Nucleic acid-containing lipid nanoparticle

Patent metadata

Field	Value
Publication number	US-11633365-B2
Application number	US-201816636177-A
Country	US
Kind code	B2
Filing date	Aug 6, 2018
Priority date	Aug 4, 2017
Publication date	Apr 25, 2023
Grant date	Apr 25, 2023

Abstract

The present invention provides a nucleic acid-containing lipid nanoparticle comprising an analog of a fatty acid ester of glycerol, and a nucleic acid, wherein the analog is not hydrolyzable by a lipase.

First claim

The invention claimed is:

1. A nucleic acid-containing lipid nanoparticle comprising
an analog of a fatty acid ester of glycerol wherein the analog is not hydrolyzable by a lipase,
a nucleic acid, and
a cationic lipid,

w
wherein the cationic lipid is lipid A represented by at least one of the following formulas (I) to (IV), (V′) and (V″), and/or lipid B represented by at least one of the following formulas (CL-I) to (CL-XIX):

formula (I)

wherein
R 1 to R 3 are the same or different and are each optionally substituted linear or branched C8-C24 alkyl, C8-C24 alkenyl or C8-C24 alkynyl;
L 1 to L 3 are the same or different and are each absent, or —Z 1 —(CY 1 Y 2 ) p1 — or —Z 2 —(CY 3 Y 4 ) p2 —Z 3 —(CY 5 Y 6 ) p3 — wherein Y t to Y 6 are the same or different and are each a hydrogen atom or optionally substituted C1-C4 alkyl; Z t to Z 3 are the same or different and are each —O—, —NY 7A —, —CO—O—, —O—CO—, —CO—NY 7B —, —NY 7C —CO— or —NY 7D —CO—O— wherein Y 7A to Y 7D are the same or different and are each a hydrogen atom or optionally substituted C1-C4 alkyl; and p 1 to p 3 are the same or different and are each an integer from 1 to 5;
X 1 is optionally substituted C1-C4 alkyl; and
A 1 is a pharmaceutically acceptable anion,

formula (II)

wherein
R 4 to R 6 are the same or different and are each optionally substituted linear or branched C8-C24 alkyl, C8-C24 alkenyl or C8-C24 alkynyl;
L 4 to L 6 are the same or different and are each absent, or —Z 4 —(CY 8 Y 9 ) p4 — or —Z 5 —(CY 10 Y 11 ) p5 —Z 6 —(CY 12 Y 13 ) p6 — wherein Y 8 to Y 13 are the same or different and are each a hydrogen atom or optionally substituted C1-C4 alkyl; Z 4 to Z 6 are the same or different and are each —O—, —NY 14A —, —CO—, —O—CO—, —CO—NY 14B —, —NY 14C —CO— or —NY 14D —CO—O— wherein Y 14A to Y 14D are the same or different and are each a hydrogen atom or optionally substituted C1-C4 alkyl; p 4 is an integer from 0 to 5; p 5 is an integer from 1 to 5; and p 6 is an integer from 0 to 5;
L 7 is absent, or —(CY 15 Y 16 ) p7 —, —(CY 17 Y 18 ) p8 —Z 7 —(CY 19 Y 20 ) p9 — or —(CY 21 Y 22 ) p10 —Z 8 —(CY 23 Y 24 ) p11 —Z 9 —(CY 25 Y 26 ) p12 — wherein Y 15 to Y 26 are the same or different and are each a hydrogen atom or optionally substituted C1-C4 alkyl; Z 7 to Z 9 are the same or different and are each —O—, —NY 27A —, —CO—O—, —O—CO—, —CO—NY 27B —, —NY 27C —CO— or —NY 27D —CO—O— wherein Y 27A to Y 27D are the same or different and are each a hydrogen atom or optionally substituted C1-C4 alkyl; p 7 is an integer from 1 to 5; p 8 is an integer from 0 to 5; p 9 is an integer from 1 to 5; p 10 is an integer from 0 to 5; p 11 is an integer from 1 to 5; and p 12 is an integer from 1 to 5;
B 1 is

wherein X 2 and X 3 are the same or different and are each optionally substituted C1-C4 alkyl, or together form an optionally substituted C4-C6 hetero ring with the adjacent nitrogen atom; X 4 is optionally substituted C1-C4 alkyl; X 5 and X 6 are the same or different and are each optionally substituted C1-C4 alkyl, or together form an optionally substituted C4-C6 hetero ring with the adjacent nitrogen atom; X 7 is optionally substituted C1-C4 alkyl; Y 28 to Y 37 are the same or different and are each a hydrogen atom or optionally substituted C1-C4 alkyl; Z 10 and Z 11 are the same or different and are each —O—, —NY 38A —, —CO—O—, —O—CO—, —CO—NY 38B —, —NY 38C —CO— or —NY 38D —CO—O— wherein Y 38A to Y 38D are the same or different and are each a hydrogen atom or optionally substituted C1-C4 alkyl; p 13 is an integer from 0 to 5; and p 14 to p 17 are the same or different and are each an integer from 1 to 5; and
A 2 is a pharmaceutically acceptable anion,

formula (III)

wherein
R 7 to R 9 are the same or different and are each optionally substituted linear or branched C8-C24 alkyl, C8-C24 alkenyl or C8-C24 alkynyl;
L 8 to L 10 are the same or different and are each absent, or —Z 1 —(CY 39 Y 40 ) p18 — or —Z 13 —(CY 41 Y 42 ) p19 —Z 14 —(CY 43 Y 44 ) p20 — wherein Y 39 to Y 44 are the same or different and are each a hydrogen atom or optionally substituted C1-C4 alkyl; Z 12 to Z 14 are the same or different and are each —O—, —NY 45A —, —CO—, —O—CO—, —CO—NY 45B —, —NY 45C —CO—, —NY 45D —CO—O— or —CO— wherein Y 45A to Y 45D are the same or different and are each a hydrogen atom or optionally substituted C1-C4 alkyl;
p 18 is an integer from 0 to 5; p 19 is an integer from 1 to 5; and p 20 is an integer from 0 to 5;
L 11 is absent, or —(CY 46 Y 47 ) p21 —, —(CY 48 Y 49 ) p22 —Z 15 —(CY 50 Y 51 ) p23 — or —(CY 2 Y 53 ) p24 —Z 16 —(CY 54 Y 55 ) p25 —Z 17 —(CY 56 Y 57 ) p26 — wherein Y 46 to Y 57 are the same or different and are each a hydrogen atom or optionally substituted C1-C4 alkyl; Z 15 to Z 17 are the same or different and are each —O—, —NY 58A —, —CO—O—, —O—CO—, —CO—NY 58B —, —NY 58C —CO—, —NY 58D —CO—O— or —CO— wherein Y 58A to Y 58D are the same or different and are each a hydrogen atom or optionally substituted C1-C4 alkyl; p 21 is an integer from 1 to 5; p 22 is an integer from 0 to 5; p 23 is an integer from 1 to 5; p 24 is an integer from 0 to 5; p 25 is an integer from 1 to 5; and p 26 is an integer from 1 to 5;
L 12 is absent, or —(CY 59 Y 60 ) p27 —, —(CY 61 Y 62 ) p28 —Z 18 —(CY 63 Y 64 ) p29 — or —(CY 65 Y 66 ) p3 —Z 19 —(CY 67 Y 68 ) p31 —Z 20 —(CY 69 Y 70 ) p32 — wherein Y 59 to Y 70 are the same or different and are each a hydrogen atom or optionally substituted C1-C4 alkyl; Z 18 to Z 20 are the same or different and are each —O—, —NY 71A —, —CO—O—, —O—CO—, —CO—NY 71B —, —NY 71C —CO—, —NY 71D —CO—O— or —CO— wherein Y 71A to Y 71D are the same or different and are each a hydrogen atom or optionally substituted C1-C4 alkyl; p 27 is an integer from 1 to 5; p 28 is an integer from 0 to 5; p 29 is an integer from 0 to 5; p 30 is an integer from 0 to 5; p 31 is an integer from 1 to 5; and p 32 is an integer from 0 to 5;
J 1 and J 2 are the same or different and are each CY 72 or N wherein Y 72 is a hydrogen atom, hydroxy, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, or optionally substituted C1-C4 acyloxy;
B 2 is

wherein X 8 and X 9 are the same or different and are each optionally substituted C1-C4 alkyl, or together form an optionally substituted C4-C6 hetero ring with the adjacent nitrogen atom; X 10 is optionally substituted C1-C4 alkyl; X 11 and X 12 are the same or different and are each optionally substituted C1-C4 alkyl, or together form an optionally substituted C4-C6 hetero ring with the adjacent nitrogen atom; X 13 is optionally substituted C1-C4 alkyl; Y 73 to Y 82 are the same or different and are each a hydrogen atom or optionally substituted C1-C4 alkyl; Z 21 and Z 22 are the same or different and are each —O—, —NY 83A —, —CO—O—, —O—CO—, —CO—NY 83B —, —NY 83C —CO— or —NY 83D —CO—O— wherein Y 83A to Y 83D are the same or different and are each a hydrogen atom or optionally substituted C1-C4 alkyl; p 33 is an integer from 0 to 5; and p 34 to p 37 are the same or different and are each an integer from 1 to 5; and
A 3 is a pharmaceutically acceptable anion,

formula (IV)

wherein

Assignees

• Kyowa Kirin Co Ltd

Inventors

• Hatanaka Kentaro
• Maemoto Michihiro
• Hosoe Shintaro

Classifications

• A61K31/713

  Double-stranded nucleic acids or oligonucleotides · CPC title

• A61K9/1272

  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

• C12N15/88

  using microencapsulation, e.g. using {amphiphile} liposome vesicle · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D211/22

  by oxygen atoms · CPC title