Multifunctional synergistic pharmaceutical composition based on adriamycin and construction method of multifunctional synergistic pharmaceutical composition

A doxorubicin and multi-functional technology, applied in the field of pharmaceutical preparations and supramolecular chemistry, can solve the problems of limiting the optimization and application of hydrophobic small molecule compounds containing phenolic hydroxyl conjugates, poor activity of phenolic hydroxyl groups, etc., to prolong the circulation time in the body, Good uniformity, avoiding the effect of protease degradation

Active Publication Date: 2018-04-24
CHINA PHARM UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Generally speaking, the activity of phenolic hydroxyl groups is poor, which greatly limits the optimization and application of conjugated hydrophobic small molecule compounds containing phenolic hydroxyl groups.

Method used

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  • Multifunctional synergistic pharmaceutical composition based on adriamycin and construction method of multifunctional synergistic pharmaceutical composition
  • Multifunctional synergistic pharmaceutical composition based on adriamycin and construction method of multifunctional synergistic pharmaceutical composition
  • Multifunctional synergistic pharmaceutical composition based on adriamycin and construction method of multifunctional synergistic pharmaceutical composition

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0073] Embodiment 1: the synthesis of curcumin-unfractionated heparin polymer

[0074] Weigh an appropriate amount of 6-bromohexylamine hydrochloride into an eggplant-shaped bottle, add dichloromethane to dissolve, and then add di-tert-butyl dicarbonate. The molar ratio of di-tert-butyl dicarbonate to 6-bromohexylamine hydrochloride is 1.5:1. Separately weigh 1-hydroxybenzotriazole and triethylamine, dissolve them in an appropriate amount of dichloromethane, and slowly drop them into the above-mentioned eggplant-shaped bottle. The molar ratio of 1-hydroxybenzotriazole to 6-bromohexylamine hydrochloride is 1:5, and the molar ratio of triethylamine to 6-bromohexylamine hydrobromide is 1.05:1. After reacting at room temperature for 40 min, wash with 0.5 mol / L dilute sulfuric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution three times respectively. After washing, the organic phase was dried with anhydrous sodium sulfate for 2 h. Suction filtra...

Embodiment 2

[0078] Embodiment 2: the synthesis of curcumin-low molecular weight heparin polymer

[0079] Weigh an appropriate amount of curcumin and place it in an eggplant-shaped bottle, add an appropriate amount of acetone to dissolve, the molar concentration of curcumin is 0.05mmol / mL, add 1.1 molar amount of sodium carbonate, and then dropwise add 1.05 molar amount of 3-bromo-1- Propanol, heat and reflux at 60°C until the raw materials disappear. After the reaction is complete, filter while it is hot, drop the filtrate into a large amount of ice water, stand for crystallization, filter with suction, and dry to obtain the curcumin derivative intermediate with a free hydroxyl group at one end 1. Weigh an appropriate amount of low-molecular-weight heparin and dissolve it in formamide, heat and dissolve at 60°C for 2 hours, add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and hydroxyl For succinimide activation, the molar ratio of low molecular weight heparin carboxyl to 1...

Embodiment 3

[0080] Embodiment 3: the synthesis of chrysin-low molecular weight heparin polymer

[0081] Weigh an appropriate amount of chrysin and put it in an eggplant-shaped bottle, add an appropriate amount of acetone to dissolve, the molar concentration of chrysin is 0.05mmol / mL, add 1.3 molar amount of potassium carbonate, and then dropwise add 1.1 molar amount of 3-bromo-1- Propanol, heated under reflux at 60°C until the raw materials disappear, after the reaction is complete, filter while hot, drop the filtrate into a large amount of ice water, let it stand for crystallization, filter with suction, and dry to obtain the intermediate of chrysin derivatives with a free hydroxyl group at one end 1. Weigh an appropriate amount of low-molecular-weight heparin and dissolve it in formamide, heat and dissolve at 60°C for 2 hours, protect it under nitrogen, and add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and hydroxyl For succinimide activation, the molar ratio of low mo...

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Abstract

The invention relates to a multifunctional synergistic pharmaceutical composition based on adriamycin. According to the pharmaceutical composition, natural hydrophobic small molecules having a conjugated structure are covalently coupled with a polysaccharide skeleton to form an anti-angiogenesis drug, the anti-angiogenesis drug is physically mixed with the conjugated structure-modifying mitochondria damage peptide derivative and adriamycin, and the pharmaceutical composition of a nano size is assembled by virtue of various supramolecular driving forces. The pharmaceutical composition has the advantages of simultaneously regulating a tumor micro environment and tumor cells, reversing the anti-apoptosis characteristics of tumor cells, and maximizing the antitumor effect of the adriamycin. Inaddition, the multifunctional synergistic pharmaceutical composition has the advantages of the adriamycin such as high load, high stability and high targeting. The multifunctional synergistic pharmaceutical composition based on the adriamycin is compatible with corresponding medicinal auxiliary materials to prepare antitumoar drug preparations for injection, oral administration or external use. The multifunctional synergistic pharmaceutical composition is prepared by virtue of a multi-component supramolecular combination construction, so that the operation is simple, and the industrialized production is easy to realize.

Description

technical field [0001] The invention belongs to the field of pharmaceutical preparations and supramolecular chemistry, and relates to a doxorubicin-based multifunctional synergistic pharmaceutical composition and a construction method thereof. Background technique [0002] The clinical application of the traditional chemotherapy drug doxorubicin often faces the dilemma of poor curative effect and severe side effects. The poor curative effect of doxorubicin alone is mainly related to the physiological complexity of the tumor. Tumor cells can continue to produce proliferation signals, anti-growth inhibitory signals, initiate anti-apoptotic mechanisms, and at the same time induce angiogenesis and promote tissue invasion and metastasis (Hanahan D, Weinberg R A. The hallmarks of cancer.[J].Cell, 2000 , 100(1):57.). Tumor resistance to apoptosis is mainly related to mitochondria. Mitochondria are originally a "suicide weapon arsenal", but due to changes in the structure and func...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/69A61K47/55A61K31/704A61K38/10A61P35/00A61K31/727A61K31/05A61K31/12A61K31/122A61K31/352
CPCA61K31/05A61K31/12A61K31/122A61K31/352A61K31/704A61K31/727A61K38/10A61K2300/00
Inventor 姚静于瑶徐程
Owner CHINA PHARM UNIV
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