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Sialic acid derivative modified ibrutinib (IBR) nanocomposite and preparation method thereof

A technology of sialic acid derivatives and nanocomposites, which is applied in the field of medicine, can solve the problems of high clinical dosage and patients' inability to take drugs orally, and achieve the effect of suppressing growth

Active Publication Date: 2020-11-24
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Aiming at the problem that ibrutinib is insoluble in water, the absolute bioavailability of capsules is only 2.9%, and the clinical dosage is large, it is made into a nanocomposite to increase the water solubility of ibrutinib, providing a Products that can be injected are used to reduce the daily dose of drugs, and can be used in clinically critical patients to solve the problem that such patients cannot take oral drugs

Method used

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  • Sialic acid derivative modified ibrutinib (IBR) nanocomposite and preparation method thereof
  • Sialic acid derivative modified ibrutinib (IBR) nanocomposite and preparation method thereof
  • Sialic acid derivative modified ibrutinib (IBR) nanocomposite and preparation method thereof

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Embodiment 1

[0079] The synthesis of embodiment 1 sialic acid methyl ester derivative MT-18

[0080] Accurately weigh 20 g of sialic acid, stir in 250 mL of methanol containing 3.68 M hydrochloric acid, and reflux at 50° C. for 2.5 h. The solvent was removed by vacuum drying and washed with cold methanol to give a residual mixture. The methylated sialic acid was obtained as a white solid after purification by recrystallization.

[0081] Accurately weigh 7.5 g of stearic acid and dissolve it in 0.233 mol of thionyl chloride with stirring for 1 h, and remove the residual solvent by evaporation under reduced pressure. Next, 3 g of methylated sialic acid and 0.1 g of 4-dimethylaminopyridine were dissolved in 30 mL of anhydrous pyridine. Subsequently, a dichloromethane solution containing 2.8 g of octadecyl chloride was added dropwise to the mixture at 0° C., and the reaction was stirred at the same temperature for 30 min. Afterwards, the temperature of the reactant was adjusted to room temp...

Embodiment 2

[0083] The synthesis of embodiment 2 sialic acid octadecanoic acid derivative SA-18

[0084] Accurately weigh 20 g of sialic acid, stir in 250 mL of methanol containing 3.68 M hydrochloric acid, and reflux at 50° C. for 2.5 h. The solvent was removed by vacuum drying and washed with cold methanol to give a residual mixture. The methylated sialic acid was obtained as a white solid after purification by recrystallization. Accurately weigh 7.5 g of stearic acid and dissolve it in 0.233 mol of thionyl chloride with stirring for 1 h, and remove the residual solvent by evaporation under reduced pressure. Next, 3 g of methylated sialic acid and 0.1 g of 4-dimethylaminopyridine were dissolved in 30 mL of anhydrous pyridine. Subsequently, a dichloromethane solution containing 2.8 g of octadecyl chloride was added dropwise to the mixture at 0° C., and the reaction was stirred at the same temperature for 30 min. Afterwards, the temperature of the reactant was adjusted to room temperat...

Embodiment 3

[0086] The synthesis of embodiment 3 ethyl sialic acid derivatives ET-18

[0087] Accurately weigh 20 g of sialic acid, stir in 250 mL of ethanol containing 3.68 M hydrochloric acid, and reflux at 50° C. for 2.5 h. The solvent was removed by vacuum drying and washed with cold methanol to give a residual mixture. Ethylated sialic acid was obtained as a white solid after purification by recrystallization.

[0088] Accurately weigh 7.5 g of stearic acid and dissolve it in 0.233 mol of thionyl chloride with stirring for 1 h, and remove the residual solvent by evaporation under reduced pressure. Next, 9.2 mmol of ethylated sialic acid and 0.1 g of 4-dimethylaminopyridine were dissolved in 30 mL of dry pyridine. Subsequently, a dichloromethane solution containing 2.8 g of octadecyl chloride was added dropwise to the mixture at 0° C., and the reaction was stirred at the same temperature for 30 min. Afterwards, the temperature of the reactant was adjusted to room temperature and th...

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Abstract

The invention relate to a high-density sialic acid modified ibrutinib (IBR) nanocomposite and a preparation method thereof. The sialic acid modified IBR nanocomposites comprises IBR, phospholipid anda sialic acid derivative, wherein the molar ratio of IBR to phospholipid is 1:0.5 to 1:5, and the molar ratio of the sialic acid derivative to phospholipid is 1:19 to 1:1. The phospholipid is one or more of phosphatidylglycerol, phosphatidic acid, phosphatidylserine, phosphatidylinositol and cardiolipin. The nanocomposite can obviously improve the drug dissolution performance, provides an injectable product for reducing the daily dose of drugs, and can be used for clinical critical patients to solve the problem that the patients cannot take drugs orally. Based on the theory of ''immunopharmaceuticals'', the sialic acid is used to modify the composite, accumulation of the preparation in tumor site and the inhibitory effect on tumor microenvironment stromal cells are increased, so that the tumor therapeutic spectrum of IBR is expanded, and the drug efficacy is improved.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to ibrutinib nanocomposites modified by sialic acid derivatives, a preparation method and application thereof, and a pharmaceutical composition using ibrutinib nanocomposites as active components. Background technique [0002] Tumor is a new organism formed by the body under the action of various carcinogenic factors, a certain cell in the local tissue loses its normal regulation of its growth at the gene level, resulting in abnormal clonal proliferation (HEIM S, MITELMANF. Cancer Cytogenetics: Chromosomal and Molecular Genetic Aberrations of Tumor Cells, Fourth Edition [M]. 2015). According to the characteristics of tumor cells and the degree of harm to the body, the medical field generally divides tumors into benign and malignant tumors. Malignant tumors are also called cancers (ENGLAND D M, HOCHHOLZER L, MCCARTHY M J. Localized benign and malignant fibrous tumors of the pleura. C...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/51A61K47/24A61K47/26A61K31/519A61P35/00A61P29/00
CPCA61K9/5123A61K31/519A61P35/00A61P29/00
Inventor 邓意辉邱秋钧李聪胡玲张红霞宋艳志刘欣荣
Owner SHENYANG PHARMA UNIVERSITY
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