Analytical Challenges and Regulatory Requirements for Nasal Drug Products in Europe and the U.S.

Abstract

Nasal drug delivery can be assessed by a variety of means and regulatory agencies, e.g., the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have published a set of guidelines and regulations proposing in vitro test methods for the characterization of nasal drug products. This article gives a summary of the FDA and EMA requirements regarding the determination of droplet size distribution (DSD), plume geometry, spray pattern and shot weights of solution nasal sprays and discusses the analytical challenges that can occur when performing these measurements. In order to support findings from the literature, studies were performed using a standard nasal spray pump and aqueous model formulations. The aim was to identify possible method-, device- and formulation-dependent influencing factors. The literature review, as well as the results from the studies show that DSD, plume geometry and spray pattern are influenced by, e.g., the viscosity of the solution, the design of the device and the actuation parameters, particularly the stroke length, actuation velocity and actuation force. The dominant factor influencing shot weights, however, is the adjustment of the actuation parameters, especially stroke length and actuation velocity. Consequently, for routine measurements assuring, e.g., the quality of a solution nasal spray or, for in vitro bioequivalence studies, the critical parameters, have to be identified and considered in method development in order to obtain reproducible and reliable results.

Feasibility Investigation of Cellulose Polymers for Mucoadhesive Nasal Drug Delivery Applications

“…In addition to the potential viscosity effect on CBF, the toxicity of cellulosic polymer solutions on nasal mucosa was assessed by monitoring changes in the CBF after a 20 min exposure (this duration was based on the reported turnover rate of mucous in the nasal cavity), 34 as one important toxicity indicator. Compared to the control that was measured without exposure to any polymer solutions, all polymer solutions, up to 1% concentrations at the highest, showed only negligible effects on CBF recovery.…”

How to characterize a nasal product. The state of the art of in vitro and ex vivo specific methods

“…Finally, a progressive increase in the light transmission may be observed in parallel with the increase in particle size during the dissipation phase (FDA, 2003;Sangolkar et al, 2012). It is thus suggested that data generated from the fully developed phase of the spray be reported (Trows et al, 2014). However, this fully developed phase has been criticized as it is not very representative of the aerosol emission in the nasal cavity.…”

“…Various parameters related to the actuation can be easily controlled with such automated stations, such as the actuation force or the time between each test (Kippax and Fracassi, 2003). Usually, the force applied for actuation is ranged between 4.5 and 6 kg, which corresponds to the usual hand actuation for an adult (Dayal et al, 2004;Trows et al, 2014;Doughty et al, 2011). Both actuation force and aerosol PSD have been shown to be inversely proportional, with a decrease in both Dv50 and Dv10 when the actuation force was increased (Dayal et al, 2004;Trows et al, 2014).…”

“…Larger amounts of surfactant induced an increase in the dynamic-viscosity, which could explain the increase in the Dv50. However, observations regarding both surfactant and surface tension effects on the size distribution have been reconsidered by different studies that could not lead to a similar conclusion (Guo et al, 2008;Trows et al, 2014). Indeed, the data collected by Trows et al and Guo et al rather suggested a strong influence of the viscosity while a slight effect of the surface tension on the droplet size distribution.…”

Caracterização físico-química de sistemas coloidais em sprays nasais

“…Um dos parâmetros que influenciam no tamanho das gotículas é a viscosidade da formulação (HARRIS et al, 1988;PENNINGTON et al, 1988;TROWS et al, 2014). No trabalho de Dayal et al,com uma formulação de viscosidade de 2,2cP obtém-se um d50 igual a 50µm, enquanto que com uma viscosidade de 32cP, obtém-se um d50 igual a 140µm, sendo que estas diferenças refletem em suas áreas de deposição: 113 e 4,8cm 2 respectivamente (DAYAL; SHAIK; SINGH, 2004).…”