Method of synthesis of an ionizable cationic lipid
Disclosed herein is a lipid composition comprising a compound having the formula IA, or a pharmaceutically acceptable salt thereof, wherein R 3 is a linear or branched alkylene of 1-6 carbons; R 4 and R 5 are the same or different, each a hydrogen, or a linear or branched alkyl of 1-6 carbons; and L 3 is a bond or an alkane of 1-6 carbons.
1. A lipid composition comprising a compound having the Formula IA, or a pharmaceutically acceptable salt thereof,
wherein
R 3 is a linear or branched alkylene of 1 to 6 carbons;
R 4 and R 5 are the same or different, each independently a hydrogen, or a linear or branched alkyl of 1 to 6 carbons; and
L 3 is a bond or an alkylene of 1 to 6 carbons.
2. The lipid composition of claim 1 , wherein the composition comprises 30% to 70% of the compound having Formula IA.
3. The lipid composition of claim 1 , further comprising 0% to 60% cholesterol.
4. The lipid composition of claim 1 , further comprising 0% to 30% phospholipid.
5. The lipid composition of claim 1 further comprising 0% to 10% polyethylene glycol.
6. The lipid composition of claim 1 wherein the composition comprises 30-40% of the compound of Formula IA, 40-50% cholesterol, and 10-20% polyethylene glycol.
7. The lipid composition of claim 1 wherein the composition comprises 50-75% of the compound of Formula IA, 20-40% cholesterol, 5-10% phospholipid, 1-10% polyethylene glycol.
8. The lipid composition of claim 1 wherein the composition comprises 60-70% of the compound of Formula IA, 25-35% cholesterol, and 5-10% polyethylene glycol.
9. The lipid composition of claim 1 wherein the composition comprises a lipid particle formulation comprising 8-30% of the compound of Formula IA, 5-30% helper lipid, and 0-20% cholesterol.
10. The lipid composition of claim 1 wherein the composition comprises a lipid particle formulation comprising 4-25% of the compound of Formula IA, 4-25% helper lipid, 2-25% cholesterol, 10-35% cholesterol-PEG, and 5% cholesterol-amine.
11. The lipid composition of claim 1 wherein the composition comprises a lipid particle formulation comprising 2-30% of the compound of Formula IA, 2-30% helper lipid, 1-15% cholesterol, 2-35% cholesterol-PEG, and 1-20% cholesterol-amine.
12. The lipid composition of claim 1 wherein the compound of Formula IA is combined with a nucleic acid to form a lipid microparticle, lipid nanoparticle, a liposome, or a micelle, wherein the lipid encapsulates the nucleic acid.
13. The lipid composition of claim 12 wherein the nucleic acid is selected from the group consisting of a messenger RNA (mRNA), a small interfering RNA (siRNA), and a micro RNA (miRNA).
14. The lipid composition of claim 1 wherein the composition is formulated for systemic delivery via intravenous, parenteral, intraperitoneal, or topical administration.
15. The lipid composition of claim 1 wherein the composition is formulated for nasal or pulmonary inhalation.
16. The lipid composition of claim 1 wherein the compound of Formula IA is selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
17. The lipid composition of claim 16 , wherein the compound of Formula IA is
or a pharmaceutically acceptable salt thereof.
18. The lipid composition of claim 16 , wherein the compound of Formula IA is
or a pharmaceutically acceptable salt thereof.
19. A method of treating a subject suffering from a protein deficiency, comprising administering a composition of claim 13 to the subject, wherein the nucleic acid in the composition is a mRNA encoding the deficient protein.
20. The method of claim 19 , wherein administration effects systemic delivery to the liver of the subject whereby the deficient protein is expressed in the liver of the subject.