Cascade-impaction studies have repeatedly demonstrated the aerodynamic performance of the NanoCluster technology using various
formulations and active pharmaceutical ingredients, including steroids, beta-agonists, antihypertension drugs, antibiotics,
and compounds to treat autoimmune diseases (17–21). Figure 2 shows the aerodynamic particle-size distribution results from
cascade-impaction tests with a budesonide NanoCluster inhalation powder at different respiratory flow rates. These results
demonstrate that the budesonide NanoCluster inhalation powder's aerodynamic performance and deposition is only minimally affected
by airflow rate, an important characteristic for pharmaceuticals delivered with passive DPIs. Passive devices rely upon the
patient's inhalation rate, which naturally varies from person to person. Consistent aerosol performance independent of inhalation
rate is therefore highly desired, particularly for lung-compromised, elderly, and pediatric patients.
Figure 2: The influence of respiratory flow rate on the Aerodynamic particle-size distribution of the budesonide NanoCluster
(Savara Pharmaceuticals, Austin, TX) inhalation powder. The authors used an Andersen cascade impactor at 25 °C and 45% relative
High-performance particle-engineering technologies will not be actualized if they cannot be scaled into robust, repeatable,
and cost-effective industrial processes. NanoCluster technology can be scaled up for industrial-quantity production. Unlike
other particle technologies that require complex, expensive processing equipment to conduct a multistep manufacturing process,
NanoCluster powders typically are produced through simplified manufacturing steps (see Figure 3). Active pharmaceutical ingredient
powders are reduced to nanosized particles by well-established and accepted processes such as precipitation or mechanical
methods such as media milling. In the postprocessing agglomeration approach shown in Figure 3, the nanoparticles are discharged
into a tank to form a quasi-stable colloid before agglomeration. Agglomeration can be accomplished through several methods,
including the metered addition of a small amount of an excipient or the simple adjustment of processing parameters. NanoCluster
formulations sometimes require little (<5%) or no excipient to achieve the desired product characteristics.
Figure 3: Flow chart of the NanoCluster (Savara Pharmaceuticals, Austin, TX) manufacturing process.
In-processing agglomeration is another approach for controlling agglomeration during the production of NanoCluster particles.
With this approach, the nanoparticle creation and agglomeration occur simultaneously, obviating the need to form a nanoparticle
suspension. As soon as a small nanoparticle is broken off of a larger particle through attrition, the nanoparticle adheres
to another nanoparticle. A significant benefit of this process is that it removes the need for excipients in the final formulation.
After nanoparticles agglomerate into micrometer-sized NanoClusters, operators remove the water used during the process through
lyophilization or spray drying to yield low-density, high-performance powders. Further development work is currently underway
to determine the technological and financial advantages of each drying method when forming NanoClusters with various active
ingredients. Despite their small aerodynamic size, the NanoCluster formulations' physical characteristics make them suitable
for downstream handling. Experience to date suggests that relatively few processing steps will be required to manufacture
product at commercial scale. Standard powder-handling and -filling techniques suffice for packaging NanoCluster formulations
into reservoir-type inhaler devices, capsules, or unit-dose blisters.