Excipient-free lyophilization of block copolymer micelles for potential lung surfactant therapy applications

Abstract

Polymer lung surfactant (PLS) is a polyethylene glycol (PEG)-brushed block copolymer micelle designed for pulmonary surfactant replacement therapy. Saccharides (e.g., sucrose and (2-hydroxypropyl)-β-cyclodextrin) and water-soluble polymers (e.g., PEG), common excipients for lyophilization, were found to severely impair the surface activity of lyophilized PLS. To investigate the feasibility of excipient-free lyophilization of PLS, we studied the effects of both PLS material parameters and lyophilization operating parameters on the redispersibility and surface availability of reconstituted PLS, all without relying on excipients. We found that the redispersibility was improved by three factors; a faster cooling rate during the freezing stage reduced freezing stress; a higher PEG grafting density enhanced dissipating effects; and the absence of hydrophobic endgroups in the PEG block further prevented micelle aggregation. Consequently, the surface availability of PLS increased, enabling the micelle monolayer at the air/water interface to achieve a surface tension below 10 mN/m, which is a key pharmaceutical function of PLS. Moreover, the lyophilized micelles in powder form could be easily dispersed on water surfaces without the need for reconstitution, which opens up the possibility of inhalation delivery, a more patient-friendly administration method compared to instillation. The successful excipient-free lyophilization unlocks the potential of PLS for addressing acute respiratory distress syndrome (ARDS) and other pulmonary dysfunctions.