Research On The Construction And Transdermal Delivery Of Sinomenine Hydrochloride-delivering Ethosomes Modified By Ascorbic Acid

Rheumatoid arthritis(RA)is the chronic disease characterized by persistent synovitis,systemic inflammation and autoantibodies,which is the significant reason of joint destruction and even loss of productivity.At present,oral and injective administrations are mainly used in clinical medication.Oral administration is convenient and suitable for long-term administration,but it is of difficulty to avoid gastrointestinal irritation,first-pass effect and the accumulation of the side effects.Injective administration can take effect rapidly,but it has poor compliance during long-term medication.And transdermal delivery system can overcome the difficulties,if it has ability of passing stratum corneum with tight junction and delivering enough drug to synovial fluid.RA site tends to oxidative state resulting from oxidative stress,where demand of reductive substances(ascorbyl acid and co-enzyme Q10 et al)and enzymes rapidly increases.Ultilizing the feature,sinomenine hydrochloride-loaded ascorbyl palmitate-modified transethosome(AP-TEs)was prepared using ultrasound-injection method.AP-TEs were multiply-layer vesicles in TEM image with size of less than 100 nm and modification rate of more than 80%.The in vitro characterizations of AP-TEs were similar with sinomenine hydrochloride-loaded tranethosomes(SH-TEs),with higher encapsulation efficiency and deformation index than sinomenine hydrochloride-loaed ethosome(SH-Es).The results using horizontal diffusion cell showed that in vitro permeation efficiency of AP-TEs,similar with SH-TEs,had about 3 times than SH-Es and about 5 times than SH aqueous solution.To solve the inconvenience of liquid TDDS,the integrity,in vitro permeation efficiency,administrative tightness and skin irritation was compared between polyacrylic resin pressure-sensitive patch and carbomer gel,resulting to that AP-TEs gel had leakage ratio of 9.8%and good integrity and administrative tightness during 24 h.AP-TEs gel had less severe acute and chronic skin irritation than patch.The RA model rats induced by complete Freund’s adjuvant were treated during 3 weeks,characterized by width and girh of ankle,inflammatory cytokines,erythrocyte sedimentation rate(ESR)and CT image.The results showed therapeutic effects of AP-TEs were similar with ig group,better than SH-TEs and much better than SH aqueous solution.In order to verify correlation between therapeutic effect and drug concentration,the rabbit pharmacokinetics in plasma showed that AP-TEs had similar concentration-time curve with SH-TEs.And the drug concentration of synovial fluid measured using micro-dialysis of AP-TEs group was significantly higher than SH-TEs.The AP-TEs were enriched at RA site and hypothesis was verified due to similar therapeutic effect with ig,better treatment and higher drug concentration in synovial fluid than SH-TEs,which is a potential drug delivery system treating RA.