Water-soluble taxol prodrug prodrug preparation method

A paclitaxel and water-soluble technology, which is applied in the field of chemical modifiers, can solve the problems of limited drug loading and achieve the effects of improving loading capacity, improving solubility, and improving performance

Inactive Publication Date: 2012-08-22
NINGBO UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the above-mentioned modification methods, the linking arms used as modifiers are small molecules that are easy to degrade and are harmless to organisms, but these modification methods all have a common disadvantage. The PEG carrier has a very limited drug loading capacity for drug molecules. , each PEG chain can only connect one paclitaxel molecule

Method used

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  • Water-soluble taxol prodrug prodrug preparation method
  • Water-soluble taxol prodrug prodrug preparation method
  • Water-soluble taxol prodrug prodrug preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034]1. Preparation of mPEG5000 carboxylate

[0035] Dissolve 10g of vacuum-dried mPEG5000 in 100ml of sodium-metal-dried 1,4-dioxane, add sodium metal cut into filaments, and stir magnetically for about 24 hours until no bubbles are released. After standing for 24 hours, use G 4 Filter under reduced pressure on a sand core funnel, and concentrate the filtrate to 20-30ml. Add 0.2g KI as a catalyst, add 6ml of tert-butyl bromoacetate drop by drop under stirring at room temperature, continue stirring for 24 hours after completion, extract with treated anhydrous ether, filter again, and dry in a vacuum oven to obtain a yellowish precipitate .

[0036] 2. Synthesis of Carboxyl mPEG5000

[0037] The resulting solid dry product was dissolved in 125ml of 0.1mol L -1 NaOH solution, hydrolysis reaction at 55℃ for 24h, with 3mol L -1 Adjust the pH value to 2.8 to 3.0 with hydrochloric acid, the color of the solution gradually becomes lighter from brownish yellow, and the water is ...

Embodiment 2

[0047] 1. Preparation of PEG6000 carboxylate

[0048] As in Example 1, 12 g of PEG6000 was used to replace mPEG5000.

[0049] 2. Synthesis of Carboxyl PEG6000

[0050] On the basis of Example 1, the same experimental method as in Example 1 was used to prepare carboxyl PEG6000.

[0051] 3. Activation of Carboxyl PEG6000

[0052] On the basis of embodiment 1, utilize the experimental method identical with embodiment 1, make carboxyl PEG6000 active ester.

[0053] 4. Synthesis of branched PEG6000 modifier

[0054] On the basis of Example 1, using the same experimental method as in Example 1, a branched PEG6000 modifier was prepared, except that the dosage of citric acid was doubled, and the dosage of other reagents was the same as in Example 1.

[0055] 5. Preparation of branched PEG6000 active ester

[0056] On the basis of Example 1, utilize the same experimental method as Example 1 to make branched PEG6000 active ester.

[0057] 6. Synthesis of branched PEG-modified pacl...

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Abstract

The invention provides a water-soluble taxol prodrug as well as a preparation method and a chemical modifier thereof. Polyethylene glycol is used as a carrier and citric acid is used as a connecting arm to prepare a branching-type polyethylene glycol derivative containing a plurality of carboxy groups. The derivative is used for modifying taxol, can greatly improve the taxol carrying capability ofthe polyethylene glycol, and obviously improves the dissolubility of the taxol so that the solubility of the decorated taxol is from 0.1mg / ml to 6.20mg / ml, and the taxol content in the prodrug is from 1 percent to 38 percent. The invention is beneficial to the improvement of medicament performance.

Description

technical field [0001] The invention relates to a polyethylene glycol-modified paclitaxel derivative, a preparation method thereof and the technical field of chemical modifiers. Background technique [0002] Paclitaxel (taxol) was extracted and separated from the bark of Taxus chinensis by Wall et al. in 1963. It is an anticancer drug that promotes microtubule polymerization and is one of the most widely used antitumor drugs. It has a good curative effect in the treatment of multi-system tumors, and is mainly used in the early treatment of breast and ovarian cancer. However, paclitaxel has disadvantages such as poor solubility in water and short half-life, which brings great difficulties to intravenous injection. The earliest method was to stabilize paclitaxel with a 1:1 mixture of surfactant polyoxyethylene castor oil (Cremphor) and absolute ethanol. Although this method can increase the water solubility of paclitaxel, the adverse reactions are serious. In order to effec...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D305/14A61K47/48A61K31/337A61K47/34A61P35/00A61K47/60
Inventor 张剑锋陈晓彬周慧
Owner NINGBO UNIV
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