Stabilized formulations
Stabilized formulations of nucleic acids, including lipid nanoparticle formulations which encapsulate nucleic acids, are provided. Methods of making and of use of the formulations stabilized by chemical compounds are also provided.
1 . A stabilized pharmaceutical composition, comprising:
a nucleic acid and a compound of Formula I′:
or a tautomer, solvate, or salt thereof, wherein:
each of R 1 , R 2 , R 3 , and R 4 are independently selected from —OH and —OC 1-4 alkyl, wherein the —OC 1-4 alkyl is optionally substituted with one or more —OH, —C(O)OH, —NR′R″, or —C(O)NR′R″, and wherein at least one of R 1 , R 2 , R 3 , and R 4 is —OH, —OC 2-4 alkyl, or —OC 1-4 alkyl substituted with one or more —OH, —C(O)OH, —NR′R″, or —C(O)NR′R″;
each instance of R′ is independently H or —C 1-4 alkyl, wherein the —C 1-4 alkyl is optionally substituted with one or more —OH;
each instance of R″ is independently H or —C 1-4 alkyl;
optionally wherein R′ and R″ taken together form a 5 to 6 membered heterocycle with one or more O or N heteroatoms, wherein the heterocycle is optionally substituted with one or more —C 1-4 alkyl or —OH;
optionally wherein R 1 and R 2 together with the intervening atoms form a 5-membered ring;
R 5 is H, —C 1-4 alkyl, or C 3-7 cycloalkyl; and
X is a pharmaceutically acceptable anion.
2 . The stabilized pharmaceutical composition of claim 1 ,
wherein the compound of Formula I′ is of Formula I:
or a tautomer, solvate, or salt thereof.
3 . The composition of claim 1 , wherein:
R 1 , R 2 , and R 3 are independently —OC 1-4 alkyl; and
R 4 is —OH or —OC 1-4 alkyl, wherein the —OC 1-4 alkyl is substituted with one or more —OH, —C(O)OH, —NR′R″, or —C(O)NR′R″.
4 . The composition of claim 3 , wherein:
R 1 , R 2 , and R 3 are —OCH 3 .
5 . The composition of claim 3 , wherein R 4 is —OC 1-4 alkyl substituted with one or more —OH, —C(O)OH, —NR′R″, or —C(O)NR′R″.
6 . A stabilized pharmaceutical composition, comprising a nucleic acid and a compound selected from:
and tautomers, solvates and salts thereof;
wherein each compound further comprises a pharmaceutically acceptable anion x.
7 . The composition of claim 1 , wherein X is chloride.
8 . The composition of claim 1 , wherein the compound, or tautomer, solvate, or salt thereof, contains fewer than 100 ppm of elemental metals.
9 . The composition of claim 1 , wherein the nucleic acid is DNA or RNA.
10 . The composition of claim 1 , further comprising an ionizable amino lipid, a PEG-lipid, a structural lipid, and/or a phospholipid.
11 . The composition of claim 1 , wherein the composition comprises lipid nanoparticles (LNPs).
12 . The composition of claim 1 , wherein the compound, or tautomer, solvate, or salt thereof, is present at a concentration of less than about 10 mM.
13 . A method of treating a disease in a subject in need thereof, comprising administering to the subject a composition of claim 1 .
14 . The method according to claim 13 , wherein the disease is caused by an infectious agent, is caused by or associated with a virus, or is caused by or associated with a malignant cell.
15 . A method for producing a protein in a subject, comprising:
administering a composition claim 1 to the subject, wherein the nucleic acid is an mRNA and wherein the mRNA encodes for the production of the protein in the subject.
16 . A pharmaceutically acceptable method of processing an mRNA-lipid nanoparticle for therapeutic injection, comprising combining an mRNA, a lipid nanoparticle, and a compound of Formula I′:
or a tautomer, solvate, or salt thereof, wherein:
each of R 1 , R 2 , R 3 , and R 4 are independently selected from —OH and —OC 1-4 alkyl, wherein the —OC 1-4 alkyl is optionally substituted with one or more —OH, —C(O)OH, —NR′R″, or —C(O)NR′R″, and wherein at least one of R 1 , R 2 , R 3 , and R 4 is —OH, —OC 2-4 alkyl, or —OC 1-4 alkyl substituted with one or more —OH, —C(O)OH, —NR′R″, or —C(O)NR′R″;
each instance of R′ is independently H or —C 1-4 alkyl, wherein the —C 1-4 alkyl is optionally substituted with one or more —OH;
each instance of R″ is independently H or —C 1-4 alkyl;
optionally wherein R′ and R″ taken together form a 5 to 6 membered heterocycle with one or more O or N heteroatoms, wherein the heterocycle is optionally substituted with one or more —C 1-4 alkyl or —OH;
optionally wherein R 1 and R 2 together with the intervening atoms form a 5-membered ring;
R 5 is H, —C 1-4 alkyl, or C 3-7 cycloalkyl; and
X is a pharmaceutically acceptable anion.
17 . A syringe or cartridge, comprising a composition of claim 1 .
18 . An infusion pump, comprising a composition of claim 1 .
19 . A photoprotective container comprising the stabilized pharmaceutical composition of claim 1 .
20 . The composition of claim 1 , wherein at least one of R 1 , R 2 , R 3 , and R 4 is —OC 1-4 alkyl substituted with one or more —OH, —C(O)OH, —NR′R″, or —C(O)NR′R″.
21 . The composition of claim 1 , wherein the compound is selected from:
and tautomers, solvates, and salts thereof;
wherein each compound further comprises a pharmaceutically acceptable anion X.
22 . The composition of claim 6 , wherein X is chloride.
23 . The composition of claim 21 , wherein X is chloride.