Biodegradable lipids for the delivery of active agents

Patent metadata

Field	Value
Publication number	US-12239709-B2
Application number	US-202418589636-A
Country	US
Kind code	B2
Filing date	Feb 28, 2024
Priority date	Dec 7, 2011
Publication date	Mar 4, 2025
Grant date	Mar 4, 2025

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 consisting of a protonatable primary group and two hydrophobic tails that are directly bonded to the protonatable primary group, wherein
each of the two hydrophobic tails are of the formula -(hydrophobic chain)-(C(O)O)-(hydrophobic chain); and
each of the two hydrophobic tails has a total carbon atom content of from 17 to 26 carbon atoms, wherein
at least one hydrophobic tail is of the formula:

wherein R 13 is a C 1 -C 17 alkyl, wherein
the maximum length of R 13 from its attachment point to the ester group is 12 carbon atoms, and
R 13 comprises (i) a carbon atom that is directly bonded to the ester, (ii) two alkyl groups directly bonded to the carbon atom that is bonded to the ester, and (iii) a hydrogen atom directly bonded to the carbon atom that is bonded to the ester.

2. The lipid of claim 1 , wherein the protonatable primary group consists of a head group and a central moiety, the central moiety is a nitrogen atom, and both hydrophobic tails are directly bonded to the central moiety.

3. The lipid of claim 2 , wherein the maximum length of R 13 from its attachment point to the ester group is 11 carbon atoms.

4. The lipid of claim 2 , wherein the ester group in each hydrophobic tail is separated from a terminus of the hydrophobic tail by from 8 to 12 carbon atoms.

5. The lipid of claim 2 , wherein R 13 is a C 17 alkyl.

6. The lipid of claim 2 , wherein the protonatable group of the protonatable primary group is located in the head group.

7. The lipid of claim 2 , wherein the head group consists of a saturated aliphatic group and a hydroxyl group.

8. The lipid of claim 7 , wherein the saturated aliphatic group is a saturated straight chain alkyl group, wherein the saturated straight chain alkyl group is a methyl, ethyl, n-propyl, n-butyl, n-pentyl, or n-hexyl group.

9. The lipid of claim 2 , wherein the ester group in the at least one hydrophobic tail is separated from a terminus of the tail by 6 to 8 carbon atoms.

10. The lipid of claim 2 , wherein the ester group in the at least one hydrophobic tail is separated from a terminus of the tail by 8 carbon atoms.

11. The lipid of claim 2 , wherein the two hydrophobic tails have different chemical formulas.

12. The lipid of claim 11 , wherein both hydrophobic tails have a chain length of 18 atoms.

13. The lipid of claim 12 , wherein, in the other hydrophobic tail, each hydrophobic chain is a saturated straight chain alkyl group.

14. The lipid of claim 13 , wherein the other hydrophobic tail has a total carbon content of 17 carbon atoms.

15. The lipid of claim 2 , wherein a protonatable group of the protonatable primary group is positively charged at a pH that is below pH 7.4, and neutral at a second pH that is at or above pH 7.4.

16. The lipid of claim 2 , wherein the protonatable group of the protonatable primary group has a pKa of about 5 to about 7, when incorporated into a lipid particle.

17. The lipid of claim 16 , wherein the lipid particle comprises, based on the total lipids in the lipid particle, 50 mol % of the lipid, 10 mol % distearoylphosphatidylcholine (DSPC), 38.5 mol % cholesterol, and 1.5 mol % 1-(monomethoxy-polyethylene glycol)-2,3-dimyristoylglycerol, with an average PEG molecular weight of 2000 (PEG-DMG).

18. The lipid of claim 17 , wherein the lipid particle consists of, based on the total lipids in the lipid particle, 50 mol % of the lipid, 10 mol % distearoylphosphatidylcholine (DSPC), 38.5 mol % cholesterol, and 1.5 mol % 1-(monomethoxy-polyethylene glycol)-2,3-dimyristoylglycerol, with an average PEG molecular weight of 2000 (PEG-DMG).

19. The lipid of claim 2 , wherein the protonatable group of the protonatable primary group has a pKa of about 5.5 to about 6.8, when incorporated into a lipid particle.

20. The lipid of claim 19 , wherein the lipid particle comprises, based on the total lipids in the lipid particle, 50 mol % of the lipid, 10 mol % distearoylphosphatidylcholine (DSPC), 38.5 mol % cholesterol, and 1.5 mol % 1-(monomethoxy-polyethylene glycol)-2,3-dimyristoylglycerol, with an average PEG molecular weight of 2000 (PEG-DMG).

21. The lipid of claim 20 , wherein the lipid particle consists of, based on the total lipids in the lipid particle, 50 mol % of the lipid, 10 mol % distearoylphosphatidylcholine (DSPC), 38.5 mol % cholesterol, and 1.5 mol % 1-(monomethoxy-polyethylene glycol)-2,3-dimyristoylglycerol, with an average PEG molecular weight of 2000 (PEG-DMG).

22. The lipid of claim 14 , wherein the protonatable group of the protonatable primary group has a pKa of about 5 to about 7, when incorporated into a lipid particle.

23. The lipid of claim 22 , wherein the lipid particle comprises, based on the total lipids in the lipid particle, 50 mol % of the lipid, 10 mol % distearoylphosphatidylcholine (DSPC), 38.5 mol % cholesterol, and 1.5 mol % 1-(monomethoxy-polyethylene glycol)-2,3-dimyristoylglycerol, with an average PEG molecular weight of 2000 (PEG-DMG).

24. The lipid of claim 23 , wherein the lipid particle consists of, based on the total lipids in the lipid particle, 50 mol % of the lipid, 10 mol % distearoylphosphatidylcholine (DSPC), 38.5 mol % cholesterol, and 1.5 mol % 1-(monomethoxy-polyethylene glycol)-2,3-dimyristoylglycerol, with an average PEG molecular weight of 2000 (PEG-DMG).

25. The lipid of claim 14 , wherein the protonatable group of the protonatable primary group has a pKa of about 5.5 to about 6.8, when incorporated into a lipid particle.

26. The lipid of claim 25 , wherein the lipid particle comprises, based on the total lipids in the lipid particle, 50 mol % of the lipid, 10 mol % distearoylphosphatidylcholine (DSPC), 38.5 mol % cholesterol, and 1.5 mol % 1-(monomethoxy-polyethylene glycol)-2,3-dimyristoylglycerol, with an average PEG molecular weight of 2000 (PEG-DMG).

27. The lipid of claim 26 , wherein the lipid particle consists of, based on the total lipids in the lipid particle, 50 mol % of the lipid, 10 mol % distearoylphosphatidylcholine (DSPC), 38.5 mol % cholesterol, and 1.5 mol % 1-(monomethoxy-polyethylene glycol)-2,3-dimyristoylglycerol, with an average PEG molecular weight of 2000 (PEG-DMG).

28. The lipid of claim 14 , wherein a protonatable group of the protonatable primary group is positively charged at a pH that is below pH 7.4, and neutral at a second pH that is at or above pH 7.4.

Assignees

• Alnylam Pharmaceuticals Inc

Inventors

• Maier Martin
• Jayaraman Muthusamy
• Akinc Akin
• Matsuda Shigeo
• Kandasamy Pachamuthu
• Rajeev Kallanthottathil G
• Manoharan Muthiah
• Nair Jayaprakash K
• Baillie Thomas A

Classifications

• 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

• A61K31/7088

  Compounds having three or more nucleosides or nucleotides · CPC title

• C07C31/125

  containing five to twenty-two carbon atoms · CPC title

• C07C323/58

  with amino groups bound to the carbon skeleton · CPC title

• C07C323/12

  the carbon skeleton being acyclic and saturated · CPC title