Development of an Aerosolized Surfactant for RDS: Technical Challenges and Developmental Aspects

Abstract

The aerosolized application of surfactants has been explored in neonatal indications, such as respiratory distress syndrome (RDS) and adult indications, such as asthma, cystic fibrosis, and chronic obstructive pulmonary disease (COPD). However, the practical application has been limited by many technical difficulties related to aerosol creation (foaming, low output rate) or inactivation of surfactant. To date, no aerosolized surfactant has been carried through preclinical and clinical development. Using the example of developing lucinactant (“KL4-surfactant“) for inhalation (Aerosurf™) for RDS, the developmental steps for aerosolized lucinactant via the capillary aerosol generator (CAG) will be described. The key features of developing a clinically viable way of aerosolizing a surfactant are related to three areas: 1. Surfactant Composition and Formulation: The optimal surfactant for aerosolization should contain both phospholipids and relevant surfactant proteins or peptides for full function, The surfactant, especially for chronic aerosol indications, should be non-immunogenic, and free of animal-derived proteins, and be preferably synthetic, The formulation needs to be stable, and easily prepared for aerosolization. 2. Device characteristics and performance: No foaming or clogging during aerosolization should occur, The aerosol particles produced need to be of appropriate size for the targeted deposition in the lung, The device should have an appropriate and sustainable output rate to assure reasonable delivery time, For chronic indications, the output rate of the aerosol needs to remain consistent over repeated uses, The surfactant, post aerosolization, needs to maintain its chemical composition, as well as its bioactivity. 3. Clinical application: The target lung dose varies widely by indication (e.g. neonatal indications such as RDS may require substantial lung doses), The clinical indication dictates the most appropriate delivery device (e.g. neonatal indications such as RDS require administration via nCPAP [nasal continuous positive airway pressure] or pulmonary ventilation), Neonatal applications require a limited number of doses, whereas ambulatory indications require chronic, daily aerosol applications. Specific Example: Objective: To determine the physical and physiologic activity of lucinactant after aerosolization using a novel capillary aerosol generator (CAG), and compare its output rate to commercially available nebulizers. Methods: Lucinactant (30mg/mL total phospholipid (TPL), 0.8mg/mL KL4 peptide) was aerosolized using the CAG. Surface activity of lucinactant was measured in vitro with a pulsating bubble surfactometer (PBS), comparing non-aerosolized lucinactant and lucinactant collected after aerosolization. In vivo physiologic activity was assessed in a 27 day gestation rabbit model. In this model, 8 mL/kg of non-aerosolized lucinactant and lucinactant collected after aerosolization were administered to fetal rabbits (n=6 animals per test group) through a cannulated trachea, followed by 30 minutes of mechanical ventilation. Respiratory system compliance was measured by whole body plethysmography. In addition, output rates of commercially available aerosol generators (Aeroneb Pro®, AirSep Mystique®, Trudell AeroEclipse®, PARI LC Star®) were compared with the Chrysalis Capillary Aerosol Generator (CAG), an investigational device. Results: Mean minimum surface tension for both aerosolized and non-aerosolized lucinactant was similar (<5 mN/m at dilutions of 1.25mg/mL, and <10 mN/m at 0.625mg/mL dilution), indicating that both aerosolized and non-aerosolized surfactant had high inherent surface activities. Similarly, improvements in lung compliance in the rabbit bioassay showed that both aerosolized and non-aerosolized lucinactant were active.1 Aerosol generation rates (Table 1) of 30mg/mL lucinactant when using commercially available devices were all below 4µL/s, which contrasted with rates >25µL/s for the CAG. Conclusions: Development of an aerosolized surfactant requires consideration of various technical and clinical parameters. While using a novel device and surfactant technology, historic roadblocks for aerosol development can be addressed and overcome. Specifically, lucinactant retains activity and chemical integrity after aerosolization by CAG as measured both by PBS in vitro and the fetal rabbit bioassay in vivo. The CAG device generated a nearly 10-fold higher aerosol output rate of lucinactant compared with currently commercially available devices. The output rate of the CAG may be ideal for effectively aerosolizing surfactant as replacement therapy for prevention and treatment of RDS in preterm infants.