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This report describes the preparation of indomethacin loaded maltodextrin based proniosome by slurry method with different surfactant to cholesterol ratio. Preparation of proniosome was optimized for highest percentage drug entrapment. Microscopy confirms that all particles are uniform in size and shape. The entrapment efficiency was determined by separating the untrapped drug using dialysis. The in vitro release studies of drug from niosomes exhibited a prolonged release as studied over a period of 24 h. The positive values of zeta potential indicated that the indomethacin niosomes were stabilized by electrostatic repulsion forces. In the stability study it was observed that the drug leakage from the vesicles was least at 4 followed by 25 and 37. On the basis of in vitro characterization, the niosome showing maximum entrapment and suitable release rate were selected for in vivo performance evaluation. In conclusion, the niosomal formulation could be a promising delivery system for indomethacin with improved bioavailability and prolonged drug release profile.