The nasal mucosa provides an easily targeted site for drug delivery. Nasal administration has been widely used for the treatment of local effects, for instance for the delivery of decongestants and anti-inflammatory steroids. However, the nasal passages are also a potential site for systemic drug delivery owing their high surface area, high permeability and the possibility of rapid plasma absorption and transfer of drugs into the central nervous system. Formulating for nasal absorption is also relatively easy, especially for “fragile” macromolecules due to avoidance of first pass metabolism and the gastro-internal (GI) tract. This has led to the development of delivery systems for vaccines and hormone treatments.
Importance Of Particle Size
The particle size delivered by nasal drug delivery devices is an important parameter in defining the drug deposition site within the nasal passages. Research has shown that a particle size of greater than 10 to 20 microns is required in order to minimise deposition in the lung and the GI tract. As the particle size decreases between 20 microns and 5 microns increased lung deposition and reduced intranasal deposition.
Laser Diffraction Particle Sizing
The importance of controlling the particle size has led the FDA to recommend that laser diffraction particle sizing be carried out for all NDAs and ANDAs for nasal drug delivery systems.
Spraytec System For Characterisation of Nasal Spray Aerosols
The Spraytec system allows for the complete characterisation of the aerosol produced by nasal spray devices, as specified in the FDA draft guidance document. In this document the FDA proposes that not only should the reproducibility of the droplet size produced by nasal spray devices be determined but also the dynamics of spray production.
Phases Of Spray Development
Data acquisition rates of up to 2500Hz (one measurement every 0.4ms) are possible using the Spraytec, allowing the different phases of spray development to be assessed during the actuation of a device (formation, stable and dissipation phases). This allows for a better understanding of the bioavailability of the drug delivered by a given device and also aids in bioequivalence studies. The Spraytec system is equipped with the Malvern Nasal Spray Actuator (Figure 1), allowing the force and speed of actuation to be controlled, thus eliminating operator bias.
Figure 1. Malvern Nasal Spray Actuator mounted on the Spraytec optical bench.
Nasal Spray Dynamics
A typical time history for the actuation of a nasal spray system as measured using the Spraytec is shown in Figure 2.
Figure 2. Chart showing the variation in the D10 (blue), D50 (red) and D90 (green) measured during the actuation of a nasal spray. The transmission (purple) relates to the concentration of particles in the measurement zone.
Particle Size And The Three Phases Of Aerosol Production
The time history output allows the three phases of aerosol production to be identified. During the formation phase (0-7msec) the device delivers a relatively large particle size, as the full atomisation pressure has not been achieved. The stable phase (7 90msec) follows this, during which a relatively constant particle size is delivered by the device. The concentration of material is also high. Finally, the particle size starts to decrease during the dissipation phase (90-125msec) as the atomisation pressure and feed-rate through the atomising device starts to tail of at the end of the actuation stroke.
Particle Size Distribution Comparisons
The Spraytec software allows the average particle size distribution during each phase of aerosol production to be easily calculated by selecting different regions of the time history. The result for the profile above is shown in Figure 3. The particle size distribution statistics are shown in table 1.
Figure 3. Average particle size distributions calculated for the Formation, Stable and Dissipation phases of the nasal spray plume.
Table 1. Particle size distribution statistics obtained for each phase of the nasal spray development.
Stable Phase Particle Size Importance
As can be seen, the particle size delivered during the stable phase is significantly smaller than for the formation and dissipation phases. It is the particle size within the stable phase that is most important in defining the bioavailability for the delivered drug. The goal of device development is to maximise the dose delivered within this zone, as well as controlling the overall particle size. In this case around 40% of the volume of the measured spray was delivered during the stable phase.
Particle Size Dependence upon Applied Force
The use of the Malvern Nasal Spray Actuator allows the effect of changes in the applied force to be easily investigated. Figure 4 shows the change in particle size delivered by a nasal spray pump at between 3kg and 8kg actuation force.
In this case a sharp decrease in the measured particle size is initially observed as the actuation force is increased. However, beyond 5kg the delivered particle size is virtually independent of the actuation force, ensuring accurate dose delivery. The large particle size delivered at low actuation forces has implications for the use of this device with certain patient groups. These studies can aid in the development of devices which deliver the desired particle size over a wide range of actuation pressures.
Figure 4. Chart showing the actuation force dependence of the D10 (red), D50 (blue) and D90 (green) measured during the actuation of a nasal spray.
The Malvern Spraytec provides a valuable technique for the characterisation of nasal pump spray devices following the FDA's guidance document. The rapid measurements possible using the Spraytec system aid in the understanding of the dynamics of spray production. The use of the Malvern Nasal Spray Actuator can help in the elimination of operator bias during bioequivalence studies. Monitoring the effect changes in the force applied during actuation of a given device can also aid in the development of new efficient devices and formulations.