Novel surface engineering of carrier particles for dry powder inhalation formulations

Dry powder inhalation formulations typically involve the co-processing of an active pharmaceutical ingredient and a relatively coarse excipient, commonly known as carrier particles, to ensure accurate dose metering, increased device clearance and the dispersion of the respirable particulates upon device actuation. It is well recognised that there is a critical relationship between the surface characteristics of the carrier particles and the overall delivery performance of a DPI formulation. Such variations in the physicochemical properties of the carrier particles have a direct influence on the de-aggregation behaviour of respirable drug particles, and typically lead to considerable batch-to-batch variations. These uncontrolled modifications threaten the overall efficiency and reproducibility of the inhalation therapy. The uncontrollable nature of the surface properties of commercial grade a-lactose monohydrate is a consequence of the rigorous industrial processing techniques utilised in the preparation of the excipient particles. To overcome these issues, a novel temperature controlled surface etching process has been developed in this study to controllably modify the physicochemical properties of commercial lactose particles. In vitro aerosolisation behaviour of surface etched lactose was investigated using salbutamol sulphate as a model drug. Significant difference (p<0.05) in the fine particle delivery of the drug was measured upon decreasing the surface roughness of lactose carrier particles. The study further highlighted that the aerosolisation efficiency was highly dependent on the degree of surface etching suggesting the importance and the need to control and optimise the degree of surface roughness of carrier particles for DPI formulations. Further work focussed on studying the potential of the surface etched lactose, produced by the temperature controlled surface etching process, as a carrier of choice for inhalation systems aimed for low dose drug delivery. The study indicated that the surface smoothing of lactose particles resulted in a significant increase in the aerosolisation performance at lower drug concentrations (minimum FPF at drug load of 63.5 pg for surface etched lactose compared to a drug load of 135 pg for commercial grade lactose), as a consequence of considerably reducing the presence of the so-called ‘active sites’. Of equal importance to modifying the surface properties of excipient particles for improved aerosolisation performance, is the physicochemical stability of the formulation upon storage at elevated temperature and relative humidity conditions. In vitro aerosolisation behaviour of the controlled surface etched lactose and commercial grade lactose formulations was investigated as a function of storage for one and three months at 25°C, 75% RH and one month at 40°C, 75%RH. No significant difference in the delivery performance was observed for the surface etched lactose formulation before and after storage. Accelerated stability testing and in vitro investigations of commercial and secondary processed lactose indicated that controlled surface etched lactose maintained drug deposition efficiency with respect to commercial, untreated lactose based formulations at elevated conditions of humidity and temperature. This study emphasised on the importance of utilising a secondary post­ treatment procedure to the bulk crystallisation process of excipient particles for DPI formulations. Improved inter and intra physicochemical characteristics of excipient particles may significantly enhance the uniformity and reproducibility of in vitro and in vivo performance of an active pharmaceutical ingredient.