Biodegradable lipids for the delivery of active agents

Patent metadata

Field	Value
Publication number	US-11612657-B2
Application number	US-202217651038-A
Country	US
Kind code	B2
Filing date	Feb 14, 2022
Priority date	Dec 7, 2011
Publication date	Mar 28, 2023
Grant date	Mar 28, 2023

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 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 .

Assignees

• Alnylam Pharmaceuticals Inc

Inventors

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

Classifications

• C07F5/022

  without C-boron linkages · CPC title

• C07D295/14

  substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• C07C327/32

  having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by carboxyl groups · CPC title

• C07C211/10

  Diaminoethanes · CPC title

• C07D317/30

  Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title