Synthesis Of Triblock Copolymer PLGA-PEG-PLGA And The Application In Eye Gels

As one of the important fields of controlled release,ophthalmic drug delivery has received entensive interests during the last two decades.The sensitivity and protection mechanisms of the eye promote more effective drug delivery systems with better compliancy to be developed,however,the applications of numerous pharmaceutical methods are limited simultaneously,which presents great challenge in designing ophthalmic dosage forms.Eye drops and ointments are most usually applicated to prevent and cure kinds of ophthalmopathy,while there are more obvious defects in them.In this dissertation,dexamethasone(DXM) was selected as the model drug,then a thermosensitive in situ gelling ophthalmic drug delivery system for DXM was developed and evaluated in vitro and in vivo,respectively.Five main sections were included in this paper:1.Synthesis and characterization of triblock copolymers PLGA-PEG-PLGAFollowing references and the conditions we actually had,we decided the way to synthesize copolymers.Details of the synthesis of PLGA-PEG-PLGA from lactic acid, glycolic acid and PEG are described.The synthetic product was characterized by ¹H-NMR and GPC.The phase transition temperature,the viscosity and particle size and other chemical and physical characteristics were determined.The results suggested that it was a kind of transparent gel with achroic or little yellowish.The structures of LA,GA and PLGA-PEG-PLGA were all fight compared with lots of references.The molecular weight can be controlled.At room temperature,the tdblock copolymer PLGA-PEG-PLGA (LA/GA=7:1,20%,w/w,in water) solution can flow freely.While the temperature is raised to about eyes temperature,it turned to be semisolid gel.It was used on eyes drug delivery systems.There is an obvious change of viscosity during the increased temperature.The particle size was below 100 nm.2.The preliminary safety evaluation of tribloek copolymers PLGA-PEG-PLGAThe results on acute toxicity test of triblock copolymers in rats indicated that the materials were saft enough.The results of irritability study indicated that there was no obvisous stimulus on rabbit eyes.And the study of ophthalmic preparation can last.3.The preparation and evaluation of DXM thermosensitive eye gelsDenpending on the velocity and strength of the gel,the triblock copolymer solutions (LA/GA=7:1,20%,w/w,in water) were chose to prepare the DXM thermosensitive ophthalmic preparations.The quality evaluation was taken on the preparations.The appearance,pH,and sedimentation ratio of the ophthalmic preparation were good enough. The detection method of DXM in thermosensitive gels was established and it has better sensitivity and specificity.The results of in vitro study showed that the release of DXM from thermosensitive gel last 8h to 12h.This preparation can be used once a day because of its sustaind release.The stablitity of ophthalmic preparation was better after the influencing factor test,accelated test and long term test.4.The in vivo evaluation of DXM thermosensitive ophthalmic preparation in rabbit eyesThe results of DXM in vivo evaluation indicated that the C_max,T_max,T_1/2,AUC and MRT of DXM thermosensitive ophthalmic in stiu gel were much more obviously better than eye drops.The time of DXM treatment last longer.In a word,the method of ring-opening polymerization for triblock copolymer PLGA-PEG-PLGA with different LA/GA ratio was described.The results of ¹H-NMR and GPC showed that the structure of the copolymer we had was farmiliar with that reported for years and it was right exactly.The molecular weight of the copolymer could be controlled by LA/GA ratio.The particle size of copolymer in water was all below 100nm. Also the copolymer solution was thermosensitive.Preliminary safety evaluation shows that was a kind of safty preparation and nerely no toxicity.And there was also no irritation after administration.R was simply to prepare the formulation and it was stable after stress testing,accelerated testing and long-term testing.The in virto release results of DXM-copolymer solution indicated there was a long time for DXM to release from the gel. The results of rabbit eye pharmacokinetics showed this kind of preparation can increase the residence time of DXM in aqua oculi.