(GLOW IMAGES/GETTY IMAGES)
|
Nasal sprays are widely used for locally acting preparations, such as decongestants and allergy treatments, as well as for
the rapid delivery of systemic therapies, hormones and migraine treatments. In each case, the effectiveness of drug delivery
depends on both the delivered dose and the size of the droplets produced by the spray pump during actuation. The latter influences
both deposition and, potentially, bioavailability. In turn, droplet size derives from the characteristics of both the device
and formulation, in combination, as recognised in the testing protocols.1–3 To achieve the desired performance of a product, developers may choose to manipulate the properties of the formulation or
the design of the device, or both; however, developers require clear and relevant data on which to base their decisions.
Laser diffraction-based particle size analysis is a powerful tool for nasal spray characterisation primarily because it is
fast enough to capture droplet size evolution in real time. This article examines its value, and describes studies that explore
the effect of formulation viscosity on droplet size, as well as device characteristics, such as orifice diameter of the nasal
actuator and spray pump mechanism. Such studies support the faster and more efficient development of nasal spray products.
The regulatory perspective
Regulatory guidance recommends that nasal sprays are tested as combined products (device and formulation together) to determine
reproducible delivery.1–3 Achieving clinical efficacy and good product consistency relies on understanding and controlling the interactions between
device and formulation, which together dictate performance. Invitro testing is specified for a range of variables, with droplet size being one of the most important parameters. Droplet size
measurements are used to assess:
Quality — the consistency of performance; for example, over the lifetime of the product, from batch-to-batch, or after storage.
Safety — droplets of 10 µm and below may pass through the nasal passages and penetrate into the lungs.3 Consequently, APIs in this fraction will enter the body by pulmonary absorption, rather than by the intended route. Quantifying
the extent of this risk and assessing the associated clinical effect is essential.
Efficacy — droplet size influences the site of deposition within the nasal passages, which may affect bioavailability.
The FDA recommends droplet size measurement at several stages of the product life cycle, including: development/optimisation
and preclinical/IND trials; stability, robustness and in vitro bioequivalence testing; and batch release.1,2 The European Medicines Evaluation Agency (EMA) sets out similar guidance for droplet sizing as part of product applications,3 although the extension to in vitro bioequivalence testing is not as clearly stated. Such testing allows developers to successfully optimise controllable parameters
to meet performance targets and provides quality control for the manufactured product.
The two droplet sizing techniques for nasal spray testing highlighted by the regulators are cascade impaction and laser diffraction.
Cascade impaction is a relatively time and labour-intensive technique that allows measurement of the amount of API in the
sub -µm aerodynamic fraction, which is important for assessing the potential for pulmonary absorption (as noted above). Laser
diffraction, in contrast, is sufficiently rapid to provide real-time size measurement of the whole droplet rather than just
the API. Because of this, laser diffraction is an excellent tool to use during the development cycle when the aim is to target
a defined droplet size and obtain an early assessment of the percentage of droplets less than 10 µm in size.
