Abstract

Abstracts: Drug Delivery to the Lungs 21
1. Idealized Throat Replicas for Inhaler Testing
Summary
For most inhalers, avoiding mouth-throat deposition is an important aspect of device performance when delivering drugs to the lungs. However, regulatory throats used in benchtop testing, such as the USP throat, are known to underestimate mouth-throat deposition quite significantly for some aerosols. This makes it more difficult to extrapolate in vivo performance based on in vitro tests with such throats. Various researchers have instead found that realistic throats, typically built using rapid prototyping of CT or MRI scans of a particular subject, may allow more representative in vitro estimation of mouth-throat deposition. However, such subject-specific realistic throats are unlikely to undergo widespread adoption as standard throats for general use. Instead, it would be useful to have throats designed for inhaler testing that are between the two extremes of complexity associated with actual subjects versus existing regulatory throats. However, the development of idealized throats that accurately mimic actual in vivo mouth-throat deposition requires replicating the principal fluid and aerosol dynamics features that occur in the mouth and throat, while at the same time keeping the geometry simple enough that it can be readily manufactured from metal in a reliable and inexpensive manner. Experimental measurements from the author's laboratory that highlight the essential fluid and aerosol mechanics of the mouth-throat will be presented. Idealized geometries that capture these mechanics will be discussed. These idealized geometries may be useful to those wanting to obtain more realistic benchtop estimates of mouth-throat deposition during inhaler development.
2. The Highs and Lows of Pharma Cokinetics in Determining the Equivalence of Inhaled Medicinal Products
Pharmacokinetic (PK) analysis is the mainstay for determining bioequivalence of oral medicinal products containing systemically-acting drugs. Bioequivalence, is logical even though the site of drug action is not usually within blood, since blood concentrations will attain equilibrium with those at the site of action.
The situation is convoluted for orally inhaled drugs acting locally in the lung, since the blood concentration is a “post-event” measure and as a minimum, PK analysis of blood concentrations must involve “back extrapolation” or deconvolution to define the drug residence profile at the site of action in the lung. The usual oral bioequivalence measures of area under the plasma concentration-time curve and peak concentration as surrogate measures of “extent” and “rate and extent” of exposure of the drug to the site of action, and the standard 0.80-1.25 limits on these parameters may not be appropriate.
A further complication of inhaled drug delivery is that the measured blood concentrations reflect a combination of drug absorbed from the lung and from non-pulmonary sites, especially the intestine and possibly the oropharynx. Hence absorption from these non-pulmonary sites needs to be minimised or rectified in the PK analysis. An additional impediment to a standardised analytical approach is evidence of regional differences within the lung for the absorption and elimination of some drugs, thus affecting the PK blood profile.
Despite these limitations, PK analysis, in defined circumstances, can aid our understanding of lung deposition and absorption and will be a useful adjunct for establishing equivalence for certain inhaled medicinal products.
3. Utilizing In Vivo Lung Imaging Techniques to Assess Pulmonary Drug Delivery
In vivo lung imaging is useful for assessing pulmonary drug delivery. It not only adds to our understanding of aerosol therapy in general, but also provides a method for assessing changes in deposition that result from improvements to aerosol delivery systems and it may be useful in assessments of bioequivalence (BE) of orally inhaled products. Three techniques have been employed for imaging aerosol deposition in the lungs: planar gamma scintigraphy, single photon emission computed tomography (SPECT), and positron emission tomography (PET). Because of technical challenges and costs associated with SPECT and PET lung imaging, the number of sites at which these studies can be conducted is reduced, compared to sites that can conduct planar imaging. In vivo lung imaging allows for quantification of the total deposition of inhaled particles within the lungs, regional deposition within the airways and deposition in extrapulmonary sites. It also can be used to quantify the effect of changes in inhalation technique and particle size on deposition, the influence of disease on deposition, clearance of particles from the lung, and the relationship between lung dose and therapeutic outcomes. This article compares and contrasts the various lung imaging techniques, providing their advantages and disadvantages. It also provides examples of how this technology can be used, discusses the possibility of using it in BE assessments and what is being done to improve the techniques.
4. Regulatory Perspectives on the Bioequivalence of Inhaled Drugs
Summary
Shallow dose response for all classes of orally inhaled products complicates the assessment of equivalence between generic and reference formulations. In Europe the regulatory guidance relating to generic OIP development has therefore been recently revised and, inter alia, advocates the use of lung deposition models (pharmacokinetic and scintigraphic studies) to compare generic and reference OIPs. This paper considers current regulatory requirements and design considerations for such studies, and the limitations of each modality.
5. A system for efficient and dose-controlled delivery of liquid substances to in vitro cell models of the lung epithelium
Summary
6. Application of a Respiratory PBPK Model for Simulating Pulmonary Administration of Fluticasone Propionate in Humans
7. Nebulisers: From jets to meshes
Nebulisers convert a drug liquid into a spray. They are single-dose devices, and the patient usually inhales by multiple tidal breaths. Nebulisers offer the advantages of ease of use by patients of any age and with any degree of lung impairment, and the ability to aerosolise virtually any drug in virtually any dose, but they are less convenient, and usually less portable, than pressurised metered dose inhalers and dry powder inhalers. Three types of nebuliser are available commercially: jet, ultrasonic, and vibrating mesh (or vibrating membrane). Today's best known jet nebulisers are breath-enhanced (or open-vent) devices, and are most commonly powered by electrically-operated compressors. Ultrasonic nebulisers create a spray from fluid placed above a piezoelectric crystal, but are used less frequently today than in the past, perhaps because of concerns that they may damage thermally sensitive compounds, and because they do not usually nebulise either drug suspensions or viscous solutions efficiently. Vibrating mesh nebulisers have the potential to deliver drug to the lungs more efficiently than other types of nebuliser, and in a relatively short treatment time. They could become the gold-standard technology for nebuliser therapy in the future. However, the need to clean the meshes regularly could be a practical limitation. For drugs which either have narrow therapeutic windows or need to be targeted to some specific lung region, systems which can precisely control the patient's mode of inhalation have proved to be useful.
8. Ventilator Aerosol Delivery System (VADS): Concept for Rapid Delivery of Aerosolized Bronchodilators to Adult Patients on Mechanical Ventilation
Summary
9. Electrostatic charge: we can measure it but does it really influence dry powder inhalation formulations?
Summary
The past two decades have seen the publication of a considerable amount of research, which have looked at the efficiency of medicinal aerosols delivered to the human lungs. Electrostatic forces of attraction and repulsion have been cited as potential influences in aerosol dispersion and deposition, resulting in investigations between particle size distribution, in vitro aerosol performance, and the electrostatic charge carried by the aerosol cloud. Possibly the most crucial question about aerosol electrostatics is whether the net aerosol charge measured has any influence on aerosol performance, or is simply a secondary parameter that may be used to identify other characteristics (i.e. drug dispersion mechanisms or crystallinity). The charge distribution of an aerosol tells us very little on its own, given the variety of tribocharging sources. The only way to extract information is to conduct a comparison between two sets of charge measurements where there is a single variable between them. The results presented imply that using the eNGI for DPIs, single-drug, drug-carrier, drug ratio-carrier and combination-drug formulation, the specific charge generated on the surface of dispersed drug particles was not influential in vitro aerosol performance, but it has provided another way to observe drug dispersion mechanisms (e.g. turbulence, detachment from carrier surface, deaggregation). However, without a workable in vitro-in vivo correlation, it remains to be seen whether these results are in any way predictive of the relationship between charge distribution in an aerosol, and deposition in the human lungs, under realistic patient inhalation flow conditions.
10. The Use of NMR in p MDI Development
Summary
COPD and Asthma are increasingly common diseases which require new medicines to meet the future unmet medical needs. Within this disease area the pMDI platform remains a good option for drug delivery. Knowing the solubility of an API in propellant is a key quality attribute in assessing new pMDI options for inhalation compounds. Combined with the predicted dose, knowing the solubility allows the formulators to decide on the ideal propellant to give the desired solution or suspension formulation. Solution state Nuclear Magnetic Resonance (NMR) is one of the most powerful analytical techniques available at the disposal of analytical chemists. Within the Pharmaceutical industry solution state NMR has been widely used and accepted by regulators for a range of issues. Since pMDIs typically consist of either a solution or suspension formulation using highly volatile non-deuterated solvents (propellants), pMDI formulations are clearly not amenable to traditional solution state NMR analysis conditions.
This paper will describe the development of a novel NMR approach to measure the solubility of APIs in pMDI propellants. The work described herein will discuss how to overcome the technical challenges with the overall result that the solubility of API's and other organic compounds can be readily quantified in a range of inhalation propellants down to concentrations as low as 10ppm (10ug/ml) using relatively small quantities of API (<50mg). The development of the NMR technique allows rapid screening of the solubility of an API within pMDI formulations, allowing formulation options to be assessed faster and thereby cutting development times.
11. Widening the Lens: Re-evaluating the Influence of Size and Morphology of DPI Carrier Particle Performance
Summary
12. Novel Engineered Particle Formulation For Inhaled PYY(3-36) And Demonstration Of Appetite Suppression In A Mouse Model
Summary
13. Singing for BreathingTM Effects of singing lessons in patients with COPD-A Randomised Control Trial
Summary
Despite optimal pharmacological therapy, patients with COPD continue to be breathless. There is a need to develop alternative strategies to improve symptoms and pulmonary rehabilitation is a good example of this. Learning to sing requires individuals to control their breathing and posture and might have benefits that translate into daily life.
To evaluate this we performed a randomised controlled trial comparing a six week course of twice weekly singing classes to usual care in COPD patients. The experience of singing was assessed via interviews with a psychologist. In addition, we surveyed participants with chronic respiratory conditions who participated in a series of open singing workshops.
In the RCT, the physical component score of the SF36 improved in the singers (n=15) compared to the controls (n=13); +7.5(14.6) vs. −3.8(8.4) p=0.02. Singers also had a significant fall in HAD anxiety score; −1.1(2.7) vs. +0.8(1.7) p=0.03. Singing did not improve single breath counting, breath hold time or shuttle walk distance. In the qualitative element, 8 patients from the singing group were interviewed. Positive effects on physical sensation, general well-being, community/social support and achievement/efficacy emerged as common themes. 150 participants in open workshops completed a questionnaire. 96% rated the workshops as “very enjoyable” and 98% thought the workshop had taught them something about breathing in a different way. 81% of attendees felt a “marked physical difference” after the workshop.
Singing classes can improve quality of life measures and anxiety and are viewed as a very positive experience by patients with respiratory disease.
14. Effect of adding micronized and milled lactose fines on fluidization properties and in vitro performance of DPI formulations
Adding fine particle lactose to dry powder inhaler (DPI) formulation is known to enhance the performance of the final product. Despite all the research that has taken place in order to understand the underlying reasons for the phenomena, there still remains a paucity of information that could explain the behavior. The current study aims to investigate how addition of lactose fines affects the fluidization behaviour of lactose carriers and the in vitro aerosolization characteristics of DPI formulations. Furthermore, the impact of addition of lactose fines with different processing histories (milled vs. micronized) on the fluidization and in vitro deposition characteristics of DPI formulations will be investigated. It is shown that addition of lactose fines increases the fluidization energy that is a measure of cohesion and was characterised on Freeman Technologies FT4 powder rheometer in case of both types of fine particle lactose. It is shown that in case of micronized fine particle lactose the increase in cohesion corresponds to better in vitro performance.
15. Optimisation of Dry Powder Inhalers Through Robust CFD Simulation of Air Classifiers
Passive dry powder inhalers (DPI) have been an attractive platform for pulmonary drug delivery in recent years, yet the complexity in design and inconsistencies in dosing with respect to patient inhalation remain an impediment to the wide acceptance of these devices. While DPI design has been a long and costly process in the past, the advancement of simulation tools and computational power allow the possibility of design iterations in much shorter timeframes. The current work investigates the effects of dimensional variations in the air classifier (reverse cyclone) on overall DPI performance. While experimental data is not widely available on such small geometries, scaled empirical and computational fluid dynamics (CFD) models allow design optimisation to be undertaken towards minimising patient breathing sensitivity and resistance.
A parameterised mesh generation script was developed for miniature cyclones under 30 mm in diameter. The grids were then used for steady CFD calculations using Reynolds averaged Navier-Stokes method with RSM turbulence modelling. Collection efficiency curves of the parameterised cyclones were obtained using Lagrangian particle-tracking method. Empirical models derived from larger scale cyclones were also used for faster performance estimations. Results were in agreement with observed cut-off diameters in available literature and patents. This work demonstrates how performance is changed in centimetre-scale cyclones based on internal shape, breathing and drug particle property variations, and contributes to the overall understanding and improvement of DPI design.
16. Surface modification of mannitol inhaler carrier particles via spray drying
Summary
The aim of this work was to investigate the influence of pilot scale spray drying process parameters on the surface topography and size of D-mannitol carrier particles. In order to address this question a full factorial design with four factors at two levels was used. The four factors were feed concentration, damper register temperature, feed rate and atomization rotation speed. Additionally the atomization spray was carefully analyzed to better understand the dependence of particle size of the final product on droplet size. Particle surface topography as well as particle size could be successfully impacted by the variation of process parameters. Spray drying at 74°C leads to particles of coarse crystalline surface. Single crystals, which can be clearly distinguished, have the shape of prismatic rods. At 86°C outlet temperature crystal edges fuse to form a relatively smooth surface. At high outlet temperature (97°C) single crystals reappear and the surface gets coarser again. In addition to this particle size could be modified by the variation of rotation speed, damper register temperature and feed concentration. Enhancing feed concentration or damper register temperature increases particles size whereas elevating the atomizer rotation speed reduces particle size. This study clearly demonstrates that spray drying mannitol at pilot scale enables the preparation of particles of appropriate size and adjustable surface topography for the use in dry powder inhalers (DPIs).
17. Comparison of in vitro methods to determine nasal versus lung deposition of a protein formulation
Summary
The aim of the study was to evaluate the deposition of a model protein formulation (representing a macromolecule for systemic delivery or an antigen used for vaccination) when administered as nasal dry powder spray or when inhaled orally. For this, the Next Generation Pharmaceutical Impactor (NGI) without or with the nasal adapter as well as a nasal cast model in different setups were used. The formulation consisted of the protein plus chitosan as mucoadhesive component facilitating prolonged contact time with the mucosa and decreased mucociliary clearance, and was produced by spray drying. To evaluate oral inhalation, the particles were delivered using the Aerolizer device. To evaluate nasal delivery, the particles were placed directly into the PowderJet, a nasal dry powder device. As the primary particle size was in the inhalable range, a considerable amount of particles may reach the lower respiratory tract when administered via the nose. The protein particles were easily dispersible resulting in an FPF in the NGI of almost 32% after application in the nasal cast (60% in the NGI from the Aerolizer). Interestingly, for distinguishing between the amount being deposited in the nose and the amount reaching the lungs, the simple nasal adapter for the NGI gave the same results as using a nasal cast model. Whereas the nasal cast allows a more profound description of the nasal deposition pattern, the NGI with nasal adapter incorporates an evaluation of lung deposition.
18. Evaluation and modelling of the aerosolisation and break-up of agglomerated systems in dry powder inhalers
This study utilized a combination of computational fluid dynamics (CFD) and standardized entrainment tubes to investigate the influence of turbulence and impaction in isolation on the break-up and aerosol performance of a model inhalation formulation. A series of entrainment tubes, with different venturi sections and impaction plate angles were designed in silico and the flow characteristics, and particle tracks, were simulated using CFD. The apparatuses were constructed using 3-dimensional printing. The deposition and aerosol performance of a model agglomerate system (496.3 - 789.2 μm agglomerates containing 3.91 μm median diameter mannitol particles) were evaluated by chemical analysis and laser diffraction, respectively. Analysis of the mannitol recovery from the assembly and CFD simulations suggested that turbulence kinetic energy and the intergral shear strain rate generated within the venturi system did not affect aerosol performance. However, it was found that with increased impact velocity on the venturi wall, aerosol performance improved. The influence of impact velocity was further investigated with the impactor system. It was observed that when a critical impact velocity exceeded, the aerosol performance was independent of impactor angle but dependent on the air velocity directly above the impactor plate suggesting that particle-wall impaction results in initial agglomerate fragmentation followed by re-entrainment into the airstream above the impaction plate. Such observations have significant implications in the design of dry powder inhaler devices.
19. Ultrafast Analysis of Pressurised Metered Dose Inhaler (pMDI) by Direct Spray Mass Spectrometry (Direct Spray-MS)
The speed with which inhaled pharmaceutical products are developed can often be compromised by the labour intensive nature of the test procedures required to evaluate their performance. Previous work, has demonstrated proportionality between MS response and active strength in a pMDI formulation, however some studies have indicated that Direct Spray MS response may be influenced by the droplet size of the input drug substance/droplet size. This abstract describes the results of a recent study carried out to assess the sensitivity of MS response to aerosol droplet/particle size. The results indicate that the response generated from the Direct Spray-MS technique correlates well to ionisation of droplets/particles in the 9.0 to 1.1 μm size range. The linearity of response displayed by the technique will allow rapid screening of pMDI performance during the early phase of inhaled product development, and can be considered a useful technique when developing a new product within a Quality by Design (QbD) environment. As an illustration of the speed potential of the technique, the Direct Spray MS data reported here was collected in approximately 4 hours. The supporting ACI data collection took 8 days to complete.
20. Pioneers of inhalation II: French kisses and steamy salons
Summary
While the history of inhalations dates back over thousands of years, the history of ‘propelled’ aerosols is much shorter. In the context of this paper, a propelled aerosol is one created by pressure, steam, or some other energy source, and excludes vapour inhalations.
The steamy salons and French kisses is a reference to the spa treatments in France in the 1840's in which Auphan and later Sales-Girons conceptualised the first atomisation processes and the earliest nebulisers, with Sales-Girons going on to receive a medal for his portable atomiser.
Perhaps the earliest propelled aerosol came before this, from the USA where Humphrey created a pressurised steam based inhaler resembling a cafetiere. His motivation being to propel the aerosol towards the patient who was too ill to draw air through a standard vapour inhaler.
That same motivation led a series of pioneers to develop a variety of different propelled aerosols. Progressing through the Victorian era; the rubber squeeze-ball was used as a means of atomisation and nebulisation. The steam-driven inhaler of Dr Siegle was created in the 1860's and manufactured into the 1930's. It incorporated the principal of Bergson tubes to deliver medication through a venturi. Even early glass nebulisers incorporated baffles to hold back the larger particles recognised as being unrespirable.
The 1900's saw great popularity of rubber squeeze bulb atomisers for adrenalin delivery and the development of the electric compressor. The 1950's brought the first of the ultrasonic nebulisers and the pressurised metered dose inhaler – an invention that propelled asthma treatment to the masses.
21. Non-destructive examination of inhalation blisters using X-ray computed micro-tomography
X-ray computed tomography is widely used in several fields from medicine to electronics to study internal structures of objects non-invasively. In the pharmaceutical industry, X-ray computed tomography is often used in the form of X-ray computed micro-tomography, i.e. resolution in the range of μm; and the vast majority of applications are aimed at tablets. This paper explores the application of X-ray computed micro-tomography for studying blisters for use in dry powder inhalers. The results show that X-ray computed micro-tomography allows visualisation of the amount of powder in blisters without opening the blisters and can be used to assess the quality of the sealing of the lid foil to the blister pocket. The technique is non-destructive to the blisters, allowing the blisters to be used in other type of further tests if needed. It is recommended that X-ray computed micro-tomography is used for trouble shooting rather than routine testing.
22. What factors dominate the performance of conventional dry powder inhalation formulations?
The formulation of dry powder inhalers containing, large inert, carrier based systems has generally been conducted through empirical observation. Furthermore, many current formulations are built using excipients and methods with historical relevance (i.e. a previous generation device or drug) with little or no knowledge of the mechanisms underpinning their performance. Carriers are used predominately as diluents and flow-aids allowing capsule and blister filling of potent drug molecules, however their role in promoting aerosolisation efficiency of the active therapeutic drug molecule is questionable. Furthermore, the study of the process of drug aerosolisation is difficult since there are many compounding variables, (including carrier and drug size, morphology, chemistry, amount of excipient fines, device design and fluid flow conditions) which may have a dominating influence in the process. It is the aim of this review to ‘tease out’ the potential mechanisms that underpin aerosolisation efficiency of DPI formulations by studying the body of work conducted by our research group over the past decade. Specifically, we will investigate the role that key variables have on the performance of drug liberation, including carrier size, carrier roughness and the relative percentage of excipient fines.
23. Direct observation of particle dispersion mechanisms in DPI using particle image velocimetry technique
Summary
Dry powder inhaler (DPI) has been extensively studied. However, the mechanism of particle dispersion has not been fully elucidated. This study employed the particle image velocimetry (PIV) technique to investigate the aerosolization process. Mixture of micronized lactose and coarse lactose carrier was placed in a model inhaler device and a high speed video imaging was used to capture the dry powder inhalation process. The flow pattern was found to be turbulent. Particles were observed to collide with one another, causing detachment of micronized particles from the surfaces of the coarse lactose particles. Impact of the powder agglomerates on the device grid also contributed to deaggregation and dispersion of the particles. The findings suggest that collision and impact are important mechanisms for the dispersion of DPI particles.
24. Engineering of Dry Powder Inhaler Formulation: The Colloidal Science Approach
Summary
The performance and aerosolisation efficiency of dry powder inhaler (DPI) formulations is controlled by the cohesive (drug-drug) and adhesive (drug-lactose) interactions. However, the cohesive/adhesive properties of DPI formulations are difficult to measure and control because they are dependent on the surface interfacial properties of the drug and carrier excipient. This paper investigates high-shear mixing and a novel liquid-suspension sono-blending strategy to manipulate and control the cohesive-adhesive force balance of formulations and therefore, aerosolisation performance. These data suggest that at defined blending energy inputs the cohesive-adhesive properties of drug and excipient material may be overcome in the final blend, which will influence aerosolisation performance. With knowledge of the cohesive-adhesive properties of the drug it will be possible to determine the blending energy to achieve the desired design space for DPI formulation performance. In addition, sono-blending of DPI formulations of FP has been successfully demonstrated. The content uniformity of the sono-blended formulation suggests the process enabled good mixing whilst enhancing the stability of the formulation. In addition, it was found that mixing in other non-polar liquids changed the performance of DPI formulations through manipulation of colloidal forces.
25. How does Airflow Resistance Affect Inspiratory Characteristics as a Child grows into an Adult?
In this study we measured the inspiratory flow characteristics of 90 healthy volunteers, aged 4 to 50, to determine the energy available and to understand the suitability of typical dry powder inhalers (DPIs) for use by children.
Almost all characteristics of the inspiratory manoeuvre change as a child grows into an adult, our data showing two to three fold increases in peak inspiratory power, flowrate and energy. The only parameter that does not increase substantially is the maximum inspiratory mouth pressure, with a 14% increase from children to adults.
The energy produced during the inspiratory manoeuvre increases with airflow resistance up to approximately 25 Pa½ L s−1, then becomes reasonably constant at resistances above this. Children produced an average inspiratory energy of ∼5 J compared to adults who produced ∼15 J. This quantity of energy is huge compared to the tens of millijoules typically required to disperse and aerosolise a dose of powdered drug formulation. A particularly strong correlation was found between an individual's height and their inspiratory energy, irrespective of age or gender.
This study of healthy adults and children suggests that current (medium to high resistance) DPIs are likely to be used by children at reasonable flowrates. In general, however, all age groups indicated a preference for lower resistance devices – this is important, because a device that is deemed too uncomfortable may not be used at all. The energy available in even a young child's inspiration is more than sufficient to disperse and aerosolise powdered drug formulation – the challenge is to design dry powder inhalers that maximise the use of this energy.
26. Inhaled nanoparticle toxicity assay optimization: dose, size and oxidative potential
Summary
The opportunities offered by nanoparticles (NP) for inhaled drug delivery will only be realized if their safety can be assured. In vitro nanotoxicology screening requires assays that are designed, conducted and interpreted with biological relevance, particularly with regard to particle dose and physico-chemical form. In this study, 2% v/v FBS in cell culture medium provided stable suspensions for cell-based toxicity assays. Cellular particle dose was calculated over a range that included an overload concentration. The oxidative potential of the test material confirmed the greater potential of copper oxide nanoparticles compared to titanium dioxide nanoparticles. In cell-based assays, TiO2 exhibited toxicity only at the overload concentration, 52.6 μg/cm2, whereas after 24 h, CuO produced adverse effects at lower concentrations. Equivalent results were found in two cell lines, although the sensitivity of alveolar-derived A549 cells was marginally greater than that of nasal-derived RPMI 2650 cells. Results from the MTT assay corresponded well with the LDH assay. Interference of copper with the LDH assay illustrated the importance of controls for assay suitability. The assay conditions and protocols established provide verified methods for in vitro screening of nanoparticulate systems for inhaled drug delivery. However, further refinements to the dosimetry calculation may be necessary if delivery systems have greater biodegradability and/or lower density.
27. Mucociliary Transport & the “Unusually Thick” Paradox
An in vitro model using bovine trachea has been used to study factors influencing transportability of clinical sputum samples from cystic fibrosis and non-CF bronchiectasis patients. Osmotic activities of sputa have been reported to be as low as 150mOsm, hypo-osmolar compared to 300mOsm for plasma. Osmolarity is a pivotal property controlling the speed of ciliary transport on the bovine trachea. Mucus and sputum samples equilibrated at 300 to 500mOsm were maximally transported. Transportability was significantly reduced at 200mOsm and almost stationary when samples were equilibrated at 100mOsm or less. Osmolarity, and
The importance of regulation of airway osmolarity in treatment of chronic lung diseases characterised by mucostasis is supported by the following fact. Inhaled 7% hypertonic saline and inhaled dry powder mannitol are currently the only existing treatments where both increased ciliary clearance of secretions from patients' lungs, and improved clinical outcomes in phase III clinical trials have been demonstrated. Next generation therapies are likely to target ion transport mechanisms that regulate osmotic activity of airway surface liquid and lung secretions.
28. “Beyond FEV1 - Assessing the Small Airways”
Summary
Small airways disease is present in patients with asthma and with chronic obstructive pulmonary disease (COPD). However, conventional pulmonary function testing used in the clinic is insensitive to detect abnormalities in the small airways. Indeed, spirometry tests such as the FEV1 (forced expiratory volume in one second), which is used as an endpoint in all large clinical therapeutic trials, mainly assess changes in the proximal conducting large airways. Better physiological biomarkers are required to assess the response of the small airways to inhaled therapy targeted to treat this area. The last decade has observed the reemergence of some physiological tests such as the multiple breath nitrogen washout, the forced oscillation technique, and development of novel methods such as alveolar nitric oxide, to assess pathology, inflammation and abnormal ventilation distribution in the small airways. Studies have been undertaken to validate that these techniques do indeed demonstrate responses arising from the small airways. Such biomarkers are necessary to support the approach that targeted therapy tailored to the predominant site of airway pathology could guide the future development of more efficient and purpose specific inhalers.
29. The development of a new rapid screening test for evaluating the non-stick performance of MDI canisters
Loss of active substance to the walls of Metered Dose Inhaler (MDI) canisters by a process of deposition is a potential failure mode for certain suspension formulations. Such deposition behaviour can be mitigated by the incorporation of a suitable non-stick (release) coating. In order to develop and improve the performance of non-stick coatings, it is highly advantageous to have a fast and reproducible screening test to assess the non-stick performance of new coating systems on MDI canisters. This paper deals with the development of such a technique.
The new rapid screening technique for MDI canister deposition employs a micronised Active Pharmaceutical Ingredient (API) dispersed in the model hydrofluoroalkane (HFA), decafluoropentane (DFP). The dispersed API is deposited onto the can surface in a controlled manner. After deposition, the deposits are sequentially rinsed in a systematic way and then the remaining deposition after rinsing is assayed using a suitable assay technique for the API. The sensitivity of the test may be modified by incorporating API with a known low or high level of surface amorphicity. The described test has been found to be fast to perform, reproducible and sensitive to subtle changes in non-stick canister behaviour and has enabled the rapid screening of a large number of new coating systems and their subsequent optimisation.
30. Monitoring Systems for Inhaled Medication
Poor adherence is an important factor that affects the efficacy of inhaled drug therapy and is associated with negative effects including poor symptom and disease control, increased exacerbations and increased visits to healthcare providers. Therefore, it is important to monitor and improve adherence to benefit the patient, clinician and reduce the demand on healthcare providers and resources. Electronic monitors are the most accurate method of recording adherence, and adherence monitoring has been shown to improve adherence. Inhaler technique is also important, and some monitors incorporate the capability to provide feedback on the use of the device. Monitoring systems which incorporate the capability to upload data to either a clinician's computer or an accessible server are a valuable tool in making a range of treatment and device use data available. Monitoring could also be important to drug development, as poor adherence may affect the outcomes of trials in terms of the effectiveness of the drug or assessing the cause of associated side effects. An effective system would require an accurate, electronic monitor which provides timely data to the patient and clinician. Comprehensive and frequent training with the device is also important and the device should give feedback when used correctly. A monitoring system which utilizes the Internet requires the necessary hardware and software for the patient to upload their data to a secure server, and a program to process and present the information in an accessible manner. Such a system would allow access to up-to-date data by the clinician and device support/clinical trial personnel, who could then intervene to maximize the effectiveness of the patient's inhaled drug therapy. This system could also be efficient in terms of reducing the number of visits to the clinician.
31. Collaborative efforts to understand the fate of drugs delivered to the lungs
The Drugs in the Lungs network was launched in 2010 to provide regular, accessible, supportive fora for technical and scientific discussions with the aim of advancing the knowledge and practice of early- to late-stage inhaled product development. At the inaugural meeting the challenges in inhaled product development and the opportunities for open innovation were explored along with current industry practices for developing inhaled products. It was recognized that for drugs to be developed as inhaled medicines, a better understanding of their fate in the lungs and how this might be modified is required. Harmonised approaches based on ‘best practice’ were advocated for dosimetry and safety studies; this would provide coherent data to help product developers and regulatory agencies differentiate new inhaled drug products. With regard to the disposition and action of drugs in the lung, there are limited reports describing full temporal relationships between pharmacokinetic (PK) and pharmacodynamic (PD) measurements. A better understanding of pulmonary PK and PK/PD relationships would help mitigate the risk of not engaging successfully or persistently with the drug target as well as identifying the potential for drug accumulation in the lung or excessive systemic exposure. Recommendations were made for (i) better industry-academia-regulatory co-operation, (ii) sharing of pre-competitive data, and (iii) open innovation through collaborative research in key topics such as lung deposition, drug solubility and dissolution in lung fluid, adaptive responses in safety studies, biomarker development and validation, the role of transporters in pulmonary drug disposition, target localisation within the lung and the determinants of local efficacy following inhaled drug administration.
32. Deposition of aerosols delivered by nasal route with jet and mesh nebulizers.
The aim of the present work was to quantify the amount of aerosol deposited into the different parts of the airways with a commercially available nasal jet nebulizer (NJN) using a sound effect and to compare its performances with a prototype nasal mesh nebulizer (NMN). Seven non-smoking healthy male volunteers aged from 21 to 36 years with a mean weight 77±10 kg were included in this single-center study. The study was conducted in three steps for each volunteer: 1) selection visit and medical examination; 2) scintigraphic study with NJN, 3) scintigraphic studies with krypton gas and NMN. Furthermore, particle size distribution of the aerosols produced by both nebulizer systems was measured. There was no statistical difference in terms of volume mean diameter (5.6±0.5μm vs 5.6±0.3μm) and fraction of particles smaller than 5μm (44±4% vs 45±2%) between both nebulizers (p>0.9). Aerosol deposition in the nasal region was 73±10% (% of deposited aerosol into airways) for the NJN whereas it was 99±3% for the NMN (p=0.01). Total nasal deposition was 9.6±1.9% of the nebulizer charge for the NJN and 28,4±8,9% for the NMN (p=0.01). 0,5%±0,5% of the nebulizer charge was deposited into the maxillary sinuses for the NJN as compared to 2,6±1,6% for the NMN (p=0.01). Similar low values were measured in the ethmoidal region with NJN and NMN (0,5±0,5% and 2,6±1,4% of nebulizer charge, p<0.01). Although the NMN had the same particle size as NJN, it significantly improves the aerosol deposition into the nasal cavity without deposition into the lungs.
33. Use of ADAM-III Infant Face-Upper Airway Model to Evaluate Performance of Pressurized Metered-Dose Inhaler (pMDI)-Valved Holding Chamber (VHC) with Facemask at Tidal Breathing Patterns Representative of Likely Use
References
Tal, A. et al. (1996), J Pediatr., 1996;128(4):479-84.
34. Visualisation of Powder Fluidisation and Particle Entrainment from Dry Powder Inhalers
Summary
The aerosolization performance of dry powder inhalers (DPIs) is fundamentally controlled by a complex relationship between the patient's inspiratory effort, device design and physicochemical properties of the formulation. Both the patient's inspiratory effort and device engine must work to overcome the bulk and surface interfacial properties of the powder formulation to enable delivery of drug particles to the lung. The fluidization of a DPI formulation is a critical step in the de-aggregation efficiency of aerosol particles, and is governed by the physicochemical properties of particles and their interfacial interactions. However, there remains a paucity of data examining the relationship between the physicochemical properties of powder formulations and their fluidization and entrainment behaviour in different device engines. This paper examines the powder fluidization process and flow behaviour inside the Cyclohaler and Handihaler DPI devices using the Oxford Laser EnVision DPI Platform High Speed Imaging System.
35. The Toxikon Europe Screener Database: a powerful tool for the identification of organic compounds during Controlled Extraction Studies for OINDP's
A “Screener Database” (TES-DB) has been developed, containing over 1600 Volatile, Semi-Volatile and Non-Volatile Organic Compounds. The use of this database allows performing a high level of first pass extractable identification in Controlled Extraction Studies. The compound identification in the Toxikon Europe Screener Database is based on both the confirmation of the retention time of the compound and on its mass spectrum, using hyphenated chromatographic techniques (Headspace-GC/MS, GC/MS and LC/MS). The Screener Database is not only built from commercially available standards, it also contains synthesized compounds or compounds which were isolated from a material extract. In addition, the “Screener Database” identifies Most Probable Compounds (M.P.C.) and Tentatively Identified Compounds (T.I.C.). These M.P.C. and T.I.C. are compounds – often encountered in Controlled Extraction Studies – where no analytical standards are available but where additional structural information can be given. Further developments of the Screener Database will focus on 2 areas: (1) increase the number of compounds – identified in Controlled Extraction Studies – of which the analytical standards are commercially available and (2) perform further identifications of unknown extractables, using advanced analytical “accurate mass” techniques such as GC-ToF-MS, LC-Q-ToF-MS and FT-MS. The identified compounds will subsequently be included into the TES-DB. This ongoing development of the TES-DB will further increase the level of identifications on a first pass basis in future Controlled Extraction Studies, performed on materials used in the manufacture of inhalation devices (MDI's, DPI's, Nasal Sprays, Nebulizers, Valve and Pump components…).
36. Characterizing a Nasal Spray formulation from droplet to API particle size
The interaction of a nasal spray product with the body depends on key variables such as the particle size of the delivered droplets as well as the particle size distribution of the suspended active pharmaceutical ingredient (API) itself. The FDA guidance recommends that droplet size is controlled, to ensure nasal rather than pulmonary deposition, and that the API particle size distribution is characterized both before and after actuation. Laser Diffraction and Automated Image Analysis techniques allow rapid analysis of critical parameters such as API particle size distribution and droplet size determination.
This paper describes how such complimentary analytical techniques, can be used to fully characterise a nasal spray formulation using the Spraytec Laser diffraction system and The Morphologi G3-ID automated image analysis system from Malvern Instruments Ltd. On one hand the laser diffraction offers the ability to monitor changes in droplet size and therefore investigation into the robustness of the delivery system can be performed. On the other hand, automated image analysis allows subtle changes in the API size distribution brought about by the spray process to be detected, which is important as it may affect the bioavailability of the product.
37. Triboelectrification of pharmaceutical powders in the mixing process regarding DPI carrier materials
Since most pharmaceutical powders are small particles of insulating material, electrostatic charge arises following every contact of the particles among themselves or other surfaces in powder handling processes. This charge strongly influences the bulk properties of the powder like flowability and dosing and may even alter the lung deposition behavior of the particles. The sign and magnitude of the arising charge in mixing processes is influenced by many variables such as mixing time, energy input, mixing ratio of the blend, relative humidity, particle size, material and wall-roughness of the mixing container. To properly use powders in the pharmaceutical industry and especially in dry powder inhaler devices (DPI) a good understanding of the charging process is necessary. The aim of this work is to study the arising of charge on mannitol powder as an alternative carrier material in the mixing process. To study the influence of the particles size the powder was mechanical sieved into different size fractions. After storing the powder under controlled relative humidity of 43%RH the powder was blended in polypropylene mixing containers using a T2F Turbula® mixer. After blending the charge was measured in a self constructed Faraday cup connected to a high resistance electrometer. It was shown that charge arises very fast on fine grained insulating powders and reaches saturation within one minute of mixing. For the 63μm-80μm and 100μm-125μm size fraction the saturation charge was about 1,0nC/g and 0,5nC/g, respectively. The results show a higher saturation charge on the finer powders and can be attributed to the higher specific surface of the fine powder which is one major influencing variable on the charging process.
38. The Influence of Crystal Form on the Primary and Secondary Processing of Ipratropium Bromide for Dry Powder Inhalation
Summary
Current pharmaceutical manufacturing for dry powder inhalers (DPIs) relies on formation of primary crystals of an active pharmaceutical ingredient, which is then secondary processed by micronisation to achieve the desired particle size. There remains a paucity of data relating the mechanical properties of the primary manufactured crystals to their secondary processing and final inclusion into the drug product. In this study, crystalline samples of ipratropium bromide (IB) monohydrate and anhydrous IB were isolated using two different crystallisation techniques. There were no significant differences in the Young's modulus of the two materials, which resulted in the production of secondary processed micronised material of each form with similar surface interfacial properties and therefore similar product performance.
39. Using nanoparticles as flowability enhancers in dry powder formulations (DPI)
API (active pharmaceutical ingredient) microparticles, which are used in dry powder formulations, have to meet special criteria. Particles exhibiting an aerodynamic diameter between 1 μm-5 μm are able to reach the deeper parts of the lungs. These microparticles are very cohesive and show poor flow properties, which leads to difficulties concerning volumetrically dosing. Mykhaylova [8] worked on an alternative DPI formulation, which avoided the use of coarse carriers. In our work the flow behaviour of the API was studied by mixing with different concentrations (0%, 0.5%, 2.5% and 12.5%) of Aerosil® R972. The Aerosil® acts as nanoparticulate spacer between the API particles and thereby reduces interparticle interactions and enhances flowability. Two different methods to prepare the mixtures were used namely a Turbula® mixer and electrostatically supported mixing using liquid nitrogen as suspending medium. The theoretical/ analytical model being the basis to calculate the appropriate microparticle/nanoparticle ratio was established by Bresges [9]. Adding spacers to cohesive powder particles yielded an increase in flowability. It was shown that even a minimal concentration of 0.5% of Aerosil® R972 influenced the flow properties in a positive way. Increasing the Aerosil® R972 concentration in order to further enhance the flowability was not successful. It was found that using the electrostatically supported mixing procedure resulted in better outcomes when compared with Turbula® mixing. In conclusion, the use of nanoparticles was shown to improve the particles flowability. Unfortunately Aerosil® R972 is not approved for use in DPI formulations which is the reason why there is need for substances which can be applied as alternatives. It is possible that the use of API nanoparticles as spacers will be of benefit as it will avoid any additional excipient.
40. Performance of the Andersen 8-Stage (ACI) and Next Generation Pharmaceutical (NGI) Impactors Sampling a Dry Powder Inhaler (DPI) with Reduced Aerosol Sample Time/Air Volume
Summary
In the pharmacopeial assessment of DPIs, unless otherwise directed, the aerosol is sampled in a volume of 4 L to permit the entire emitted dose from the inhaler to enter the impactor system and aerodynamic particle size distribution (APSD) determination to be completed. In this way, it is believed that assessment of DPIs can take place without bias imposed by the magnitude of this volume. Recently, however, there has been an interest from those seeking greater clinical realism in the in vitro evaluation of all types of inhaler. In the context of DPI testing, it is recognized that the temptation exists to reduce this volume closer to 1 L in order to replicate more closely the total inhaled volume of an adult patient. The present studies were undertaken in order to investigate how the NGI, which was developed to provide more accurate assessment of APSD than its predecessors following the compendia procedure, performed compared with the ACI when the total volume sampled was reduced from the recommended value.
The continued normal behaviour of the ACI when sampling duration was greatly reduced was unexpected and not easily explained without implying some form of anomalous flow through this impactor ‘short circuiting’ the expected flow pathway. Evidence for this is discussed in the poster. It is recommended that the current compendia volume of 4 L be retained for DPI testing and noted that regardless of the sampling volume, the design of the NGI provides for more accurate inertial size fractionation than that of the ACI.
41. An in Vitro Assessment of the Inhaled Fraction and Particle Size Distribution of a Nebulized Orphan Drug
AP301 is a synthetic and non-proinflammatory peptide version of a structural motif of the human Tumour Necrosis Factor alpha. It is being developed by Apeptico as a promising substance for the treatment of diverse lung diseases and has already received Orphan Drug Designation both in Europe and USA. Its clinical applications include diseases accompanied by hyper-permeable capillaries.
As it is necessary to apply this orphan drug to the lungs, the intended clinical route of administration is delivery as an aerosol. Aerosolization is accomplished by nebulizing the aqueous solution with an active membrane nebulizer. As a prior study has already shown, AP301 as an aqueous solution in combination with this active nebulizer retains its pharmacological effect on ion channels in the alveolar epithelia tested in a patch clamp assay.
Further, it is essential to gather information about the nebulizing efficiency of this novel combination of device and protein solution. Therefore, the output rate and particle size distribution of the produced aerosol were investigated using a modified Pari Compas breath simulator, a Next Generation Pharmaceutical Impactor (NGI) and laser diffraction. Quantification was carried out via UV spectroscopy.
In addition, it was tested whether a variation of the drug solution concentration from 1 mg/mL to 25 mg/mL changed the nebulization behaviour and with it the particle size distribution and output rate, respectively. The study showed that an efficient nebulization of AP301 peptide solutions in a concentration range of 1 mg/mL to 25 mg/mL is possible. High fine particle fractions were obtained together with good inhalation efficiency.
42. Measuring the regional deposition of tobacco smoke in the human respiratory system
Summary
A human volunteer smoking study was conducted with a 7mg (ISO pack tar) commercial cigarette in 6 volunteer smokers to measure the deposition of tobacco smoke particles at varying inhalation depths (as perceived by the volunteer). Simultaneous real time measurements of puffing behaviour, inhalation behaviour and the aerosol properties (particle size and concentration) were taken. The exhaled particle size and concentration was measured directly, whilst the inhaled particle size and concentration was measured by replaying the puffing profile on a smoking simulator thus allowing the particle deposition to be estimated by comparing the inhaled and the exhaled particle concentrations.
The results show that real time measurements of particle number and volume based concentration of inhaled and exhaled cigarette smoke, combined with measurements of inhalation depth and time can be used to estimate the regional deposition of particles in the human lung. The average deposition fractions over six volunteers in terms of percentage of inhaled mass deposited per anatomical region were: Mouth/Throat 18.9%; Bronchi 1.3%; Bronchioles 0.9%; respiratory bronchioles 5.7%; alveoli 14.9%.
The model showed differences in the regional deposition of smoke particles between different inhalation regimes, with normal and deep inhalation increasing the deposition of particles in the alveoli, and a shallower inhalation increasing the deposition of particles in the bronchi.
43. Erect vs. Supine: A Physical Analysis of Aerosol Deposition in the Lungs Based on Results from Human Subject Experiments
Summary
The goal of this work was to carry out a computational analysis of the mechanisms involved in erect and supine inhalation. A recent study for controlled, parametric, individualised 3D Single Photon Emission Computed Tomography (SPECT) showed clear differences in both regional and generational aerosol deposition between the two inhalation positions. Distribution is deeper and overall lung deposition decreases for the supine case. An analytical model was used to simulate aerosol deposition and investigate the role of the extrathoracic (ET) region as a prefilter to the lung, sedimentation as a mechanism of deposition, and lung volume changes. The results suggest that increased ET filtering and decreased lung volume caused by tissue movement on adopting the supine position have a large effect on the differences observed in aerosol deposition distribution.
44. Exploring dose proportionality strategies for dry powder inhaler dose ranging studies
Summary
45. Delivery of si RNA using pressurised metered dose inhalers and nebulisers
Summary
This study was performed to explore the ability of low molecular weight chitosan (CS) nanoparticles associated with different grades of PEG and CS-grafted PEG (CS-g-PEG) nanoparticles as a carrier of siRNA for lung delivery using pMDIs and nebulisers. siRNA encapsulated nanoparticles were prepared (50 to 200 nm) with positive zeta potential at all N:P ratios. Nanoparticle dispersion properties were studied in propellants (HFA 134a and 227ea) visually and using a dispersion stability analyser. CS was labelled with a fluorescent marker and the nanoparticles were tested for their aerosolisation properties when delivered through a jet nebuliser (aqueous) and a pMDI (HFA). Gel electrophoresis was used to assess the association of siRNA with nanoparticles and cytotoxicity was performed using the WST-1 assay. The nebulised fine particle fraction (FPF) was ∼50% for CS-g-PEG nanoparticles and ∼60% for PEG associated CS. PEG-1000 based formulation displayed good dispersion properties with greatest physical stability in HFA 227ea. After 10 min sonication, pMDI formulations with PEG-1000 had a FPF of 45% and <20% for PEG-600, PEG-5000 and non PEG based formulations. Complete binding of siRNA was observed with non-PEG and PEG associated CS nanoparticles when the N:P ratio approached 100:1 whereas CS-g-PEG nanoparticles showed a trailing band. Improved cell viability was found in PEG associated nanoparticles (>90%), whereas CS-g-PEG nanoparticles resulted in higher toxicity at higher concentrations. Confocal images showed efficient uptake of FITC labelled CS-g-PEG nanoparticles to A549 cells. The results suggest that PEG-1000 associated CS nanoparticles have potential for delivery of siRNA to the lung.
46. Evaluation of Surface Energy of Inhalation Powders and Changes in In Vitro Performance
Summary
Micronisation is used in the manufacture of dry powder inhaler formulations to reduce the particle size of the drug substance. This is a process with few control mechanisms that can yield materials with extremely different physical properties. The aim of this study was to investigate the effects of changing micronisation equipment on final product performance. Two batches of a drug substance were prepared to a comparable particle size, using small and large volume commercially available mills. Physicochemical evaluation revealed no evidence for any amorphous material but did show a significant increase in surface energy (SE) of the material prepared in the large mill compared with the small mill. These changes in surface energy correlated with significant changes in the fine particle fraction (FPF) and fines content of the final formulations as measured by Sympatec powder dispersion. Material with the highest SE had a lower FPF and fines content. This indicated that the changes in SE have a significant effect on the adhesive/cohesive forces in the final blend. Blending experiments were also performed using the high SE material with a carrier for use in a dry powder inhaler (DPI). The data showed that increasing blend time decreased the fines content and fine particle fraction (FPF) of the formulations. This relationship was such that optimum blend time to provide the required FPF could be predicted.
In conclusion the data show that changing micronisation equipment can give rise to surface energy changes in a material that can lead to significant differences in final product performance. However, with sufficient understanding of the blending process these changes can be overcome to provide consistent product performance.
47. Characterisation of high dose dry powder aerosols by cascade impaction and laser diffraction analysis.
48. Structural influence of cohesive mixtures of salbutamol sulphate and lactose on aerosolisation and extent of interaction on flow-titration
Summary
49. Further Developments of a mathematical model for simulation of Aerodynamic Particle Size Distributions on Cascade Impactors
Summary
A mathematical model has been developed to simulate the performance of the Andersen Cascade Impactor (ACI) and the Next Generation Impactor (NGI) for pharmaceutical inhaled products. This is an extension of the model developed previously for the ACI by the same group. The model has been validated for both the ACI and NGI over a range of air flowrates using CITDAS Version 3.0 software to confirm accuracy. The maximum error observed in MMAD and GSD calculations is typically less than 0.5% and 0.8% respectively for a wide range of air flowrates and product particle size distributions.
50. Investigation of mechanically dry coated lactose using Inverse Gas Chromatography via both infinite and finite dilution techniques
51. A Collaborative Study by the European Pharmaceutical Aerosol Group (EPAG) to Assess the Flow-Time Profile of Test Equipment Typically Used for p MDI/DPI testing – Part 1: Volume test
52. Correlations between particle size distribution of micronised drug substances and the performance of drug inhalation powders delivered from the Genuair® inhaler
Summary (222/250)
Particle size distribution (PSD) of drug substances used in dry powder inhalers is of critical importance for the development of drug inhalation powders. The definition of particle size depends on several factors including the clinical target in the lung, the type of formulation used, de-aggregation and performance characteristics of the inhaler device, physicochemical properties of the drug formulation, and the stability of the drug substance and the product. This study evaluated the aerodynamic performance of different Genuair® dry powder inhalation products as a function of the drug substance particle size.
Almirall has a range of molecules in different stages of development that are intended for use in the Genuair® inhaler. One micronised active drug substance was chosen with several particle sizes in the range of 2.7 μm to 4.4 μm (D50%) and 4.8 μm to 8.7 μm (D90%). The impact of dose strength was evaluated using a high and a low concentration of micronised drug substance in the lactose blend. The leverage of PSD on the stability of the drug product was also investigated.
The results show a clear correlation between the particle size distribution of the micronised drug substance and the aerodynamic performance of the drug product. Additionally, the stability of the inhalation powder formulations was unaffected during 6 months at storage conditions of 25°C/60% relative humidity (RH) and 40°C/75% RH.
53. The effect of lactose carrier properties on the fine particle dose from dry powder inhalers in dependence of the inhaler design
54. Relating aerosol charge with dosage in a salbutamol sulphate-lactose carrier blend
Investigating the role of electrostatic forces in aerosol particle deposition requires the measurement of aerosol charge generated during inhalational airflow. Five blends of lactose carrier-salbutamol sulphate blend (equivalent to 50, 100, 200, 300 and 400μg salbutamol per 33mg dose) were dispersed into the electrical Next Generation Impactor (eNGI) at 60 L/min, to assess the electrostatic characteristics and in vitro aerosol performance of each blend. The 50μg blend produced a particle size distribution distinctly different to the other blends, with 80% of the dose deposited in the pre-separator, and a fine particle fraction of 5.9±1.4%. By comparison, the 100, 300 and 400μg blends leveled out at 50% mass deposition in the pre-separator, and a fine particle fraction of 18-20%. These results were attributed to the filling of high-energy binding sites on the lactose carrier surface with micronized salbutamol, until fully occupied, whereupon maximum aerosolisation efficiency was achieved. The specific charge distributions (net charge divided by mass, plotted against particle size) overlapped well between the 100, 200, 300 and 400μg blends, showing that increased dosage did not have an effect on the charging mechanism. However, within eNGI stage 1, there was declining charge with increased salbutamol dosage, which was attributed to the increase in the number of salbutamol multiplets on the carrier surface. That fine particle fraction increased from 100 to 200μg dose, but the specific charge profile did not, suggests that electrostatic charge forces were not a significant influence in aerosol performance.
55. Extension of the Abbreviated Impactor Measurement (AIM) Concept to Incorporate Simultaneous Determination of Delivered Dose Uniformity with Efficient Data Analysis Metrics Pertinent to Aerodynamic Particle Size (AIM-DDU Apparatus)
56. Application of NIST-Traceable Size Standards to Ingredient-Specific Particle Sizing
Particle sizing method was validated on NIST-traceable polystyrene size standards. A calibration model was built on polystyrene data to account for the scattering nature of Raman light and achieve more accurate size data. Calibrated PSD of budenoside was compared to raw data.
57. Pulmonary delivery of encapsulated chloroquine phosphate using polyester polymer-based microparticles for potential treatment of lung cancers
58. Evaporation- and Residence Time of Micron Sized Droplets in a Lab Spray Dryer
Summary
In Order to produce powders for inhalation by spray drying, small droplets which are drying within only a view milliseconds have to be generated. The evaporation time of droplets plays an important role during particle formation and influences solid state properties or particle morphology and therefore powder deagglomeration. In order to compare the evaporation time with the residence time of droplets in a modified Büchi-B191 Spray Dryer, evaporation time calculations by adapting the equation of HEIN and CFD analysis using Cosmos FloWorks® are carried out.
In case of a drying gas inlet of 35 m3/h with temperatures between 100°C and 150°C and outlet temperatures between 60°C and 120°C the evaporation time for 10 μm droplets is estimated as 11 to 23 ms for H2O and 3 and 7 ms for ethanol. The residence time in the spray tower varies between 30 and 70 ms for 1 to 10 μm particles depending mainly on the process- and nozzle-gas flow. A further reduction in drying time may be limited by the temperature sensitivity of the spray dried material. Longer evaporation times can result in an incomplete evaporation. Based on theoretical considerations, it could be shown that the evaporation time is mainly influenced by the droplet size, the introduced heat flow, heat losses to the surrounding and the heat flow which is needed for a total evaporation.
59. The Performance of a Tape Based DPI Device
60. Investigating the effect of nano-scale surface coating on the aerosolization of micronized drug powders
Summary
61. Understanding the influence of surface modification via mechanical dry coating on the flowability of a cohesive fine lactose powder
Summary
62. Modelling of Raman Spectral Data for Potency Prediction of DPI Blends
Dry powder inhalation (DPI) blends are routinely analysed by liquid chromatography-ultraviolet spectroscopy (LC-UV) for potency and homogeneity. The aim of this study was to utilise the speed of Raman spectroscopic measurements in order to significantly reduce the burden and cost of testing. By building univariate or Projection on Latent Structures (PLS) regression models for potency the required chromatographic testing for future batches would be greatly reduced. The objectives of the study were to identify an efficient way to create calibration blends, to assess the suitability of univariate versus multivariate models, and to determine the capability of Raman spectroscopy to substitute the current practice of LC-UV for blend potency testing.
Investigations were made to define the best way to produce samples for model building. Due to homogeneity and sampling issues, high shear blending was deemed to be the preferred option. The univariate models based on rationing of spectral bands assigned to API and lactose had good fits but the errors of prediction were higher than the target of 3%. PLS models built using pre-treated spectra again had good fits but also achieved error terms <2%. This study demonstrates that it is possible to create models for predicting blend potency with very low error terms using Raman spectroscopy. Further studies will be conducted in order to assess the suitability of the method to determine homogeneity.
63. Delivering Improved Respiratory Medicines with Industrial Ultrasonic Particle Engineering
The integration of the established processes of spray drying (to confer spheroidal geometry) and sonocrystallization, (for stability and crystallinity) for the manufacture of inhalable particles with optimal size, shape, surface rugosity and surface free energy, has been established. The ultrasound assisted particle engineering technology - UMAX® (Ultrasound Mediated Amorphous to Crystalline transition) - is now undergoing development for the manufacture of corticosteroids, beta agonists, anticholinergics and other drug classes, designed and formulated as inhalable drug products for respiratory disorders.
The technology described requires the use of robust industrial ultrasonic equipment operating at 20 - 100 kHz and facilitates the manufacture of spheroidal and more regular shaped particles for both Dry Powder Inhalation (DPI) and Metered Dose Inhalation (MDI). The inhalable pharmaceutical materials, when formulated, show comparable and often superior in vitro performance when compared to conventional micronized drug product. The use of the particles described can be expected to deliver a proportionate increase in clinical performance and patient compliance, regardless of the device used to deliver the drug substance.
The manufacture of highly crystalline combination particles, whereby two or more pharmaceutical ingredients, such as a corticosteroid and a beta agonist, can also be facilitated by the process technology described. This is particularly beneficial if there is a synergistic action between the multiple drugs, requiring them to be delivered together or when the ratios are very diverse to ensure a consistent dose content uniformity of the drugs in the formulation.
Advanced ultrasonic particle engineering technology can now be incorporated into the manufacture of the next generation of respiratory generic, super-generic and new chemical entity (NCE) medicines.
64. Validating Particle Size and Mass Concentration of Micronized Fluticasone Propionate Delivered as Monodisperse Aerosols
Summary
Aerosol particle size is a major issue for targeting therapeutic drugs via the inhalation route. Existing devices for delivering inhaled drugs produce polydisperse aerosols. Monodisperse aerosols are designed to deliver a drug mass with a narrow particle size distribution and can be used to target therapy. We developed 3 monodisperse aerosols with MMAD's of 1.5, 3, and 6 μm from fluticasone propionate (FP) using a spinning-top aerosol generator. Aerodynamic Particle Sizer's (APS) can measure particle MMAD and mass concentration in near real time but assume that particles are spherical with uniform density. Validation tests of APS measurements were warranted before in vivo experimentation. For validation of APS particle MMAD aerosols were sampled by an Andersen Cascade Impactor (ACI) at a flow rate of 28 L/min for 2 minutes and MMAD was determined by high-liquid performance chromatography (HPLC). For validation of APS particle mass concentration aerosols were drawn through total trap filters using a 2 L volume syringe and concentration mass from filters was determined by HPLC. Regression analysis showed a linear relationship between methods for particle MMAD (r2=0.98) and for mass concentration for the 3 monodisperse aerosols, 1.5 (r2=0.88), 3 (r2=0.89), and 6 MMAD (r2=0.92). Although there was not a one to one correspondence between the two methods for measuring mass concentration this can be resolved by appropriate correction factors. The APS can therefore be used to measure both particles size and mass concentration of a given monodisperse FP distribution.
65. Rapid development of a patient preferred nasal p MDI actuator
Summary
Pharmaceutical devices and products have historically taken many years from initial concept to realisation into a physical product. In this study we have used modern advances in technologies and processes to significantly reduce the development lead times of a nasal pMDI actuator. Improvements in the quality of rapid prototyped samples enabled patient focus groups to interact with a range of realistic representations of the proposed nasal actuator options, and give more relevant feedback. Automated rapid tooling facilities were used to provide moulded parts early in the project. Additionally the use of Computed Tomography made inspection of the nasal actuator components and assemblies rapid, reliable and non destructive. Using sophisticated software to produce chromatic evaluation (colour-coded deviation displays) it was immediately obvious which features of the moulded samples had not been moulded in tolerance. This approach facilitated the moulding of high quality samples which have been physically and pharmaceutically tested to generate better product understanding.
66. Controlling Product Through Predication of Formulation Concentration During Pressurized Metered Dose Inhaler (p MDI) Manufacturing Processes – A Comparision of Theoretical and Empirical Data
The concentration of propellant-based aerosol formulations is known to change during pMDI batch production processes. This is a result of the dynamic liquid-vapor equilibrium for the hydrofluoroalkane (HFA) propellant contained at constant vapor pressure within a closed environment and is caused by evaporation of the propellant to the increasing mixing vessel head space and subsequently concentrating of the pressurized liquid formulation during filling. To maintain the consistent can content, nitrogen purging or addition of propellant are required to either suppress propellant evaporation or compensate the loss. This, however, adds complexity to the process.
Mathematical modeling has been used trying to establish the correlation between the can content and vessel head space changes during filling in order to better understand how the process can be controlled.
In this study, we derived an equation of
Drug Content to the Nominal (%)= Mf/[Mf – a×Dp×(V – b×Mf/Df)]×100%
to predict the can content change at a 10 L scale process. Mf and Df are the mass and density of the remaining liquid formulation when the can is filled; Dp is HFA134a vapor density; V is the mixing vessel volume; a, b are adjustment factors attributed to suppression of propellant evaporation due to presence of the co-solvent.
A formulation containing ∼30% co-solvent was manufactured at 10L scale in a 10 Liter vessel. Aerosol cans filled at different stages were assayed by HPLC. The results showed a good correlation between the actual can assay and the values predicted by the equation when a=0.08 and b=−1 were selected.
The study concluded that the derived equation can be used in predicting and controlling aerosol can content during filling at the scale tested.
67. Flow effects on the accuracy of particle dose reaching a fast-fill/fast-drain p MDI metering valve
Summary
For a typical pressurised Metered Dose Inhaler, the dose of Active Pharmaceutical Ingredient (API) in each actuation increases slightly over the inhaler's life. It is important to minimise this dose increase, but the causes are not fully understood. The current work investigated the possibility that flow effects influence the dose accuracy of suspended API particles. The flow was simulated using Computational Fluid Dynamics, specifically ANSYS FLUENT software. The model was restricted to a liquid-only region, upstream of the complicated region involving vapour/liquid flow. The flowrate was estimated from choked conditions downstream, and imposed on the liquid-only flow as a constant. Particles were released from rest and tracked for the time taken for the liquid to fill the metering chamber. The number of particles reaching the model's outlet was compared to the number representative of the initial particle concentration. Large particles were under-represented when the flow was fast, because they accelerate slowly. Unexpectedly, smaller particles were slightly over-represented. The results were insensitive to the value assumed for Coefficient of Restitution when particles rebounded from wall collisions. However, if particles did not rebound, then the number of particles reaching the model exit was under-represented by approximately 6%. If these particles were released for later actuations, this would contribute to Through Container Life dose increases. Using simulations, it would be possible to minimise undesirable aspects of an inhaler design, such as wall collisions and dead spots.
68. Prediction of Tribological Phenomena in Drug Delivery Devices
Summary
In recent times, the pharmaceutical industry's focus has shifted to the use of hydrofluoroalkane (HFA) propellants for pressure Metered Dosed Inhalers (pMDI). This has meant packaging changes, particularly for the metering valve. The valve contains a number of components of different materials, including elastomeric gaskets. Valve tribology has become an important issue, because of poor HFA lubricity and their complex contact mechanics, in fitment and during valve actuation. Tribology of seals are influenced by their global deformation and mechanisms of film formulation and their rough boundary interactions. The predictive method highlighted here allows for the prediction of prevailing tribological conditions in the seals, which is obtained by Finite Element Method (FEM), determining their globally deformed in-situ shape, also subjected to canister pressure. A combination of tribological phenomena, ranging from viscous action of the formulation through to asperity pair interactions accounts for the generated pressures in the valve seals' conjunctions. The employed methods build upon the work of Karaszkiewicz (1,2,3) and Greenwood and Tripp (4). The results indicate that within these conjunctions the dominant mechanism of friction is the adhesion of asperities. It also shows that only an ultra-thin film of fluid may be adsorbed on the contiguous surfaces with a negligible contribution due to viscous shear. The current method allows for parametric analysis of the assembled inhaler valves, variations in components' dimension and actuation studies. Therefore, a useful tool is made to examine metered dose variability and overall device robustness.
69. The effect of NGI cooling methodologies on aerodynamic particle size
Summary
Research suggests that cooling a Next Generation Impactor (NGI) may give a more realistic distribution of particles from a nebulised product than is seen at ambient conditions. It is postulated that reduced evaporation of droplets occurs at lower temperatures as the heat transfer from the NGI is reduced. This study focuses on the effects of temperature changes on aerodynamic particle size and examines differences between solution and suspension formulations. We also look at the effects of continuous cooling during nebulisation compared with using a fridge.
The NGI was operated as per Ph. Eur. Chapter 2.9.44 (draft) at a flow rate of 15L/min using a commercially available jet nebulizer and testing was performed at a range of temperatures. A solution of Salbutamol sulphate and a suspension of Fluticasone Propionate (FP) were nebulised until exhaustion. Results show that as the temperature decreases there is a corresponding decrease in the fine particle fraction (FPF) of Salbutamol, suggesting that cooling the NGI assists in minimising droplet evaporation. This trend is not as apparent for the suspension formulation which may be a consequence of the size of the particles in the suspension limiting further evaporation. There is an observed difference between the mean FPF for Salbutamol at 5°C in the NGI Cooler compared with the fridge indicating that the temperature rising after the NGI is removed from the fridge also has an effect on performance of the test.
70. Polar and total surface energy distributions determination by inverse gas chromatography
71. Measurement of solution-state salbutamol ion-pair interactions
72. Development of a computational model with predictive capabilities to describe actuation of pressurized metered dose inhalers
Summary
73. The influence of the ambient relative humidity during cooled NGI Testing
Summary
For the purposes of in vitro characterisation of aerodynamic particle size from nebulisers, cooling the Next Generation pharmaceutical Impactor (NGI) for at least 90 minutes to 5°C before use has become an accepted standard in vitro test method. However, the influence of the ambient relative humidity of the nebuliser is critical as the NGI is mostly operated under laboratory conditions with fluctuating relative humidity.
The study was designed to identify the effect of different levels of ambient relative humidity of the nebuliser. Therefore a Safetech Climate Controlled Cabinet where the nebuliser was operated in was connected to a Copley Scientific NGI Cooler which kept the NGI at a temperature of 5±2°C. Aerosol of a drug for inhalation was delivered by two different types of nebulisers: a vibrating mesh and breath enhanced jet nebuliser, Aeroneb Go and Pari LC Sprint operated with Turboboy S compressor respectively. The NGI was operated as per ISO/ DIS 27427 at 15l/min at three different levels: 30, 50 and 70% relative humidity. Results showed that the differences in MMAD measured for Aeroneb GO are less sensitive to changes in relative humidity than for Pari LC Sprint. It is suggested that this may result from differences in the degree of aerosol evaporation within the different types of nebulisers and the humidity of the environment.
74. Determination of Volatile Organic Compounds from the Prohaler Dry Powder Inhaler
Dry Powder Inhalers need to be fully characterized in terms of leachables and extractables, compounds that could be released by the device materials to the powder formulation and subsequently inhaled by the patient, as these compounds could either interact with the formulation and degrade it, or be harmful to the patient. In this study, a method was developed to recover and quantify the volatile organic compounds, coming from the device itself, which could potentially be inhaled by a patient. The method consists in connecting the DPI to an analytical cartridge and to a pump, and to circulate a large volume of air through the device and then the cartridge. The volatile compounds present in the device will be collected and absorbed onto the cartridge. The cartridge is then de-sorbed thermically or chemically and compounds are analysed by GC or HPLC. The study was carried out on a Prohaler DPI device manufactured by Aptar. The following species were identified from mass spectra analysis and quantified : hexamethyl-disiloxane, methyl-6,5-hepten-2-one, nonaldehyde, dodecane, styrene and formaldehyde. All these compounds were identified as coming mainly from silicone rubber, ABS (Acrylonitrile, 1,3-Butadiene, Styrene polymer), polypropylene and polyacetal components. They were all much lower than the Safety Concern Threshold defined in the PQRI guideline for Extractables and Leachables.
75. Making Use of Mensuration Data: ACI and NGI
The particle size distribution of the respirable dose delivered from an inhaler is commonly characterized by the Andersen Cascade Impactor Mk II, (ACI) or the Next Generation Impactor (NGI). The United States Pharmacopeia states that due to occlusion and blockage of jet nozzles, ‘in-use’ mensuration tolerances need to be justified. This is commonly performed by optically counting and measuring each nozzle jet on each stage. The mensuration procedure is often sub-contracted because specialized equipment is required, meaning that at regular intervals impactors are sent off site for a period of up to a month. On return, the user must assess the mensuration data and make a decision with regard to the impactor's suitability for use. In the worst case, the mensuration data identifies the impactor to be unfit for use and all the data collected between the last two mensuration points becomes suspect and unusable. Therefore, it is very important to ensure that in-use mensuration specifications do not unnecessarily fail impactors. In some cases, failure might be considered as one nozzle marginally larger than the critical engineering tolerance. However, since mensuration is its self subject to error, it is important to make a more detailed consideration of what mensuration tolerances are acceptable. To this end, this paper describes a method for defining ‘in use’ mensuration tolerances for the ACI (plus 60lpm and 90lpm conversion kits) and the NGI.
76. Processing Impactor Data using Citdas V3.10
Summary
The pharmaceutical industry generates significant amounts of cascade impactor deposition data during phases of product development, stability testing and batch release. Copley Inhaler Testing Data Analysis Software (CITDAS) is commonly used to rapidly process cascade impactor data.
CITDAS V3.10 allows standardized data processing over the operating conditions of four alternative impactors; Andersen Cascade Impactor (ACI), Multi-Stage Liquid Impinger (MSLI), Marple-Miller Impactor (MMI) and the Next Generation Impactor (NGI).
The latest release, CITDAS V3.10, accurately reports the mass median aerodynamic diameter (MMAD), geometric standard deviation (GSD) and up to five fine particle dose (FPD) groups defined by either impactor stage or aerodynamic particle diameter.
This paper presents the performance of the software for a variety of challenging input distributions and highlights the ability of CITDAS to appropriately report results or identify limits of detection accordingly.
For the twelve distributions evaluated over the operating flow rates of the four impactors CITDAS V3.10 was found to calculate MMAD to within±0.003% of the actual value and GSD to within±0.007%. When calculating FPD ≤5μm using ACI, NGI or MMI the greatest difference in the input and output data was 0.06% of the total drug mass per dose collected on the impactor stages. For the MSLI this value increased to 0.8%. Subdivision of the FPD into five groups found that the respective values increase to 0.7%, 0.3%, 2.1% and 1.5% for the ACI, NGI, MSLI and MMI respectively.
77. Effect of PEGylation on spray dried PGA-co-PDL pulmonary carrier microparticles
78. Dynamic release from lipid nanoparticles for controlled drug delivery to the airways
79. An in Vitro Model to Simulate Inhalation and Exhalation in Mechanically Ventilated Neonates An in Vitro Model to Simulate More Realistically Aerosol Lung Deposition in Mechanically Ventilated Neonates
Summary
Many in vitro models that have been considered to study aerosol delivery to mechanically ventilated patients do not include the expiration part of the inhalation cycle. As a result the estimated drug lung depositions by these methods overestimate in vivo data. Here, we suggest a simple in vitro experimental setup that closely simulates total drug lung deposition in mechanically ventilated neonates. In this approach, two test lungs (Fisher & Paykel Healthcare, UK) using a Y connector were linked to a neonatal endo-tracheal tube (ET tube). This assembly was placed in a Perspex chamber (30x18X18 cm) that was located over an incubator set at 37°C. The test lungs were moisturised by methanol/water solution to simulate wet conditions in the lungs. The ET tube was connected to a ventilator equipped with humidifier. A spacer (Aerochamber MV for use in ventilation circuits (Trudell medical International, London, Ontario, Canada)) was placed between the ET tube and ventilator. The ventilator was adjusted for neonatal settings, and the Qvar 50 was selected to generate drug aerosol particles. It was found that 6.7% of the nominal dose was deposited in the test lungs. This was similar to reported in vivo data. It was found that when a T-shaped connector with one-way valve was placed between the ET tube and the ventilator, and the spacer was placed before the valve, the test lung deposition increased to 9.5% of the nominal dose. This side-aerosol delivery has the advantage that humidity does not deposit in the spacer and a more consistent aerosol delivery to the patient may be achieved.
80. Formulation and in-vitro characterisation of liposomal systems for salmon calcitonin (sCT) delivery to the lung
In the present study, liposomal formulations for aerosol delivery of salmon calcitonin (sCT) were developed and characterised.
Liposomes were prepared by the dry film hydration method. Unilamellar vesicles were obtained by extrusion using an extruder (Lipex), non-encapsulated sCT was separated by gel filtration through polyacrylamide gel columns. Size and ζ-potential were measured with a Zetasizer Nano (Malvern). sCT concentration was determined using RP-HPLC and phospholipid concentration by Stewart's assay. The influence of the loading buffer's pH value (3.5 - 10) and that of the liposomal membrane charge (using PG/DPPG and SA) as well as fluidity (DPPC:Chol vs. PC:Chol), on sCT encapsulation were studied. Moreover, Liposomes (0, 10 and 20% SA) with and without 5% DSPE-PEG2000 were aerosolised using an Aeroneb Pro vibrating mesh nebuliser (Aerogen).
Our data suggested that DPPC liposomes with positive surface charge, hydrated at pH 3.5 were the optimal formulation, obtaining encapsulation efficiencies of 35±4%, particle size of 140 nm (PDI of 0.06). The ζ-potential (in buffer pH 7.4) was 24±1 mV. All liposomes investigated proved to be stable during nebulisation.
Liposomal systems for sCT delivery to the lungs were successfully optimised. Ongoing PK studies will determine if these results can be translated into an in vivo setting.
This study was funded by Science Foundation Ireland. JS is recipient of a Postgraduate Ussher Fellowship.
81. A Formulation/ Device Combination for Systemic Drug Delivery by Inhalation
Summary
82. Structural Phase Transformation in Crystalline Lactose Monohydrate
Summary
For inhalable dosage forms, drug actives and/or excipients usually undergo high energy mechanical processing to reduce particle size (e.g. micronisation). Such materials often experience considerable damage to the crystal lattice, resulting in the generation of defects and surface amorphous content. The bulk properties of these materials in terms of stability, flowability and others are significantly impacted during the process. This is very likely to be linked to the occurrence of these regions. Recently, Phase-Imaging (an advanced feature of atomic force microscopy (AFM)) has been employed to detect changes in the physico-mechanical properties of crystalline materials that have undergone high-energy processing. Phase-Imaging involves the oscillation of a micro-fabricated AFM imaging probe over a sample at a specific resonant frequency. By measuring the lag in oscillation (phase lag) it becomes possible to concurrently measure variations in the physico-mechanical properties of a surface (e.g. viscoelastic response). In this study, selected particles of an active were imaged by AFM before and after mechanical activation. In addition to phase lag data, force-volume measurements of the same areas were conducted.
83. Effect of crystallisation conditions and feedstock morphology on the aerosolozation performance of micronised salbutamol sulphate delivered by DPI
Summary
Dry powder inhalers (DPIs), an important method of drug delivery to the lungs, require drug particles in the respirable size range of 1-5 μm. Micronisation used in the production of particles in this size range, however often leads to heterogeneous product containing mechanically activated surfaces with amorphous content. The aim of this study was to determine strategies for control of drug substance characteristics pre and post-crystallisation to facilitate the production of micronised salbutamol with desirable particle attributes for optimal delivery as an inhaled aerosol. Impact of crystallisation conditions (cooling rate, supersaturation ratio and stirring rate) were evaluated to produce three batches of salbutamol sulphate with different morphology and size. These batches were micronised using FPS spiral jet mill (FPS, Italy) with assessment of the impact of process variables. The particulate and surface characteristics of starting material and micronised samples were characterised using a range of methods. To study the effect of morphology on processing and its impact on aerosolisation performance, salbutamol sulphate without any carrier was evaluated using an in-vitro twin-stage liquid impinger, when delivered using the Aerolizer (Novartis) DPI device. In-vitro study data indicated that % fine particle fraction and % dose emission were dependent on the surface free energy and particle size distribution of micronised drug, which were directly linked to the morphology of feedstock and the crystallisation conditions applied to its production. These results suggest that arosolization performance of micronised salbutamol sulphate can be improved markedly by manipulation of feedstock characteristics through crystal engineering.
84. Phospholipid microparticle based cosuspensions enable the consistent delivery of potent drugs intended for p MDI combination therapy
The clinical benefit of combination therapy for asthma and COPD has been highlighted with the recent FDA approval of combination pMDI products. Their development demands the clinical comparison between the combination pMDI and single component pMDI, administered alone and coadministered sequentially in several doses. The clinical comparison is often complicated by the fact that the in vitro aerodynamic properties of the individual components in the combination are not equivalent to those obtained from a single component pMDI. In addition, maintaining aerodynamic properties while varying the dose of one or more of the combination components is a difficult goal to achieve using conventional pMDI technology. A novel approach utilizes phospholipid microparticles to form uniform, stable cosuspensions in hydrofluoroalkane of a LAMA, a LABA and/or an ICS in mono, dual, or triple combinations. Notable features of the cosuspension pMDI include the fact that the fine particle fraction of a given drug remains constant when emitted from a single, double or triple therapy product, or from different products at various doses. The observed in vitro dose proportionality and lack of coformulation effect translates to the clinic in a straightforward manner.
85. Characterization of NanoGENTTM: Inhaled Gentamicin Dry-Powder Formulation for Prophylaxis and Treatment of Respiratory Infections
Summary
NanoGENT™ is being developed as an inhaled antibiotic treatment for administration to the lungs following exposure to plague (yesrsinia pestis), tularemia (Francisella tularensis) and potentially tuberculosis. The NanoGENT™ gentamicin sulfate inhalation powder from Nanotherapeutics is in preclinical development and was tested using the Respirics ACU-30™ dry-powder inhaler (DPI) with a 30 multi-dose cartridge blister pack. NanoGENT™ was manufactured using the NanoQUAD® cryogenic jet-milling process, which can effectively cryo-mill 50+ kg/hr of unprocessed powders, creating particles <10μm that are suitable for inhalation. NanoGENT™ powder filling in the ACU-30™ DPI was performed at Harro Hofliger using the Omnidose drum filler.
Next Breath has developed and validated test methods for characterization of NanoGENT™ through a 12-month R&D stability study in accordance with the 1998 FDA Draft Guidance for DPI/MDI and ICH guidelines. Parameters such as appearance, assay, impurities and degradants, uniformity of dosage units, dose content uniformity, aerodynamic particle size distribution, moisture content, insoluble particulate matter, particle size distribution, activity, and microbial content were monitored for stability. At the 6 month time-point, no significant change in the stability parameters was observed. Emitted Dose (ED) was 85%-90% and the average fine particle fraction (FPF <9.0μm) by Andersen Cascade Impactor (ACI) was 25%-30%. The other 60% was deposited in the USP induction port and pre-separator. Airborne plague, tularemia and tuberculosis spores may deposit in the upper oropharyngeal region, allowing this deposition profile to target the site of infection. For each 25mg blister dose inhaled, about 4-12mg of gentamicin sulfate may be deposited per dose in the respiratory tract for treatment.
86. The influence of co-solvent on co-spray dried sodium carboxymethylcellulose and a model protein
Summary
The aim of this study was to investigate the influence of co-solvents on co-spray dried sodium carboxymethylcellulose and alkaline phosphatase (a model protein) and analyse the stability of the formulations produced. This investigation also seeks to assess the in vitro suitability of utilising either pressurised metered dose inhaler (pMDI) or dry powder inhaler (DPI) in the delivery of the various spray dried powders to the lungs. Four spray dried powders were investigated: a control comprising of 2% w/v spray dried enzyme alone, and three test formulations comprising of combinations of sodium carboxymethylcellulose (80%) and enzyme (20%) spray dried from a water based suspension feedstock and two water-ethanol (70:30 and 90:10) suspension feedstocks, with suitably adjusted spray drying parameters. The alkaline phosphatase activity, molecular weight, particle size, moisture content, crystallinity and yield of the spray dried formulations were assessed. Both DPI and pMDI formulations were prepared. In vitro deposition studies of the various DPI formulations indicate that both co-solvent modified formulations had a significantly higher % emission from the devices (p<0.01) and % fine particle fraction (<5 μm) (p<0.01) than both the control and the spray dried formulations prepared from non-modified (water only) solvent system. In vitro deposition studies of the pMDI formulations shows no significant difference between the % emission of the various formulations but significantly higher percent respirable fraction for the water only (p<0.05) and the water-ethanol (90:10) (p<0.01) solvent system. The selection of appropriate solvent systems offers the ability to prepare spray dried powders suitable for the pulmonary delivery of peptides and proteins since they possess very low inter-particulate cohesion and the requisite particle size needed for alveolar deposition.
87. Feasibility Study of OSCN− and Lactoferrin (Meveol®) Nebulization for Cystic Fibrosis Patients.
88. Development of I-neb Insight Online for Home Monitoring of Inhaled Medication- a New Telemedicine Option
Summary
The I-neb Adaptive Aerosol Delivery (AAD) System is an efficient nebulizer system which provides feedback on use to the patient. The I-neb AAD System also incorporates a Patient Logging System (PLS) which stores data relating to treatment. An infra-red cradle and the I-neb Insight software can be used to download the PLS data, which can be used by the patient's clinician to identify and address any issues with the patient's adherence to prescribed regimen or use of the device. A new I-neb Insight Online was developed that consists of an Internet based system which allows the patient to upload their data regularly from home and the clinician to remotely access the up to date data in order to effectively manage the patient's inhaled therapy. The use of Internet based technology such as this is rapidly increasing due to the role that telehealth services can play in improving patient care. For the development of I-neb Insight Online, a secure multi-access information hub was created to allow patients, clinicians and the patient support programme (PSP) personnel to access data uploaded by the patient. This information is automatically analyzed and presented in an accessible graph form. The patient's actual data is displayed in comparison to prescribed treatment data to highlight any differences and flag up potential issues. The PSP personnel are able to identify patients not using the device optimally and address these in a timely manner and the clinician can view all the data and intervene to address any difficulties with adherence or device use. The I-neb Insight Online software could be used to optimize the clinician's patient management through access to regular, up to date data on various aspects of treatment. The I-neb Insight Online software is currently being tested in a pilot study.
89. EPAG-Sponsored Workshop on Abbreviated Impactor Measurement (AIM) and Efficient Data Analysis (EDA) Concepts in Inhaler Testing: Overview of AIM-EDA
Summary
90. Further Evaluation of the Fast-Screening Impactor for determining Fine Particle Fraction of Dry Powder Inhalers
The M185 - Fast-Screening Impactor (FSI, MSP Corp., St. Paul, MN) has been evaluated for the rapid generation of fine particle fraction (FPF) data as an alternative to full resolution cascade impaction. Data obtained from the FSI was compared with that from the Next Generation Impactor (NGI, MSP Corp.) for dry powder inhaler (DPI) products in four devices. In all cases, FPF from the FSI was higher than inferred from the aerodynamic particle size distribution (APSD) obtained by NGI. The difference between FSI and NGI data was substantially greater for one of the 4 products, where the estimate of FPF from the FSI was approximately 70 % higher than that from the NGI. This product was known to be highly flow-dependent, and could therefore be sensitive to differences in the pressure drop profile experienced by the device as a result of the substantially lower internal volumes of the FSI compared to the NGI. This hypothesis was supported by data showing that the initial acceleration of flow through the devices was higher with the FSI and the NGI. While the FSI may in many cases generate sufficiently comparable data to full-resolution impactors to be of utility for rapid screening of formulations in early development, the data presented suggests that caution should be exercised in the use of the FSI to compare products in different devices, and in the testing of highly flow-rate dependent products, where the small internal volume of the FSI may affect its comparability with other impactors.
91. Assessment of Abbreviated Impactor Measurement (AIM) Methods for Nebulizer Characterization
92. Measuring the fine particle dose using inter-stage filters in the NGI – an overview of two methods
93. Comparison of Next Generation Impactor and Fast-Screening Impactor for determining Fine Particle Fraction of Dry Powder Inhalers
Summary
Multi-stage cascade impactor testing is now a well accepted pharmacopoeial technique for determining fine particle fractions (<5μm) of orally inhaled drug products (OIPs). This study investigates the use of a Fast Screening Impactor (FSI, MSP Corp., St. Paul, MN, USA) which employs a single cut-off giving information about the fine (respirable) and coarse fractions in comparison with the NGI (Next Generation Impactor). Comparisions were obtained using a DPI currently in development. The objectives of the study were to look at several aspects of impaction testing including:
- the performance of the FSI vs the NGI; - the effect of coating the collection surface of the insert in the impactor; - the comparison of emitted dose data from the FSI vs. a dose unit sampling apparatus (DUSA); - a comparison of testing parameters for the NGI and FSI; - estimation of time and cost advantages of FSI testing vs. NGI testing.
Analysis of the data collected revealed substantially similar performance between the NGI and FSI. In the case of the DPI and powder formulation used in this study, coating the collection surfaces of the FSI did not have any notable effect. Emitted dose data from the NGI (total amount recovered) compared favourably with DUSA data. Testing parameters were seen to be similar between the two impactors, the only difference being that the FSI had lower air resistance. Significant time (58%) and cost savings (33%) were achieved with the FSI equipment.
94. Feasibility of Fast Screening Impactor as a Screening Tool
This work demonstrated the feasibility of using the Fast Screening Impactor® (FSI) as a quick screening tool for early development of pressurized metered dose inhaler (pMDI) and nebulizer formulations. Formulations with different excipients, sizes, morphologies, and concentrations were tested using the standard Anderson cascade impactor (ACI) or Next Generation pharmaceutical Impactor (NGI) and the abbreviated (FSI) impactor. Screening of pMDI formulations by FSI with different excipients resulted in fine particle dose (FPD) measurements comparable to NGI. Similarly, excellent correlation (R2 ∼ 0.97) between FPD generated from the FSI and NGI were observed during the nebulizer formulation screening. In addition, comparability of FSI performance to ACI and NGI for fine particle fraction (FPF) was explored. The FSI generated a slightly larger FPF than the ACI but a similar FPF to values from the NGI. This outcome could be due to the inherent difference in collection efficiency curves between the impactors. The results proved the utility of FSI as a screening tool for both pMDI and nebulizer formulations.
95. Comparison of NGI and the Fast Screening Impactor (FSI) for Suitability for Analytical Drug Development
Summary
An evaluation was conducted to establish the suitability of the fast screening impactor (FSI) as a viable alternative to the Next Generation Impactor (NGI) in applications where the full aerodynamic particle size distribution (APSD) is not required and to increase efficiency in technical development. The main aspect evaluated was the fine particle fraction (FPF) using a 5 μm cut-off plate for the FSI and interpolation of data between cups to give a 5 μm FPF for the NGI at 90 L/min and at 30 L/min. Total recovery from the FSI was compared to recoveries typically achieved with NGI. Three dry powder inhaler (DPI) products were analyzed to evaluate a wide product portfolio to determine the general applicability of the FSI over a range of product types and strengths. Results showed that the FSI generates FPFs up to 20% higher FPF than those from the NGI when the pre-separator of both devices were used in the same manner. It was determined that by using a coating on the bottom plate of the pre-separator of the FSI the difference in FPF between FSI and NGI could be reduced to less than 6%. This suggests that the addition of the cut-off plate in the pre-separator of the FSI results in the re-entrainment of larger particles, which then deposit onto the fine particle filter. This result was consistent across all product types and confirmed the suitability of the FSI as a general performance testing replacement for the NGI when full APSD testing is unnecessary and/or too time consuming.
Abstract Author Index by abstract number
A
Adi, H., 18
Ahmed, S.M., 77
Alzoubi, T., 79
Anja Cerstiaens, I., 35
Arp, J., 51
Avvakoumova, V., 8, 33
B
Balmpakakis, D., 62
Batykefer, L., 56
Behara, S.R.B., 48
Berg, E., 92
Beusen, J.-M., 35
Biddiscombe, M.F., 64
Biggs, P., 42
Blagden, N., 83
Blatchford, C., 49, 51
Bogard, H., 90
Bolger, M.B., 6
Bonfils, P., 32
Bordeau, P., 87
Boyden, T., 12
Bresges, C., 39
Brewer, R., 65
Brody, R., 62
Brown, M.B., 71
Buske, S., 41
C
Caillibotte, G., 43
Casper, R., 85
Cave, P., 13
Chambers, F., 19, 51
Chan, H.K., 18
Chan, L.W., 23
Chana, J., 78
Chantrel, G., 32
Cheng, S.J., 15
Chew, Y.D., 95
Childerhouse, N., 46
Christiaens, P., 35
Cole, P.J., 27
Colombani, A., 45
Conway, J., 43
Cooper, A., 49, 90
Copley, M., 40, 51, 89
Cordts, E., 41
Coultes, B., 8
Crapper, J., 18
Cummings, H., 84
D
Dailey, L.A., 26
Das, S.C., 50, 70
Dasani, A., 65
David Christopher, J., 55
Davidson, I., 46
Davies-Cutting, C., 66
de Beaunay, B., 62
de Boer, A.H., 47, 53
De Gersem, R., 32
de Matas, M., 83
De Smedt, F., 35
De, S., 85
Decressaint, S., 74
Denmen, J.A., 61
Denyer, J., 30, 88
Despres-Gnis, F., 93
Dickens, C., 42
Dimaguila, M., 49
Diot, P., 32
Dissanayake, S., 4
Dobry, D.E., 12
Donovan, M., 11
Doyle, C., 8, 33
Doyle-Eisele, M., 12
Dulsat, J.F., 52
Dwivedi, S., 84
Dyche, T., 30, 88
E
Egen, M., 58
Ehrhardt, C., 80
Ehtezazi, T., 79
Eppler, B., 85
Evans, A., 13
F
Feilden, A., 19
Fichant, E., 87
Finlay, B., 8, 33
Finlay, W.H., 1
Finney, C., 66
Fischer, B., 41
Fleming, J., 43
Fletcher, D.F., 18
Fletcher, S., 26
Flude, L., 13
Flynn, B., 84
Folger, S., 52
Forbes, B., 26, 31, 78
Fowdar, N., 69
Friedman, K., 43
Friesen, D.T., 12
Frijlink, H.W., 47, 53
Fuhrman, M., 56
Fyrnys, B., 52
G
Garde, F., 52
Gardner, D., 85
Gengenbach, T., 60, 61
Georgi, E., 87
Geys, P., 35
Glaab, V., 51
Golden, M., 84
Govind, N., 45
Grasmeijer, F., 47
Greguletz, R., 51
Grimble, D.W., 68
Grosjean, B., 74
Gruben, K., 53
H
Habel, L., 35
Hagedoorn, P., 47, 53
Hall, R.L., 27
Hammond, M., 40, 69
Hammoud, B.E., 85
Harang, M., 72
Harris, D.S., 25
Heath, V., 90
Hebbink, G., 14
Heng, P.W.S., 23
Hipkiss, D., 38
Hodson, D., 67, 68
Hoe, S., 9, 54
Hopkinson, N.S., 13
Huck, D., 36
Hume, V., 13
Hutcheon, G.A., 57, 77
I
Iley, T., 51
Ingham, A., 86
Ismail, F.M.D., 57
Ivey, J., 84
J
Jamar, F., 32
Jinks, P.A., 29
Jones, C., 63
Jones, S., 78
Jones, S.A., 71
K
Kalsi, H.S., 64
Karner, S., 37
Katz, I., 43
Kelly, J.L., 13
Khidr, S.H., 77
Kinnunen, H., 14
Kippax, P., 36
Kirk, J.F., 85
Klueva, O., 56
Kocinsky, J., 81
Kou, X., 23
Kroneberg, P., 43
Kubavat, H., 82
Kubavat, H.A., 38
Kuehl, P.J., 12
Kuhli, M., 41
Kumar, A., 26
Kumb, J., 51
L
Lacombe, J., 66
Larson, I., 48, 70
Laube, B.L., 3
Le Corre, B., 74
Le Guellec, S., 32, 87
Le Pennec, D., 32
Lechuga-Ballesteros, D., 84
Lee, K.C., 72
Lenz, A.-G., 5
Leone-Bay, A., 81
Levoguer, C., 36
Lewis, D.A., 75, 76
Lien Nguyen, K., 21
Limbrick, M., 33
Littringer, E.M., 16
Lord, V.M., 13
Lucius, M., 62
Lukacova, V., 6
Lyapustina, S., 55
Lyon, D.K., 12
M
MacKay, H., 8, 33
Mao, L., 66
Marino, M., 81
Martin, A.R., 43
Martin, D., 10
Masso, A., 52
Matthews, L., 85
Matzer, J., 66
McAughey, J., 42
McAulay, E., 90
McGrath, C., 42
Merolla, L., 26
Mescher, A., 16
Michelet, O., 74
Mitchell, J., 8, 33, 40, 51, 55, 89, 91
Mohammed, H., 40, 51
Monsallier, E., 90
Morrical, B., 95
Morton, D.A.V., 48, 50, 60, 61, 70
Mudway, I., 26
Muellinger, B., 43
Muresan, A.S., 14
Murnane, D., 44, 72
Murphy, S.D., 34
Mykhaylova, V., 39
N
Nagel, M., 8, 33
Newman, S.P., 7
Nichols, S., 51
Noga, B., 84
Nuttall, M., 8, 33
O
Oguejiofor, W., 86
Olkhovyk, O., 56
Orevillo, C., 84
Otero, R., 52
P
Page, C.P., 71
Parikh, D., 63
Parisini, I., 26
Patel, A., 71
Pearce, L., 30, 88
Perkins, J., 42
Perkins, M., 46
Perraudin, J.P., 87
Pichelin, M., 43
Pietschmann, H., 41
Pitance, L., 32
Polkey, M.I., 13
Price, R., 14, 24, 34, 38, 82
Priore, R., 56
Q
Qu, L., 60, 61
R
Rabbetts, I., 30, 88
Raghvani, H., 19
Rahnejat, H., 68
Ray Chaudhuri, S., 6
Reisner, C., 84
Reychler, G., 32
Richardson, E., 85
Roberts, D., 40, 51
Robison, T., 59
Rogueda, P., 95
Ruecroft, G., 38, 63
Russell-Graham, D., 51, 90
S
Saleem, I.Y., 57, 77
Samy, E.M., 77
Sanchez-Antequera, Y., 5
Sanders, M., 20
Scherließ, R., 17
Schmid, O., 5
Schnepfleitner, S., 39
Schröttner, H., 16
Schultz, R., 84
Scott, N., 25
Serrano, L., 52
Seville, P., 86
Shariare, M.H., 83
Sharma, K., 45
Shelton, C., 51
Sheng, G., 94
Shur, J., 14, 24, 34, 38, 82
Silva, N., 51
Smith, R., 49
Smutney, C., 81
Smyth, H., 11
Solomon, D., 69
Somaraju, S., 85
Somavarapu, S., 45
Sommerville, M., 84
Speck, J.H., 84
Spindle, R.W., 12
Stahl, K., 52
Steckel, H., 41
Stein, S., 59
Stewart, P., 48, 50, 70
Stewart, P.J., 60, 61
Stobbs, B., 90
Stordeur, P., 87
Suman, J., 85
Svensson, M., 51, 92
Swaminathan, J., 80
Symons, D.D., 15
T
Talton, J.D., 85
Tawfeek, H.M., 57, 77
Taylor, G., 2
Taylor, K.M.G., 45
Teresa Carvajal, M., 23
Theodossiades, S., 68
Tougas, T., 55
Traini, D., 9, 18, 54
Tservistas, M., 91
Turner, M.A., 79
U
Uhlig, M., 91
Urbanetz, N.A., 16, 37, 39
Usberti, F., 51
Usmani, O.S., 28, 64
V
Valand, M., 44
Vecellio, L., 32, 87
Vehring, R., 84
Virden, A., 36
Vodak, D.T., 12
W
Wagenseil, L., 41
Walzel, P., 16
Wang, Z., 59
Watanabe, W., 94
Waters, C., 85
Weiler, C., 58
Wereley, S., 23
Williams, G., 74, 93
Williams, K., 73
Willoughby, A., 25
Wills, P.J., 27
Woltosz, W.S., 6
Wong, W., 18
Wynn, E., 67
Y
York, P., 83
Young, P.M., 9, 18, 22, 54
Z
Zhou, Q., 50
Zhou, Q.T., 60, 61
Zhuravskaya, A., 42
