Lipids for therapeutic agent delivery formulations

Patent metadata

Field	Value
Publication number	US-10441659-B2
Application number	US-201514872951-A
Country	US
Kind code	B2
Filing date	Oct 1, 2015
Priority date	Jun 8, 2012
Publication date	Oct 15, 2019
Grant date	Oct 15, 2019

Abstract

The description is directed to ionizable lipids useful for enhancing the delivery of therapeutic agents in liposomes.

First claim

What is claimed:

1. A composition comprising lipid molecules comprising an ionizable lipid compound of formula I:

wherein
n and m are independently 1, 2, 3, or 4;
R 1 and R 2 are independently C 10-18 alkyl-;
X is —CH 2 —, wherein L is —OC 1-4 alkylene- or
—OC(O)C 1-4 alkylene-; or
X is absent, wherein L is —C 1 alkylene-, —C 3 alkylene-, —C 4 alkylene-, —OC 1-4 alkylene-, or —OC(O)C 1-4 alkylene-; or
X is O or N, wherein L is —C 1-4 alkylene-, or
—C(O)C 1-4 alkylene-;

or a pharmaceutically acceptable salt form thereof;
and a cationic lipid, wherein the cationic lipid is

2. The composition of claim 1 , comprising the compound of formula I, wherein n and m are 1 or 2.

3. The composition of claim 1 , comprising the compound of formula I, wherein X is absent.

4. The composition compound of claim 3 , comprising the compound of formula I, wherein L is —OC 1-4 alkylene-, or —OC(O)C 1-4 alkylene-.

5. The composition of claim 3 , comprising the compound of formula I, wherein L is —CH 2 —, —CH 2 CH 2 CH 2 —, or —CH 2 CH 2 CH 2 CH 2 —.

6. The composition of claim 1 , comprising the compound of formula I, wherein X is —CH 2 —.

7. The composition of claim 6 , comprising the compound of formula I, wherein L is —OC 1-4 alkylene-.

8. The composition of claim 7 , comprising the compound of formula I, wherein L is —OCH 2 CH 2 — or —OCH 2 CH 2 CH 2 —.

9. The composition of claim 6 , comprising the compound of formula I, wherein L is —OC(O)C 1-4 alkylene-.

10. The composition of claim 9 , comprising the compound of formula I, wherein L is —OC(O)CH 2 CH 2 CH 2 —.

11. The composition of claim 1 , comprising the compound of formula I, wherein X is O.

12. The composition of claim 1 , comprising the compound of formula I, wherein R 1 and R 2 are each C 10-18 alkyl-.

13. The composition of claim 12 , comprising the compound of formula I, wherein R 1 and R 2 are each C 13 alkyl-.

14. A composition comprising a compound selected from the group consisting of

or a pharmaceutically acceptable salt form thereof;
and a cationic lipid, wherein the cationic lipid is

15. The composition of claim 1 , wherein the ionizable lipid compound is 5 to 50 mol % of the total lipid molecules.

16. A composition comprising lipid molecules comprising an ionizable lipid compound of formula I:

wherein
n and m are independently 1, 2, 3, or 4;
R 1 and R 2 are independently C 10-18 alkyl-;
X is absent;
L is —CH 2 CH 2 —;

or a pharmaceutically acceptable salt form thereof;
and a cationic lipid, wherein the cationic lipid is

17. The composition of claim 16 , wherein the ionizable lipid compound of formula I consists of

18. A composition comprising lipid molecules comprising an ionizable lipid compound of formula I:

wherein
n and m are independently 2, 3, or 4;
R 1 and R 2 are independently C 12-18 alkenyl-;
X is absent;
L is —CH 2 CH 2 —;

or a pharmaceutically acceptable salt form thereof;
and a cationic lipid, wherein the cationic lipid is

19. A composition comprising lipid molecules comprising an ionizable lipid compound of formula I:

wherein
n and m are independently 2, 3, or 4;
R 1 and R 2 independently are a C 12-18 alkenyl-;
X is —CH 2 —, wherein L is —OC 1-4 alkylene or —OC(O)C 1-4 alkylene-; or
X is absent, wherein L is C 1 -C 4 alkylene, —OC 1-4 alkylene, or
—OC(O)C 1-4 alkylene-; or
X is O or N, wherein L is —C 1-4 alkylene-, or
—C(O)C 1-4 alkylene-;

or a pharmaceutically acceptable salt form thereof;
and a cationic lipid, wherein the cationic lipid is

20. The composition of claim 19 , wherein the ionizable lipid compound of formula I consists of i-Pr-DODC

21. A composition comprising lipid molecules comprising an ionizable lipid compound of formula I:

wherein
n and m are 1;
R 1 and R 2 independently are a C 12-18 alkenyl;
X is —CH 2 —, wherein L is —OC 1-4 alkylene- or —OC(O)C 1-4 alkylene-; or
X is absent, wherein L is —C 1-4 alkylene-, —OC 1-4 alkylene-, or —OC(O)C 1-4 alkylene-; or
X is O or N, wherein L is —C 1-4 alkylene-, or
—C(O)C 1-4 alkylene-;

or a pharmaceutically acceptable salt form thereof;
and a cationic lipid, wherein the cationic lipid is

22. The composition of claim 21 , wherein the ionizable lipid compound of formula I consists of C104-DO

Assignees

• Nitto Denko Corp

Inventors

• Payne Joseph E
• Gaudette John A
• Hou Zheng
• Ahmadian Mohammad
• Yu Lei
• Knopov Victor
• Akopian Violetta
• Karmali Priya
• Witte Richard P
• Safarzadeh Neda
• Ying Wenbin
• Zhang Jun

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P1/18

  for pancreatic disorders, e.g. pancreatic enzymes · CPC title

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title

• C07D207/16

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• C07C271/16

  to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms · CPC title