Dry powder inhalation of liposomal Ketotifen fumarate: formulation and characterization.

摘要

The purpose of the experiment was to formulate and characterize the dry powder inhalation (DPI) formulation of liposomally entrapped anti-asthmatic drug, Ketotifen fumarate (KF). Liposomes composed of saturated egg phosphatidyl choline (EPC) and cholesterol (CHOL) were prepared by lipid film hydration and sonicated to have the desired size (<5 microm). Process variable such as vacuum, presonication hydration, postsonication hydration, purification and lamellae composition, were optimized for encapsulation efficiency of KF. Liposomal dispersion was blended with cryoprotectant (sugar) in varying bulk and mass ratios and assessed for its influence on retention of encapsulated drug on lyophilization. Characterization of liposomal dispersion was done for size, lamellarity, entrapped volume and oxidation index. DPI formulation was characterized for angle of repose, compressibility index, dispersibility and respirable fraction (British Pharmacopoeia, apparatus A). Process optimization revealed that a vacuum, 20 in.; presonication hydration, 60 min; postsonication hydration, 2 h and purification by dialysis gave maximum encapsulation efficiency. Sucrose was found to be the most suitable cryoprotectant at bulk strength of 500 mM and mass ratio of lipid/sugar, 1/12. Blending of sorbolac before lyophilization showed better retention of encapsulated KF (97.92+/-0.54%). In the preparation of sonicated MLVs, the presence of nitrogen atmosphere, alpha-tocopherol and EDTA could not totally eliminate EPC oxidation, expressed as the change in oxidation index from 0.427+/-0.01 to 1.510+/-0.01. The respirable fraction of the developed formulation (21.59+/-1.53%) is comparable with the control (26.49+/-1.52%). From studies, it may be concluded that an optimal bulk and mass ratio of sucrose, relative to the size of liposomes is necessary for effective cryoprotection. In this investigation, DPI of liposomal KF was successfully prepared and delivered to the required site in the lungs.