Spray-dried powder particles for treating pulmonary tuberculosis

Background Tuberculosis (TB) is a major global health burden. Rapid emergence of drug-resistant TB has aggravated the current situation of global TB. High dose delivery of drugs to the lung using a dry powder inhaler (DPI) is an emerging approach to combat drug-resistant TB. To achieve this, highly aerosolizable powders are required. The hygroscopic nature of powder particles is a particular risk for good aerosolization. Hydrophobic surface enrichment of dry powder particles may be a potential approach to improve the aerosolization of a hygroscopic drug. Purpose The objective of this thesis was to produce a highly aerosolizable dry powder of a hygroscopic drug by hydrophobic surface enrichment and a systematic study of spray-drying conditions to achieve hydrophobic surface enriched powder particles. We hypothesized that co-spray-drying of a hygroscopic drug with a hydrophobic compound, would produce inhalable particles with surfaces enriched in hydrophobic compound. Such particles would have higher aerosolization than hygroscopic drugs alone. Methods A model hygroscopic drug, kanamycin sulphate was co-spray dried with a hydrophobic compound (excipient, L-leucine or drug, rifampicin) using Buchi B-290 Mini Spray-Dryer. Kanamycin-L-leucine co-spray dried powders were produced with different concentrations (0, 5, 10, 15 and 20 % w/w) of L-leucine. The kanamycin-rifampicin composite dry powder formulations were produced by systematically (23 factorial design) varying the drug ratio, co-solvent composition and inlet temperature. X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS) were used to study the surface composition. In vitro aerosolization efficiency was investigated using a next generation impactor (NGI). Physicochemical properties of the powders were evaluated by laser diffraction, scanning electron microscopy, X-ray diffractometry, ATR-FTIR, Karl Fischer titration and thermogravimetric analysis. Humidity effects were investigated by storing the powders for one-month in an open Petri dish at different relative humidities (RHs) and 25 ± 2°C. Powders were also evaluated for cytotoxicity on human respiratory cell-lines (Calu-3 and A549 cells) by MTT assay. Results All spray-dried powder particles were in the inhalable size range (aerodynamic diameter 77.6%) was higher than that of kanamycin-only powder (FPF: