A kind of phthalic dihydroxy polymer carrier and its application in the construction of drug complex nano-delivery system

A nano-drug delivery system and o-phthalic dihydroxy technology, applied in the field of pharmacy, can solve the problems of reducing the pharmacological activity of drugs and difficult prototype drugs, etc., achieve reversible release of drugs with drug loading, enhance drug stability, and improve therapeutic effects Effect

Active Publication Date: 2022-01-18
FUDAN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although the above-mentioned covalent bonding method is the most widely used in current drug-carrier complexes, this covalent bonding method requires complex chemical reactions to complete
In addition, because the covalent bond is irreversible, the drug molecule is not easy to break in the body, so it is difficult to function in the body in the form of the prototype drug, which in turn greatly reduces the pharmacological activity of the drug

Method used

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  • A kind of phthalic dihydroxy polymer carrier and its application in the construction of drug complex nano-delivery system
  • A kind of phthalic dihydroxy polymer carrier and its application in the construction of drug complex nano-delivery system
  • A kind of phthalic dihydroxy polymer carrier and its application in the construction of drug complex nano-delivery system

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Preparation and characterization of embodiment 1 polyethylene glycol-dopamine

[0029] Synthetic roadmap as figure 1 As shown, the specific process is as follows:

[0030] Synthesis of Intermediate A-4:

[0031] Under nitrogen protection, weigh 1,1-dihydroxypropionic acid (50.0 g, 0.37 mol) and suspend it in 500 mL of acetone, add acetonide (46.5 g, 0.45 mol) and a catalytic amount of p-toluenesulfonic acid at room temperature Stir until the solution is clear, and spin to remove acetone to obtain a white solid. The resulting solid was dissolved in 500 mL of ethyl acetate, washed three times with saturated brine (3×50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 63.1 g of a white solid (98% yield). Dissolve 50 g of the above solid in 500 mL of tetrahydrofuran, add DCC (47.8 g, 0.23 mol) and DMAP (1.0 g, 0.01 mol) and stir at room temperature for 12 h, check by TLC until the raw material disappears, filter, concentrate the...

Embodiment 2

[0039] Embodiment 2 Preparation and characterization of bortezomib-polymer complex

[0040] Weigh the carrier material polyethylene glycol-dopamine (5.0mg, 8.62×10 -4 mmol) and bortezomib (2.65mg, 6.90×10 -3 mmol) was dissolved in 0.5mL chloroform, and after the solution was clarified, it was vortexed at room temperature for 1 h to form a bortezomib-polymer complex. 1 H-NMR characterizes its structure, showing that the structure is correct (attached image 3 ). 1 H-NMR characterization (solvent: DMSO-d6), the results are shown in the attached figure 2 , Visible: δ8.99 (2H, s) δ8.73-8.64 (4H, m), δ7.70-7.06 (13H, m), δ6.52 (2H, m), δ6.38 (2H, s) , δ6.11(5H, m), δ4.88(3H, m), δ4.69(3H, m), δ4.24(275H, s), δ2.89(9H, m) δ1.54-1.16 (21H, s), δ1.02-0.98 (5H, s), δ0.76-0.71 (9H, m).

Embodiment 3

[0041] Example 3 Preparation and Characterization of Nanoparticles Constructed by Bortezomib-Polymer Complex

[0042] Polyethylene glycol-dopamine (5.0mg, 8.62×10 -4 mmol) and bortezomib (2.65mg, 6.90×10 -3 mmol) was dissolved in 0.5 mL chloroform, and after the solution was clear, vortexed at room temperature for 1 h. Add 1 mL of 0.5% sodium cholate solution to the system, emulsify and ultrasonically form an O / W emulsion, and slowly add it dropwise to 5 mL of 10 mmol / L phosphate buffer saline (PBS, pH 7.6) at a stirring rate of 600 rpm. After dropping, continue to stir for 4h, concentrate under reduced pressure to remove chloroform, centrifuge 3 times (rotating speed 2500rpm / min), discard the supernatant, PBS is dispersed, and the volume is set to 1mL to prepare nanoparticles, and the obtained nanoparticles are rounded. Uniform size (such as Figure 4 Shown in A), the drug loading capacity of its bortezomib is 7.9%;

[0043] The in vitro release experiments of nanoparticl...

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Abstract

The invention belongs to the field of pharmacy, and relates to an o-phthalic dihydroxy polymer carrier capable of reversibly combining with a drug, a drug-polymer complex formed by the polymer carrier and a drug, and a drug-delivery drug constructed by the drug-polymer complex system. The o-phthalic dihydroxy polymer carrier prepared by the present invention can be reversibly combined with drugs to form a drug-polymer complex and a nanoparticle drug delivery system, which has the significant advantage of high drug loading, can reduce drug toxicity, improve drug stability, The purpose of improving the in vivo targeting of drugs and enhancing drug efficacy, the experimental results show that: the drug-polymer complex and its nanoparticle drug delivery system has the characteristics of pH-responsive drug release, which can significantly reduce drug toxicity and improve drug efficiency. The stability of the drug can exert passive targeting in vivo or active targeting after further modification of the target molecule, which can significantly improve the efficacy of the drug. It has a good clinical application prospect.

Description

technical field [0001] The invention belongs to the field of pharmacy, and relates to a polymer carrier capable of reversibly combining with drugs and its application in the construction of drug-macromolecule complexes and nano drug delivery systems. It specifically relates to the phthalic dihydroxy polymer carrier and the drug-macromolecular complex formed by combining with the drug through borate bonds or chelation, and the nanoparticle drug delivery system further constructed by the drug-macromolecular complex to achieve the reduction of drug toxicity, improving drug stability, improving drug targeting and enhancing drug efficacy. Background technique [0002] In recent years, with the increasing perfection and improvement of nanotechnology, nano-preparation has been widely used clinically as a new type of preparation. Although nanomedicine can prolong drug systemic circulation time, reduce drug toxicity, improve drug therapeutic index, and improve patients' quality of l...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/18A61K38/05A61P35/00
CPCA61K38/05A61K47/18
Inventor 陆伟跃胡雪峰柴芝兰
Owner FUDAN UNIV
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