Nucleic acid-containing lipid nanoparticles

Patent metadata

Field	Value
Publication number	US-11298326-B2
Application number	US-201615560854-A
Country	US
Kind code	B2
Filing date	Mar 24, 2016
Priority date	Mar 24, 2015
Publication date	Apr 12, 2022
Grant date	Apr 12, 2022

Abstract

The present invention provides nucleic acid-containing lipid nanoparticles containing a lipid (lipid A) which has a hydrophilic unit having a single quaternary ammonium group, and three independent, optionally substituted hydrocarbon groups, a lipid derivative or fatty acid derivative of a water-soluble polymer, and a nucleic acid.

First claim

What is claimed is:

1. Nucleic acid-containing lipid nanoparticles, comprising: a lipid (lipid A), which has a hydrophilic unit having a single quaternary ammonium group and three independent, substituted and either unsubstituted or substituted hydrocarbon groups; a lipid derivative or fatty acid derivative of a water-soluble polymer; and a nucleic acid,
wherein the number of moles of the quaternary ammonium group in the lipid A is 0.1 to 10 times the number of moles of phosphorous atoms in the nucleic acid,

the average particle size is 20 nm to 65 nm, and
the lipid A is a lipid represented by:

(wherein,
R 4 to R 6 , the same or different, are a linear or branched, and either unsubstituted or substituted C8-C24 alkyl, C8-C24 alkenyl or C8-C24 alkynyl,
L 4 to L 6 , the same or different, are absent or are —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 , the same or different, are a hydrogen atom or optionally substituted C1-C4 alkyl, Z 4 to Z 6 , the same or different, are —O—, —NY 14A —, —CO—O—, —O—CO—, —CO—NY 14B —, —NY 4C —CO— or (wherein, Y 14A to Y 14D the same or different, are a hydrogen atom or optionally substituted C1-C4 alkyl), p 4 is an integer of 0 to 5, p 5 is an integer of 1 to 5, and p 6 is an integer of 0 to 5),
L 7 is (CY 15 Y 16 ) p7 —, —(CY 17 Y 18 ) p8 —Z 7 —(CY 19 Y 20 ) p9 — —(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 , the same or different, are a hydrogen atom or optionally substituted C1-C4 alkyl, Z 7 to Z 9 , the same or different, are —O—, —NY 27A —, —CO—O—, or —O—CO—, (wherein, Y 27A , the same or different, is a hydrogen atom or optionally substituted C1-C4 alkyl), p 7 is an integer of 1 to 5, p 8 is an integer of 0 to 5, p 9 is an integer of 1 to 5, p 10 is an integer of 0 to 5, p 11 is an integer of 1 to 5, and p 12 is an integer of 1 to 5),
B 1 is

(wherein, X 2 and X 3 , the same or different, are an optionally substituted C1-C4 alkyl or are combined together to form an optionally substituted C4-C6 heterocycle with an adjacent nitrogen atom, X 4 is an optionally substituted C1-C4 alkyl, X 5 and X 6 , the same or different, are an optionally substituted C1-C4 alkyl or are combined together to form an optionally substituted C4-C6 heterocycle with an adjacent nitrogen atom, X 7 is an optionally substituted C1-C4 alkyl, Y 28 to Y 37 , the same or different, are a hydrogen atom or optionally substituted C1-C4 alkyl, Z 10 and Z 11 , the same or different, are —O—, —NY 38A —, —OO—O—, —O—CO—, —CO—NY 38 B, —NY 38C —CO— or —NY 38D —CO—O— (wherein, Y 38A to Y 38D , the same or different, are a hydrogen atom or optionally substituted C1-C4 alkyl), p 13 is an integer of 0 to 5, and p 14 to p 17 , the same or different, are an integer of 1 to 5), and
A 2 is a pharmaceutically acceptable anion);
and a lipid (lipid B), which has a hydrophilic unit having one secondary or tertiary amino group or one substituted secondary or tertiary amino group, and a hydrophobic unit having two independent linear C8-C24 alkyl or alkenyl groups or two independent substituted linear C8-C24 alkyl or alkenyl groups;
wherein the ratio of the number of moles of lipid A to the number of moles of lipid B is 0.01 to 2;
wherein the nucleic acid has a molecular weight of 1,000 kDa or less.

2. The lipid nanoparticles according to claim 1 , wherein the lipid A is represented by formula (II), and in formula (II), one of L 4 to L 6 is —CO—O—(CY 8 Y 9 ) p4 —, —O—CO—(CY 8 Y 9 ) p4 — or —O—CO—(CY 10 Y 11 ) p5 —O—(CY 12 Y 13 ) p6 — or two or more of L 4 to L 6 , the same or different, are —CO—O—(CY 8 Y 9 ) p4 —, —O—CO—(CY 8 Y 9 ) p4 — or —O—CO—(CY 10 Y 11 ) p5 —O—(CY 12 Y 13 ) p6 — and), R 4 to R 6 are linear or branched C15-C20 alkenyl or C9-C18 alkyl and are the same.

3. The nucleic acid-containing lipid nanoparticles of claim 1 , wherein the number of moles of lipid A is smaller than the number of moles of lipid B.

Assignees

• Kyowa Kirin Co Ltd

Inventors

• Hatanaka Kentaro
• Yagi Nobuhiro
• Kuboyama Takeshi
• Yagi Kaori
• Hosoe Shintaro

Classifications

• A61K31/7088

  Compounds having three or more nucleosides or nucleotides · CPC title

• C12N2320/51

  modulating the chemical stability, e.g. nuclease-resistance · CPC title

• C07C237/22

  having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated (peptides C07K) · CPC title

• C12N2310/14

  interfering nucleic acids [NA] · CPC title

• A61K9/0019

  Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00) · CPC title