High molecular adriamycin bonded medicament and preparation method thereof

A doxorubicin and polymer technology, applied in the direction of pharmaceutical formulations, medical preparations with non-active ingredients, medical preparations containing active ingredients, etc., can solve the problem of low drug loading, cumbersome preparation process, poor biocompatibility, etc. problem, achieve good biocompatibility, simple preparation process, and enhance the effect of the drug

Active Publication Date: 2012-12-12
CHANGZHOU INST OF ENERGY STORAGE MATERIALS &DEVICES
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the above two bonded drugs have problems such as too stable chemical bonds, low drug loading, and lack of intelligence in the release of doxorubicin.
Biomaterials (Vol.31, p1360-1371, 2010) discloses a carboxyl group modified by polyethylene glycol monomethyl ether and cis-3-carboxyglutaconic anhydride on the surface amino group of polyamide-amine dendrimers The polymer doxorubicin-bonded drug obtained by doxorubicin can be quickly released under the acidic conditions of tumor tissues and cells, thereby realizing the intelligence of drug release, but the carrier used in the bonded drug The material is polyamide-amine dendrimer, and its preparation process is cumbersome and its biocompatibility is poor, which is not conducive to the practical application of bonded drugs.

Method used

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  • High molecular adriamycin bonded medicament and preparation method thereof
  • High molecular adriamycin bonded medicament and preparation method thereof
  • High molecular adriamycin bonded medicament and preparation method thereof

Examples

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preparation example Construction

[0053] The present invention also provides a method for preparing a polymer doxorubicin-bonded drug, comprising the following steps:

[0054] a) polyethylene glycol monomethyl ether, carboxylated doxorubicin derivatives, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide is reacted in an organic solvent to obtain a reaction mixture, and the carboxylated doxorubicin derivative has formula (IV-a), formula (IV-b), formula (IV-c) or formula (IV-d) structure:

[0055]

[0056] In formula (III), n is the degree of polymerization, 10≤n≤120;

[0057]

[0058]

[0059] b) adding poly(L-lysine) or chitosan to the reaction mixture obtained in step a), and reacting to obtain a polymer doxorubicin-bonded drug.

[0060] The present invention uses poly(L-lysine) or chitosan, which has a wide source of raw materials and a simple preparation process, as a raw material, and the prepared polymer doxorubicin-bonded drug has a hydrophilic group and a hy...

Embodiment 5

[0088] Weigh 580.0mg (0.001mol) doxorubicin hydrochloride, 156.1mg (0.001mol) cis-3-carboxyglutaconic anhydride and 101.2mg (0.001mol) triethylamine into a dry reaction flask, add Dissolve 5mL of anhydrous N,N-dimethylformamide and react at 25°C for 24h under stirring with a stirrer. Wash with aqueous sodium solution, dry, filter, and concentrate to obtain carboxylated doxorubicin derivatives.

[0089] Carry out nuclear magnetic resonance analysis to the doxorubicin derivative of described carboxylation, the result sees image 3 , image 3 The H NMR spectrum of the carboxylated doxorubicin derivatives obtained in Example 5 of the present invention; infrared analysis is carried out on the carboxylated doxorubicin derivatives, and the results can be found in Figure 4 , Figure 4 For the infrared analysis spectrogram of the carboxylated doxorubicin derivative obtained in Example 5 of the present invention, by image 3 and Figure 4 It can be seen that the carboxylated doxor...

Embodiment 6

[0090] The synthesis of the doxorubicin derivative of embodiment 6 carboxylation

[0091] Weigh 580.0mg (0.001mol) doxorubicin hydrochloride, 152.2mg (0.001mol) 1,2-dicarboxycyclohexene anhydride and 101.2mg (0.001mol) triethylamine into a dry reaction flask, add Dissolve 5mL of anhydrous N,N-dimethylformamide and react at 25°C for 24h under stirring with a stirrer. After washing with aqueous sodium solution, drying, filtering and concentrating, carboxylated doxorubicin derivatives are obtained.

[0092] The nuclear magnetic resonance analysis and infrared analysis of the carboxylated doxorubicin derivatives show that the carboxylated doxorubicin derivatives prepared in the examples of the present invention have the structure of formula (IV-a).

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Abstract

The invention provides a high molecular adriamycin bonded medicament having a structure shown as a formula (I) or a formula (II). The invention further provides a preparation method of the high molecular adriamycin bonded medicament. The preparation method comprises the following steps of: (a) reacting polyethylene glycol monomethyl ether having a structure shown as a formula (III), a carboxylated adriamycin derivative, 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide.hydrochloride and N-hydroxyl succimide in an organic solvent to obtain a reaction mixed solution, wherein the carboxylated adriamycin derivative has a structure shown as a formula (IV-a), a formula (IV-b), a formula (IV-c) or a formula (IV-d); and (b) adding poly(L-lysine) or chitosan into the reaction mixed solution obtained in the step (a), and reacting to obtain the high molecular adriamycin bonded medicament. In the invention, polyamino acid or the chitosan is taken as a raw material, so that the high molecular adriamycin bonded medicament has high biocompatibility; and moreover, the preparation process is simple, and deep utilization of the high molecular adriamycin bonded medicament is facilitated.

Description

technical field [0001] The invention belongs to the technical field of chemically bonded drugs, in particular to a polymer doxorubicin bonded drug and a preparation method thereof. Background technique [0002] Doxorubicin, also known as daunorubicin, daunorubicin, doxorubicin or ADR, is a broad-spectrum anti-tumor drug of anthracycline antibiotics. It is a non-specific drug for the cell cycle and has the strongest effect on the S phase , It also has effects on M, G1 and G2 phases, and its mechanism of action is mainly to embed DNA molecules, destroy nucleic acid structures and inhibit the synthesis of biological macromolecules. Doxorubicin is mainly used in the treatment of acute leukemia, malignant lymphoma, liver cancer, lung cancer, gastric cancer, esophageal cancer, cervical cancer, bladder cancer, testicular cancer, thyroid cancer, soft tissue tumors, osteosarcoma and neuroblastoma, etc. At present, intravenous infusion is the main clinical administration method of do...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/48A61K31/704C08G81/00A61P35/00A61P35/02
Inventor 庄秀丽丁建勋张建成陈学思
Owner CHANGZHOU INST OF ENERGY STORAGE MATERIALS &DEVICES
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