delivering a nucleic acid, comprising administering to a subject the pharmaceutical composition of claim 1 .
26. A method for delivering a nucleic acid, comprising administering to a subject the pharmaceutical composition of claim 15 .
27. A method for delivering a nucleic acid, comprising administering to a subject the pharmaceutical composition of claim 21 .
28. A method for delivering a nucleic acid, comprising administering to a subject the pharmaceutical composition of claim 22 .
29. A method for delivering a nucleic acid, comprising administering to a subject the pharmaceutical composition of claim 23 .
30. A method for delivering a nucleic acid, comprising administering to a subject the pharmaceutical composition of claim 24 .