A novel continuous powder aerosolizer (CPA) for inhalative administration of highly concentrated recombinant surfactant protein-C (rSP-C) surfactant to preterm neonates.

BACKGROUND: In pulmonary medicine, aerosolization of substances for continuous inhalation is confined to different classes of nebulizers with their inherent limitations. Among the unmet medical needs is the lack of an aerosolized surfactant preparation for inhalation by preterm neonates, to avoid the risks associated with endotracheal intubation and surfactant bolus instillation. In the present report, we describe a high-concentration continuous powder aerosolization system developed for delivery of inhalable surfactant to preterm neonates. METHODS: The developed device uses a technique that allows efficient aerosolization of dry surfactant powder, generating a surfactant aerosol of high concentration. In a subsequent humidification step, the heated aerosol particles are covered with a surface layer of water. The wet surfactant aerosol is then delivered to the patient interface (e.g., nasal prongs) through a tube. RESULTS: The performance characteristics of the system are given as mass concentration, dose rate, and size distribution of the generated aerosol. Continuous aerosol flows of about 0.84 L/min can be generated from dry recombinant surfactant protein-C surfactant, with concentrations of up to 12 g/m(3) and median particle sizes of the humidified particles in the range of 3 to 3.5 µm at the patient interface. The system has been successfully used in preclinical studies. CONCLUSION: The device with its continuous high-concentration delivery is promising for noninvasive delivery of surfactant aerosol to neonates and has the potential for becoming a versatile disperser platform closing the gap between continuously operating nebulizers and discontinuously operating dry powder inhaler devices.

The non-intubated, spontaneously breathing, continuous positive airway pressure (CPAP) ventilated pre-term lamb: a unique animal model.

Neonatologists prefer non-invasive ventilation methods for pre-term neonates, who often require surfactant treatment. Therefore, a technology for non-invasive surfactant administration would be highly appreciated. We have developed a Continuous Powder Aerosolization (CPA) system for the generation of a humidified recombinant surfactant protein-C (rSP-C) surfactant aerosol for non-invasive administration to pre-term neonates via bi-nasal prongs. Before conducting clinical trials, safety testing in an adequate pre-clinical animal model is necessary. In contrast to existing pre-term lamb models, this model should use non-intubated animals to include upper airways for safety testing. Pre-term animals should have already a sufficient respiratory drive to breathe spontaneously on non-invasive continuous positive airway pressure (CPAP) support, but their lungs should still be pre-mature to be comparable with the clinical situation for the treatment of pre-term infants. The aim of this feasibility study was therefore to establish a CPAP-stable, non-intubated pre-term lamb model for the investigation of safety, efficacy, and pulmonary deposition of a humidified rSP-C surfactant aerosol. For this purpose, 19 pre-term lambs with a gestational age of 135-137 days (term: about 144 days) were delivered via Caesarean section. Four animals died before start of treatment, while the remaining animals were treated via customized bi-nasal prongs with rSP-C surfactant aerosol or humidified air as vehicle control. To determine pulmonary deposition, selected animals received rSP-C surfactant labelled with samarium oxide as non-radioactive tracer. Treatment was started at 30 min of age and was continued for 1 or 2.5 h. Investigations during the in-life phase included observation of clinical signs, haematology, blood gas analysis, and determination of minute volume. At 3 h of age, animals were euthanized and organs removed for histopathology investigation or for determination of pulmonary deposition. Administration of humidified, aerosolized rSP-C surfactant was well tolerated, and histopathology investigation of upper airways and lungs revealed no aerosol-related changes. Mean body weight-corrected pulmonary deposition of rSP-C surfactant ranged from 1.7 to 7.7 mg/kg depending on the duration of treatment and aerosolization parameters used. A trend towards reduced spontaneous minute volumes indicating reduced breathing efforts and towards reduced lung weights indicating less fluid in the lungs of surfactant-treated animals compared to animals of the vehicle control group could be seen. Taken together, a CPAP-stable, non-intubated pre-term lamb model was successfully established and the parameters for the investigation of safety, efficacy, and pulmonary deposition of aerosolized rSP-C surfactant for the subsequent main study were identified.