Lipids and lipid nanoparticle formulations for delivery of nucleic acids
Compounds are provided having the following structure: or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R 1 , R 2 , R 3 , L 1 , L 2 , G 1 , G 2 and G 3 are as defined herein. Use of the compounds as a component of lipid nanoparticle formulations for delivery of a therapeutic agent, compositions comprising the compounds and methods for their use and preparation are also provided.
1 . A compound having one of the following structures (IC) or (ID):
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
one of L 1 and L 2 is —O (C═O)—, —(C═O)O—, —C(═O)—, —O—, —S(O) x —, —S—S—, —C(═O)S—, —SC(═O)—, —NR a C(═O)—, —C(═O)NR a —, NR a C(═O)NR a —, —OC(═O)NR a — or —NR a C(═O)O—, and the other of L 1 and L 2 is —O(C═O)—, —(C═O)O—, —C(═O)—, —O—, —S(O) x —, —S—S—, —C(═O)S—, SC(═O)—, —NR a C(═O)—, —C(═O)NR a —, , NR a C(═O)NR a —, —OC(═O)NR a — or —NR a C(═O)O— or a direct bond;
R a is H or C 1 -C 12 alkyl;
R 1 and R 2 are each independently branched C 6 -C 24 alkyl or branched C 6 -C 24 alkenyl;
R 3 is H, OR 5 , CN, —C(═O)OR 4 , —OC(═O)R 4 or —NR 5 C(═O)R 4 ;
R 4 is C 1 -C 12 alkyl;
R 5 is H or C 1 -C 6 alkyl;
A is a 3 to 8-membered cycloalkyl or cycloalkylene ring;
R 6 is, at each occurrence, independently H, OH or C 1 -C 24 alkyl;
n is 3, 4, 5 or 6;
y and z are each independently an integer ranging from 4 to 9; and
x is 0, 1 or 2.
2 . The compound of claim 1 , wherein L 1 and L 2 are each independently —O(C═O)— or —(C═O)O—.
3 . The compound of claim 1 , having one of the following structures (IG), (IH), (II) or (IJ):
4 . The compound of claim 1 , wherein R 1 or R 2 , or both, is branched C 6 -C 24 alkenyl.
5 . The compound of claim 1 , wherein R 1 or R 2 , or both, is branched C 6 -C 24 alkyl.
6 . The compound of claim 5 , wherein R 1 and R 2 each, independently have the following structure:
wherein:
R 7a and R 7b are, at each occurrence, independently H or C 1 -C 12 alkyl; and
a is an integer from 2 to 12,
wherein R 7a , R 7b and a are each selected such that R 1 and R 2 each independently comprise from 6 to 20 carbon atoms, and R 1 and R 2 are branched.
7 . The compound of claim 6 , wherein a is an integer from 8 to 12.
8 . The compound of claim 6 , wherein at least one occurrence of R 7a is H.
9 . The compound of claim 6 , wherein R 7a is H at each occurrence.
10 . The compound of claim 6 , wherein at least one occurrence of R 7b is C 1 -C 8 alkyl.
11 . The compound of claim 10 , wherein C 1 -C 8 alkyl is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-hexyl or n-octyl.
12 . The compound of claim 5 , wherein R 1 or R 2 , or both, has one of the following structures:
13 . The compound of claim 1 , wherein R 3 is OH.
14 . The compound of claim 1 , wherein R 3 is CN.
15 . The compound of claim 1 , wherein R 3 is —C(═O)OR 4 , —OC(═O)R 4 or —NHC(═O)R 4 .
16 . The compound of claim 15 , wherein R 4 is methyl or ethyl.
17 . A compound having one of the following structures:
18 . A composition comprising the compound of claim 1 and a therapeutic agent.
19 . The composition of claim 18 , further comprising one or more excipient selected from neutral lipids, steroids and polymer conjugated lipids.
20 . The composition of claim 19 , wherein the composition comprises one or more neutral lipids selected from DSPC, DPPC, DMPC, DOPC, POPC, DOPE and SM.
21 . The composition of claim 20 , wherein the neutral lipid is DSPC.
22 . The composition of claim 18 , wherein the molar ratio of the compound to the neutral lipid ranges from about 2:1 to about 8:1.
23 . The composition of claim 19 , wherein the steroid is cholesterol.
24 . The composition of claim 23 , wherein the molar ratio of the compound to cholesterol ranges from 5:1 to 1:1.
25 . The composition of claim 19 , wherein the polymer conjugated lipid is pegylated lipid.
26 . The composition of claim 25 , wherein the molar ratio of the compound to pegylated lipid ranges from about 100:1 to about 20:1.
27 . The composition of claim 25 , wherein the pegylated lipid is PEG-DAG, PEG-PE, PEG-S-DAG, PEG-cer or a PEG dialkyoxypropylcarbamate.
28 . The composition of claim 25 , wherein the pegylated lipid has the following structure (II):
or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:
R 8 and R 9 are each independently a straight or branched, saturated or unsaturated alkyl chain containing from 10 to 30 carbon atoms, wherein the alkyl chain is optionally interrupted by one or more ester bonds; and
w has a mean value ranging from 30 to 60.
29 . The composition of claim 28 , wherein R 8 and R 9 are each independently straight, saturated alkyl chains containing from 12 to 16 carbon atoms.
30 . The composition of claim 28 , wherein the average w is about 49.
31 . The composition of claim 18 , wherein the therapeutic agent comprises a nucleic acid.
32 . The composition of claim 31 , wherein the nucleic acid is selected from antisense and messenger RNA.
33 . A method for administering a therapeutic agent to a patient in need thereof, the method comprising preparing or providing the composition of claim 18 , and administering the composition to the patient.