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PH responsive polymer carrier, micelle prepared from same, preparation method and application

A technology of polymers and mixed micelles, which is applied in the directions of drug combinations, pharmaceutical formulations, and medical preparations with non-active ingredients, etc., can solve the problem of increased CMC value of mixed micelles, large drug release amount, and reduced drug target release ability. And other issues

Active Publication Date: 2019-01-04
GUANGDONG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Chufen Yang et al. (RSC Adv., 2017, 7, 27564) studied MPEG-PDEAEMA and MPEG-PCL mixed micelles with three different degrees of polymerization, and found that the drug loading was significantly affected by the degree of polymerization. The decrease of the degree of polymerization of PCL will gradually increase the drug loading; however, the decrease of the degree of polymerization of PDEAEMA and PCL will increase the CMC value of the mixed micelles and reduce the stability of the micelles, resulting in the drug-loaded micelles in the Under neutral conditions, the amount of drug released is too large, which reduces the targeted release ability of the drug

Method used

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  • PH responsive polymer carrier, micelle prepared from same, preparation method and application
  • PH responsive polymer carrier, micelle prepared from same, preparation method and application
  • PH responsive polymer carrier, micelle prepared from same, preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] The preparation process of diblock copolymer A (PDEAEMA-PPEGMA):

[0069] (1) Synthesis of small molecule initiator: Weigh n-butanol (4.575ml, 0.05mmol) and add it into a dry 250mL anhydrous and anaerobic reaction bottle together with the solvent, seal it with a reverse rubber stopper, vacuum-pass After 3 times of nitrogen, under the protection of nitrogen, add the dehydrated solvent dichloromethane (50mL) and dehydrated triethylamine (TEA, 6.95mL) successively with a syringe, then cool to 0°C in an ice bath, and stir Slowly add 2-bromoisobutyryl bromide (6.183mL) drop by drop under the conditions. After the dropwise addition, react at 0°C for 2h, then raise the temperature to 30°C, and continue the reaction for 12h. After the reaction, use dilute hydrochloric acid and pure water respectively Wash three times, drop the organic phase into 0°C n-hexane of ten times its volume to precipitate, filter, and finally vacuum-dry at 40°C for 48 hours;

[0070] (2) Synthesis of P...

Embodiment 2

[0073] The preparation process of diblock copolymer B (PCL-PPEGMA):

[0074] (1) Synthesis of PCL-OH: Lactone monomer ε-CL (10g), n-butanol (0.1482g), initiator Sn(Oct) 2 (78.6mg) and solvent were added to a 100mL anhydrous and oxygen-free reaction bottle, sealed with a reverse rubber stopper, vacuumed-nitrogen three times, and reacted in an oil bath at 130°C for 24h under the protection of nitrogen. After the reaction, the organic phase Slowly add dropwise to 200mL cold aqueous methanol solution (v / v=1:1) to precipitate, filter, and finally vacuum-dry at 45°C for 48h, Mn=6000, PDI=1.2;

[0075] (2) Synthesis of brominated polycaprolactone (PCL-Br): Weigh PCL-OH (6g, Mn=6000) and add it into a dry 100mL anhydrous anaerobic reaction bottle together with the solvent, and use a reverse rubber stopper Carry out sealing, after evacuation-nitrogen 3 times, under the protection of nitrogen, add the solvent dichloromethane (30mL) that removes water and the triethylamine (TEA, 0.3mL) ...

Embodiment 3

[0079] With reference to the preparation process of diblock copolymer A in embodiment 1, PDEAEMA is prepared 35 -PPEGMA 13 , the specific process is as follows: pH responsive monomer DEAEMA (7.5g), small molecule initiator (0.233g), catalyst CuBr 2 (2.78mg) and solvent were added to a 150mL anhydrous and oxygen-free reaction bottle, sealed with a reverse rubber stopper, vacuumed-nitrogen three times, and under the protection of nitrogen, THF (35mL) dewatered was added successively with a syringe, and prepared Body PMDETA (69.2mg) and reducing agent Sn (Oct) 2 (243 mg), after freezing in liquid nitrogen, vacuumize and blow nitrogen three times. After thawing, stir for 15 minutes and then start to heat up. After reacting in an oil bath at 65°C for 5 hours, add monomer PEGMA (4 g, Mn=300) and continue the reaction for 24 hours. After the reaction, the solution obtained was passed through a neutral alumina chromatography column to remove the catalyst, and then most of the THF wa...

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Abstract

The invention discloses a pH responsive polymer carrier, micelle prepared from the same, a preparation method and application. The pH responsive polymer carrier is formed by self-assembling diblock copolymer A and diblock copolymer B in an aqueous solution; the diblock copolymer A is PDEAEMA-PPEGMA, and the structure is as shown in the formula (I); the diblock copolymer B is PCL-PPEGMA, and the structure is as shown in the formula (II); y is a positive integer from 20 to 35, n is a positive integer from 10 to 30, x is a positive integer from 50 to 70, and m is a positive integer from 5 o 25. Accordingly, the pH responsive polymer mutual compatibility is good, the carrier drug loading capacity is high, the CMC is low, the pH controlled release performance is good, pH responsive polymers canexist stably for a long time under the neutral condition, and the drug release amount is low; under the acidic condition, drugs are subjected to slow controlled release, and then drug target positioning control release is achieved. In addition, the different drug release environments and different release rates can be achieved by adjusting the polymerization degree and mixing ratio of the to polymers. The formula is defined in the description.

Description

technical field [0001] The present invention relates to the technical field of pharmaceutical functional carrier materials, and more specifically, relates to a pH-responsive polymer carrier and the prepared micelle, preparation method and application thereof. Background technique [0002] Chemotherapy is widely used as a conventional therapy for cancer. However, most chemotherapeutic drugs have some shortcomings in medical application and efficacy, such as poor solubility, large toxic and side effects, easy degradation, poor pharmacokinetics, No target tissue selectivity, etc. As a nano-drug-loading system, polymer drug-loaded micelles are a new type of drug carrier with a particle size of 20-300nm, which can avoid phagocytosis by the reticuloendothelial system in the body or be absorbed by tissues such as liver and spleen. It can reduce drug toxicity, Nano has unique advantages in increasing the solubility of hydrophobic drugs and improving the bioavailability of drugs. ...

Claims

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Application Information

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IPC IPC(8): C08G81/02C08F293/00C08F220/34A61K9/107A61K47/34A61K31/704A61P35/00
CPCA61K9/1075A61K31/704A61K47/34A61P35/00C08F220/34C08F293/005C08F2438/01C08G81/027
Inventor 杨楚芬肖佳宇林文静郭建维林佳瑜
Owner GUANGDONG UNIV OF TECH
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