Together, the techniques of laser diffraction and automated particle imaging support the fast, cost-effective development of nasal spray products, simultaneously providing the data required for regulatory compliance; this article examines their application.
Introduction
Nasal spray products are increasingly valued for delivering systemic as well as locally-acting therapies, most notably hormone and migraine treatments. The large surface area and rich blood supply of the nasal passages aid the rapid absorption of drug entities, with their close proximity to the central nervous system being of particular benefit. The regulatory guidance for nasal sprays emphasizes the importance of testing the device and the formulation together since it is in combination that they define the unique characteristics of the delivered dose. The success of drug delivery is strongly influenced by the particle size of the delivered droplets, and for suspension formulations the particle size of the suspended active as well.According to the guidance, delivered droplet size 'is an important property influencing the nasal deposition of aerosols and sprays". Very fine droplets, lying in the sub-10 micron range, are likely to be drawn into the lungs while those that are excessively large may remain at the front of the nasal passages rather than depositing at the intended site. The particle size of a suspended active pharmaceutical ingredient (API) potentially influences dissolution rate in vivo, and also availability to sites of action within the nose. The recommendation is that particle size should be measured pre- and post-actuation to ensure that requirements for clinical efficacy are met and that the API particles are unchanged by the delivery process. Laser diffraction is the recommended technique for measuring droplet size, while imaging or microscopy methods are the usual choice for analyzing suspended API, a task that can be complicated by the presence of visually similar excipient particles. This paper reviews the use of laser diffraction (Spraytec, Malvern Instruments) and automated imaging coupled with spectroscopic identification (Morphologi G3-ID, Malvern Instruments) in the development of nasal spray products, showing how the two techniques combine to provide the understanding and regulatory data required to develop and optimize nasal spray products in a cost and time-efficient way.
Developing nasal sprays
Conventional nasal sprays usually consist of an API which is dissolved or suspended in an aqueous medium. They are self-administered by the patient via the nasal cavity. Effective drug delivery depends on a number of factors: patient technique and physiology; the properties of the formulation; and the characteristics of the spray pump. Nasal spray development focuses on optimizing the device and formulation to deliver robust performance for the target user group, which may be very broad. In terms of droplet size the target range tends to be 20-120μm. Droplets in this size range usually deposit beyond the nasal valve, in the posterior two thirds of the nasal cavity, thereby maximizing therapeutic effect. Particles smaller than 10 microns are prone to inhalation into the lungs, so their generation or presence necessitates an assessment of the clinical risks associated with pulmonary delivery of the API concerned. Conversely, overly large droplets tend to remain in the front of the nose and fail to deliver API to the intended site. In a nasal spray product, a metered spray pump atomizes and delivers the drug dose and its performance depends on the physical properties of the formulation. The nasal spray developer's task is to understand and control device-formulation interactions and manipulate the parameters that dictate performance with the goal of better clinical efficacy. In terms of the device, key variables include: the action of the pump and pre-compression ratio; and the length, geometry and orifice size of the actuator. Together these determine the shear force applied to the formulation during use. The response of the formulation to this applied shear is a function of its physical properties. Viscosity is a particularly important parameter and is routinely manipulated through the inclusion of modifiers and additives. By tuning some or all of these variables, product developers can tailor nasal spray devices to deliver the required droplet size under conditions that apply during patient use. Reliable and timely droplet size measurement supports this optimization process. Developing suspension-based products is complicated by the fact that the size of both the API and the droplets in the delivered dose are important. Formulating a stable suspension with particles of a size that will ensure the required dissolution rate and bioavailability in vivo is one part of the development challenge. The other is to make sure that particle size is unaffected by the delivery process, a check that relies on measuring the particle size of the active, before and after delivery.Introducing laser diffraction
Laser diffraction is a non-destructive particle sizing technique, able to measure across a wide dynamic range (0.1 - 3000 microns), in real time. Suitable for characterizing both wet and dry spray samples, and with minimal calibration requirements, it is applicable in the study of both dispersed particle size and spray formation and dynamics. In the development and manufacture of nasal sprays, laser diffraction is used to ensure:- Efficacy: to target a droplet size range that will maximize clinical efficacy.
- Quality: to verify the consistency of performance: over the lifetime of the product; from batch-to batch; or after storage
- Safety: to detect and quantify the presence of a sub-10 micron fraction.
Malvern provides the materials and biophysical characterization technology and expertise that enables scientists and engineers to investigate, understand and control the properties of dispersed systems. These systems range from proteins and polymers in solution, particle and nanoparticle suspensions and emulsions, through to sprays and aerosols, industrial bulk powders and high concentration slurries. Used at all stages of research, development and manufacturing, Malvern’s instruments provide critical information that helps accelerate research and product development, enhance and maintain product quality and optimize process efficiency. Our products reflect Malvern’s drive to exploit the latest technological innovations. They are used by both industry and academia, in sectors ranging from pharmaceuticals and biopharmaceuticals to bulk chemicals, cement, plastics and polymers, energy and the environment. Malvern systems are used to measure particle size, particle shape, zeta potential, protein charge, molecular weight, mass, size and conformation, rheological properties and for chemical identification, advancing the understanding of dispersed systems across many different industries and applications. www.malvern.com Material relationships http://www.malvern.com/en/ [email protected]
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