Biodegradable lipids for the delivery of active agents

Patent metadata

Field	Value
Publication number	US-11633479-B2
Application number	US-202217651017-A
Country	US
Kind code	B2
Filing date	Feb 14, 2022
Priority date	Dec 7, 2011
Publication date	Apr 25, 2023
Grant date	Apr 25, 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 lipid compound, comprising a head group, two 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;
each of the two hydrophobic tails independently consists of an aliphatic group interrupted by an ester group; and
at least one of the 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;
the total carbon atom content of the at least one hydrophobic tail is 21 to 26 carbon atoms; and
wherein the lipid compound contains a protonatable group such that the lipid compound is positively charged at a pH at or below pH 7.4.

2. The lipid compound of claim 1 , wherein both hydrophobic tails have the formula —R 12 -M 1 -R 13 , wherein M 1 is —OC(O)—.

3. The lipid compound of claim 2 , wherein the two hydrophobic tails are identical.

4. The lipid compound of claim 3 , wherein the head group consists of a saturated aliphatic group and a hydroxyl group.

5. The lipid compound of claim 1 , wherein the ester group in each hydrophobic tail is —C(O)O—.

6. The lipid compound of claim 5 , wherein the at least one hydrophobic tail has the formula:

where R 13 is branched at the α-position relative to the —C(O)O— group, and
where R 13 is a C 13 -C 17 alkyl and the maximum length of R 13 is 11 carbon atoms.

7. The lipid compound of claim 6 , wherein the hydrophobic tails have different chemical formulas.

8. The lipid compound of claim 7 , wherein the head group consists of a saturated aliphatic group and a hydroxyl group.

9. The lipid compound of claim 8 , wherein, in the at least one hydrophobic tail, R 13 is a C 17 alkyl.

10. A lipid compound, comprising a head group, two identical 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;
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)—, 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.

11. The lipid compound of claim 10 , wherein R 12 is n-hexyl.

12. The lipid compound of claim 11 , wherein the head group consists of a saturated aliphatic group and a hydroxyl group.

13. A method for delivering a nucleic acid comprising administering to a subject a lipid particle comprising a nucleic acid, a lipid compound, a neutral lipid, a PEG-lipid, and a sterol, wherein:
the lipid compound comprises a head group, two 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;
each of the two hydrophobic tails independently consists of an aliphatic group interrupted by an ester group; and
at least one of the 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 the at least one hydrophobic tail is 21 to 26 carbon atoms; and
wherein the lipid compound contains a protonatable group such that the lipid compound is positively charged at a pH at or below pH 7.4.

14. The method of claim 13 , wherein the nucleic acid comprises RNA.

15. The method of claim 14 , wherein the ester group in each hydrophobic tail is —C(O)O—.

16. The method of claim 15 , wherein the at least one hydrophobic tail has the formula:

where R 13 is branched at the α-position relative to the —C(O)O— group, and
where R 13 is a C 13 -C 17 alkyl and the maximum length of R 13 is 11 carbon atoms.

17. The method of claim 16 , wherein the hydrophobic tails have different chemical formulas.

18. The method of claim 17 , wherein the lipid particle is administered in a pharmaceutical composition, which further comprises a pharmaceutically acceptable diluent and sodium acetate.

19. The method of claim 18 , wherein the head group consists of a saturated aliphatic group and a hydroxyl group.

20. The method of claim 19 , wherein, in the at least one hydrophobic tail, R 13 is a C 17 alkyl.

21. The method of claim 14 , wherein both hydrophobic tails have the formula —R 12 -M 1 -R 13 , wherein M 1 is —OC(O)—.

22. The method of claim 21 , wherein the two hydrophobic tails are identical.

23. The method of claim 22 , wherein the lipid particle is administered in a pharmaceutical composition, which further comprises a pharmaceutically acceptable diluent, potassium chloride, and sodium chloride.

24. The method of claim 23 , wherein the head group consists of a saturated aliphatic group and a hydroxyl group.

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

• A61K31/713

  Double-stranded nucleic acids or oligonucleotides · 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

• C07C327/28

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

• A61K47/18 Primary

  Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids · CPC title