The Ocular Drug Delivery Of Chitosan-coated Dexamethasone Lipid Emulsion

Dexamethasone is one of the strongest biological hormone in synthetic glucocorticoid. It is effective on anti-inflammatory, anti-endotoxin, suppress immune and enhance emergency response in ophthalmology. But ophthalmic administration features and its physicochemical property limit its clinical application, which need frequent administration. Therefore, improving the ocular bioavailability of poorly water-soluble dexamethasone as well as to reduce side effect were considered. This paper designed chitosan-coated dexamethasone lipid emulsion. Its formulation design, characterization, drug release, eye irritation and intraocular pharmacokinetics have been studied. This paper includes these four parts:The frist part established the method of high performance liquid chromatography(HPLC) for determining the concentration of dexamethasone and research its solubility in different solvents. As a result, its solubility would be influenced by the ionic strength, the type and concentration of polymer and different type of oil, which most effective were PVP and MCT or GTCC.Chitosan-coated lipid emulsion contained dexamethasone, soybean, soy lecithin as oil phase and Poloxamer188, glycerol, chitosan as aqueous phase, then prepared by high pressure homogenization technology. Its appearance is milky white and good liquidity, showed blue opalescent when diluted with water. Chitosan-coated lipid emulsion looks spherical and smooth edge by TEM. Because chitosan wrapped surface of lipid emulsion made its edge was slightly darker, comparing with lipid emulsion. The chitosan-coated lipid emulsion’s droplet size, Zeta potential were(177.30±3.32) nm and(31.58±1.43)mV by laser diffractometer, respectively. Its particle size was bigger than the lipid emulsion, but was acceptable and ζ- potential changed from negative to positive. The concentration of drug in chitosan-coated lipid emulsion was 0.97 mg·mL-1 that nearly 10 times than the water. Its entrapment was 86.49%±0.82 measured by micro gel column centrifugation, which enhanced nearly 35% than lipid emulsion. Combined the results of phase distribution suggested that chitosan can improve the distribution of the drug in the oil phase and the oil-water interface. The stability of lipid emulsion and chitosan-coated lipid emulsion were investigated. Influencing factors result showed the loaded dexamethasone improved stability than water solution. Acceleration and long-term results of 6 months showed that the nano-features and concentration did not change significantly but high temperature. They should stored in 4℃.The third part presented the cornea penetration behavior of dexamethasone aqueous suspensions, lipid emulsion and chitosan-coated lipid emulsion that investigated by the isolated cornea experiments. The apparent permeability coefficient of lipid emulsion and chitosan-coated lipid emulsion were 5.52 and 5.91 times higher than the water suspensions. It means that lipid emulsion system helped dexamethasone to pass the cornea barrier. But there is no significant differences between the two emulsions of cumulative permeation(P<0.05). The in vitro results showed that the release model of aqueous suspensions, lipid emulsion and chitosan-coated lipid emulsionfollowed zero-order kinetics, Riger-Peppasand Higuchi, respectively. The difference between the two lipid emulsions probable due to the positively charged on the emulsion droplets surface by chitosan Coated and the dexamethasone different distribution between each phase.The fourth part investigated the in vivo behavior of rabbit eyes. The result showed that, comparing with the Tobradex and lipid emulsion, chitosan-coated lipid emulsioncan significantly prolonged dexamethasone intraocular, increase drug concentration in aqueous humor and intraocular tissues. It turned out that lipid emulsion and chitosan-coated lipid emulsion could extend the MRT of Tobradex by 1.1 and 1.18 times, when AUC was enhanced by 1.54 and 2.36 times than aqueous humor, respectively. The biodistribution test showed that the dexamethasone of Tobradex mainly in the cornea and sclera and eliminated fast while lipid emulsion while chitosan-coated lipid emulsion eliminated slower and enhanced dexamethasone concentration in cornea, sclera, lens and vitreous body, meanwhile chitosan coated is better.Evaluate ophthalmic biocompatibility of lipid emulsions in rabbit eyes by multiple administrations. Draize test showed both lipid emulsion were no irritation in eye. Histopathological examination showed the cornea, iris and retina were structural integrity and no tissue adhesion, inflammatory cell infiltration and necrosis observed.In this study, the formulation and preparation, physicochemical characteristics, stability, corneal penetration, rabbit aqueous humor pharmacokinetics, eye tissues distribution and safety test of chitosan-coated lipid emulsion were studied. The results show that this novel formulation has the following advantages:(1) Increasing drug-loaded capability of insoluble drugs, which increase eye drop concentration;(2) Extend the residence time and sustained release the drug;(3) After lipid emulsion coated by chitosan, positive charge helps to improve the elimination kinetics and help to open tight junctions of epithelial cells;(4) Chitosan-coated lipid emulsion can change the tissues distribution of dexamethasone in the eye, to provide a reference for treatingthe posterior segment diseases through eye drops administred.