Influence of engineered particulate lactose on the performance of DPI formulations
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Development of dry powder inhaler (DPI) formulations for respiratory diseases, such as Tuberculosis (TB), is challenging. The major limitation of current marketed DPIs is low delivery efficiency. In addition, delivered dose variation is also a challenging problem in the development and design of DPI formulations due to the poor flowability and dispersibility of the powder formulation. Furthermore, antibiotic drugs used in TB or other respiratory infectious diseases have to be administered in a relatively large dose for pulmonary delivery. However, currently there is no high dose conventional lactose based DPI formulations available. Therefore, I propose an innovative approach to solve these problems through the engineering of particulate lactose by wet granulation. Lactose is the commonly used carrier particle for DPI formulations. Although it was widely believed that carrier particles with smaller diameters were preferable to maximize aerosolization efficiency (the ability of the drugs to be delivered to the lung), it was found recently that lactose carriers with large size also can improve aerosol performance, especially when combined with greater surface roughness and an appropriately designed inhaler device. In the first study, after the engineered particulate lactose was manufactured, the relationship between the physico-chemical properties, e.g. size, of the granulated lactose and the DPI aerosol performance was investigated. It was concluded that poorer or enhanced dispersion performance is not an inherent property to the significantly large size of granulated lactose carriers as previously contended. Relatively large granulated lactose has improved flowability and increased surface roughness with increasing size fraction, which were properties for formulating high drug loaded DPI formulations. It was found that the aerosol performance of the high drug loaded DPI formulation depended significantly on the specific APIs and also the inhalation flow rate used in the cascade impactor study. DPI aerosol performance is the interplay of formulation, patient inhalation effort and device design. The device design was therefore modified and optimized to further improve the aerosol performance. In the end, with the optimized device and granulated lactose as the carrier, a high drug loaded rifampicin DPI formulation with improved aerosol performance (fine particle fraction around 70%), better blending uniformity and potential low systemic toxicity was achieved.