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pH-responsive nano preparation based on click reaction and preparation method and application thereof

A click-reaction, nano-formulation technology, which is applied in non-active ingredients medical preparations, medical preparations containing active ingredients, microcapsules, etc., can solve problems such as long biological half-life, reduce toxic and side effects, and achieve active targeting Sexuality, the effect of reducing the number of clinical injections and doses

Inactive Publication Date: 2019-10-18
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Heparin-like polysaccharides have good biocompatibility and long biological half-life, which has laid a good foundation for their clinical application. Howeve

Method used

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  • pH-responsive nano preparation based on click reaction and preparation method and application thereof
  • pH-responsive nano preparation based on click reaction and preparation method and application thereof
  • pH-responsive nano preparation based on click reaction and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] Example 1: Preparation of gambogic acid-desulfated heparin derivative conjugate

[0069] Weigh p-formyl benzoic acid, propargyl alcohol and N,N-dimethyl-4-pyridinamine and place them in eggplant-shaped flasks. The molar ratio of propargyl alcohol to p-formyl benzoic acid is 1.2:1, N,N - The molar ratio of dimethyl-4-pyridinamine to p-formylbenzoic acid is 1:1, dissolve in 20mL of dichloromethane, seal the mixture with a rubber stopper, cool to 0°C, and stir at this temperature for 10min , DCC was added, the molar ratio of DCC to p-formylbenzoic acid was 1.5:1, the mixture was warmed to room temperature, and reacted overnight. The completeness of the reaction was monitored by TLC. After the reaction was complete, DCC was removed by suction filtration, the solvent methylene chloride was distilled off under reduced pressure, an appropriate amount of silica gel was added to make sand at 30°C, and intermediate I was obtained by separation and purification by column chromatog...

Embodiment 2

[0073] Example 2: Preparation of neogambogic acid-low molecular weight heparin derivative conjugate

[0074] Weigh glyoxylic acid, 3-butyn-1-ol, N,N-diisopropylethylamine and 4-pyrrolidinylpyridine into an eggplant-shaped bottle, 3-butyn-1-ol and acetaldehyde The molar ratio of acid is 2:1, the molar ratio of N,N-diisopropylethylamine to glyoxylic acid is 3:1, the molar ratio of 4-pyrrolidinylpyridine to glyoxylic acid is 2:1, and the In 20 mL of ethanol, the mixture was sealed with a rubber stopper, cooled to 0 ° C, and stirred at this temperature for 10 min, DCC was added, the molar ratio of DCC to glyoxylic acid was 1.5:1, the mixture was warmed to room temperature, and reacted overnight. The completeness of the reaction was monitored by TLC. After the reaction was complete, DCC was removed by suction filtration, the solvent ethanol was evaporated under reduced pressure, an appropriate amount of silica gel was added to make sand at 30°C, and intermediate I was obtained by sep...

Embodiment 3

[0078] Example 3: Preparation of ursolic acid-unfractionated heparin derivative conjugate

[0079] Weigh o-aldobenzoic acid, ethinylestradiol and 1-hydroxybenzotriazole and place them in eggplant-shaped bottles, the molar ratio of ethinylestradiol and o-aldobenzoic acid is 1.5:1, 1-hydroxybenzotriazole and The molar ratio of o-aldehydobenzoic acid is 1.5:1, dissolved in 20mL N,N-dimethylformamide, the mixture is sealed with a rubber stopper, cooled to 0°C, and stirred at this temperature for 10min, DCC is added, The molar ratio of DCC to o-aldehydobenzoic acid was 1.5:1, and the mixture was warmed to room temperature and reacted overnight. The completeness of the reaction was monitored by TLC. After the reaction was complete, DCC was removed by suction filtration, the solvent N,N-dimethylformamide was evaporated under reduced pressure, and an appropriate amount of silica gel was added to make sand at 30°C. Intermediate I was separated and purified by column chromatography. . ...

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Abstract

The invention relates to a pH-responsive nano preparation based on a click reaction and a preparation method and an application thereof. The pH-responsive nano preparation based on the click reactionis formed by that a hydrophobic carboxylic acid small molecule antitumor drug coupled with the heparinized heparin polysaccharide by a Schiff base reaction and the click reaction to form an amphipathic conjugate, and the amphipathic conjugate is subjected to self-assembly in a water body to obtain the nano preparation. The click reaction is simple and environmentally friendly, the reaction conditions are mild, the product is easy to separate, and the yield is high. After the pH-responsive nano-preparation reaches the acidic microenvironment of the tumor, the Schiff base bond is broken, and a carboxylic acid derivative intermediate is obtained. Further rearrangement results in a prototype of a small molecule of carboxylic acid, which can well avoid the influence of other groups on the activity of the carboxylic acid molecule. In addition, the pH-responsive nano preparation can physically entrap the hydrophobic anti-tumor drug, and obtains a physical drug-loaded pH-responsive nano preparation to achieve synergistic anti-tumor effect.

Description

technical field [0001] The invention belongs to the preparation of nano-preparations in the field of pharmaceutical preparations, and relates to a pH-responsive nano-preparation based on a click reaction and its preparation method and application. Background technique [0002] Cancer is difficult to cure due to its complex pathogenesis and is the second leading cause of death worldwide. Cancer treatment mainly includes chemotherapy, surgery and radiotherapy, but all have their own limitations. Among them, most chemotherapy drugs lack selectivity and have killing effect on normal cells; surgical treatment is mainly aimed at early solid tumors, and its application range is limited. The treatment time of radiotherapy is long, and its toxic and side effects are very obvious. At present, chemotherapy is the most widely used in tumor treatment, but most chemotherapeutic drugs have poor water solubility and lack of selectivity, and can cause toxic and side effects to normal cells ...

Claims

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Application Information

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IPC IPC(8): A61K9/51A61K47/61A61K45/06A61K9/00A61P35/00A61K31/352A61K31/56A61K31/4184A61K31/519A61K31/196
CPCA61K9/5161A61K47/61A61K45/06A61K9/0019A61P35/00A61K31/352A61K31/56A61K31/4184A61K31/519A61K31/196
Inventor 姚静乔佳男张萍邓雨荻
Owner CHINA PHARM UNIV
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