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Dasatinib grafted polymer micelle, its freeze-dried powder injection, preparation method and application

A technology of freeze-dried powder injection and polymer glue, which is applied in the field of dasatinib grafted polymer micelles, which can solve the problems of slow release and absorption of dasatinib, limited improvement of bioavailability, and long preparation process, etc. problems, to achieve the effects of strong operability and repeatability, improved bioavailability, and good application value

Active Publication Date: 2020-09-25
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the stability problem of liposomes has been improved to a certain extent, the preparation process is time-consuming and requires high quality work, and there is a problem of slow release and absorption of dasatinib after the preparation enters the body
Dasatinib albumin nanoparticles reported in other literature (Malarvizhi GL, Chandran P, Retnakumari A P, et al. A rationally designed photo-chemo core-shell nanomedicine for inhibiting the migration of metastatic breast cancer cells followed by photodynamic killing[J]. Nanomedicine, 2014, 10(3):579-587.), Dasatinib prodrug (Sun J, Liu Y, Chen Y, et al.Doxorubicin delivered by a redox-responsive dasatinib-containing polymericprodrug carrier for combination therapy[J ].Journal of Controlled ReleaseOfficial Journal of the Controlled Release Society, 2017,258:43-55.), dasatinib block polymer micelles (Yao Q, Choi J H, Dai Z, et al. Improving Tumor Specificity and Anticancer Activity of Dasatinib by Dual-Targeted Polymeric Micelles[J]. ACS Applied Materials & Interfaces, 2017, 9(42): 36642-36654.) Both have low drug loading in preparations (both less than 9%) and limited improvement in bioavailability , complex preparation process and other issues limit the development process of dasatinib high-efficiency nano-preparation

Method used

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  • Dasatinib grafted polymer micelle, its freeze-dried powder injection, preparation method and application
  • Dasatinib grafted polymer micelle, its freeze-dried powder injection, preparation method and application
  • Dasatinib grafted polymer micelle, its freeze-dried powder injection, preparation method and application

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Embodiment 1

[0030] (1) Preparation of hyaluronic acid-ursodeoxycholic acid amphiphilic graft polymer

[0031] Dissolve 1 g of ursodeoxycholic acid in N-N, dimethylformamide, add 500 mg of N, N'-dicyclohexylcarbodiimide and 250 mg of N-hydroxysuccinimide to activate for 4 hours, then add 5 ml of ethylenediamine, React for 12 hours under the protection of nitrogen. After the reaction, remove the insoluble by-products by filtration, add water to the supernatant to precipitate the product, and collect the precipitate to obtain ursodeoxycholic acid with a free amino group at one end. Dissolve 1g of hyaluronic acid in formamide, add 403mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 200mg of N-hydroxysuccinimide for activation for 30 minutes, then add 100mg Ursodeoxycholic acid with a free amino group at one end was stirred and reacted at room temperature for 20 hours. After the reaction was completed, the reaction solution was transferred to a dialysis bag for dialysis fo...

Embodiment 2

[0037] (1) Preparation of Dasatinib grafted polymer micelles

[0038] Weigh 25 mg of the hyaluronic acid-ursodeoxycholic acid amphiphilic graft polymer prepared in step (1) of Example 1, add 5 ml of deionized water, and stir to obtain a 5 mg / ml graft polymer micelle solution; Take 9 mg of dasatinib and dissolve it in N,N-dimethylformamide to obtain a dasatinib solution. Under high-speed stirring, add the dasatinib solution to the above-mentioned grafted polymer micelle solution, after ultrasonication with a 200W probe for 20 minutes, dialyze with deionized water overnight, and pass through a 0.45 μm filter membrane to obtain the grafted dasatinib type polymer micellar solution. In view of the presence of free carboxyl groups on the surface of the micelles, CaCl was slowly added dropwise during the stirring process. 2 solution, Na 2 HPO 4 solution, a layer of insoluble Ca is formed on the surface of the micelles by charge interaction 3 (PO 4 ) 2 The mineralized layer was...

Embodiment 3

[0042] (1) Preparation of Dasatinib grafted polymer micelles

[0043] Weigh 25 mg of the hyaluronic acid-ursodeoxycholic acid amphiphilic graft polymer prepared in step (1) of Example 1, add 5 ml of deionized water, stir to obtain 5 mg / ml to obtain the graft polymer micelle solution ; 9 mg of dasatinib was dissolved in N, N-dimethylformamide to obtain a dasatinib solution. Under high-speed stirring, the dasatinib solution was added to the above-mentioned grafted polymer micelle solution, and after homogenization by a high-pressure homogenizer (homogeneous pressure: 750Pa; number of homogenization cycles: 5 times), deionized Dialyze with water overnight and pass through a 0.45 μm filter membrane to obtain a dasatinib grafted polymer micelle solution. The micelles have an average particle size of 166.4±2.5nm and a Zeta potential of -20.31±1.12mV. The drug loading of dasatinib was 14.9%.

[0044] (2) Preparation of Dasatinib Grafted Polymer Micelle Freeze-dried Powder Injectio...

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Abstract

The invention provides a dasatinib grafted polymeric micelle which comprises an amphiphilic grafted polymer and dasatinib entrapped by the amphiphilic grafted polymer. The invention also provides a preparation method of the dasatinib grafted polymeric micelle, a freeze-dried powder injection of the dasatinib grafted polymeric micelle, a preparation method of the freeze-dried powder injection, andapplications of the dasatinib grafted polymeric micelle and the freeze-dried powder injection. The dasatinib grafted polymeric micelle has the advantages of high drug loading rate, good stability andgood biocompatibility, and capability of being efficiently accumulated in tumor tissues through active targeting and / or passive targeting when being used for treating solid tumors and increasing the drug concentration in the tumor tissues, so as to achieve the purpose of increasing efficiency and reducing toxicity.

Description

technical field [0001] The invention belongs to the field of pharmaceutical preparations, in particular to a dasatinib grafted polymer micelle, its freeze-dried powder injection, its preparation method and application. Background technique [0002] Dasatinib is a small molecule multi-target receptor tyrosine kinase inhibitor (TKI), which has inhibitory effects on BCR-ABL, Src, Lck, YES, EPH receptor A2 (EPHA2), PDGFR and other kinases Inhibition, belonging to the second generation of signal transduction inhibitors. Dasatinib was developed by Bristol-Myers Squibb in the United States and was approved for marketing in the United States in the form of tablets in 2006. Its trade name is Sprycel. The drug is mainly used clinically to treat adult patients with Philadelphia chromosome-positive chronic myeloid leukemia (CML) who are resistant or intolerant to imatinib mesylate and Philadelphia chromosome-positive patients who are resistant or intolerant to other therapies adult pa...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K9/107A61K9/19A61K47/36A61K31/506A61P35/00
CPCA61K9/1075A61K9/19A61K31/506A61K47/36A61P35/00
Inventor 殷婷婕霍美蓉刘艳红
Owner CHINA PHARM UNIV
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