Inhalable microparticle platform based on a novel shell-forming lipid excipient and its feasibility for respirable delivery of biologics.

Administration of biologics such as proteins, vaccines, and phages via the respiratory route is becoming increasingly popular. Inhalable powder formulations for the successful delivery of biologics must first ensure both powder dispersibility and physicochemical stability. A lipid-based inhalable microparticle platform combining the stability advantages offered by dry powder formulations and high dispersibility afforded by a rugose morphology was spray dried and tested. A new simplified spray drying method requiring no organic solvents or complicated feedstock preparation processes was introduced for the manufacture of the microparticles. Trehalose was selected to form the amorphous particle core, because of its well-known ability to stabilize biologics, and also because of its ability to serve as a surrogate for small molecule actives. Phospholipid distearoyl phosphatidylcholine (DSPC), the lipid component in this formulation, was used as a shell former to improve powder dispersibility. Effectiveness of the lipid excipient in modifying trehalose particle morphology and enhancing powder dispersibility was evaluated at different lipid mass fractions (5%, 10%, 25%, 50%) and compared with that of several previously published shell-forming excipients at their effective mass fractions, i.e., 5% trileucine, 20% leucine, and 40% pullulan. A strong dependence of particle morphology on the lipid mass fraction was observed. Particles transitioned from typical smooth spherical trehalose particles without lipid to highly rugose microparticles at higher lipid mass fractions (>5%). In vitro aerosol performance testing demonstrated a significant improvement of powder dispersibility even at lipid mass fractions as low as 5%. Powder formulations with excellent aerosol performance comparable to those modified with leucine and trileucine were achieved at higher lipid mass fractions (>25%). A model biologic-containing formulation with 35% myoglobin, 35% glass stabilizer (trehalose), and 30% lipid shell former was shown to produce highly rugose particle structure as designed and excellent aerosol performance for efficient pulmonary delivery. A short-term stability at 40 °C proved that this protein-containing formulation had good thermal stability as designed. The results demonstrated great potential for the new lipid microparticle as a platform for the delivery of both small-molecule APIs and large-molecule biologics to the lung.