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Preparation method of HA/RGD double-receptor multi-target-point drug administration system

A drug delivery system and multi-target technology, which is applied in the direction of pharmaceutical formulations, medical preparations with non-active ingredients, medical preparations containing active ingredients, etc., can solve the problems of unsatisfactory drug targeting and poor stability, and achieve Improve drug loading, improve binding, and stabilize composite particles

Inactive Publication Date: 2016-06-22
WUHAN UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The purpose of the present invention is to overcome the problem of unsatisfactory drug targeting and poor stability in the prior art, and provide a new targeting solution, which can rapidly accumulate drugs in cancer cells through synergistic treatment

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] 1) Deacetylation of HA

[0027] Dissolve 0.2g of HA in 10ml of anhydrous hydrazine, and add 1% hydrazine sulfate to it, react at 60°C for 1h, and blow dry nitrogen through the process. After the reaction is over, add cold ethanol for precipitation separation, dissolve the precipitate in 5% glacial acetic acid and add 2ml 0.5mol / L HIO to it 3 . Ice bath (at 4℃) for 2h, add an appropriate amount of 55~58% HI solution to remove excess HIO 3 . Add ethyl acetate and shake repeatedly, add 0.2mol / L NaOH to the water layer until the solution is neutral, and finally add ethanol for separation to obtain the product. The degree of deacetylation of HA reaches more than 70%.

[0028] 2) Preparation of HA-RGD

[0029] Dissolve 0.05g of RGD and add 0.25g of ethyl (3-dimethylpropyl) carbodiimide hydrochloride (EDC) and 0.013g of N-hydroxysuccinimide (NHS) (EDC / NHS) ) For activation, then take 0.05g of deacetylated HA into an aqueous solution and slowly add dropwise, react for 1 hour, dial...

Embodiment 2

[0035] 1) Deacetylation of HA

[0036] Dissolve 0.1 g of HA in 8 ml of anhydrous hydrazine, and add 2% hydrazine sulfate to it, react at 100° C. for 6 hours, and pass dry neon gas throughout the process. After the reaction is over, add cold ethanol for precipitation separation, dissolve the precipitate in 10% glacial acetic acid and add 1.5ml 0.5mol / L HIO to it 3 . Ice bath (at 4℃) for 2h, add an appropriate amount of 5-15% HI solution to remove excess HIO 3 . Add ethyl acetate and shake repeatedly, add 0.1 mol / L NaOH to the water layer until the solution is neutral, and finally add ethanol for separation to obtain the product.

[0037] 2) Preparation of HA-RGD

[0038] Dissolve 0.1g of RGD and add 0.07g of ethyl (3-dimethylpropyl) carbodiimide hydrochloride (EDC) and 0.04g of N-hydroxysuccinimide (NHS) (EDC / NHS) For activation, take 0.05g of deacetylated HA into an aqueous solution and slowly add dropwise, react for 4 hours, dialyze to remove unreacted substances, and freeze-dry ...

Embodiment 3

[0044] 1) Deacetylation of HA

[0045] Dissolve 0.2 g of HA in 5 ml of anhydrous hydrazine, and add 5% hydrazine sulfate to it, react at 80° C. for 8 hours, and pass dry helium through the entire process. After the reaction is over, add cold ethanol for precipitation separation, dissolve the precipitate in 15% glacial acetic acid and add 1.5ml 0.5mol / L HIO to it 3 . Ice bath (at 4℃) for 2h, add an appropriate amount of 25-30% HI solution to remove excess HIO 3 . Add ethyl acetate and shake repeatedly, add 0.2mol / L NaOH to the water layer until the solution is neutral, and finally add ethanol for separation to obtain the product.

[0046] 2) Preparation of HA-RGD

[0047] Dissolve 0.05g of RGD and add 0.08g of ethyl (3-dimethylpropyl) carbodiimide hydrochloride (EDC) and 0.06g of N-hydroxysuccinimide (NHS) (EDC / NHS) ) For activation, take 0.03 g of deacetylated HA into an aqueous solution and slowly add dropwise, react for 4 hours, dialyze to remove unreacted substances, and freeze...

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Abstract

The invention discloses a preparation method of a HA / RGD double-receptor multi-target-point drug administration system.The method includes the following steps that hyaluronic acid and hydrazine sulfate are dissolved in hydrazine, reaction is performed for 1-12 h under the protection of inert gas at the temperature of 60-115 DEG C so that deacetylated HA can be obtained; RGD is dissolved in water, an EDC / NHS solution is activated, pH of the solution is adjusted to be 3.5-6.5, the deacetylated HA aqueous solution is dropwise added, reaction is performed for 1-12 h at 4-38 DEG C, and HA-RGD is obtained; a CLB-ADH aqueous solution is dropwise added into the HA-RGD aqueous solution, reaction is performed for 1-12 h under the condition of stirring, and the double-receptor multi-target-point drug administration system is obtained.HA and RGD can more effectively enhance combination of drugs and tumor cells, effective concentration on the tumor parts is improved, an effect-enhancing and toxicity reducing effect is achieved, meanwhile tumor cells are killed, growth of tumor microvasculature is inhibited, the effect that one drug is multipurpose is achieved, and tumor drug resistance can be effectively reversed.

Description

Technical field [0001] The invention relates to the field of medicines, in particular to a preparation method of a dual receptor-mediated multi-target drug delivery system. Background technique [0002] Cancer is one of the serious diseases endangering human life and health, and the incidence is increasing year by year. It is urgent to find effective prevention and treatment methods for malignant tumors. Chemotherapy is one of the main methods for cancer treatment today, but chemotherapeutic drugs often involve normal cells when they act on target cells, resulting in toxic side effects such as weakened immune function, bone marrow suppression, and organ damage, severe side effects and multi-drug resistance. Drugs and other issues have greatly restricted its application. [0003] Targeted drug delivery system is an ideal drug delivery method for a new type of drug formulation. Using the characteristics of the targeted drug delivery system, the release of drugs to specific tissues,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/36A61K47/42A61K31/196A61P35/00A61K47/61
CPCA61K31/196A61K47/36A61K47/42
Inventor 许沛虎吴峰政徐海星黄志军李依萍李燕周汇敏郭玉凤郭兴蕾
Owner WUHAN UNIV OF TECH
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