Biodegradable compound, lipid particles, composition and kit comprising lipid particles

Patent metadata

Field	Value
Publication number	US-10945956-B2
Application number	US-201916567895-A
Country	US
Kind code	B2
Filing date	Sep 11, 2019
Priority date	Mar 16, 2018
Publication date	Mar 16, 2021
Grant date	Mar 16, 2021

Abstract

[Problem]
To provide a biodegradable compound having a structure decomposed in a cell, lipid particles containing the compound, and a pharmaceutical composition comprising the lipid particles.
[Solution]
The compound of the embodiment is represented by the formula (1): P—[X—R—Y—R′-Q] 2 (1). In the formula,
P is an alkyleneoxy having an ether bond, X is a divalent linking group having a tertiary amine structure, R is a divalent linking group, R′ is a single bond or a C 1 to C 6 alkylene, and Q is a liposoluble vitamin residue, a sterol residue, or a C 12 to C 22 aliphatic hydrocarbon group. The structure of the compound contains at least one biodegradable group. From the compound in combination with other lipids such as a lipid capable of reducing aggregation, lipid particles can be formed. Further, the compound can be used for a pharmaceutical composition to deliver an activator into cells.

First claim

The invention claimed is:

1. A compound represented by the formula (1):
P—[X—R—Y—R′-Q] 2   (1)

wherein
P is an alkyleneoxy having one or more ether bonds in the main chain,
each X is independently a divalent linking group having a tertiary amine structure,
each R is independently a C 1 to C 6 alkylene,
each Y is independently a divalent linking group selected from the group consisting of single bond, ether bond, carboxylic ester bond, thiocarboxylic ester bond, thioester bond, amide bond, carbamate bond, and urea bond,
each R′ is independently a single bond or a C 1 to C 6 alkylene, and
each Q is independently a liposoluble vitamin residue; provided that
the structure contains at least one biodegradable group selected from the group consisting of carboxylic ester bond, thiocarboxylic ester bond, dithiocarboxylic bond, amide bond, carbamate bond, carboxydioxy bond, and urea bond.

2. The compound according to claim 1 , wherein said P contains 3 to 8 carbons and 1 to 2 oxygens.

3. The compound according to claim 1 , wherein said P contains only carbons and oxygens.

4. The compound according to claim 1 , wherein each of said Xs is independently selected from the group consisting of methylimino, 1,2-pyrrolidinediyl and 1,3-pyrrolidinediyl.

5. The compound according to claim 1 , wherein said liposoluble vitamin residue is a group derived from a liposoluble vitamin selected from the group consisting of retinol, retinal, ergosterol, 7-dehydrocholesterol, calciferol, cholecalciferol, dihydroergocalciferol, dihydrotachysterol, tocopherol, tocotrienol, and compounds in which hydroxy groups in those vitamins are replaced with thiohydroxy, carboxy, thiocarboxy or dithocarboxy.

6. The compound according to claim 1 , wherein said Q has a cyclohexane structure.

7. The compound according to claim 1 , represented by any of the following formulas (1-01) to (1-12):

8. Lipid particles containing the compound according to claim 1 .

9. The lipid particles according to claim 8 , which further contains a lipid forming a membrane and a lipid capable of reducing aggregation.

10. The lipid particles according to claim 9 , wherein
said lipid forming a membrane is selected from the group consisting of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE),
1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE),
1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC),
1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine (POPC),
1,2-di-o-octadecyl-3-trimethylammoniumpropane (DOTMA),
1,2-dioleoyl-3-dimethylammoniumpropane (DODAP),
1,2-dimyristoyl-3-dimethylammoniumpropane (14:0 DAP),
1,2-dipalmitoyl-3-dimethylammoniumpropane (16:0 DAP),
1,2-distearoyl-3-dimethylammoniumpropane (18:0 DAP),
N-(4-carboxybenzyl)-N,N-dimethyl-2,3-bis(oleoyloxy)propane (DOBAQ),
1,2-dioleoyl-3-trimethylammoniumpropane (DOTAP),
1,2-dioleoyl-sn-glycero-3-phosphochlorin (DOPC),
1,2-dilinoleoyl-sn-glycero-3-phosphochlorin (DLPC),
1,2-dioleoyl-sn-glycero-3-phospho-L-serine (DOPS), and
cholesterol; and
said lipid capable of reducing aggregation is a polyethylene glycol (PEG)-modified lipid.

11. The lipid particles according claim 8 , which furthermore contains an activator.

12. The lipid particles according to claim 11 , wherein said activator is a nucleic acid selected from the group consisting of plasmid, oligonucleotide, polynucleotide, siRNA, microRNA, DNA, mRNA, aptamer, and ribozyme.

13. The lipid particles according to claim 12 , which further contains a compound combinable with the nucleic acid.

14. The lipid particles according to claim 13 , wherein said compound combinable with the nucleic acid is a basic protein or a basic peptide.

15. The lipid particles according to claim 13 , wherein said compound combinable with the nucleic acid is protamine or histone.

16. The lipid particles according to claim 13 , which further contains a compound controlling expression of the nucleic acid in cells.

17. A composition comprising the lipid particles according to claim 8 and a medium.

18. A kit comprising the lipid particles according to claim 8 and a composition containing a medium that introduces said lipid particles into cells.

Assignees

• Toshiba Kk

Inventors

• Ishihara Mitsuko
• Akahoshi Eiichi
• Naito Katsuyuki

Classifications

• C07D207/08

  with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms · CPC title

• C12N15/00

  Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor (mutants or genetically engineered microorganisms, per se C12N1/00, C12N5/00, C12N7/00; new plants per se A01H; plant reproduction by tissue culture techniques A01H4/00; new animals per se A01K67/00; use of medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases, gene therapy A61K48/00) · CPC title

• A61K47/16

  containing nitrogen, {e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates} · CPC title

• C07C2601/10

  the ring being unsaturated · CPC title

• C12N2310/141

  MicroRNAs, miRNAs · CPC title