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Crizotinib prodrug polymeric micelle co-loaded with chemotherapeutic drug and preparation method thereof

A technology for crizotinib and chemotherapeutic drugs, which is applied in the field of polymer materials and new dosage forms of pharmaceutical preparations, can solve the problems of destroying the micellar structure, residual active groups, side effects, etc., achieves efficient co-loading, and improves immunogenicity. , the effect of synergistic anti-tumor efficacy

Active Publication Date: 2020-11-06
NINGXIA MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this method often involves many complicated synthetic steps, and is susceptible to steric hindrance, leading to the possibility that some active groups may remain in the polymer after coupling, thereby destroying the micellar structure or reacting with biologically active molecules. produce side effects in the body

Method used

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  • Crizotinib prodrug polymeric micelle co-loaded with chemotherapeutic drug and preparation method thereof
  • Crizotinib prodrug polymeric micelle co-loaded with chemotherapeutic drug and preparation method thereof
  • Crizotinib prodrug polymeric micelle co-loaded with chemotherapeutic drug and preparation method thereof

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preparation example Construction

[0030] The invention relates to a crizotinib prodrug polymer micelle co-loaded with chemotherapeutic drugs and a preparation method thereof. The present invention is based on polymer micelles combined with prodrug technology, and polymerizes POEG monomer and crizotinib monomer, a tyrosine kinase inhibitor drug, into a hydrophilic diblock copolymer through RAFT polymerization method, and further physically entraps other chemotherapeutic agents. The drug self-assembles into prodrug polymer micelles. The invention can polymerize crizotinib prodrug polymers with different molecular weights by effectively regulating the number of POEG monomers and crizotinib monomers, so as to increase the effective loading capacity of chemotherapy drugs. Under the long cycle mediated by EPR, the co-drug-loaded micelles can be precisely and effectively co-accumulated in tumor tissue. After endocytosis, the co-drug-loaded micelles disintegrated and released the two drugs. The released crizotinib pr...

Embodiment 1

[0054] Crizotinib Prodrug Polymer POEG 15 -b-Cro 9 Synthesis.

[0055] Synthesis of crizotinib monomer.

[0056] 0.2 g of crizotinib, 0.068 g of chloromethylstyrene and 0.14 g of anhydrous sodium carbonate were co-dissolved in 5.5 mL of DMF, and reacted with magnetic stirring in an oil bath at 50°C for 4 h. After the reaction was completed, after three extractions with ethyl acetate and water, the filtrate was collected and rotary evaporated, with dichloromethane and methanol (10:1, v / v) as the mobile phase, dichloromethane and methanol (10:1, v / v) is the developer, and the product is purified by gradient elution of silica gel column chromatography. The purified product is collected and rotary evaporated, and vacuum-dried at room temperature to obtain a pale yellow oily crizotinib monomer.

[0057] Synthesis of POEG monomers.

[0058] Add 1.52g of OEGMA, 60mg of 4-cyano-4-(thiobenzoyl)valeric acid and 5mg of azobisisobutyronitrile into a dry eggplant-shaped reaction flask,...

Embodiment 2

[0062] Crizotinib Prodrug Polymer POEG 10 -b-PCro 6 Synthesis.

[0063] (1) Synthesis of crizotinib monomer.

[0064] 0.2 g of crizotinib, 0.068 g of chloromethylstyrene and 0.14 g of anhydrous sodium carbonate were co-dissolved in 5.5 mL of DMF, and reacted with magnetic stirring in an oil bath at 50°C for 4 h. After the reaction was completed, after three extractions with ethyl acetate and water, the filtrate was collected and rotary evaporated, with dichloromethane and methanol (10:1, v / v) as the mobile phase, dichloromethane and methanol (10:1 , v / v) as the developer, the purified product was eluted by gradient elution of silica gel column chromatography, collected and rotary evaporated the purified product, and vacuum-dried at room temperature to obtain light yellow oily crizotinib monomer.

[0065] Synthesis of POEG monomers.

[0066] Add 1.52g of OEGMA, 60mg of 4-cyano-4-(thiobenzoyl)valeric acid and 5mg of azobisisobutyronitrile into a dry eggplant-shaped reaction ...

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Abstract

The invention relates to crizotinib prodrug polymeric micelle co-loaded with a chemotherapeutic drug and a preparation method thereof, belongs to the field of a high molecular material and a new dosage form of a medicinal preparation, and particularly relates to crizotinib prodrug polymeric micelle co-loaded with a chemotherapeutic drug, which has an effect of reinforcing tumor immunogenicity, anda preparation method thereof. The prodrug polymeric micelle is characterized by being formed by firstly polymerizing a hydrophilic POEG block and hydrophobic crizotinib through a Reversible Addition-Fragmentation chain Transfer (RAFT) method to obtain an amphiphilic diblock copolymer and then physically loading the chemotherapeutic drug into the diblock copolymer to carry out self-assembling. According to the invention, a co-delivery mode of adopting conventional predrug polymer physical loading or adopting a polymer predrug to carry out self-assembling and physically loading another drug small molecules is broken through, and by a polymerization method using a drug as a monomer, high-efficiency co-loading of the combined drug and in-vivo accurate co-delivery are effectively implemented.

Description

technical field [0001] The invention relates to a crizotinib prodrug polymer micelle co-loaded with chemotherapy drugs and a preparation method thereof, belonging to the field of polymer materials and new formulations of pharmaceutical preparations, and in particular to a co-loaded chemotherapy with enhanced tumor immunogenicity Drug crizotinib prodrug polymer micelles and preparation method thereof. Background technique [0002] Cancer is a disease of malignant cells that interact and regulate each other with their surrounding environment in complex ways to stimulate tumor growth, invasion, and metastasis, resulting in an immune-stressed tumor microenvironment resistant to multiple anticancer drugs. The monotherapy based on chemotherapy drugs can no longer meet the needs of clinical tumor treatment due to serious side effects and multidrug resistance. At present, the combination therapy of two or more drugs with different anti-tumor mechanisms can effectively overcome the ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4545A61K45/06A61K9/107A61K47/58A61P35/00C08F293/00
CPCA61K31/4545A61K45/06A61K9/1075A61K47/58A61P35/00C08F293/005C08F2438/03A61K2300/00
Inventor 刘艳华梁蔷薇刘金霞兰杨朱溶月李莉
Owner NINGXIA MEDICAL UNIV
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