Lipids and compositions for the delivery of therapeutics

Patent metadata

Field	Value
Publication number	US-9707292-B2
Application number	US-201514884489-A
Country	US
Kind code	B2
Filing date	Oct 15, 2015
Priority date	Nov 10, 2008
Publication date	Jul 18, 2017
Grant date	Jul 18, 2017

Abstract

The present invention provides lipids that are advantageously used in lipid particles for the in vivo delivery of therapeutic agents to cells. In particular, the invention provides lipids having the following structure

wherein:

R 1 and R 2 are each independently for each occurrence optionally substituted C 10 -C 30 alkyl, optionally substituted C 10 -C 30 alkenyl, optionally substituted C 10 -C 30 alkynyl, optionally substituted C 10 -C 30 acyl, or -linker-ligand; R 3 is H, optionally substituted C 1 -C 10 alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 -C 10 alkynyl, alkylhetrocycle, alkylphosphate, alkylphosphorothioate, alkylphosphorodithioate, alkylphosphonates, alkylamines, hydroxyalkyls, ω-aminoalkyls, ω-(substituted)aminoalkyls, ω-phosphoalkyls, ω-thiophosphoalkyls, optionally substituted polyethylene glycol (PEG, mw 100-40 K), optionally substituted mPEG (mw 120-40 K), heteroaryl, heterocycle, or linker-ligand; and E is C(O)O or OC(O).

First claim

We claim:

1. A lipid particle comprising mRNA as a therapeutic agent and a lipid having the structure

or a salt or isomer thereof,
wherein:
R 1 and R 2 are each independently for each occurrence optionally substituted C 10 -C 30 alkenyl or optionally substituted C 10 -C 30 alkynyl;
R 3 is ω-aminoalkyls or ω-(substituted)aminoalkyls; and
E is C(O)O;
provided that when R 3 is 2-(dimethylamino)ethyl, R 1 and R 2 are not each linoleyl.

2. The lipid particle of claim 1 , wherein R 3 is ω-aminoalkyl.

3. The lipid particle of claim 1 , wherein R 3 is ω-(substituted)aminoalkyl.

4. The lipid particle of claim 1 , wherein R 3 is 2-(dimethylamino)ethyl, 3-(diisopropylamino)propyl, or 3-(N-ethyl-n-isopropylamino)-1-methylpropyl.

5. The lipid particle of claim 1 , wherein R 3 is alkylaminoalkyl or dialkylaminoalkyl.

6. The lipid particle of claim 1 , wherein R 1 and R 2 are each optionally substituted C 10 -C 20 alkenyl.

7. The lipid particle of claim 1 , wherein R 1 and R 2 are each linoleyl.

8. The lipid particle of claim 1 , wherein the particle further comprises a neutral lipid and a lipid capable of reducing aggregation.

9. The lipid particle of claim 8 , wherein the lipid capable of reducing aggregation is a PEG-lipid.

10. The lipid particle of claim 1 , further comprising a neutral lipid, cholesterol, and a PEG lipid.

11. The lipid particle of claim 10 , wherein the lipid of formula XXXIII or a salt or isomer thereof, the neutral lipid, the cholesterol, and the PEG lipid are present in molar ratios of 20-70%:5-45%:20-55%:0.5-15%, respectively.

12. A pharmaceutical composition comprising a lipid particle of claim 1 and a pharmaceutically acceptable excipient, carrier, or diluent.

Assignees

• Arbutus Biopharma Corp

Inventors

• Manoharan Muthiah
• Jayaraman Muthusamy
• Rajeev Kallanthottathil G
• Eltepu Laxman
• Ansell Steven
• Chen Jianxin

Classifications

• A61P33/00

  Antiparasitic agents · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/04

  Immunostimulants · CPC title

• A61K9/5123

  Organic compounds, e.g. fats, sugars · CPC title

• A61K31/713

  Double-stranded nucleic acids or oligonucleotides · CPC title