| Objectives: As a new drug delivery system,microspheres can deliver drugs at a continuous speed to reduce drug delivery frequency and reduce drug side effects.At present,most insoluble small molecule drugs are limited in clinical application due to poor solubility and other reasons.In this study,a novel three-phase focused microfluidic device was used to prepare drug-loaded microspheres to develop a sustained-release drug delivery system for insoluble small molecule drugs.Using bicalutamide(BCL)as the model drug and polylactic acid-glycolic acid copolymer(PLGA)as the carrier material,the preparation process and prescription of drug-loaded sustained-release microspheres was optimized,and their in vivo and in vitro properties were studied.It will solve the problems such as uneven and controllable particle size,poor sustained release effect and complex operation in the preparation process of insoluble small molecule drug sustained-release microspheres,and provide new ideas and solutions for the preparation of insoluble small molecule drug sustained-release microspheres.Methods:(1)A three-phase flow-focused microchannel structure was designed,and a microfluidic device was constructed by using quartz capillary,ptfe tube and polydimethylsiloxane material.The droplet microfluidic generation system was further constructed by combining CCD camera and injection pump.(2)Oil-in-oil-in-water(O/O/W)microdroplets were generated by droplet microfluidic system and further prepared to microspheres by curing,washing and freeze-drying processes.To complete the prescription optimization,single factor analysis was used to investigate the effects of PLGA concentration,BCL concentration and volume ratio of dichloromethane to acetone in the internal phase solvent on drug loading and encapsulation rate of microspheres.(3)The drugloaded sustained-release microspheres prepared under the optimized prescription conditions were characterized,including particle size and particle size distribution,morphology,differential scanning calorimetry(DSC)and infrared spectroscopy(FTIR).(4)The in vitro release behavior of drug-loaded sustained-release microspheres was studied by High Performance Liquid Chromatography(HPLC)and the morphology degradation of microspheres was monitored by scanning electron microscopy(SEM).The cumulative release rate of microspheres in vitro was calculated and the data were fitted to different kinetic models to explore the drug release mechanism of microspheres.(5)Drug-loaded sustained-release microspheres were intramuscular injected into New Zealand rabbits,and the plasma concentration at different time points was detected by HPLC.Relevant pharmacokinetic parameters and results were calculated and analyzed.Results:(1)A droplet microfluidic generation system was successfully constructed,which can generate microdroplet with uniform particle size and stable properties.(2)The optimal conditions of PLGA concentration in different phases were 1 wt%,BCL concentration was 7.5μg/m L,and the volume ratio of dichloromethane to acetone in the inner phase was 3:1.Under the optimized conditions,the drug loading capacity and encapsulation efficiency of sustained release microspheres were15.60 ± 0.26% and 63.47 ± 1.05% respectively.(3)Scanning electron micrograph showed that the surface of drug loaded sustained release microspheres was smooth and had high monodispersity.The particle size of the microspheres was 51.33 ± 2.16 μm,and the CV value was 4.43%.The results of DSC showed that the drugs were mainly encapsulated in the microspheres in an amorphous form.The results of FTIR spectra showed that no additional covalent bonds were formed during the preparation of microspheres.(4)The sustained-release microspheres could sustainably release drugs for 40 days in vitro,and the total cumulative release rate was 94.78%.The kinetic behavior of drug release was consistent with Korsmeyer-Peppas model.The release of drugs from microspheres was realized under the joint action of drug diffusion and polymer erosion.In vitro degradation studies showed that pores appeared on the surface of microspheres during the degradation process,and the size of pores gradually increased with the passage of time.(5)In vivo pharmacokinetic results showed that the microspheres could slowly release the drug in vivo for up to 30 days.Compared with the control group,the MRT value was significantly increased,realizing the slow and continuous release of the drug in vivo.Conclusions: In this paper,a novel three-phase focused microfluidic device was used to prepare PLGA microspheres to develop a sustained-release drug delivery system for insoluble small molecule drugs.The drug-loaded sustained release microspheres prepared by microfluidic technology had smooth surface,uniform particle size and high monodispersity.The effects of different preparation parameters on drug loading and entrapment efficiency were studied to develop the optimal formula.In vitro release and degradation studies showed that the mechanism of drug release is driven by both diffusion and polymer erosion.The results of pharmacokinetics in vivo proved the long-term sustained-release ability of microspheres in vivo.Therefore,the microfluidic device in this study is a simple and convenient device for the development of uniform monodisperse microspheres.PLGA sustained-release microspheres developed by microfluidic devices have good application prospects in precise delivery and controlled release of insoluble small molecule drugs.19 figures,18 tables,51 references... |
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