Efficient interfacially driven vehiculization of corticosteroids by pulmonary surfactant

Abstract

Pulmonary surfactant is a crucial system to stabilize the respiratory air-liquid interface. Furthermore, pulmonary surfactant has been proposed as an effective method for targeting drugs to the lungs. However, few studies have examined in detail the mechanisms of incorporation of drugs into surfactant, the impact of the presence of drugs on pulmonary surfactant performance at the interface under physiologically meaningful conditions, or the ability of pulmonary surfactant to use the air-liquid interface to vehiculise drugs to long distances. This study focuses on the ability of pulmonary surfactant to interfacially vehiculize corticosteroids such as beclomethasone dipropionate (BDP) or Budesonide (BUD) as model drugs. The main objectives have been to (a) characterize the incorporation of corticosteroids into natural and synthetic surfactants, (b) evaluate whether the presence of corticosteroids affects surfactant functionality, and (c) determine whether surfactant preparations enable the efficient spreading and distribution of BDP and BUD along the air-liquid interface. We have compared the performance of a purified surfactant from porcine lungs and two clinical surfactants: Poractant alfa, a natural surfactant of animal origin extensively used to treat premature babies, and CHF5633, a new synthetic surfactant preparation currently under clinical trials. Both, natural and clinical surfactants spontaneously incorporated corticosteroids up to at least 10% by mass with respect to phospholipid content. The presence of the drugs did not interfere with their ability to efficiently adsorb into air-liquid interfaces and form surface active films able to reach and sustain very low surface tensions (<2 mN/m) under compression-expansion cycling mimicking breathing dynamics. Furthermore, the combination of clinical surfactant with corticosteroids efficiently promoted the active diffusion of the drug to long distances along the air-liquid interface. This effect could not be mimicked by vehiculisation of corticosteroids in liposomes or in micellar emulsions similar to the formulations currently in use to deliver anti-inflammatory corticosteroids through inhalation.