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Taxol-based small-molecule hydrogel and preparation method thereof

A technology of small molecule water and paclitaxel, which is applied to medical preparations with non-active ingredients, medical preparations containing active ingredients, and pharmaceutical formulas. Improvement effect, the effect that the composition method is simple

Inactive Publication Date: 2012-11-14
NANKAI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, no small molecule hydrogel based on the paclitaxel molecule itself has been found

Method used

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  • Taxol-based small-molecule hydrogel and preparation method thereof
  • Taxol-based small-molecule hydrogel and preparation method thereof
  • Taxol-based small-molecule hydrogel and preparation method thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] (1) Synthesis of Taxol-SA (referring to literature J.Med.Chem., 1989, 32 (4), pp 788-792), the structural formula of Taxol-SA is as follows:

[0020]

[0021] (2) Synthesis of Taxol-SA-GSSG (compound 1), the steps are as follows:

[0022]

[0023] Weigh 100 mg (104.8 μmol) Taxol-SA, dissolve it in 20 mL of anhydrous dichloromethane (DCM), and add the following substances in sequence: 13.3 mg (115.3 μmol) N-hydroxysuccinimide (NHS) and 25.7 mg (125.4 μmol) N, N'-dicyclohexylcarbodiimide (DCC), stirred at room temperature in the dark for three hours, filtered, and the filtrate was collected and spin-dried. Add 10mL of acetone (Acetone), and at the same time add 6mL of an aqueous solution of oxidized glutathione (GSSG) (the content of oxidized glutathione is 96.2mg, add NaHCO 3 About 40 mg was adjusted to pH=7.4), reacted in the dark for 12 hours, spin-dried in acetone, then freeze-dried, separated by high-performance liquid chromatography, and the yield was 83.2%. ...

Embodiment 2

[0025] Synthesis of Taxol-SA-PEG2000 (compound 2)

[0026]Weigh 200 mg (209.6 μmol) of Taxol-SA, add 10 mL of anhydrous dichloromethane (DCM), and add the following substances in sequence on an ice bath: 98.4 μL (628.8 μmol) of N, N′-dicyclohexylcarbodiimide (DIC ) and 10 mg DMAP, finally added 482 mg (241.04 μmol) of PEG2000, then returned to room temperature, stirred in the dark for 12 hours, spin-dried, washed once with 0.1N hydrochloric acid (10 mL), isopropanol crystallized, and the yield was 83.5%. 1 HNMR (300MHz, DMSO-d 6 ( m, 1H), 5.53(t, 1H), 5.31-5.41(m, 3H), 4.87-4.91(m, 2H), 4.54-4.63(m, 5H), 3.99-4.05(m, 6H), 3.71- 3.75(m, 4H), 3.43-3.65(s, PEG), 3.37-3.41(m, 8H), 3.22-3.28(m, 3H), 2.55-2.66(m, 3H), 2.23(s, 3H), 2.05-2.11(m, 3H), 1.75-1.77(m, 3H), 1.49(s, 3H), 1.09-1.15(m, 3H), 0.99-1.02(m, 6H).

[0027]

Embodiment 3

[0029] Synthesis of Taxol-PEG 600 (compound 3) (referring to literature J.Med.Chem.1996, 39, 424-431) Use a pipette to draw 120 μL of PEG 600 (polyethylene glycol dicarboxylic acid) carboxylated at both ends, As for the ice bath, add 10mL of dichloromethane, add 79uL N,N'-dicyclohexylcarbodiimide (DIC) and 10mg DMAP at the same time, then add 200mg paclitaxel, let it slowly return to room temperature, avoid light at room temperature Reacted for 12 hours, spin-dried, washed once with 0.1N hydrochloric acid (10 mL), freeze-dried, crystallized from isopropanol, and the yield was 80.2%. 1 HNMR (300MHz, CHCl 3 -d 6 )δ8.10-8.14 (m, 2H), 7.75-7.77 (m, 3H), 7.26-7.53 (m, 13H), 6.20-6.28 (m, 2H), 5.99-6.03 (m, 1H), 5.67- 5.70(d, 1H), 5.50-5.53(m, 1H), 4.95-4.98(d, 1H), 4.17-4.31(m, 7H), 4.07-4.12(m, 4H), 3.50-3.67(m, PEG ), 3.43-3.51(m, 5H), 2.47(s, 3H), 2.23(s, 2H), 2.14-2.17(m, 2H), 1.96(d, J=13.5, 3H), 1.80(s, 2H ), 1.68(s, 2H), 1.12-1.23(m, 11H)

[0030]

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Abstract

The invention relates to taxol-based small-molecule hydrogel and a preparation method thereof. The preparation method of the taxol-based small-molecule hydrogel comprises the following steps of: (1) dissolving taxol derivatives obtained by ester bond connection of taxol and hydrophilic compounds through hydroxyl groups into an aqueous medium, wherein the quality of the taxol derivatives dissolved in 1ml of aqueous medium is 5-200mg; and (2) hydrolyzing ester bonds for connecting the taxol and the hydrophilic compounds to obtain taxol, thereby forming the taxol-based small-molecule hydrogel. The degree of hydrolyzing can be defined according to specific conditions so long as the hydrogel can be formed. The invention has the following beneficial effects: the synthesis method is simple and only needs 1-2 reaction steps, and the normal saline or buffer solution of the taxol derivatives forms the small-molecule hydrogel capable of being injected through self-hydrolyzing of the ester bonds; and secondly, a slow-release system takes drug molecules as carriers, and the hydrogel can be locally injected to tumor parts, thereby improving the chemotherapy effect.

Description

technical field [0001] The invention relates to a paclitaxel-based small molecule hydrogel and a preparation method thereof. Background technique [0002] Now many hydrophobic drugs such as paclitaxel and camptothecin limit their clinical application due to their poor water solubility. Take paclitaxel as an example: Paclitaxel is a new generation of broad-spectrum anticancer drug that was clinically used in the 1990s. Paclitaxel is mainly applicable to ovarian cancer and breast cancer, and also has a certain effect on lung cancer, colorectal cancer, melanoma, head and neck cancer, lymphoma, and brain tumor. Due to its poor water solubility, most paclitaxel preparations currently used clinically use a mixture of polyoxyethylene castor oil (CremophorEL) and absolute ethanol (1:1) as a co-solvent. Dilute with normal saline or 5% glucose to a final concentration of 0.4-1.4mmolL before administration -1 , these co-solvents can cause a variety of adverse reactions, including al...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/00A61K47/48A61K31/337A61K31/704A61P35/00
Inventor 杨志谋王玲王怀民杨成彪
Owner NANKAI UNIV
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