Lipid particles with asymmetric cationic lipids for RNA delivery

Patent metadata

Field	Value
Publication number	US-9580711-B2
Application number	US-201615146783-A
Country	US
Kind code	B2
Filing date	May 4, 2016
Priority date	Nov 18, 2013
Publication date	Feb 28, 2017
Grant date	Feb 28, 2017

Abstract

What is described is a lipid particle comprising the compound of formula I

wherein
R 1 consists of alkyl, alkenyl, alkynyl, or cholesteryl; R 2 consists of alkyl or alkenyl; L 1 consists of alkyl, alkylene or alkenyl; X 1 consists of —O—(CO)— or —(CO)—O—; X 2 consists of S or O; L 2 consists of a bond or alkylene; R 3 consists of alkylene; and R 4 and R 5 are the same or different, each consisting of alkyl;

or a pharmaceutical preparation thereof.

First claim

What is claimed:

1. Lipid particles comprising a cationic lipid, wherein the cationic lipid comprises a compound of formula I

wherein
R 1 consists of a linear or branched alkyl consisting of 1 to 20 carbons, an alkenyl or alkynyl consisting of 2 to 12 carbons, or a cholesteryl;
R 2 consists of a linear or branched alkyl consisting of 1 to 20 carbons or an alkenyl consisting of 2 to 20 carbons;
L 1 consists of a linear alkylene consisting of 3 to 9 carbons or, when R 1 consists of a cholesteryl then L 1 consists of a linear alkylene or alkenylene consisting of 3 to 4 carbons;
X 1 consists of —O—(CO)— or —(CO)—O—;
X 2 consists of S or O;
L 2 consists of a bond or a linear alkylene of 1 to 6 carbons;
R 3 consists of a linear or branched alkylene with 1 to 6 carbons; and
R 4 and R 5 are the same or different, each consisting of a linear or branched alkyl of 1 to 6 carbons;

or a pharmaceutical preparation thereof.

2. The lipid particles of claim 1 , further comprising a nucleic acid.

3. The lipid particles of claim 2 , wherein the nucleic acid comprises a mRNA or a siRNA.

4. The lipid particles of claim 3 , wherein the mRNA or siRNA is encapsulated by the lipid particles.

5. The lipid particles of claim 4 , wherein 30-100% of the lipid particles have mRNA or siRNA encapsulated therein.

6. The lipid particles of claim 2 , comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more mRNA that express one or more polypeptides.

7. The lipid particles of claim 1 , further comprising a phospholipid.

8. The lipid particles of claim 7 wherein the phospholipid is phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidic acid, palmitoyloleoyl phosphatidylcholine, lysophosphatidylcholine, lysophosphatidylethanolamine, dipalmitoylphosphatidylcholine, dioleoylphosphatidylcholine, distearoylphosphatidylcholine, or dilinoleoylphosphatidylcholine.

9. The lipid particles of claim 1 , further comprising a conjugated lipid.

10. The lipid particles of claim 9 , wherein the conjugated lipid is a polyethylene glycol (PEG) coupled to dialkyloxypropyls, PEG coupled to diacylglycerols, PEG coupled to cholesterol, PEG coupled to phosphatidylethanolamines, PEG conjugated to ceramides, cationic PEG lipids, polyoxazoline (POZ)-lipid conjugates, polyamide oligomers, and mixtures thereof.

11. The lipid particles of claim 10 , further comprising cholesterol, 5α-cholestanol, 5α-coprostanol, cholesteryl-(2′-hydroxy)-ethyl ether, cholesteryl-(4′-hydroxy)-butyl ether, 6-ketocholestanol, 5α-cholestane, cholestenone, 5α-cholestanone, 5α-cholestanone, cholesteryl decanoate, or mixtures thereof.

12. The lipid particles of claim 1 , further comprising a variety of lipids, wherein the cationic lipid comprises 30-70 mole % of lipids in the lipid particles.

13. The lipid particles of claim 1 , wherein the lipid particles have a mean diameter of 30 nm to 150 nm.

14. The lipid particles of claim 1 , wherein the cationic lipid comprises a compound of formula I wherein X 1 consists of —O—(CO)—.

15. The lipid particles of claim 1 , wherein the cationic lipid comprises a compound of formula I wherein X 2 consists of S.

16. The lipid particles of claim 1 , wherein the cationic lipid comprises a compound of formula I wherein R 3 consists of ethylene, n-propylene, or isopropylene.

17. The lipid particles of claim 1 , wherein the cationic lipid comprises a compound of formula I wherein R 4 and R 5 separately consist of methyl, ethyl, or isopropyl.

18. The lipid particles of claim 1 , wherein the cationic lipid comprises a compound of formula I wherein L 2 consists of a bond or a methylene.

19. The lipid particles of claim 1 , wherein the cationic lipid comprises a compound of formula I wherein R 1 and R 2 each consist of a branched alkyl; or each consists of 13-20 carbon atoms.

20. The lipid particles of claim 1 , wherein the cationic lipid is selected from the compounds of formula ATX-A-1 to ATX-A-22

or a pharmaceutically acceptable salt thereof.

Assignees

• Arcturus Therapeutics Inc

Inventors

• Payne Joseph E
• Chivukula Padmanabh
• Webb David

Classifications

• C07C333/04 Primary

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

• C12N15/113 Primary

  Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)} · CPC title

• A61K31/713

  Double-stranded nucleic acids or oligonucleotides · CPC title

• A61K9/1075

  Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers (A61K9/0026 takes precedence) · CPC title

• C12N15/111

  General methods applicable to biologically active non-coding nucleic acids · CPC title