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Cell-penetrating peptide modified nanoparticle and its preparation method

A technology of nanoparticles and membrane-penetrating peptides, which is applied to medical preparations with non-active ingredients, medical preparations containing active ingredients, and pharmaceutical formulas to increase cell uptake, bioavailability, and oral bioavailability Effect

Inactive Publication Date: 2013-03-27
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The invention utilizes the method of encapsulation of nanoparticles to solve the problem that the membrane-penetrating peptide can only carry negatively charged polypeptides or proteins under physiological conditions through electrostatic interaction, and expands the application scope of the membrane-penetrating peptide in the field of oral administration

Method used

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  • Cell-penetrating peptide modified nanoparticle and its preparation method

Examples

Experimental program
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Effect test

Embodiment 1

[0049] Weigh 40mg PLGA and 40mg MAL-PEG-PLGA respectively and dissolve in 5mL acetone and ethanol (8:2) mixed solvent to form the organic phase. Under continuous stirring, the organic phase was dropped into 30 mL of 0.2% polysorbate-80 (Tween80) aqueous solution. After stirring for half an hour, spin evaporate to completely volatilize the acetone-ethanol, and solidify to obtain the PLGA / MAL-PEG-PLGA nanoparticle dispersion system. Add an appropriate amount of Poly(Arg) to the neutral nanoparticle solution n -Cys(n=4-20) solution, stirred for half an hour, dialyzed to remove free Poly(Arg) n -Cys get the required Poly(Arg) n modified nanoparticles.

Embodiment 2

[0051] Weigh PLGA and MAL-PEG-PLGA at a mass ratio of 90:10, dissolve them in 1.0 mL of dichloromethane, add 50 μL of 7.5 mg / mL insulin aqueous solution, perform ultrasonic emulsification for 30 seconds, and then add 0.5% sodium cholate aqueous solution 2 mL, intermittent ultrasonic emulsification for 30 s, the prepared double emulsion was transferred to 20 mL of aqueous solution containing 0.5% sodium cholate, rotary evaporation for 20 min to remove the organic solvent, 25000 g / min low temperature centrifugation for 30 min to obtain the desired nanoparticles. Redisperse nanoparticles with Hepes buffer salt, add appropriate amount of Poly(Arg) n -Cys(n=4-12) solution, stirred for half an hour, dialyzed to remove free Poly(Arg) n -Cys, get the desired surface modification Poly(Arg) nAnd nanoparticles loaded with insulin. After testing, the drug loading capacity of the nanoparticles is 2.1% (w / w).

Embodiment 3

[0053] Weigh PLGA and MAL-PEG-PLGA at a mass ratio of 80:20, dissolve them in 1.0 mL of dichloromethane, add 50 μL of 2 mg / mL leuprolide aqueous solution, perform ultrasonic emulsification for 30 seconds intermittently, and then add 0.5% cholic acid Sodium aqueous solution 2mL, intermittent ultrasonic emulsification for 30s, the prepared double emulsion was transferred to 20mL aqueous solution containing 0.5% sodium cholate, rotary evaporation for 20min to remove the organic solvent, 25000g / min low temperature centrifugation for 30min to obtain the desired nanoparticles. Redisperse nanoparticles with Hepes buffer salt, add appropriate amount of Poly(Arg) n -Cys(n=6-10) solution, stirred for half an hour, dialyzed to remove free Poly(Arg) n -Cys, get the desired surface modification Poly(Arg) n And the nanoparticles containing leuprolide. After testing, the drug loading capacity of the nanoparticles is 1.4%.

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Abstract

The invention belongs to the medicinal preparation field, relates to a cell-penetrating peptide modified nanoparticle, and concretely relates to a nanoparticle delivery system for oral polypeptide and protein medicines, and its preparation method. The medicine delivery system is composed of the nanoparticle, cell-penetrating peptides modified on the surface of the nanoparticle, and the polypeptide protein medicines sealed by the nanoparticle, wherein the average particle size range of the medicine delivery system is 10-500nm. The cell-penetrating peptide modified nanoparticle and glucosaminoglycan having electronegative cell surfaces undergo electric property attraction and then undergo endocytosis, so the cell-penetrating peptide modified nanoparticle and the glucosaminoglycan are integrally taken into cells; and the cell-penetrating peptide modified nanoparticle has an alimentary canal mucous membrane penetrating capability after the cell-penetrating peptide modified nanoparticle is orally taken, and can deliver the polypeptide protein medicines carried by the cell-penetrating peptide modified nanoparticle to the whole body for blood circulation, so the oral biological utilization degree of the medicines are improved. The cell-penetrating peptide modified nanoparticle has the advantages of improvement of the stability of polypeptide and protein medicines in the alimentary canal, reduction of the application amount of cell-penetrating peptides, and reduction of possible toxic side effects caused by the cell-penetrating peptides.

Description

technical field [0001] The invention belongs to the field of pharmaceutical preparations, and relates to a nanoparticle modified by a membrane-penetrating peptide, in particular to a nanoparticle delivery system for oral polypeptide and protein drugs and a preparation method thereof. Background technique [0002] It is well known in the art that protein and polypeptide drugs have large molecular weight and strong hydrophilicity, and it is difficult to penetrate the phospholipid bilayer of the biomembrane to reach the cell; protein and polypeptide drugs will be quickly degraded by various enzymes in the body, such as digestion Trypsin in the tract, aminopeptidase in the cytoplasm, etc. Therefore, the oral administration of protein and polypeptide drugs has always been a difficult point in the research of pharmaceutical circles. In order to improve the in vivo absorption of these macromolecular drugs, some studies have added absorption enhancers (Pharm. Res., 2000, 17 (7): 82...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/14A61K47/34A61K47/36A61K47/42A61K38/24A61K38/28
Inventor 魏刚刘晓丽张文见刘畅陆伟跃
Owner FUDAN UNIV
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