Preparation And Evaluation Of Ketoconazoleloaded MPEG-PVL Copolymeric Micelles For Transdermal Preparation

Ketoconazole(KET)is a lipophilic imidazole antifungal drug,which is usually used in the treatment of local fungal infections with broad spectrum activities.KET acts by impairing the synthesis of ergosterol,the essential component of the fungal cell membrane.However,its clinical application is limited due to its low water-solubility,high molecular weight of 531.43 g/mol and high logP of 4.31.Amphiphilic copolymers like methoxy poly(ethylene glycol)-poly(?-valerolactone)(MPEG-PVL)is able to self-assemble to form micelle with a specific core-shell structure above critical micelle concentration.These micellar systems seem to have small particle diameter,stability and capability of encapsulating hydrophobic drugs due to interaction between micelle's core and hydrophobic drug.In this study,the MPEG-PVL copolymer was synthesized through ring-opening polymerization reaction with methoxy polyethylene glycol(Mw=2000 Da)and ?-valerolactone as raw materials.The structure of copolymer was confirmed by 1H-NMR,IR.KET loaded MPEG-PVL polymeric micelle(KET-M)was prepared by hydration film method,and the optimum prescription and craftsmanship were determined.KET-M preparation and crystal morphology of KET in micelle were confirmed by XRD and IR.On that basis,the KET-M's study of stability,skin irritation,in vitro release behavior,in vitro antifungal activity,Frans skin permeation and deposition were performed.Results indicated that the optimal KET-M with entrapment efficiency and loading capacity for 86.39 ± 2.21%,10.80 ± 0.28%,respectively,were prepared by thin-film hydration at 60?.The optimized conditions included: molecular weight of MPEG-PVLwas 5400 Da,the weight ratio of MPEG-PVL and KET was 7 and the volume of water was 10 m L.KET-M showed single sphere shape in transmission electrical microscopy photograph.The micelles made KET aqueous solubility increase to 0.86 mg/mL,which was 86-fold higher than crude one.XRD and IR analysis proved that KET was loaded into micelles with the amorphous in micelles.Mean particle diameter and zeta potential of the drug-loaded micelles were 12.22 ± 0.58 nm,2.89 ± 0.15 mV,respectively.And KET-M's mean particle diameter hardly changed within 21 days after lyophilization with cryoprotectant.The in vitro release showed that KET-M could sustained release of drug with slow release rate for a long time.Meanwhile,Ketoconazoleloaded micelles had no obviously irritation to the skin of mice.The permeation and deposition test demonstrated that the drug-loaded micelles obviously enhanced skin deposition without skin permition of KET,and the in vitro antifungal experiment demonstrated that KET-M displayed similar antifungal activity to crude KET.