CN113813449A

CN113813449A - Preparation method of nanoparticle rapamycin drug-loaded coating balloon

Info

Publication number: CN113813449A
Application number: CN202111007975.3A
Authority: CN
Inventors: 孟繁宇
Original assignee: Individual
Current assignee: Individual
Priority date: 2021-08-30
Filing date: 2021-08-30
Publication date: 2021-12-21

Abstract

The invention discloses a preparation method of a nanoparticle rapamycin drug-loaded coating balloon, belonging to the technical field of drug manufacturing. The polylactic acid-polyglycolic acid mixes and coats the mesoporous silicon dioxide nano particles loaded with the rapamycin on the surface of the balloon, the nano particles are bridged to prepare the drug with excellent histocompatibility, biodegradability, high encapsulation efficiency, stable drug-loading rate control, small particle size and constant in vitro released drug, can ensure that the effective action concentration of the drug in local tissues is reached and maintained under the condition of influencing blood flow as little as possible, can overcome the negative influence of a drug-loaded matrix on vascular repair, and improves the effects of the rapamycin on resisting intimal hyperplasia and restenosis. Inorganic nano particles can be compounded with the up-conversion rare earth luminescent fluorescent agent, 4f electrons of the rare earth inner shell layer can emit light under laser irradiation, the balloon is simulated in vitro to be conveyed and expanded in plasma, the concentration of the nano particles left in the plasma is monitored, and the balloon carrying stability is detected in an earlier stage.

Description

Preparation method of nanoparticle rapamycin drug-loaded coating balloon

Technical Field

The invention relates to the technical field of medicine manufacturing, in particular to a preparation method of a nanoparticle rapamycin drug-loaded coating balloon.

Background

Most of the currently marketed drug balloons are paclitaxel, and multiple studies show that rapamycin has better effect on resisting intimal proliferation of coronary arteries. Rapamycin is loaded on hollow mesoporous silica nano particles, the nano particles are alcoholized and coated on a common balloon through polylactic acid-polyglycolic acid (PLGA), the balloon is expanded at the arteriosclerosis vascular site, the nano particles loaded with the rapamycin are released on the vascular endothelium, and the loaded drugs are sequentially released through the permeability and the slow release of the nano particles to prolong the time of the drug action, so that the effects of resisting the endoarterial hyperplasia and resisting the restenosis of the rapamycin can be improved.

Biodegradable materials are hot research at home and abroad, and among them, polyester materials represented by polylactic acid (PLA), polyglycolic acid (PGA) and copolymers thereof (poly (1 active-glycolic acid) copolymer, PLGA) attract wide attention due to their unique degradability. PLGA has the advantages of two materials, namely PLA and PGA, has good biocompatibility and degradability, is easy to be decomposed and metabolized by various microorganisms or animal and plant in vivo enzymes in the nature, and is widely applied to the fields of medicine and pharmacy. In the field of pharmaceutical preparations, PLGA is mainly used as a carrier for the preparation of microspheres or implants. At present, one of the difficulties in preparation is the phenomenon of burst release and unstable release behavior of the drug. Foreign documents have reported that D, L2 lactide, glycolide, and glucose are subjected to melt polycondensation to prepare star-shaped polylactic acid-2-glycolic acid copolymer (star-poly (lactic acid-glycolic acid) copolymer, which has a spatial three-dimensional structure compared with a linear polymer, and can be used for reducing burst release and stabilizing release behavior of a microsphere preparation. At present, the synthesis of PLGA in China is still in a laboratory stage, and both random copolymer (Ran-PLGA) and alternating copolymer (Alt-PLGA) are chain structures. According to the research, the drug-loaded nanoparticles are alcoholized and coated on the common balloon through polylactic acid-polyglycolic acid (PLGA), so that the processes of hydrophilic pretreatment, hydrophilic coating, drug air drying and spraying of the balloon are simplified, the drug carrying capacity is increased and uniform, and the delivery loss in blood vessels is small. And then the blood vessel is expanded at the local part of the stenosis through the saccule, and the drug-loaded nano particles coated by the PLGA enter the endothelial tissue of the blood vessel, so that the negative influence of the drug-loaded polymer on the blood vessel repair is overcome to the maximum extent.

Disclosure of Invention

The invention aims to provide a preparation method of a nanoparticle rapamycin drug-loaded coating balloon, so as to solve the problems in the background technology.

In order to achieve the purpose, the invention provides the following technical scheme:

the preparation method of the nanoparticle rapamycin drug-loaded coating balloon specifically comprises the following steps:

step one, up-conversion fluorescent agent composite nano particles: cetyl Trimethyl Ammonium Chloride (CTAC) is used as template micelle, Tetraethoxysilane (TEOS) cyclohexane solution is hydrolyzed at an oil-water interface (oil phase is on, water phase is on) to form MSNs, and then ammonium nitrate ethanol solution is used for extraction to remove CTAC, thus obtaining the final product. Degradable MSNs can be degraded from outside to inside gradually along with the time extension in Krebs solution simulating physiological conditions, after 4d, MSNs nano particles disappear and are completely degraded, the size of the nano particles can be controlled by controlling the reaction time in the preparation process of the degradable MSNs, the size of the aperture can be adjusted by adjusting the amount of TEOS or the type of an oil phase, and an up-conversion nano particle fluorescent agent NaYF 4: mixing Yb/Er with the prepared hollow mesoporous silica, and stirring for 24 hours at room temperature;

step two, carrying medicine by the up-conversion fluorescent agent and the composite nano particles: adding rapamycin into the solution, reacting for 24 hours under ice bath stirring, and repeatedly washing with ethanol hydrate for 3 times to obtain the rapamycin-loaded up-conversion fluorescent agent composite mesoporous silica nanoparticles;

step three, carrying the drug nanoparticle bridging saccule: mixing and coating 0.5g of rapamycin-loaded up-conversion fluorescent agent composite mesoporous silica nano particles and 2.0 mm-10 mm specification sacculus on the surface of the sacculus through polylactic acid-polyglycolic acid to form a particle coating similar to a traditional medicine sacculus;

step four, monitoring the stability of the in vitro simulated saccule carried medicine: simulating the balloon conveying and expanding process in biological plasma for 5 minutes, monitoring the concentration of the left nano particles in the plasma, emitting fluorescence of a corresponding wave band under the irradiation of 980nm laser, and judging and monitoring the concentration of the left nano ions in the plasma according to the fluorescence intensity.

Compared with the prior art, the invention has the beneficial effects that:

rapamycin (RPM) -loaded hollow Mesoporous Silica Nanoparticles (MSNs) are coated on the surface of the balloon through polylactic acid-polyglycolic acid (PLGA). The polylactic acid-polyglycolic acid mixes and coats the rapamycin-loaded mesoporous silica nanoparticles on the surface of the balloon, the nanoparticle bridging preparation has excellent histocompatibility, biodegradability, high encapsulation efficiency, stable drug-loading rate control, small particle size and constant in-vitro release of drugs, can ensure that the effective action concentration of the drugs in local tissues is reached and maintained under the condition of influencing blood flow as little as possible, and can overcome the negative influence of a drug-loaded matrix on vascular repair. Compared with the current marketed medicine saccule, the balloon has better effects of resisting intimal hyperplasia and vascular restenosis, and provides a better treatment means for patients with cardiovascular diseases.

Detailed Description

The technical solution of the present invention will be described in further detail with reference to specific embodiments.

Compared with organic polymer nano-carriers, the inorganic nano-particles have the advantages of good size and appearance controllability and large specific surface area, and meanwhile, the unique optical, electric and magnetic properties endow the inorganic nano-particles with potential functions of imaging development, targeted delivery, synergistic drug therapy and the like, so that reports of the inorganic nano-materials serving as carriers of chemical drugs, DNA, proteins and the like are gradually increased in recent years. Among them, hollow mesoporous silica nanoparticles (mesoporus silica nanoparticles) have been rapidly developed as a drug delivery system. The mesoporous material has larger specific surface area than the macroporous material, and the pore diameter of the mesoporous material is larger than that of the microporous material, so that the mesoporous material has wide application in the fields of catalysis, adsorption, separation, drug delivery and the like, and can realize the slow release of the loaded drug. The pore canal structure, the high specific surface area and the high modification of the MSNs are very beneficial to drug loading. MSNs have many distinct advantages as carriers for drug delivery systems. Firstly, MSNs have huge specific surface area (600-1000m2/g) and specific pore volume (06-10cm3/g), so that more drugs can be loaded on the surface or in the interior of nanopores; secondly, the MSNs have abundant silicon hydroxyl groups on the surface, and the MSNs are easily modified or modified by a silane coupling agent and the like, so that different functionalized surfaces are designed to meet the biological requirements; finally, MSNs are non-toxic, biocompatible and biodegradable, making them useful in clinical diagnostics and therapy. The hollow mesoporous silica has more advantages, has one more large hollow hole than common mesoporous silica nanoparticles, has higher drug loading capacity and high permeability, and achieves the purpose of slow release.

The inorganic nano particles can be compounded with the up-conversion rare earth luminescent fluorescent agent. The optical transition of the rare earth ions is from 4f electrons of an inner shell layer, so that the rare earth ions have excellent narrow band emission characteristics, the spectral positions of the rare earth ions are slightly influenced by a microenvironment, and the rare earth ions can be used as ideal fluorescent probe ions to obtain good application in biomolecule detection and cell process tracking. In order to enable the rare earth doped fluorescent nanoparticles to be applied as biological probes, the surfaces of the fluorescent nanoparticles are modified to form a shell/core structure nano composite, and the surface modification reagents can control the size of the particles and endow the nanoparticles with the property of biocompatibility, so that the detection purpose of certain special biological indexes is achieved. The research is used for simulating the transportation and expansion of the saccule in plasma in vitro, monitoring the concentration of the left nano particles in the plasma and detecting the stability of the saccule carrying medicine in the early stage.

While the preferred embodiments of the present invention have been described in detail, the present invention is not limited to the above embodiments, and various changes can be made without departing from the spirit of the present invention within the knowledge of those skilled in the art.

Claims

1. The preparation method of the nanoparticle rapamycin drug-loaded coating balloon is characterized by comprising the following steps: