Clofarabine and methotrexate double-medicine preparation and preparation method thereof

A technology of clofarabine methotrexate and clofarabine, which is applied in the field of clofarabine methotrexate double-drug preparation and its preparation, and achieves the effects of good stability, good responsive release characteristics, and strong tumor inhibitory effect

Inactive Publication Date: 2019-07-30
XIAMEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, clinically, the simple combined drug can only reduce the toxic and side effects of the drug t

Method used

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  • Clofarabine and methotrexate double-medicine preparation and preparation method thereof
  • Clofarabine and methotrexate double-medicine preparation and preparation method thereof
  • Clofarabine and methotrexate double-medicine preparation and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] (1) Clofarabine and methotrexate were dissolved in dimethyl sulfoxide respectively to obtain 2 mg / mL clofarabine solution and 3 mg / mL methotrexate solution;

[0031] (2) Mix 500 μL clofarabine solution and 500 μL methotrexate solution (molar ratio 1:1) and react at 25° C. for 0.5 h;

[0032] (3) Add 10 μL of sodium hydroxide solution with a concentration of 5 mg / mL to the material obtained in step (2), and continue to react at 25° C. for 0.5 h;

[0033] (4) In step (3), add 10 times the volume of deionized water for super-dispersion for 0.5 h, and then use a dialysis bag with a molecular weight of 3500 to perform dialysis for 12 h to remove dimethyl sulfoxide to obtain a dialysate;

[0034] (5) Filter the dialysate with a microporous membrane of 0.22 μm to obtain a clofarabine methotrexate double-drug nanomicelle solution with an average particle diameter of 110 nm;

[0035] (6) Add 5wt% dextran to the above-mentioned clofarabine methotrexate double-drug nano-micelle s...

Embodiment 2

[0037] (1) Clofarabine and methotrexate were dissolved in N,N-dimethylformamide respectively to obtain 2mg / mL clofarabine solution and 3mg / mL methotrexate solution;

[0038] (2) Mix 500 μL clofarabine solution and 500 μL methotrexate solution (molar ratio 1:1) and react at 30° C. for 0.5 h;

[0039] (3) Add 10 μL of sodium hydroxide solution with a concentration of 5 mg / mL to the material obtained in step (2), and continue to react at 30° C. for 0.5 h;

[0040] (4) Add 10 times the volume of deionized water in step (3) and ultrasonically disperse for 0.5 h, then use a dialysis bag with a molecular weight of 3500 to perform dialysis for 12 h to remove N, N-dimethylformamide to obtain a dialysate;

[0041] (5) Filter the dialysate with a microporous membrane of 0.22 μm to obtain a clofarabine methotrexate double-drug nanomicelle solution with an average particle diameter of 110 nm;

[0042] (6) Add the clofarabine methotrexate double-drug nano-micelle solution to the lyoprotect...

Embodiment 3

[0044] (1) Clofarabine and methotrexate were dissolved in tetrahydrofuran respectively to obtain 2mg / mL clofarabine solution and 3mg / mL methotrexate solution;

[0045] (2) Mix 500 μL clofarabine solution and 500 μL methotrexate solution (molar ratio 1:1) and react at 25° C. for 0.5 h;

[0046] (3) Add 10 μL of sodium hydroxide solution with a concentration of 5 mg / mL to the material obtained in step (2), and continue to react at 25° C. for 0.5 h;

[0047] (4) In step (3), add 10 times the volume of deionized water to ultrasonically disperse for 0.5 h, and then use a 3500 molecular weight dialysis bag to perform dialysis for 12 h to remove tetrahydrofuran and obtain a dialysate;

[0048] (5) Filter the dialysate with a microporous membrane of 0.22 μm to obtain a clofarabine methotrexate double-drug nanomicelle solution with an average particle diameter of 120 nm;

[0049] (6) The clofarabine and methotrexate double-drug nano-micelle solution was added with sucrose as a freeze-...

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Abstract

The invention discloses a clofarabine and methotrexate double-medicine preparation and a preparation method thereof. The clofarabine and methotrexate double-medicine preparation is prepared from the effective components of clofarabine and methotrexate according to the molar ratio of (0.8-1.2):(0.8-1.2), wherein the clofarabine serves as main medicine, the methotrexate serves as auxiliary medicineand targeting molecules, the methotrexate and the clofarabine are connected through the hydrogen-bond effect to form micelle, and the micelle is freeze-dried under vacuum. The grain diameter of the clofarabine and methotrexate double-medicine nano-micelle is 100-200 nm, the stability of the preparation obtained after freeze-drying is good, a good responsiveness release characteristic is achieved after the preparation is injected into the human body, it is proved through the cytotoxicity test that compared with pure double-medicine use of the clofarabine and the methotrexate, a higher tumor suppression effect is achieved, and the preparation is suitable for serving as an intravenous injection preparation, and has the advantages of being high in targeting performance, long in circulation andlow in toxicity and achieving synergistic treatment.

Description

technical field [0001] The invention belongs to the technical field of antineoplastic drugs, in particular to a clofarabine methotrexate double drug preparation and a preparation method thereof. Background technique [0002] Clofarabine (Clofarabine, CA), Mr 303.68, is a deoxynucleoside anti-metabolite drug, which is a class of anti-tumor drugs that hinder enzymes in DNA synthesis in various ways. Clofarabine has an effect on a variety of solid tumors, and is particularly effective in the treatment of acute leukemia. CA is a weakly lipophilic prodrug. As a new purine nucleoside analogue, it can not only enter cells through glandular carriers, but also enter cells through lipid membranes through passive diffusion at high concentrations. After entering the cell, CA is phosphorylated by deoxycysteine ​​to the active product triphosphate in a stepwise manner. After entering the cell, CA is gradually phosphorylated by deoxycysteine ​​(dCK) to the active product clofarabine tri...

Claims

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Application Information

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IPC IPC(8): A61K31/7076A61K9/19A61K47/55A61P35/00A61K31/519A61K9/107
CPCA61K9/0019A61K9/1075A61K9/19A61K31/519A61K31/7076A61K47/55A61P35/00A61K2300/00
Inventor 侯振清王凡凡朱富凯
Owner XIAMEN UNIV
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