Preparation and Aerosolization Studies of Fine Powders Composed of Poorly Soluble Drugs for Pulmonary Drug Delivery

摘要

Drug delivery via the pulmonary route has increasingly received much attention in recent years. Inhalable particles that are capable of reaching the deep lungs for the intended application can be achieved by particle engineering methods and use of appropriate inhalation device. This study seeks to develop a carrier-free formulation for poorly water soluble drugs with desirable aerosol properties for pulmonary therapy. The Active Pharmaceutical Ingredients (APIs) used in this work, Pirfenidone and Budesonide are treatment drugs for some pulmonary diseases hence their delivery via the pulmonary route will be better suited for fast local action. Carrier-free drug powders were formulated using particle engineering methods to achieve the desirable aerosol properties for inhalation therapy. The aerosol flow reactor method was utilized in this study and the leucine coating on the powder particles were formed by physical vapour deposition of leucine. Prior to the aerosol flow reactor step, precursor solutions were prepared with varying concentrations of leucine and also an exogenous surfactant, Dipalmitoylphosphatidylcholine (DPPC). The precursor solutions were prepared by wet milling of leucine and DPPC in ethanol. The drug was then added to the milled suspension to get the precursor solution ready for the aerosol process. In the aerosol flow reactor, the leucine formed nanocrystals which were deposited onto the dried drug particles by physical vapour deposition (PVD). Two poorly-water soluble drugs were formulated using varying leucine concentrations and the resulting powders were investigated with different inhalers for their aerosolization behaviours. The morphologies of the coated fine powders were also studied by scanning electron microscopy. Pirfenidone powders showed agglomerated particles with the degree of agglomeration increasing with decreasing leucine concentration. This made the powders less flowable and dispersible, but the deagglomeration principle of the inhalation device improved the aerosolization properties. The powder with less leucine content had agglomerates which were rather difficult to separate even with the inhalation device’s deagglomeration principle. The particle size distribution was much higher and most likely to be too large for inhalation. The Budesonide particles, having sustained the heat in the aerosol flow reactor showed much spherical particles with minimal surface contact. The powders showed good aerosolization properties for deep lung deposition. The particle size distributions of all Budesonide powders with leucine coating were also well within the appropriate inhalable range.