rifapentine and stearylamine

Quality by Design (QbD) is a systematic approach to develop drug products which includes evaluation of formulation parameters to achieve defined final product quality. In the present study principles of QbD were extended to the preparation, in-vitro and in-vivo performance of rifapentine-loaded proliposomes for pulmonary inhalation where final product needs to comply with specific properties. The rifapentine-loaded proliposomes for the treatment of tuberculosis were prepared in single step by spray drying method and independent variables were optimized using factorial design approach. Contour plots and multiple regression analysis were used to study the effect of selected independent variables on dependent variables. The effect of presence of drug: hydrogenated soya phosphatidylcholine (HSPC) and type of charged lipid in the formulation at three levels were studied on mass median diameter (MMD), liposomal vesicle size, % encapsulation efficiency (% EE), mass median aerodynamic diameter (MMAD) and fine particle fraction (FPF) as critical quality attributes. Optimized formulation (R-LDPI-7) with drug: HSPC ratio of 1:2 and stearyl amine as charged lipid were found to give respirable proliposomes with MMAD of 1.56 ± 0.16 μm and FPF of 92.5 ± 1.5%. Sustained drug release with Higuchi diffusion kinetics was achieved from liposomally encapsulated rifapentine. Pulmonary pharmacokinetics of optimized batch R-LDPI-7 revealed longer retention of drug in lungs with 7 fold increase in both, the mean residence time and t1/2 as compared to R-DPI-0. The study results demonstrated the application of QbD principles and design of experiment (DOE) approach to develop drug encapsulated proliposomes for inhalation by spray drying in single step.

Topics: Administration, Inhalation; Amines; Animals; Antibiotics, Antitubercular; Chemistry, Pharmaceutical; Delayed-Action Preparations; Drug Liberation; Female; Glycine max; Half-Life; Liposomes; Lung; Male; Particle Size; Phosphatidylcholines; Rats; Regression Analysis; Rifampin; Tissue Distribution