This thesis concerns investigations of novel pressurised metered dose inhaler (pMDI) formulations containing tiotropium (Tio) in association with a secondary particulate (SP). A number of formulation and hardware variables were studied using in vitro methods to determine their influence on the performance of these novel formulations. Initial studies indicated that Tio was practically insoluble in HFA propellants and its solubility was not increased under raised moisture levels during long-term stability tests. Formulations with L-leucine (Leu) or lactose (Lac) as SP’s were investigated in Tio:SP ratios ranging from 1:2.5 to 1:25 and with different SP sieve fractions from < 20 μm to < 63 μm. Many formulations demonstrated improved aerosol characteristics compared with Tio alone, particularly in through life performance (TLP). The inclusion of fine SP’s (< 20 μm) was found to significantly improve dose uniformity, fine particle fraction (FPF) and fine particle dose (FPD). Tio:Lac formulated in HFA 227 resulted in slightly greater FPF and FPD but also a higher mass median aerodynamic diameter (MMAD) than when formulated in HFA 134a. With respect to the hardware parameters investigated, smaller actuator orifices (in the range 0.25-0.46 mm) and lower valve volume (25 μl instead of 50 μl) were generally associated with significantly increased FPF and reduced MMAD, whereas a smaller canister volume and fluorocarbon polymerization canisters tended to improve TLP. In comparison with marketed Tio products, comparable FPF’s to Spiriva Handihaler® (41%) and Spiriva Respimat® (53%) were demonstrated with bespoke Tio:Lac and Tio:Leu formulations respectively. The Tio:Leu formulation also had a much lower submicron fraction of Tio than Spiriva Respimat®. This research concerning Tio:SP pMDI formulations has demonstrated the advantages of including a SP to promote drug-SP association in the HFA suspension and promoting particle de-aggregation during propellant atomisation. Further research regarding direct measurement of particle interactions and aerodynamic behavior is warranted.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:753540 |
| Date | January 2017 |
| Creators | Zheng, Chen |
| Publisher | Cardiff University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://orca.cf.ac.uk/113171/ |
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