DEVELOPMENT AND OPTIMIZATION OF LIPOSOMAL KETOTIFEN FUMARATE DRY POWDER USING RESPONSE SURFACE METHODOLOGYAbstract
The aim of this study was to develop and optimize nano-liposomally entrapped ketotifen fumarate (KTF) loaded dry powder inhalation (DPI) formulation using response surface methodology (RSM). Based on the 33 full factorial design (33FFD), the mass ratio of KTF solution to soybean phosphatidylcholine (SPC94), KTF/ SPC94 to 0.5 M lactose solution that after lyophilization produce lyophilized liposomal powder (LLP) and LLP to coarse lactose carrier (CLC) were selected as independent variables with KTF liposomal encapsulation efficiency (%EE), liposomes particle size (PS) and fine particle fraction (%FPF) as dependent variables. The aerosolized liposomal dry powder was prepared utilizing vesicular phospholipid gel technique followed by lyophilization after incorporating it into lactose solution as a cryoprotectant. A full and reduced second-order polynomial models were developed for each response using multiple linear regression analysis. Applying a desirability function method, the optimum parameters were: KTF: SPC94 of 0.045, KTF/ SPC94: 0.5 M lactose of 0.389 and LLP: CLC of 0.080. At this optimum point, the %EE, PS and %FPF were found to be 52.68%, 444.00 nm and 20.46%, respectively. The powder bulk density of (0.31 gm/cm3) is within the acceptable range for pulmonary delivery, whereas the angle of repose of (30.14 θ) indicates good powder flowability. The in vitro release study of KTF from the optimize liposome suspension revealed that Korsmeyer – Peppas model of release gives the best fitness and the mechanism of release was non-Fickian, whereas Weibull 3 model was the best for fitting the data obtained indicating that the curve of release was parabolic (b<1, case 3). Thus, response surface methodology aid in developing in situ generated sphere liposomal vesicles on lactose carrier particles that will impart a continued drug release for more than 12 hours without a significant burst effect.
Department of Pharmaceutics, College of Pharmacy, Tikrit University, Tikrit, P.O. Box (42), Saladin, Iraq
10 January, 2014
16 March, 2014
12 May, 2014
01, June 2014