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Brain targeted amphotericin B (AmB) polymer micelle administration system

A technology of polymer glue and amphotericin, which is applied in the directions of non-active components of polymer compounds, pharmaceutical formulations, anti-tumor drugs, etc., can solve the problems of large toxic and side effects, low brain entry efficiency, etc., and achieves reduced toxicity and good solubilization. Effects, Effects of Extending Cycle Time

Inactive Publication Date: 2012-08-01
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The purpose of the present invention is aimed at current clinical existing amphotericin B preparations such as amphotericin B for injection ? In order to solve the problems of low brain entry efficiency and high toxicity and side effects, a brain-targeted polymer micelle drug delivery system modified by low-density lipoprotein receptor-related protein ligand polypeptides is provided, especially a new brain-targeted amphotericin B-loaded drug delivery system. polymer micellar drug delivery system

Method used

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  • Brain targeted amphotericin B (AmB) polymer micelle administration system
  • Brain targeted amphotericin B (AmB) polymer micelle administration system
  • Brain targeted amphotericin B (AmB) polymer micelle administration system

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Example 1. Preparation of drug-loaded polymer micelles by thin film hydration method

[0061] Weigh 10 mg PE-PEG fixedly and place it in a round bottom flask, add 2 ml chloroform to dissolve it, weigh AmB and dissolve it in methanol to prepare a stock solution of 0.25 mg / ml, add a certain amount to the chloroform solution of PE-PEG A certain amount of AmB methanol solution was mixed evenly, then rotary evaporated to form a uniform drug-polymer film, dried overnight in vacuum, added a certain volume of 10 mM HBS pH 7.4, stirred at room temperature for 2 h to balance the solution, molecular exclusion chromatography to remove untreated The encapsulated AmB is the PE-PEG / AmB ordinary polymer micelle drug delivery system.

[0062] The preparation process of AmB encapsulated in polymer micelles was optimized by star-point design-response surface optimization method. Firstly, a single-factor investigation was carried out to examine the effects of dosage, hydration med...

Embodiment 2

[0068] Weigh 10 mg of the prescribed amount of PE-PEG and PE-PEG-Mal in a round bottom flask, add 2 ml of chloroform to dissolve it, weigh AmB and dissolve it in methanol to prepare a 0.25 mg / ml stock solution, pipette Add 6.8 ml of AmB methanol stock solution into a round-bottomed flask, mix well, and then rotary evaporate to form a uniform drug-polymer film, dry it in vacuum overnight, add 1.5 ml 10 mM HBS pH 7.4, stir at room temperature for 2 h to balance the solution, and obtain the loaded AmB’s PE-PEG / PE-PEG-Mal mixed micelles solution, add Angiopep-2 at a molar ratio of PE-PEG-Mal:Angiopep-2 of 2:1, stir at room temperature in the dark for 12 h, and remove by molecular exclusion chromatography Unencapsulated AmB is the PE-PEG-Angiopep / AmB brain-targeted polymer micelle drug delivery system.

Embodiment 3

[0070] Prepare blank PE-PEG ordinary polymer micelles according to Example 1. After freeze-drying, weigh two portions of 1.0 mg each, dissolve them in 0.5 ml deuterated chloroform and 0.5 ml heavy water, and use Mercury Plus 400 MHz superconducting NMR spectrum Instrument identification, to obtain the ideal NMR spectrum (such as figure 2 shown), the results showed that PE-PEG formed a stable core-shell structure in aqueous solution.

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Abstract

The invention which belongs to the biotechnical field concretely relates to a brain targeted AmB polymer micelle administration system. The brain targeted AmB polymer micelle administration system is prepared by utilizing brain targeted head base Angiopep-2 modified polymer micelles extremely having a clinical application potential, and entrapping micromolecular hydrophobic drugs. The prepared brain targeted AmB polymer micelle administration system can effectively improve the uptaking of the hydrophobic drugs on brain capillary endothelial cells, and can effectively improve the accumulation amount of the drugs in the brain and the brain entrance efficiency of the drugs especially in a noninvasive intravenous injection mode; compared with present clinical preparations of the drugs, such as AmB for injection, the system of the invention has a substantially improved brain targeting efficiency; and the constructed polymer micelle administration system can obviously reduce the hemolyticity and the cytotoxicity of the AmB. The Angiopep-2 modified brain targeted AmB polymer micelle administration system of the invention can be used to promote the accumulation of hydrophobic drugs with low brain entrance efficiencies in the brain.

Description

technical field [0001] The invention belongs to the field of biotechnology, and relates to a brain-targeted polymer micelle drug delivery system modified by a low-density lipoprotein receptor-related protein ligand polypeptide. In particular, it relates to a brain-targeted amphotericin B-loaded polymer micelle drug delivery system. Background technique [0002] According to reports, the morbidity and mortality of invasive systemic fungal infection in critically ill patients are high, and the mortality rate is maintained at 40% to 90%. The fungi, such as Cryptococcus neoformans, Candida albicans and Aspergillus, can easily invade the central nervous system of patients, especially for immunosuppressed patients, and then develop into intracranial fungal infections. Studies have shown that due to the existence of the blood-brain barrier, it is difficult for hydrophobic antifungal drugs to enter the brain autonomously. At present, the main means of clinical treatment of intracr...

Claims

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Application Information

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IPC IPC(8): A61K9/00A61K31/7048A61K47/34A61K47/36A61K47/42A61P31/18A61P35/00
Inventor 蒋晨邵堃柯伟伦黄容琴
Owner FUDAN UNIV
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