Embargoed until July 2016. / Active Pharmaceutical Ingredients (APIs) are frequently prepared for delivery to the
lung for local topical treatment of diseases such as Chronic Obstructive Pulmonary
Disease (COPD) and asthma, or for systemic delivery. One of the most commonly
used devices for this purpose is the pressurised metered dose inhaler (pMDI) whereby
drugs are formulated in a volatile propellant held under pressure. The compound is
aerosolised to a respirably sized dose on actuation, subsequently breathed in by the
user.
The use of hydrofluoroalkanes (HFAs) in pMDIs since the Montreal Protocol initiated a
move away from chlorofluorocarbon (CFC) based devices has resulted in better
performing products, with increased lung deposition and a concomitant reduction in
oropharyngeal deposition. The physical properties of HFA propellants are however
poorly understood and their capacity for solubilising inhaled pharmaceutical products
(IPPs) and excipients used historically in CFCs differ significantly. There is therefore a
drive to establish methodologies to study these systems in-situ and post actuation to
adequately direct formulation strategies for the production of stable and efficacious
suspension and solution based products.
Characterisation methods have been applied to pMDI dosage systems to gain insight
into solubility in HFAs and to determine forms of solid deposits after actuation. A novel
quantitative nuclear magnetic resonance method to investigate the physical chemistry
of IPPs in these preparations has formed the centrepiece to these studies, accessing
solubility data in-situ and at pressure for the first time in HFA propellants. Variable
temperature NMR has provided thermodynamic data through van’t Hoff approaches.
The methods have been developed and validated using budesonide to provide limits of
determination as low as 1 μg/mL and extended to 11 IPPs chosen to represent
currently prescribed inhaled corticosteroids (ICS), β2-adrenoagonists and
antimuscarinic bronchodilators, and have highlighted solubility variations between the
classes of compounds with lipophilic ICSs showing the highest, and hydrophilic β2-
agonist / antimuscarinics showing the lowest solubilities from the compounds under
study.
To determine solid forms on deposition, a series of methods are also described using
modified impaction methods in combination with analytical approaches including
spectroscopy (μ-Raman), X-ray diffraction, SEM, chromatography and thermal
analysis. Their application has ascertained (i) physical form / morphology data on
commercial pMDI formulations of the ICS beclomethasone dipropionate (QVAR® /
Sanasthmax®, Chiesi) and (ii) distribution assessment in-vitro of ICS / β2-agonist
compounds from combination pMDIs confirming co-deposition (Seretide® /
Symbicort®, GlaxoSmithKline / AstraZeneca).
In combination, these methods provide a platform for development of new formulations
based on HFA propellants. The methods have been applied to a number of ‘real’
systems incorporating derivatised cyclodextrins and the co-solvent ethanol, and
provide a basis for a comprehensive study of solubilisation of the ICS budesonide in
HFA134a using two approaches: mixed solvents and complexation. These new
systems provide a novel approach to deliver to the lung, with reduced aerodynamic
particle size distribution (APSD) potentially accessing areas suitable for delivery to
peripheral areas of the lung (ICS) or to promote systemic delivery.
| Identifer | oai:union.ndltd.org:BRADFORD/oai:bradscholars.brad.ac.uk:10454/10098 |
| Date | January 2013 |
| Creators | Telford, Richard |
| Contributors | Scowen, Ian J., Munshi, Tasnim |
| Publisher | University of Bradford, Department of Chemical and Forensic Science |
| Source Sets | Bradford Scholars |
| Language | English |
| Detected Language | English |
| Type | Thesis, doctoral, PhD |
| Rights | <a rel="license" href="http://creativecommons.org/licenses/by-nc-nd/3.0/"><img alt="Creative Commons License" style="border-width:0" src="http://i.creativecommons.org/l/by-nc-nd/3.0/88x31.png" /></a><br />The University of Bradford theses are licenced under a <a rel="license" href="http://creativecommons.org/licenses/by-nc-nd/3.0/">Creative Commons Licence</a>. |
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