Lipids and lipid nanoparticle formulations for delivery of nucleic acids

Patent metadata

Field	Value
Publication number	US-9737619-B2
Application number	US-201715432771-A
Country	US
Kind code	B2
Filing date	Feb 14, 2017
Priority date	Jun 25, 2014
Publication date	Aug 22, 2017
Grant date	Aug 22, 2017

Abstract

Compounds are provided having the following structure:

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5 , R 6 , R 7 , R 8 , R 9 , L 1 , L 2 , a, b, c, d and e 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.

First claim

The invention claimed is:

1. A pegylated lipid having the following structure (II):

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:
R 10 and R 11 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
z has a mean value ranging from 30 to 60;

provided that R 10 and R 11 are not both n-octadecyl when z is 42.

2. The pegylated lipid of claim 1 , wherein R 10 and R 11 are each independently straight, saturated alkyl chains containing from 12 to 16 carbon atoms.

3. The pegylated lipid of claim 1 , wherein z is about 45.

4. The pegylated lipid of claim 1 , having one of the following structures:

wherein n has a mean value ranging from 40 to 50.

5. A composition comprising the pegylated lipid of claim 1 and a cationic lipid.

6. The composition of claim 5 , wherein the cationic lipid has a structure of Formula I:

or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof, wherein:
L 1 and L 2 are each independently —O(C═O)—, —(C═O)O— or a carbon-carbon double bond;
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 methyl or cycloalkyl;
R 7 is, at each occurrence, independently H or C 1 -C 12 alkyl;
R 8 and R 9 are each independently unsubstituted 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 comprising one nitrogen atom;
a and d are each independently an integer from 0 to 24;
b and c are each independently an integer from 1 to 24; and
e is 1 or 2.

7. The composition of claim 6 , wherein one of L 1 or L 2 is —O(C═O)—.

8. The composition of claim 6 , wherein one of L 1 or L 2 is —(C═O)O—.

9. The composition of claim 6 , wherein the cationic lipid has one of the following structures (Ia), (Ib) or (Ic):

10. The composition of claim 9 , wherein a, b, c and d are each independently an integer from 2 to 12.

11. The composition of claim 9 , wherein a, b, c and d are each independently an integer from 5 to 9.

12. The composition of claim 9 , wherein at least one of R 1a , R 2a , R 3a and R 4a is H.

13. The composition of claim 9 , wherein at least one of R 1a , R 2a , R 3a and R 4a is C 1 -C 8 alkyl.

14. The composition of claim 13 , wherein C 1 -C 8 alkyl is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-hexyl or n-octyl.

15. The composition of claim 9 , wherein each of R 5 and R 6 is methyl.

16. The composition of claim 9 , wherein e is 2.

17. The composition of claim 9 , wherein each of R 8 and R 9 is methyl.

18. The composition of claim 5 , wherein the cationic lipid has one of the following structures:

19. The composition of claim 5 , further comprising a nucleic acid.

20. The composition of claim 19 , wherein the nucleic acid is selected from antisense and messenger RNA.

21. The composition of claim 5 , further comprising one or more excipient selected from neutral lipids and steroids.

22. The composition of claim 21 , wherein the composition comprises one or more neutral lipids selected from DSPC, DPPC, DMPC, DOPC, POPC, DOPE and SM.

23. The composition of claim 22 , wherein the neutral lipid is DSPC.

24. The composition of claim 21 , wherein the steroid is cholesterol.

25. The pegylated lipid of claim 1 , wherein R 10 and R 11 are each independently a straight or branched, saturated or unsaturated alkyl chain containing 12 carbon atoms.

26. The pegylated lipid of claim 1 , wherein R 10 and R 11 are each independently a straight or branched, saturated or unsaturated alkyl chain containing 14 carbon atoms.

27. The pegylated lipid of claim 1 , wherein R 10 and R 11 are each independently a straight or branched, saturated or unsaturated alkyl chain containing 16 carbon atoms.

Assignees

• Acuitas Therapeutics Inc

Inventors

• Ansell Steven M
• Du Xinyao

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• C07C219/06

  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

• C07C219/10

  having at least one of the hydroxy groups esterified by a carboxylic acid having the esterifying carboxyl group bound to an acyclic carbon atom of a carbon skeleton containing rings · CPC title

• C07C235/06

  having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms · CPC title

• A61K47/22

  Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones · CPC title