Lung diseases such as asthma and chronic obstructive pulmonary disease (COPD) are major health burdens on the global population. To treat diseases of the lung, topical therapies using dry powder inhalers (DPIs) have been employed. However, a relatively small amount of dose (5.5 - 28 %) reaches the lung during DPI therapy leading to high inter-patient variability in therapy response and oropharyngeal deposition. Strategies were assessed to take patient variability in inhalation performance into account when developing devices to reduce throat deposition and to mitigate flow rate dependency of the emitted aerosol. A cyclone-spacer was manufactured and evaluated with marketed and in-house manufactured formulations. An in vivo study showed that a high resistance inhaler would produce longer inhalation times in lung disease patients and that a spacer with high resistance may prove a suitable approach to address inter-patient variability. Two spacer prototypes were evaluated with cohesively- and adhesively-balanced particle blends. The data suggested that the throat deposition dramatically decreased for the emitted particles when the spacers were used with the inhalers (e.g. 18.44 ± 2.79% for salbutamol sulphate, SS 4 kPa) due to high retention of the formulation within the spacer (87.61 ± 2.96%). Moreover, variation in fine particle fraction and dose was mitigated when increasing the flow rate (82.75 ± 7.34 %, 92.2 ± 7.7 % % and 77.0 ± 10.1 % at 30, 45 and 60 Lmin-1, respectively). The latter was an improvement over previous proposed DPI spacers, where variability in emitted dose due to airflow rate was a major issue. Due to the different physicochemical properties of the active pharmaceutical ingredients used in the formulation, throat deposition and respirable fraction for adhesively-balanced particles (e.g. SS) were double that of the cohesively- balanced particles (salmeterol xinafoate, SX) (e.g. 65.83 ± 8.99 % vs. 45.83 ± 5.04 % for SS:Coarse Lactose (CL) and SX:CL, respectively). Scanning electron microscopy revealed that surface-bound agglomerates were more freely removed from the carrier, but subject to decreased impaction-type deagglomeration forces in the spacer than for carrier-bound drug. An ex vivo study using breath profiles from healthy volunteers identified the minimization of differences between adhesively- and cohesively-balanced blends when full breath profiles were studied compared to square-wave airflow. Therefore the use of constant flow for in vitro testing should not be the sole flow regime to study aerosolization when developing new inhalation devices and formulations.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:650578 |
| Date | January 2015 |
| Creators | Parisini, Irene |
| Publisher | University of Hertfordshire |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/2299/15931 |
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