In vitro aerosol characterization of Staccato(®) Loxapine.

Medicinal aerosol products (metered dose and dry powder inhalers) require characterization testing over a wide range of use and pre-operating stress scenarios in order to ensure robust product performance and support submissions for regulatory approval. Aerosol characterization experiments on Staccato(®) Loxapine for inhalation (Staccato Loxapine) product (emitted dose, particle size, and purity) were assessed at different operating settings (flow rates, ambient temperature and humidity, altitude, and orientation) and at nominal test conditions following exposure to various stresses on the device (mechanical shock, vibration, drop, thermal cycling, and light exposure). Emitted dose values were approximately 90% of the coated dose at every condition, meeting target specifications in each case. Aerosol purity was consistently >99.5% for every test setting, with no reportable impurities according to ICH standards (>0.1%). Particle size averaged 2µm (MMAD) and was independent of the different test conditions with the exception of different airflow rates. Particle size decreased slightly with airflow, which may assist in maintaining constant deep lung deposition. The combination of high emitted dose efficiency and a particle size range ideally suited for lung deposition, along with the consistency of these key aerosol attributes, suggests that the Staccato system has distinct advantages over more traditional aerosol systems.

Assessing the temperature of thermally generated inhalation aerosols.

BACKGROUND: Condensation aerosols are produced when a drug is vaporized and then cools in the inhalation air. Because energy is applied to vaporize the drug, there is a potential concern that the air temperature might not be well tolerated. A literature review indicates that the proper metric for this is the wet-bulb temperature (T(wb)) of the inhaled air. T(wb) measures the total energy of the air, including moisture content, and reflects the potential impact on safety and tolerability. METHODS: The Staccato® system (Alexza Pharmaceuticals, Mountain View, CA) uses thermal vaporization for aerosol generation and was used in a series of studies to characterize the peak transient value (peak T(wb)) of the air coming out of the device. These studies evaluated peak T(wb) over a range of air flow rates (15-45 L/min), ambient conditions [15-30°C and 15 to 90% relative humidity (RH)] and vaporization temperatures. RESULTS: Under nominal conditions (30 L/min air flow, 25°C and 50% RH), peak T(wb) was 28.8 ± 0.6°C (mean ± standard deviation). Over the range of operating conditions tested, mean values for peak T(wb) ranged from 26.2 to 33.3°C with similarly low variances. When operated under a combination of extreme conditions, peak T(wb) was measured to be 39.9 ± 0.1°C (mean ± standard deviation). CONCLUSIONS: Technical standards indicate that the upper limit on inhaled T(wb) for safety and tolerability is 50°C, and inhalation at that temperature can be sustained for 1 h. Peak values of T(wb) from the Staccato system are well below that threshold, approximately 30°C at nominal conditions and approximately 40°C at a combination of extreme conditions. Moreover, the peak lasts for only a few seconds, well under the time limit of 1 h. These results suggest that aerosols generated with the Staccato system will be safe and well tolerated.

In vitro aerosol deposition in the oropharyngeal region for Staccato loxapine.

BACKGROUND: The Staccato system employs a thermal vaporization technology to generate pure drug aerosols with a particle size optimized for alveolar deposition, leading to rapid absorption of the drug into the systemic circulation. Unlike most traditional aerosol-generation techniques, the particle size of the thermally generated aerosols is significantly affected by the airflow rate going through the device. The objective of this study was to determine the effects of flow rate and other operating conditions on predicted oropharyngeal and lung deposition when using the Staccato system. METHODS: In vitro oropharyngeal deposition was measured at airflow rates of 15-80 L/min through the device. Oropharyngeal deposition was also measured for different inhalation profiles, different ambient temperatures and humidities, and device orientations. Deposition was measured using the Alberta geometry model, which was derived based on information available in the literature, CT scans of patients, and observations of living subjects. RESULTS AND CONCLUSIONS: Deposition in the oropharyngeal geometry was consistently approximately 11% of the emitted dose throughout the entire range of flow rates. Such consistency in deposition was due to the fact that mass median aerodynamic diameter (MMAD) varied inversely as the square root of the flow rate, resulting in an approximately constant value for the inertial deposition parameter. Thus, an increase in flow rate, which would increase the momentum of a fixed particle size and generally lead to higher oropharyngeal deposition, was almost exactly counterbalanced by the accompanying decrease in MMAD. Results also showed that deposition in the oropharyngeal region was unaffected by other potentially relevant factors such as different airflow ramp rates, inhalation time, ambient temperature and relative humidity, and device orientations.

The effect of film thickness on thermal aerosol generation.

PURPOSE: Rapid heating of thin films of pharmaceutical compounds can vaporize the molecules, which leads to formation of aerosol particles of optimal size for pulmonary drug delivery. The aim of this work was to assess the effect of coated film thickness on the purity of a thermally generated (condensation) drug aerosol. MATERIALS AND METHODS: Pharmaceuticals in their free base form were spray-coated onto stainless steel foils and subsequently heated and vaporized in airflow via a rapid resistive heating of the foil. Aerosol particles were collected on filters, extracted, and analyzed using reverse phase HPLC to assess the amount of degradation induced during the vaporization process. RESULTS: Condensation aerosols of five pharmaceuticals were formed from a wide range of film coating thicknesses. All five showed a roughly linear trend of increasing aerosol purity with decreasing film thickness, although with quite different slopes. These findings are consistent with a model based on general vaporization and degradation kinetics. Small non-uniformities in the film do not significantly alter aerosol purity. CONCLUSIONS: Rapid vaporization of pharmaceuticals coated as thin films on substrates is an efficient way of generating drug aerosols. By controlling the film thickness, the amount of aerosol decomposition can be minimized to produce high purity aerosols.