Granted Patent
B2
US 12,350,338 · App. 18/589,688 · Granted Jul 8, 2025
Biodegradable lipids for the delivery of active agents
Inventors:
Martin Maier (Cambridge, MA); Muthusamy Jayaraman (Cambridge, MA); Akin Akinc (Cambridge, MA); Shigeo Matsuda (Cambridge, MA); Pachamuthu Kandasamy (Cambridge, MA); Kallanthottathil G. Rajeev (Cambridge, MA); Muthiah Manoharan (Cambridge, MA); Jayaprakash K. Nair (Cambridge, MA); Thomas A. Baillie (Cambridge, MA)
Assignee:
ALNYLAM PHARMACEUTICALS, INC.
A61K47/18A61K9/1272A61K9/5123A61K31/7088A61K31/7105A61K31/713C07C31/125C07C211/09C07C211/10C07C211/11C07C217/08C07C229/12C07C235/06C07C251/38C07C323/12C07C323/58C07C327/22C07C327/28C07C327/32C07D207/32C07D233/54C07D295/08C07D295/12C07D295/14C07D317/30C07F5/022
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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.
Claims (22)
1. A lipid consisting of a protonatable primary group and two hydrophobic tails directly bonded to the primary group, wherein:
the primary group consists of a head group and a central moiety; and
the central moiety is a nitrogen atom, wherein:
a) both of the two hydrophobic tails have a chain length of 18 atoms;
b) each of the two hydrophobic tails
(i) is of the formula: -(hydrophobic chain)-(C(O)O)-(hydrophobic chain), and
(ii) has a total carbon atom content of from 17 to 26 carbon atoms, and
c) at least one of the two hydrophobic tails has the formula:
wherein R 13 is a C 17 alkyl, wherein the maximum length of R 13 from its attachment point to the ester group is 11 carbon atoms.
2. The lipid of claim 1 , wherein the two hydrophobic tails have different chemical formulas.
3. The lipid of claim 1 , wherein, in the other hydrophobic tail, each hydrophobic chain is a saturated straight chain alkyl group.
4. The lipid of claim 2 , wherein, in the other hydrophobic tail, the number of carbon atoms in the hydrophobic chain between the primary group and the biodegradable group is 5 to 10.
5. The lipid of claim 1 , wherein, the head group consists of a saturated aliphatic group and a hydroxyl group.
6. The lipid of claim 5 , 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.
7. The lipid of claim 1 , wherein the other hydrophobic tail has a total carbon atom content of 17 carbon atoms.
8. The lipid of claim 1 , 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.
9. The lipid of claim 7 , wherein the protonatable group of the protonatable primary group has a pK a of about 5.5 to about 6.8, when incorporated into a lipid particle.
10. The lipid of claim 9 , 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).
11. The lipid of claim 10 , 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).
12. The lipid of claim 1 , wherein the protonatable group of the protonatable primary group has a pK a of about 5.5 to about 6.8, when incorporated into a lipid particle.
13. The lipid of claim 12 , 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).
14. The lipid of claim 12 , 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).
Assignments (4)
SECURITY INTEREST
Recorded Oct 1, 2025
From: ALNYLAM PHARMACEUTICALS, INC.; SIRNA THERAPEUTICS, INC.
To: BANK OF AMERICA, N.A.
Reel/Frame 072996/0337 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Feb 28, 2024
From: MAIER, MARTIN; JAYARAMAN, MUTHUSAMY; AKINC, AKIN; MATSUDA, SHIGEO; KANDASAMY, PACHAMUTHU; RAJEEV, KALLANTHOTTATHIL G; MANOHARAN, MUTHIAH
To: ALNYLAM PHARMACEUTICALS, INC.
Reel/Frame 066591/0641 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Feb 28, 2024
From: NAIR, JAYAPRAKASH K.
To: ALNYLAM PHARMACEUTICALS, INC.
Reel/Frame 066591/0721 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Feb 28, 2024
From: BAILLIE, THOMAS A
To: ALNYLAM PHARMACEUTICALS, INC.
Reel/Frame 066591/0773 →
Continuity (9)
Continuation
17302311
· Apr 29, 2021
Provisional Application
61623274
· Apr 12, 2012
Provisional Application
61568133
· Dec 7, 2011
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