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Application of ionizable lipid compound in nucleic acid drug delivery system

A nucleic acid drug and delivery system technology, which is applied in the direction of drug delivery, nano-drugs, and medical preparations of non-active ingredients, etc., can solve the problems of increased drug dose, low delivery system delivery efficiency, toxic and side effects, etc., to reduce accumulation side effects

Active Publication Date: 2022-03-18
WUHAN BINHUI BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Most of the existing nucleic acid drug carriers are easy to accumulate in the liver after entering the body, increasing the metabolic burden of the liver and causing obvious toxic and side effects
Or there is a phenomenon that due to the low delivery efficiency of the delivery system, it is easy to increase the dosage of the drug and cause toxic side effects

Method used

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  • Application of ionizable lipid compound in nucleic acid drug delivery system
  • Application of ionizable lipid compound in nucleic acid drug delivery system
  • Application of ionizable lipid compound in nucleic acid drug delivery system

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0092] The synthetic route of compound 1:

[0093]

[0094] Step 1: Synthesis of compound 1-1:

[0095] Add linalyl alcohol (0.267g, 1mmol) and triethylamine (0.133g, 1.3mmol) into the reaction flask in an ice-water bath, add dichloromethane (6mL), and dissolve acryloyl chloride (0.11g, 1.2mmol) in dichloromethane (2.2 mL) was slowly added dropwise into the reaction bottle, and the reaction lasted for 10 minutes. The reaction was kept below 10° C., and finally the ice bath was removed, and the reaction solution was reacted at room temperature for 2 hours. Wash with saturated brine to obtain a crude product, which is purified by chromatography (silica gel column, eluent is petroleum ether containing 0.5% EA (volume percentage)), and the pure product is evaporated to obtain light yellow oily compound 1 -1 (2-allylic acid (9Z, 12Z)-octadecadienyl ester) (0.173g, yield: 50%) The hydrogen spectrum of compound 1-1 is shown in figure 1 .

[0096] 1H NMR (400MHz, CDCl 3 )δ: 6.4...

Embodiment 2

[0101] Synthetic route of compound 2

[0102]

[0103] Step 1: Synthesis of Compound 2-1

[0104]Dissolve 6-bromohexanoic acid (1.0g, 5.13mmol) and undecyl alcohol (1.77g, 10.25mmol) in dichloromethane (60mL), add 1-(3-dimethylaminopropyl)-3-ethane Carbodiimide hydrochloride (EDC hydrochloride, 0.98g, 5.13mmol) and DMAP (0.125g, 1.03mmol). The mixture was stirred at room temperature for 18 hours. After the reaction, dilute with DCM (200mL) and wash with saturated NaHCO 3 (100 mL) and brine (100 mL). Combine the organic layers with anhydrous Na 2 SO 4 Drying and removal of the solvent in vacuo afforded the crude product, which was purified by chromatography (silica gel column, eluent petroleum ether containing 0.5% EA (volume percent)), and the pure product was evaporated to give compound 2 as a pale yellow oil -1(undecyl 6-bromohexanoate) (0.69 g, yield 38.6%). The hydrogen spectrum of compound 2-1 is shown in Figure 5 .

[0105] 1H NMR (400MHz, CDCl 3 )δ: 4.10(t...

Embodiment 3

[0110] Synthetic route of compound 3

[0111]

[0112] Step 1: Synthesis of compound 3-1

[0113] 8-Bromooctanoic acid (1.139 g, 5.13 mmol) and 3,7-dimethyloct-6-en-1-ol (citronellol, 1.599 g, 10.25 mmol) were dissolved in dichloromethane (60 mL), fully After dissolution, EDC hydrochloride (0.98 g, 5.13 mmol) and DMAP (0.125 g, 1.03 mmol) were added. The mixture was stirred at room temperature for 18 hours. After the reaction, dilute with DCM (200mL) and wash with saturated NaHCO 3 (100 mL) and brine (100 mL). Combine the organic layers with anhydrous Na 2 SO 4 Drying, removal of solvent in vacuo gave a crude product, which was purified by chromatography (silica gel column, eluent was petroleum ether containing 0.5% EA (volume percentage)), and the pure product was evaporated to give light yellow oily compound 3 -1(3,7-dimethyloct-6-enyl 6-bromohexanoate) (0.648g, 35%) The hydrogen spectrum of compound 3-1 is shown in Figure 8 .

[0114] 1H NMR (400MHz, CDCl 3 )δ:...

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Abstract

The invention provides an application of an ionizable lipid compound in a nucleic acid drug delivery system. Most of existing nucleic acid drug carriers have the problems of low in-vivo delivery efficiency or accumulated toxic and side effects in the liver and the like, and in order to solve the problems, the invention provides a novel drug delivery system. The nucleic acid drug delivery system is suitable for various drug delivery modes, has small toxic and side effects on the liver and high nucleic acid delivery efficiency, and even can efficiently deliver nucleic acid drug molecules into the spleen with high specificity and effectively translate the nucleic acid drug molecules into target molecules.

Description

technical field [0001] The invention belongs to the technical field of nucleic acid drug delivery, and in particular relates to the application of an ionizable lipid compound in a nucleic acid drug delivery system. Background technique [0002] The active molecules of nucleic acid drugs include messenger RNA (mRNA), small interfering RNA (siRNA), antisense oligonucleotide (ASO) or plasmid DNA (pDNA), which have great application potential in vaccines and gene therapy in vitro or in vivo . How to successfully deliver nucleic acid drug molecules to cells in the body and express them efficiently, so as to achieve the purpose of prevention or treatment is one of the urgently needed technologies. Most of the existing nucleic acid drug carriers are easy to accumulate in the liver after entering the body, increasing the metabolic burden of the liver and causing obvious toxic and side effects. Or there is a phenomenon that due to the low delivery efficiency of the delivery system,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/18
CPCA61K47/18A61K48/0033A61K31/7105A61K31/715A61K9/5123A61K9/0019B82Y5/00
Inventor 崔艳芳吉帅洁张宝倩刘滨磊
Owner WUHAN BINHUI BIOTECH CO LTD
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