Lipid nanoparticles for delivery of agents

A composition comprising a plurality of lipid nanoparticles, wherein the lipid nanoparticles comprise an agent, an ionizable lipid, and a cationic lipid, wherein the ionizable lipid is a lipid according to formula I or a pharmaceutically acceptable salt thereof:

• wherein
• X is —NR1— or —O—;
• R1 is a hydrogen atom, a hydrocarbon group having 6 to 24 atoms, or R21-L1-R22—;
• R21 is a hydrocarbon group having 1 to 24 carbon atoms;
• L1 is —O(CO)O—, —O(CO)—, —(CO)O—, —O—, or
• R22 is a divalent hydrocarbon linking group having 1 to 18 carbon atoms;
• R2 and R3 are each independently a hydrogen atom, a hydrocarbon group having 3 to 24 carbon atoms, or R31-L1-R32—;
• R31 is a hydrocarbon group having 1 to 24 carbon atoms;
• L2 is —O(CO)O—, —O(CO)—, —(CO)O—, —O—, or
• R32 is a divalent hydrocarbon linking group having 1 to 18 carbon atoms;
• R4, R5, R6, R7, R8, R9, R10, R11, and R12 are each independently a hydrogen atom or an alkyl group having 1 to 18 carbon atoms optionally substituted with R33, where one or more pairs of groups selected from R4 and R5, R10 and R5, R5 and R12, R4 and R6, R5 and R6, R6 and R7, R6 and R10, R12 and R7, and R7 and R8 may be linked to each other to form a 4- to 7-membered ring of carbon and nitrogen atoms which may contain an oxygen atom;
• R33 is a hydroxyl group, a carboxyl group, —NR45R46, —O(CO)O—R41, —O(CO)—R42, —(CO)O—R43, —O—R44, or an aryl or heteroaryl group optionally substituted with R34,
• R34 is an alkyl group having 1 to 18 carbon atoms, a hydroxyl group, a carboxyl group, —NR45R46, —O(CO)O—R41, —O(CO)—R42, —(CO)O—R43, or —O—R44;
• R41, R42, R43, R44, R45, and R46 are each independently a hydrocarbon group having 1 to 18 carbon atoms;
• and
• a, b, c, and d are each independently an integer from 0 to 3, where a+b is 1 or more and c+d is 1 or more.

A composition comprising a plurality of lipid nanoparticles, wherein the lipid nanoparticles comprise an agent, an ionizable lipid, and a cationic lipid, wherein the ionizable lipid is a lipid according to formula VII or a pharmaceutically acceptable salt thereof:

• wherein
• R1 and R2 are each independently a hydrocarbon group having 1 to 18 carbon atoms, and R3 is a hydrocarbon group having 2 to 8 carbon atoms, wherein the hydrocarbon groups represented by R1, R2, and R3 are each independently optionally substituted with one or more substituents selected from —OH, COOH, —NR51R52, —OC(O)O—R53, —C(O)O—R54, —OC(O)—R55, and —O—R56;
• R4 is a hydrocarbon group having 1 to 8 carbon atoms;
• R5 and R6 are each independently a hydrocarbon group having 1 to 8 carbon atoms or —R8-L1-R9, excluding a case where both R5 and R6 are hydrocarbon groups having 1 to 8 carbon atoms;
• R7 is —R10-L2-R11-L3-R12;
• R51 and R52 are each independently a hydrocarbon group having 1 to 8 carbon atoms;
• R53, R54, R55, and R56 are each independently a hydrocarbon group having 1 to 24 carbon atoms;
• the hydrocarbon groups represented by R53, R54, R55, and R56 are each independently optionally substituted with an aryl group having 6 to 20 carbon atoms or —S—R58, wherein the aryl group having 6 to 20 carbon atoms is optionally substituted with —OH, COOH, —NR51R52, —OC(O)O—R53, —C(O)O—R54, —OC(O)—R55, —O—R56, or —R59—R57 wherein
• R58 and R59 are each independently a hydrocarbon group having 1 to 12 carbon atoms;
• R57 is —OH, COOH, —NR61R62, —OC(O)O—R63, —C(O)O—R64, —OC(O)—R65, or —O—R66;
• R61 and R62 are each independently a hydrocarbon group having 1 to 8 carbon atoms;
• R63, R64, R65, and R66 are each independently a hydrocarbon group having 1 to 24 carbon atoms;
• the hydrocarbon groups represented by R63, R64, R65, and R66 are each independently optionally substituted with an aryl group having 6 to 20 carbon atoms or —S—R68 wherein the aryl group having 6 to 20 carbon atoms may be substituted with —OH, COOH, —NR61R62, —OC(O)O—R63, —C(O)O—R64, —OC(O)—R65, —O—R66, or —R69—R67,
• R68 and R69 are each independently a hydrocarbon group having 1 to 12 carbon atoms;
• R67 is —OH, COOH, —NR61R62, —OC(O)O—R63, —C(O)O—R64, —OC(O)—R65, or —O—R66;
• L1, L2, and L3 are each independently —OC(O)O—, —C(O)O—, —OC(O)—, or —O—;
• R8 is a hydrocarbon group having 1 to 12 carbon atoms;
• R9 is a hydrocarbon group having 1 to 24 carbon atoms;
• R10 is a hydrocarbon group having 1 to 8 carbon atoms;
• R11 is a hydrocarbon group having 1 to 24 carbon atoms;
• R12 is a hydrocarbon group having 1 to 24 carbon atoms;
• the hydrocarbon groups represented by R9 and R12 are each independently optionally substituted with an aryl group, —OC(O)O—R53, —C(O)O—R54, —OC(O)—R55, or —S—R58;
• and
• the hydrocarbon groups represented by R11 are each independently optionally substituted with —OC(O)O—R53, —C(O)O—R54, or —OC(O)—R55.

A composition comprising a plurality of lipid nanoparticles, wherein the lipid nanoparticles comprise an agent, an ionizable lipid, and at least one of EDPPC and DPTAP, wherein the ionizable lipid is a lipid according to formula I or II or a pharmaceutically acceptable salt thereof:

• wherein
• X is —NR1— or —O—;
• R1 is a hydrogen atom, a hydrocarbon group having 6 to 24 atoms, or R21-L1-R22—;
• R21 is a hydrocarbon group having 1 to 24 carbon atoms;
• L1 is —O(CO)O—, —O(CO)—, —(CO)O—, —O—, or
• R22 is a divalent hydrocarbon linking group having 1 to 18 carbon atoms;
• R2 and R3 are each independently a hydrogen atom, a hydrocarbon group having 3 to 24 carbon atoms, or R31-L1-R32—;
• R31 is a hydrocarbon group having 1 to 24 carbon atoms;
• L2 is —O(CO)O—, —O(CO)—, —(CO)O—, —O—, or
• R32 is a divalent hydrocarbon linking group having 1 to 18 carbon atoms;
• R4, R5, R6, R7, R8, R9, R10, R11, and R12 are each independently a hydrogen atom or an alkyl group having 1 to 18 carbon atoms optionally substituted with R33, where one or more pairs of groups selected from R4 and R5, R10 and R5, R5 and R12, R4 and R6, R5 and R6, R6 and R7, R6 and R10, R12 and R7, and R7 and R8 may be linked to each other to form a 4- to 7-membered ring of carbon and nitrogen atoms which may contain an oxygen atom;
• R33 is a hydroxyl group, a carboxyl group, —NR45R46, —O(CO)O—R41, —O(CO)—R42, —(CO)O—R43, —O—R44, or an aryl or heteroaryl group optionally substituted with R34;
• R34 is an alkyl group having 1 to 18 carbon atoms, a hydroxyl group, a carboxyl group, —NR45R46, —O(CO)O—R41, —O(CO)—R42, —(CO)O—R43, or —O—R44;
• R41, R42, R43, R44, R45, and R46 are each independently a hydrocarbon group having 1 to 18 carbon atoms;
• a, b, c, and d are each independently an integer from 0 to 3, where a+b is 1 or more and c+d is 1 or more;
• R51 and R52 are each independently an alkyl group having 1 to 18 carbon atoms optionally substituted with R35,
• R35 is a hydroxyl group, -G20-CH(R55)(R56), —N(R58)(R59), or -G20-R60;
• G20 is —(CO)O— or —O(CO)—;
• R55 and R56 are each independently hydrogen or an alkyl group having 1 to 18 carbon atoms;
• R58 and R59 are each independently hydrogen or a cycloalkyl group having 3 to 6 carbon atoms, optionally substituted with R36;
• R60 is alkyl group having 1 to 18 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms;
• R36 is —N(R61)(R62), or -G20-R65;
• R61 and R62 are each independently hydrogen or a cycloalkyl group having 3 to 6 carbon atoms;
• R65 is an alkyl group having 1 to 18 carbon atoms, -L40-CH(R66)(R67), or -G20-R66;
• L40 is a divalent alkyl group containing 1 to 6 carbon atoms;
• R66 and R67 are each independently an alkyl group containing 1 to 10 carbon atoms or an alkoxy group containing 1 to 10 carbon atoms;
• L10 is a divalent alkyl group containing 1 to 10 carbon atoms;
• G30 is —S(CO)N(R64)—;
• R64 is -L30-G20-CH(R55)(R56);
• a′ is 0 or 1;
• G10 is G20, —O(CO)O—, or —N(R63)C(O)—;
• R63 is an alkyl group containing 1 to 18 carbon atoms;
• L20 is a divalent alkyl group containing 1 to 6 carbon atoms;
• b′ is 0 or 1;
• R53, R54, and R57 are each independently hydrogen or an alkyl group containing 1 to 18 carbon atoms optionally substituted with R36;
• and
• L30 is a single bond or an alkyl group containing 1 to 18 carbon atoms.