Cationic lipids for therapeutic agent delivery formulations

Patent metadata

Field	Value
Publication number	US-9242001-B2
Application number	US-201414256306-A
Country	US
Kind code	B2
Filing date	Apr 18, 2014
Priority date	Jun 8, 2011
Publication date	Jan 26, 2016
Grant date	Jan 26, 2016

Abstract

Here described are compounds of formula I:

wherein R 1 and R 2 is independently selected from a group consisting of C 10 to C 18 alkyl, C 12 to C 18 alkenyl, and oleyl group; wherein R 3 and R 4 are independently selected from a group consisting of C 1 to C 6 alkyl, and C 2 to C 6 alkanol; wherein X is selected from a group consisting of —CH 2 —, —S—, and —O— or absent; wherein Y is selected from —(CH 2 ) n , —S(CH 2 ) n , —O(CH 2 ) n —, thiophene, —SO 2 (CH 2 ) n —, and ester, wherein n=1-4; wherein a=1-4; wherein b=1-4; wherein c=1-4; and wherein Z is a counterion; as well as compositions and pharmaceutical formulations including compounds of formula I which are useful for the delivery of therapeutic agents; and methods of using these compositions and formulations.

First claim

What is claimed:

1. A stellate-cell-specific drug carrier comprising a stellate cell specific amount of a retinoid molecule and a liposomal composition wherein the liposomal composition comprises a cationic lipid of formula I

wherein R 1 and R 2 are independently selected from the group consisting of C 10 to C 18 alkyl, C 12 to C 18 alkenyl, and oleyl; wherein R 3 and R 4 are independently selected from the group consisting of C 1 to C 6 alkyl, and C 2 to C 6 alkanol; wherein X is selected from the group consisting of —CH 2 —, —S—, and —O—, or is absent; wherein Y is selected from —(CH 2 ) n —, —S(CH 2 ) n —, —O(CH 2 ) n —, -thiophene-, —SO 2 (CH 2 ) n , and ester, wherein n=1-4; wherein a=1-4; wherein b=1-4; wherein c=1-4; and wherein Z is a counterion.

2. The drug carrier of claim 1 , wherein the liposomal composition comprises a lipid vesicle comprising a bilayer of lipid molecules.

3. The drug carrier of claim 1 , wherein the retinoid molecule is a compound of formula II:

wherein q, r, and s are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; or an enantiomer, diastereomer, or mixture of stereoisomers thereof.

4. The drug carrier of claim 3 , wherein the retinoid molecule is

5. The drug carrier of claim 2 , wherein the retinoid molecule is at least partially exposed on the exterior of the drug carrier before the drug carrier reaches the stellate cell.

6. The drug carrier of claim 1 , wherein the retinoid molecule is 0.1 mol % to 20 mol % of the lipid molecules.

7. The drug carrier of claim 1 , wherein the cationic lipid is at a concentration of 5 mol % to 50 mol %.

8. The drug carrier of claim 2 , wherein cationic lipid is

9. The drug carrier of claim 2 , wherein the lipid molecules further comprise a PEG-lipid.

10. The drug carrier of claim 9 , wherein the PEG-lipid is at a concentration of 1 to 10 mol %.

11. The drug carrier of claim 9 , wherein the PEG-lipid is polyethyleneglycol-dimyristoyl-phosphatidylethanolamine.

12. The drug carrier of claim 2 , wherein the lipid molecules further comprise an ionizable cationic lipid.

13. The drug carrier of claim 12 , wherein the ionizable cationic lipid is

14. The drug carrier of claim 12 , wherein the ionizable cationic lipid is present at a concentration of 5 to 45 mol %.

15. The drug carrier of claim 2 , wherein the lipid molecules further comprise a combination of a quaternary amine cationic lipid and an ionizable cationic lipid.

16. The drug carrier of claim 15 , wherein the ionizable cationic lipid is the immediate synthetic precursor to the quaternary amine cationic lipid.

17. The drug carrier of claim 15 , wherein the quaternary amine cationic lipid is HEDC and the ionizable cationic lipid is S104.

18. The drug carrier of claim 2 , wherein the lipid molecules further comprise a non-cationic lipid.

19. The drug carrier of claim 18 , wherein the non-cationic lipid is a phospholipid.

20. The drug carrier of claim 19 , wherein the phospholipid is 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine.

21. The drug carrier of claim 19 , wherein the phospholipid is at a concentration of 0 to 55 mol %.

22. The drug carrier of claim 18 , wherein the non-cationic lipid is cholesterol.

23. The drug carrier of claim 22 , wherein cholesterol is at a concentration of 0 to 55 mol %.

24. The drug carrier of claim 1 , further comprising a nucleic acid.

25. The drug carrier of claim 24 , wherein the nucleic acid is an siRNA that is capable of knocking down expression of hsp47 mRNA in the stellate cell.

26. The drug carrier of claim 1 , further comprising siRNA.

27. The drug carrier of claim 26 , wherein the siRNA is encapsulated by the liposome and is inaccessible to an aqueous medium.

28. The drug carrier of claim 26 , wherein the siRNA is complexed on the outer surface of the liposome and accessible to an aqueous medium.

29. The drug carrier of claim 1 , wherein the cationic lipid is selected from the group consisting of

Assignees

• Nitto Denko Corp

Inventors

• Niitsu Yoshiro
• Knopov Victor
• Payne Joseph E
• Hou Zheng
• Gaudette John A
• Akopian Violetta
• Witte Richard P
• Ahmadian Mohammad
• Perelman Loren A
• Tanaka Yasunobu
• Karmali Priya
• Nagarajan Sridhar C

Classifications

• A61K9/1271

  Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers (liposomes as conjugates {A61K47/6911}) · CPC title

• C07C323/60

  with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms · CPC title

• A61K47/6911

  the form being a liposome · CPC title

• C07C237/08 Primary

  having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms · CPC title

• A61K9/10

  Dispersions; Emulsions · CPC title