Lipid nanoparticle formulations

Patent metadata

Field	Value
Publication number	US-11712481-B2
Application number	US-201716345592-A
Country	US
Kind code	B2
Filing date	Oct 26, 2017
Priority date	Oct 28, 2015
Publication date	Aug 1, 2023
Grant date	Aug 1, 2023

Abstract

Improved formulations of lipid nanoparticles are provided. Use of the lipid nanoparticles for delivery of a therapeutic agent and methods for their preparation are also provided.

First claim

The invention claimed is:

1. A lipid nanoparticle comprising:
i) from 47 to 48 mol percent of a cationic lipid;
ii) a neutral lipid;
iii) a steroid;
iv) a polymer conjugated lipid; and
v) a nucleic acid, or a pharmaceutically acceptable salt thereof, encapsulated within or associated with the lipid nanoparticle,
wherein the cationic lipid has a structure of Formula II:

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:
one of L 1 or 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 or L 2 is —O(C═O)—, —(C═O)O—, —C(═O)—, —O—, —S(O)—, —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;
G 1 is C 1 -C 2 alkylene, —(C═O)—, —O(C═O)—, —SC(═O)—, —NR a C(═O)— or a direct bond;
G 2 is —C(═O)—, —(C═O)O—, —C(═O)S—, —C(═O)NR a — or a direct bond;
G 3 is C 1 -C 6 alkylene;
R a is H or C 1 -C 12 alkyl;
R 1a and R 1b are, at each occurrence, independently either: (a) H or C 1 -C 12 alkyl; or (b) R 1a is H or C 1 -C 12 alkyl, and R 1b together with the carbon atom to which it is bound is taken together with an adjacent R 1b and the carbon atom to which it is bound to form a carbon-carbon double bond;
R 2a and R 2b are, at each occurrence, independently either: (a) H or C 1 -C 12 alkyl; or (b) R 2a is H or C 1 -C 12 alkyl, and R 2b together with the carbon atom to which it is bound is taken together with an adjacent R 2b and the carbon atom to which it is bound to form a carbon-carbon double bond;
R 3a and R 3b are, at each occurrence, independently either (a): H or C 1 -C 12 alkyl; or (b) R 3a is H or C 1 -C 12 alkyl, and R 3b together with the carbon atom to which it is bound is taken together with an adjacent R 3b and the carbon atom to which it is bound to form a carbon-carbon double bond;
R 4a and R 4b are, at each occurrence, independently either: (a) H or C 1 -C 12 alkyl; or (b) R 4a is H or C 1 -C 12 alkyl, and R 4b together with the carbon atom to which it is bound is taken together with an adjacent R 4b and the carbon atom to which it is bound to form a carbon-carbon double bond;
R 5 and R 6 are each independently H or methyl;
R 7 is C 4 -C 20 alkyl;
R 8 and R 9 are each independently C 1 -C 12 alkyl; or R 8 and R 9 , together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring;
a, b, c and d are each independently an integer from 1 to 24; and
x is 0, 1 or 2.

2. The lipid nanoparticle of claim 1 , comprising from 47.2 to 47.8 mol percent of the cationic lipid.

3. The lipid nanoparticle of claim 1 , wherein the neutral lipid is present in a concentration ranging from 5 to 15 mol percent.

4. The lipid nanoparticle of claim 1 , wherein the steroid is present in a concentration ranging from 32 to 40 mol percent.

5. The lipid nanoparticle of claim 1 , wherein the molar ratio of the cationic lipid to the steroid ranges from 1.0:0.9 to 1.0:1.2.

6. The lipid nanoparticle of claim 1 , wherein the cationic lipid has one of the following structures:

7. The lipid nanoparticle of claim 1 , wherein the molar ratio of cationic lipid to the neutral lipid ranges from about 4.1:1.0 to about 4.9:1.0.

8. The lipid nanoparticle of claim 1 , wherein the molar ratio of cationic lipid to steroid ranges from 5:1 to 1:1.

9. The lipid nanoparticle of claim 1 , wherein the molar ratio of cationic lipid to polymer conjugated lipid ranges from about 100:1 to about 20:1.

10. The lipid nanoparticle of claim 1 , wherein the neutral lipid is distearoylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylcholine (DPPC), dioleoylphosphatidylglycerol (DOPG), dipalmitoylphosphatidylglycerol (DPPG), dioleoyl-phosphatidylethanolamine (DOPE), palmitoyloleoylphosphatidylcholine (POPC), palmitoyloleoyl-phosphatidylethanolamine (POPE) and dioleoyl-phosphatidylethanolamine 4-(N-maleimidomethyl)-cyclohexane-1 carboxylate (DOPE-mal), dipalmitoyl phosphatidyl ethanolamine (DPPE), dimyristoylphosphoethanolamine (DMPE), distearoyl-phosphatidylethanolamine (DSPE), 16-O-monomethyl PE, 16-O-dimethyl PE, 18-1-trans PE, 1-stearioyl-2-oleoylphosphatidyethanol amine (SOPE) or 1,2-dielaidoyl-sn-glycero-3-phosphoethanolamine (transDOPE).

11. The lipid nanoparticle of claim 1 , wherein the steroid is cholesterol.

12. The lipid nanoparticle of claim 1 , wherein the polymer conjugated lipid is present in a concentration ranging from 1.0 to 2.5 molar percent.

13. The lipid nanoparticle of claim 1 , wherein the polymer conjugated lipid is a pegylated lipid.

14. The lipid nanoparticle of claim 1 , wherein the nucleic acid is selected from antisense and messenger RNA.

15. A pharmaceutical composition comprising a lipid nanoparticle of claim 1 and a pharmaceutically acceptable excipient.

16. A method for administering a therapeutic agent to a patient in need thereof, the method comprising administering the lipid nanoparticle of claim 1 to the patient.

17. A method for treating a disease in a patient in need thereof, the method comprising administering the lipid nanoparticle of claim 1 to the patient, wherein the therapeutic agent is effective to treat the disease.

18. The lipid nanoparticle of claim 1 , wherein a plurality of the lipid nanoparticles has a polydispersity of less than 0.12.

19. A lipid nanoparticle comprising:
i) from 47 to 48 mol percent of a cationic lipid;
ii) a neutral lipid;
iii) a steroid;
iv) a polymer conjugated lipid; and
v) a nucleic acid, or a pharmaceutically acceptable salt thereof, encapsulated within or associated with the lipid nanoparticle,
wherein the cationic lipid has one of the following structures:

20. The lipid nanoparticle of claim 19 , comprising from 47.2 to 47.8 mol percent of the cationic lipid.

21. The lipid nanoparticle of claim 19 , wherein the neutral lipid is present in a concentration ranging from 5 to 15 mol percent.

22. The lipid nanoparticle of claim 19 , wherein the steroid is present in a concentration ranging from 32 to 40 mol percent.

23. The lipid nanoparticle of claim 19 , wherein the molar ratio of the cationic lipid to the steroid ranges from 1.0:0.9 to 1.0:1.2.

24. The lipid nanoparticle of claim 19 , wherein the molar ratio of cationic lipid to the neutral lipid ranges from about 4.1:1.0 to about 4.9:1.0.

25. The lipid nanoparticle of claim 19 , wherein the molar ratio of cationic lipid to steroid ranges from 5:1 to 1:1.

26. The lipid nanoparticle of claim 19 , wherein the molar ratio of cationic lipid to polymer conjugated lipid ranges from about 100:1 to about 20:1.

27. The lipid nanoparticle of claim 19 , wherein the neutral lipid is distearoylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylcholine (DPPC), dioleoylphosphatidylglycerol (DOPG), dipalmitoylphosphatidylglyce

Assignees

• Acuitas Therapeutics Inc

Inventors

• Hope Michael J
• Mui Barbara
• Lin Paulo Jia Ching
• Barbosa Christopher J
• Madden Thomas D
• Ansell Steven M
• Du Xinyao

Classifications

• A61K48/0033 Primary

  the non-active part being non-polymeric · CPC title

• A61K9/127 Primary

  Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant · CPC title

• A61K47/18

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

• C07C219/06 Primary

  having the hydroxy groups esterified by carboxylic acids having the esterifying carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms of an acyclic saturated carbon skeleton · CPC title

• C07C229/12

  to carbon atoms of acyclic carbon skeletons · CPC title