Sustained Ocular Drug Delivery Based On Contact Lenses

Contact lenses(CLs),which was one type of hydrogel with good biocompatibility,was employed for ophthalmic drug delivery to provide longer residence time,higher bioavailability and better patient compliance comparing with eye drops.However,low drug loading efficiency,limited sustained release and poor stability hindered the further development of CLs.The object of this study was to develop therapeutic CLs with suitable drug loading,controlled drug release behavior and excellent storage stability,which would prolong drug precorneal residence time and provide the basis of improving ocular drug bioavailability.Firstly,a simple and effective drug loading method based on salt induced modulation was proposed and demonstrated with mechanism elucidation.Using poly(2-hydroxyethyl methacrylate)(p-HEMA)as the CLs material,Betaxolol hydrochloride,diclofenac sodium and betaxolol base as the model drugs with different solubility,influence of salt concentration,salt type and drug properties in the loading solution on drug loading efficiency was investigated.The absorption isotherms studies indicated that the nature of drug loading might be absorption on CLs.By investigating the influence of salts on the water content of CLs,we speculated that the mechanism for improved drug loading minght related to the reduced drug solubility in loading solutions and the reduced bound water content in contact lenses.Moreover,in vitro drug release and light transmittance was not affected using this method.Based on the premise that drug loading had been improved using salt induced modulation,we probe the influence of using layer-by-layer coated lens on drug release.Formation of self-assembled films on lens using chitosan and sodium carboxymethyl cellulose had been proved by morphology,light transmittance and dye lable study.Comparing with uncoated lens,coated lens using layer-by-layer technology showed a relative sustained drug release behavior.In the meantime,both crosslinking degree and micropore structure would influence drug release rate.Considering the short release duration of layer-by-layer coated CLs and poor storage stability of multilayer CLs.We investigated the feasibility of using a novel mulitilayer contact lens,in which blend film of ethyl cellulose and Eudragit S100 was used as the inner layer,with good storage stability capable of pH-triggered drug delivery.Diclofenac sodium was selected as drug model.Influence of polymer ratio in the blend film,EC viscosity,drug/polymer ratio,inner layer thickness and outlayer thickness of pHEMA hydrogel on drug release behavior was studied.The pH-triggered drug eluting pattern enables the inner layer-embedded contact lens being stored in phosphate buffer solution pH 6.8 with ignorable drug loss and negligible changes in drug release pattern.In vivo pharmacokinetic study in rabbits showed sustained drug release for over 24 hours in tear fluid,indicating significant improvement in drug corneal residence time.Based on the blend system of ethyl cellulose and Eudragit S100,we further investigated the feasibility of using inner layer-embedded CLs,in which blend film of cellulose acetate and Eudragit S100 was used as the inner layer,to achieve sustained release of highly water soluble drug,betaxolol hydrochloride on the ocular surface.Influence of polymer ratio in the blend film on in vitro drug release behavior was studied and drug-polymer interaction,erosion and swelling of the blend film were characterized to better understand drug-release mechanism.Storage stability of the inner layer-embedded contact lenses showed good storage stability in phosphate buffer solution at 5℃,with ignorable drug loss and negligible change in drug release pattern within 30 days.In vivo pharmacokinetic study in rabbits showed sustained drug release for over 240 hours in tear fluid,indicating prolonged drug precorneal residence time.It was noted that there are plentiful of electrolytes existed in tear fluid,which might be used as the basis for developing ocular ion-sensitive drug delivery system.A novel inner layer-embedded contact lens capable of ion-triggered drug release for extended ocular drug delivery was designed.Using betaxolol hydrochloride-ion exchange resin complex dispersed polymer film was used as an inner layer.Composition of the inner film and crosslinking degree of the outer hydrogel on drug release profile would affect drug release rate.The ion-triggered drug eluting property enables the inner layer-embedded contact lens being stable when stored in distilled water at 5℃ for at least 30 days with ignorable drug loss and negligible changes in drug release kinetics.In vivo pharmacokinetic study in rabbits showed sustained drug release for over 168 hours in tear fluid,indicating significant improvement in drug corneal residence time.In conclusion,the phenomena of low drug loading and short drug release duration of soaked CLs had been eliminated to some extent through this study.In the meantime,the problem of poor stability of multilayer CLs had been solved,which providing a certain basis of developing efficient sustained ocular drug delivery products successfully.