Design And Evaluation Of Ibuprofen Ocular Delivery System Based On Corneal Permeability Enhancing

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.In this study,a preparation platform for ocular drug delivery,which consists of cationic liposomes,microemulsuion and nanostructured lipid carries,was established based on the research of "Stusy on cationic liposome ocular drug delivery system and its mechanism".Ibuprofen was selected as model drug,the permeability through the isolated cornea,in vivo pre-corneal retention,intraocular tissue distribution,cytotoxicity and cell uptake mechanism and intraocular pharmacokinetics were evaluated;the ocular irritantion of a new ophthalmic penetration enhancer,Pharmasolve,and its impact on the permeability through the isolated cornea of 4 drugs was studied.A UV method was development to determine the concentration of ibuprofen in vitro and the basic physical and chemical properties of ibuprofen were investigated.The result of corneal permeability test showed that when administrated in the form of eye drops,ibuprofen can not penetrate though the cornea very well.In order to increase the transcorneal influx of the drugs,suitable dosage form and should be explored. After formulation and technology study,the optimize formulation of ibuprofen cationic liposome were select and the shape,particle distribution,zeta potential, stability and the cornea permeability were studied.The results showed that the particle size distribution of Ibu-CL was uniformity,the particle was positively charging and the apparent permeability coefficient of the cationic liposomes was 1.64 times compared to the eye drops.The results ofγ-scintigraphy suggested that the pre-corneal retention activity of the ibuprofen cationic liposomes is superior to the neutral liposomes and the ophthalmic solution.A novel microemulsion was prepared to increase the solubility and enhace the in vitro transcorneal delivery of ibuprofen.For the microemulsions,types of oil phase, surfactants,cosurfactant were chosen and the double-distilled water was purified as water phase.Pseudo-ternary phase diagrams were constructed to obtain the concentration range of each component for the microemulsion formation.According to the result of the experiment,15%labrifilm 1944 CS,65%the double-distilled water and 20%S/CoS(8:2) as the optimization of microemulsions was select. Besides,irritation of Ibu-ME was investigated primitively,and microemulsion preparation showed good stability and low toxicity and irritation.The P_app was 2.67-fold compared to eye drops.Ibuprofen nanostructured lipid carriers were prepared by melted-ultrasonic methods; Gelucire 44/14 was screened as one of the solid lipid matrix materials due to the good particle size dispersion and excellent contribution to the corneal permeability of model drug.The intraocular tissue distribution of Ibu-NLC was studied,and the resulted showed that concentrations of ibuprofen in the cornea and lens were much higher than that of eye drops,it suggested that the epithelial cells of the two tissue may have a special mechanism for uptake.In Chapter v,the cytotoxicity of NLC in corneal epithelial and lens epithelial cells were determined by MTT assay and toxicity of NLC on these two cell lines could be observed.In cell uptake study,RdB-NLC were employed,the uptake behaviors were observed by fluorescence microscopy and RdB-NLC were uptaken by cells.Combined with nuclear staining of Hoechst 33342, the observation via laser confocal microscopy also confirmed this point.The pharmacokinetics of these there preparations were studied by microdialysis method.The in vivo recovery for ibuprofen was 59.42%,determined by retrodialysis method.The area under the aqueous humor concentration vs.time curve for Ibu-CL increased more than1.25-fold in contrast with that of the conventional ophthalmic solutions.And the t_max for Ibu-CL was 40 min,and the concentration of drug was constant at the fist 100 minute,the C_max of Ibu-ME was 3.33-fold than that of the control,and the relative bioavailability was 249.9%.there were three concentration peak of Ibu-NLC,which were 20 min,60 min and 120 min.Meanwhile, the relevant bioavailability for the reference was 263.5%.Effects of pharmasolve on the corneal permeability of 4 drugs was evaluated.The results of the ocular irritation studies showed that pharmasolve was non-irritant at the concentrations studied(2.5% to 10%),It was also found that pharmasolve did not cause any visible ocular damage or abnormal clinical signs involving the cornea,iris or conjunctivae at all concentrations.In the presence of Trans at a concentration between 2.5%and 10%, the maximum increase in the apparent permeability coefficient(P_app) was1.47-,2.67-, 4.04-and 5.09-fold for ibuprofen,puerarin,ribavirin nand,enoxacirespectively.The results indicated that pharmasolve has potential clinical benefits in improving the ocular drug delivery of both hydrophilic and lipophilic compounds,which could be used in clinical.