Extended Pharmacopeial Characterization of Surfactant Aerosols Generated by a Customized eFlow Neos Nebulizer Delivered through Neonatal Nasal Prongs

Abstract

The delivery of nebulized medications to preterm infants during Non-Invasive Ventilation (NIV) remains an unmet clinical need. In this regard, the effective delivery of nebulized surfactant has been particularly investigated in preclinical and clinical studies. In this work, we investigated the feasibility of delivering nebulized surfactant through various commercially available nasal prong types. We first performed a compendial characterization of surfactant aerosols generated by the eFlow Neos nebulizer, customized to be used in neonates, determining the amount of surfactant delivered by the device as well as the aerodynamic characteristics of surfactant aerosols. Additionally, we extended the compendial characterization by testing the effect of different nasal prong types on the estimated lung dose using a realistic Continuous Positive Airway Pressure (CPAP) circuit that included a cast of the upper airways of a preterm neonate. The compendial characterization of surfactant aerosols delivered through different nasal prongs achieved relatively high delivered surfactant doses (in the range 63–74% of the nominal dose), with aerodynamic characteristics displaying mass median aerodynamic diameters ranging between 2.52 and 2.81 µm. Nevertheless, when using a representative in vitro setup mimicking NIV in a clinical setting, significant differences were observed in terms of the estimated lung dose accounting for up to two-fold differences (from 10% to 20% estimated lung deposition of the nominal dose) depending on the chosen nasal prong type. Considering that surfactant lung deposition rates are correlated with therapeutic efficacy, this study points out the relevance of choosing the appropriate NIV interface to maximize the lung dose of nebulized medications.

A Compartment-Based Mathematical Model for Studying Convective Aerosol Transport in Newborns Receiving Nebulized Drugs during Noninvasive Respiratory Support

“…For the baseline scenario, the volume of the nebulizer was set equal to 10 mL (eFlow Neos, PARI Pharma, Starnberg, Germany); the volume of patient upper airways compartment was 1 mL, as extrapolated from anatomical models reported in literature [ 31 ]; and aerosol production estimates to 0.3 mL/min as extrapolated from literature [ 32 ].…”

Aerosol drug delivery to spontaneously-breathing preterm neonates: lessons learned

“…The relevance of incorporating a cast of the upper airway in the circuit was highlighted recently by Bianco et al [182]. In this study, the authors assembled two different NIV ventilation circuits to determine the delivered dose of nebulized surfactant.…”

“…The aerosol output rate is usually determined by collecting the aerosol emitted by the aerosol generator in specific drug-collection filters placed directly after the nebulizer [105,111]. The particle size distribution can be determined using different techniques and devices such as the Next Generation Impactor (NGI) [181,182], Andersen Cascade Impactor (ACI) [183], Laser Diffraction [184], or Time of Flight (TOF) [177] technologies. The theoretical principles of these methods were reviewed by Mitchell and Nagel [185].…”

“…The set-up is composed of a neonatal ventilator to provide NIV support followed by a temperature and humidity control unit, a nebulizer placed immediately after the Y-piece, a patient interface (nasal prongs), a cast of the upper airways of a premature neonate (PrINT model), a backup trap to collect the aerosol that impacts in the cast and moves forward as a liquid, drug collecting filters to determine the lung dose and the amount of aerosol reaching the expiratory limb, and a breath simulator programmed with a sinusoidal breathing pattern of a premature neonate. adapted from [182,184] to circumvent these limitations. Figure 8 shows a representative scheme of an in vitro neonatal NIV circuit designed for aerosol deposition studies [184].…”

“…Therefore, advanced neonatal NIV circuits provide a controlled framework to carry out more insightful aerosol deposition studies. These types of neonatal in vitro models have been used to investigate the aerosol delivery efficiency using different NIV types [109], to compare the performance of jet and vibrating-membrane nebulizers [76,94,121], the effect of the bias flow on aerosol deposition [94,187], the influence of nebulizers positioning in different locations of the circuit [94,184], the feasibility of using different NIV interfaces [182], and to estimate the lung dose in dose-escalating studies [184]. Nevertheless, the "model" concept implies a simplification of reality and thus gives rise to a number of limitations.…”