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Disulfide bond bridged docetaxel-fatty acid prodrugs and self-assembled nanoparticles thereof

A technology of self-assembled nanoparticles and disulfide bond bridging, which is applied in drug combinations, pharmaceutical formulations, anti-tumor drugs, etc., to achieve the effects of easy surface modification, improved tolerance and compliance, and small particle size

Pending Publication Date: 2021-04-06
スゾウユタイファーマシューティカルテクノロジーカンパニーリミテッド
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among them, nano-preparations of paclitaxel, including paclitaxel liposomes, paclitaxel albumin nanoparticles, etc., have been used in the clinical treatment of cancer; The nano dosage form of cetaxel has not been clinically applied yet

Method used

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  • Disulfide bond bridged docetaxel-fatty acid prodrugs and self-assembled nanoparticles thereof
  • Disulfide bond bridged docetaxel-fatty acid prodrugs and self-assembled nanoparticles thereof
  • Disulfide bond bridged docetaxel-fatty acid prodrugs and self-assembled nanoparticles thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Embodiment 1: the synthesis of the docetaxel-stearic acid prodrug (DTX-S-S-SA) of disulfide bond bridge

[0032] Measure excessive ethylene glycol and place it in a 50mL three-necked flask, add an appropriate amount of p-toluenesulfonic acid into the three-necked flask, and return the spherical condenser to N 2 Protected and heated to 110°C, the stearic acid solution dissolved in toluene was slowly dripped into the reaction bottle through a constant pressure dropping funnel, and reacted for 2 hours. After the reaction, the layers were left to stand, extracted three times with toluene, the toluene layers were combined, and then saturated NaHCO 3 The solution was washed until neutral, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, separated and purified to obtain 2-hydroxyethyl stearate. 2,2'-dithiodiacetic anhydride with CH 2 Cl 2 Dissolve and transfer to a 100mL eggplant-shaped bottle, add HOBt, EDCI and 2-hydroxyethyl stearate, N 2 Cool down ...

Embodiment 2

[0034] Embodiment 2: the synthesis of the docetaxel-oleic acid prodrug (DTX-S-S-OA) of disulfide bond bridge

[0035] Measure excessive ethylene glycol and place it in a 50mL three-necked flask, add an appropriate amount of p-toluenesulfonic acid into the three-necked flask, and return the spherical condenser to N 2 Protected, heated to 110°C, and the oleic acid solution dissolved in toluene was slowly dripped into the reaction bottle through a constant pressure dropping funnel, and reacted for 2 hours, and the reaction was complete as monitored by TLC. After the reaction is over, let the layers stand, extract with toluene until the ethylene glycol layer TLC has no product point, combine the toluene layers, and then use saturated NaHCO 3 The solution was washed until neutral, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, separated and purified to obtain oleic acid-2-hydroxyethyl ester. 2,2'-dithiodiacetic anhydride with CH 2 Cl 2 Dissolve and transfe...

Embodiment 3

[0037] Example 3: Synthesis of disulfide bridged docetaxel-elaidic acid prodrug (DTX-S-S-EA)

[0038] Measure excessive ethylene glycol and place it in a 50mL three-necked flask, add an appropriate amount of p-toluenesulfonic acid into the three-necked flask, and return the spherical condenser to N 2 Protected, heated to 110°C, and the solution of elaidic acid dissolved in toluene was slowly dripped into the reaction bottle through a constant pressure dropping funnel, and reacted for 2 hours, and the reaction was complete as monitored by TLC. After the reaction is over, let the layers stand, extract with toluene until the ethylene glycol layer TLC has no product point, combine the toluene layers, and then use saturated NaHCO 3 The solution was washed until neutral, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, separated and purified to obtain elaidic acid-2-hydroxyethyl ester. 2,2'-dithiodiacetic anhydride with CH 2 Cl 2 Dissolve and transfer to a 10...

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Abstract

According to the invention, a series of reduction-sensitive disulfide bond bridged docetaxel fatty acid prodrugs are designed and synthesized. The series of prodrugs can be self-assembled into a nano drug delivery system through a one-step nano precipitation method. The nano drug delivery system has the following advantages that: docetaxel is prepared into a disulfide bond connected prodrug, so that the system toxicity of a docetaxel parent drug is reduced, the parent drug can be specifically released in a high reduction environment in tumor cells, and the effects of synergy and toxicity reduction are achieved; the drug loading capacity is high, the use of a solubilizer with higher toxicity is avoided, and the tolerance and the compliance of a patient are expected to be improved; through the one-step nano precipitation method, the preparation process is simple, and large-scale production is easy; the nanoparticles are small and uniform in particle size and are easily enriched at a tumor part through an EPR effect; and surface modification is easy, and removal of a reticuloendothelial system can be slowed down through modification of PEG modification.

Description

technical field [0001] The invention belongs to the field of new excipients and new dosage forms of pharmaceutical preparations, and relates to the construction of disulfide bond-bridged docetaxel-fatty acid prodrugs and self-assembled nanoparticles, as well as their application in drug delivery. Background technique [0002] Today, cancer is still one of the diseases with a high mortality rate, which seriously threatens human health. Common cancer treatment options mainly include surgical resection, chemotherapy, radiation therapy and biological therapy. Among them, surgical resection is effective for early-stage tumors, but for advanced or metastatic tumors, chemotherapy has obvious advantages. Taxane chemotherapeutic drugs are a class of anti-tumor drugs that act on microtubules, which can promote the rapid aggregation of tubulin into microtubules, and bind to microtubules to inhibit the depolymerization of microtubules, thereby terminating cell mitosis and inducing tumo...

Claims

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Application Information

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IPC IPC(8): A61K47/54A61K47/60A61K47/69A61K31/337A61P35/00A61P35/04
CPCA61K47/542A61K47/543A61K47/54A61K47/60A61K47/6929A61K31/337A61P35/00A61P35/04
Inventor 孙进王悦全何仲贵王永军邱诗罗聪
Owner スゾウユタイファーマシューティカルテクノロジーカンパニーリミテッド
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