Study Of Surface-Modified Nanostructured Lipid Carriers With Water-Soluble Chitosan For Ocular Drug Delivery

To overcome the low bioavailability of the traditional eye drops,in this study a novel surface-modified nanostructured lipid carriers with partially deacetylated water-soluble chitosan(NLC-PDSC)was proposed and formulated,which was used as an ocular drug delivery system.The surface properties of NLC and its drug delivery efficiency were modified by chitosan.Additionally,the innovated ocular drug delivery system with high transcorneal penetration and prolonged precorneal retention was evaluated thoroughly.Highly deacetylated chitosan was used to synthesize partially deacetylated water-soluble one under homogeneous phase condition and it was characterized by IR spectrum and X-ray diffraction.After that,the degree of deacetylation(DD)and viscosity were determined.Flurbiprofen(FB)was chosen as a model molecule and its properties were studied,such as solubility and thermor stability.A HPLC analytical method was developed.NLC loaded with FB were prepared by a melt-emulsification method and PDSC coating was accomplished by the adsorptive interaction.Furthermore,physicochemical parameters of NLC-PDSC were characterized in terms of particle size,zeta potential,morphology,entrapment efficiency,drug state form and stability.The results showed that the particle sized distribution was homogeneous and the zeta potential was positive.The enhanced transcorneal penetration of the coated NLC was evaluated using isolated rabbit corneas,with significantly increased apparent permeability coefficient being 1.40-and 1.75-fold of the NLC and FB phosphate solution(P<0.05),which suggested that PDSC along with NLC could enhance transcorneal penetration to the utmost.Precorneal retention assessed by gamma scintigraphy in vivo showed that the residence could be prolonged by 0.15%PDSC.After NLC-PDSC was labeled with fluorescent marker,its transcorneal mechanism was investigated by confocal laser scanning microscopy,suggesting that NLC-PDSC nanoparticles penetrate corneal epithelia through a transcellular pathway.Furthermore,the in vitro release study using liposome dispersions as mimic biomembranes revealed an efficient transfer of fluorescence marker into the liposomes,which demonstrated that it transported through biomembranes by a collision-induced process entailing partitioning of a fraction of the entrapped substance directly from the surface of donor particles into the receiving cells.In vivo ocular tolerance study indicated that there was a well tolerance.SRA01/04 cell uptake behavior of C6-labeled NLC-PDSC was visualized via fluorescence microscopy,confirming that PDSC could increase the transport amount of fluorescence into cells.Moreover,cell toxicity study provided that the formulation could decrease the toxicity of FB eye drops.In vivo anti-inflammatory efficacy was assessed in the rabbit eye after topical instillation of sodium arachidonate(SA).A higher decrease of the SA-induced inflammation was obtained for the NLC-PDSC formulation.To sum up,this novel NLC-PDSC demonstrates the high potential for ophthalmic drug delivery to overcome constrains of the conventional eye drops.