Abstract
The overarching goal of this thesis was to gain improved understanding of the delivery efficacy and safety of aerosolised medications used in an off-label manner via laboratory and computational investigation. The series of experiments described were intended to generate an empirical evidence base for solid particles and liquid droplet aerosols – the two forms of aerosols generated by devices that produce aerosolised medications. The
computational investigation was intended to study the physics of aerosolised medicines that comprise of solid particles and to make considerable progress towards the development of improved computational models. A long-term goal of the work is to further develop the computational methods to have suitable validity to be integrated with (or eventually replace) laboratory investigations for applications involving both solid and liquid aerosolised medications.
The aerosolised medications investigated were primarily those given to children off-label in a hospital setting (Chapters 2, 3 & 5) but also the widely used and “unapproved” electronic cigarette (Chapter 6) – used “off-label” by all users. Specifically:
• Chapter 2, 3 & 5: inhaled salbutamol produced by a pressurised metered dose
inhaler to children using an artificial airway (a solid particle aerosol);
• Chapter 4 inhaled tobramycin produced by a nebuliser to children using a
tracheostomy airway (a liquid droplet aerosol);
• Chapter 6 inhaled “e-liquid” aerosol produced by the electronic cigarette (a liquid
droplet aerosol). The “e-liquid” is the “base” excipient component to which
nicotine can be added.
As the first two studies involved drugs which have already been approved in children (who breathe through their native airways) and therefore have known safety profiles, the aim of the first two studies was primarily to determine the efficacy of delivery of the aerosolised medication. Efficacy was determined via obtaining data on the estimated delivered dose, which was previously unknown in the settings described above (i.e. to patients with artificial airways or using a tracheostomy airway). The first two studies were conducted via laboratory investigation. The first experimental study (involving a solid
particle aerosol) was then supplemented with computer modeling and simulation. Results from Chapter 3 indicated that aerosolised delivery was not comparable in efficacy across all methods used to deliver aerosolised salbutamol and, in some cases, methods were completely inefficacious and therefore unlikely to deliver expected doses. These results helped inform clinical practice at Perth Children's Hospital and those methods that were completely inefficacious (where delivered dose was negligible) were discontinued. Results from Chapter 4 indicated that the delivered dose of aerosolised medication was
comparable to the dose that a child breathing through their native airway would receive, and similar to the dose that an adult would receive via a tracheostomy airway. However, results also indicated that delivery of the medication was unlikely to be via aerosolization as expected – it was more likely that aerosol delivery was via larger droplets formed when aerosol formed liquid film in the tracheostomy tube. This has important implications, as if large droplets are the primary method of medicine delivery, medication is unlikely to
reach the lungs to provide therapeutic effect. Results from Chapter 4 will be used to help inform the development of standardized guidelines, which do not exist for children using tracheostomy airway. While efficacy of delivery was the primary reason for investigation in both Chapter 3 & 4, it was found that safety is also an important concern where the delivered dose is not being received, or unlikely to be received at all, particularly if the medication is potentially lifesaving, as with salbutamol.
In Chapter 6 the primary concern was to determine safety before efficacy given the completely “unapproved” (in any population) status of the electronic cigarette. To study safety, my research developed a novel method to produce an electronic cigarette aerosol in a way that enabled it to be easily quantified and that was improved on current more difficult and time-consuming methods. This novel method was then used in further laboratory investigation, to determine the safety of the inhaled aerosol, via quantification of the chemical composition of the produced (thermochemically altered) aerosol, which
appears in the appendix of this thesis. Results from study (3) (both the thesis and the appendix) indicated that the aerosol produced by the base e-liquid component contained chemicals that were unsafe to be inhaled, either at all, or at certain quantities, and some chemicals/ingredients should be entirely banned. The results in the appendix of this thesis were used to inform government consultation processes that eventuated in an update to
the Therapeutic Goods Order 110 in 2021 with a list of banned ingredients. Later in 2023, a full ban on importation of electronic cigarettes was announced.
In summary, this work has:
• Added to the empirical evidence base to guide clinical best practice of off-label use for two commonly prescribed aerosolised medicines in Australia.
• Added to the empirical evidence base which can be used to develop
international standardized guidelines for inhaled medicine delivery to
children with tracheostomy airways.
• Generated an empirical evidence base to support development of credible
computational models to investigate solid and liquid particle aerosolised
medication delivery to children.
• Made substantial progress toward a credible in silico method to study solid
particle aerosolised medications, particularly in off-label settings, in addition
to identifying key issues/limitations with current approaches.
• Developed an improved method to study the chemical composition and safety
of the e-liquids that are used with electronic cigarettes.
• Advised government consultation for the safe use of electronic cigarettes.
computational investigation was intended to study the physics of aerosolised medicines that comprise of solid particles and to make considerable progress towards the development of improved computational models. A long-term goal of the work is to further develop the computational methods to have suitable validity to be integrated with (or eventually replace) laboratory investigations for applications involving both solid and liquid aerosolised medications.
The aerosolised medications investigated were primarily those given to children off-label in a hospital setting (Chapters 2, 3 & 5) but also the widely used and “unapproved” electronic cigarette (Chapter 6) – used “off-label” by all users. Specifically:
• Chapter 2, 3 & 5: inhaled salbutamol produced by a pressurised metered dose
inhaler to children using an artificial airway (a solid particle aerosol);
• Chapter 4 inhaled tobramycin produced by a nebuliser to children using a
tracheostomy airway (a liquid droplet aerosol);
• Chapter 6 inhaled “e-liquid” aerosol produced by the electronic cigarette (a liquid
droplet aerosol). The “e-liquid” is the “base” excipient component to which
nicotine can be added.
As the first two studies involved drugs which have already been approved in children (who breathe through their native airways) and therefore have known safety profiles, the aim of the first two studies was primarily to determine the efficacy of delivery of the aerosolised medication. Efficacy was determined via obtaining data on the estimated delivered dose, which was previously unknown in the settings described above (i.e. to patients with artificial airways or using a tracheostomy airway). The first two studies were conducted via laboratory investigation. The first experimental study (involving a solid
particle aerosol) was then supplemented with computer modeling and simulation. Results from Chapter 3 indicated that aerosolised delivery was not comparable in efficacy across all methods used to deliver aerosolised salbutamol and, in some cases, methods were completely inefficacious and therefore unlikely to deliver expected doses. These results helped inform clinical practice at Perth Children's Hospital and those methods that were completely inefficacious (where delivered dose was negligible) were discontinued. Results from Chapter 4 indicated that the delivered dose of aerosolised medication was
comparable to the dose that a child breathing through their native airway would receive, and similar to the dose that an adult would receive via a tracheostomy airway. However, results also indicated that delivery of the medication was unlikely to be via aerosolization as expected – it was more likely that aerosol delivery was via larger droplets formed when aerosol formed liquid film in the tracheostomy tube. This has important implications, as if large droplets are the primary method of medicine delivery, medication is unlikely to
reach the lungs to provide therapeutic effect. Results from Chapter 4 will be used to help inform the development of standardized guidelines, which do not exist for children using tracheostomy airway. While efficacy of delivery was the primary reason for investigation in both Chapter 3 & 4, it was found that safety is also an important concern where the delivered dose is not being received, or unlikely to be received at all, particularly if the medication is potentially lifesaving, as with salbutamol.
In Chapter 6 the primary concern was to determine safety before efficacy given the completely “unapproved” (in any population) status of the electronic cigarette. To study safety, my research developed a novel method to produce an electronic cigarette aerosol in a way that enabled it to be easily quantified and that was improved on current more difficult and time-consuming methods. This novel method was then used in further laboratory investigation, to determine the safety of the inhaled aerosol, via quantification of the chemical composition of the produced (thermochemically altered) aerosol, which
appears in the appendix of this thesis. Results from study (3) (both the thesis and the appendix) indicated that the aerosol produced by the base e-liquid component contained chemicals that were unsafe to be inhaled, either at all, or at certain quantities, and some chemicals/ingredients should be entirely banned. The results in the appendix of this thesis were used to inform government consultation processes that eventuated in an update to
the Therapeutic Goods Order 110 in 2021 with a list of banned ingredients. Later in 2023, a full ban on importation of electronic cigarettes was announced.
In summary, this work has:
• Added to the empirical evidence base to guide clinical best practice of off-label use for two commonly prescribed aerosolised medicines in Australia.
• Added to the empirical evidence base which can be used to develop
international standardized guidelines for inhaled medicine delivery to
children with tracheostomy airways.
• Generated an empirical evidence base to support development of credible
computational models to investigate solid and liquid particle aerosolised
medication delivery to children.
• Made substantial progress toward a credible in silico method to study solid
particle aerosolised medications, particularly in off-label settings, in addition
to identifying key issues/limitations with current approaches.
• Developed an improved method to study the chemical composition and safety
of the e-liquids that are used with electronic cigarettes.
• Advised government consultation for the safe use of electronic cigarettes.
Original language | English |
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Qualification | Doctor of Philosophy |
Awarding Institution |
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Award date | 6 Jun 2024 |
DOIs | |
Publication status | Unpublished - Feb 2024 |