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Combination of mPEG-PLA-tree alkali medicament

A technology of conjugates and camptothecin, which is applied in the field of camptothecin prodrugs, can solve problems such as high toxicity and side effects, unsatisfactory clinical trial results, and severe side effects

Active Publication Date: 2008-06-18
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These published patents only use water-soluble polymers, intending to increase the solubility, improve tumor targeting, and overcome the shortcomings of large toxic and side effects and inconvenient administration.
However, some water-soluble polymer-camptothecin conjugates have unsatisfactory results in clinical trials, showing relatively large toxic and side effects, and clinical trials have been stopped (such as IT-101 and MAG-CPT).

Method used

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  • Combination of mPEG-PLA-tree alkali medicament
  • Combination of mPEG-PLA-tree alkali medicament
  • Combination of mPEG-PLA-tree alkali medicament

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Preparation of Methoxypolyethylene Glycol Polylactic Acid

[0034]

[0035] 6 g of methoxypolyethylene glycol and 0.13 g of succinic anhydride (the molar ratio of the two is 1:1.1) were dissolved in pyridine, and reacted at 50° C. for 5 hours. After the reaction was completed, pyridine was removed by rotary evaporation, recrystallized in isopropanol three times, and vacuum-dried at 40°C.

[0036] Dissolve 1.0 g of stannous octoate in 25 ml of toluene to obtain a 0.04 g / mL catalyst-toluene solution. Weigh 2.33g of lactide and 1.33g of succinylated methoxypolyethylene glycol into a dry polymerization tube, and add 70ul of toluene-stannous octoate solution. Vacuumize to remove toluene, then flush with nitrogen protection. Then place the polymer tube in an oil bath and heat it to 140-160°C, the lactide crystals will melt, shake and mix thoroughly, N 2 Under the protection, keep warm and polymerize for 5 hours. After natural cooling, the polymer ...

Embodiment 2

[0038] Preparation of methoxypolyethylene glycol-polylactic acid-camptothecin conjugate

[0039]

[0040] Take 0.5g mPEG-PLA-COOH and 30mg camptothecin and pre-lyophilize for 2 hours. Under the protection of nitrogen, put it into a 50ml round bottom flask, dissolve it with 20ml of chloroform, then add 0.6ml of pyridine and 0.3ml of phenoxyphosphoric acid chloride. The reaction was carried out under magnetic stirring at room temperature for 24 hours. After the reaction is complete, wash with 1N hydrochloric acid, 25ml each time, twice. Anhydrous sulfuric acid was used to remove residual moisture, and concentrated under reduced pressure to obtain a yellow product. Wash off the unreacted drug camptothecin with excess isopropanol, and then wash off the yellow color with anhydrous ether to obtain a pale white solid product.

Embodiment 3

[0042] Preparation of Methoxypolyethylene Glycol Polylactic Acid-10 Hydroxycamptothecin Conjugate

[0043]

[0044] Take 0.5g mPEG-PLA-COOH and 30mg 10-hydroxycamptothecin (10-HCPT) and pre-lyophilize for 2 hours. Under the protection of nitrogen, put it into a 50ml round bottom flask, dissolve it with 20ml of chloroform, then add 0.6ml of pyridine and 0.3ml of phenoxyphosphoric acid chloride. The reaction was carried out under magnetic stirring at room temperature for 24 hours. After the reaction is complete, wash with 1N hydrochloric acid, 25ml each time, twice. Anhydrous sulfuric acid was used to remove residual moisture, and concentrated under reduced pressure to obtain a yellow product. Wash off the unreacted drug 10-hydroxycamptothecin with excess isopropanol, and then wash off the yellow color with anhydrous ether to obtain a light yellow solid product.

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Abstract

The invention relates to a novel amphiphilic-block-copolymer-based pro-camptothecin drug, which is a compound of methoxy polyethylene glycol- polylactic acid and camptothecin derivatives (mPEG-X-PLA-T), wherein, mPEG refers to methoxy polyethylene glycol; X refers to linking group, for example, succinic acid; PLA refers to polylatic acid; T refers to drug molecule, that is, camptothecin derivatives such as, camptothecin, 10-hydroxycamptothecine, 7-ethyl-10- hydroxycamptothecine. Polylactic acid is connected with camptothecin derivatives through ester bond.

Description

(1) Technical field [0001] The present invention relates to a novel class of camptothecin prodrugs based on amphiphilic block polymers: methoxypolyethylene glycol-polylactic acid-camptothecin drugs (mPEG-PLA-camptothecin drugs) . (2) Background technology [0002] Camptothecin (CPT) was first extracted from camptotheca japonica in 1966. It is a kind of efficient topoisomerase inhibitor and has high antitumor activity. The obvious disadvantages of such drugs are their poor water solubility and large toxic and side effects (such as severe bladder toxicity and severe diarrhea), which limit their clinical use. The solution is mainly structural modification. Drugs that have been developed and marketed include irinotecan (irinotecan, CPT-11, Campto, Camptosar) and topotecan (topotecan, Hycamtin), both of which are prodrugs of camptothecin. Due to good water solubility, it exhibits excellent activity against colon-cecum cancer. Among them, irinotecan is widely used. Irinotecan...

Claims

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Application Information

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IPC IPC(8): A61K47/48A61K31/4745A61P35/00A61K47/59
Inventor 栾立标吴小涛
Owner CHINA PHARM UNIV
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