The Study On The Ophthalmic Drug Delivery System Of Azithromycin

Azithromycin is a second-generation macrolide that has rapid tissue distribution, sustained high tissue levels, uptake and transport by phagocytic cells. A post-antibiotic effect has been demonstrated. By oral route, its ocular bioavailability is good, since a single oral administration maintains prolonged azithromycin concentrations in tears and conjunctiva. To avoid the adverse effect of gastrointestinal tract, we produced two formulations of azithromycin for topical use.In vitro analytical method of azithromycin was established. The solubility of azthromycin in PBS was measured. Azithromycin can be hardly dissolved in the water, and the dissolution decreased with the increasing of pH. The degradation kinetics of azithromycin in aqueous solutions was studied. Degradation of azithromycin in aqueous solutions followed first-order kinetics, and the pH_m for azithromycin was 6.41. The degradation rate increased with ionic strength and temperature. Azithromycin was relatively stable in PBS than the other buffers.Azithromycin tablets were prepared by means of freeze drying method. Through the formulation screening and procedure optimizing, gelatin, mannitol and HPMC was chosen as the supporting, protecting and adhesive agent respectively. The results suggested the best proportion of the agent was 0.5、3 %、2 % for HPMC, gelatin and minnitol respectively.Iso-osmia buffer was prepared to match the azithromyicn tablet for ophthalmic use. Drop the tablet into the buffer and jog lightly until dissolved before using the formulation. The results of quality studies on azithromycin freeze-dried eye drops showed that the quality were good. The stability test showed that azithromycin freeze-dried eye drops were stable to light and heat, but severe moisture absorption was observed under high humidity environment. In-package desiccation was suggested to solve the problem. The results of irritant study indicated that azithromycin freeze-dried eye drops were non-irritant to rabbit eyes and met the demand of ophthalmic formulations.Azithromyicn in-situ gel for ophthalmic use was prepared using poloxamer 407, poloxamer 188 and sodium hyaluronate. A membraneless dissolution model was used to study the influence of shaking frequency and surface area on both gel dissolution and drug release. The results showed that the drug release was controlled by gel dissolution. The results of quality studies on azithromycin in-situ gel for ophthalmic use showed that the quality were good. The results of irritant study indicated that azithromycin in-situ gel for ophthalmic use were non-irritant to rabbit eyes and met the demand of ophthalmic formulations.The LC-MS method for determination of azithomycin in rabbit tears was developed. The results of the elimination kinetics study showed that the AUC_0-t、MRT for azithromycin freeze-dried eye drops were 4.07 and 1.78 folds than the control, and that of azithromycin in-situ gel for ophthalmic use was 4.24 and 2.91 respectively. The two new formulations of azithromycin had significantly improved bioavailability and prolonged the drug resident time in eyes.