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Bi-component drug micromolecule hydrogel based on hexadecadrol and taxol and preparation method thereof

A technology of dexamethasone and small molecule water, applied in the direction of drug combination, pharmaceutical formula, chemical instrument and method, etc., to save the life of patients, prevent recurrence and metastasis, simple synthesis steps and purification methods

Inactive Publication Date: 2012-07-04
NANKAI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although many domestic scientists have conducted useful explorations on paclitaxel, many patents are now owned by foreign countries; so far, there is no domestically developed anticancer drug such as paclitaxel, and most of these technologies are owned by foreign countries

Method used

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  • Bi-component drug micromolecule hydrogel based on hexadecadrol and taxol and preparation method thereof
  • Bi-component drug micromolecule hydrogel based on hexadecadrol and taxol and preparation method thereof
  • Bi-component drug micromolecule hydrogel based on hexadecadrol and taxol and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0014] (1) Synthesis of Taxol-SA and Taxol-SA-NHS (compound 3 and compound 3a), the synthesis steps are shown in the appendix figure 1

[0015] 0.50 g (0.59 mmol) of paclitaxel was dissolved in 12 mL of pyridine, then 0.90 g (0.76 mmol) of succinic anhydride was added, and stirred at room temperature for 3 hours. The solution was removed by a rotary evaporator, then 20 mL of double-distilled water was added, stirred at room temperature for 20 minutes, then filtered, the precipitate was dissolved in acetone, and then water was added for crystallization, left to stand for 4 overnight, and the crystals were collected to obtain the product (yield 90%). (2) Synthesis of Dex-SA (Compound 4)

[0016] In the same reaction as above, weigh 1 g of dexamethasone and dissolve it in 20 mL of pyridine, add 3 equivalents of succinic anhydride at the same time, then add 0.1 equivalent of 4-dimethylaminopyridine, stir at room temperature for 24 hours, and remove the solution with a rotary evap...

Embodiment 2

[0019] Embodiment 2: the synthesis of compound Dex-FFFKESSEE and Dex-KESSEE

[0020] It was synthesized by standard Fmoc solid-phase synthesis method, and the amino acids used were all amino acids protected by Fmoc at the amino terminal, and the compound 4 added at the end can be regarded as an amino acid, and the way of connecting the peptide chain is the same as that of amino acids. The specific synthesis steps are as follows: (taking Dex-FFFKESSEE as an example)

[0021] ① Weigh 1mmol of resin, add it to a solid-phase synthesizer, add an appropriate amount of DCM to immerse the resin, and expand it for 5min under the blowing action of nitrogen; remove the solvent, add 1mmol of the first amino acid (glutamic acid protected by Fmoc in this experiment, and at the same time The side chain is also protected by OtBu) in DCM solution, add 2mmol DIEA, react for 2h;

[0022] ②Washing: wash with DCM, wash 5 times, each time for 1min;

[0023] ③ Sealing: react with a solution with a...

Embodiment 3

[0029] Example 3: Synthesis of colloidal precursor molecules Dex-FFFK (taxol-SA) ESSEE and Dex-K (taxol-SA) ESSEE (taking Dex-FFFK (taxol-SA) ES SEE as an example)

[0030] Dissolve 60mg (0.06mmol) 3a in 3mL dimethylformamide solvent, add 50μl DIEA at the same time, then add 121mg (0.07mmol) Dex-FFFKE-ss-EE to react overnight at room temperature, and use high performance liquid phase to purify the compound to obtain Dex -FFFK(taxol-SA)ESSEE, yield 87.0%. 1 H NMR (400MHz, DMSO-d6) δ8.12-8.19 (m, 4H), 8.02-8.09 (m, 4H), 7.97-7.99 (m, 3H), 7.86 (d, J=7.13, 1H), 7.72 -7.76(m, 1H), 7.64-7.67(m, 2H), 7.54-7.58(m, 1H), 7.48-7.50(m, 2H), 7.44-7.47(m, 4H), 7.28-7.31(m, 1H), 7.24-7.26(m, 4H), 7.16-7.20(m, 12H), 6.30(s, 1H), 6.21-6.24(m, 1H), 6.01(s, 1H), 5.80-5.85(m, 1H), 5.51-5.55(m, 1H), 5.40-5.42(m, 2H), 5.33-5.35(m, 1H), 5.17(s, 1H), 4.99-5.04(m, 1H), 4.90-4.95( m, 2H), 4.73-4.78(m, 1H), 4.64(s, 1H), 4.59-4.61(m, 1H), 4.44-4.50(m, 2H), 4.23-4.28(m, 3H), 4.09- 4.17(m, 4H), 3.98-4...

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Abstract

The invention relates to a synthesis and gluing method of bi-component drug micromolecule hydrogel precursors, which includes connecting an anti-inflammatory agent hexadecadrol and taxol through short peptide to form micromolecule hydrogel precursor molecules, and phosphate buffer solution (PBS) (pH=7.4) of the precursor molecules cuts off disulfide bonds under the effect of glutathione, dithiothreitol or the like to form hydrogel containing two drug components. The drug transmission system effectively overcomes the shortcoming of poor water solubility of the taxol, and the hexadecadrol serving as synergic drug of the taxol can effectively reduce toxic and side effects of the taxol.

Description

technical field [0001] The technical scheme of the present invention relates to a class of small molecule hydrogel precursor molecules containing dexamethasone and paclitaxel and the preparation method and the method of disulfide bond reduction impels the precursor molecules to form a hydrogel similar to jelly, specifically It is a hydrogel precursor molecule containing two kinds of drug molecules at the same time, its preparation method and its method of forming hydrogel Background technique [0002] Paclitaxel is a new generation of broad-spectrum anticancer drug that was clinically used in the 1990s. Due to its poor water solubility, most paclitaxel preparations currently used clinically use a mixture of polyoxyethylene castor oil (Cremophor EL) 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 allerg...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/02A61K31/573A61K31/337A61K47/48A61P35/00A61P35/04
Inventor 杨志谋王玲孔德领毛丽娜王怀民
Owner NANKAI UNIV
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