Carbonate containing lipid compounds and compositions for intracellular delivery of therapeutic agents

Patent metadata

Field	Value
Publication number	US-12595226-B2
Application number	US-202017761984-A
Country	US
Kind code	B2
Filing date	Sep 18, 2020
Priority date	Sep 19, 2019
Publication date	Apr 7, 2026
Grant date	Apr 7, 2026

Abstract

The disclosure features novel lipids and compositions involving the same. Lipid nanoparticles (e.g., empty LNPs or loaded LNPs) include a novel lipid as well as additional lipids such as phospholipids, structural lipids, and PEG lipids. Lipid nanoparticles (e.g., empty LNPs or loaded LNPs) further including therapeutic and/or prophylactics such as RNA are useful in the delivery of therapeutic and/or prophylactics to mammalian cells or organs to, for example, regulate polypeptide, protein, or gene expression.

First claim

The invention claimed is:

1 . A compound of Formula (A):

or its N-oxide, or a salt thereof, wherein
m is selected from 5, 6, 7, 8, and 9;
R 2 and R 3 are each independently selected from the group consisting of H, C 1-14 alkyl, and C 2-14 alkenyl;
R 4 is selected from —(CH 2 ) n OH, wherein n is selected from 1, 2, 3, 4, and 5, and

wherein n2 is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; and R 10 is —N(R) 2 , wherein each R is independently selected from the group consisting of C 1-6 alkyl, C 2-3 alkenyl, and H;
M and M′ are each independently selected from —OC(O)O— and —C(O)O—;
wherein at least one of M and M′ is —OC(O)O—;
R′ a is C 1-18 alkyl or C 2-18 alkenyl; and
R″ is a C 3 -C 13 alkyl, optionally substituted with OH.

2 . The compound of claim 1 , wherein R″ is selected from

wherein

denotes a point of attachment with N, and

denotes a point of attachment with M.

3 . The compound of claim 1 , wherein the compound has one of the following structures:

4 . The compound of claim 1 , wherein R′ a is:

wherein

denotes a point of attachment;
R aα , R aβ , and R aγ are each independently selected from the group consisting of H, C 1-12 alkyl, and C 2-12 alkenyl, wherein at least one of R aα , R aβ , and R aγ is selected from the group consisting of C 1-12 alkyl and C 2-12 alkenyl; and
R′ is a C 1-12 alkyl or C 2-12 alkenyl.

5 . The compound of claim 4 , wherein:
R aβ and R aγ are each H and R aα is C 1-6 alkyl; R aα and R aγ are each H and R aβ is C 1-6 alkyl; and/or R aα and R aβ are each H and R aγ is C 1-6 alkyl.

6 . The compound of claim 5 , wherein R aβ is C 2 alkyl.

7 . The compound of claim 5 , wherein R aγ is a C 5 or a C 6 alkyl.

8 . The compound of claim 4 , wherein R′ is a C 5 or a C 6 alkyl.

9 . The compound of claim 1 , wherein the compound has the following structure:

10 . The compound of claim 1 , wherein R 4 is —(CH 2 ) n OH.

11 . The compound of claim 1 , wherein R 4 is —(CH 2 ) 2 OH.

12 . The compound of claim 1 , wherein R 4 is

13 . The compound of claim 1 , wherein R 4 is

14 . The compound of claim 1 , wherein n2 is 2 or 4.

15 . A compound selected from:

and N-oxides and salts thereof.

16 . An empty lipid nanoparticle (empty LNP) comprising a compound of claim 1 , a phospholipid, a structural lipid, and a PEG lipid.

17 . The empty LNP of claim 16 , comprising about 40 mol % to about 60 mol % said compound, about 0 mol % to about 20 mol % phospholipid, about 30 mol % to about 50 mol % structural lipid, and about 0 mol % to about 5 mol % PEG lipid;
wherein the phospholipid is selected from the group consisting of: 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2-dimyristoyl-sn-glycero-phosphocholine (DMPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-diundecanoyl-sn-glycero-phosphocholine (DUPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-di-O-octadecenyl-sn-glycero-3-phosphocholine (18:0 Diether PC), 1-oleoyl-2-cholesterylhemisuccinoyl-sn-glycero-3-phosphocholine (OChemsPC), 1-hexadecyl-sn-glycero-3-phosphocholine (C16 Lyso PC), 1,2-dilinolenoyl-sn-glycero-3-phosphocholine, 1,2-diarachidonoyl-sn-glycero-3-phosphocholine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2-diphytanoyl-sn-glycero-3-phosphoethanolamine (ME 16.0 PE), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinoleoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinolenoyl-sn-glycero-3-phosphoethanolamine, 1,2-diarachidonoyl-sn-glycero-3-phosphoethanolamine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphoethanolamine, 1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt (DOPG), sphingomyelin, and mixtures thereof; wherein the structural lipid is selected from the group consisting of cholesterol, fecosterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, and mixtures thereof; and/or wherein the PEG lipid is selected from the group consisting of a PEG-modified phosphatidylethanolamine, a PEG-modified phosphatidic acid, a PEG-modified ceramide, a PEG-modified dialkylamine, a PEG-modified diacylglycerol, a PEG-modified dialkylglycerol, and mixtures thereof.

18 . The empty LNP of claim 16 , wherein the PEG lipid is selected from PEG 2k -DMG and PEG-1:

and mixtures thereof.

19 . A loaded lipid nanoparticle (loaded LNP), which comprises the empty LNP of claim 16 , and one or more therapeutic and/or prophylactic agents.

20 . The loaded LNP of claim 19 , wherein the one or more therapeutic and/or prophylactic agents is a nucleic acid; wherein the nucleic acid is an RNA, and wherein the RNA is selected from the group consisting of a short interfering RNA (siRNA), an asymmetrical interfering RNA (aiRNA), a RNA interference RNAi) molecule, a microRNA (miRNA), an antagomir, an antisense RNA, a ribozyme, a Dicer-substrate RNA (dsRNA), a small hairpin RNA (shRNA), a messenger RNA (mRNA), and mixtures thereof.

21 . The loaded LNP of claim 20 , wherein the RNA is an mRNA.

22 . A pharmaceutical composition comprising the loaded LNP of claim 19 , and a pharmaceutically acceptable carrier.

23 . A method of delivering a therapeutic and/or prophylactic agent to a cell within a subject, and/or to the organ of a subject, the method comprising admin

Assignees

• Modernatx Inc

Inventors

• Benenato Kerry E
• Biswas Souvik
• Cornebise Mark
• Hennessy Edward
• Kumarasinghe Ellalahewage S

Classifications

• A61K9/1272 Primary

  comprising non-phosphatidyl surfactants as bilayer-forming substances, e.g. cationic lipids or non-phosphatidyl liposomes coated or grafted with polymers (lipids as modifying agents {A61K47/543}) · CPC title

• C07C2601/04

  with a four-membered ring · CPC title

• C07C2601/02

  with a three-membered ring · CPC title

• A61K9/5123

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

• A61K9/127

  Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant · CPC title