Biodegradable lipids for the delivery of active agents

Patent metadata

Field	Value
Publication number	US-11679158-B2
Application number	US-202117644914-A
Country	US
Kind code	B2
Filing date	Dec 17, 2021
Priority date	Dec 7, 2011
Publication date	Jun 20, 2023
Grant date	Jun 20, 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 cationic lipid comprising a head group, hydrophobic tails, and a central moiety to which the head group and the hydrophobic tails are directly bonded, wherein
(a) the central moiety is a nitrogen atom;
(b) the hydrophobic tails consist of two hydrophobic tails, wherein each hydrophobic tail, independently, has the formula —R 12 -M 1 -R 13 , wherein R 12 is a C 4 -C 14 alkylene or C 4 -C 14 alkenylene, M 1 is —OC(O)—, and R 13 is a branched C 10 -C 20 alkyl where the branching occurs at the α-position relative to M 1 ;
(c) the total carbon atom content of each hydrophobic tail is 21 to 26 carbon atoms;
(d) in each hydrophobic tail, M 1 is separated from a terminus of the hydrophobic tail by from 6 to 12 carbon atoms; and
(e) the lipid has at least one protonatable group.

2. The cationic lipid of claim 1 , wherein, in each hydrophobic tail, the chain length of —R 12 -M 1 -R 13 is at most 21 atoms from the first atom after the central moiety to a terminus of the hydrophobic tail.

3. The cationic lipid of claim 2 , wherein, in each hydrophobic tail,
(i) R 12 is a C 5 -C 10 alkylene or C 5 -C 10 alkenylene;
(ii) the total number of carbon atoms between the central moiety and a terminus of the hydrophobic tail ranges from 15 to 20; and
(iii) M 1 is separated from a terminus of the hydrophobic tail by from 8 to 12 carbon atoms.

4. The cationic lipid of claim 3 , wherein the lipid has a pKa of from about 5 to about 7 when incorporated into a lipid particle.

5. The cationic lipid of claim 1 , wherein:
(b) in each hydrophobic tail, R 12 is a C 5 -C 10 alkylene or C 5 -C 10 alkenylene, and R 13 is a branched C 10 -C 20 alkyl where the branching occurs at the α-position relative to M 1 ;
(d) in each hydrophobic tail, M 1 is separated from a terminus of the hydrophobic tail by from 8 to 12 carbon atoms;
(f) the chain length of each hydrophobic tail is at most 21 atoms from the first atom after the central moiety to a terminus of the hydrophobic tail; and
(g) in each hydrophobic tail, the total number of carbon atoms between the central moiety and a terminus of the hydrophobic tail ranges from 15 to 20.

6. A method for delivering a nucleic acid comprising administering to a subject a lipid particle comprising a nucleic acid, a cationic lipid, a neutral lipid, a PEG-lipid, and a sterol, wherein
the cationic lipid comprises a head group, hydrophobic tails, and a central moiety to which the head group and the hydrophobic tails are directly bonded, wherein
(a) the central moiety is a nitrogen atom;
(b) the hydrophobic tails consist of two hydrophobic tails, wherein each hydrophobic tail, independently, has the formula —R 12 -M 1 -R 13 , wherein R 12 is a C 4 -C 14 alkylene or C 4 -C 14 alkenylene, M 1 is —OC(O)—, and R 13 is a C 10 -C 20 alkyl, where
M 1 is separated from a terminus of the hydrophobic tail by from 6 to 12 carbon atoms; and

(c) R 13 is branched at the α-position relative to M 1 , where the total carbon atom content of the at least one hydrophobic tail is 21 to 26 carbon atoms; and
(d) the lipid has at least one protonatable group.

7. The method of claim 6 , wherein the nucleic acid comprises RNA.

8. The method of claim 7 , wherein the chain length of —R 12 -M 1 -R 13 is at most 21 atoms from the first atom after the central moiety to a terminus of the tail.

9. The method of claim 8 , wherein, in at least one hydrophobic tail,
(i) R 12 is a C 5 -C 10 alkylene or C 5 -C 10 alkenylene;
(ii) the total number of carbon atoms between the central moiety and a terminus of the at least one hydrophobic tail ranges from 15 to 20; and
(iii) M 1 is separated from a terminus of the at least one hydrophobic tail by from 8 to 12 carbon atoms.

10. The method of claim 9 , wherein in each hydrophobic tail,
(i) R 12 is a C 5 -C 10 alkylene or C 5 -C 10 alkenylene;
(ii) the total number of carbon atoms between the central moiety and a terminus of the hydrophobic tail ranges from 15 to 20; and
(iii) M 1 is separated from a terminus of the hydrophobic tail by from 8 to 12 carbon atoms.

11. The method of claim 10 , wherein the lipid particle comprises
the nucleic acid,
35-65 mol % of the cationic lipid,
3-12 mol % of distearoylphosphatidylcholine (DSPC),
15-45 mol % cholesterol, and
0.5-10 mol % of the PEG-modified lipid,
wherein the mol % is based on 100% total moles of lipids in the lipid particle.

12. The method of claim 11 , wherein the lipid particle comprises 45-65 mol % of the cationic lipid, 5-10 mol % distearoylphosphatidylcholine (DSPC), 25-40 mol % cholesterol, and 0.5-5 mol % of the PEG-modified lipid.

13. The method of claim 12 , wherein the PEG-modified lipid comprises a PEG molecule having an average molecular weight of 2,000 Da.

Assignees

• Alnylam Pharmaceuticals Inc

Inventors

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

Classifications

• A61K31/713

  Double-stranded nucleic acids or oligonucleotides · CPC title

• C07C229/12

  to carbon atoms of acyclic carbon skeletons · CPC title

• A61K31/7088

  Compounds having three or more nucleosides or nucleotides · CPC title

• C07C323/58

  with amino groups bound to the carbon skeleton · CPC title

• C07F5/022

  without C-boron linkages · CPC title