Spray-dried powder particles for treating pulmonary tuberculosis
|dc.identifier.citation||Momin, M. (2018). Spray-dried powder particles for treating pulmonary tuberculosis (Thesis, Doctor of Philosophy). University of Otago. Retrieved from http://hdl.handle.net/10523/8325||en|
|dc.description.abstract||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 <5.0 μm). Co-spray dried powders with L-leucine or rifampicin were wrinkled and amorphous. Among the kanamycin-L-leucine co-spray dried powders, kanamycin with 5% (w/w) of L-leucine showed the best aerosolization efficiency (FPF: 73.0 ± 2.5%). Aerosolization efficiency of kanamycin-rifampicin combination powder (FPF: >77.6%) was higher than that of kanamycin-only powder (FPF: <29.5%). Hydrophobic surface enrichment was achieved in kanamycin-rifampicin composite powders, significantly affected by co-solvent composition used during spray-drying. Increase in hydrophobic surface enrichment increased FPF. At high humidity (75% RH), the FPF of all the co-spray-dried powders significantly decreased. The formulations were non-toxic to both of the cell-lines. Conclusions Co-spray drying hygroscopic kanamycin with L-leucine or with rifampicin improves aerosolisation. Improved aerosolization is related to morphology change by L-leucine and hydrophobic surface enrichment by rifampicin. Solvent composition used in spray-drying can affect hydrophobic surface enrichment of composite dry powder particles. Hydrophobic surface enrichment could not protect moisture uptake but it protected agglomeration of kanamycin-rifampicin combination particles up to 43% RH. Improved aerosolization may help to deliver high doses of these drugs to the deep lung to treat tuberculosis. Further studies are required to explore particle interactions of the composite powders to understand the mechanisms for improved aerosolization.|
|dc.publisher||University of Otago|
|dc.rights||All items in OUR Archive are provided for private study and research purposes and are protected by copyright with all rights reserved unless otherwise indicated.|
|dc.title||Spray-dried powder particles for treating pulmonary tuberculosis|
|thesis.degree.name||Doctor of Philosophy|
|thesis.degree.grantor||University of Otago|
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