Abstracts from The Aerosol Society Drug Delivery to the Lungs 21 Edinburgh International Conference Centre Edinburgh,Scotland,UK December 9–11,2010

1. Idealized Throat Replicas for Inhaler Testing

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

5. A system for efficient and dose-controlled delivery of liquid substances to in vitro cell models of the lung epithelium

6. Application of a Respiratory PBPK Model for Simulating Pulmonary Administration of Fluticasone Propionate in Humans

Background: A recently developed physiologically-based multi-compartment mathematical model of the lung (within GastroPlus™) was used to simulate the absorption, distribution and pharmacokinetics (PK) of inhaled fluticasone propionate (FP) in humans.

Methods: Systemic PK was described by a physiologically-based pharmacokinetics (PBPK) model. The built-in pulmonary and gastrointestinal (GI) physiologies within GastroPlus were used without modification. Physicochemical properties of FP were predicted from structure using ADMET Predictor™ v5.0 as well as additional QSAR models based on literature data. The initial distribution of the inhaled aerosol in the different lung compartments was given by the built-in ICRP66 deposition model, with default airflow and physiological inputs. All parameters were used at their suggested defaults without further adjustments to simulate pulmonary administration across multiple doses. A parameter sensitivity analysis on particle size was performed to analyze its effect on predicted bioavailability.

Results & Discussion: The simulated plasma concentration-time (Cp-time) profiles provided reasonable agreement with observed data across all doses. Discrepancies for the highest dose can be attributed to mechanisms that have not been accounted for (such as concentration-dependent binding) or limitations of the predicted values of the physicochemical parameters.

Conclusion: This model and methodology provides useful information for the design and selection of drug candidates during lead optimization, as well as a means to predict the therapeutic dose and window for associated toxicological studies.

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

9. Electrostatic charge: we can measure it but does it really influence dry powder inhalation formulations?

10. The Use of NMR in pMDI Development

11. Widening the Lens: Re-evaluating the Influence of Size and Morphology of DPI Carrier Particle Performance

12. Novel Engineered Particle Formulation For Inhaled PYY(3-36) And Demonstration Of Appetite Suppression In A Mouse Model

13. Singing for Breathing^TM Effects of singing lessons in patients with COPD-A Randomised Control Trial

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

17. Comparison of in vitro methods to determine nasal versus lung deposition of a protein formulation

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

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

24. Engineering of Dry Powder Inhaler Formulation: The Colloidal Science Approach

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 Pa^½ 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

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 not ionic strength, was demonstrated to be the critical property since addition of NaCl, glucose, mannitol or urea all similarly increased the transportability of sputum samples. An important, counter-intuitive observation was that sputum samples concentrated by evaporation of water were transported more rapidly. Both osmolarity and mucus polymer gel concentration were increased in these samples. The pivotal role of osmolarity explains the paradox that ciliary transport speed was increased by making “thick” mucus “thicker”!!.

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”

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

Background: Aerosol delivery performance of pMDI-infant VHCs with facemask (anti-static AeroChamber Plus^® with Flow Vu^® Inspiratory Flow Indicator (IFI)) has been investigated as a function of tidal breathing metrics appropriate to infant use.

Methods: A model infant face having realistic mechanical response to that of skin and underlying soft tissues together with an anatomically correct nasopharynx was used to explore the effect of varying tidal volume (30 to 90-mL) and respiration rate (15 to 35-breaths/min) on delivery of salbutamol.

Results: Although most trends were small, delivered drug mass at the distal end of the upper airway, representing delivered mass to the lungs, tended to increase with tidal volume, reflecting more efficient aerosol transport. Drug deposition to the face/nares and also within the airway of the model also increased. Interestingly, although breathing rate increases had a smaller effect on delivered mass, retention of drug in the airway increased significantly at the two highest tidal volumes (70 and 90-mL), indicative of the onset of enhanced inertial deposition at the relatively larger instantaneous flow rates associated with these high respiration rates. Delivered mass values at a standard condition (50-mL tidal volume and 25 breathing cycles/min) were consistent with previously measured data and were also in qualitative agreement with clinical data reported by Tal et al. (1).

Conclusions: The ADAM-III infant model provides insights into likely VHC delivery performance to the lower airway, within a range of breathing patterns appropriate to patient use.

34. Visualisation of Powder Fluidisation and Particle Entrainment from Dry Powder Inhalers

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

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

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

43. Erect vs. Supine: A Physical Analysis of Aerosol Deposition in the Lungs Based on Results from Human Subject Experiments

44. Exploring dose proportionality strategies for dry powder inhaler dose ranging studies

45. Delivery of siRNA using pressurised metered dose inhalers and nebulisers

46. Evaluation of Surface Energy of Inhalation Powders and Changes in In Vitro Performance

47. Characterisation of high dose dry powder aerosols by cascade impaction and laser diffraction analysis.

Background: Developments in high dose dry powder inhalation continue to challenge the viability of pharmacopoeial methods for drug aerosol characterisation. Especially the occurrence of bounce effects can cause the amount of fines (<1 μm) to be highly overestimated in particle size distributions (PSDs) obtained by cascade impaction (CI).

Methods: In this study the most suitable technique for the characterisation of dry powder aerosols from the Twincer^© inhaler containing 5-50 mg of colistin sulphomethate has been determined. To investigate the occurrence of bounce effects, results from cascade impaction analysis with the Next Generation Impactor (NGI) and the Multi Stage Liquid Impinger (MSLI) have been compared with data from laser diffraction analysis.

Results: In the MSLI bounce effects do not occur, but the low number of stages severely limits accurate data interpretation. With the NGI used with a standard impaction plate coating the particle fraction <1 μm is higher than what can be expected from RODOS dispersion data for all doses dispersed. Only when solvent soaked glass fibre filters are used as an impaction surface in the NGI, bounce effects are minimised and PSDs obtained with this impactor are very similar to those from laser diffraction.

Conclusions: Bounce effects can be minimised when testing high dose dry powder aerosols from the Twincer^© with the MSLI and NGI. A reduced measurement time, a higher reproducibility and a greater number of size classes in the particle size range of interest for inhalation make laser diffraction a very useful alternative technique for development purposes.

48. Structural influence of cohesive mixtures of salbutamol sulphate and lactose on aerosolisation and extent of interaction on flow-titration

49. Further Developments of a mathematical model for simulation of Aerodynamic Particle Size Distributions on Cascade Impactors

50. Investigation of mechanically dry coated lactose using Inverse Gas Chromatography via both infinite and finite dilution techniques

Background: The flowability of cohesive lactose powders significantly improves when mechanically dry coated with magnesium stearate. For improved flow, cohesive forces have been shown to decrease, and therefore, it is assumed that surface energy will also decrease. However, previous studies found an increase in dispersive surface energy (γ^D) determined at infinite dilution by inverse gas chromatography (IGC). Total surface energy (γ^T) is a combined result of dispersive (γ^D) and polar contributions (γ^P). Moreover, surface energy measurement at infinite dilution reflects interactions with only the highest energy sites and so may not truly represent total surface energy status.

Methods: Using a finite dilution technique in IGC, this study compared γ^D, γ^P and γ^T distributions and work of cohesion (W_co) between uncoated lactose and dry coated lactose (lactose dry coated with 1% MgSt w/w using a Nobilta AMS-Mini mechanofusion).

Results: At infinite dilution, the γ^D of dry coated lactose (51.4±1.2 mJ/m²) was higher than uncoated lactose (45.4±1.2 mJ/m²) although γ^P, γ^T and W_co decreased. At higher surface coverage determined at finite dilution, the γ^D of dry coated lactose was lower than that of uncoated lactose. Similarly the γ^P, γ^T and W_co of the dry coated lactose were lower than corresponding values for uncoated lactose at higher surface coverage.

Conclusions: The study concluded that the surface energy distribution measurement at finite dilution could aid in understanding dry coated lactose characteristics and behaviour. The decreased surface energy measured with this new approach, and W_co of dry coated powders were consistent with improved flow behaviour.

51. A Collaborative Study by the European Pharmaceutical Aerosol Group (EPAG) to Assess the Flow-Time Profile of Test Equipment Typically Used for pMDI/DPI testing – Part 1: Volume test

Background: We report here on the first of a two-part study aimed at characterizing the flow-time profiles of typical test equipment used for pMDI/DPI testing. The study focussed on assessing methodology to determine the sampled volume as indicative parameter and assessing the flow-time characteristics generated by typical test equipment as used for pMDI/DPI. The objectives were to define a test method and conditions for determination of volume, to assess the applicability and variability of the method, and to generate typical volume data that may be useful for comparison or definition of system suitability tests (SSTs).

Methods: The flow measurement method used a thermal mass flow sensor that internally integrates the flow-time curve to display the volume sampled by the cascade impactor respectively sampled by collection tubes for delivered dose testing. Three orifices were used to simulate a typical DPI device resistance by generating a pressure drop of approx. 4 kPa at the respective test flow rate. The volume that results from a defined inhalation time of 4 seconds at different air flow rate levels was measured. In total, 34 experimental arrangements were examined and a total of 306 individual volume measurements were performed.

Results: The mean sample volumes per flow rate level of 30, 60, and 90 L/min were 1.99 L (n=102, RSD=3.24%), 4.00 L (n=102, RSD=2.53%), and 6.07 L (n=102, RSD=2.03%) respectively.

Conclusion: The results showed that the method is both straightforward and precise, and can be used for verification tests during the operating life of test equipment.

52. Correlations between particle size distribution of micronised drug substances and the performance of drug inhalation powders delivered from the Genuair^® inhaler

53. The effect of lactose carrier properties on the fine particle dose from dry powder inhalers in dependence of the inhaler design

Background: Various lactose carrier particle properties are recognised as being relevant to the fine particle dose (FPD) from dry powder inhalers (DPIs). Particularly the presence of a certain amount of lactose fines and smooth, clean carrier surfaces are believed to have a positive effect on drug re-dispersion during inhalation.

Methods: Adhesive mixtures were prepared with budesonide and different marketed carrier products from different manufacturers, having different particle size distributions, and tested upon FPD from two different DPI concepts, having different de-agglomeration principles, at 4 kPa. FPDs were related to different carrier properties to investigate whether the claims and suppositions made in literature regarding the effects of these properties are irrefutably true.

Results: The effects of carrier size distribution, carrier surface payload, the amount of lactose fines and surface rugosity on FPD in this study appeared to depend on the type of DPI concept used. In a number of examples the effects were even opposite for the two different DPIs used.

Conclusions: The findings underline the hypothesis that parameters and variables relevant to drug re-dispersion from adhesive mixtures during inhalation interact with each other. The effect of any of these parameters on FPD may depend on the choices made for the others, as for the choice of DPI in this study. It can be shown that the effect of variations in carrier properties on FPD may widely be eliminated by using an effective (e.g. classifier based) de-agglomeration principle, as in the Novolizer.

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)

Background: The Cascade Impactor Working Group of the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS) has extended the AIM concept to include an apparatus for oral inhaled product testing that could be used for the simultaneous determination of delivered dose uniformity (DDU) and efficient data analysis (EDA) metrics pertinent to aerodynamic particle size (AIM-DDU Apparatus).

Methods: We present an outline of the concept together with considerations driving the design as well as statistical arguments for combining these measurements.

Results: Although the design is a concept at this stage, statistical considerations associated with combining both methods predict improved decision making by virtue of eliminating variability associated with the need to make two separate measurements with different inhalers at different times etc.

Conclusion: The AIM-DDU apparatus will be made available in the public domain in early 2011 for user experience to be gained. A designed experiment to compare separate with combined measurements is the logical conclusion to demonstrate the prediction.

56. Application of NIST-Traceable Size Standards to Ingredient-Specific Particle Sizing

Background: Inhaled drug efficacy closely correlates with the particle size of the active pharmaceutical ingredient. Formation of polymorphs, hydration, and agglomeration can severely perturb drug bioavailability in the final formulation. Ingredient-specific particle sizing (ISPS™) technology based on Raman Chemical Imaging (RCI) is a promising method for particle size analysis to benefit the NDAs and ANDAs bioequivalence requirements for nasal spray suspensions. Advancements in RCI processing were employed to measure drug particle size distribution (PSD) in commercial aqueous nasal spray suspension.

Methods: Optical microscopy and RCI were used to characterize the budesonide PSD in Rhinocort Aqua^® (AstraZeneca, Wilmington, DE) using FALCON II™ Wide-Field RCI System (ChemImage Corporation, Pittsburgh, PA) with 532 nm laser.

Results: Carbon-carbon stretch at 1656 cm⁻¹ served as a spectroscopic marker of the active ingredient. Sizing the objects of interest was performed by processing intensity of each detected object in individual FOVs. Over 2500 particles of the API were counted and PSD based on equivalent circle diameter was evaluated for D10, D50, D90, mean and standard deviation.

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.

Conclusions: Wide-field RCI has shown promise for objective measurement of drug-specific PSD in Rhinocort Aqua® nasal spray. A calibration model was developed using NIST-traceable polystyrene microspheres. Automated data acquisition and image processing produce objective, accurate drug particle sizes with sufficient sampling required for product quality assessment.

57. Pulmonary delivery of encapsulated chloroquine phosphate using polyester polymer-based microparticles for potential treatment of lung cancers

Background: Chloroquine a potent antimalarial also demonstrates potency against selected cancers. In this study, we demonstrate pulmonary delivery of encapsulated chloroquine phosphate (CQP) using three poly(glycerol adipate-co-ω-pentadecalactone) microparticles, PGA-co-PDL, PEG₁₅₀₀-PGA-co-PDL and PEG₄₅₀₀-PGA-co-PDL, and its effects on lung cancer cell growth.

Methods: Microparticles encapsulated with CQP were prepared using spray drying-double emulsion technique. Encapsulation efficiency, water content, density, morphology and in-vitro release (PBS, pH 7.4) was characterised. Furthermore, aerosolisation behaviour was performed using the next generation impactor at 60L/min via HandiHaler^® containing 20mg powder in HPMC capsule (size 2). MTT assay quantified the effect of encapsulated CQP and carrier-free CQP on human lung cancer bronchial epithelial cell (NCI-H727) proliferation.

Results: PGA-co-PDL (11.4KDa), PEG₁₅₀₀-PGA-co-PDL (12.4KDa) and PEG₄₅₀₀-PGA-co-PDL (13.6KDa) resulted in low encapsulation efficiency (13.11±1.23, 10.52±0.86, 9.25±1.02). Furthermore, a biphasic release profile was predominant for all formulations, with ∼40-45% of payload released after 24h. The aerosolisation performance (%FPF) was significantly greater for PEG₁₅₀₀-PGA-co-PDL (13.05±0.46%) and PEG₄₅₀₀-PGA-co-PDL(14.66±0.46%) compared to PGA-co-PDL (9.52±0.50%) microparticle carriers. The higher FPF achieved with PEG₄₅₀₀-PGA-co-PDL microparticles was due to the significantly lower water content and true density (0.76±0.12%, 0.98±0.07g/cm³) respectively, as opposed to PEG₁₅₀₀-PGA-co-PDL (1.04±0.25%, 1.17±0.12g/cm³) and PGA-co-PDL (1.73±0.84, 1.24±0.35g/cm³), indicating less aggregation and enhanced flow properties. Treatment, 240-0.25μM, using carrier-free CQP (61.71±9.25–9.78±2.59) and encapsulated CQP (PGA-co-PDL: 63.88±11.13–19.38±8.55, PEG₁₅₀₀-PGA-co-PDL: 56.73±9.41–26.75±13.58, PEG₄₅₀₀-PGA-co-PDL: 62.46±8.57–25.24±5.41) resulted in a decrease in cell viability.

Conclusion: Results from this investigation indicate CQP encapsulated with in PGA-co-PDL and PEG-PGA-co-PDL microparticles show promise as a pulmonary delivery system for treatment of lung cancers.

58. Evaporation- and Residence Time of Micron Sized Droplets in a Lab Spray Dryer

59. The Performance of a Tape Based DPI Device

Background: The 3M™ Taper dry powder inhaler (DPI) utilizes a microstructure carrier tape (MCT) containing small dimples filled with drug to define the dose to be delivered to the patient. The dose is adjusted by varying the size and number of dimples on the MCT. The dimples are filled with drug using a roller coating process and do not require the addition of lactose carrier particles. Doses up to 1 mg can be delivered from the Taper DPI.

Methods: The delivery of albuterol sulfate from the Taper DPI was characterized. The aerodynamic particle size distribution was measured using the Next Generation Impactor (NGI). The emitted dose was characterized using USP methods. The drug delivery was also characterized before and after vibration and dropping stress tests.

Results and Conclusions: The emitted dose after various storage conditions was shown to be consistent with all 70 of the measured doses being within +/−25% of the target dose and 69 of the 70 doses measured being within +/−10% of the target dose. The fine particle fraction obtained from NGI tests was 53%. There was no statistically significant difference in the emitted dose before and after exposure of the device to high intensity vibration or drop testing. The data indicates that the Taper DPI is capable of efficient and reproducible drug delivery, even after dropping and exposure to vibration.

60. Investigating the effect of nano-scale surface coating on the aerosolization of micronized drug powders

61. Understanding the influence of surface modification via mechanical dry coating on the flowability of a cohesive fine lactose powder

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

65. Rapid development of a patient preferred nasal pMDI actuator

66. Controlling Product Through Predication of Formulation Concentration During Pressurized Metered Dose Inhaler (pMDI) 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 pMDI metering valve

68. Prediction of Tribological Phenomena in Drug Delivery Devices

69. The effect of NGI cooling methodologies on aerodynamic particle size

70. Polar and total surface energy distributions determination by inverse gas chromatography

Background: Surface energy distributions determined at finite dilution reveal information about different surface energies present on material surface. The determination of dispersive surface energy distribution has been recently reported. However, without polar and total surface energy distributions, dispersive surface energy distribution is an incomplete picture of surface energy status of a material. This study reports a technique of measuring polar and total surface energy distributions of lactose at extended coverage using an inverse gas chromatography (IGC).

Methods: Three alkanes octane, nonane and decane; a monopolar acidic probe, dichloromethane and a monopolar basic probe, ethyl acetate were run at concentrations of 0.03, 0.10, 0.25, 0.35, 0.55, 0.70, 0.80, 0.90 and 0.95 p/p⁰ to construct adsorption isotherms.

Results: The surface coverage by each probe was calculated by dividing the adsorbed amount with monolayer capacity. At each surface coverage, dispersive surface energy and specific free energies for interaction with dichloromethane and ethyl acetate were calculated using Schultz approach. Using the van Oss concept, polar energy was calculated from the basic and acidic characters of the solid, which were calculated from the specific free energies for interaction with dichloromethane and ethyl acetate, respectively. The addition of dispersive and polar surface energies gave estimation of total surface energy at each surface coverage.

Conclusions: Polar and total surface energy distribution profiles have been constructed successfully. In contrast to reporting a single value at infinite dilution, these profiles will be extremely useful in understanding the particulate interactions especially of heterogeneous solids.

71. Measurement of solution-state salbutamol ion-pair interactions

Background: The disposition of an inhaled drug may be modified by presenting the active agent as a pharmaceutical salt. If an active agent and its co-formulated counter ion are both ionised they may form an ion pair in solution which could influence transport into the tissue of the lung (Sarveiya et al., 2004). Thus, ion-pair formation using pharmaceutical salts already approved for inhaled use could be an effective strategy to optimise the pharmacokinetics of therapeutic agents. The aim of this study was to assess the potential for salbutamol to interact with simple anionic electrolytes in the solution state.

Methods: High performance liquid chromatography (HPLC) analysis include a mobile phase composed of de-ionised water (pH 6.5) and methanol (80:20), an injection volume of 20 μL and a salbutamol concentration of 0.42 mM. A fixed ratio of an anionic counter ion (sulphate, chloride or phosphate) was added to both the HPLC mobile phase and the salbutamol sample. Fourier transform infrared (FT-IR) spectroscopy was employed using an Omni cell (SpecAc, UK) with CaF₂ windows and 0.1 spacer. A total of 4 to 32 scans were taken at a resolution of 4 cm⁻¹ over the 550 – 4000 cm⁻¹ range.

Results: Increasing the concentration of the sulphate counter ion from 0.0 to 2.94 mM led to a gradual reduction in salbutamol retention time from 50.13±0.45 min (base) to 5.09±0.30 min. The chloride counter ion had no effect on the retention of salbutamol (47.96±0.82 min) and the phosphate effect mimicked that of sulphate (retention time changed from 50.13 to 7.95 min). The decrease in the retention of salbutamol was attributed to salbutamol interacting with the anionic counter ion, an effect that was confirmed using FT-IR through a shift in the secondary amine (1606 cm⁻¹ salbutamol alone to 1617 cm⁻¹ with sulphate).

Conclusions: Salbutamol interacts with sulphate and phosphate in solution and this may have a significant effect on the biopharmaceutics of this molecule.

72. Development of a computational model with predictive capabilities to describe actuation of pressurized metered dose inhalers

73. The influence of the ambient relative humidity during cooled NGI Testing

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

77. Effect of PEGylation on spray dried PGA-co-PDL pulmonary carrier microparticles

Background: The current study investigates the effect of incorporating polyethylene glycol (PEG) into the backbone of a biodegradable polyester polymer, poly(glycerol adipate-co-ω-pentadecalactone), PGA-co-PDL, as carriers for pulmonary drug delivery. PEG could be used to engineer the particle surface to reduce particle–particle interactions, enhance the hydrophilic nature of the polymer and improve their aerodynamic properties.

Methods: Microparticles encapsulated with fluorescein sodium (SF) were prepared by spray drying directly from double emulsion and characterised for their encapsulation efficiency, density, morphology and in-vitro release in phosphate buffer saline (pH 7.4). Aerosolisation behaviour was investigated by placing 20mg powder into HPMC capsule (size 2) and aerosolised via HandiHaler^® using the next generation impactor at 60L/min.

Results: PGA-co-PDL (12.2KDa) and PEG-PGA-co-PDL (19.9KDa) had similar low encapsulation efficiency (17.11±0.45% and 15.02±0.07%), and density (0.81±0.03g/cm³ and 0.86±0.16g/cm³) respectively. However, a biphasic release profile was predominant for both polymers, with PEG-PGA-co-PDL having an enhanced release profile, with ∼80% of payload release after 24h compared to ∼60% for PGA-co-PDL microparticles. The FPF and MMAD were similar for SF loaded microparticles and ranged from 42.92±1.39%, 3.53±0.91μm (PGA-co-PDL), 41.65±2.62%, 3.80±1.47μm (PEG-PGA-co-PDL).

Conclusion: PEG-PGA-co-PDL microparticles may be a promising carrier for pulmonary drug delivery due to its enhanced sustained drug release profile, with excellent aerosolisation behaviour.

78. Dynamic release from lipid nanoparticles for controlled drug delivery to the airways

Background: Nanoparticles have the potential to increase the residence times of drugs in the airways, however their rigid structure presents a barrier to drug release following administration. The aim of this study was to design and manufacture nanoparticles suitable for inhalation and capable of dynamic release in situ.

Methods: Lipid nanoparticles (LN) were fabricated via phase inversion-precipitation. The amounts and types of oil and surfactant used to form the pre-emulsion were varied and resultant particles were characterised using photon correlation spectroscopy. Drug loading and release was modelled using the fluorescent probe rhodamine and quantified using fluorescence spectroscopy. Release from LN was triggered using Pluronic^® surfactant (375 mg per mL of LN suspension) and changes in LN size and rhodamine content were monitored.

Results: The mean diameter of LN varied between 48.9 and 81.3 nm as a consequence of modifying emulsion composition. It was possible to generate LN using oils of differing hydrophobicity and to switch the surfactant employed as the stabilising outer layer. The majority of loaded rhodamine was found to reside within the LN (82.1±3.4 %), with the remainder being present in the surrounding aqueous phase. Upon exposure of the LN to Pluronic^® surfactant, rhodamine content decreased significantly (to 16.5±21.1 %) and particle size increased (139.7±86.2 nm at 2 h post trigger).

Conclusions: LN with different core and surface components were generated. Rhodamine was incorporated into LN with high efficiency. Pluronic^® surfactant was capable of causing LN disruption and triggering release, which was accompanied by an increase in particle size.

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

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

82. Structural Phase Transformation in Crystalline Lactose Monohydrate

83. Effect of crystallisation conditions and feedstock morphology on the aerosolozation performance of micronised salbutamol sulphate delivered by DPI

84. Phospholipid microparticle based cosuspensions enable the consistent delivery of potent drugs intended for pMDI 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 NanoGENT^TM: Inhaled Gentamicin Dry-Powder Formulation for Prophylaxis and Treatment of Respiratory Infections

86. The influence of co-solvent on co-spray dried sodium carboxymethylcellulose and a model protein

87. Feasibility Study of OSCN⁻ and Lactoferrin (Meveol^®) Nebulization for Cystic Fibrosis Patients.

Background: The hypothiocyanite (OSCN⁻) and Lactoferrin (Lf) system, described as the major human host defense system against infection, is completely defective in cystic fibrosis (CF) patients. Breathing difficulty is the most serious symptom, resulting from frequent lung infections which were mostly treated but not completely cured. Meveol^®, [Lf/OSCN⁻] complex, is a new anti-infectious orphan drug developed by Alaxia for CF patients. The aim of this study was to verify the antimicrobial activity of Meveol^® and to investigate the feasibility to develop an aerosol Meveol^® treatment.

Methods: Meveol^® activity was tested in vivo on a mice model infected with P. aeruginosa mucoïd (Pam), and, in vitro, on Mycobacterium abscessus (Ma), an emerging lung pathogen. Meveol^® (5mL) was nebulized with jet and mesh nebulizers. Aerosols were tested for the OSCN⁻ and Lf stability and then characterized in terms of particle size distribution, inhalable and respirable mass.

Results: Mice treated with Meveol^® presented a significantly lower level of lung colonization (1.5±0.5 logCFU Pam/g vs. 3.08±0.4 logCFU Pam/g in control mice). Moreover, Meveol^® has allowed the total eradication of Ma, within 48h of in vitro incubation. After nebulization, OSCN⁻ and Lf are both preserved in the aerosol form of Meveol^®. The 57.3±1.4% of inhalable fraction obtained with the Aeroneb^®Go/IdehalerPocket^® nebulizer has conducted to select this device for further clinical development.

Conclusion: Meveol^® can be efficiently administered by inhalation route. Thanks to its wide antimicrobial activity, aerosols of Meveol^® could contribute to improve, daily, the quality of life of CF patients, reducing antibiotic resistances.

88. Development of I-neb Insight Online for Home Monitoring of Inhaled Medication- a New Telemedicine Option

89. EPAG-Sponsored Workshop on Abbreviated Impactor Measurement (AIM) and Efficient Data Analysis (EDA) Concepts in Inhaler Testing: Overview of AIM-EDA

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

Background: There is a need to expand the AIM Concept to the evaluation of wet aerosol generators such as nebulizers.

Methods: Aerosols formed from aqueous droplets containing salbutamol from a vibrating membrane electronic nebuliser (investigational eFlow^®), have been evaluated, comparing the performance of the fast screening impactor (FSI) used both cooled and at ambient conditions with that of a cooled full-resolution Next Generation Pharmacopeial Impactor (NGI). Laser diffractometer (LD)-based measurements were also made.

Results: Substantially equivalent values of the respirable fraction (RF, volume %<5 μm) were obtained by LD, cooled NGI (controls) and the FSI operated both cooled and at room ambient temperature [83±2%, 78±5%, 73±5% and 77±5%, respectively]. The effect of making measurements under cooled or room ambient conditions was sufficiently small to be ignored with the FSI. As expected, the LD provided data almost instantaneously, but this method is non-specific for active pharmaceutical ingredient, hence the requirement for cascade impaction based measurements for this class of inhaler. The main time saving with the FSI was associated with the reduced number of samples that are generated for API assay by this procedure, allowing sample analysis time to be reduced to almost a third of that needed for NGI determinations. Additionally, data processing time was halved and experimental time was reduced from 8 hours to either 7 or 5 hours, depending on whether or not cooling of the FSI took place.

Conclusion: The FSI when used as described in this presentation has the potential to provide accurate estimates of fine droplet fraction from nebulisers.

92. Measuring the fine particle dose using inter-stage filters in the NGI – an overview of two methods

Background: Assessment of the fine particle size distribution of drug in the aerosol cloud from inhalers is currently performed by using cascade impactors, such as NGI or Andersen Sampler. Recently, several studies has demonstrated the possibility to replace full impactor tests with more simplified impactor set-up's. Such a set-up, denoted abbreviated impactor measurement (AIM), is less tedious to work with, but does not lose sharpness in assessing the inhaler product quality. The AIM method can be experimentally realised in various ways, based on different impactor platforms. In this study we present a filter method based on the NGI impactor.

Methods: Different inhalers and formulations have been assessed using inter-stage filters in the NGI with two different experimental set-ups; 1) a filter inside the NGI placed upstream the jets and 2) a filter placed outside the NGI body. This study is a summary of different development projects performed in our laboratory over the last years (over 650 individual fine particle dose determinations). The analyses were performed with the collection filter positioned between different impactor stages and at different air flow rates.

Results: Both methods worked very well and good correlation versus the full impactor method was demonstrated. Filter based AIM methods can, when found appropriate, replace full impactor tests in inhalation product development. This will reduce experimental workload and shorten analytical cycle time without any significantly increased risk for taking wrong project decisions.

Conclusion: Simple, fast and accurate determination of the fine particle dose in inhaler testing can be realized using filters between stages in the NGI.

93. Comparison of Next Generation Impactor and Fast-Screening Impactor for determining Fine Particle Fraction of Dry Powder Inhalers

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