Innovative approaches for inhaled aerosol therapies

The important role of inhaled aerosol therapies in medicine has been acknowledged for several decades. Besides the traditional applications for local treatment of obstructive pulmonary diseases, the use of inhaled aerosols for treating lung infections and for vaccination has been gaining increasing interest. Furthermore, systemic administration of active pharmaceutical ingredients by inhalation is getting more and more important. Compared with other routes of administration (intake of tablets), however, drug dosing is challenging for the inhaled aerosol route, as it depends on aerosol and breathing parameters and the patient’s current health status.

Because of the important role of aerosol therapies, a broad range of stationary and mobile devices for inhaled administration of pharmaceutical agents via the solid or liquid phase are already available, however, substantial gaps still remain as well. The amount of active pharmaceutical ingredient that can be administered by inhalation within an acceptable time span is limited, in particular if the drug product is a dry powder; for portable inhalers it is < 50 mg per single dose. Due to their insolubility in water, numerous pharmaceuticals are, as yet, not available for continuous inhalation treatment and for high dosage. Furthermore, the use of powder inhalers is not yet state of the art in patients receiving ventilation support, neither in adults nor in children or infants. This means that whole groups of patients are excluded from treatment with certain drugs, or else administration of the drug is associated with considerable risks. The aim of the research activities at Fraunhofer ITEM is to close the existing gaps and minimize risks.

A technology allowing administration of high doses of dry-powder medication, as needed, for example, for inhalation treatment of lung infections or surfactant deficiency, will substantially enhance the application spectrum of surfactant formulations and other non-soluble drug substances or even enable their administration. This holds true for both mechanically ventilated and spontaneously breathing patients.

There is, in fact, a substantial medical need for inhaled administration of aerosolized drugs in children, infants, and preterm neonates. Another need that has not yet been sufficiently met is local antibiotic treatment of lung infections, in particular in patients receiving ventilation support. In order to close this gap, Fraunhofer ITEM scientists are working to develop dry-powder administration systems for adults and preterm neonates, including appropriate test methods for such devices. This work is based on more than 30 years of experience in the areas of aerosol technology and aerosol administration to humans. The measurement methods we use include both traditional aerosol measurement technology and special measurement methods for inhaler characterization. Methods of fluid dynamics and thermodynamics complement our instrumentarium.

The CPA (continuous powder inhaler) technology that is being developed at Fraunhofer ITEM is based on the idea of combining the benefits of two technologies – nebulizers and dry-powder inhalers (DPI) –, thereby enabling previously impossible treatments and at the same time avoiding the drawbacks of the currently available treatment options. The CPA [1] enables continuous dry-powder inhalation for the first time ever. Furthermore, it provides patients with the highest drug concentration that is physically possible. This allows treatment periods to be reduced to a minimum. The novel technology enables simple adjustment of the dose and dose rate to a patient’s specific requirements, without compromising particle quality or quantity. In principle, the system can thus be used for adults, children, and babies as well. A first clinical prototype is available for use in clinical trials with adults.

Administration of dry aerosols over a prolonged period of time and with high dose rates can lead, among other unwanted effects, to dehydration of the mucous membranes, so that this is not an eligible option. The gas used for ventilation of patients is normally humidified. The available humidification technology, however, is not designed for adequate humidification of dry-powder aerosols. Aerosol flow through this type of humidifiers causes unwanted deposition and may result in dangerous clogging. Feeding dry-powder aerosols into the system downstream of the ventilation gas humidifiers is equally prone to formation of agglomerates and clogging of tubes. This is where the humidifying technology [2] co-developed by Fraunhofer ITEM comes in: it takes into account the special behavior of aerosols and is suitable for use both with aerosols and within a ventilation cycle.

Aerosols have become firmly established as an effective form of drug administration to the lungs and the development of new, innovative products for aerosol generation is steadily progressing. Before a medical device can be approved for commercialization or clinical application, it has to undergo comprehensive testing to ensure functionality and safety of its use. As a natural consequence of an increasingly broad spectrum of application areas, testing of medical devices is also getting more and more sophisticated. Treatment of intubated and ventilated neonates, for example, continues to be a particular challenge.

Characterization of aerosol generator performance places the main focus on the emitted dose, particle size distribution, and concentration of the generated aerosol. Measurement of these parameters has to comply with the relevant standards (e.g. DIN EN 13544-1, ISO/FDIS 27427).

For performance testing of inhalers for use in ventilated infants and neonates, however, no appropriate test methods have been described [3], and consequently no suitable test systems are commercially available, because the available devices have not been engineered for their specific requirements regarding ventilation support and breathing depth. In this special case, a suitable test system had to take into account in particular the breathing physiology of preterm neonates as well as integration of both the aerosol generator to be tested and the measurement device into the ventilation cycle. In addition, for physical characterization of the aerosol at the patient interface (tube, prong) the test bench had to be suitable for the inherent minimal volume flow rates. Fraunhofer ITEM has developed and validated a test bench tailored to these special requirements. The system enables simulation of the physiological respiratory parameters of preterm neonates and other parameters affecting aerosol generation, such as temperature and humidity, and thus allows the applied doses to be evaluated also for use in infants and preterm neonates.