Prediction of pharmacokinetic studies outcome for locally acting nasal sprays by using different in vitro methods.

Demonstration of bioequivalence of locally acting nasal spray formulations is a challenging task and the regulatory agencies have different approach towards this goal. The pharmacokinetic bioequivalence studies are recognized as necessary for assessment of equivalent systemic exposure. We utilized three different in vitro methods for nasal spray evaluation and compared those results with the results of pharmacokinetic studies of different formulations of four intranasal corticosteroids, in order to evaluate their in vivo relevance. Two cell lines, RPMI 2650 and Calu-3, Transwell® polycarbonate membranes with different pore size and lipid-oil-lipid tri-layer membrane in the parallel artificial membrane permeability assay (PAMPA) system were used for this purpose. The in vitro results correlated with the results of pharmacokinetic studies and correctly predicted (non)equivalence of the nasal sprays, showing that in vitro methods are good indicator of the in vivo outcome. The Transwell® and PAMPA in vitro methods were additionally implemented for testing batch-to-batch variability of reference nasal spray formulations. The results from the Transwell® assay for the two poorly soluble corticosteroids are possibly over-discriminatory in showing differences between batches of reference nasal sprays. Overall, the three in vitro methods have potential to predict the results of bioequivalence testing of nasal spray products.

Elucidation of Formulation and Delivery Device-Related Effects on In Vitro Performance of Nasal Spray with Implication to Rational Product Specification Identification.

BACKGROUND: The aim of this work is to use an experimental design approach to identify and study influential formulation and delivery device properties, which can be controlled by final product manufacturer, to establish design space, within which desired in vitro performance can be reached. METHODS: Combining three factors, viscosity of suspension, nozzle orifice diameter (OD), and shot weight (SW), at three levels resulted in D-optimal experimental design with 20 runs. Responses within this study were droplet size distribution (DSD) and spray pattern (SP) in vitro tests. In addition, the amount of mechanical work needed for actuation was integrated from force profiles and used as a response. Results were fit to quadratic model by regression, which allowed also for determination of second-order and interaction effects between factors. Models were further optimized by keeping significant terms only. Optimized models were used to create response surfaces and design space with confidence levels. RESULTS: Viscosity has a dominant effect on DSD and modest effect on SP, with lower viscosities related to generation of smaller DSD and larger SP. Orifice diameter was found to have the highest impact on SP, with larger diameter resulting in larger SP. This effect was additionally confirmed by results of Plume Geometry in vitro test. Shot weight factor exerts significant influence on all tested metrics. Work, however, did not vary greatly with suspension viscosity or orifice diameter. Shot weight is the most dominant factor for work and important for DSD having a positive effect on both responses. In the case of SP, its relationship with shot weight is described by second-order polynomial fit. Inspection of raw data revealed that density of droplets within SP area is different for different shot weights. CONCLUSION: Presented study elucidated an inherent relationship between factors and responses and established mathematical models (response surfaces) for predictive purposes to target specific in vitro performance of nasal sprays by appropriate specification of factors, taking into account control space with included risk and uncertainty analysis.