Abstracts from

the International

Society for Aerosols

in Medicine

15th International Congress

Perth, Western AustraliaMarch 14–18, 2005

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B-1QUANTIFYING THE CRITICAL TURBULENCE

LEVELS FOR OPTIMAL DRY POWDER INHALER PERFORMANCE

Coates MS1,2*, Chan H-K2, Fletcher DF1, Raper JA1

1Department of Chemical Engineering, University ofSydney, Sydney, Australia

2Faculty of Pharmacy, University of Sydney, Sydney,Australia

Inspiratory airflow through a dry powder inhaler con-trols the turbulence levels generated in the device, whichis pivotal to the dispersion performance. A critical tur-bulence level must exist at which the inhaler performancewill be maximized. However details of this important in-formation is lacking in the literature. The current workuses Computational Fluid Dynamics (CFD) analysis inconjunction with experimental powder dispersions (per-formed between 30-120 l min�1 in 15 l min�1 increments)to relate flow turbulence levels with the performance ofan Aerolizer®. A significant performance increase was ob-served between 30 l min�1 and 75 l min�1 (FPF 43% and63%, respectively), but no further increase occurred above75 l min�1. Analysis of the flowfield at this critical flowrate showed that turbulence kinetic energy of 10.7 J kg�1

and turbulence strain rates of 6000 s�1 maximized the in-haler performance. This work represents another impor-tant step in the optimization of dry powder inhalers andadds our studies work previously performed to under-stand the effect of design and the role of the capsule.

This work is funded by the Australian Research Council.

B-2INFLAMMATION PRODUCED BY PARTICULATE

MATTER EXPOSURE IS TLR-4 DEPENDENT.

*AM Fonceca1, GR Zosky2, DJ Turner2, PD Sly2, DA Knight3, SD Stick1.

1Respiratory Medicine, Princess Margaret Hospital forChildren, Subiaco, Western Australia 6008

2Telethon Institute for Child Health Research, Subiaco,Western Australia 6008

3University of British Columbia, Vancouver, Canada.

Background: Endotoxin is known to exacerbate asthma,paradoxically, exposure in early life might protect againstasthma.

One important vehicle for endotoxin is inert, fine par-ticulate matter (PM). PM exposure is also implicated in in-flammatory conditions in the lung i.e., chronic pulmonaryobstructive disorder (COPD) and asthma. We are inter-ested in determining the inflammatory and airway re-sponses elicited following exposure to endotoxin and PM.

Method: Female, 7 week old C3H/HeJ (�/�TLR-4)and C3H/HeN (�/�TLR-4) mice were exposed to neb-ulised 50ug/ml endotoxin and PM. 6 exposures were

completed 24hrs apart. Airway response measures of re-sistance, compliance and elastance were taken 6hrs afterthe final exposure using forced oscillation technique.BAL’s were collected for differential counts.

Results: Preliminary findings indicate no significantdifference in respiratory function between endotoxin andPM exposed C3H/HeJ mice. Significantly greater inflam-matory cell infiltrate was measured by differential countsin PM exposed C3H/HeN mice, compared to PM exposedC3H/HeJ mice.

Conclusion: C3H/HeJ mice exposed to PM did notdemonstrate a change in lung function, despite evidencefor inflammatory changes in the lung. This result pointsto a role for TLR-4 in signalling of PM.

Funding: National Health and Research Council ofAustralia; Princess Margaret Hospital for Children Foun-dation.

B-3CHARGE OF AEROSOLS GENERATED FROM

VENTOLIN® HFA METERED DOSE INHALERS—CONTINUOUS VERSUS NON-CONTINUOUS

ACTUATION

Kwok, PCL* and Chan, H-K

Faculty of Pharmacy, University of Sydney, New SouthWales 2006, Australia

Purpose: To investigate the electrostatic characteris-tics of aerosols produced from Ventolin® HFA metereddose inhalers (MDIs) via continuous and non-continu-ous actuations. Method: Charge and mass distributionsof aerosols were determined using a modified electricallow pressure impactor (ELPI, Dekati Ltd., Tampere, Fin-land) and HPLC. The corona charger of ELPI was re-moved to allow measurement of inherent charges on theparticles. Single puffs generated by continuous and non-continuous actuations were sampled. The inhalers wereactuated at 30-second intervals in the continuous schemeand resting interludes of an hour or more were em-ployed in the non-continuous scheme. Results: Aerosolsproduced from continuous actuation were unipolar neg-ative whereas those from non-continuous actuation wereelectrostatically bipolar. The particles detected on ELPIstages 9 and 10, which comprise approximately 70% ofthe fine particle dose (�6.06 �m), were the main oneswith opposite polarity. The cutoff diameters of thesestages are 1.62 and 2.42 �m, respectively. The mass pro-files of the aerosols remained unchanged. Conclusions:The differences in the electrostatic characteristics sug-gest that the charging mechanisms may depend on themode of MDI actuation. Since the particles involved inpolarity inversion comprise a large proportion of the fineparticle dose, this may have an impact on the depositionof the particles in a patient’s airways.

This work was financially supported by the AustralianResearch Council.

Best Oral Presentation Abstracts

84

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BEST ORAL PRESENTATION ABSTRACTS 85

B-4THE DELIVERY SITE OF AN INFLUENZA

VACCINE WITHIN THE LUNGS IMPACTS ONTHE IMMUNE RESPONSE

A Minne1*, J Louahed2, J-C Renauld2, P Rousseau3, B Baras3 and R Vanbever1

1. Department of Pharmaceutical Technology, UniversitéCatholique de Louvain, Brussels, B-1200, Belgium

2. Experimental Medicine Unit, Ludwig Institute for CancerResearch, Université Catholique de Louvain, Brussels,

B-1200, Belgium3. Viral DAP Preclinical Virology, GlaxoSmithKline

Biologicals, Rixensart, B-1330, Belgium

PURPOSE. To assess the impact of the delivery site ofan influenza vaccine within the respiratory tract on theimmune response induced in mice.

METHODS. The split-subunit influenza vaccine wasadministered to the respiratory tract of mice using dif-ferent techniques, each targeting a specific region, i.e. thenasal fossae, the central airways, the peripheral airwaysor the entire respiratory tract. The vaccine was also ad-ministered intra-muscularly. The humoral immune re-sponse was assessed by measuring serum IgG, haemag-glutinin-inhibitory and neutralizing antibody titres, aswell as mucosal IgA and IgG levels. The cellular immuneresponse was characterized by the in vitro production ofIL-4 and IFN-ã by splenocytes.

RESULTS. Systemic humoral and cellular immune re-sponses induced by the vaccine increased with depth ofvaccine delivery within the lungs. Administration of thevaccine to peripheral airways generated a systemic im-mune response that was equivalent (p � 0.05) to intra-muscular vaccination. Moreover, vaccine administrationto peripheral airways induced local influenza-specific IgAin the lungs, in contrast with intra-muscular vaccinationwhich did not.

CONCLUSIONS. Influenza vaccine administration toperipheral airways generated systemic immune re-sponses comparable to those induced by intra-muscularvaccination while mucosal immune response was higher.

This work was supported by a “FIRST EUROPE Ob-jectif 3” grant n° EPH3310300R0382/215297 subsidized bythe Walloon Region (Belgium). We thank GlaxoSmith-Kline Biologicals (Rixensart, Belgium) for kindly donat-ing the influenza vaccine and providing technical assis-tance. Rita Vanbever is a Chercheur Qualifié of the FondsNational de la Recherche Scientifique (FNRS, Belgium).

B-5IMPACT OF AEROSOLS ON GROUND REACHING

UV-B RADIATION

K. Madhavi Latha and K.V.S. Badarinath

Forestry & Ecology Division, National Remote SensingAgency (Dept. of Space-Govt. of India) Balanagar,

Hyderabad—500 037,India. Email:badrinath_kvs@nrsa.gov.in

Biologically harmful ultraviolet erythemal dosage iscomputed as convolution of appropriate action spectrum

for human skin with the surface reaching global UV irra-diance spectrum. The amount of solar ultraviolet (UV) ra-diation penetrating the earth’s surface is critically impor-tant to health of biological systems and practically nosolar radiation reaches the ground at wavelengths shorterthan 290nm due to strong attenuation by atmosphericozone. Solar ultraviolet radiation reaching the earth’s sur-face has been extensively discussed during the lastdecades because of its biological and photochemical ac-tivity. Great emphasis has been placed on potential in-crease in surface UV radiation due to depletion of stratos-pheric ozone. The present study reports for the first timeon seasonal variation of UV-B and its relation withaerosols over a typical urban environment of Hyderabad,India during 2001–2003. Drastic reduction in UV intensi-ties has been observed during periods of high aerosolloading. Comparison of UV-B intensities with AerosolOptical Depth(AOD) on normal summer day and a dayafter heavy rainfall suggests �45% increase in UVB in-tensities because of scavenging of particles in the atmos-phere. Total columnar ozone showed negative correlationwith UV-B. The variation of UVerythema (UVery) withrespect to relatively low and high pollution days has beenstudied over the study area. Aerosol Optical Depth (AOD)at 500nm ranges from 0.43 to 0.58 on high pollution daysand during low pollution days AOD ranges from 0.32 to0.41 and corresponding UVery ranges from 1.9 to 4.9MED/hr and 1.7 to 4.1 MED/hr respectively. UVB de-creases at the rate of 0.21 MED/hr per unit increase inaerosol optical depth. The results have been discussed indetail in the paper.

Keywords: UVerythema, Scattering, Forcing efficiency,Irradiance, Aerosols

B-6INVESTIGATING PARTICLE INTERACTIONS IN

NON-AQUEOUS MODEL SUSPENSIONS BYSURFACE ENERGY AND AFM MEASUREMENTS

D Traini1*, P Rogueda2, P Young1 and R Price1.

1. Pharmaceutical Technology Research Group, Departmentof Pharmacy, University of Bath, Bath BA2 7AY, UK

2. AstraZeneca R&D Charnwood, Bakewell Road,Loughborough, LE11 5RH, UK

The purpose of this investigation was to characterisecohesion/adhesion interactions of micronised drug par-ticles experimentally and compare them with availabletheories. In particular it aimed at testing the van Oss the-ory of surface tension components as a potential predic-tive tool for the characterisation of pressurised MeteredDose Inhalers suspensions.

Separation forces between micronised drugs used in in-haled therapies were investigated using in situ atomic forcemicroscopy (AFM) in a model propellant. Data were cor-related with the theoretical work of adhesion/cohesion (cal-culated using the van Oss theory for polar/ a-polar inter-facial forces) obtained from contact angle measurements.

Results show that the surface energy of drugs is sig-nificantly affected by the polar components of the forceof interaction. A clear correlation was observed betweenthe theoretical work of adhesion/cohesion and AFM de-rived measurements.

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In conclusion, experimental surface energy results andAFM separation force measurements have been used todevelop a theoretical understanding of particle interac-tions using the van Oss theory for interfacial forces in nonaqueous media. This approach appears to be sufficiently

sensitive to be able to differentiate between the adhesiveand cohesive properties of various pharmaceutical sam-ples. This study shows that understanding microscopicinterparticle interactions is fundamental to accurately pre-dict the final macroscopic state of such system.

INVITED SPEAKER ABSTRACTS86

Invited Speaker Abstracts

IS-1ESTABLISHING BIOEQUIVALENCE OF GENERIC

LOCALLY ACTING ORALLY INHALED ANDNASAL DRUG PRODUCTS (OINDP):

AN FDA PERSPECTIVE

Wallace P. Adams

US Food and Drug Administration, Rockville, MD

Bioequivalence (BE) may be established based on phar-macokinetic, pharmacodynamic, or clinical studies, or withsuitable justification, in vitro studies (21 CFR 320.24). Lo-cally acting OINDP are intended for delivery to pulmonaryor nasal sites, and do not rely on the systemic circulationto deliver the drugs to the sites of action. For these drugs,PK studies provide information regarding systemic expo-sure, but are in general not appropriate for establishing lo-cal delivery BE. For abbreviated new drug applications(ANDAs) of locally acting nasal sprays, BE is establishedbased on the following recommended approach: (1) inac-tive ingredients in the test product formulation qualita-tively the same and quantitatively essentially the same asthe inactive ingredients in the reference drug formulation;(2) devices (particularly the metering valve or pump andactuator) the same or comparable; (3) a series of compara-tive in vitro tests to establish equivalence; (4) systemic ex-posure or systemic absorption BE; and (5) local deliveryBE. For solution formulation nasal sprays, BE may be es-tablished based on comparative formulation, device, andin vitro studies (Draft FDA Guidance: BA and BE studiesfor nasal aerosols and nasal sprays for local action, April2003). This presentation will discuss the above approach.Although FDA draft guidance is not available for BE of lo-cally acting orally inhaled drug products, the presentationwill also discuss currently recommended approaches forthese products.

IS-2POTENTIAL OF AEROSOL IMMUNIZATION:

THE MEASLES AEROSOL PROJECT

Teresa Aguado1, Ana-Maria Henao-Restrepo2 and theWHO Product Development Group for Measles

Aerosol Project3

1Initiative for Vaccine Research, Department ofImmunization, Vaccines and Biologicals, World Health

Organization2Initiative for Vaccine Research, Department of Immunization,

Vaccines and Biologicals, World Health Organization3The WHO Measles Aerosol Product Development Group(PDG) is an expert clinical and scientific advisory body to

WHO established to advice the Initiative for Vaccine

Research independently and with scientific rigour regardingthe development plan of the measles aerosol vaccine.

4WHO coordinates the Measles Aerosol Project (MAP). TheCenters for Disease Control and Prevention, USA and theAmerican Red Cross are partners to the MAP. The MAPhas received financial support from the Bill and Melinda

Gates Foundation.

Measles remains a major cause of morbidity and mor-tality due to vaccine preventable diseases. In some coun-tries the availability of trained personnel to administerinjections safely is limited and, there are concerns overinadequate waste management and waste disposal. Al-ternative routes for measles vaccines administration, us-ing currently existing measles vaccine, may facilitate fur-ther progress in controlling the disease and reducing therelated logistics and safety concerns.

Studies using measles aerosol jet nebulizers indicates that:(i) seroresponse rates in infants and school children afteraerosol immunization are at least as good as subcutaneous(SC) route; (ii) frequency of adverse events following vac-cination (AEFI) is lower than with percutaneous route; (iii)additional cost benefits could be accrued. The potentialelimination of syringe and needle costs, including disposalcould results in important savings in supplies costs.

Bearing in mind the above, WHO has given priority tothe Measles Aerosol Project4. The goal of this project is tolicense at least one method for respiratory delivery of cur-rently licensed measles vaccines. At least three devicesfor aerosol administration of reconstituted vaccine, andif feasible in the time frame, a dry powder device, willenter the studies. The assumptions of the project are thatthe aerosol vaccination devices will use current vaccinesand, it will be aimed to children 12–59 months for rou-tine vaccination and 9 months to 18 years for measlesmass campaigns. It is expected that clinical testing couldbe completed by 2007–9. During the first two years of theproject the regulatory pathway was defined, safety con-cerns enumerated, preclinical studies have been com-pleted and, devices for clinical trials selected. Phase I andPhase II studies are due to begin in early 2005.

IS-3IMAGING THE AIRWAYS IN 2005

DL Bailey

Department of Nuclear Medicine, Royal North ShoreHospital, Sydney, Australia.

Imaging has traditionally been separated into two dis-tinct disciplines: functional imaging and structural imag-ing. Functional imaging encompasses applications suchas nuclear medicine (SPECT and PET), autoradiography,

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INVITED SPEAKER ABSTRACTS 87

magnetic resonance spectroscopy (MRS) and magneto-encephalography (MEG) while structural, or anatomical,imaging includes planar radiography, X-ray CT and MRI.However, today, the distinctions between these are blur-ring due to advances in software fusion and the devel-opment of multi-modality (SPECT/CT, PET/CT) scan-ners. This combines with new techniques for imaging theairways, such as MRI using hyper-polarised gases (3H and129Xe), to present the airways researcher with a variety ofways to probe airway distribution of pharmaceuticals andtheir subsequent uptake and biodistribution. This paperwill review advances in imaging to present a contempo-rary view of the tools available.

IS-4FUTURE RESEARCH DIRECTIONS IN THE DRY

POWDER AEROSOL DELIVERY SYSTEMS

Hak-Kim Chan

Faculty of Pharmacy, A15, University of Sydney, NSW2006, Australia

The performance dry powder aerosol delivery systemshas been improved significantly over the last decadethrough the use of engineered drug particles and excipientsystems which are i) of low aerodynamic diameters (beingporous or of low particle density), and/or ii) less cohesiveand adhesive (due to corrugated surfaces, low bulk density,reduced surface energy and particle interaction, hydropho-bic additives and fine carrier particles). Although the exactmechanisms are still not clear, some early insights into par-ticle forces and surface energy which help explain the im-provement have been provided by analytical techniquessuch as AFM and IGC. Relative humidity is critical to theperformance of DPI products via capillary force and elec-trostatic interaction. Recently it has become feasible to mea-sure the electrostatic charge of different particle size frac-tions of an aerosol using a modified electrical low pressureimpactor. Micron-sized drug particles required for inhala-tion DPI products are conventionally produced by drymilling which undesirably also creates physically unstableamorphous materials. Novel precipitation processes basedon micro-mixing (i.e. mixing on the molecular scale) can beused as a suitable alternative to milling. Although it is wellknown that the performance of a powder aerosol deliverysystem depends not only on the powder formulation butalso the inhaler device, much less work has been done at afundamental level on DPIs compared with powders. Mostrecently, computational fluid dynamics has been applied tounderstand the inhaler design (such as mouthpiece, gridstructure, air inlet) and on how the powder interacts withthe device during dispersion.

Funding: Australian Research Council.

IS-5UPDATE ON INNOVATIONS IN

AEROSOL DELIVERY

A R Clark

Nektar Therapeutics, San Carlos, USA

Over the last decade, fueled by the need for increaseddelivery efficiency of proteins and peptides, aerosol de-

livery has made great advances in targeting the lung. Be-tween 1990 and 2000 the highest reported lung deposi-tion efficiency rose from �20% to �70%. In addition tothese increases a large number of novel device conceptshave evolved. Whilst some of these are on the verge ofcommercialization, many have fallen by the wayside—testament either to the difficulties of handling and me-tering “respirable” powders or to the simple commercialimperatives of the market place.

In addition to novel devices, powder technologies havealso evolved in an attempt to reduce the device designengineer’s burden. Examples of these would be: ternaryblends (drug/lactose and a “chain breaker”), lipid basedporous particles (large and small) and spray dried sys-tems using amino acid dispersion aids. All of these ap-proaches produce powders which are inherently easier todisperse than convention micronised materials and henceall make device design simpler from a dispersion per-spective. However, metering small quantities of powderinside small devices remains a major challenge and thetrend towards multi-dose devices seems to be reversingin favour of unit dose packaging.

In addition to performance the patient interface seemsto be getting more attention, with new breath activatedpMDI devices reaching the market and more attentionbeing paid to flow and resistance with dry powder de-vices.

IS-6NEKTAR PULMONARY DELIVERY

TECHNOLOGIES

A R Clark

Nektar Therapeutics, San Carlos, USA

With the exception of only a few products, current in-haler technologies used for the delivery of asthma andCOPD medications are relatively inefficient. Large por-tions of the delivered dose are either lost in the mouthand pharynx or impact fairly centrally in the upper air-ways. For systemic therapy with expensive macromole-cules, where inhalation is being used as an alternative toinjection, efficiency is an important factor in determiningthe economic viability. Macromolecules deposited in thelung periphery can undergo degradation prior to ab-sorption and a large fraction of the overall bioavailabilityof a macromolecule is controlled by lung biology. It istherefore essential that delivery efficiency be as high as ispossible. Nektar has developed a range of technology in-novations that combine to address this need. These tech-nologies are the basis of Exubera®, inhaled insulin, andother systemic delivery programs.

Nektar has also been developing high dose technolo-gies capable of delivering efficacious doses of drugs suchas anti-infectives to the lung for local treatment. Thesetechnologies are based on highly dispersible powderscontaining lipids. They are currently being tested in To-bramycin powder for inhalation, which is being co-de-veloped with Chiron Corporation as an alternative to neb-ulized Tobramycin in the treatment infections in cysticfibrosis patients. This capability is important in CF as pa-tients use multiple medications delivered by nebulizerand any reduction in dosing times is seen as a consider-able advantage.

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IS-7HYPEROSMOLAR AGENTS AND CLEARANCE OF

MUCUS IN THE DISEASED AIRWAY

Evangelia Daviskas and Sandra D Anderson

Respiratory Medicine, Royal Prince Alfred Hospital, Sydney,Australia.

Clearance of mucus is an important function of the air-ways to maintain hygiene. In disease, persistent inflam-mation leads to excessive mucus of high viscoelasticityand adhesivity that is not easily transported by cilia orcough interactions. Accumulated mucus in the airwayscan lead to airway obstruction, bacterial colonisation andrecurrent infections resulting in poor quality of life. Hy-perosmolar agents have the potential to alter the physi-cal properties of mucus and facilitate its clearance by in-creasing the airway surface fluid and by reducing theentanglements of the mucin network. Clinical studies us-ing radioaerosols have demonstrated that hypertonicsaline (HS) (3–14.4%) and mannitol (300–400mg) increaseclearance of mucus acutely in mild asthma, bronchiecta-sis and cystic fibrosis (CF). Further in sputum studies, areduction in the viscoelastic properties, surface tensionand spinnability and an increase in the hydration of mu-cus have been measured in response to HS, mannitol andother sugars. Two week treatment with mannitol (400 mg)twice daily improved the quality of life in patients withbronchiectasis. Two week treatment with 7% HS, fourtimes daily, improved the baseline mucus clearance rateand lung function in CF patients. In addition, 7% HS twicedaily over twelve months showed similar results to theshort-term studies without a change in the bacterial loadin CF patients. Further studies of the long-term clinicaleffect of hyperosmolar agents are needed.

IS-8SPECT IMAGING OF RADIOAEROSOL

DEPOSITION AND CLEARANCE

S Eberl

PET and Nuclear Medicine Dept., Royal Prince AlfredHospital, Sydney, Australia

Planar gamma camera scintigraphy is well establishedfor measuring the deposition and clearance of radio-aerosols. Single Photon Emission Computed Tomography(SPECT) provides 3D reconstructions of the radioactivitydistribution, thus avoiding the compression of 3D datainto 2D images and potentially offering superior assess-ment of aerosol deposition patterns. However, SPECT hastraditionally been associated with long imaging times,making it unsuitable for measuring deposition and clear-ance of radioaerosols with fast clearance. Multi-detectorSPECT systems can collect complete SPECT studies in �1min, allowing both initial deposition and clearance overtime to be assessed by dynamic SPECT. Simultaneoustransmission measurement with an external source pro-vides attenuation correction for absolute activity quan-tification as well as aiding in the definition of the lungvolume of interest. A dynamic SPECT imaging protocolhas also been developed to allow fast imaging from the

oropharynx to the abdomen with gamma cameras withlimited axial field of views. This allows activity quantifi-cation not only in the lungs, but also in areas outside thethorax. However, fast dynamic SPECT imaging is techni-cally and computationally more demanding and providesless scope for reducing the radioactivity administered tothe subjects. It has been shown that dynamic SPECT ismore sensitive in detecting changes in deposition as mea-sured by PI than planar imaging and thus can better dif-ferentiate between large and small airways, which is im-portant for lung regional analysis.

IS-9UTILIZING MECHANICAL AND

NANO-TECHNOLOGY APPROACHES TOOPTIMIZE BOLUS LIQUID AEROSOL

DELIVERY FROM AERx®

Farr* SJ, Schuster JA, Holst P and Noymer P

Aradigm Corporation, Hayward, CA 94545 USA

The electro-mechanical AERx® pulmonary delivery sys-tem for liquid formulations was developed with featuresfor efficient and reproducible aerosolized administrationof drugs, with the option of precisely adjusting from a sin-gle strength formulation the dose delivered in an inhala-tion. Electronics play a key role in the performance of thedelivery system. We report on the development of a com-plementary platform technology (AERx Essence), stillbased on the principles of Rayleigh jet-breakup for aerosolgeneration, which, in an all-mechanical format, preservesin a smaller and lighter platform many elements of thelung-dose control achieved with the electro-mechanicalAERx system. This was achieved via advances in mechan-ical design and nozzle fabrication. A closed-loop methodof fabricating nozzle-holes in polyimide film facilitated thedevelopment of nano-scale structures through which liq-uid can be extruded at suitable pressures for a handhelddevice fitted with a spring actuation mechanism. In addi-tion the use of mechanical valves has provided the abilityto control the patients’ inhalation profiles to ensure re-peatable dosing for a given patient as well as from patientto patient. In vitro and non-dosing in vivo testing of AERx-Essence has shown the system is able to maintain a levelof aerosol and breath-control performance very similar tothe existing AERx® system even without electronics. Bothsolution and nanosuspension-based formulations havebeen aerosolized efficiently from the system.

IS-10LIQUID ATOMISING—NEBULIZING AND OTHER

METHODS OF PRODUCING AEROSOLS

Carlos F. Lange and Warren H. Finlay

Aerosol Research Laboratory of AlbertaUniversity of Alberta

Liquid nebulization is the most traditional method ofdrug delivery to the lung. Although other methods seemto often be preferred for the delivery of new drugs, neb-

INVITED SPEAKER ABSTRACTS88

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INVITED SPEAKER ABSTRACTS 89

ulizers are experiencing a revival with new devices basedon different atomization techniques, and the more tradi-tional jet nebulizers evolving to become “smart nebuliz-ers”. These smart devices synchronize delivery with thepatient’s breath, estimate or measure delivered dose, pro-vide feedback and data storage, and in some cases con-trol breathing manoeuvres.

Besides adding new features, new nebulizers are alsoaddressing traditional shortcomings, namely reducingsize, bulkiness, and power consumption. But in the longerterm nebulizers are expected to offer even more impor-tant features. Following the trend toward individually optimized therapy, nebulizers will be able to estimate deposited dosage and concentrations in the lung. In ad-dition, as progress in nanotechnology allows the devel-opment of smart drug carrying particles, advanced liquidnebulization is expected to be the delivery mode of choicefor these smart particle aerosols.

IS-11PARTICULATES: INDOOR/OUTDOOR

RELATIONSHIPS AND PERSONAL EXPOSURE

Peter Franklin

School of Paediatrics and Child Health, University ofWestern Australia

Perth, Western Australia

Particulate air pollution has been associated with arange of cardio-respiratory health problems. Epidemio-logical studies have predominately focused on outdoorparticulate pollution, however, in developed countriespeople spend the majority of their time indoors. Airborneparticles are important components of the indoor envi-ronment and indoor particulates should be considered instudies concerning the health impact of particulate mat-ter (PM). Indeed it has been estimated that 70% of popu-lation mean exposure to PM occurs inside homes and only5% occurs outdoors.

Indoor particulate levels are predominately a functionof infiltration from outdoors, direct emissions from in-door sources, deposition onto indoor surfaces, resuspen-sion from indoor surfaces and removal from indoor airby ventilation. These processes affect the different sizefractions of particles (coarse, fine and ultrafine) differen-tially. Important indoor sources of PM include cigarettesmoking, cooking and cleaning, however, indoor particleemission events are brief, intermittent and highly variable.

The indoor/outdoor relationship for PM is strongly in-fluenced by both ambient levels and indoor emissionsources. When ambient PM levels are low indoor levelscan be twice as high as outdoor while in areas of high am-bient PM pollution indoor levels are about 10% lower thanoutdoors. Similarly, in the absence of major indoorsources indoor levels are generally less than outdoors butare greater than outdoors if there is a major source suchas smoking or gas cookers.

Personal exposure is generally poorly correlated withoutdoor PM levels, particularly in cross-sectional studies.The relationship can be improved in studies using longitu-dinal regression analyses. Personal exposure levels are of-ten more strongly correlated with indoor than outdoor con-centrations, however, it is usually significantly greater thanboth. The source of the ‘personal cloud’ remains a mystery.

IS-12WHEN BUILDINGS FALL DOWN

Stephen H. Gavett, Ph.D.

Pulmonary Toxicology Branch, Experimental ToxicologyDivision; National Health and Environmental Effects

Research Laboratory, Office of Research and Development;U.S. Environmental Protection Agency Research Triangle

Park, North Carolina 27711 U.S.A.

Airborne pollutants can rise to extreme levels when largebuildings fall down. The terrorist attack on New York’sWorld Trade Center (WTC) towers caused the release of anenormous quantity of pulverized building materials andcombustion products into the local environment. Particu-late matter (PM) from crushed WTC building materials isprimarily non-respirable (�96% larger than 10 �m MMAD)and composed of fibrous and nonfibrous components suchas gypsum, calcite, silica, glass fibers, cellulose, and as-bestos. Respirable fine WTC PM (PM2.5) may include finelycrushed building materials as well as combustion productssuch as dioxins and polycyclic aromatic hydrocarbons(PAHs). Rescue workers at the WTC site had exposure-re-lated increases in the incidences of nasal congestion,bronchial hyperreactivity to aerosolized methacholine, gas-troesophageal reflux disease, and persistent cough. Toxico-logical studies in mice indicate that WTC PM2.5 causes air-flow obstruction above a critical dose. The study of physicalcharacteristics and health effects of major pollutants derivedfrom the collapse of the WTC towers has assisted in risk as-sessment efforts related to the collapse of large buildings.

IS-13DOES SIZE MATTER? DOSE CONSIDERATIONS

IN ANIMAL MODELS

M Ian Gilmour

U.S. Environmental Protection Agency, North Carolina USA 27711

Airborne particulate matter (PM) is a heterogenous mixbroadly classified into 3 size fractions; coarse (PM�10), fine(PM�2.5) and ultrafine (PM�0.1) which differ in origin andphysico-chemical makeup, and hence may cause quite dif-ferent health effects after exposure. We utilize PM gener-ated from coal and diesel combustion as well as ambientPM samples which have been extracted from filter samplesfrom different regions. The principal endpoints for assess-ment of toxicity after intratracheal instillations in mice arethe pro-inflammatory mediators IL6, TNF-alpha and MIP-2, acute lung injury and inflammation. Ultrafine PM in coalfly ash is enriched with trace metal elements such as cad-mium and nickel and is more toxic than the fine or coarsefractions. Ambient PM samples show a quite different pat-tern however, with mixed chemistry and inflammatory re-sponses across all size ranges. Endotoxin-resistant and sen-sitive mice which differ in the functionality of the Tlr4receptor have contrasting responses depending on the sizeand origin of the particle. A comparison of two diesel sam-ples shows that automotive diesel which is rich in hydro-

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carbons has stronger adjuvant effects than a more car-bonaceous diesel sample derived from a forklift truck. Thispresentation will demonstrate how the size and chemistryof ambient and combustion particulates affect biological ac-tivity and describe an approach for extrapolating betweenanimal and human exposures. (This abstract does not re-flect EPA policy)

IS-14SYSTEMIC DELIVERY OF DRUGS TO

HUMANS VIA INHALATION

GONDA, Igor

Unwanted systemic absorption of drugs delivered for thelocal treatment of respiratory disease has been documentedfor a long time. Methods to prevent this have been designed,especially in the form of reduction of oropharyngeal depo-sition that would lead to systemic absorption from the gas-trointestinal tract. The alveolated regions of the human res-piratory tract provide a large and relatively permeablesurface for drug absorption into the systemic circulation. Infact, the lung has been used for centuries as a portal of de-livery of substances with systemic effects such as anesthet-ics, nicotine and a number of currently illicit drugs. Overthe last 2 decades, much academic and industrial researchhas lead to the solution of the fundamental technical chal-lenges of practicable delivery of drugs in milligram quan-tities to the lung region efficiently and reproducibly. Largescale manufacturing processes exist for production of de-livery systems suitable for this purpose. Generally, the deposition of small molecules in the “deep lung” leads torelatively high absorption rates compared to other non-par-enteral routes of administration, making the inhalation de-livery attractive for drugs with intended rapid onset of ac-tion. Many therapeutics, especially peptides and proteins,that cannot be delivered systemically non-invasively, canbe absorbed with various degrees of bioavailability via in-halation. The critical factor for the efficiency and repro-ducibility of systemic delivery is deposition in the deep lungwhich in turn depends on the properties of the drug parti-cles (size, shape, density, hygroscopicity, velocity, charge)and the state of the respiratory system (including the indi-vidual’s anatomy, age, sex, disease, lung volume changesduring inhalation). While concerns exist about the potentialadverse reactions of the immune system to therapeutic pro-teins and peptides delivered to and through the lung, thereis not much data on the presence of such immune responseor its link to any safety issues with inhaled biologics. De-sirable systemic immune effects have been demonstratedby cytokine delivery to the lung.

IS-15AEROSOLS GENERATED BY BUSHFIRES—

BUSHFIRE CONTRIBUTIONS TO PARTICULATEPOLLUTION IN AUSTRALIA

J Gras, C Meyer and M Keywood.

CSIRO Atmospheric Research, Aspendale, Vic., Australia

Bushfires are a pervasive and controversial aspect ofthe Australian environment. In a broad sense the termbushfire includes both wildfires and fires used as an eco-

logical and risk management tool. Annually around250,000 M tonne of biomass is consumed across Australia,about 90% of this is savannah and the other 10% is for-est. Frequently this results in exposure to relatively con-centrated smoke, for fire workers and nearby populations.On some occasions entire large urban centers have beenimpacted. Interestingly, the few epidemiological studiesthat have been conducted in Australia using opportunis-tic exposure data from these population fumigations havenot shown strong, nor consistent, impacts on respiratoryhealth. A general picture of bushfire smoke properties in-cluding particle mass, number and selected toxic com-pound concentrations will be drawn from field measure-ments carried out through a number of recent programsat CSIRO Atmospheric Research. Coupled with new dis-persion modeling capability, these allow estimates of typ-ical exposure of these different aerosol components bothnear-field and at distance. An illustration of this capacitywill be given for the 2003 S.E. Australian fires.

IS-16CHARACTERIZING DELIVERY DEVICES AND

SELECTING DEVICES FOR OPTIMAL AEROSOLDELIVERY OF VACCINES IN CHILDREN

Ana-Maria Henao-Restrepo1 and the WHO ProductDevelopment Group for Measles Aerosol Project2

1Initiative for Vaccine Research, Department ofImmunization, Vaccines and Biologicals, World Health

Organization2The WHO Measles Aerosol Product Development Group(PDG) is an expert clinical and scientific advisory body to

WHO established to advice the Initiative for Vaccine Researchindependently and with scientific rigour regarding the

development plan of the measles aerosol vaccine. The author isthe focal point for the Measles Aerosol project at WHO.

The goal of the Measles Aerosol Project is to license atleast one method for respiratory delivery of currently li-censed measles vaccines that is safe, immunogenic and eas-ier to administer than injections. Evidence on immuno-genicity and safety of this route of administration has beenobtained with the Classical Mexican Device (CMD). Thisdevice has been established by the Product DevelopmentGroup (PDG) as the reference device for the MAP.

WHO commissioned a bench study to define the per-formance characteristics of the CMD. A panel of expertsfrom the International Society for Aerosols in Medicine(ISAM) reviewed the results from this study and the stan-dard operating procedures (SOPs) for candidate charac-terization of candidate devices. A method for rapid as-sessment of vaccine degradation by the nebulizers wasdeveloped by one of the Global Measles Specialized Lab-oratories. To ensure that any aerosol delivery systemcould be operated safely, effectively and reliably underthe field conditions design requirements for vaccineaerosol delivery devices were drawn up. It was also de-fined that companies proposing a candidate deviceshould have potential capacity to manufacture the devicesunder Good Manufacturing Practices, in sufficientamounts and, at an affordable price to the public healthsector of the developing countries.

WHO identified 12 companies that have available de-vices that could, in principle, meet the desired require-ments. Sixteen devices were assessed and three devices

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were selected using: (i) critical performance data as com-pared to CMD (i.e. size distribution, output, time to dose,doses per fill); (ii) device usability assessment (iii) vaccinepotency retention and (iii) company characteristics. Selected devices will assessed during the clinical trialsplanned in Mexico and India. Selected devices are licensedproducts available in several countries worldwide. Someadditional modifications will be required in order to fur-ther enhance their usability and logistics characteristics.

IS-17INHALED ANTIBIOTIC THERAPY

Anthony Hickey

The treatment of pulmonary infectious diseases withpharmaceutical aerosols is an attractive option consideringthe accessibility of the lungs for topical drug delivery.Aerosols have been targeted to the lungs for the treatmentof asthma with great success. Current therapies for otherdiseases, including Pseudomonas aeruginosa, Pneumocystisjirovecii (formerly Pneumocystis carinii) and mycobacterial in-fections, remain suboptimal due to the efficacy/safety pro-file. This profile may be improved by aerosol targeted pul-monary drug delivery. Azithromycin is a broad spectrumantibiotic that acts by inhibiting protein synthesis. It is as-sociated with side effects that might be avoided by aerosoldelivery to the lungs. In the present study three concentra-tions of azithromycin (10, 50 and 100mg/mL) were deliv-ered from three nebulizers (Acorn II, Updraft and LC Plus)operated at 8L/min. Particles size analyses were conductedby inertial impaction and laser diffraction. In addition, emit-ted doses were determined. A linear proportionality existedacross the concentration range between nominal dose andboth fine particle dose/fraction and emitted dose, with R2 �0.999 in all cases. The mass median aerodynamic diameterincreased from 1.4 to 1.9�m between 10 and 100 mg/mLof azithromycin solution concentration for the Acorn II. Theparticle size distributions were not all log-normally dis-tributed. The median particle size delivered from the de-vices was largest for the Updraft (2.8�m) and smallest forthe Acorn II (1.9�m) for 100mg/mL azithromycin solutionconcentrations. The efficiencies of small particle delivery(%�4.7�m) were as follows, LC Plus � Acorn II (85%) �Updraft(75%). However, the emitted dose from the LC Plus(55mg/min) was higher than the Acorn II (31mg/min) Tomaximize lung exposure to the aerosol, small median di-ameters and broad particle size distributions would be mosteffective. This study demonstrates that the dose deliveredto the lungs will be maximized, under the current operat-ing conditions by adopting the LC Plus, and high(100mg/mL) azithromycin concentrations.

IS-18NASAL CLEARANCE—IMPACT ON NASAL

DELIVERY OF DRUGS

Illum L

IDentity, 19 Cavendish Crescent North, The Park,Nottingham NG7 1BA, UK

The nasal route has been exploited for some years fordelivery of systemically acting drugs, eg anti-migraine

drugs, calcitonin, desmopressin. However, the nasalbioavailability is normally low for such small molecularweight polar drugs and peptides and proteins. This is duemainly to the rapid mucociliary clearance of drug for-mulations from the nasal cavity into the nasopharynx andthe poor transport of the drugs across the nasal mem-brane. The mucociliary clearance mechanism, transportsthe mucus layer posteriorly in the nasal cavity by a coor-dinated movement of the cilia, and clears formulationsfrom the nasal cavity with a half-time of 15–20 min.Hence, drugs that are poorly and slowly transportedacross the nasal membrane will have little chance of a highdegree of absorption. The paper will discuss the impor-tance and the impact of the nasal clearance mechanismon the therapeutic efficiency of nasal delivery of chal-lenging drugs and various approaches that have been em-ployed to overcome this barrier. We have exploited a va-riety of bioadhesive delivery systems that enablesprolonged residence time of drug formulations in thenasal cavity and significantly improves the nasal bioavail-ability of challenging drugs. For example, morphine ad-ministered nasally to man in a bioadhesive chitosan for-mulation showed a six fold increase in bioavailability to70%. The mechanism of action for such systems is oftena combination of bioadhesion and a modification of mem-brane transport pathways.

IS-19ULTRAFINE AEROSOLS—HEALTH EFFECTS

Kreyling WG1,2, Semmler M1, Möller W1

GSF—National Research Center for Environment andHealth; 1Institute for Inhalation Biology, 2Focus-Network:

Aerosols and Health; 85758 Neuherberg / Munich, Germany

Since about a decade, epidemiological studies con-tinue to indicate associations between exposure to in-creased concentrations of ambient ultrafine particles andadverse health effects in susceptible individuals. Yet, thedosimetry including deposition patterns in the respira-tory tract and the biokinetic fate of ultrafine particles isnot fully understood. Cardio-vascular effects observedin epidemiological studies triggered the discussion onenhanced translocation of ultrafine particles from therespiratory epithelium towards circulation and subse-quent target organs, like heart, liver and brain, eventu-ally causing adverse effects on cardiac function andblood coagulability as well as on functions of the cen-tral nervous system.

Toxicological studies on the effects of ultrafine parti-cles still aim to provide biological plausibility and toidentify cascades of mechanisms which are causal for thegradual transition from the physiological status towardspatho-physiological disease. Considering the interactionbetween insoluble ultrafine particles and biological sys-tems, like body fluids, proteins, cells etc., it seems un-likely that the ultrafine particles per se cause adverse re-actions. There is growing evidence that specificcomponents and the structure of the ultrafine particlesurface will trigger reactive radical formation leading tooxidative stress and subsequently to a cascade of signaltransduction pathways mediating orinitiating pro-in-flammatory processes by induction of a variety of cy-tokines and mediators.

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IS-20STACCATO™ TECHNOLOGY: A NOVEL MEANSOF GENERATING DRUG AEROSOLS FOR RAPID

SYSTEMIC DELIVERY

Peter Lloyd, Ramesh Damani, Ron Hale, Craig Hodges,Daniel Mufson, Patrik Munzar, Dan Myers, Reynaldo

Quintana, Josh Rabinowitz, William Shen, RomanSkowronski, Dennis Solas, Soonho Song, Pravin Soni,

and Martin Wensley

A novel approach, termed Staccato™ thermal aerosolgeneration technology, has been developed for the gen-eration of pharmaceutical aerosols for rapid delivery tothe systemic blood circulation through the pulmonaryroute. The technology involves rapid vaporization of athin film of pure drug to yield a pure drug vapor, whichsubsequently cools and condenses to form an aerosol ofappropriate size for deep lung delivery.

A compact, disposable, single-dose breath-actuated de-vice has been developed using this technology. In the de-vice, drug without excipients is coated onto a stainless steelsurface located within a plastic airway. Patient inspirationtriggers rapid heating of the surface, vaporizing the drugand delivering the aerosol dose to the lung within less than1 second. The aerosol thus produced has an MMAD of �2microns with a GSD of �2. The rapid heating of the drugproduces minimal thermal decomposition products.

Two preclinical and one clinical pharmacokinetic stud-ies using the Staccato system have been conducted usingtwo different small molecule drugs. In the preclinicalstudies, blood samples were collected from the left ven-tricle and the superior vena cava. These studies showrapid and complete absorption of the drug with Tmax inthe left ventricle achieved in about 20–30 seconds. Resultsof clinical and preclinical studies including pharmacoki-netic and absolute bioavailability data will be presented.

IS-21REGULATION OF INHALED PRODUCTS IN

THE EU—AN ASSESSOR’S VIEW

F C Mortimer

Medicines and Healthcare products Regulatory Agency,London, SW8 5NQ, UK

The presentation will focus on the legal basis for sub-mitting an application in the EU for an inhaled productwishing to gain a Marketing Authorisation with the samesummary of product characteristics to that of a marketedoriginal product. The key requirements relating to thepharmaceutical, preclinical and clinical data to achievethis aim will be emphasised.

Additional to demonstration of the overall safety, qual-ity and efficacy of the proposed inhaled product, where‘essential similarity’ to an original product is beingclaimed therapeutic equivalence must be shown and thesafety profiles of the products must be comparable. Ref-erence will be made to the specific guidelines publishedby the Committee for Medicinal Products for Human Use(CHMP) that facilitate industry in their development ofinhaled products. The future changes to these guidelineswill also be reviewed. The in vitro evaluation of the pro-

posed product and the original product will be discussedand the circumstances where supportive preclinical andclinical data are essential will be highlighted.

IS-22INDUSTRIAL AEROSOLS—

ASBESTOS AND OTHER DUSTS.

Aw Musk

The deposition of inhaled particles is influenced bytheir physical properties and their effects are influencedby physical and chemical properties and also by host fac-tors. The physical properties include size, density, shape,penetrability, surface area, electro-static charge and hy-groscopicity. Chemical properties are pH and solubility.Fibrogenicity and antigenicity are also important.

The inhalable fraction of a dust in the inspired air is themass of airborne particulates which is inhaled throughthe nose and mouth.

The thoracic fraction is the mass of inhalable particlespenetrating beyond the larynx.

The respirable fraction is the mass of inhalable parti-cles penetrating to the unciliated airways of the lung.

Ultrafine particles are those with a (physical or diffu-sion) diameter �100nm.

Five physical processes are involved in particle depo-sition:

➣ Sedimentation or gravitational settling➣ Inertial impaction➣ Diffusion/Brownian movement➣ Electrostatic precipitation➣ Interception➣ Particles deposited in the anterior third of the nose

are removed by blowing, wiping, sneezing or other me-chanical means. Clearance from the posterior portions ofthe nose and the conducting airways to the terminal bron-chioles is by muco-ciliary action. Beyond the terminalbronchiole alveolar macrophages (derived from the tissuehistiocyte) phagocytose particles which are deposited andmigrate through the alveolar wall into the interstitiumand hence into the blood stream and the lymphatic chan-nels or migrate to the terminal bronchiole from wherethey are cleared by the muco-ciliary apparatus. Alveolarclearance is related to particle size but also density, chem-ical composition and toxicity.

The patterns of response of the body are limited anddepend on the site of deposition and the nature of thehost response. Nasal deposition: rhinitis, hay fever, nasalperforation, nasal cancer. Deposition in trachea and con-ducting airways: acute tracheitis and bronchitis/bronchi-olitis, asthma, chronic bronchitis/bronchiolitis/bronchi-olitis obliterans, lung cancer. Parenchymal deposition:acute bronchiolitis/alveolitis, extrinsic allergic alveolitis,pneumoconiosis, alveolar proteinosis, emphysema, lungcancer and systemic effects.

Asbestos related diseases: pleural plaques, progressivepleural fibrosis (diffuse pleural thickening), rolled atelec-tasis, transpulmonary bands (crow’s feet), benign as-bestos pleural effusion, lung cancer, malignant mesothe-lioma of the pleura and peritoneum, asbestosis.

Silica-related diseases: silicosis, lung cancer.Copper, Manganese, Zinc and other metals: fume fevers.Vanadium: asthmaBerylium: berylliosis

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IS-23DELIVERING GENES TO AIRWAYS: VIROLOGY,

BIOLOGY, TECHNOLOGY.

Parsons DW.

Pulmonary Medicine, Women’s & Children’s Hospital, NthAdelaide, 5006, Sth Australia.

Gene therapy agents can produce a significant and ex-tended biological change following a single dose deliv-ery. The limitations of non-biological gene vectors meansthat the most promising gene therapy approaches for cys-tic fibrosis airway disease uses biological vectors, i.e.modified viruses. These vectors can achieve gene expres-sion that is short-term (adenoviruses) and also long-term(adeno-associated viruses, lentiviruses).

Achieving efficient delivery of viral vectors is compli-cated by the variety of defences to deposited particles thathave evolved on the conducting-airway surface; some ofthese airway defences have only become apparent duringthe development of airway gene therapy during the last 10years. Our new understandings of CF disease, and of theimmune difficulties caused by vector re-dosing, show thatCF airway gene correction should be focussed on conduct-ing airways, before disease initiation, and must endure.

We employ a lentivirus as the preferred integrating vec-tor, with the ideal target cells being deeper-lying airwayprogenitor/stem cells. An airway pre-conditioning phasepermits vectors to evade airway defences, allowing im-proved access to surface ciliated cells as well as to the deepertarget cells.

Viral vectors are challenging to manufacture in bulk, andviability can be compromised by production conditions.Standard in vivo vector delivery in animal models isachieved via bolus instillation and coarse sprays, whilenew-generation electronic devices are now available forproducing respirable aerosols from small volumes of genevector.

IS-24INHALED COMBINATION THERAPY:

A NEW DRY POWDER INHALER PLATFORM

Dr Julie-Ann Penton

Combination therapy for asthma represents a signifi-cant therapeutic option, with the increasing use of con-current inhaled corticosteroids (ICS) and long-actingbeta2-agonists (LABAs). This effective therapy is set togrow in importance with the addition of new treatmentregimens, product variants, indications and delivery plat-forms. The development of combination products is not,however, straightforward with, for example, intellectualproperty and formulation challenges.

A new dry powder inhaler (DPI) platform, termedC200, has been developed specifically to meet the chal-lenges of effective combination therapy delivery. TheC200 device differs from other pressurized metered doseinhaler or DPI delivery options in that it incorporates twoseparate storage, metering, and delivery systems for thetwo drugs in a single inhaler. C200 can therefore use twosingle-entity drug formulations, and can also alter thedose of one active by means of the metering system, as

well as by reformulation. Pharmaceutical data generatedusing different ICS and LABA combinations supportsconsistent dose metering and dose delivery in line withpharmacopoeial and regulatory requirements. The air-ways have been optimised to provide efficient aerosoli-sation for a passive DPI system, which is also relativelyindependent of flow rate.

The proprietary C200 dual reservoir DPI offers a ro-bust and more versatile approach to combination ther-apy than the current single reservoir or fixed formula-tion devices.

IS-25PRENATAL DEVELOPMENT OF THE IMMUNE

SYSTEM AND HOW IT CAN BE MODIFIED

A/Prof Susan L Prescott

School of Paediatrics and Child Health, University ofWestern Australia, Perth, Australia

The escalating rates of allergic disease suggest that ahigh proportion of the population carry some form of ge-netic predisposition that is increasingly unmasked by en-vironmental change. As the first signs of allergic diseaseare often manifest within weeks or months of life, it islogical that factors that influence very early immune de-velopment are likely to play a significant role in themounting propensity for allergy. There is an urgent needto identify the responsible factors in order to develop safeand effective prevention strategies.

Many aspects of immune function are less mature atbirth. Although neonatal T cells can respond to antigens(including allergens) these responses are atypical and donot appear to represent classical memory responses. Thepattern of cytokines produced during activation is also dif-ferent from mature responses, with a relative dominanceof Th2 cytokines and a significant immaturity of Th1 sig-nalling. There has been growing speculation that allergicdisease may be the result of less efficient postnatal Th1 mat-uration. Mounting evidence of presymptomatic differencesin the immune function of newborns who later develop al-lergic disease, suggests that events during fetal life are ofcrucial interest. These differences seem to affect a numberof different “read outs” of immune activity at birth, in-cluding the magnitude and pattern of cellular responses invitro, circulating neonatal levels of cytokines or cytokineproducing cells, and activity of progenitors that give riseto pro-allergic inflammatory cells (eosinophil progenitors).Proteins involved in microbial-driven activation of APCand pro-Th1 signalling (such as sCD14) have also been de-tected in amniotic fluid and are reduced in those who goon to develop atopic dermatitis.

At this stage it is not clear if these early differences aremerely a detectable measure of increased genetic predis-position, or whether they are indicative of early (in utero)environmental influences that are already promoting thedevelopment of the allergic phenotype. It seems increas-ingly likely that both are true, particularly as a) diseaseis increasing and, b) these conditions (such as atopic der-matitis and food allergies) may be manifest withinmonths of life. It is remains intuitive that the processesthat promote allergic inflammation are initiated in thisvery early period.

Both maternal environmental exposures and direct ma-ternal immune interactions have the capacity to influence

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the developing fetal immune system. Although many cur-rent models (such as the “hygiene hypothesis”) to explainrecent rises in allergic diseases are generally applied inthe postnatal period, effects could begin in utero. In-trauterine bacterial exposure is associated with increasedcapacity for neonatal Th1 responses, confirming the po-tential to influence maturation of Th1 function antena-tally. Thus, it is possible that “cleaner environments”could also be having an effect even before birth. Manyother “western” environmental changes may also have ef-fects during pregnancy. The role of prenatal exposure toallergens, dietary nutrients, microbial elements and pol-lutants (particularly maternal smoking) will be discussedin this context.

The capacity to modify immune development throughearly environmental exposures clearly raises the potentialof preventing disease through the same pathways. Manycurrent targets for prevention such as early aeroallergenexposure and infant feeding practices, are proving to beineffective and may not be directly implicated in risingrates of disease. This is leading to new ways of modify-ing early immune development, including novel vacci-nation strategies and dietary modifications (includinganti-oxidants, polyunsaturated fatty acids and probi-otics). Some of these factors may contribute to future av-enues of primary allergy prevention in pregnancy andearly postnatal life, and are already under investigationby a number of groups.

With the development of more effective allergy pre-vention strategies there will be a growing need to moreaccurately predict atopy and/ or airways disease. Ideallythis will allow early, more targeted prevention whenmore definitive strategies become available.

IS-26ADVANCES IN AEROSOLS:

ADULT RESPIRATORY DISEASE

GC Smaldone* MD, PhD.

SUNY at Stony Brook NY

In the last decade, our practical understanding ofaerosol delivery has improved. Recognition of the im-portance of breathing pattern in aerosol delivery anddeposition has led to the design of devices that allowtargeting of deposition to airways and alveoli. Systemsincorporating patient feedback provide control of fac-tors affecting deposition and the control of dose to thelung can now be expected. New devices combined witha medical realization of therapeutic need are beginningto affect the range of drugs now available to the care-giver or in development for the immediate future. Re-cently completed clinical trials have demonstrated theusefulness of therapy targeted to the lungs in reducingsystemic toxicity with enhanced efficacy. A prime ex-ample of this approach is aerosolized cyclosporine, usedto prevent rejection in lung transplantation. This agenthas recently been shown to reduce mortality in trans-plant recipients and will lead to an NDA. For larger pa-tient populations, the pursuit of therapies to reduceVentilator Associated Pneumonia can affect the out-come of illness in the intubated patient in the Intensive

Care Unit. Patients with Idiopathic Pulmonary Fibrosismay benefit from high doses of aerosolized interferongamma. The interface between the patient and the de-vice represents a new area of practical research. Face-masks have been shown to be important in terms ofdrug delivery for multiple types of delivery systemswith different behavior in MDI/valved holding cham-bers compared to nebulizers. Patient and caregiversafety are additional factors that will affect future ap-proaches to therapy.

IS-27MEASURING SPRAY VELOCITY AND SPRAYDURATION OF METERED—DOSE INHALERS

AND RESPIMAT® SOFT MIST™ INHALER

M Spallek*, D Hochrainer, H Hölz, C Kreher, LScaffidi, H Wachtel.

Boehringer Ingelheim Pharma GmbH & Co. KG, D 55216Ingelheim, Germany

The objective of this study was to compare the sprayduration—the time period over which the aerosol is re-leased – and the velocity of aerosol clouds produced byRespimat® SMI with those from a variety of chlorofluo-rocarbon (CFC) and hydrofluoroalkane (HFA) pMDIs. Allinhalers contained solutions or suspensions of bron-chodilators.

A video recording method was used to determine theaerosol velocity. For spray duration, the time for genera-tion of the Soft Mist™ by Respimat® SMI was initially de-termined using three different methods (video recordinglaser light diffraction and rotating disc). Video recordingwas then used to compare the spray duration of Respi-mat® SMI with those from the other inhalers.

The Soft Mist™ produced by Respimat® SMI movedmuch more slowly and had a more prolonged durationthan aerosol clouds from pMDIs (mean velocity at a 10cm distance from the nozzle: Respimat® SMI, 0.8 m/s;pMDIs, 2.0–8.4 m/s; mean duration: Respimat® SMI, 1.5s; pMDIs, 0.15–0.36 s). These characteristics should resultin improved lung and reduced oropharyngeal deposition,and are likely to simplify co-ordination of inhaler actua-tion and inhalation compared with pMDIs.

IS-28RAPID RESPONSE UNIT DOSES FOR ED AND

OTHER SYSTEMIC AEROSOL THERAPIES

J N Staniforth, M Main, M J Shott, M Newton and M J Tobyn

Vectura Group plc, Chippenham, Wiltshire, SN14 6FH, UK

Although highly efficient drug formulation-devicecombinations are desirable for treating lung diseases,especially COPD, they are an essential feature of sys-temic aerosol therapies (SAT) for diseases including onefor erectile dysfunction (ED) containing apomorphine(VR004). In addition to circumventing bioavailabilityand toxicity issues, a major aim of developing VR004 asa SAT was to provide a rapid and effectively durable

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action through non-injection systemic delivery. In ED,rapid response is rated the second most important fac-tor by patients after efficacy. In the case of VR004aerosol delivery, Cmax occurred 1–3 mins post-dosing(Fig 1), with a correlation between tmax and action on-set. VR004 showed ‘IV type’ dose-proportional PK. By

comparison, sub-lingual delivery of more than doublethe aerosol apomorphine dose showed Cmaxs around10% of those given by inhalation. Furthermore the rapidresponse provided by VR004 aerosols was not accom-panied by serious AEs, unlike those reported for thesub-lingual presentation. The beneficial clinical out-comes for VR004, including good and rapid responserates, effective, durability and low dose requirement,were made possible by the generation of a high qualityaerosol. The aerosol system combines an active unit-dose DPI device with a particle engineered formulation.This high efficiency system is considered capable of pro-viding a rapid response unit dose system for ED as wellas other systemic aerosol therapies.

IS-29CELLS—INNATE AND ADAPTIVE IMMUNITY

TO INHALED ANTIGENS.

Upham JW

Division of Cell Biology, Telethon Institute for Child HealthResearch, PO Box 855, West Perth WA 6872 Australia.

In the face of continual exposure to a variety of in-haled pathogens, a remarkable umbrella of local de-fences exist to protect the lung from infection and in-jury. These include mechanical barriers such as nasalfiltration, mucociliary clearance and the cough reflex.Epithelial cells provide not only a barrier to the passageof inhaled particles, but they also secrete a variety ofmolecules that are important in host defence and im-mune regulation. Cells of the innate immune systemsuch as neutrophils, macrophages and natural killer ex-press pattern recognition receptors and are able torecognise and respond rapidly to microbial challenge.In contrast, while T-cells and B-cells of the adaptive im-mune system respond much more slowly to inhaledantigens, they have the unique capacity to develop im-munological memory, such that upon rechallenge, en-suing immune responses are more rapid and efficient.

Antigen presenting dendritic cells bridge innate andadaptive immunity. They are highly receptive to envi-ronmental signals, and are able to mould the ensuingadaptive immune response. While an effective immuneresponse within the lung is required for effective de-fence against inhaled micro-organisms, non-pathogenicantigens are far more numerous in inspired air, so a va-riety of regulatory and tolerogenic mechanisms havedeveloped in order to avoid lung damage or disease associated with inappropriate or excessive immuno-inflammatory responses. An understanding of theseprocesses is central to improved understanding of a va-riety of pulmonary diseases.

IS-30AEROSOL DELIVERY OF VACCINES:

THE CHALLENGE OF ACHIEVING IMMUNITYWHILE ENSURING SAFETY.

José Luis Valdespino MD, MPH1 and the MeaslesAerosol Product Development Group2

1National Institute of Public Health of Mexico (INSP),jvaldesp@insp.mx

2The WHO Measles Aerosol Product Development Group(PDG) is an expert clinical and scientific advisory body to

WHO established to advice the Initiative for VaccineResearch independently and with scientific rigour regarding

the development plan of the measles aerosol vaccine. Theauthor is a member of the PDG.

WHO launched the Measles Aerosol Project with thegoal to develop and license at least one method for res-piratory delivery of currently licensed measles vaccinesby 2007. Since the 80’s, trials in Mexico have demon-strated that delivering measles aerosol vaccine with theClassical Mexican Device is safe and immunogenicamong infants �9 months of age as a first dose andamong school-aged children as a booster dose. It in-duces mucosal and cellular immunogenicity amongschool-aged children. It is well accepted by users; andprevents safety risks associated with percutaneous ad-ministration.

Because previous studies were not carried out with li-censure as an aim, WHO is supporting GLP and GCPcompliant studies to attain licensure by 2007.

Potential safety concerns were identified early in theproject: risk to HIV and immunosuppressed individuals,adverse events in the respiratory tract and the central ner-vous system, risk of environmental contamination andcontamination of the devices. Expert groups reviewed theevidence and provided advice on the methods to assessthem. GLP animal safety, immunogenic and toxicologystudies have been completed. Results confirm good im-munogenic response and no evidence of local or systemictoxic effects.

A Phase I (safety) trial in India of measles aerosol vac-cine using three different aerosol delivery devices isplanned. Also a Phase 2 (immunogenicity and safety) trialis planned in Mexico. Aerosol measles vaccine will be ad-ministered as primary dose to 12 month old children andas booster dose to 6 years old children using four devicesas compared to SC measles vaccine.

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IS-31EQUIVALENCE CRITERIA FOR AEROSOL

DEVICES FROM AN INDUSTRY PERSPECTIVE

VanDervanter, D

Background: In the past decade, two chronic inhala-tion therapies (dornase alpha inhalation solution andtobramycin inhalation solution [TIS]) have been regis-tered for the preservation of lung function in personswith cystic fibrosis. Advances in device and formula-tion technology have led to the possibility of registra-tion of improved delivery formats for registered inhaledtherapies. By definition, an “improved” format mustmodify the delivery of an inhaled medication in someway. However, the equivalent safety and efficacy of twofundamentally different aerosols cannot be inferredfrom the physical properties of the aerosols as deter-mined by in vitro methodologies. For this reason, therereally is no viable alternative to a clinical demonstra-tion of the safety and efficacy of an improved format.Traditionally, placebo-controlled trials would not be ap-propriate for follow-on or second-to-market therapiesseeking registration, particularly if these products havefilled an unmet medical need in a progressive disease.Rather, a new product would have to be shown to be“equivalent” or “non-inferior” to a previously regis-tered product with respect to relevant endpoints (e.g.change from baseline in pulmonary function, adverseevents, etc.). Unfortunately, power estimates of suchnon-inferiority tests for an inhaled CF therapy suggestthat the number of subjects [n] required to achieve rea-sonable test power (�90%) can exceed the size of thelargest CF trials ever run by an order of magnitude. Con-sider a parallel arm study of a new therapy and a pre-viously registered product with efficacy measured bythe relative change from baseline of FEV1 % predicted,and a one-sided non-inferiority test at alpha � 0.025.Non-inferiority tests require the establishment of arange of non-inferiority limit “delta” [d] within whichobserved means for treatments is not clinically differ-ent. The correct value of [d] for a pulmonary functionclinical trial has been the subject of some debate, withvalues of 4–5% of FEV1 % predicted often proposed.When the standard deviation is assumed to be �20% ofFEV1 % predicted (as estimated from previous experi-ence with inhaled tobramycin), isotherms for the rela-tionship between and sample size [n] per arm can beplotted for a study result in which the true mean treat-ment effect of the new therapy (MN) differs from thetreatment effect of the comparator (MC) by 0%, 1%, 2%and 3% of FEV1 % predicted. A curve establishing sam-ple sizes per arm necessary to maintain a power of 90%or greater as a function of the value of [MN-MC] demon-

strates that even when [MC-MN] � 0, 90% power re-quires a study with approximately 350 subjects per arm.When [MC-MN] � 2%, 950 subjects per arm are re-quired in order to assure 90% power. Such sample sizesare impossible to achieve, and therefore non-inferioritytesting for new versions of existing registered therapiesis not feasible unless sponsors are willing to operate atan increased risk of rejecting a therapy that is clinicallyequivalent. Development and registration of such ther-apies will therefore require creative study designsagreed upon by sponsors and regulatory authorities,and those designs will probably need to employ effi-cacy tests of significantly abbreviated duration that al-low comparison to a placebo, combined with additionalcomprehensive comparative studies that adequatelydemonstrate safety of the new aerosol format.

IS-32POTENTIAL NEW APPROACHES TO SOLVING

PROBLEMS OF DELIVERY TO CHILDREN

Wildhaber JH1, Minocchieri S2, Schueepp KG1.Swiss Paediatric Respiratory Research Group

1Division of Respiratory Medicine, University Children’sHospital of Zürich, Switzerland.

2Division of Neonatology, University Children’s Hospital ofBerne, Switzerland.

Inhalation therapy is currently the most commonmethod of delivering drugs to children with lung dis-eases. Despite the overall importance of aerosol therapy,surprisingly little is known about the technical and prac-tical aspects of aerosol administration to children in gen-eral and to preschool children in particular. Most of theknowledge has so far been transposed from adult studiesand may partly apply to older children and adolescentsbut not to preschool children. The efficiency of aerosoltherapy with currently available inhalation devices anddrug formulations in preschool children is low. However,early and efficient therapy in preschool children, andhence in early life, is crucial for the long-term prognosisof most lung diseases. This underlines the importance ofaerosol research in young children, who form an agegroup requiring special aerosol delivery devices and tech-niques. New optimised combinations of inhalation deviceand drug formulation based on individual patient-relatedfactors greatly improve the efficiency of aerosol deliveryto young children. In addition, solutions to improve co-operation and compliance have added to the possibilitiesto deliver aerosols in a child friendly way. These techni-cal and practical improvements may greatly improveaerosol therapy in children.

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P-1INFLUENCE OF FINE LACTOSE ON SALMETEROLXINAFOATE DISPERSION FROM CARRIER-FREE

MIXTURES FOR INHALATION

Adi H*, Stewart PJ, Larson I

Victorian College of Pharmacy, Monash University,Parkville, Vic 3052 Australia

Purpose. The aim was to investigate the dispersion ofsalmeterol xinafoate (SX) in SX-fine lactose (FL), carrier-free powder mixtures for inhalation.

Methods. Mixtures (SX: FL: 1:4) consisting of SX(2.3�m) and FL (3.0, 7.9, 17.7 and 33.3�m) were prepared.Particle size distributions were determined by laser dif-fraction (Malvern Mastersizer, UK) and the particulate in-teractions in mixtures were observed by SEM. The in vitrodeposition of SX was measured using a twin stage im-pinger (TSI, Copley, UK) at a flow rate of 60L/min viaRotahaler® for four second. SX was analysed using vali-dated HPLC method.

Results. The FPF of SX from SX-FL (7.9 �m) was sig-nificantly higher than other mixtures (P � 0.05). No sig-nificant difference was observed between the formula-tions of SX alone and SX-FL (3.0 �m) (P � 0.05), and aslight increase in FPF occurred with SX-FL (33.3�m). Max-imum dispersion occurred when the drug and FL formedloose mixed agglomerates; however, further increases inthe particle size of FL (e.g. FL of 17.7 and 33.3 �m) pro-duced decreased FPF due to strong adhesion of SX on thelarger lactose particles.

Conclusions. The outcomes demonstrated that thepresence of loose SX-FL agglomerates played a significantrole in powder dispersion. The results obtained in thisstudy reflect the importance of the fine lactose propertiesin optimising drug dispersion.

P-2LUNG DEPOSITION PROPERTIES OF

THERAPEUTIC AEROSOLS AT DIFFERENTPARTICLE SIZES AND BREATHING METHODS

B Alföldy1, I Balásházy1, W Hofmann2

1. KFKI Atomic Energy Research Institute, POB 49, H-1525 Budapest 114, Hungary

2. Institute of Physics and Biophysics, University ofSalzburg, Hellbrunner Str. 34, A-5020 Salzburg, Austria

The magnitude and distribution of the deposition of inhaled aerosol particles, such as therapeutic aerosoldroplets, within the human respiratory system princi-pally depend on particle size and air velocities in the air-ways. In this study, the authors analyse the depositionproperties of the inhaled particles as a function of theparticle size and breathing conditions for a wide diam-

eter range at several breathing conditions. The calcula-tions have been carried out using the stochastic lung de-position model of Koblinger and Hofmann. Depositionin the tracheobronchial and the acinar lung region hasbeen studied separately. The differences of the deposi-tion concluded uniform and bolus inhalation alsoanalysed.

As it is cleared up from the calculations, the optimalsize diameter is around 10 �m for the tracheobronchialexposition. Because of the high extrathoracic depositionefficiency of this particle size the principal breathing pa-rameter is the airflow. Maximal tracheobronchial deposi-tion has been obtained with extremely slow, 75 cm3/sflow rate. For exposition the acinar region using 1.5 �mdiameter particle is recommended, because the deposi-tion efficiency of this particle size is close to the maximumand the ratio of the acinar and the bronchial depositionefficiency is high enough.

P-3EVALUATION OF THE INAMED AKITA

SMART NEBULISER AS A RADIOSEROSOLDELIVERY DEVICE

Witherow J1, *Bailey DL1,2, Adams E1, and Roach PJ2.

1.School of Medical Radiation Science, University of Sydney,Australia

2.Department of Nuclear Medicine, Royal North ShoreHospital, Sydney, Australia

We have compared the AKITA delivery of [99mTc]-DTPA with [99mTc]-Technegas, considered to be the goldstandard for ventilation imaging. The aim of this work isto obtain a system in which the deposition of radioaerosolcan be (a) well controlled, (b) targeted to different airwaysand (c) highly reproducible. Twelve subjects referred fornon-urgent V/Q lung scans were enrolled. One hour priorto V/Q scanning, the participants were given the ra-dioaerosol and eight planar views were acquired on adual-head gamma camera. Three sets of anterior/poste-rior (A/P) views were acquired to aid in determining halfclearance time. The administered dose of [99mTc]-wasused to quantify the radioaerosol delivered. The scanswere assessed blindly by 4 experienced physicians for de-position homogeneity and overall clinical acceptability, inaddition to measuring the normalised penetration index(relative to technegas, PI*). All participants were able touse the AKITA device and produced acceptable lungscans. Mean radioactivity deposited in 3–5 breaths was38.8MBq (range 26.9–52.6MBq). Decay-corrected clear-ance half-time ranged from 36–87 mins with a mean of 63minutes. Mean PI* was 87.1 � 6.7%. AKITA ventilationimages overall were rated as slightly inferior to techne-gas, but acceptable. We have found the AKITA nebuliserto be highly efficient and clinically acceptable in this pi-lot study.

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P-4MODELLING LOCAL DEPOSITION PATTERNS OF

INHALED AEROSOLS IN BRONCHIAL HUMANAIRWAYS

I Balásházy1,2, Á Farkas1, A Czitrovszky*3, D Szigethy4, J. Nagy5

1. KFKI Atomic Energy Research Institute, H-1525Budapest, P.O. Box 49, Hungary

2. Respirisk Co., H-1133 Budapest, Ronyva u. 6, Hungary3. Research Institute for Solid State Physics and Optics,

H-1525 Budapest, P.O. Box 49, Hungary4. Technoorg-Linda Co., H-1077 Budapest Rózsa u. 24,

Hungary5. I-Lab Co., H-1118 Budapest, Regös u. 9

Local deposition patterns in bronchial airways of in-haled aerosol drugs and measured urban aerosols wereanalysed and compared applying computational fluid dy-namics techniques. A wide range of particle sizes of ther-apeutic aerosols has been studied. The size distributionand concentration of urban aerosols have been measuredwithin the city of Budapest and it’s surrounding by a mo-bile aerosol laboratory installed with high concentrationlaser particle counters and beta-ray absorption monitorand cascade impactors. A computer programme has gen-erated the geometry of the airways. Flow fields within theairways were simulated by the FLUENT CFD code. Par-ticle deposition patterns have been simulated by a parti-cle trajectory code. Computed deposition patterns arestrongly inhomogeneous at all realistic parameter selec-tions. Hot spots of deposition are found at the carina re-gion of the bifurcations during inhalation and at the topand bottom sides of parent airways during exhalation. Inhot spots, the cellular doses are about 10–100 times higherthan the average values at both types of aerosols.

The research was supported by the Hungarian NKFP-1/B-047/2004 & NKFP-3/A-089/2004 Projects.

P-5NASAL FILTERING OF FINE PARTICLES IN

CHILDREN VS. ADULTS.

WD Bennett* and KL Zeman.

Center for Environmental Medicine, Asthma and LungBiology, UNC Chapel Hill, N.C. 27599.

Nasal efficiency for removing fine particles may be af-fected by developmental changes in nasal structure asso-ciated with age. In healthy Caucasian children (age 6–13,n � 17) and adults (age 18–28, n � 11) we measured thefractional deposition (DF) of fine particles (1 and 2umMMAD) for oral and nasal breathing using individualbreathing patterns previously determined by respiratoryinductance plethysmography during a graded exerciseprotocol. DF for both nasal and mouth breathing weremeasured separately by laser photometry at the sametidal volume and breathing rate for resting and light ex-ercise (20% max work load) conditions. From these DFmeasures, nasal deposition efficiency (NDE) was calcu-lated for each condition. We found that NDE for 2um par-ticles was significantly less in the children vs. adults for

their light exercise ventilation patterns, 0.25�/�0.16 vs.0.44�/�0.11 respectively, p � 0.002, i.e. the condition forhighest deposition by impaction in the nasal airways.NDE under this condition increased significantly withchild’s height and age (r � 0.62 and 0.59, p � 0.05). NDEdid not differ between children and adults for the 1umparticles and/or resting breathing conditions. These re-sults suggest that due to less efficient nasal filtering ofparticles the lungs of children may be exposed to higherconcentrations of inhaled, ambient particles than adults.Supported by USEPA Cooperative Agreement CR829522but does not necessarily reflect EPA policy.

P-6SUSTAINED CORRECTION OF ABNORMAL

MUCOCILIARY CLEARANCE AND LUNGFUNCTION IN CYSTIC FIBROSIS (CF) WITHAEROSOLIZED HYPERTONIC SALINE (HS).

WD Bennett*, SH Donaldson, KL Zeman, MR Knowles,and RC Boucher.

Division of Pulmonary and Critical Care; Department ofMedicine; University of North Carolina at Chapel Hill

Abnormal airway surface liquid volume homeostasis inCF airways produces defects in mucociliary clearance(MCC). Inhaled HS, without or with amiloride (an epithe-lial sodium channel blocker) pretreatment, may producesufficient osmotic rehydration of airway surfaces to restoreMCC and benefit lung function. CF patients (n � 24) withmild-moderate lung disease were randomized to inhaled7% NaCl without or with amiloride pretreatment fourtimes daily for two weeks. MCC and lung function weremeasured at the beginning and end of the 2 week treat-ment period. Both hypertonic saline with and withoutamiloride pretreatment acutely accelerated MCC (mea-sured as clearance of an inhaled, radiolabeled aerosol). Butonly hypertonic saline (without amiloride) led to a sus-tained increase in MCC and improved lung function after2 weeks of treatment. MCC through 24 hours improvedfrom 37�/�8% pretreatment to 48�/�12% post 2-weektreatment (p � 0.05), approaching that of healthy, normalsubjects (53�/�11%). During the treatment period, theFEV1 increased by 1.10% in the amiloride/HS (NS) treatedgroup, and 5.74% (P � 0.05) in the placebo/HS group.These data support the use of aerosolized, hypertonicsaline for the treatment of CF lung disease. Supported by theCFF (DONALD00A0) and GCRC (NIH R0000046).

P-7THE VERSATILITY OF THE SPINNING-TOP

AEROSOL GENERATOR IN PRODUCINGMONODISPERSE PHARMACOLOGICAL

AEROSOLS

Biddiscombe MF1*, Barnes PJ2, Usmani OS2

1Nuclear Medicine, 2Thoracic Medicine, Royal BromptonHospital and National Heart & Lung Institute, Imperial

College London, U.K.

Rationale: Pharmacological aerosols of precisely con-trolled particle size and narrow dispersity can be gener-ated using the spinning-top aerosol generator (STAG). Ouraim was to demonstrate the versatility of the STAG by

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aerosolising a range of commercially available pulmonarytherapy drugs. Methods: Nebules of Flixotide® (fluticas-one propionate), Pulmicort® (budesonide), Combivent®(salbutamol sulphate & ipratropium bromide), Bricanyl®(terbutaline sulphate), Atrovent® (ipratropium bromide)Salmol® (salbutamol sulphate) and micronised salbutamolsulphate and salmeterol xinafoate were each mixed withethanol and delivered to the STAG. Results: Monodisperseaerosol distributions (GSD �1.22) between 1.5�m and 7�mMMAD were generated by various disc-rotor speeds. AnAerodynamic Particle Sizer verified each distribution. Con-clusions: The STAG is able to accommodate a variety oftherapeutic drugs as either solutions or suspensions, anda range of monodisperse particle sizes can be generated.This technology can be utilised to accurately explore drugparticle size and clinical effects in vivo.

P-9THROAT DEPOSITION CAN EXPLAIN THE

VARIABILITY IN LUNG DEPOSITION

L Borgström*, L Asking, B Olsson and L Thorsson

AstraZeneca R&D, SE-224 60 Lund, Sweden

Lung deposition is the key bridging parameter betweenin vitro and in vivo performance and the literature wassearched for human lung deposition studies. Seventystudies contained relevant information including extentof lung deposition and its variability. Further character-istics of the studies, such as if the subjects were healthyor asthmatics, adults or children, and what device thatwas used, were added to the database. In all 186 datapoints were included.

Variability in lung deposition was depicted as a func-tion of extent of lung deposition; for the entire data setand for subsets thereof.

The primary analysis showed that high lung depositionwas associated with low relative variability and low lungdeposition was associated with a high relative variability.Independent of device type or subject category.

Using the throat deposition model of Rudolf et al., theobserved correlation of lung deposition variability to ex-tent of lung deposition could be explained as being de-termined largely by the extent of and variability in throatretention.

Thus, we hypothesize that throat retention is the majordeterminant for lung deposition of an inhaled aerosol, andits absolute variability will largely be determined by the ab-solute variability in throat retention. The relative variabil-ity in lung deposition will therefore tend to be high for lowlung deposition and low for high lung deposition.

P-10INHALATION OF LOW MOLECULAR

WEIGHT HEPARIN

S. Häußermann1, G. Scheuch1, P. Brand1, Chr.Herpich1, J. Brom2, G. Weidinger2, Th.Meyer1

1Inamed Research GmbH & Co. KG, 82131 Gauting,2Novartis Pharma, 90429 Nürnberg

In several studies it has been shown that inhaled He-parins have a number of attractive properties. Favourablepharmacokinetic properties may improve thrombosisprophylaxis and the anti-inflammatory effects of Heparinare supposed to have a benefit in the treatment of Asthmaand interstitial lung diseases. In this study the pharma-cokinetic properties of inhaled low-molecular-weight He-parin (LMWH) (Certoparin—Mono-Embolex®) were in-vestigated in healthy subjects.

5 healthy non-smokers inhaled 3000, 6000, and 9000 IUanti-Xa Certoparin. The highest dose and a sub-cutaneousapplication of 3000 IU were applied in 10 subjects. Thepharmacokinetics was assessed from the 48 course of fac-tor Xa activity in the plasma.

Inhaled Certorparin showed a pharmacokinetic whichcan be explained by a two-compartment model. A firstmaximum of factor Xa activity was observed after 2 hours(similar to s.c.). The second component led to a delayedrelease of Heparin with a maximum after 6 hours (9000

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P-8AN IN VITRO MODEL OF THE RESPIRATORY

TRACT WALL TO STUDY PARTICLE CELL INTERACTIONS

F. Blank*, B. Rothen-Rutishauser, and P. Gehr.

Institute of Anatomy, University of Bern, CH-3012 Bern,Switzerland

Given that respiratory diseases are frequent and in-creasing it is important to investigate how particulateantigens interact with the respiratory tract wall. We de-signed an in vitro model of the respiratory tract wall tostudy the interaction of the three cell types, epithelialcells, macrophages and dendritic cells, after particle de-position.

Human A549 epithelial cells were grown for 7 days onmicroporous membranes in a two chamber system.Macrophages and dendritic cells, both derived from humanperipheral blood monocytes, were seeded on top of the ep-ithelial cells and on the undersurface of the inserts, respec-tively. The apical side of this co-culture system was exposedto air for one day to let A549 cells produce surfactant. Flu-orescent polystyrene particles of 1 �m in diameter weresprayed on the epithelial surface with a Microsprayer, andthen the cultures were incubated for 4h and 24h.

The cell cultures were studied with confocal laser scan-ning and transmission electron microscopy. (1) A surfac-tant film was found at the air-liquid interface of the cul-tures. (2) After 4h many particles were found on theepithelial cells, some in macrophages and only a few indendritic cells. (3) After 24h many particles were inmacrophages and dendritic cells but only a small num-ber in epithelial cells.

It remains to be investigated how the particles reachedthe dendritic cells.

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IU) respectively 24 hours (3000, 6000 IU). After inhalationof 6000 IU the factor Xa activity in the blood remainedconstant over 48 hours. If the area under the curve (AUC)for inhaled 9000 IU and 3000 IU s.c. is compared, inhala-tion lead to 65% higher AUC with lower variability.

The delayed release of inhaled LMWH may be favourablein thrombosis prophylaxis and the therapy of Asthma in-terstitial lung diseases.

P-11EFFECT OF FORMOTEROL ON MUCOCILIARY

CLEARANCE IN PATIENTS WITH COPD

P. Brand1, S. Häussermann*1, Ch. Herpich1, P. Zeising2,K. Sommerer1, G. Scheuch1, Th. Meyer1

1Inamed Research GmbH & Co. KG, 82131 Gauting,2Novartis Pharma, 90429 Nürnberg, Germany

One of the main characteristics of COPD is a severeimpairment of mucociliary clearance (MCC). However,it is not clear if this impairment of mucociliary clearanceis responsible for the development of the disease orsolely one of its results. Effects of drugs on MCC mightinfluence the progression of the disease—either positiveby stimulation of an impaired MCC or negative by re-duction of its efficacy. In this study, the effect of For-moterol (Foradil P®) on MCC has been investigated inpatients with COPD.

13 patients with moderate-severe COPD (Gold II–III)participated in this study. In a randomized cross-overdouble-blind design, patients were treated for 7–9 dayseither with twice 12 �g per day Formoterol or withplacebo. After each treatment phase, MCC was measuredover 24 hours with boluses of radiolabeled, inert, and in-soluble iron oxide particles.

This study did not show any significant influence of achronic treatment with Formoterol on MCC.

Although it has already been shown in-vitro that For-moterol stimulates ciliar activity, a clinical relevant im-provement of MCC could not be shown in these COPDpatients.

A potential explanation for this finding may be thatthese patients already had rarification of intact cilia, al-ternatively impaired MCC may be efficiently compen-sated by increased coughing.

P-12DETERMINATION MOUTH-THROAT SIZE IN

HUMAN EX-VIVO STUDIES

PKP Burnell* and WK Young

GlaxoSmithKline Research and Development, Park Road,Ware, Hertfordshire, UK SG12 0DP

IntroductionThe inhaled ex-throat dose (�g and �m) is an essential

parameter in the correlation of its attributes to clinical re-sponse. Previous work has indicated the importance ofmouth-throat size in the assessment of ex-throat dose.GSK has assessed the use of a novel technique to mea-

sure the dimensions of the oropharyngeal region to pro-vide a means of assessing the correct throat model for ex-vivo studies.

PurposeAssessment of a novel application for rapid, non-inva-

sive determination of oropharyngeal dimensions.

MethodA commercially available instrument was sourced. MRI

scans provided solid models of defined volume and cross-sectional area. Readings from the instrument were corre-lated to the (reference) MRI data.

Data, using the new technique, was acquired fromhealthy volunteers (n � 30).

ResultsThe results from the new technique showed remark-

able closeness to the MRI—derived models. Data from theHVT study showed a large range of throat dimensions.

ConclusionsMultiple oropharyngeal models may be needed for ex-

vivo tests if the formulation is sensitive to filtration as afunction of throat size.

P-13PM2.5 METALS IN AMBIENT AIR DOWNWIND OFAGRICULTURAL OPERATIONS IN CALIFORNIA’S

SAN JOAQUIN VALLEY

O. F. Carvacho*. L. L. Ashbaugh, and R. G. Flocchini

Crocker Nuclear Laboratory, University of California, One Shields Ave, Davis, California 95616 USA.

PM2.5 are considered to be among the most harmful ofall air pollutants. When inhaled these particles evade nat-ural defenses of the respiratory system and lodge deep inthe lungs causing serious health problems. According toDr. M. Waalkes of the National Cancer Institute, metalshave the a tendency to donate electrons and to form ba-sic oxide. Biologically , many metals are essential to liv-ing systems and are involved in a variety of cellular, phys-iological, and structural functions. But at high doses,many metals become toxic. The route of exposure may af-fect the dose and the site where the metal concentrates,and thus the observed toxic effect.

In California’s San Joaquin Valley, California agricul-tural operations are highly complex and potentially sig-nificant source of PM2.5 especially during late summerand fall.

We collected PM2.5 samples using traditional up-wind-downwind ambient sampling arrays in a varietyof locations in the San Joaquin Valley. We analyzed thenfor elemental content using Proton Induced X-RayEmission (PIXE) and X-Ray Fluorescence (XRF) analy-sis. This paper will discuss the elemental compositionsof PM2.5 samples collected downwind of agricultural

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activities on a variety of soil types in California’s SanJoaquin Valley.

Figure: Concentration (ng/m3) of Metals downwindfor soil texture Silty Clay Loam

P-14STABILIZING EFFECT OF PHOSPHOLIPIDS ON

SPRAY DRIED THERAPEUTIC PEPTIDE POWDERSFOR INHALATION

C Charan1*, H Chan2, M Kuo1.

1. Nektar Therapeutics, San Carlos, CA 94070, USA2. Faculty of Pharmacy, University of Sydney, NSW 2006,

Australia

Purpose. To determine if phospholipids can be used asa stabilizing excipient for spray dried therapeutic pep-tides.

Methods. A model peptide was spray dried in a mod-ified büchi 190 spray drier with and without phospho-lipids as an excipient. Primary particle size distributionwas determined by cascade impaction using the Ander-sen Impactor. Particle morphology was assessed by SEM.Stability studies under accelerated and normal conditionswere conducted. RP-HPLC and SEC was used to assesspeptide chemical and physical stability. FTIR was used toprobe peptide-lipid interactions.

Results. Phospholipid based spray dried powdersdemonstrated acceptable aerosol performance for pul-monary delivery (MMAD � 1.8 �m). Particle morphol-ogy, assessed by SEM, of these powders is consistent withacceptable characteristics for pulmonary delivery. Peptidechemical and physical stability, determined by HPLC, wassignificantly enhanced by the presence of phospholipidsin the formulations when stored at accelerated stabilityconditions for up to 30 days. FTIR studies show evidenceof peptide-lipid interactions in formulated powders.

Conclusions. These comparative studies on acceleratedstability of a spray dried model peptide using phospho-lipids, and excipient free formulations establish the su-periority of phospholipids as a stabilizing excipient whencompared to neat formulations. Aerosol performance ofthese phospholipid based powers is acceptable for pul-monary delivery.

P-15THE USE OF MANNITOL AS A CARRIER IN

BLENDS FOR INHALATION DRUG DELIVERY

Gysi B1,2, Chiou H1*, Chan H-K1

1. Faculty of Pharmacy, The University of Sydney, NewSouth Wales, 2006, Australia

2. Institute of Pharmacy, Free University of Berlin, Berlin,12169, Germany

Purpose: The aim of this study is to study the effect ofthe inhalation performance of dry powders blended withmannitol. Method: Mannitol solutions were spray driedto produce powders of varying particle size. Bovineserum albumin (BSA) of different sizes was also spraydried as a model protein drug. Raw or spray dried man-nitol was blended with spray dried mannitol of a differ-ent size or with BSA, in various ratios and sizes. Particlesize distributions of mannitol, BSA, and the blends weremeasured by laser diffraction. The performance of theblends by two inhalers (Aeroliser® and Rotahaler®) wasmeasured using a multi-stage liquid impinger andanalysed either by high-performance liquid chromatogra-phy, osmometry or ultra-violet spectroscopy. Lactoseblends were used as a control. Results: The blending oftwo different sized mannitols together did not improve thedispersion performance. There was no observable differ-ences in the performances of mannitol-BSA blends with theAeroliser® and only minor improvement (around 5%),was observed with the Rotahaler®. Lactose blendsshowed more improvement than mannitol blends (19%increase with raw lactose versus 5% with raw mannitolfor 2.43 �m BSA). Conclusion: Mannitol is not as effec-tive in improving the dispersion performance of BSAcompared to lactose.

P-16FEASIBILITY OF PULMONARY DELIVERY OF

NANO-SUSPENSION FORMULATIONS USINGTHE AERx® SYSTEM

Yim D, *Cipolla D, and Boyd B

Aradigm Corporation, 3929 Point Eden Way, Hayward, CA 94545 USA

Aradigm’s AERx® Pulmonary Delivery System has beenused previously to efficiently deliver solution formulationsto the lung. However the micron-sized to sub-micron-sizednozzle holes have been perceived as a barrier to deliveringparticulate suspensions of water-insoluble drugs. Thiswork describes the feasibility of delivering such suspen-sion formulations using the AERx system. Suspensions ofDanazol, were tested at concentrations as high as 150mg/mL using the AERx Single Dose Platform with mi-cron-sized nozzles. The maximum delivered dose oc-curred with formulations between 100 and 150 mg/mL,with emitted doses in the range of 30 to 52% of the loadeddose. Suspensions of Ketoprophen and Ibuprophen, weretested at a concentration of 60 mg/mL using both the

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AERx Single Dose Platform (electronic AERx) with mi-cron-sized nozzles and the all mechanical AERx Essencewith sub-micron-sized nozzles. The emitted doses werein the range of 49 to 60% of the loaded dose. The particlesize distribution of aerosols using the Single Dose Plat-form were consistent with systemic delivery (MMAD2.6–3.1 �m, GSD 1.2–1.3). This work demonstrates thatnano-suspension formulations can be successfully deliv-ered using either the AERx Single Dose Platform with mi-cron-sized nozzles, or the AERx Essence all-mechanicalsystem with sub-micron-sized nozzles.

P-17FEASIBILITY OF PULMONARY DELIVERY OF

HYDROCHLOROQUINE SULFATE USING THEAERx® SYSTEM

Dayton F1, Cipolla D1, Xu A1, Owen S.G.1, Otulana B1,Di Sciullo G2 and. Charous B.L.3

1Aradigm Corporation, 3929 Point Eden Way, Hayward,CA 94545 USA

2Advanced Pulmonary Therapeutics, 101 North WilmotRoad, Suite 600, Tucson, AZ 85711-3365

3Advanced Healthcare SC, 3003 W Good Hope Rd,Milwaukee, WI 53217

Aradigm’s AERx® Pulmonary Delivery System can effi-ciently deliver liquid formulations to the lung with loworopharyngeal deposition. This work describes the feasi-bility of delivering a high concentration solution of hy-drochloroquine sulfate (HCQ) solution using the AERx®

Single Dose Platform (electronic AERx®) system. Previousstudies suggesting therapeutic benefit of oral HCQ in hu-man asthmatics and low dose aerosolized HCQ in animalmodels has prompted further development of this agent.

A 100 mg/ml HCQ formulation is packaged underaseptic conditions into the AERx Strip, to create a steriledosage form. The AERx strips containing 100 mg/mlHCQ have shown good chemical stability out to 6 monthsat controlled room temperature storage conditions. Noadsorptive loss of HCQ to the polymeric packaging ma-terials was observed, even at the accelerated conditionsof 40°C/15%RH. Consistent and efficient aerosol perfor-mance was observed at all time points with emitted dosesin the range of 60 to 70% of the loaded dose. The particlesize distribution of the aerosol was unchanged over timewith an MMAD of 2.8–3.1 �m and a GSD between 1.2–1.3.

These data indicate that the AERx System generates athigh efficiency a nearly monodisperse aerosol suitable forlocal lung delivery. In a recent clinical study, data demon-strated the safety and tolerability of aerosolized HCQ viathe AERx® system, which supports further studies in hu-man asthmatics.

P-18NOVEL TEMPERATURE CONTROLLED SURFACE

ETCHING OF EXCIPIENT PARTICLES:INVESTIGATION INTO THE INFLUENCE OFSTORAGE CONDITIONS ON INHALATION

PROPERTIES OF SURFACE ETCHED DPIFORMULATIONS.

D El-Sabawi*, P Young, S Edge and R Price.

Pharmaceutical Technology Research Group, University ofBath, Bath, BA2 7AY, UK

Dry powder inhaler formulations regularly involve theincorporation of relatively coarse excipient particles to en-sure accurate dose metering, increased device clearanceand dispersion of micronised drug particles. Since par-ticulate interactions are effectively a surface phenomenon,the morphology of the excipient surface will have a crit-ical effect on the adhesive properties of interactive parti-cles. The surface texture of commercial grade alpha lactose monohydrate is typically rough, exhibiting pref-erential areas of high energy, to which active drug parti-cles may strongly adhere. In an attempt to passify thesesites a novel temperature controlled surface etchingprocess has been developed to controllably modify thesurface roughness of commercially available lactose par-ticles. In vitro aerolisation behaviour of surface modifiedlactose as a function of elevated temperature and hu-midity conditions was investigated using salbutamol sul-phate as a model drug. A significant difference (p � 0.05)in the fine particle delivery performance of the drug wasobserved for untreated lactose and upon the addition offines. No significant difference in the delivery perfor-mance was observed for the surface etched lactose. Thestudy indicated that storage conditions strongly influenceboth aerolisation behaviour and physico-chemical stabil-ity of the dry powder formulation. Furthermore, it high-lighted the negative influence of fines when consideringlong term stability of the formulations.

P-19SIMULATION OF THERAPEUTIC

AND RADIOAEROSOL DEPOSITION IN DISEASED AIRWAYS

Á Farkas1, I Balásházy1,2, A Czitrovszky*3,4, A Nagy3

1. KFKI Atomic Energy Research Institute, H-1525Budapest, P.O. Box 49, Hungary

2. Respirisk Co., H-1133 Budapest, Ronyva u. 6, Hungary3. Research Institute for Solid State Physics and Optics, H-

1525 Budapest, P.O. Box 49, Hungary4. Technoorg-Linda Co., H-1077 Budapest Rózsa u. 24,

Hungary

Modelling of aerosol transport in healthy lung was thesubject of several previous studies. However, airflow,particle deposition and related health consequences maychange in the presence of airway disorders. Numericalsimulations of airflow fields and deposition patterns ofinhaled therapeutic and radio-aerosols in the central hu-man airways are the primary objective of this work. For

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this purpose, a computational fluid and particle dynam-ics (CFPD) based numerical model has been developed,validated and applied. Aerosol-particle trajectories havebeen simulated in a three-generation airway model. Ourresults reveal that the aerosol deposition in the diseased(tumoured, constricted, blocked etc.) airways is highly in-homogeneous and the related deposition patterns signif-icantly differ from those obtained for healthy airways. Incase of inhalation of radioactive aerosols, changes in lo-cal deposition patterns due to the studied diseases mayhave significant microdosimetric consequences having al-tered the radiation burden at cellular level. Since theaerosol therapy is a potential alternative to treat the lungdiseases, current model was applied also for aerosol drugdelivery optimisation and might be integrated intoaerosol therapy protocols.

The research was supported by the Hungarian NKFP-1/B-047/2004 and NKFP-3/A-089/2004 Projects.

P-20IMPROVING AEROSOL DELIVERY FOR

NASAL CPAP IN INFANTS.

J. Fink*, E. Ivri, and A. Perera. Aerogen, Inc., Mountain View, CA.

Purpose: Aerosol delivery via nasal continuous posi-tive airway pressure (nCPAP) using an in vitro model ofpreterm infants with the Aeroneb® Professional Nebu-lizer System in the inspiratory limb of an unheated cir-cuit was 1.3 � 1% of nominal dose (Fink, AARC 2004). Aprototype Pulmonary Drug Delivery System (PDDS) wasdeveloped to minimize rebreathed volume and generateaerosol proximal to the patient’s airway during nCPAP.

Methods: A model consisting of infant size nares andan absolute filter was attached to a reciprocating pump(Harvard Apparatus) set to infant ventilatory parameters(VT 15 mL, resp rate 40 bpm). Gas flow of 10 Lpm wasused to generate a CPAP of 5 cm H2O. Albuterol sulfate(0.083%) was aerosolized continuously (CONT) or inter-mittently (INT) with the PDDS placed between the flowof the CPAP circuit and a nasal cannula for nCPAP (Ar-gyle; n � 3). Drug was collected on a filter placed distalto the nasal cannula, and assayed using HPLC.

Results: The percent of albuterol deposited (�SD) was26 � 9% with CONT and 40 � 9% INT. The inhaled masswith both aerosol generation patterns is an order of mag-nitude greater than previously reported with in vitro mod-els of infant ventilation.

Conclusions: The high efficiency delivery of aerosol toan infant model with the nCPAP PDDS suggests futureopportunities for administration of active medications tothe airways of infants.

Funded by Aerogen, Inc.

P-21EXPERIMENTAL STUDY OF THE EFFECT

OF CARTILAGINOUS RINGS ON PARTICLEDEPOSITION IN AN IDEALIZED UPPER

AIRWAY MODEL

Y. Zhang and W. H. Finlay*

*Author to whom correspondence should be addressed:4–9 Mechanical Engineering Building, University of Alberta

Edmonton, Alberta, Canada, T6G 2G8Phone: (780) 492-4707, Fax: (780) 492-2200

E-mail: warren.finlay@ualberta.ca

Although cartilaginous rings are important morpho-logical features present on the wall of the trachea andmain bronchi, experimental studies to examine their ef-fect on particle deposition have not been previously con-ducted, despite the importance of cartilaginous rings seenby Martonen et al., (1994) in a numerical simulation inhuman upper airway segments. In the present study, par-ticle deposition in an idealized upper airway models withcartilaginous rings is investigated experimentally. Thismodel consists of the mouth-throat, trachea, and firstthree generations (G1–G3) of the lungs. Cartilaginousrings are included on the wall of trachea to determinetheir influence on particle deposition. The mass of parti-cles deposited within the model is determined usinggravimetry. Significantly enhanced deposition was ob-served in the model with cartilaginous rings present onthe wall of trachea, and deposition in mouth-throat andbifurcation is influenced little by the presence of carti-laginous rings. This result implies that the usual approachto approximate the trachea by using a smooth-walledcylinder could underestimate particle deposition withinthe trachea. Therefore, future modelling of human air-ways should consider adopting cartilaginous rings as anessential morphological feature of the trachea.

This study was supported financially by the Alberta In-genuity Fund and NSERC.

P-22EXPERIMENTAL MEASUREMENTS OF PARTICLE

DEPOSITION IN THREE PROXIMAL LUNGBIFURCATION MODELS WITH AN IDEALIZED

MOUTH-THROAT

Y. Zhang and W. H. Finlay*

*Author to whom correspondence should be addressed:4-9 Mechanical Engineering Building, University of Alberta

Edmonton, Alberta, Canada, T6G 2G8Phone: (780) 492-4707, Fax: (780) 492-2200

E-mail: warren.finlay@ualberta.ca

Particle deposition efficiency in three idealized prox-imal lung bifurcation models with an idealized mouth-

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throat were measured experimentally. These bifurcationmodels included: (1) a small symmetric bifurcation, (2)an intermediate asymmetric bifurcation and (3) a largesymmetric bifurcation. An idealized mouth-throatgeometry was used as the inlet of these bifurcation mod-els. Monodisperse aerosol particles (DEHS) with massmedian diameters in a range of 2.5–7.5�m were em-ployed at three steady flow rates of 30, 60 and 90 l/min.Particle deposition measurements were conducted bygravimetry technique. Results showed that particle de-position in the mouth-throat and trachea is primary, andparticle deposition fraction in the proximal lung bifur-cation is secondary compared with that deposited in theregions upstream (mouth-throat and trachea). Particledeposition efficiency increases with increasing either in-ertial parameter or Stokes number. The laryngeal jet isthe key factor dominating particle deposition within thetrachea. Deposition efficiency in the trachea is also af-fected by Reynolds number. In addition, deposition inbifurcation region is influenced little by the upstreamflow condition, and therefore the effect of the laryngealjet seemingly does not propagate to the bifurcationdownstream. This study was supported financially bythe Alberta Ingenuity Fund and NSERC.

P-23COMPARISON OF INTRA-PULMONARY AEROSOL

DEPOSITION DISTRIBUTION BY 3D IMAGINGAND 24 HOUR CLEARANCE

JS Fleming*1, L Bolt1, JH Conway2, M Quint3, TB Martonen4

1. Department of Medical Physics and Bioengineering,Southampton University Hospitals NHS Trust,

Southampton UK SO16 6YD2. School of Medicine, University of Southampton,

Southampton, UK3. Department of Respiratory Medicine, Queen Alexandra

Hospital, Portsmouth, UK4. NHEERL, US Environmental Protection Agency, North

Carolina, USA

Background: Measurement of the intra-pulmonary dis-tribution of inhaled aerosol deposition is potentially valu-able in the optimisation of inhalation therapy. This can beachieved by 24 h clearance measurements or by radionu-clide imaging.

Purpose: The aim of the study is to compare 24 hourclearance measurements of deposition distribution to3D single photon emission computed tomography(SPECT).

Method: Nine normal male subjects inhaled a Tc-99mlabelled aerosol of mass median aerodynamic diameter1.5 microns from a nebuliser. Planar and SPECT imag-ing of the lungs was performed immediately followingadministration. A further planar image was performedapproximately 24 hours later. The fraction of the lungdeposition in the conducting airway (CADF) was esti-mated from 24 h clearance and from the SPECT data.The error in the SPECT value was assessed by simula-

tion and that in the 24 h clearance value by repeat mea-surement.

Results: The mean SPECT CADF calculated using theICRP definition of conducting airways (generations 0–15)was 0.19. The corresponding 24 h clearance value was0.23. These values were not significantly different. Therewas a weak but non-significant correlation between theSPECT and 24 h measurements (r � 0.48). The standarderror of the difference was 0.12. The corresponding errorson the SPECT and 24 h clearance measurements were 0.04and 0.05 respectively.

Conclusion: There was no systematic difference betweenthe values of conducting airways deposition obtained from24 h measurements and SPECT. However, there were ran-dom differences on individual subjects, which were largerthan the estimated measurement errors.

Funding: Physiotherapy Research Foundation UK.

P-24INFLAMMATION PRODUCED BY PARTICULATE

MATTER EXPOSURE IS TLR-4 DEPENDANT.

*AM Fonceca1, GR Zosky2, DJ Turner2, PD Sly2, DA Knight3, SD Stick1.

1Respiratory Medicine, Princess Margaret Hospital forChildren, Subiaco, Western Australia 6008

2Telethon Institute for Child Health Research, Subiaco,Western Australia 6008

3University of British Columbia, Vancouver, Canada.

Background: Endotoxin is known to exacerbate asthma,paradoxically, exposure in early life might protect againstasthma.

One important vehicle for endotoxin is inert, fine par-ticulate matter (PM). PM exposure is also implicated in in-flammatory conditions in the lung i.e., chronic pulmonaryobstructive disorder (COPD) and asthma. We are inter-ested in determining the inflammatory and airway re-sponses elicited following exposure to endotoxin and PM.

Method: Female, 7 week old C3H/HeJ (�/�TLR-4)and C3H/HeN (�/�TLR-4) mice were exposed to neb-ulised 50ug/ml endotoxin and PM. 6 exposures werecompleted 24hrs apart. Airway response measures of re-sistance, compliance and elastance were taken 6hrs afterthe final exposure using forced oscillation technique.BAL’s were collected for differential counts.

Results: Preliminary findings indicate no significantdifference in respiratory function between endotoxin andPM exposed C3H/HeJ mice. Significantly greater inflam-matory cell infiltrate was measured by differential countsin PM exposed C3H/HeN mice, compared to PM exposedC3H/HeJ mice.

Conclusion: C3H/HeJ mice exposed to PM did notdemonstrate a change in lung function, despite evidencefor inflammatory changes in the lung. This result pointsto a role for TLR-4 in signalling of PM.

Funding: National Health and Research Council ofAustralia; Princess Margaret Hospital for Children Foun-dation.

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P-25AEROSOL DEVICE ANALYSIS FOR DELIVERY OF

A NOVEL INHALED ANTIBIOTIC

DE Geller,* KC Kesser

Aerosol Research Laboratory, The Nemours Children’sClinic, Orlando, Florida USA

A novel, small (450 Dalton MW), water-soluble antibi-otic (“X”) is under investigation to treat airway infectionsby inhalation. We investigated the in vitro performance ofaerosol delivery systems with “X.” The PARI LC PLUS(LC�) nebulizer and PulmoAide compressor with a 5 mLfill volume was the standard for comparison. Other de-vices evaluated were the Trudell AeroEclipse (AE) breath-actuated jet nebulizer and 4 new-generation vibratingmesh devices: AeroGen AeroNeb GO Clinical (ANG) andcustom-adapted AeroNeb Pro (ANP), PARI eFlow, andOmron NE-U22 MicroAir (MA). Nebulizer charge was 5mL (90 mg) for LC� and ANP, and 3 mL (54 mg) for the“more efficient” AE, ANG, eFlow and MA. We used laserdiffraction, breath simulation, and drug assay to defineinhaled fine particle mass (iFPM).

Results

Conclusion: The eFlow delivered the highest iFPM inthe shortest amount of time. Other devices had longer nebtimes, larger particles, or higher residual doses. These fac-tors must be considered when matching “X” with a de-vice for clinical testing.

P-26BLOW-BY NEBULIZATION REVISITED

KC Kesser,* DE Geller

Nemours Children’s Clinic Aerosol Research Lab, Orlando,Florida USA

Rationale: Crying (Murakami 1990) and blow-byaerosols (Everard 1992) may significantly decrease aerosoldelivery to infants. However, using a simple model wereported the “inhaled” dose of albuterol was equivalentbetween close-fitting facemasks and corrugated tubingheld within 4 cm of the “nose” (Geller, 2004 AAAAI). Weexamined whether the same was true of “lung” dose us-ing the SAINT infant nose-throat model. Methods: Weused VixOne nebulizers with unit dose albuterol (2.5mg/3mL). A PARI COMPAS simulated infant breathingpattern (rate 30/min; tidal volume (Vt) range 50–150mL).Aerosol was delivered via either close-fitting facemask,blow-by with facemask, or tubing held 2, 4, or 7 cm awayfrom the nose. Albuterol captured on a filter at the distalend of the SAINT model (lung dose) or washed from the

model (throat dose) was analyzed by spectrometry. In-haled dose � lung � throat doses. Results: At Vt �100mL, lung dose was similar between close-fitting maskand the tube at 2 and 4 cm (0.057, 0.065, and 0.061 mg).There was a decrease with either the mask held 2 cm fromthe nose (0.051 mg), or the tube held 7 cm away (0.038mg). When Vt increased, the inhaled dose increased butthe lung dose did not. Conclusion: Our model predictstargeting the lungs in infants can be accomplished with“tube” blow-by within 4cm of the nose. This may improveaerosol delivery in infants who fuss with facemasks.

P-27DEPOSITION OF MANNITOL POWDER IN

HUMAN AIRWAYS

W Glover1*, H-K Chan1, S Eberl2, E Daviskas3, S Anderson3

1Faculty of Pharmacy, University of Sydney, Australia2PET and Nuclear Medicine, Royal Prince Alfred Hospital,

Australia3Respiratory Medicine, Royal Prince Alfred Hospital,

Australia

The aim of this study was i) to investigate the depo-sition of dry powder mannitol administered with theInhalator™ and ii) to determine if the distribution ofthe deposition and the lung dose was dependent on theinhalation flow profile. Radiolabelled mannitol parti-cles (3�m) were prepared by spray drying a sterilemannitol solution containing 99mTc-DTPA. The MarpleMiller Impactor was used to validate the radiolabellingtechnique and quantify the performance of the powder.Ten healthy volunteers inhaled a 60mg dose (3 �20mg/capsule) of radiolabelled mannitol, then wereimaged using a triple head gamma camera and dy-namic SPECT. During inhalation each subject’s flowprofile was recorded on an oscilloscope connected toan inline flowmeter. The amount of mannitol deliveredto the lung ranged between 16 to 34% of the loadeddose. This large variation in deposition could be ex-plained by the range (43 to 63L/min) of peak inspira-tory flow (PIF). A strong relationship exists betweenthe lung deposition and PIF (r2 � 0.86). This comparesfavourably with the dependence of the in vitro disper-sion on the air flow rate. Other flow parameters suchas flow acceleration and total volume showed muchweaker correlations.

This study was funded by the University of SydneySesqui Research Grant.

P-28DEVELOPMENT OF A PACKED BED INHALATION

SYSTEM FOR THE STUDY OF PARTICLEDEPOSITION IN THE HUMAN LUNG

JaeHark Goo*

Department of Environmental Engineering, WoosukUniversity, Jeonbuk 565-701, South Korea

The purpose of this work was to develop an inhalationsystem to investigate the characteristics of particle depo-

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sition in the human lung. A packed bed was used as anapproximate substitute for the lung. As a prerequisite tomulti lobe packed bed deposition model, single pack beddeposition system was developed in this work.

The packed bed was made by cylindrical tube with 8cm I.D and 90 cm length. Glass beads of the diameter from2 to 10 mm were filled in the tube to simulate the airwaydeposition for each generation. A piston pump pulled inand pushed out the air in the packed bed in a sinusoidalmanner through the Y shape branch hose which was con-nected to inhalation and exhalation valves. Monodispersefluorescent microspheres were aerosolized by atomizerand were dried by diffusion dryer. Glass filters were usedto collect particles at the inlet and outlet of packed bed,and the fluorescence on the particles was dissolved inethyl acetate by sonication.

By analyzing the intensity of the fluorescence with flu-orescent spectrophotometer, the deposition efficienciesfor each breathing pattern and particle size were calcu-lated. The results showed reasonable agreements withother works. Thus, based on this system the multi lobepacked bed inhalation system is under development.

(This work was supported by KOSEF under contractNo. R05-2003-000-11649-0)

P-29STOCHASTIC MODEL FOR MUCOCILIARY

PARTICLE CLEARANCE IN CYSTIC FIBROSIS LUNGS

R Sturm, R Winkler-Heil and W Hofmann*

Division of Physics and Biophysics, Department ofMolecular Biology, University of Salzburg, A-5020

Salzburg, Austria

Cystic fibrosis (CF) represents a genetic form of chronicbronchitis, which due to its severity and chronicity leadsto bronchiectasis, emphysema and, ultimately, respira-tory failure. As a main feature of the disease, the innateairway defense system, i.e., mucus clearance, undergoesa continuous failure, increasing the probability of ep-ithelial infection by bacteria and other pathogens. Ac-cording to a largely accepted theory, successive degen-eration of mucociliary clearance may be regarded as theresult of a periciliary liquid (PCL) depletion due to H2O,Cl�, and Na� absorption by defect epithelial cells. At thesame time, the highly viscous mucus layer donates all itsavailable liquid, i.e., about 50% of its normal volume.Both effects lead to a continuous flattening of the ciliaand thus reduction of the mucus velocity by about 75%after 24 hours. In the stochastic model presented here,time-dependent degeneration of mucus clearance is sim-ulated according to the above theory, based on initial mu-cus velocities and the correlation between mucus veloc-ity and airway geometry from a previously publishedmodel. Reduction of mucus velocity is individually cal-culated for each airway by application of respective prob-ability density functions. Preliminary results obtainedfrom clearance computations after inhalation of 3-�munit density particles under sitting breathing conditionsindicate an increase of the 24-hour retention by a factorof 1.5 to 2.5.

P-30CUSTOMIZING AN ELECTRONIC NEBULIZER

Stangl R.*, Seemann S., Knoch M.

PARI GmbH, Germany

The PARI eFlow® is a new nebulizer platform that cre-ates maximum benefit for the patient when the device isoptimized together with the drugs to be administered. Adevice platform for use with approved drugs and drugsin development faces a number of challenges: e.g. higherviscosities of the formulations, fragile molecules, suspen-sions, variable fill volumes, dose reproducibility, avoid-ance of side effects, patient compliance, novel therapyforms. Additionaly, it should satisfy these needs with areasonable change effort. The flexible vibrating mem-brane technology used in eFlow can be optimized for awide range of applications with respect to treatmenttimes, particle size distribution, drug delivery rates, de-vice efficiencies and patient guidance.

Aztreonam, a new antibiotic for CF patients, was for-mulated parallel to developing a customized device, thusachieving substantially reduced treatment times and in-creased patient compliance.

For babies and small children, a more convenient devicewas developed that minimizes side effects by optimizedparticle size distributions. In parallel, a budesonide solu-tion has been formulated to further improve the therapy.

For Europe, the eFlow rapid was designed to deliveran equivalent dose compared to established treatmentsusing current CF drugs, however, with decreased treat-ment times and increased patient compliance.

In a different way, the eMotion was designed for theJapanese market in order to support asthma therapies.

For novel inhaled medications, the rate of drug deliv-ery can be maximized for a target droplet size, allowingcustomization of specific drug/device combinations.

P-31THE EFFECT OF NOMINAL DOSE ANDTREATMENT DURATION ALTERS THE

PULMONARY DEPOSITION OF ANTIBIOTICS

KW Stapleton1, R Gibson2, G Retsch-Bogart3, AI Phase2 Study Group, R Markus1

1.Corus Pharma2.Seattle Childrens Hospital

3.UNC at Chapel Hill

Aztreonam Lysinate for Inhalation (AI) is an inhaled an-tibiotic being developed for the treatment of Pseudomonasaeruginosa pulmonary infections in cystic fibrosis. Phase Itrials evaluated doses from 75 mg to 285 mg and all dosesappeared well tolerated.

A Phase II randomized, double-blind, placebo-con-trolled study evaluated 75 mg AI and 225 mg AI com-pared to placebo, with treatments twice daily for 14 daysdelivered using the eFlow® Electronic Nebulizer. Onehundred and five patients were enrolled in 20 U.S. clin-ics. The primary endpoint was change in FEV1 from base-line, and secondary endpoints included reduction in spu-tum bacterial density. At Day 0, drug deposition in the

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sputum and plasma after the first dose was comparableto the results from phase I. However, the 225 mg dosegroup experienced an unexpected decrease in plasma lev-els after one week of treatment, and the reduced deposi-tion may account for the decreased microbiologic and pul-monary function responses observed from day 7 to day14. This likely indicates a shift in drug deposition fromthe peripheral airways to the central airways after the firstweek of treatment in the high dose group. A subgroupanalysis showed that bronchodilator use was associatedwith increased plasma levels at both doses over time, andability to maintain peripheral deposition.

P-32SURFACE ROUGHNESS EFFECTS ON ADHESION

FORCE DISTRIBUTIONS.

Stewart PJ*1, Islam N1, Larson I1, and Hartley P2

1 Victorian College of Pharmacy, Monash University,Parkville Vic 3052, Australia.

2 Division of Molecular Science, CSIRO, Clayton Vic 3168,Australia

Purpose: Adhesion force distributions of silica spheres(5 and 20 �m) and salmeterol xinafoate (SX) (4�m) parti-cles with lactose and spin coated lactose films were de-termined by atomic force microscopy (AFM) to investi-gate the influence of surface roughness.

Methods: AFM studies used the colloid probe tech-nique (Nanoscope Multimode IIIa, Digital Instruments).X-ray Photoelectron Spectroscopic (XPS) analysis wasperformed using an AXIS-HSi spectrometer (Kratos An-alytical Inc.). The surface roughness of the lactose parti-cles was measured by confocal microscopy (Leica TCSNT, Leica Microsystems) and by AFM.

Results: The lactose particles showed RMS Rq valuesbetween 0.93 and 2.2 �m. The adhesion force distribu-tions for silica and SX probes were significantly differ-ent for the different lactose carriers and broad, e.g. 5 to105 nN for the 5 �m silica sphere. This contrasted withdistributions on smooth spin coated lactose films (RMSRq of 0.28 nm) which were not significantly different andwere narrow, e.g. 42–68 nN for the 5 �m silica sphere.No significant difference in adhesion force distributionoccurred with silica probe size on the lactose surface.XPS confirmed that the lactose surface was free of im-purities.

Conclusion: Although the almost atomically flat filmsshowed some adhesion variability, the surface roughnessof the lactose particles was a major contributing factor tothe broad distributions.

P-33MODEL FORMULATIONS FOR NEBULISATION

DEVICE TESTS

J O Svensson* and E Berg.

AstraZeneca R&D Lund, SE-221 87 Lund, Sweden

PurposeIn order to gain relevant information about a nebulisa-

tion device, it is important to consider the combination

device-formulation and their interaction. In order to getdescriptive and comparable device data, model formula-tions covering a wide range of properties are preferablyused.

MethodModel formulations were manufactured, reflecting

commercially available formulations. In the model for-mulations, Tween 80 was used to decrease the surface ten-sion and PVP to increase the viscosity. A commerciallyavailable �-suspension was also included in the study.

A commercial jet nebuliser was used and a breathingpattern was created using a breathing simulator. The doseleaving the nebuliser were collected on filters in 3-minuteintervals in order to get time-resolved output informa-tion. The filters were analysed using liquid chromatogra-phy. The droplet size distribution was assessed with a re-frigerated Next Generation Impactor.

ResultsThe nebuliser were characterised with respect to In-

halable dose and Droplet size distribution. The formu-lation properties strongly affected the inhalable dose, seeFigure 1.Conclusions

It is important to select relevant model formulations,when characterising a nebulisation device, in order to geta complete picture of the device performance.

P-34LIPOSOMAL AND NANOPARTICLE INHALED

AEROSOL FORMULATIONS FOR DOXORUBICIN

W H Finlay*, Z. Wang, L G Sweeney, H. Chen, X. Tao,R. Loebenberg, W. Roa

University of Alberta, Edmonton, Alberta, Canada, T6G2G8

Treating lung cancer with chemotherapy through tradi-tional routes, such as intravenous injection, often leads totoxic systemic side effects. A more direct aerosol deliveryto the cancer cells may decrease toxicity and the drugdosage. This study produced spray-freeze dried powderscontaining the anti-cancer drug doxorubicin. Both liposo-mal and nanoparticle formulations were examined.

The liposomal powder contained doxorubicin, lactose,and dimyristoyl phosphatidylglycerol in a weight ratio1/7/156. The powder demonstrated similar LC50 activityon the H460 cell line as with unencapsulated doxorubicin.Utilizing an Anderson cascade impactor, the mass me-dian aerodynamic diameter (MMAD) of the powder was3.0 � 0.2 mum. Upon powder reconstitution in isotonicsaline, the mean volume particle size was 168 nm.

The nanoparticle powder contained doxorubicin, butyl-cyanoacrylate monomer, dextran, and lactose. This pow-der displayed a 6 to 8 times lower LC50 on the H460 cell

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line compared to the liposomal formulation. The powdercan be visualized using the “cluster bomb” concept wheredoxorubicin nanoparticles are bound together by a ma-trix to form functional particle groups. The MMAD of thispowder was measured using a cascade impactor to be 2.8mum. Average particle diameter was measured uponpowder reconstitution in isotonic saline to be 263 nm.

This study demonstrates the feasibility of producing li-posomal and nanoparticle dry powder aerosols loadedwith doxorubicin.

P-35LIPOSOMAL CIPROFLOXACIN IN A SPRAY-

FREEZE DRIED POWDER FORM

L G Sweeney, Z L Wang, R Loebenberg, J P Wong1, W H Finlay*

University of Alberta, Edmonton, Alberta, Canada, T6G2G81Defense R&D Canada-Suffield, Box 4000, Medicine Hat,

AB, Canada, T1A 8K6

The objective of this study was to create a dry powderciprofloxacin formulation which, upon reconstitution in an ionic media, would form liposomal particles.Ciprofloxacin demonstrates sustained release and de-creased toxicity when delivered liposomally. A suspen-sion was created containing dimyristoyl phosphatidyl-glycerol, lactose, and ciprofloxacin in a weight percentratio 5:17:1, respectively. The mixture was atomized intoliquid nitrogen, where the contents were collected afterthe liquid evaporated. The powder was placed in a freeze-drying system for 48 hours.

The powder was reconstituted in distilled water, iso-tonic saline, bovine mucin, fluid collected from porcinelung lavage, and cystic fibrosis patient expectorate di-luted fivefold with isotonic saline. The amount of lipo-somal encapsulation was measured to be 50%, 94%, 80%,75%, and 73%, respectively. The mass median diameterand fine particle fraction of the powder was measuredto be 2.8 mum (SD 1.0 mum) and 61%, respectively us-ing a cascade impactor. Following reconstitution in iso-tonic saline, a mean volume analysis showed 91% of theliposomal particles had a diameter less than 600 nm. Thepowder morphology was examined using scanning elec-tron microscopy.

This study examined a spray-freeze dried powder for-mulation containing a broad-spectrum antibiotic that dis-played effective in vitro liposome formulation and aero-dynamic characteristics.

P-36ENTRAINMENT FORCES ON A SPHERE

ATTACHED TO A WALL IN A LAMINARBOUNDARY LAYER

L Sweeney*, W Finlay

Mechanical Engineering, University of Alberta, Edmonton,Alberta, Canada, T6G2G8

This study examines the lift and drag forces acting ona spherical particle attached to a wall in laminar flow.Non-dimensional analysis indicates that the coefficients

of lift and drag will be functions of Reynolds number andthe ratio of boundary layer thickness to sphere diameter,and the objective of the study is to generate the functionalrelationship. The results of this research can be utilizedin the modeling of aerosol entrainment.

This work utilizes commercial computational fluid dy-namics software to simulate the flow around the spheri-cal particle. Accuracy of the model was determined bygrid and boundary convergence studies, as well as vali-dation with experimental and analytical results.

Grid independence in the model occurred at �400 000nodes for drag force and �800 000 nodes for lift force;the discrepancy is due to the order of magnitude differ-ence in the forces. The free-slip boundary above thesphere had the largest influence on the flow solution.The model was validated using an existing analytical so-lution to the problem at low Reynolds number. The pre-dicted value of CL � 5.9 agreed within 1% of the ana-lytic value. A considerable portion of the modeling hasbeen completed, and it appears the coefficients of lift anddrag decrease exponentially with Reynolds number toasymptotic values.

Application of this work can be found in any topic thatincludes study of impending motion of a spherical parti-cle attached to a wall in a laminar boundary layer.

P-37INHALED PARTICLE DEPOSITION IN

UNSTEADY-STATE RESPIRATORY FLOW AT ANUMERICALLY CONSTRUCTED MODEL OF THE

HUMAN ORAL AIRWAYS

Hiroshi Takano, Naohiro Nishida, Masayuki Itoh, KeiAsai* and Kiyotsugu Kuki*

Department of Chemical Engineering and Materials Science,Doshisha University, Kyoto 610-0321, Japan

*Omron Healthcare Co., Ltd., Kyoto 615-0084, Japan

To evaluate the clinical effectiveness of aerosol therapyfor the lower airways, particle deposition at the humanoral airways has been analyzed numerically with variousunsteady-state respiratory flow-patterns. The flow pro-files were obtained by 3-D thermo-fluid analysis with re-construction of the human oral airways, which was mod-ified from the images of Magnetic Resonance Imaging(MRI). analyzed by Rhinoceros, which has 3-D CAD mod-eling function. 52 MRI images were taken vertically at in-tervals of 2mm on the oral cavity, and 52 MRI imageswere also done horizontally at intervals of 2mm on thepharynx and the larynx. By using those data, the 3-Dmodel of the human oral airway was constructed.

The numerical results of flow profile showed that vortexflow was occurred near larynx, showing uniform flow pro-file in both the oral cavity and the upper side of trachea. Inthese cases, the particle deposition was taken place mostlyat the oral cavity and the oropharynx. In the region of vo-cal cord, most particles deposited at the upper side of vo-cal cord. On the other hand, the relationship between theparticle deposition efficiency and the impaction parameterin pharyngeal-laryngeal region was compared with theICRP data (1994). The obtained numerical results of the par-ticle deposition indicated within the limits of 95% of confi-dence bounds. Therefore, the particle deposition efficiencywas increased with larger values of the aerodynamic di-ameter and the flow rate of respiration, because the inertia

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impaction was sufficiently effective. In the case of high vol-ume of respiration, most of the inhaled particles were de-posited at the upper airways such as the oral cavity and thepharynx-larynx, and then the deposition efficiency of in-haled particle became considerably small.

P-38DISSOCIATION OF DRUG AND EXCIPIENT

PARTICULATES DURING AEROSOLISATION OFNOVEL pMDI FORMULATIONS.

G Taylor1*, R Jones1, & R Evans2

1Welsh School of Pharmacy, Cardiff University, CathaysPark, Cardiff, UK,

2Inspire Pharmaceuticals Inc., 4222 Emperor Blvd, Durham,NC 27703, USA,

PURPOSE: pMDIs formulated with novel excipient par-ticulates have been developed to improve aerosol perfor-mance. The aim of this study was to investigate particlesize distributions (PSDs) in aerosol plumes from theseformulations and to determine the extent of drug disso-ciation from excipient during aerosolisation.

METHODS: pMDIs were prepared containing; drugalone (either salbutamol sulphate (SS) or fluticasone propi-onate (FP)), excipient alone (L-leucine (L-leu)) and orderedblends of SS:L-leu and FP:L-leu. Drug particle size was lessthan 5 �m and various sieve fractions of L-leu were chosenin the range 38–125 �m. PSDs in aerosol plumes at differ-ent distances from actuation were determined by laser dif-fraction using a Sympatec Helos Inhaler Module.

RESULTS: Multi-modal PSDs were seen for the pMDIformulations containing drug with excipient. Convolu-tion of the scaled PSDs measured at 12.5 cm from thepoint of actuation, for drug alone or excipient alone, re-sulted in PSD patterns with high degrees of similarity tothose shown by the various drug with excipient formu-lations.

CONCLUSIONS: Whilst it is known that drug and ex-cipient associate in propellant, the PSD results indicatethat they rapidly dissociate during aerosolisation. Thus,it seems unlikely that particle size of the L-leu excipientwill influence aerodynamic properties of the drug.

P-39AEROSOL THERAPY BY pMDI-SPACER

IN SLEEPING YOUNG CHILDREN: TO DO OR NOT TO DO?

J.E. Esposito-Festen1, H.IJsselstijn2, W.C.J. Hop3, F.J.M.van Vliet4, J.C. de Jongste1, H.A.W.M Tiddens1

1 Department of Pediatrics, division of RespiratoryMedicine, Erasmus MC-Sophia, Rotterdam, The Nethrelands

2St. Franciscus Gasthuis, Rotterdam, The Netherlands3Department of Biostatistics, Erasmus MC, Rotterdam, The

Netherlands4Department of Hospital Pharmacy, Erasmus MC,

Rotterdam, The Netherlands

One-third of young children receiving inhalation ther-apy is distressed. It has been suggested that inhalation

therapy during sleep could be a good alternative for thesechildren. In a laboratory study it was shown that a higherlung dose could be obtained with sleep-breathing pat-terns compared to wake-breathing patterns (1). Aim to in-vestigate the feasibility of aerosol administration bymeans of pMDI-spacer in sleeping young children. Meth-ods In a three-week daily life study, 27 children (6-23months) with recurrent wheeze inhaled 1 puff of budes-onide (Pulmicort® 200 �g, AstraZeneca) while awake and1 puff during sleep. A filter positioned between the Neb-uChamber® (AstraZeneca) and facemask trapped thebudesonide aerosol. Parents scored the child’s asthmasymptoms, degree of cooperation, and feasibility of theadministration on diary cards.

Results In 69% of the administration procedures dur-ing sleep the children woke up and 75% of these childrenbecame distressed. Mean filter dose (� SD) while awakewas 47% (26) of the nominal dose and during sleep 16%(13) (p � 0.007). Median filter dose variability (range)while awake was 50% (21–198) and during sleep 110%(47–152) (p � 0.007).

Conclusion Aerosol administration during sleep is notan option for most young children.

This study was supported by AstraZeneca, The Nether-lands.

1. Janssens HM, van der Wiel EC, Verbraak AF, de Jong-ste JC, Merkus PJ, Tiddens HA. Aerosol therapy and thefighting toddler: is administration during sleep an alter-native? J Aerosol Med 2003;16(4):395–400.

P-40ARE CHILDREN WITH CYSTIC FIBROSIS (CF)

OF 4 TO 6 YEARS ABLE TO USE DRY POWDERINHALERS: THE EFFECT OF VARYING

RESISTANCE ON INSPIRATORY VOLUMES AND FLOWS

Tiddens HAWM* and van der Zanden T

Department of Pediatric Pulmonology, ErasmusMC-Sophia,3000 Rotterdam, The Netherlands

The time burden for daily nebulizer therapy is signifi-cant for CF patients. Dry Powder Inhalers (DPI) are be-ing developed for the inhalation of antibiotics. Inhalationflow rate and device resistance (Rd) interact to dispersedrug from a DPI. Most children of 6 years are able toinhale with an inspiratory flow 30 LPM or higher andwith inspired volume (V) 1 L. Aim: To assess the feasi-bility of CF patients of 4 to 6 years to use DPIs effectivelyMethods: 6 stable CF patients, age 4 to 6 years, were en-rolled to date. Subjects inhaled 3 times forcefully through4 different Rd (0.05, 0.07, 0.12, 0.17 cmH2O0.5/L/min)while inspiratory time (IT), peak inspiratory flow (PIF),mean inspiratory flow (MIF) and V were measured. Re-sults mean (�SD): V was 0.7(�0.23), 0.69(�0.29),0.58(�0.31), 0.57(�0.29) L, PIF 68(�17), 61(� 19), 50(�12),44(�8.1) LPM, MIF (40.4�11.3), 37.6(�13.4), 33(�7.7)29(�6.7) LPM, IT 1.06(�0.46), 1.09(�0.44), 0.98(�0.5), 1.12(�0.54) sec for, Rd 0.05, 0.07, 0.12, and 0.17 cmH2O0.5/L/min, respectively. There was a linear relation between MIFand V. V was above 1 L in only 2 out of 72 inspiratory ma-neuvers. Conclusion: CF patients 4 to 6 years are probablyable to generate inspiratory flows between 30 and 60 LPM

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though most DPIs. The inspiratory volume is critically lowto empty a high drug load in a single inhalation.

P-41EFFECT OF PARTICLE INERTIA ON REGIONAL

DEPOSITION OF INHALED AEROSOLS IN ACOMPUTATIONAL FLUID DYNAMICS MODEL OF

HUMAN NASAL AIRWAYS

Schroeter J*, Asgharian B, and Kimbell J

CIIT Centers for Health Research, Research Triangle Park,NC, 27709, USA

The nasal route has received much recent attention asa means of delivering aerosolized drugs for systemic ac-tion. The complex airway passages formed by protru-sion of the turbinates from the lateral walls of the noseoffer efficient particle filtering capabilities and also sup-ply a large surface area for absorption. In this study, acomputational fluid dynamics (CFD) and particle trans-port model was used to predict regional deposition ofinhaled aerosols in the nose under natural breathing sce-narios. The CFD model of the human nasal passages wasformed from MRI scans of a healthy adult male. Steady-state, inspiratory airflow was simulated at 7.5, 15, and30 L/min. Trajectories and deposition sites of 5–50 �mparticles in diameter were computed. The nasal valve,turbinates, and olfactory region were defined in the CFDmodel so that regional particle deposition could be an-alyzed. When regional deposition fractions were plottedagainst impaction parameter, the data collapsed into asingle curve for each region with a clearly defined max-imum. For example, the maximum turbinate depositionwas 20%, occurring at a flow rate of 15 L/min with aparticle size of 10 �m. These results can be used to pre-dict the optimal particle size range and breathing con-ditions necessary to target inhaled aerosols to specificnasal regions.

P-42INCORPORATING RECORDED

BREATHING PATTERNS INTO RESPIRABLE DOSE MEASUREMENT

Schultz A1*, Devadason S2, LeSouef P2, Sly PD1

1. Dept Respiratory Medicine, Princess Margaret Hospitalfor Children, WA

2. UWA School of Paediatrics and Child Health, WA

Traditionally in vitro measurements of ‘respirabledose’ from pMDI-spacer combinations have been mea-sured using cascade impaction, with a constant flow(normally 28L/min) through the spacer. The respirabledose derived from this technique is not representativeof the drug dose inhaled by the patient as the patient’sbreathing is not taken into account. Attempts have beenmade to incorporate breathing patterns into respirabledose measurement[1–4]. Until now all these techniquesmade use of artificial breathing patterns using flow andtime parameters deemed to represent tidal breathing. Itis known that a patient’s breathing pattern changeswhen the patient is exposed to external stimuli [5]eg a

spacer mouthpiece or the actuation of a pMDI. In theplanned study, breathing patterns from children of dif-ferent ages will be recorded during the actuation of aplacebo pMDI through spacer devices. A flow volumesimulator will then be used to determine the effect ofthese recorded breathing patterns on spacer depositionand ‘respirable dose’ measured using the Andersen cas-cade impactor.

Methodology: Breathing was recorded from a humansubject while using a spacer using a paediatric flow sen-sor (Series 100, Hans Rudolph) of a Pneumotach System(Hans Rudolph Inc. RSS100-HR). The breathing patternswere transferred to a Flow-Volume simulator (FVS)(Flow Volume Simulator series 1120, Hans Rudolph).The Andersen Cascade Impactor was connected to theFVS using a similar set-up as described by Foss et al1.However, rather than artifical sinusoidal waveforms,we utilised the exact breathing patterns recorded froma subject while utilising a pMDI-spacer. This breathingpattern, as simulated by the FVS, was drawn through apMDI/spacer attached to an Andersen cascade im-pactor. The drug “inhaled” from the spacer would stillbe drawn into the cascade impactor using a calibrated28.3L/min flow.

Results: We then validated this system in two ways:(i) by comparing the airflow recorded from the subject,

the airflow generated by the FVS and the airflow throughthe spacer/cascade impactor. There was no significantdifference in tidal volume(VT), inspiratory time(Ti), totalbreath time(Ttot) or peak inspiratory flow(PIF). For a typ-ical 12-breath recoring mean VT � 51.6 decilitres; meandifference � 1.9 decilitres (95CI � 1.5% to 5.9%).

Mean Ti � 1.6sec; mean difference � 0.03sec (95CI ��7% to 2.9%). Mean Ttot(h) � 2.78sec; mean difference ��0.01sec (95CI � �3.3% to 2.5). Mean PIF(h) � �74.7LPM;mean difference � 1.37LPM (95CI � �3.4% to �7.0%)

(ii) by comparing drug delivery (salbutamol pMDI) toinspiratory filters after inhalation by the subject andthrough the FVS system. Preliminary data indicates thatthere is no significant difference in drug delivery.

Conclusion: Our preliminary data indicates that this isan effective method for performing paediatric ex vivoevaluations of commercial inhaler systems.

Reference1. Foss AS et al. Respiratory Care, 1999. 44:1474–84.

P-43IMPROVEMENTS IN DELIVERY TO THE

LUNG PERIPHERY

Schuster, J.1*, Rosell, J4, Wilbanks, T1, Clyde, D1,Eliahu, A1, Chan, HK2, Daviskas, E3, and Eberl, S3

1: Aradigm Corporation, Hayward, California, USA2: Faculty of Pharmacy, University of Sydney, Sydney,

Australia3: Depts. of Respiratory and PET and Nuclear Medicine,

Royal Prince Alfred Hospital, Sydney, Australia4: ICREA, Barcelona, Spain, and Departament d’Enginyeria

Química, Universitat Rovira i Virgili, Catalunya, Spain

We have developed smaller and more cost effectivetechnologies based on the AERx® system. Smaller tem-perature controlling modules and smaller nozzle holeshave been studied. This work led to Aradigm’s new AERx

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Essence™ platform1. Performance was quantified in a pre-viously described gamma-scintigraphic trial2.

In the work presented here, subjects from the previousstudy returned to the clinic and were dosed with a com-bination of the new temperature controller and thesmaller nozzle holes. SPECT imaging was used to quan-tify lung dose, oropharyngeal deposition, and penetrationindex (PI). Statistically significant improvements in thesemeasures were seen relative to the previous study.Oropharyngeal deposition averaged 0.22% vs. 3.68% (p �0.04), dose to lung averaged 72.0% vs. 62.4% (p � 0.01),and PI averaged 0.67 vs. 0.53 (p � 0.04). These data es-tablish a new state of the art for pulmonary drug deliv-ery systems.

1. Peter Noymer et. al. “AERx® Essence™: Efficiencyand Breath Control without Electronics, in RespiratoryDrug Delivery IX, Dalby, Byrn, Peart, Suman, and Farr,eds. (2004)

2. Jeff Schuster et. al. “New AERx In-Vivo Results”ISAM 13th Congress, Interlaken (2001)

P-44PARTICLE-PROTEIN COMPLEXES: A SPECIFIC

VEHICLE FOR INSOLUBLE ULTRAFINEPARTICLES TO PASS THE AIR-BLOOD BARRIER

OF THE LUNG?

M. Semmler1, S. Fertsch1, G. Oberdoerster2

and W.G. Kreyling1.

1Institute for Inhalation Biology, GSF-National ResearchCentre, Munich, Germany;

2Department of Environmental Medicine, University ofRochester, Rochester, NY, United States;

Currently the role of translocation of inhaled ultrafineinsoluble particles (UFP) into systemic circulation anddistribution to extrapulmonary organs is debated. Thereare conflicting reports about the fraction of UFP translo-cated across the alveolar-capillary barrier into the bloodcirculation. Reported varying amounts of translocatedUFP may be due to different UFP-specific chemistry andsurface properties. We have studied binding of lung-lin-ing fluid proteins obtained from broncho-alveolar lavagefluids (BALF) of rats in an in-vitro system with differentUFPs (TiO2, Printex-90, SiO2). In the same in-vitro systemwe also studied binding of human and rat blood serumproteins with UFPs. Proteins forming particle-proteincomplexes were separated from unbound proteins andsize-analyzed by gel electrophoresis. A number of spe-cific particle-protein complexes were observed for eachtype of UFP, but also proteins binding unspecific to eachUFP such as albumin. For both BALF and serum proteinsbands were found at 95 kDa for SiO2, at 44 and 49 kDafor Printex-90 and at 16, 24, 65, 74, 80 kDa for both UFPs.Conclusion: All UFP studied bind to several BALF andserum proteins. These complexes may be an importantparticle-specific determinant of UFP translocation into thecirculation.

P-45MUCOSAL INFLUENZA VIRUS VACCINE FOR

AEROSOL DELIVERY.

V.I. Sigaev*, R.V. Borovick, N.R. Dyadishchev, K.G.Soloviev; A.D. Tolchinsky, I.G. Ananieva.

Research Centre for Toxicology and Hygienic Regulation ofBiopreparations at the Ministry of Health of the Russian

Federation (RCT&HRB), Bld. 102A, Lenin Street,Serpukhov, Moscow Region, 142253 RUSSIA,

toxic@online.stack.net, S. G. Markushin, AndzhaparidzeResearch Institute for Vaccine Preparations at the Russian

Academy of Medical Sciences (RIVP RAMS), Bld. 15,Ulitsa Pervaya Dubrovskaya, Moscow, 109088, RUSSIA

Influenza is the disease of significant concern for peo-ple and health protection services worldwide. Duringthe annual epidemics of influenza, around one-tenth ofthe population are affected and the figure is 4–6fold in-creased during the pandemics. Influenza epidemicscause serious consequences and losses both for individ-uals and for the economics of the country since they areconnected not only with payments for drugs and med-ical personnel services, but also with long-term disable-ment of people.

For prophylaxis of influenza, inactivated vaccines are cur-rently being used, namely, VACCIGRIP (France), FLUARIX(Belgium), BEGRIVAC (Germany), INFLUVAC (Neder-land), or GRIPPOL (Russia) intended for parenteral de-livery. Unfortunately, because of the high cost of the ex-isting inactivated vaccines and generally acceptedparenteral route of delivery, their application is rathercomplicated. Sharp decrease of the influenza incidencerate might be only achieved by mass vaccination of largegroups of population, primarily children, who easily com-municate the infection. In our opinion, aerosol method ismore efficacious for the vaccine delivery.

The benefits of the aerosol method for the vaccine de-livery are as follows: no damage of muscular tissues;natural way of administration; no risk of infection withany hazardous infectious diseases (AIDS, hepatitis, etc)during medical manipulations; the possibility to delivervaccine to any target portion of the respiratory tract dueto the use of aerosol with pre-fixed particle size; avoid-ance of the drug inactivation in blood flow thanks to noneed to pass through the liver; active formation of bothhumoral and cellular immunity; induction of both sys-temic and local immunity. It is also possible to increasethe efficacy of inactivated vaccines by including in theircomposition the mucous-adhesive adjuvants, which assure getting the major part of influenza antigen intothe cells of mucous membranes of pharyngeal lym-phatic circle.

The main task of the research is the development of mu-cosal inactivated influenza vaccine for aerosol delivery.

During the research work, a commercial inactivated in-fluenza vaccine and mucoso-adhesive adjuvant havingthe highest immunological effecacy for laboratory ani-mals while inhaling will be identified.

As mucoso-adhesive adjuvants of inactivated influenzainhalation vaccine, chitosan and its derivatives, namely,N –trimethyl oligomers of chitosan, will be used. As sta-bilizing component, polyethylenimine will be used foraerosol variant of influenza mucosal vaccine.

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A mucosal inactivated influenza vaccine will be devel-oped with the use of the synthesized in Russia mucoso-adhesive adjuvants of different nature. This vaccine willbe capable of inducing both systemic and local immuni-ties at aerosol delivery.

The research will be carried out in the framework ofthe Project #2442 through the International Science andTechnology Center (ISTC), Moscow.

P-46BENCH PERFORMANCE AND IN VIVO

DEPOSITION EFFICIENCY

GC Smaldone* MD, PhD.

SUNY at Stony Brook NY

The I-neb AAD system nebulizer incorporates vibratingmesh technology, breath actuation, bolus inspiration andfeedback. We characterized prototype I-neb devices pro-grammed either to tidal breathing mode (TBM, Vt 450mL)or target inhalation mode (TIM, Vt 1621mL). All nebulizedparticles were captured on a filter and aerodynamic distri-butions measured by low flow cascade impaction. Aerosolsof albuterol (1.4mL, labeled with 99mTc-sulphur colloid)were tested in vitro and then inhaled by a normal volun-teer. In vitro results: In TBM and TIM inhaled mass rangedbetween 77 and 80% of nebulizer charge. Aerodynamic di-ameters were 1.6�m in TBM and 3.7�m in TIM. In vivo re-sults: Gamma camera scans showed peripheral depositionwith both TBM and TIM. Central:peripheral ratios were 1.32with TIM with negligible oropharyngeal deposition. Simi-lar distributions were seen with TBM. Analyzed per breath,aerosol deposition for TIM was 51 times more efficient thanfor TBM; this ratio represented combined efficiencies in de-livery and deposition. Analysis of in vitro data suggestedthat TIM was 5 times more efficient per breath than TBMin particle delivery to the lungs (delivery). Combining in vitroobservations with gamma camera analysis, it appeared thatthe fraction of inhaled particles deposited per breath was10 times greater for TIM than TBM (deposition).

P-47MINIMIZING FACIAL AND OCULAR

DEPOSITION OF NEBULIZED BUDESONIDE:IMPORTANCE OF FACEMASK DESIGN

GC Smaldone* MD, PhD.

SUNY at Stony Brook NY

Aerosol therapy using nebulizers and facemasks can re-sult in drug deposition on the face and in the eyes. Thepresent study tests different nebulizers and mask designsfor budesonide to determine the optimal configuration forsafe and adequate drug delivery to children. Drug deliv-ery (Inhaled Mass) and facial deposition of nebulizedbudesonide aerosol were studied in vitro with a ventilatedmodel of a face facsimile: tidal volume 50 mL, respiratoryrate 25 per minute and duty cycle 0.4. Facial and eye de-position were measured with HPLC for a tight fitting testmask (Laerdal), a standard commercial mask (Salter) anda prototype mask designed to reduce the local ballisticcomponent of aerosolized particles near the eyes. Particle

size was measured by cascade impaction. All three com-binations produced large particle aerosols ranging from7.8 �m to 9.9 �m. Inhaled mass with the Salter facemaskwas 3.55�0.38% (of drug in the nebulizer). Drug deposi-tion on the face and in the eyes was 3.95�0.53% and1.51�0.08% respectively. The Laerdal facemask promotedincreased inhaled mass (14.43�0.67%) with increased fa-cial (6.51�0.13%) and eye (4.77�0.23%) deposition. Theprototype mask preserved inhaled mass (13.21�1.83%)with reduced facial (1.33�0.24%) and minimal eye(0.35�0.05%) deposition. Facemask modifications de-signed to reduce the local ballistic component ofaerosolized particles enhanced drug delivery to the pa-tient and virtually eliminated eye deposition.

P-48VARIATION IN PEDIATRIC AEROSOL DELIVERY:

IMPORTANCE OF FACEMASK

GC Smaldone* MD, PhD.

SUNY at Stony Brook NY

We have quantified in vitro the influence of the facemaskon inhaled mass (IM) by jet nebulizer and pressurized me-tered dose inhaler (pMDI) valved holding chamber (VHC)combinations (non-detergent and detergent coated). Pedi-atric breathing patterns were used with a breathing simu-lator and a face facsimile onto which each device was po-sitioned. Budesonide inhalation suspension (BIS, 0.25 mg)was used with the jet nebulizers and fluticasone propionate(FLP, 220 �g) pMDI with the VHCs. Breathing pattern ef-fects were assessed for sealed devices (no leaks) and withcommercial facemasks (possible leaks). IM from both neb-ulizers and pMDI VHCs was affected by breathing pattern,but compared to nebulizers the pMDI VHCs were signifi-cantly more variable and sensitive to several factors. Theinfluence of VHC conditioning combined with effects ofbreathing pattern resulted in IM ranging from 0.7 � 0.5 to53.3 � 6.2%. Nebulizers were less variable (9.6 � 0.7 to24.3 � 3.1%). Detergent coating of VHC markedly increasedIM and reproducibility of drug delivery (27.2 � 1.4 to 53.3 �6.2%) for pMDI VHC combinations but these effects werelost in the presence of facemasks. Using pediatric patternsof breathing, nebulizer/facemask combinations delivered4.1 � 0.8 to 19.3 � 2.3% of the label dose whereas pMDI anddetergent coated VHC delivered 4.0 � 1.6 to 28.6 � 2.5%.Facemask seal is a key factor in drug delivery. Leaks aroundthe facemask reduce drug delivery and for pMDI VHCs cannegate effects of detergent coating.

P-49CONSISTENT DRUG DELIVERY INTO EIGHT

BREATHING PATTERNS USING A PROTOTYPE I-neb™ ADAPTIVE AEROSOL DELIVERY (AAD®)

DEVICE—AN IN VITRO STUDY

*Potter R, Prince I, Dyche T, Hatley RHM, Smith NJ.

Profile Therapeutics, a Respironics Company. Heath Place,Bognor Regis, West Sussex PO22 9SL, UK.

The I-neb™ AAD® (Adaptive Aerosol Delivery, ProfileTherapeutics) system[1] is a portable, silent, internally

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powered inhalation device that provides audible, visualand tactile feedback about progress of the treatment tothe user. I-neb utilises Vibrating Mesh Technology (VMT)to generate an aerosol, and an AAD Disc to provide aproduct specific configuration of output rate and vialcount, which allows the tie-in of medicinal product withdelivery device. Delivered dose using I-neb is achievedby selection of a medication chamber with a pre-set vol-ume designed to give delivered volumes in the range0.25ml to 1.4ml. The volume delivery of a prototype I-nebwith a 250�l medication chamber was tested using 8 sim-ulated breathing patterns (VT � 0.15L to 1.24L, PIF � 19.7l/min to 88.9 l/min, I:E Ratio � 1:0.62 to 1:1.97). Each pat-tern was run in triplicate into an inhalation filter, salbu-tamol was eluted and analysed using HPLC. The meanresults ranged from 207.8�l to 257.5�l with an average of234.1�l. The data had a co-efficient of variation of 14.8%.The I-neb AAD system delivers a pre-set volume consis-tently over a range of breathing patterns, with a similaraccuracy to predecessor AAD systems.

[1] Denyer J, Nikander K, Smith NJ. Adaptive AerosolDelivery (AAD) technology. Expert Opin. Drug Del.2004;1(1):165–176.

Funded by Profile Therapeutics

P-50OUTPUT CHARACTERISTICS OF THE NEW

I-NEB™ AAD® SYSTEM WHEN DELIVERING PROMIXIN™

*Potter R, Hatley RHM, Dyche T, Smith NJ.

Profile Therapeutics, a Respironics Company. Heath Place,Bognor Regis, West Sussex, PO22 9SL, UK.

The I-neb™ AAD® (Adaptive Aerosol Delivery, ProfileTherapeutics) system delivers precise, reproducible dosingin a portable device that has negligible residual volume. I-neb is the first AAD system to utilise Vibrating Mesh Tech-nology (VMT, Omron Healthcare). With VMT the degra-dation issues with delicate peptide/protein structuresshould be minimal. We tested the ability of three I-neb pro-totypes to deliver an aerosol of Promixin™ (colistimethatesodium, Profile Pharma), into the CEN test pattern, andcompared the delivered activity with that of three ProdoseAAD system devices. A bioassay was used to ensure thatthe activity of Promixin against bacteria was retained fol-lowing the nebulisation process. Promixin was reconsti-tuted with de-ionised water. 1 vial of Promixin in 1ml ofwater (1MIU/ml) was used for I-neb tests due to the lowresidual volume of I-neb. Prodose tests had to be run using2 vials of Promixin in 2ml of water (1MIU/ml). The aver-age activity of Promixin recovered from the inhalation fil-ters using I-neb and Prodose was 325kIU and 332kIU, re-spectively. I-neb produced particles with an average MMDof 3.28�m compared with 3.32�m for Prodose. The activ-ity resulting from respirable (�5�m) particles was 262kIUfor I-neb and 250kIU for Prodose. The I-neb AAD systemdelivers an aerosol that has similar activity and particle sizecharacteristics as Prodose with half the fill volume.

Funded by Profile Therapeutics

P-51DYNAMIC SURFACE PROPERTIES OF

PULMONARY SURFACTANT (PS) SAMPLES—APOTENTIAL DIAGNOSTIC VALUE

T R Sosnowski*, M Pirozynski, L Gradon

Department of Chemical and Process Engineering, WarsawUniversity of Technology, Warsaw, Poland

INTRODUCTION: Surface activity exhibited by thepulmonary surfactant under dynamic conditions is be-lieved to be tightly connected to main physiological func-tions fulfilled by the whole PS system. It is known thatmany lung diseases are related to impairment of PS func-tionality what may lead to ventilatory- and defense-re-lated pulmonary dysfunctions.

METHOD: The measurements of the dynamic surface ac-tivity were done for BAL samples obtained from patientswith various diagnosis of lung disease. Dynamic surfaceproperties of surfactant samples were evaluated with an os-cillating bubble tensiometer (PBS, Electronetics, USA) at37°C at 20 cycles/min. The resultant surface tension—area(�-A) hysteresis curves were analyzed to obtain the com-monly used quantitative criteria (HAN, SI, �min, etc).

RESULTS: It was shown that all diseases were relatedto noticeable decrease of dynamic surface activity of PSsamples as indicated by drop of the HAN value by 30 to80% of the control (i.e. value obtained for BAL of a healthyperson). Different lung diseases were associated with var-ious extent of physicochemical inactivation of PS sampleswhat may suggest using dynamic surface tensiometry asan auxiliary diagnostic tool in medical diagnosis.

P-52ORO-PHARYNGEAL SEPARATION OF

PHARMACEUTICAL POWDER UNDER REALISTICFLOW CONDITIONS

T R Sosnowski*, L Gradon, A Moskal

Department of Chemical and Process Engineering, WarsawUniversity of Technology, Warsaw, Poland

INTRODUCTION: Drug formulation and powder in-haler aerodynamics must guarantee proper resuspensionof particles allowing penetration of aerosolized drug tothe tracheobronchial tree with reduced particle deposi-tion in the mouth, throat and the pharyngeal region. Thisstudy was focused on aerosol deposition measurementsin a model of oro-pharyngeal airways under the realistic,non-stationary flow conditions.

METHOD: The measurements were done using a sili-cone rubber cast prepared according to the CT-image ob-tained for an adult male. The realistic inspiratory flowswere simulated with the computer-controlled breathingsimulator constructed in our group. A test pharmaceuti-cal aerosol was generated from a commercial single-cap-sule DPI containing formoterol and lactose. WELAS 2100spectrometer (Palas, Germany) was used to measure par-ticle size distribution of aerosol at the outlet of the inhalermouthpiece and after passing the cast.

RESULTS: Particle size distribution obtained from the in-haler was characterized by MMD of 8 �m and 20% FPF(mass of particles below 5 �m). MMD of the aerosol after

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passing the oro-pharyngeal cast at the sinusoidal inspiration(Qmax � 100 LPM) was reduced to 3.6 �m while FPF in-creased to 82%. Similar trends were observed for differentinspiration patterns. The results demonstrated that particleslarger than 8 �m are effectively captured in the oro-pha-ryngeal region during inspiration and should be consideredtherapeutically useless for treatment of lung diseases.

P-53IMPROVING DRUG DELIVERY

PERFORMANCE BY CUSTOMIZATION OFFORMULATION AND NEBULIZER

M. Tservistas, M. Hug, F.-C. Lintz, M. Keller and M. Knoch,

PARI Aerosol Research Institute, Steinerstr. 15C, 81369Munich, Germany

Introduction:Performance of nebulized products is highly dependent

on the interaction between formulation and nebulizer aswell as the characteristic breathing manoeuvre of the pa-tient group addressed. Most conventional nebulizer sys-tems are designed for adults and are likely to function lesseffectively when used by children or infants. Our approachis to combine formulation development and nebulizer de-sign to develop customized systems with increased effi-ciency. This study uses the eFlow® technology platform tocustomize a budesonide system tailored for children.

Methods:Budesonide formulations for an eFlow® configuration

for children (MMD � 3.5�m) were prepared as colloidaldispersions in aqueous excipient mixtures and comparedto the conventional treatment regime Pulmicort® Re-spules (Astra Zeneca, Sweden) nebulized using PARI LCPLUS® / Boy N compressor (PARI GmbH, Germany). Thein-vitro delivered dose was determined by breath simu-lation experiments mimicking a child breathing pattern(20 breaths/minute, 150ml tidal volume, inh:exh�40:60).Budesonide was quantified by HPLC and UV-detection.

Results:Delivered doses between 56–69�g were obtained with

the conventional 500�g/2ml budesonide suspension.Equivalent or higher doses could be obtained with a cus-tomized 125�g/0.5ml formulation. Nebulization timeranged between 3–5min for Pulmicort®/LC PLUS® and1–2min for the customized system.

Conclusion:Customization of both, formulation and nebuliser of-

fers a tailored treatment regime with significantly re-duced drug requirements. Additionally, a shortenedtreatment time can help to increase patient compliance.

P-54AEROSOL PARTICLE SIZE AND CLINICALEFFECTS OF INHALED LONG-ACTING �2-

AGONIST.

Usmani OS1*, Biddiscombe MF2, Meah S1, Barnes PJ1.

1Thoracic Medicine, 2Nuclear Medicine, Royal BromptonHospital and National Heart & Lung Institute, Imperial

College London, U.K.

Rationale: Aerosol particle size influences the site ofairway drug deposition and the clinical response. We pre-viously showed 6�m and 3�m particles of short-acting�2-agonist (salbutamol) aerosols were more efficaciousthan 1.5�m sized particles. Our aim was to investigate thebronchodilator response of long-acting �2-agonist (sal-meterol) as a function of aerosol particle size. Methods:Twelve stable asthmatics (FEV1 72.0%pred) inhaledmonodisperse salmeterol particles of size 1.5�m, 3�m,6�m (10�g) produced by a spinning-top aerosol genera-tor, MDI salmeterol (50�g) and placebo. Efficacy (spirom-etry) and tolerability variables (pulse rate, blood pressure,plasma potassium) were recorded for 12 hours post-in-halation Results: Larger particles produced the greatestpeak effect and overall improvement in FEV1; 6�m & 3�mvs. 1.5�m (p � 0.05). The 6�m and 3�m particles (10�g)achieved comparable bronchodilation to MDI (50�g) upto 12 hours. All particles showed highly significant ther-apeutic responses vs. placebo (p � 0.001). No clinical dif-ference was noted in tolerability variables for all treat-ments vs. placebo. Conclusions: Aerosol particle sizeeffects hold true for short and long-acting �2-agonists.Particles in the higher part of the respirable range pro-duce the greatest clinical benefit. Monodisperse salme-terol aerosols enable large reductions of the inhaled dosewithout loss of efficacy or duration of action, and allowthe study of aerosol delivery science.

Funding: An academic grant from GlaxoSmithKline, R&D,UK

P-55ALVEOLAR MACROPHAGES INHIBIT THE

IMMUNE RESPONSE TO PULMONARY ANTIGEN DELIVERY

C Lombry1, J Louahed2, B Ucakar1, J-C Renauld2, VPréat1 and R Vanbever1*

1. Department of Pharmaceutical Technology, School ofPharmacy, Université catholique de Louvain (UCL),

Brussels, Belgium.2. Ludwig Institute for Cancer Research, UCL, Brussels,

Belgium.

Purpose. To assess the impact of alveolar macrophages(AM) and of the uptake of vaccine molecules by AM onthe immune response generated by intratracheal instilla-tion of a model antigen, ovalbumin.

Methods. The uptake of FITC-ovalbumin (FITC-OVA)by AM in the mouse lungs was visualized by confocallaser scanning microscopy. The time course of uptake of

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FITC-OVA by AM was determined by flow cytometry.AM that had or not taken up OVA for 24h, were intra-tracheally instilled in inbred mice (BALB/c). One or 24hafter administration of AM, mice were immunized intra-tracheally against OVA. Control mice received OVA orsaline intratracheally or OVA by intramuscular injection.Measurement of antibody titers and of lymphoprolifera-tion was used to assess the humoral and cellular immuneresponse.

Results. Confocal imaging showed an intense uptakeof FITC-OVA by AM within 4h. The uptake reached itsmaximum within 4h with a steady-state until 24h. Im-mune responses were induced only in groups immunizedagainst OVA without intratracheal instillation of addi-tional macrophages. When mice were pretreated with AMexposed or not to OVA, the immune responses were to-tally inhibited.

Conclusions. The increase in the number of AM locallytotally suppressed the immune response to intratrachealinstillation of OVA, whether macrophages had previouslybeen in contact with OVA or not, and whatever the timebetween delivery of AM and OVA.

P-56IN VITRO STUDY OF SONIC AEROSOL TO

MAXILLARY SINUSES TREATMENT

M Durand1, G Aubert2, L Vecellio3, P Diot3, G Chantrel4

1. Service d’ORL, Centre Hospitalier, 12 bd Doct AndréChantemesse, 43000 Le Puy en Velay.

2. Laboratoire de Bactériologie, 42055 CHU St Etienne3. INSERM U-618, IFR 135, Faculté de Médecine, Tours,

France4. Atomisor, DTF, 114 rue Bergson, 42003 St Etienne,

France

Aim of this study: To determine the effects of soundwaves on aerosol (sonic aerosol) deposition in a model ofmaxillary sinuses.

Methods: First, sound optimisation was realized usinga maxillary sinus model. Atomisor NL11 (DTF, France)was used with sound generator and was loaded with NaFsolution at 1%. After 10 min of nebulization, NaF de-posited in maxillay sinus model was assayed by electro-chemical method. After sound optimisation, gemtamicinedeposition in maxillary sinuses using a plastinated modelwas measured with sonic aerosol and aerosol producedby a classical jet nebulizer (without sound). Gemtamicinewas assayed by FPIA method.

Results: There was a major influence of sound fre-quency on aerosol deposition in maxillary sinus. Com-parison between sonic aerosol and classical aerosol interms of gentamicine deposition in the model of maxil-lary sinuses shows a statistical difference (p � 0.001, n �30). There was twice more gemtamicine deposited in max-illary sinuses when sonic aerosol was used in compari-son to aerosol whithout sound.

Conclusion: Addition of a specific sound to an aerosolincreases aerosol deposition efficiency in maxillary si-nuses. This nebulization system could be used for ENTtreatement.

P-57MACROSCOPIC MODELISATION OF GAS

CLEARANCE IN THE LUNGS

L Vecellio, E Boissinot, D Grimbert, P Diot

INSERM U-618, IFR 135, Faculté de Médecine, Tours, France

The aim of this study was to define and assess a math-ematical model of gas clearance in the lungs. The modelwas validated in reference to radioactive gas for clearanceimaging. A first lung model was based on respiratorydead space and residual volume (model with 1 compart-ment). An iterative processus demonstrated that gas clear-ance in this lung model can be modelized by a powerfunction (normalised gas concentration in the lungs(GCL) in ordinate and breath cycle number in abscice (n)).This model is a function of dead volume (Dv), tidal vol-ume (Tv) and residual volume in the lungs (Rv).

GCL � 1–(A � An)/[(1 � A)(Dv � Rv)], with A � 1 �(Tv � Dv)/(Tv � Rv) and n � 0

In a second time, the lung model was modelised by twocompartments with 2 different dead volumes. These mod-els were applied on a radioactive gas. A new modelisationwas realized to show the influence of radioactive decreas-ing on the imaging measurement. The result of the modeli-sation showed the influence of the activity decreasing on thelung clearance imaging. As a consequence, Krypton gas can-not be used to measure the total lung clearance because itsactivity decreasing is more important than lung clearance.

Lung clearance modelisation for a patient with a tidalvolume at 500ml, a frequency at 12/min, a dead volumeof 200ml.

P-58INFLUENCE OF VENTILATORY PARAMETERS ON

OUTPUT OF STANDARD JET NEBULIZERS :EXPERIMENTAL STUDY AND MATHEMATICAL

MODELISATION

L Vecellio, D Grimbert, P Diot

INSERM U-618, IFR 135, Faculté de Médecine, Tours, France

Introduction: The aim of this study was to determinethe influence of ventilatory parameters on output of stan-

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dard jet nebulizers. A mathematical model was constructedand compared with experimental in vitro results. Materialsand methods: Mathematical model: Breathing patterns wasmodelised by a 2 sinusoidal functions. Nebulizer was de-fined by a system with an air flow rate and a drug massoutput flow constant. The interface to the patient was de-fined by its geometry. We hypothetized that aerosol trans-port and sampling efficiencies through patients interfacewere close to 100%. Output was calculated by the productbetween inhaled air volume and aerosol concentration cor-rected by the interface geometry. Experimental study: A fil-ter was connected between a nebulizer and a piston pumpset at a frequency of 15/min to 35/min, tidal volume of50ml to 500ml, and inspiratory time/total time of 0.35 to0.50. At the end of the nebulization, filters were assayed todetermine the output mass. 3 types of nebulizers(Mistyneb®, Intersurgical®, Microneb®) tested with face-mask and mouthpiece were charged with Bricanyl®(10mg/4ml) or NaF solution (40mg/4ml). Results: Therewas a good correlation between the mathematical modeland in vitro results (p � 0.00001). Conclusion: This studyshows that output flow rate, nebulization time, air flow rateand interface geometry are the most important parametersto predict output of standard jet nebulizers.

P-59NEW BRONCHODILATATOR FORMULATION TO

DECREASE NEBULIZATION TIME

L Vecellio1, D Grimbert1, M de Monte1, C Le Guellec2,C Minois3, E Cordeau3, G Paintaud2, Y Furet2, P Diot1

1. INSERM U-618, IFR 135, Faculté de Médecine, Tours, France

2. Service de Pharmacologie, CHU Bretonneau, Tours, France

3. Faculté de Pharmacie, Tours, France

Rationale: Decreasing liquid volume to nebulize couldallow to decrease nebulization time for patients. The newformulation of Atrovent® (Boehringer-Ingelheim, France)is twice more concentrated than the 2ml formulation. Aimof this study: To determine the effects of this new formu-lation on aerosol characteristics and on nebulization du-ration. Methods: New formulation of Atrovent® (0.5mg/

1ml) was compared to Atrovent® (0.5mg/2ml). New for-mulation of Atrovent® (0.5mg/1ml) and Atrovent®(0.5mg/2ml) were also compared when mixed withBricanyl® (5mg/2ml) (Astra Zeneca, Sweden). Aerosolwas produced with different jets nebulizers : PariLC�®nebulizer with Turbo BoyN® compressor (Pari, Germany); Atomisor NL9M® nebulizer with Atomisor Abox�®compressor (La Diffusion Technique Française, France) ;Sidestream® nebulizer with Portaneb® compressor(Rusch Pilling, France) and Mistyneb® nebulizer (Alle-giance, France) with air flow at 8l/min. Output mass wasmeasured with a method based on aerosol filtration. Atro-vent® was assayed by HPLC and Bricanyl® by spec-trophotometry. Aerosol particle size distribution wasmeasured by Mastersizer X. Results: The new formula-tion of Atrovent® added with Bricanyl® allowed a 25%decrease of nebulization time without changing aerosoloutput and particle size distribution (except Mistynebnebulizer). When Atrovent® was used alone, aerosol out-put was decreased with Atrovent® 0.5mg/1ml comparedto Atrovent® 0.5mg/2ml.

P-60EVALUATION OF NEBULIZERS PERFORMANCESWITH SMALL FILL VOLUMES IN ACCORDANCE

WITH EUROPEAN STANDARD EN13544-1

L. Vecellio1, D. Foret2, J-P. Laaban2, O. Roqued’Orbcastel2, D. Gimbert1, P. Diot1

1. INSERM U-618, IFR 135, Faculté de Médecine, Tours, France

2. ANTADIR, Paris, France

Aim: To evaluate the performances of 9 nebulizers with2ml of NaF reference solution in accordance with the Eu-ropean standard EN13544-1. Output measurement: A Parifilter was connected between nebulizer and a sinus pump(TV � 500ml, f � 15/min, I/E � 1). After one minute ofsputtering, filters were assayed by electrochemical method.Particle size measurement: A cascade impactor (Andersen,Marple Personal 298, USA) was connected by a T-piece be-tween the nebulizer and a vacuum pump aspirating con-tinuously at 13 lmin�1. After 3 minutes’ continuous sam-pling, stages were assayed by electrochemical method.

Table 1: Aerosol characteristics results for 2ml volumecharge in accordance with European standard EN13544-1(*jet nebulizer/compressor, **ultrasonic nebulizer, ***mi-cropump nebulizer)

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P-61IN VITRO EVALUATION OF A NOVEL

INHALATION CHAMBER FOR NEBULIZERS ANDMDI (ATOMISOR CHAMBER®)

L. Vecellio1, G. Chantrel2, P. Diot1

1. INSERM U-618, IFR 135, Faculté de Médecine, Tours, France

2. Atomisor, 114 rue Bergson, 42003, Saint Etienne, France

Introduction: Aerosol drug therapy is limited by theaerosol generator efficency. Nebulizers deliver a smallproportion of drug filled in the nebulizer with a low par-ticle velocity and MDI deliver the totality of the drug dosewith a high particle velocity. A new device (Atomisorchamber®, Atomisor, France) adapted on jet nebulizer,micro pump nebulizer and MDI was in vitro evaluatedas a potential tool to increase generators efficiency. Meth-ods: One jet nebulizer (Atomisor NL9M®, Atomisor,France), one micro pump nebulizer (Aeroneb®, Aerogen,USA) were tested with and without Atomisor chamber®.Nebulizers were filled with 2ml of NaF reference solutionat 1%. One MDI (Bricanyl®, Astra Zeneca, Sueden) wastested with Nebuhaler® chamber (Astra Zeneca, Sueden)and with Atomisor chamber®. Inhaled fraction was mea-sured with a filter placed between nebulizer and sinuspump (500ml, 1/1, 15/min). NaF was assayed by elec-trochemical method and Bricanyl® was assayed by spec-trophotometric method. Mass Median Aerodynamic Di-ameter (MMAD) was measured with a Mastersizer-X.Conclusion: The Atomisor chamber® is a new device de-signed to increase inhaled drug mass and aerosol drugflow. The use of Atomisor chamber® with the micropump nebulizer allows the administration of 91% of druginto the patient mouth in a form of aerosol with a low ve-locity.

Influence of Atomisor chamber® on aerosol character-istics produced by jet nebulizer, micro pump nebulizerand MDI (n � 6 for all measurements)

P-62HPLC DETERMINATION OF NICOTINE AND

VOC’s FROM CIGARETTE OUTPUT UNDER INVITRO CONDITIONS

Wahdan, A, LeSouëf PN, Devadason SG

School of Paediatrics and Child Health, University ofWestern Australia, Perth, Australia.

Introduction: Regulatory bodies require cigarettes to betested for nicotine and tar output. The tobacco industryperforms these measurements using a standard testing

set-up to categorise products as being high, medium andlow tar yield. This testing fails to incorporate smoker be-haviour and hence we hypothesise that this method of as-sessment does not reflect the true level of toxicity to thesmoker.

Methods: We aim to independently quantify differ-ences between high, medium and low cigarette types (1)prior to burning, by digestion of unburnt cigarette leaves,(2A) after burning where the cigarette is artificially‘smoked’ and compounds from cigarette smoke are mea-sured using HPLC. In vitro measurements will includeoutput of nicotine and organic compounds (BTX).

Results: Nicotine and BTEX standards were linear to2000 �g/L with an R2 � 0.9998, the limit of detection fornicotine was 40 �g/L and 1 �g/L for BTEX. Mean (SD)nicotine levels (n � 7) (mg/cigarette) from three brandsof unburnt cigarettes ranged from 10.3mg (1.14) to 12.6mg(1.52) for Winfield 2–16mg tar cigarettes; 11.6mg (1.81) to12.6mg (0.47) for Peter Jackson 2–16mg tar cigarettes; and9.4mg (0.96) to 9.5mg (1.28) for Horizon 2–12mg tar cig-arettes.

Cigarette smoke was analysed for nicotine and BTX.Nicotine values for burnt Winfield 8mg and 12 mg ciga-rettes smoked at 25L/min with a puff duration of 3 sec-onds at an interval of 30 seconds were 2.2 and 2.4 mg/cig-arette respectively which is significantly more than thereported values of 0.8 and 1.2 mg/cigarette on the pack.Preliminary BTX levels from one brand of burnt cigarettes(Peter Jackson; n � 2) show that benzene, toluene and xy-lene levels significantly increased from 29.24, 27.43, 9.28ug/ml respectively, in 2mg tar cigarettes to 106.16, 77.92and 24.05 ug/ml for 16mg tar cigarettes.

Conclusions: Levels of nicotine in unburnt cigarettesof low and high tar cigarettes are similar. When artificiallysmoked using more realistic smoking parameters, nico-tine values in cigarette smoke are double that specifiedon the package labelling. When ‘smoked’ using the sameparameters, BTX levels increase with increasing tar yields.The final phase of this ongoing study is to artificially‘smoke’ the cigarettes incorporating smoker respiratoryparameters and behaviour to confirm that in vivo, smok-ers are exposed to higher nicotine and BTX levels than in-dicated on package labelling.

Funding Source: Cancer Council, Australia

P-63HPLC DETERMINATION OF COTININE AND

NICOTINE IN URINE: BIOMARKER FORENVIRONMENTAL TOBACCO SMOKE EXPOSURE.

Wahdan, A, LeSouëf PN, Devadason SG

School of Paediatrics and Child Health, University ofWestern Australia, Perth, Australia.

Environmental Tobacco Smoke (ETS) contains the sametoxic substances as identified in mainstream tobaccosmoke. Cotinine is a metabolite of nicotine and can bemeasured in urine of smokers and non-smokers exposedto ETS and reflects the degree of exposure. We report asimple and rapid extraction method for the detection ofcotinine and nicotine in urine.

Method: Standards and urine samples were diluted with50mm ammonium acetate buffer (pH 6) and spiked withinternal standard (2-phenylimidazole). DVB 100mg/ml ex-

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traction cartridges were preconditioned with methanoland rinsed with buffer before sample application. Inter-fering compounds were removed by washing, and the ex-tract was eluted with 1ml methanol:ammonium hydrox-ide (95:5). This was evaporated, reconstituted with mobilephase and analysed by HPLC. 25 �l of the extract was in-jected onto an Apollo C18 250mm column. Cotinine mo-bile phase consisted of water, methanol, 50mmol/L am-monium acetate buffer (pH 4) and acetonitrile (64:20:12:4);the flow rate was 1 ml/min and the absorbance was 260nm.The mobile phase for nicotine was 70:30 methanol:1% tri-ethylamine (pH 8). Absorbance was 254nm and the flowrate was 1ml/min. Area was calculated for standards andsamples.

Results: Cotinine standards were linear to 4000 �g/Lwith an R2 � 0.9998, the limit of detection was 80 �g/L.The run time was 12.5 minutes with cotinine and I.S. elut-ing at 7.5min and 9.8min respectively. Cotinine concentra-tions in smoker urine ranged from 1123–1545ug/L. Nico-tine standards were linear to 4000ug/L with a lower limitof detection of 40 �g/L and an R2 � 0.9999. Run time was7.5 minutes with nicotine eluting at 5.9 mins. Nicotine con-centrations in smoker urine ranged from 1049–1401�g/L.These preliminary data will be corrected for urinary crea-tinine to account for dilution of urine samples.

Conclusion: This reliable assay for quantifying coti-nine from urine samples will enable us to study passivesmokers in high risk groups such as hospitality work-ers, children of smokers and to determine passive andactive smoker exposure from low versus high tar ciga-rettes.

P-64PARTICLE DOSES FOR IN-VITRO STUDIES

R Phalen* and M Oldham

C&E Medicine, University of California, Irvine, CA 92697-1825, USA

For cell culture studies with particles to be relevantto human exposures, the number of particles appliedper cm2 surface should be similar to that deposited inliving subjects. Matching averaged surface doses in-vivo underestimates surface doses at heavily-exposedregions of the respiratory tract, which may underesti-mate the toxic or therapeutic effects. Advances, includ-ing Computational Fluid Dynamics models, have quan-tified enhanced deposition of particles at local regionsin the bronchial tree. Calculated enhancement factors innormal bronchi (multiples of average surface doses) canexceed 100 depending on particle size, airflows andcharacteristics of the target surface. Additional local de-position is expected in individuals who are small, areexercising, are mouth breathing, have lung disease orhave an unusual airway anatomy. Such individuals mayhave local surface doses that are enhanced by an addi-tional factor of 125 or more above those for averageadults. Thus, the number of particles per cm2 appliedto cell cultures may be thousands of times the averagesurface deposition in bronchi. Uncertainties in suchdose estimates include: the critical cells and cell num-

bers are usually unknown; local particle deposition en-hancement factors are poorly validated; and the effectsof particle clearance is not taken into account. Never-theless, it is often reasonable for in-vitro surface dosesto greatly exceed those calculated using average surfaceparticle depositions. (USEPA grant R827352)

P-65DOES LACK OF COORDINATION EFFECT THE

DEPOSITION OF AEROSOLS GENERATED BY THEMDI DEVICE?

M.Pirozynski1*, T.Sosnowski2, L.Gradon2

1. Postgraduate Medical School,2. Warsaw University of Technology, Poland

The pMDI was introduced in 1956. Its use is limited byone major disadvantage, it is difficult to use correctly. Prob-ably the most often seen error in inhalation technique is thefailure to coordinate or synchronize the actuation of the in-haler with the inhalation. We have compared aerosol de-position following inhalation from a breath actuated MDIdevice (BApMDI) and after simulation of the most oftenseen errors of inhalation technique with a pMDI device.During perfect synchronization 32% of the dose penetratedto the lower airways, while only 15% of the dose reachedthe lower airways when inspiration was delayed by 1 s or4% when the actuation was delayed by 2 s when usingpMDI. Using BApMDI the respirable fraction shifted to-wards the smaller particle range. Particles � 10 �m madeup 53% of the mass contribution of the aerosol generatedby BApMDI, 95% were particles smaller than 1�m. We haveshown that the problem of coordination is not a minor onebut reflects very severe problems in the aspect of deposi-tion. It has been shown that with a poor coordinating tech-nique as much as 90% of the dose of the drug does not reachthe airways, producing very serious therapeutical prob-lems. BApMDI help overcome this problem allowing morethat 30% of the generated dose to be available in the lowerairways.

P-66THE INFLUENCE OF FORCE CONTROL AGENTSON THE FORCE BALANCE AND AEROLISATION

PROPERTIES OF DRY POWDER INHALERFORMULATIONS

Philippe Begata, Haggis Harrisb, David A.V. Mortonb,John N. Staniforthb and Robert Pricea,*

aPharmaceutical Technology Research Group,Department of Pharmacy & Pharmacology,

University of BathBath, BA2 7AY

bVectura Ltd,1 Prospect West,

Chippenham, SN14 6FH

The study investigated the specific influence of forcecontrol agents (FCAs) (leucine, lecithin and magnesium

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stearate) on the interfacial properties of a carrier basedDPI formulation. The influence of FCAs on the cohesiveand adhesive force balance was directly assessed via anAFM colloid probe technique, with a recently developedCAB-graph analysis procedure. The in vitro depositionprofile of the model salbutamol sulphate formulationswas investigated using a Monohaler® DPI device. TheCAB-graph analysis of a salbutamol and budesonide sys-tem suggested a predisposition for an adhesive and co-hesive interactive mixture, respectively. To modify thecharacteristic properties of these systems, the processingof FCAs with lactose particles and subsequently the ac-tive ingredients were investigated. The AFM analyses in-dicated dramatic variations in force balances dependingon the selective introduction of the FCAs. Formulationswith pre-conditioned drug, in contrast to conditioned lac-tose, offered the optimum drug delivery performances.The use of colloid AFM technique in combination withthe cohesive-adhesive balance (CAB) system provided avery accurate means of predicting dry powder formula-tion behaviour and the specific influence of particulate in-teractions on aerosol performance.

P-67AN INVESTIGATION INTO THE USE OF

COHESIVE ADHESIVE BALANCES TO PREDICTFINE PARTICLE FRACTION OF NOVEL SUGAR

CARRIERS IN DRY POWDER INHALERFORMULATIONS

Hooton J C, Jones M D, Price R*

Pharmaceutical Technology Research Group, Department ofPharmacy and Pharmacology, University of Bath, Bath, BA2

7AY, UK

Due to limitations with lactose, such as its reducing prop-erties, the use of alternative sugars, such as xylitol, manni-tol and trehalose, as carriers in dry powder inhalation (DPI)formulations have become a more attractive option. How-ever, while numerous different sugars have been used fora range of different formulations, directly relating the phys-ical properties of the carrier to DPI performance has re-ceived more limited attention.

In this study, a novel atomic force microscopy (AFM)technique has been used to relate the relative cohesive-ad-hesive balance (CAB) of forces of the drug salbutamol sul-phate against a substrate of salbutamol, and specificallygrown sugars (lactose, cyclodextrin, xylitol, raffinose andtrehalose). The resulting relative order of adhesion was cyclodextrin � lactose � trehalose � raffinose � xylitol. Inaddition, in vitro testing of formulations of the drug andsugars was performed using an Anderson Cascade Im-pactor. The order of the fine particle fraction (FPF%) wascyclodextrin � lactose � raffinose � trehalose � xylitol.This data was then plotted against the AFM CAB adhesiondata. It was observed that a good correlation (R2 � 0.9572)was found between the FPF% and gradients of the CABgraphs. This shows that quantitative AFM data can give avaluable insight into the performance of DPI formulations.

JCH acknowledges the EPSRC for funding.

P-68DETERMINING FLOW AND FLOW

ACCELERATION CONDITIONS FOR IN-VITROTESTING OF DRY POWDER INHALERS

Prime D*

GlaxoSmithKline Research and Development, Park Road,Ware, Hertfordshire, UK SG12 0DP

Purpose:To determine how key inhalation characteristics such

as peak inspiratory pressure drop, peak inspiratory flowand flow acceleration are affected by patient inspiratoryeffort and device resistivity.

Method:A Hydraulic Lung has been designed and constructed

which can inhale through a Dry Powder Inhaler with con-sistent, pre-determined levels of inspiratory effort. Thisapparatus was used to generate inhalation profiles acrossa range of inspiratory efforts and device resistivities. Thecharacteristics of the inhalation profiles were determinedand used to derive relationships. A clinical study was alsoperformed to generate comparative data from human vol-unteers.

Results and Conclusions:A simple empirical equation derived from the Hy-

draulic Lung data was found to describe the peak pres-sure drop (or flow rate) achieved for a given level of in-spiratory effort and device resistivity. A second simpleempirical equation was found to describe the flow ac-celeration rate. A comparison between the relationshipsderived from the Hydraulic Lung data and the (morevariable) human inhalation data demonstrated the va-lidity of the key equation for pressure drop as a tool forpredicting human inhalation characteristics. The equa-tion for flow acceleration rate was found to underesti-mate the flow accelerations achieved by human volun-teers, though a small correction factor was establishedto rectify this.

P-69AEROSOL DEPOSITION IS UNAFFECTED BY

FLOW REVERSALS IN THE LUNG.

GK Prisk* and C Darquenne

Dept. Medicine, University of California, San Diego, USA

It has been suggested that complex mixing patterns ofstreamlines increase aerosol deposition in the lung. Westudied the effect of small flow reversals (FR) on deposi-tion using boluses of 0.5 �m latex particles in 8 healthysubjects at penetration volumes (Vp) of 300 and 1200mlin normal-gravity (1G) and microgravity (�G). Inspira-tion was from RV to 1 liter above FRC at a flow (Q) of450ml/s, followed by a 10–sec breath hold and expirationto RV at the same Q. Small volume flow reversals (Vp �300ml, VFR � 100ml, QFR � 200ml/sec; Vp � 1200ml,VFR � 500ml, QFR � 500ml/sec) were imposed during thebreath hold to induce complex mixing. Aerosol concen-tration and Q were measured at the mouth. Data are re-

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ported for 8 subjects at Vp � 300, and at Vp � 1200 for the3 subjects with identifiable exhaled boluses. At both Vp,deposition was greater in 1G than in �G as expected, butthere was no effect of the imposed flow reversals.

The results show that deposition is unaffected by flowreversals imposed during a breath-hold. The lack of achange in deposition suggests that the small flow rever-sals were not an effective mechanism of increasing aerosoldeposition.

Support NIH-R01-ES11184

P-70AEROSOL LUNG DEPOSITION OF A NEW

NEBULISER DEVICE IN VENTILATED PATIENT

*S Roeder1, T Kolb1, S Ehrle3, J Geiseler2, G Scheuch1

1Inamed GmbH, Gemünden, Germany2Asklepios Fachkliniken Gauting, Germany

3Inamed Research GmbH&CoKG, Gauting, Germany

The response to inhaled drugs in ventilated patientsmainly depends on efficient drug deposition in the targetairways. Drug deposition is not only dependent on theinhalation device but also on the ventilation-manoeuvreperformed with the ventilator and the status of the pa-tient.

In this study 3 long-term ventilated patient and 4healthy subjects participated. Half of the volunteers wereventilated with volume controlled ventilation (VCV) andthe others with Bi-Level Ventilation (Bi-L). Nebuliserswere a Pari vibrating orifice filled with 99mTc labelledNaCl. Lung deposition was measured using a gamma-scintigraphy. Patients were intubated during inhalationwhereas healthy participants used a inhalation-mask.

Healthy subjects ventilated with Bi-L showed an aver-age lung deposition of 80% of the emitted dose. Healthysubjects inhaling with VCV showed 90% lung depositionwhereas patients reached 70% (Bi-L) respectively 73%with VCV. Extrathoracic deposition in healthy subjectswas 20% (Bi-L) and 10% (VCV) and in patients 30% (Bi-L) and 27% (VCV).

It has been shown that, using the new nebulizer inves-tigated in this study, leads to a high lung depositionwhich has the potential to considerably improve inhala-tion therapy in the ventilated patient. Lung depositionseems to be lower in patients and/or if the Bi-L ventila-tion mode is used.

This abstract is funded by: Salvia Lifetec, Tim GmbH,and Inamed GmbH.

P-71DEPOSITION OF 99mTc-HFA-BDP INHALED VIA

pMDI-SPACER IN ASTHMATIC CHILDREN

*CM Roller1, RG Troedson2, PN LeSouef1, SG Devadason1.

(1) UWA School of Paediatrics and Child Health, Perth6008, Western Australia.

(2) Department of Nuclear Medicine, Princess MargaretHospital for Children, Perth 6008, Western Australia

PURPOSE: Childhood asthma is often treated with inhaled corticosteroids. Lung deposition of HFA-be-clomethasone dipropionate (BDP) extrafine aerosol(QVAR™) has been assessed in children after inhalationvia Autohaler™. AIM: Assess the total body depositionof 99mTc-QVAR™ in children, after inhalation via pMDI-spacer (Aerochamber PlusTM ). METHOD: 24 children (allmale; 5–17 years) with mild asthma, inhaled the labelleddrug (2–4 MBq). 12 children took 5 tidal breaths after eachactuation and 12 children used a slow maximal inhala-tion followed by a 5–10 s breath hold. Simultaneous an-terior and posterior planar images(120 s acquisition) wererecorded and attenuation factors were obtained using a99mTc transmission image. RESULTS: With tidal breath-ing, mean (SD) lung deposition (%ex-actuator, attenua-tion corrected) was 35.2 (18.7)%, 47.5 (13.0)% and 54.9(11.2)% in children aged 5–7(n � 4), 8–10(n � 4) and11–17(n � 4). Gastrointestinal deposition was 25.0(11.9)%, 10.3 (4.4)% and 10.1 (6.2)%. With the maximal in-halation technique, lung deposition was 58.1(6.7)%,56.3(5.4)% and 58.4(9.2)% and gastrointestinal depositionwas 12.9(3.3)%, 20.6(9.8)% and 20.8(8.8)%. CONCLU-SION: Lung deposition was significantly higher with themaximal inhalation technique compared to tidal breath-ing across all ages (p � 0.03). Inhalation via pMDI-spacershowed much lower gastrointestinal deposition after usethan inhalation via Autohaler™, regardless of inhalationtechnique applied.

P-72IN VITRO VALIDATION OF 99mTc- HFA-

FLUTICASONE PROPIONATE DELIVERED VIApMDI-SPACER(AEROCHAMBER PLUS™).

*CM Roller1 and SG Devadason1.

1. School of Paediatrics and Child Health, University ofWestern Australia, Perth, WA, 6008.

PURPOSE: HFA-fluticasone propionate (FP) is used forasthma therapy. Our aim was to validate that 99mTc acts asa suitable marker for FP, when delivered via pMDI-spacer.METHOD: Sodium pertechnetate was mixed with 5mL bu-tanone. 99mTc was extracted into butanone and transferredinto an empty FP canister. The 99mTc lined canister washeated, and the butanone evaporated to dryness. A super-cooled commercial FP canister was decrimped and the con-tents transferred to the 99mTc lined canister and recrimped.

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Particle size distribution of FP and 99mTc from 6 radiola-belled canisters was measured using an Anderson cascadeimpactor calibrated to 28.3 L/min, and compared to com-mercial FP. Drug (FP) content of each particle size fractionwas measured using UV spectrophotometry. 99mTc levelfor each fraction was measured using an ionization cham-ber. %Particles �4.7�m(respirable) and %99mTc from com-mercial and radiolabelled canisters were compared. RE-SULTS: Mean (SD)% FP respirable particles, before andafter label was 43.0(2.5)% and 43.7(4.0)%. Mean (SD)%99mTc in the respirable fraction was 41.7(4.9)%. CON-CLUSIONS: The mean %FP exiting spacer �4.7�m beforelabelling, was not significantly different to the mean % FPafter labelling (p � 0.05) . The mean % 99mTc for parti-cles � 4.7�m after radiolabelling was not significantlydifferent to the mean % FP levels (p � 0.05). Our valida-tion confirms that 99mTc acts as a suitable marker for HFA-FP, delivered via pMDI-spacer.

Funded By: Child Health Research Foundation of West-ern Australia

P-73DEPOSITION OF INFLUENZA VIRUS AEROSOL

PARTICLES IN MICE AND RATS: DIFFERENCE INANIMAL SUSCEPTIBILITY TO INFECTION

AS Safatov*, OV Pyankov, AN Sergeev, SA Kiselev, EI Ryabchikova, VS Toporkov, VA Yashin,

NM Belyaev, LN Shishkina, BN Zaitsev, AA Sergeev and VA Zhukov.

State Research Center of Virology and Biotechnology“Vector”, Koltsovo, Novosibirsk Region, Russia

The usage of targeted delivery aerosolized formula-tions which block virus replication for prevention andhealing of respiratory virus infections looks very promis-ing. One needs to know regions of viral aerosol particlesdeposition in respiratory tract and its susceptibility to in-fection for development of such formulations.

These characteristics were experimentally determinedfor influenza virus aerosol particles (diameter 3 micro-meters) for mice and rats with the help of early describedspecial set-up for study of particles of different nature de-position in laboratory animals’ respiratory tract.

The deposition coefficients of 3.0 micrometers aerosolparticles in mice and rats was determined. These coeffi-cients (%) are: for mice 2.6 � 0.2 for lung and 1.2 � 0.1 fortrachea and for rats 11.8 � 0.9 for lung and 3.2 � 0.2 fortrachea. The data obtained are in good agreement withthat presented in literature.

It was shown that for mice the probability of infectiousprocess development practically did not depend on theplace where virions deposited. For rats the probability ofinfection at the virus deposition in trachea was by an or-der of magnitude higher than at deposition in lungs.

Acknowledgements. The work was partially sup-ported by ISTC (project # 0450p).

P-74AN IN VITRO COMPARISON OF THE FUNHALER

TO COMMERCIAL SPACERS

Schaefer NC, Roller CM, Le Souëf PN and Devadason SG.

School of Paediatrics and Child Health, University ofWestern Australia, Subiaco, Western Australia, 6008

The Funhaler (FH) is a paediatric spacer that incorpo-rates incentive toys. Previous studies have shown that theFH improves compliance and administration technique tochildren. We compared the respirable drug delivery fromFH to commercial devices: Aerochamber Plus (AC�), Op-tichamber (Opt) and metered dose inhaler (pMDI).METHOD: Using salbutamol, fluticasone propionate andsodium cromoglycate (SCG), spacers (n � 5) were as-sessed in duplicate via cascade impaction (AndersenUSA). Drug content of each particle fraction was deter-mined by UV spectrophotometry. RESULTS: AC� deliv-ered a higher proportion of respirable salbutamol parti-cles than FH (p � 0.001), but respirable particle mass wasequivalent (p � 0.1). FH and AC� showed a higher salbu-tamol output than Opt and pMDI (p � 0.005). The pro-portion of respirable fluticasone and SCG from AC�, FHand Opt was no different (p � 0.05), but FH delivered ahigher mass (p � 0.001). All spacers had a higher res-pirable mass recovered for all drugs than pMDI (p �0.001). The total salbutamol and fluticasone output fromAC� was lower than all devices (p � 0.002). AC� had asignificantly lower MMAD for all drugs than all other de-vices (p � 0.001). There was no difference in FH and OptMMAD for all drugs (p � 0.1), but spacers had lowerMMADs than pMDI (p � 0.002). CONCLUSIONS: FH iscomparable to commercial spacers for delivery of salbu-tamol, fluticasone and SCG. All spacers delivered agreater respirable mass for all drugs than pMDI. Spaceruse considerably reduced particle size of the emittedaerosol for all drugs tested.

Funding: NHLBI/NIH

P-75EFFECT OF PATIENT SIMULATION ON

NEBULISERS OF VARYING OPERATINGPRINCIPLES

Schaefer NC* and Devadason SG

School of Paediatrics and Child Health, University ofWestern Australia, Subiaco, Western Australia, 6008

RATIONALE: Certain nebulisers rely on the patient’sinteraction to enhance drug output while others emit acontinuous aerosol independent of patient respiration.We assessed nebulisers of differing operating principlesin vitro, with and without patient respiratory simulation.METHODS: The Malvern Mastersizer X was used to de-termine the fine particle fraction (FPF) and volumetricmean diameter (VMD) for breath-assisted, open-vent neb-

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ulisers, LC Plus (LCP) and LC Star (LCS; Pari); open-ventpassive entrainment nebuliser, Sidestream (SS; Medic-Aide); and conventional jet nebuliser, Micromist (MM;Hudson RCI). Six of each model were tested in triplicate.Data was obtained from each nebuliser with no patientrespiratory simulation, and with adult (a respiratory flowof 30l/min), child (10l/min flow) and infant simulation(5l/min flow). RESULTS: The LCP and LCS showed a sig-nificantly higher FPF and a significantly lower VMDwhen applying the child and adult respiratory flow (p �0.005), but the infant simulation had no significant effect(p � 0.05). There was no significant effect of patient sim-ulation on the SS and MM. The MM showed considerablevariability in FPF (p � 0.006) and VMD (p � 0.005) com-pared to the LCP, LCS and SS.

CONCLUSIONS: Breath-assisted nebulisers require pa-tient simulation for accurate in vitro estimations of FPF andVMD for adult and child use. There was no significant ad-vantage to using active entrainment nebulisers in infantscompared to the passive entrainment nebuliser. Passive en-trainment and conventional jet nebulisers do not require pa-tient simulation for measuring FPF and VMD in vitro.

P-76INNOVATIVE OTSUKA DRY POWDER

INHALATION (ODPI) SYSTEM FOR PROTEINS,PEPTIDES AND NCEs

Chikamasa Yamashita* and Akituna Akagi

R&D, ODPI division, Otsuka Pharmaceutical, Co., Ltd.,224-18 Ebisuno Hiraishi Kawauchi-cho Tokushima

771-0182, Japan

The conventional dry powder inhalation system isbased on the preconception that the inhalant formulationmust be suitably pre-micronized during the manufactur-ing process. However, when we considered the essentialqualities of the inhalant, we realized that micronizationupon inhalation would be optimal. After intensive stud-ies of formulations, manufacturing methods and inhalers,we developed an innovative inhalation system for pro-teins, peptides and NCEs named ODPI System. ThisODPI system employs a freeze-dried cake, which at a mi-cro-level, has a unique mesh-like porous construction.When air flows into gaps in the mesh it causes immedi-ate breakdown of the mesh structure into fine particlessuitable for inhalation. This freeze-dried cake is definedby the disintegration index using n-hexane.

For example, the non-powder form freeze-dried cakesof IFN-alfa having a disintegration index of 0.002 or lesswere not disintegrated by the air impact arising throughan air speed of about 35m/sec and an air flow rate ofabout 40ml/sec, and hence it was not possible to makefine particles. On the other hand, the non-powder formfreeze-dried cakes of IFN-alfa having a disintegration in-dex of 0.077 or more were disintegrated by the air impactarising under the same conditions, becoming fine parti-cles of mass median aerodynamic diameter less than 5 mi-crons suitable for inhalation.

P-77COARSE CARRIERS, ACTIVE SITES AND STICKY

DRUGS.

Paul M Young & Robert Price

Pharmaceutical Technology Research Group, University ofBath, Bath, UK

A common approach to formulating dry powders forinhalation is to blend the respirable micronised drug ma-terial with larger inert carrier particles to form an orderedmix. The efficiency of liberating drug particles from thecarrier material (during inhalation) is of prime impor-tance, and especially significant when considering lowdose formulations. Here the authors investigate the rela-tionship between drug/lactose ratio and aerosolisationperformance of conventional carrier based formulations.A dose range of �10 to 450 �g of drug in a 50 mg lactosecarrier formulation was studied. Statistical differences inboth the fine particle dose and fine particle fraction wereobserved across the dosage range (ANOVA p � 0.05). Ingeneral, no statistically significant difference (FishersPairwise, p � 0.05) in fine particle dose was observed be-tween drug levels of approximately 10 �g and 135 �g,whereas a linear decrease in fine particle fraction was ob-served across the same drug level range (R2 � 0.977). In-creasing the dose from �135 �g to 450 �g resulted in astatistically significant increase in both fine particle doseand fraction (ANOVA p � 0.05). Such observations maybe attributed to the occupation of ‘active’ carrier sites bydrug particles at low drug concentration, since the quan-tity of drug particles liberated from the carrier duringaerosolisation remains constant at the lower dosingregimes.

P-78PATIENT FRIENDLY, HIGH DOSE DRY POWDER

INHALER FOR DELIVERY OF PUMACTANT INSEASONAL ALLERGIC ASTHMA

1Paul M Young, 2Joy Conway, 1Robert Price, 3Derek Woodcock

1Pharmaceutical Technology Research Group, University ofBath, Bath, UK

2School of Medicine, University of Southampton , UK3Britannia Pharmaceuticals Limited, 41-51 Brighton Road,

Redhill, Surrey, UK

Pumactant (Britannia Pharmaceuticals, UK) is a syn-thetic, protein-free surfactant containing the naturalphospholipids dipalmitoylphosphatidylcholine (DPPC)and unsaturated phosphatidylglycerol (7:3) that hasbeen formulated as a novel, micronised dry powder suit-able for inhalation. A laboratory allergen challenge sug-gested Pumactant protected asthmatic subjects againstearly phase allergen induced broncho-constriction. Thestudy involved delivery of two doses (each containingdoses of 100 mg) administered 8h and 0.5h prior to the

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challenge using a laboratory bench-top system. Subse-quently, a handheld delivery device capable of deliver-ing similar high doses to the patient was developed. Pa-tient actuation of the device releases pressurised medicalgrade gas (from a gas canister) into a vial containing asingle dose of micronised Pumactant. This facilitates theaerosolisation and displacement of the drug from thevial. The fluidised drug passes through a series of Ven-turi tubes and exits the device via a conventional mouth-piece as a slow velocity aerosol suitable for comfortableand controlled inhalation. In vitro evaluation of the de-vice suggested 37.2% � 3.0% Pumactant would pene-trate the lower airways (aerodynamic diameter �5�m)(loaded dose �120 mg). Such observations indicated animproved efficiency over both the bench-top clinical trialdevice (25%) and a conventional dry powder inhaler, Cy-clohaler (0%).

P-79PHARMACOKINETICS OF INHALED

MONODISPERSE BECLOMETHASONE AS AFUNCTION OF PARTICLE SIZE

JE Esposito-Festen1*, P Zanen2*, HAWM Tiddens1, J-WJ Lammers21

1Department of Pediatrics, Division of Respiratory Medicine,Erasmus Medical Center Rotterdam-Sophia, The

Netherlands. 2Heart Lung Center Utrecht, UniversityMedical Center Utrecht, The Netherlands

To achieve optimal efficacy anti-asthma drugs have tobe delivered to the desired region of the airways. To date,the optimal particle size for steroids in adults is notknown. Objective: to evaluate the pulmonary bio-avail-ability for inhaled beclomethasone dipropionate (BDP)aerosols. Method: In a randomized single-blind cross-over trial 10 mild asthmatic patients inhaled monodis-perse BDP-aerosols of 1.5, 2.5 and 4.5 �m. Gastro-intesti-nal absorption was blocked by activated charcoal. Plasmalevels of 17–beclomethasone monopropionate (17-BMP)were measured through liquid chromatography plusmass spectrometry. Results: Aerosols with MMAD of 1.5�m gave mean maximum concentrations (Cmax) and areaunder the curve (AUC) values of 17-BMP of 475 pg mL�1

and 825 pg h mL�1, respectively. For aerosols with aMMAD of 2.5 �m, Cmax and AUC were 1300 pg mL�1

and 2629 pg h mL�1, respectively. For aerosols with aMMAD of 4.5 �m, Cmax and AUC were 1161 pg mL�1

and 2276 pg h mL�1, respectively. The mean terminalhalf-time of 17-BMP for all three aerosol sizes was around1.5 hr. Conclusions: Monodisperse BDP aerosols with aMMAD of 1.5 �m gave 2–3 fold lower values for Cmaxand AUC than those with MMADs of 2.5 and 4.5 �m. Thelower systemic absorption could indicate a reduced prob-ability for systemic adverse effects.

GlaxoSmithKline provided financial support and sup-ported the analysis of the blood samples.

P-80DEVELOPMENT OF THE HUMAN LUNG

MEASURED BY AEROSOL-DERIVED AIRWAYMORPHOMETRY (ADAM)

KL Zeman* and WD Bennett

Center for Environmental Medicine, Asthma and LungBiology, University of North Carolina, Chapel Hill, NC

USA 27599

We measured, in vivo, the airspace calibers of thesmall airways and alveoli by ADAM in the lungs of chil-dren of ages 6 to 18 years and adults aged 18 to 80 years.ADAM utilizes the gravitational settling time of inhaledmonodisperse particles to infer the vertical distance tothe airway surfaces at sequential depths into the lung.Previously, we identified anatomical lung features,EADtrans and EADmin, associated with the caliber of thetransitional respiratory bronchioles and the alveoli, re-spectively, and VLDtrans, a measure of conducting air-way volume. In the current study we found that EAD-min increased with age from 6 to 22 years (p � 0.003,EADmin �m � 2.97(age years) � 166), which generallyaccounts for the increase in TLC observed over this agerange: TLC increased approximately with the thirdpower of EADmin (p � 0.001, TLC ml � 0.002(EADmin�m)2.7). EADtrans did not increase with age nor TLC, av-eraging 572 �m, but increased primarily with subjectheight (p � 0.03, EADtrans �m � 2.15(height cm) � 220).VLDtrans scaled linearly with lung volume (p � 0.001),but VLDtrans relative to TLC did not change with age,7.04 � 1.55%. The data indicates that lung volume en-larges by increasing the size rather than number of alve-oli after 6 years. Funded by USEPA Cooperative Agree-ment CR829522 but does not necessarily reflect EPApolicy.

P-81CHARACTERISTICS OF INSPIRATORY FLOW-

VOLUME CURVES IN ELDERLY SUBJECTS WITHAIRWAY OBSTRUCTION

Jinping Zheng1, Hua He1

1.Guangzhou Institute of Respiratory Disease, Guangzhou, China

Background: Inhalation capacity is one of the key is-sues when considering inhalation therapy. Objective: Toanalyze the inhalation profiles of elderly subjects and thecorrelation between the inspiratory flow and the expira-tory flow as well as the airway resistance, 60 subjects withbronchial asthma, 70 subjects with COPD and 30 normalsubjects were studied. The subjects were 50�79 years old(mean 62 years). Inspiratory flow at the first 150ml of in-spiratory volume (IF150), inspiratory flow at 10% and 20%of forced inspiratory vital capacity (IF10%FIVC), IF20%FIVC),peak inspiratory flow (PIF), area under curve of over30l/m and 60l/min in inspiration (AUC30 and AUC60),forced expiratory volume in one second (FEV1), and air-way resistances were measured. Results: IF150 were above

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0.5L/s in all subjects. IF was significantly related to theseverity of airway obstruction, with over 2L/s in thosewithout severe airway obstruction. Among all parametersin the inhalation curve, the sensitivity were highest inAUC30 and AUC60 (89% in both) the specificity werehighest in IF10%FIVC and IF20%FIVC (62.9%). The highest ac-curate parameter was IF20%FIVC, with the like-hood ratioof 2.31. There were good correlations between the para-meters of inspiration and expiration as well as airway’sresistances. Conclusion: IF20%FIVC was considered as thebest parameter in predicting the capacity of inspiration.The capacity of the inspiration can also be estimated byspirometry.

P-82INSPIRATORY FLOW IN VARY INHALERS

WITH DIFFERENT RESISTANCES

Jinping Zheng, Hua He

Guangzhou Institute of Respiratory Disease, First affiliatedhospital of Guangzhou Medical College, Guangzhou, China

Inhalation therapy is essential for the treatment of respi-ratory disease, however, the efficacy was influencedstrongly by the inspiratory flow (IF) and devices. To un-derstand the IF in elderly subjects when using commonlyused inhalers and the correlations between IF and spirom-etry as well as airway resistances parameters, 160 subjectsaged 50�79 years old (mean 62), (60 with bronchialasthma,70 with COPD and 30 normal subjects) were en-rolled. Peak inspiration flow (PIF) were measured withoutand with resistances, which mimic the internal resistancesof several inhalers, Diskhalar, Turbuhalar, Autohaler, andEasyhaler, by PIF meter (In-check DIAL). The resultsshowed that PIFs were vary in different inhaler devices,with the lowest PIF in Turbuhalar. All subjects can gener-ate adequate peak inspiratory flow rate with Diskhaler, au-tohaler or easyhaler. PIF higher than 60L/min were foundin all of normal subjects, 94.8% of asthma and 50% of COPDpatients. PIF higher than 60L/min could be generated by83.3% of subjects with mild airway obstruction, 81.8% withmoderate, and 57.1% with severe, respectively. There weregood correlations between the PIFs in different resistancesand parameters of inspiratory curve as well as ventilationfunction and airway resistance. In conclusion, the inspira-tion capacity is important for the patients with airway ob-struction before selecting inhalation devices by performingPIF test or spirometry test.

P-83IN VITRO TESTING OF THREE PROTOTYPE

I-neb™ ADAPTIVE AEROSOL DELIVERY DEVICESOPERATING IN TARGET INHALATION

MODE™, A NEW MODE OF OPERATION FOR AAD® DEVICES.

*Prince I, Barnes M, Dyche T, Hatley RHM.

Profile Therapeutics, a Respironics company. Heath Place,Bognor Regis, West Sussex, PO22 9SL, UK.

Target Inhalation Mode™ (TIM) is a new feature in-corporated into the I-neb™ AAD® (Adaptive Aerosol De-

livery) system, which is designed to improve the effi-ciency of aerosol treatment for respiratory patients. TIMguides patients to their optimal inhalation manoeuvre byanalysing each patient’s response to increasingly lengthy,restricted flow rate, inhalations. Visual and tactile feed-back is provided during each inhalation to encourage thepatient to attain their optimal inhalation length. The po-tential of TIM to increase lung deposition of aerosol andreduce treatment times has been investigated elsewhere1.We tested the ability of TIM to achieve the consistent dos-ing expected from an AAD system, using three I-neb pro-totype devices with a pre-set delivered volume (DV) of250�l. Each device was run in triplicate using threebreathing patterns recorded from an in vivo study inChronic Obstructive Pulmonary Disease1. Salbutamolmarker deposited on a filter inserted between the I-neband the MiMiC Breathing Emulator was analysed usingHPLC. Average DV was 236�l, with 96% of deliverieswithin �25% of the nominal DV, and 100% within �35%.We conclude that I-neb operating in Target InhalationMode offers the same reproducible dosing as predecessorAAD devices.

[1]Denyer J, et al. Adaptive Aerosol Delivery (AAD)technology. Expert Opin.Drug Del.2004;1(1):165–176.

Funded by Profile Therapeutics

P-84PERFORMANCE RESULTS OF A NEW, PORTABLEAEROSOL DELIVERY DEVICE COMPARED TO A

CONVENTIONAL JET NEBULISER

*Von Hollen D1, Lieberman E1, Dalby R2, Wu H2.

1. Respironics Drug Delivery, New Jersey, USA.2. University of Maryland, Baltimore, USA.

Direct Aerosol Delivery™ (Respironics Drug Delivery) isa new electronic aerosol generation technology thatpromises rapid and complete nebulization of respiratorymedications. Most patients receiving nebulized medicationare dosed by noisy jet nebulizers that require connection toa bulky compressor. Direct Aerosol Delivery technology isdesigned to yield a high Fine Particle Dose (FPD, fractionof emitted dose �4.7�m) with minimal residual volume,from a portable device that delivers medication directlyfrom its point of generation without any mediating parts inits path. We compared the time to sputter and FPD of a pro-totype, against that of a conventional jet nebulizer (PariLC�). The testing of each device was performed separately.In each test the device was loaded with albuterol inhalationsolution (2.5mg in 3ml) and run until sputtering occurred.Aerosol output was directed into a Marple Miller impactoroperated at 30 L/min. Drug recovered from the impactorwas quantified by HPLC.

The prototype generated a larger FPD and achieved afaster rate of delivery than the Pari LC� jet nebulizer.This performance from a highly portable advanced neb-

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ulizer could greatly increase the convenience of aerosoltherapy for respiratory patients.

Funded by Respironics Drug Delivery

P-85COMPARATIVE ANALYSIS OF DIFFERENT

SCINTIGRAPHIC METHODS TO ASSESSVENTILATION IN COPD

J Magnant1, D Grimbert1, L Vecellio-None1, M de Monte1, C Valat1, P Diot1.

1. INSERM U 618, IFR 135, CHU Bretonneau, 2 Bd Tonnellé, 37044 Tours cedex 9, France

Purpose: To analyze the 81mKr distribution and 99mTcaerosols (4.5 �m MMAD, Aeroneb pro, Aerogen, USA,and �0.2 �m MMAD, Technegas, Cyclopharma, France)deposition in comparison with ventilation measured by133Xe lungs scintigraphy. Method: 20 patients withCODP. Comparative analysis of the 81mKr distributionand the 99mTc aerosols deposition with the 133Xe distri-bution at equilibrium and clearance. Multivariate analy-sis of the correlations between the 81mKr distribution, theaerosols deposition and the respiratory parameters of pa-tients. Results: a predominant distribution of 81mKr inthe upper lobes in the more obstructive patients (p � 0.05)and a predominant deposition of Technegas in the lowerlobes in the less obstructive patients (p � 0.05) were ob-served. A predominant deposition of the 4.5 �m 99mTcaerosol in the central parts of the lungs was also demon-strated (p � 0.0001). Positive and negative predictive val-ues for the detection of ventilatory abnormalities revealedby 133Xe were respectively 0.54 and 0.58 for 81mKr and0.54 and 0.55 for Technegas. The 81mKr and Technegascentral distribution depended on airflow obstruction andthe 4.5 �m 99mTc aerosol central deposition on the ratioinspiratory volume/expiratory volume. Conclusion: inCOPD, lungs scintigraphies with 81mKr and 99mTcaerosols do not reflect exactly ventilation measured by133Xe.

P-86TRANSIENT SIZE CHANGES UNDERGONE BY

METERED-DOSE INHALER PARTICLES RELEASEDINTO HUMID AIRFLOW

AR Martin and WH Finlay*.

Mechanical Engineering, University of Alberta, Edmonton,Alberta, Canada T6G 2G8.

Humidification of air supplied during mechanical ven-tilation is known to greatly reduce the mass of drug de-livered to intubated patients. It is generally agreed thatin the presence of humidity, increased metered-dose in-haler (MDI) particle sizes enhance aerosol deposition ef-ficiencies in the ventilator circuit. We have recently per-formed studies to examine metered-dose inhaler (MDI)particle size changes in humid (�95% relative humidity[RH]), compared to dry (�10% RH), airflow at 37°C.

Particle size distributions from two commercial MDIs(Airomir® and Ventolin® HFA) were measured, by cas-cade impactor, at points downstream from an inline hold-ing chamber (Aerochamber®). At a distance of 15cm fromthe holding chamber exit, the aerosol mass median aero-dynamic diameter (MMAD) increased from 1.93 � 0.11 to3.72 � 0.05 �m for Airomir®, and from 2.01 � 0.09 to3.85 � 0.12 �m for Ventolin® HFA, with the addition ofhumidity to the entraining airflow. However, at 45 cmfrom the holding chamber exit, these differences de-creased due to decreasing particle sizes in humid air. Thatis to say, after an initial spike in size, MDI particles en-trained in humid air decreased in size towards values mea-sured in dry air.

We conclude that MDI particles act as condensation nu-clei in humid air. However, given sufficient time and ap-propriate conditions, condensed water may evaporateback into the entraining airflow.

Funding: Alberta Ingenuity Fund and the Natural Sci-ences and Engineering Research Council of Canada.

P-873-D SIMULATIONS OF AIRWAYS WITHIN

HUMAN LUNGS

*Martonen, T.,1 and Isaacs, K.1,2

1Experimental Toxicology Division, NHEERL, USEPA,Research Triangle Park, NC 27711 USA

2Department of Environmental Sciences and Engineering,University of North Carolina, Chapel Hill, NC 27599 USA

The fate of inhaled particles, and thus the targeted de-livery of inhaled pharmacological drugs, may be for-mulated using three families of variables: respiratorysystem morphologies, aerosol characteristics, and ven-tilatory parameters. PURPOSE: We propose that theseminal role is played by morphology, because thestructures of the airways and their orientations withinlungs affect the motion of the air and the trajectories oftransported particles. METHODS: We have previouslydeveloped algorithms to describe airway networks andemployed them as templates to interpret single photonemission computed tomography (SPECT) images. Wehave now advanced the simulations to produce three-dimensional (3D) images. RESULTS: We have tested thenew in silico model by studying an inclusive (all airwayspresent) system and a single “typical” pathway system.When viewed with 3D glasses, the 3D nature of airwaybranching networks within lungs, as displayed via ouroriginal computer graphics software, is clear. CON-CLUSIONS: We submit that the new technology willhave numerous functions in future medical and toxico-logical regimens, including the creation of a platform toassociate natural structures with related biologicalprocesses (e.g., disposition of inhaled pollutants orpharmaceuticals). [Disclaimer: This is an abstract of aproposed presentation and does not necessarily reflectEPA policy. K.K. Isaacs is supported by NHEERL-UNCDESE Agreement EPA CT826513]

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P-88LEFT TO RIGHT ASYMMETRY OF LUNG

DEPOSITION AFTER SHALLOW AEROSOL BOLUSINHALATION IS AN EFFECT OF LUNG

VENTILATION

W. Moeller1*, K. Felten1, K. Haeussinger2, G. Meyer2, J. Seitz3, W.D. Bennett4, W.G. Kreyling1,

and G. Scheuch3

1GSF—Institute for Inhalation Biology, 2Asklepios Clinic forRespiratory Medicine, 3Innovations in Aerosol Medicine,

Gauting, Germany, 4University of North Carolina,Department of Medicine, Chapel Hill, NC, USA; email:

moeller@gsf.de

After shallow bolus inhalation of radiolabelledaerosols, gamma camera imaging has shown a left-rightasymmetry, with a higher fraction of particles in the leftlung. It was not clear, whether this phenomenon was aneffect of lung ventilation or of aerosol deposition.

Lung ventilation was studied by 81m-Kr-gas inhalationand gamma camera imaging in 20 healthy subjects. 100mL81m-Kr-gas boli were administered to the phase1 and tothe Fowler dead space volume, respectively. In addition,single breath inhalation of 1L 81m-Kr-gas was performed.Subjects also inhaled 100mL boli of 100nm 99m-Tc la-belled carbonaceous particles with shallow and deep pen-etration.

The single breath 81m-Kr-gas inhalation revealed asimilar activity distribution over the left and rightlungs, according to their respective volumes (L/R-ra-tio � 0.83�/�0.03; mean�/�SE). In contrast the shal-low bolus inhalation of 81m-Kr-gas revealed more ac-tivity in the left lung (L/R-ratio � 1.25�/�0.15). Thissame left-right asymmetry was observed for the carbonaerosol distribution after shallow bolus inhalation(L/R-ratio � 1.36�/�0.10). The data show that theasymmetry in aerosol deposition seems to be an effectof lung ventilation. The reason for this asymmetry is un-clear.

P-89IMPAIRED PARTICLES CLEARANCE FROM THE

AIRWAYS DURING AIRWAY INFECTION AND INPCD PATIENTS AFTER SHALLOW BOLUS

INHALATION

W. Moeller1, K. Haeussinger2, L. Ziegler-Heitbrock2,and J. Heyder1

Clinical research group ‘Inflammatory Lung Diseases’ of the 1GSF-Institute for Inhalation Biology and the

2Asklepios Clinic for Respiratory Medicine, Gauting, Germany, email: moeller@gsf.de

Ferromagnetic particles with 1.9 �m geometric (4.2�m aerodynamic) diameter were inhaled by 14 healthynon-smokers, 7 healthy non-smokers during an acuteairway infection, and by 7 patients with primary ciliarydyskinesia (PCD), using the shallow bolus technique.The aerosol penetration was confined to the phase1

dead space. Deposition was enhanced by an eight sec-ond breath holding. Clearance was measured by themagnetopneumographic method over a period of 9month.

In healthy subjects particle clearance showed twophases: about 50% of the deposited particles were clearedrapidly (half-time 3.0�/�1.6 hours) due to mucociliarytransport. The remaining fraction was cleared with a halftime of 109�/�78 days. During an acute airway infec-tion clearance was impaired, only 30% of particles wererapidly clearance (half-time 6.1�/�7.1 hours), and thelong term clearance was not different from healthy sub-jects. In PCD patients the fast clearance phase was de-layed. 46% of the particles were cleared with a half-timeof 16.3�/�8.3 hours. After one week the retention over-lapped with the healthy subjects. Acute AW infection andPCD show impairment of airway clearance, which is re-versible within weeks in patients with AW infection. Thelong-term phase of airway clearance was not influencedby ciliary dysfunction.

P-90MODELING OF AEROSOL PARTICLES

DEPOSITION IN ORO-PHARYNGEAL REGION OFUPPER AIRWAYS DURING REALISTIC

UNSTEADY INSPIRATION.

A. Moskal, L. Gradon, T. R. Sosnowski

Department of Chemical and Process Engineering, WarsawUniversity of Technology, Warsaw, Poland

INTRODUCTION: Information about temporary andspatial distribution of deposited aerosol particles inoro-pharyngeal region during the inspiration is veryimportant for aerosol therapy. This allows us to designthe treatment, which minimizes the undesirable depo-sition of the drug in the mouth, throat and pharyngealregion.

METHOD: Based on the CT-image obtained for anadult male, the numerical 3D model of oro-pharyngealregion was implemented into the CFD package FLUENT.The CFD allowed us to calculate the airflow conditions inoro-pharynx during inspiration, as well as the corre-sponding aerosol deposition in this region. Two differentbreathing curves were used: fast-deep and slow-weakbreath. The calculations were carried out for aerosol par-ticles with diameters: 0.3, 1, and 10 �m.

RESULTS: The temporary and spatial distributions ofaerosol deposition in the oro-pharynx were obtained.For the smallest particles the highest deposition was re-ported in the beginning and in the end of the inspira-tion. The spatial distribution shows the rather equalcoverage with intensification in the anterior region. Forthe largest particles the temporal distribution during in-spiration is almost uniform. The spatial distribution ofdeposited matter concentrates in the palate region. Theresults show that the aerodynamic conditions during in-spiration strongly influence the deposition process, andshould be taken into account instead of time-averagedflows.

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P-91MORPHOMETRIC AND MICRODOSIMETRIC

MEASUREMENTS, IN METHACHOLINE-EXPOSEDA/J, Balb/c, AND B6C3F1 MICE, IDENTIFY

DIFFERENCES THAT HAVE IMPLICATIONS INDETECTION OF ASTHMA SUSCEPTIBILITY.

*O Moss1, M DeLorme2, and M Oldham3

1. CIIT Centers for Health Research, RTP, NC,27709–2137, USA

2. DuPont Haskell Lab, Newark, DE, 19714–0050, USA3. University of California, Irvine, CA 92697–1825, USA

Previous research, with B6C3F1 and BALB/c mice ex-posed to aerosolized methacholine, demonstrated thatdifferences in airway reactivity, based on changes in air-way resistance, are due to dosimetry within the respira-tory tract. It was also demonstrated that these differencescould be used to calculate airway morphometry of themouse strains. We extended these observations to the A/Jmouse: Replica lung casts were prepared in situ; Airwaymorphometry was performed on generations 1–6; Awhole-body plethysmograph was used to measure air-way resistance; And, a published aerosol dosimetry com-puter code was used to predict methacholine deposition.For the A/J, BALBc and B6C3F1 mice, two variables wereincorporated into the dosimetry calculations: ventilationrates at 50, 100, and 150 ml/min; and particle diametersfrom 0.1 to 10 microns. The A/J mice were most sensitiveto methacholine; yet the A/J and the B6C3F1 mice hadsimilar predicted deposition efficiency. The dosimetry ofmethacholine implied that either A/J mice have a mole-cular-based pulmonary hypersensitivity or, compared tothe B6C3F1 mice, their airways, during normal breathing,are held at a higher state of constriction. This work sug-gests that similar measurements may distinguish types ofasthma susceptibility.

P-92CHARACTERIZATION OF TWO DEVICES FOR

THE INHALATION OF COLISTIN

B Müllinger1, K Sommerer2, O Pechtold2, G Scheuch1

1Inamed GmbH, 35285 Gemünden2Inamed Research GmbH & Co. KG,

82131 Gauting, Germany

The inhalation of Colistin is an important interventionin the therapy of patients with cystic fibrosis. In order toimprove inhalation of Colistin, it has been proposed toperform inhalations with controlled breathing patternsusing the AKITA inhalation system. In this in-vitro study,a conventional nebulizer (PARI LC PLUS plus TURBOBOY N compressor) was compared with the controlledinhalation using the PARI LC STAR plus AKITA com-pressor.

Particle size distribution was measured using laser dif-fraction (Helos, Sympatec). Emitted dose was captured bya filter adapted at the mouthpiece. Amount of radiola-beled Colistin was detected by a scintillation counter. Aslow and deep breathing pattern (tidal volume: 1.0 l, flowrate: 0.2 l/sec, clean air at end of inspiration: 0.15 l) was

used for the AKITA and a typical pattern performed bya breath simulator (tidal volume: 0.5 l, 15 breath/min)was used for the PARI BOY. Lung deposition was calcu-lated using the ICRP model.

Results: In-vitro measurements and deposition calcula-tions.

Using optimized and controlled breathing patternsopens the opportunity to reduce the drug amount filledinto the nebulizer for future products.

P-93IMPROVED PULMONARY DEPOSITION FROM A

NOVEL ELECTRONIC-MESH NEBULISER

SP Newman1*, GR Pitcairn1, A Gee-Turner2

and K Asai3.

1. Pharmaceutical Profiles Ltd., Nottingham, UK2. Omron Healthcare Ltd., Milton-Keynes, UK

3. Omron Life Science Corporation, Kyoto, Japan

The MicroAir NE-U22 nebuliser (Omron Healthcare) is anovel battery-operated electronic-mesh nebuliser. Its designmay permit the use of smaller volume fills than those in jetnebulisers. Lung deposition of placebo solution has beencompared from the MicroAir and from a Pari LC Plus jetnebuliser, using gamma scintigraphy. Six patients withchronic obstructive lung disease (COPD, 2 males, 4 females;aged 57–82 years; forced expiratory volume in one second43–119 % predicted) inhaled 0.9% saline labelled with theradiopharmaceutical 99mTc- DTPA (diethylene triaminepenta-acetic acid) from each nebuliser on different days (0.5mL volume fill for MicroAir; 2.5 mL volume fill for LC Plus).The MicroAir was triggered to deliver aerosol only duringthe inhalation phase of breathing; the LC Plus nebuliser wasoperated continuously. Mean (SD) lung deposition was 18.1(8.0) % of the nebuliser fill for the MicroAir, compared with6.4 (2.8) % for the LC Plus (P � 0.05). The dead volumes ofsolution retained in the nebuliser averaged 0.3 mL for Mi-croAir and 1.7 mL for LC Plus. In addition to its good drugdelivery characteristics, the MicroAir offers several advan-tages for nebuliser therapy: it works efficiently using onlysmall volume fills, and is portable, compact, lightweightand silent. These advantages should enhance patient com-pliance with nebuliser therapy.

The study was funded by Omron Healthcare.

P-94NANOMEDICINE AND NANOTOXICOLOGY—

NEW FRONTIERS FOR AEROSOLS IN MEDICINE

G Oberdörster*

University of Rochester, Dept. of Environmental MedicineRochester, NY, USA

Nanotechnology is defined as research and technologydevelopment at the atomic, molecular or macromolecular

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levels, in the length scale of �1–100 nm range. One of themany promising applications of engineered nanoparticles(NP) is in the area of medicine, for example, targeted drugdelivery as aerosols and to tissues which are difficult toreach. The discipline of nanomedicine has arisen to de-velop, test, and optimize these applications. However, thesame properties that makes NP attractive for develop-ment in nanomedicine and for specific industrialprocesses could also prove deleterious when NP interactwith cells. An emerging discipline – nanotoxicology,which can be defined as safety evaluation of engineerednanostructures and nanodevices, is gaining increased at-tention. Nanotoxicology research will not only provideinformation for risk assessment of NP based on data forhazard identification, dose response relationships andbiokinetics but will also help to advance further the fieldof nanomedicine by providing information to alter unde-sirable NP properties. This presentation summarizes re-sults of studies with nano-sized particles with a focus onthe respiratory tract as portal-of-entry. Results demon-strate that their highly desirable properties, which makesthem attractive as medicinal aerosols, as well as their po-tential to induce toxicity, depend not only on their sizebut on a variety of surface properties. To establish theprinciples which govern nanoparticle-cell interactionswill be a major challenge for the field of Aerosols in Med-icine.

P-95CORTICOSTEROID (ICS) AND LONG-ACTING � AGONIST (LABA) DELIVERY BY A NOVEL

DRY POWDER INHALER (DPI)

*J-A Penton1, M Doorbar1 and C Townsend2

Innovata Biomed Ltd, The Respiratory Division of MLLaboratories PLC, St. Albans1, Al1 3HW, and Tewkesbury2,

GL20 8NB; UK

The C200 is a new DPI for the delivery of combinationtherapy. The device design incorporates separate storageof two drug blends, separate metering of the typicallyhigh ICS and low LABA doses, and simultaneous but sep-arate delivery of the two drugs. Studies with develop-ment blends have demonstrated consistent delivery ofboth types of drug through the life of the inhaler, and inline with regulatory requirements. Mean delivered dosesfor each drug formulation are close to target, with indi-vidual doses within �/�25% of the mean for both ICSand LABA. Device design also supports delivery of lowand high doses of ICS using the same blend by changingthe size of the dose metering element. Mean delivereddose for the low and high dose ICS are 87 �g (7mm3 dosemetering element) and 173 �g (14mm3 dosing element),respectively, giving a low:high dose ratio of 0.5 and fineparticle delivered dose ratios (determined by AndersenCascade impaction) are in the range of 0.5–0.7. Relativeflow independence of delivery and dispersion perfor-mance have been established at a range of pressures dropsacross the device. The C200 represents a robust and con-sistent DPI platform for combination therapy.

Funded by Innovata Biomed Ltd

P-96USE OF THE NEXT GENERATION

PHARMACEUTICAL IMPACTOR FOR PARTICLESIZE DISTRIBUTION MEASUREMENTS OF LIVE

BIOLOGICAL AEROSOLS

Kitty Leung1*, Emily Louca1, Michael Gray2, Graham Tipples2, Allan L. Coates1

1Division of Respiratory Medicine, Hospital for SickChildren, Toronto, Ontario, CANADA. 2National

Microbiology Laboratory, Health Canada, Winnipeg,Manitoba, CANADA

Currently there are no standardized techniques for mea-suring the particle size of live biological agents. This studyevaluated the Next Generation Pharmaceutical Impactor’s(NGI) ability to measure the particle size distribution oflive measles vaccine from the IPI nebulizer used duringmass immunization campaigns. Albuterol aerosolized us-ing a Pari LC Star acted as a control since it is soluble andevenly distributed throughout the droplets, thereforelaser diffraction (LD) measurements should agree withthose from the NGI as long as the NGI is cooled to pre-vent heat transfer to the aerosol. Albuterol was also usedas a control for the IPI using quantitative ultraviolet spec-trophotometry. Studies with albuterol showed closeagreement in MMD (mean � 95%CI) for both the LC Starmeasured by LD (3.24 � 0.06 �m) and NGI (2.93 � 0.22�m), and for the IPI (4.55 � 0.14 �m and 4.4 � 0.25 �m,respectively). Studies for the measles vaccine assayed forplaque forming units showed significant differences be-tween NGI MMD (6.14 � 0.39 �m) versus LD (4.95 � 0.16�m) indicating that the vaccine is not evenly distributedamong the droplets of various sizes. This is likely clump-ing of the virus due to gelatin in the formulation. Thesedata indicate that the NGI is capable of particle sizing livebiological agents.

Supported in part by the World Health Organization

P-97THE PULMONARY DOSE OF ADENO-

ASSOCIATED VIRUS (AAV) VECTOR FOR LUNGGENE THERAPY IN CYSTIC FIBROSIS (CF)

ASSOCIATED WITH IMPROVEMENT IN LUNGFUNCTION.

AL Coates1*, K Munson2, K Leung1, E Louca1, P Anklesaria2

1Hospital for Sick Children, Toronto, Canada2Targeted Genetics, Seattle, WA, USA

An AAV vector to transfer cystic fibrosis transmem-brane regulator in CF patients was associated with a 5%improvement in lung function measured by FEV1 (Chest125:509,2004). The delivery system was a compressor

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driven Pari LC Jet nebulizer activated on inspiration bythe AutoNEB, with an operator set inspiratory time (IT).If complete synchronization of IT occurred, the devicefunctioned as a breath-actuated/breath-enhanced neb-ulizer. Dis-sychronization resulted in the nebulizer pro-gressively performing like a breath-enhanced device.Characterization of the system involved determiningthe rate of output and particle size distribution, whichwas measured by inertial impaction using the Next Gen-eration Pharmaceutical Impactor (NGI). Algorithms foroutput in both the respirable fraction (RF) (�5 �m) andtotal were created in relation to patient flow. Using flowtracings from four patients with CF, expected pul-monary deposition was calculated. The expected per-cent deposition of the initial charge during completesynchronization of IT was 47 � 0%, and 26 � 1% for anIT equal to the entire respiratory cycle. Based on an ini-tial charge of 1.2 � 1013 of deoxyribonuclease-resistantparticles (DRP), the pulmonary dose resulting in the im-provement in FEV1 varied between 5.6 � 1012 and 3.1 �1012 DRP. These data can be used in the design of sub-sequent trials to allow better estimates of the effectivedose required.

Supported in part by Targeted Genetics

P-98LUNG GENE THERAPY DELIVERY

WITH AN INTERTRACHEAL MULTILUMENCATHETER IN RABBITS

K Leung*, E Louca, DR Koehler, H Frndova, P Ng, JHu, AL Coates

Research Institute of the Hospital for Sick Children, Toronto,Ontario, Canada

This study used a multilumen catheter to deliver lunggene therapy products to large animals. Adult rabbitswere intubated with a 3.5 ETT through which a 1 mmdiameter multilumen catheter (AeroProbe*INC) was in-serted and used to deliver helper-dependent adenoviralvector (HD-Ad) expressing the â-galactosidase gene. Thecentre lumen contained the HD-Ad solution, and theoutside lumens carried high pressure air that aerosolizedthe HD-Ad. The MMD measured by laser diffraction was13 �m. The aerosolized HD-Ad was administered aspulses of air equivalent to the tidal volume of the rab-bit. Lung compliance and resistance were measured be-fore and after administration, and at five days using theMead-Whittenberger technique. Post sacrifice the lungswere removed and stained with X-gal to detect �-galac-tosidase. Pre, post and 5 day values for compliance andresistance were1.85 � 0.62, 1.31 � 0.88 & 1.91 � 0.84mL/cmH2O/kg, and 0.037 � 0.13, 0.53 � 0.024 &0.020 � 0.012 cmH2O/L/sec, respectively (p � 0.05 preversus post, n � 5). Gene expression at 5 days was seenin the proximal and distal airways, with the majority ofepithelial cells in the right lung showing expression inairways as small as the terminal bronchioles. We con-

clude that the AeroProbe*INC is an effective way to de-liver lung gene therapy products in large animals, andHD-Ad is very efficient at gene transfer to multiple lungepithelial cell types.

Supported in part by the Canadian Cystic FibrosisFoundation

P-99NANOSCALE CHARACTERISATION AND

MODELLING OF DRUG PARTICULATEINTERACTIONS

Davies M J*1, Brindley A2, Chen X1, Doughty S W1,Marlow M2, Roberts C J1 and Shrubb I2

1LBSA, School of Pharmacy, University of Nottingham,University Park, Nottingham, NG7 2RD, UK

2AstraZeneca, Bakewell Road, Loughborough, Leicestershire,LE11 5RH, UK

Purpose

This study aims to quantitatively estimate characteris-tics of inhaled drug particles, such as work of adhesion(WA), free energy (�) and Young’s modulus (E), by inte-grating atomic force microscopy (AFM), molecular mod-elling (MM) and inverse gas chromatography (IGC). Theproperties and dynamics of simulated pulmonary surfac-tant are investigated using Langmuir-Blodgett (LB) tech-nology. The approaches are combined to examine drugparticle—pulmonary surfactant interaction.

Method

AFM was used to acquire WA, � and E values for drugparticles against model substrates. IGC was applied to es-timate � and MM to establish drug molecule interactionregions. LB was utilised to prepare isotherms and filmsof Survanta®, a surfactant replacement, at various pres-sures. AFM was applied to image and conduct force workon the films.

Results

The IGC � result was 68.5mJm�2, comparable to AFManalysis. MM data illustrated regions of interaction be-tween the drug molecule and substrate ‘probe groups’.LB isotherms and AFM images show a relationship be-tween pressure and film structure. AFM measured forcesof interaction between inhaled particles and Survanta®films.

Conclusions

This multidisciplinary strategy provides a quantitativeand qualitative understanding of the formulation issuesgoverning the nature and efficacy of inhaled particle—pulmonary surfactant interaction.

Funding: Nottingham University & AstraZeneca

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P-100AEROSOL DEPOSTION IN THE UPPER AIRWAYS

OF A YOUNG CHILD

F.H.C. de Jongh1,2,3*, M. Rinkel1and H.W.M. Hoeijmakers1

1. Engineering Fluid Dynamic, University of Twente,Enschede, The Netherlands

2. Neonatology, Acadamic Medical Centre, University ofAmsterdam, The Netherlands

3. Lungfunction Lab, Medisch Spectrum Twente hospital,Enschede, The Netherlands

PurposeAerosol administration to infants results in very low

lung deposition in which the upper airways play an im-portant role. In the past H. Janssens has performed aerosoldeposition measurements with an anatomical model(SAINT) based on the CT-scan data of a child. We triedto verify these results with a computational fluid dy-namics package (CFX).

MethodTo verify CFX, a bend pipe with a plug velocity profile

and a horizontal pipe with a parabolic velocity profilewere investigated to test inertial impaction and sedimen-tation. The upper airways were modelled with 330.000tetrahedral elements.

ResultsIn the two test cases deposition fractions for 3 and 5 mi-

cron particles were correctly calculated. For 1 micron theerror in the velocity generated by CFX gets the same or-der as the terminal settling velocity, thereby yielding in-accurate results. Calculated upper airway deposition with3.7 micron particles resulted in experimentally compara-ble values for low flow rates, but gave till 50% lower re-sults for higher flow rates.

ConclusionsAt low flow rates computational results matched ex-

perimentally measured aerosol deposition, but large de-viations where found for higher flow rates. Most proba-bly inertial effects due to turbulence might not correctlybe calculated in this complex geometry.

P-101ESTIMATION OF PEAK INSPIRATORY FLOW

RATES (PIFR)

Mark DeLong and Craig Dunbar

Alkermes, Inc., Cambridge, MA 02139, USA.

Introduction: Dry powder inhalers (DPIs) vary in theirresistance to air flow. Comparing the dose delivery char-acteristics of different DPIs can be difficult because of therelationship between inhaler resistance (R) and inspira-tory flow (Q). Testing DPIs using a pressure gradientmodel (P � R2Q2) or power model (P � R2Q3) have beenproposed. The purpose of this study was to determine thebest model for estimating PIFR and to define constantsrepresenting different patient populations.

Methods: PIFRs through various resistances in healthy,COPD and cystic fibrosis (CF) patients were used to ob-tain non-linear least square fits for the power and pres-sure gradient models (Sarinas et al., Chest, 114, 988–992,1998). Model suitability (goodness-of-fit) was measuredusing the Model Selection Criteria (MSC), a maximumlikelihood estimate based on the Akaike Information Cri-terion. An increase in the MSC value represents an im-provement in the goodness-of-fit.

Conclusions: The power model provided a better esti-mate of PIFR relative to the pressure gradient model. Thepower representing healthy, COPD and CF patient pop-ulations were estimated.

P-102SIZING NEBULIZED AEROSOL USING NGI AND

Marple298 IMPACTORS

Dennis JH* & Pieron CA

University of Bradford BD7 1DP, UK.

European Standard EN13544-1 specifies methods tosize nebulized aerosol using Marple 298X cascade im-pactor sampling air from a 15 L/min flow. The drug in-dustry’s Pharmacopoeias’ long established test methodsfocus on pMDI and DPI using higher simulated inhala-tion flows (30–60 L/min). Pharmacopoeia methods are in-appropriately applied to nebulized aerosol as higherflows cause excessive evaporation from nebulizeddroplets. The New Generation Impactor (NGI) was de-veloped to replace Pharmacopoeia reliance on dated im-pactors. With a view to simplify all aerosol testing, theNGI has been recently calibrated at 15 L/min. We havemeasured nebulized aerosol size from the NGI andMarple impactors using a Sidestream jet nebulizer (6L/min, open venture) nebulizing a solution (2.5% NaF)and suspensions of budesonide (0.125 & 0.25 mg/ml Pul-micort).

Shape of particle distributions were similar. Resultsfrom NGI showed a 5–10% drop in MMAD compared toMarple. We believe this is due more to excessive evapo-ration within NGI than any inherent difference in accu-racy of particle size determination. Whether this error canbe compensated or can be ignored deserves further in-vestigation. Evaluation of paired data shows both Marpleand NGI can distinguish subtle differences in drugaerosol formulation.

Funding: Breath Ltd

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P-103FACTORS INFLUENCING EPI-hNE4 AEROSOL

DEPOSITION IN CYSTIC FIBROSIS

M de Monte1, D Grimbert1, C Valat1, L Vecellio None1,JC Dubus2, E Boissinot1 and P Diot1.

1. INSERM U618, IFR 135, Faculté de médecine, CHUBretonneau, Tours, France

2. Hôpital Timone, Marseille, France

The aim of the study was to verify if an aerosol pul-monary deposition of EPI-hNE4, a high affinity proteininhibitor of human neutrophil elastase (HNE), can be ob-tained and quantified in CF patients and to establish thecorrelation between pulmonary deposition and patient’spulmonary function. A 3 ml solution of radioactive EPI-hNE4 was nebulized with a Pari LC Star jet nebulizer(MMAD � 1.4�m) in 9 patients among whom differentrespiratory parameters were recorded. Aerosol depositedin the different parts of the lungs was quantified bygamma imaging and expressed as a percentage of nebu-lizer charge. The results showed that: 1) about twenty per-cent of the EPI-hNE4 charged in the nebulizer was de-posited in the lungs 2) the total deposition correlated withpreserved values in term of FEV1, FVC and FEF 25–75%,3) deposition in the lungs correlated with a preserved VC,4) the higher values in term of FEV1, FVC, FEF 25–75%and FEV1/FVC were associated with upper lung deposi-tion whereas these lower values were associated with cen-tral deposition.

These data are in agreement with previous data foundin CS with aerosolized antibiotics and DNase.

P-104CANADIAN STANDARDS ASSOCIATION

STANDARD Z264.1-02:2002: A NEW VOLUNTARYSTANDARD FOR SPACERS-HOLDING CHAMBERS

USED WITH pMDIs

Dolovich MB1*, Mitchell JP 2.

1McMaster University, Hamilton, Canada and 2TrudellMedical International, London, Canada

A Canadian Standard (CAN/CSA/Z264.1–02:2002) totest spacer-holding chambers (S-HC) used by asthmat-ics and COPD patients was drafted under the sponsor-ship of the Canadian Standards Association. Support indeveloping the standard was enlisted from pharma-ceutical companies and manufacturers of S-HCs, as wellas clinicians, retail pharmacists and representatives ofinterest groups advocating for patients with respiratorydiseases. Advice was sought from expert groups out-side of Canada to ensure that the standard would berelevant internationally. The purpose in developing thisstandard was to ensure the safety, efficacy and func-tionality of S-HC products used with pMDIs. Tests ofrobustness of device construction and integral compo-nents, tests to establish in vitro efficacy at constant flowand recommendations for marking and labeling the de-vice and its associated packaging are outlined. A seriesof formulas are defined that benchmark S-HC perfor-mance (emitted dose, fine particle- and extra-fine par-

ticle doses) to that of the pMDI alone. Additionally, sim-ulation measurements are detailed for 5 differentbreathing patterns to assess drug delivery from the HCwhen patients coordinate actuation of the pMDI into theHC with inhalation of the spray, compared to when notcoordinated. Whereas monographs in the pharmaceuti-cal compendia and guidance documents published byregulatory bodies provide information that is largely directed at the drug product and inhaler, this is the onlystandard whose focus is primarily on these add-on devices.

P-105IMPROVING DELIVERY EFFICIENCY OF

AQUEOUS CORTICOSTEROID SUSPENSIONSUSING ELECTRONIC MICROPUMP TECHNOLOGY

Bosco, AP and Dolovich, MB*

Department of Medicine, McMaster University, Hamilton,Ontario, CANADA

Delivery efficiency of aqueous suspension (ASP) for-mulations via conventional jet nebulization is inefficient.Delivery efficiency of three ASPs and one aqueous solu-tion (ASL) were compared using a device incorporatingelectronic micropump (EMP) technology, which may re-sult in more efficient ASP delivery.

The Aerodose 5.7 EMP inhaler (AD; Aerogen Inc., USA)was used to deliver three ASPs, human serum albuminmicroaggregates (MIA, 0.75 mg/ml, Firestone ResearchAerosol Laboratory); budesonide (BUD, Pulmicort® Re-spules, 0.5 mg/ml, AstraZeneca, CAN); fluticasone pro-pionate (FP; Flixotide®, 0.25 mg/ml GSK, UK) and asalbutamol sulphate ASL (SS, Ventolin® Respirator Solu-tion in 0.9% saline, 1.25 mg/ml; GSK). The COMPAS®Breath Simulator was used to simulate a slow deepbreath/breath-hold manoeuver (Vt: 2000 ml, 5 bpm).Emitted mass of aerosol was captured on absolute filtersplaced distal to the mouthpiece of the AD.

Emitted mass to the mouth (% nominal dose) was asfollows: SS (84.08 (3.63)%) � MIA (75.26 (5.33)%) � FP(73.93 (7.69)%) � BUD (47.49 (9.07)%). SS was signifi-cantly more efficient than each ASP (p � 0.001); FP &MIA were significantly greater than BUD (p � 0.001).Emitted mass of each ASP had greater variability (SD �5%) than SS.

Aerosolization of ASPs using EMP technology is for-mulation dependent. EMP technology might be an idealdelivery system for corticosteroids and other drugs thatare being reformulated as ASLs rather than ASPs.

Funded by Aerogen, Inc.

P-106IN VITRO CHARACTERIZATION OF THE AIR®

HIGH DOSE PULMONARY DELIVERY SYSTEM ATLOW FLOW RATES AND LOW VOLUMES.

Colleen Ellwanger and Mark DeLong

Alkermes, Inc., Cambridge, Massachusetts, USA.

Introduction: Delivering large lung doses to patientswho generate low inspiratory flow rates and volumes (e.g.

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children, elderly, COPD and CF patients) through passiveDPIs can be difficult to achieve because the patients’ in-spiratory efforts provide insufficient energy to effectivelydisperse and emit the powder. The purpose of this studywas to evaluate the in vitro dose delivery characteristicsof an AIR high dose pulmonary delivery system at lowflow rates and low volumes.

Methods: An inhaled therapeutic protein formulationwas spray-dried to produce a low density powder. Size00 capsules were filled with approximately 20 mg ofpowder and placed in a simple, passive DPI of high re-sistance (�0.18 cmH2O1/2/(L/min)). Emitted doses wereobtained over a range of flow rates (15–28.3 L/min) andvolumes (0.35–0.5 L). Fine particle fractions less than 3.3microns (FPF) were obtained using a 3–stage Andersencascade impactor at 28.3 L/min and 2 L.

Results: The mean emitted dose over the entire rangeof flow rates and volumes was 89% of the filled dose witha CV of 8%. The mean FPF of the filled dose at 28.3 L/minwas 56% with a CV of 6%.

Conclusions: The AIR high dose pulmonary deliverysystem produced repeatable emitted doses and high fineparticle fractions at low flow rates and volumes, demon-strating the potential to consistently deliver high lungdoses to patients with low inspiratory flow rates and vol-umes.

Funding: Alkermes Inc., Cambridge, MA & Eli Lillyand Co., Indianapolis, IN

P-107DISEASE-SPECIFIC STOCHASTIC MODEL FOR PARTICLE DEPOSITION IN CYSTIC

FIBROSIS LUNGS

R Sturm, R Winkler-Heil and W Hofmann*

Division of Physics and Biophysics, Department ofMolecular Biology, University of Salzburg, A-5020

Salzburg, Austria

A Monte Carlo model has been developed for the sim-ulation of particle deposition in lungs affected by cystic fi-brosis (CF). Bronchial airway diameters are first scaled tothe subject-specific functional residual capacity (FRC) toadjust total lung volume and subsequently reduced by arandom scaling procedure to account for the measured air-way resistance (Raw) of the respective lung. Besides a ran-dom variation of airway calibers between different airwaygenerations, the model also enables diameter variationswithin a specific airway generation. To account for the oc-currence of CF mainly in the upper lung regions, the five-lobe lung model was subdivided into an upper part (up-per lung lobes, right middle lobe) with random scaling anda lower part (lower lung lobes) without such scaling. Theeffect of changes of the peripheral lung architecture (em-physema) on particle deposition is simulated by a recentlypublished emphysema model, which allows the variationof morphometric parameters regarding type and severityof emphysema. To illustrate model simulations, results pre-sented are based on sitting breathing conditions, an FRCof 3300 ml, a stepwise increase of the Raw (i.e., decrease ofthe airway calibers), and a continuous increase of emphy-sematous changes. For 3–�m unit-density particles,bronchial deposition in the upper lung region increased

significantly relative to that in healthy subjects, while alve-olar deposition exhibited the opposite trend.

P-108ANALYSIS OF PARTICLES IN EXHALED BREATHOF SMOKERS WITH AND WITHOUT CHRONICOBSTRUCTIVE PULMONARY DISEASE (COPD)

J M Hohlfeld, M Lavae-Mokhtari, N Krug, H Windt, W Koch.

Fraunhofer Institute of Toxicology and ExperimentalMedicine, Hannover, Germany

Exhaled breath condensate (EBC) has been suggestedas a non-invasive method to detect inflammation in pa-tients with airway diseases. Non-volatile inflammatorymediators are thought to be released from the airway lin-ing fluid by aerosol generation. So far, it is unknownwhether patients with COPD differ from healthy subjectsin their capacity to generate and release particles.

Exhaled particles were counted in smokers with nor-mal pulmonary function (n � 6, mean FEV1 105%pre-dicted) and patients with COPD (n � 9, mean FEV155%predicted) during breathing at rest (tidal volume /frequency: smokers 597 ml / 13, COPD 600 ml / 14), deep-ened ventilation (smokers 1141 ml / 11, COPD 1044 ml /10), and breathing at increased frequency (490 ml / 29,COPD 484 ml / 30). Exhaled particles were counted witha condensation nucleus counter (TSI).

The average number of exhaled particles under normalbreathing was higher in smokers with normal lung func-tion compared to patients with COPD (mean: 1367 ver-sus 542). Deepened ventilation led to marked increase ofparticle output in healthy smokers (16400) which was lesspronounced in COPD patients (4178).

We conclude that patients with COPD differ in their ca-pacity to generate and release droplets from the airwaylining fluid which needs to be further investigated andconsidered for interpretation of EBC data.

P-109FINE EXCIPIENTS IN CARRIER-BASED DRY

POWDER INHALATIONFORMULATIONS–INVESTIGATION USING

ATOMIC FORCE MICROSCOPY

Jones MD1, Price R1*, Hooton JC1, Dawson ML2

and Ferrie AR2

1. Pharmaceutical Technology Research Group, Departmentof Pharmacy and Pharmacology, University of Bath, Bath,

BA2 7AY, UK.2. Inhalation Product Development, GlaxoSmithKlineResearch and Development, Park Road, Ware, Herts,

SG12 0DP, UK.

The inclusion of a fine excipient in a carrier-based drypowder system is a well recognised method for increasingformulation performance, yet there is disagreement as tothe mechanism by which this effect is achieved. This study

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utilizes the recently developed cohesive-adhesive balance(CAB) approach to adhesive force measurement by colloidprobe AFM, for the study of fine excipients, in an attemptto further elucidate the mechanisms at work. The adhesionof a corticosteroid drug to four fine excipients was quanti-fied using the CAB AFM technique and found to be of theorder lactose�mannitol�trehalose�erythritol. Lactose car-rier-based formulations containing 2.5% drug and 10% mi-cronised fine excipient were produced and tested byaerosolisation into a reduced Anderson Cascade Impactor.The formulation containing mannitol fines produced a sig-nificantly greater FPF than any other formulation. These re-sults suggest that the formation of agglomerates of a criti-cal size but without excessive internal forces is necessaryfor improved formulation performance, as has been re-cently suggested in the literature. Additional work is re-quired to investigate this phenomenon further.

The authors wish to thank the Engineering and Physi-cal Sciences Research Council and GlaxoSmithKline fortheir support of this research.

P-110SCREENING DRY POWDER INHALER

FORMULATIONS USING LASER DIFFRACTION

Kippax PG 1, Higgs D 2, Ward-Smith RS3, Barrett P4

1,2,3. Malvern Instruments Ltd, Malvern, Worcestershire,WR14-1XZ, UK.

4. ATA Scientific Ltd, Sutherland, NSW 1499

Reproducible delivery of drug particles to the respira-tory system can only be achieved if processes of particleentrainment and dispersion during inhalation are opti-mised. This is particularly true of dry powder inhaler de-vices, where the patient’s inspiratory effort provides theenergy required. This requires developers to understandhow entrainment and dispersion occurs in order to de-velop devices that can be used by a range of patientgroups.

Traditionally, analysis of the particle size produced bydry powder inhaler formulations has been carried out us-ing cascade impaction (CI). The time-averaged size dis-tributions produced by CI measurements make it difficultto assess how dispersion is achieved during inhalation.For this reason laser diffraction is becoming accepted asa means of screening formulations for the correct disper-sive properties. Rapid data acquisition speeds possible us-ing laser diffraction allow powder release to be followedduring single device actuation, aiding an understandingof drug delivery dynamics.

We present results where laser diffraction has beenused to understand how the dispersion properties of pow-der formulations change according to the drug morphol-ogy and addition of excipients. These show that laser dif-fraction is sensitive to changes in the efficiency of powderentrainment and dispersion. The issues associated withcomparing laser diffraction and CI results are discussedwith regard to how the fine particle fraction is deter-mined.

P-111IN-UTERO EFFECTS OF INHALED MANGANESE

IN RATS

A. Rinderknecht1, M. Kleinman2, S. Ali3 and J. Ericson1

1Department of Environmental Health Science and Policy2Department of Community and Environmental Medicine

3FDA, Fayetteville, AKUniversity of California, Irvine, California

This study tested the hypothesis that in utero exposureto Mn via inhalation would increase susceptibility of pupsto the effects of the neurotoxin methamphetamine later inlife. Pregnant Sprague-Dawley rats were exposed to Man-ganese Sulfate at a concentration of 600 �g/m3 for 3 con-secutive days during their second week of pregnancy.Control animals were exposed to purified air. Pups fromthe control dams were divided into 2 groups of 6 pus each.One group was treated with methamphetamine by i.p. in-jection and the other group was treated with saline. Thepups from the Mn-treated dams were separated into 2groups and similarly treated. Mn and methamphetamine.Methamphetamine treatment significantly reduced totaldopamine and the dopamine metabolites DOPAC andHVA in the brain striatum. Methampheamine-induceddopamine depletion was significantly enhanced in thepups that had been treated with Mn in utero comparedto pups that had not been Mn-treated. Mn-treated pups,in addition to increased susceptibility to dopamine de-pletion, also exhibited significant differences in size anddensity of neuron bundles in the striatum. These data sug-gest that in utero exposure to inhaled Mn may signifi-cantly alter neurological development and render thebrain more susceptible to the effects of dopaminergicagents later in life.

P-112IMPROVING COMPLIANCE AND CONSTANCYOF DELIVERY IN CHILDREN WITH A NOVEL

SPACER DEVICE

*T Kolb1,S Roeder1, K Sommerer2, G Scheuch1

1Inamed GmbH, 35285 Gemünden, Germany2Inamed Research GmbH&CoKG, 82131 Gauting, Germany

Metered dose inhalation devices (MDI) are widelyknown to have a high variability in drug delivery. Thisfluctuation is not caused by the drug but by the individ-ual breathing pattern (BP). It has been shown that evenin adults, only 35% of the patients were able to performinhalation correctly. In children lung deposition is lessthan 5%. Commercially available spacer devices improvedelivery since they overcome coordination difficulties inactuating the MDI and inhaling the drug, yet the prob-lem of variance remains unsolved. A novel spacer for chil-dren is presented in this paper.

A balloon buffers the aerosolised drug and limits theinhalation volume. A patented valve restricts the inhala-tion flow. During inhalation the balloon folds together tosignalise a succeeded inhalation and to incite the child tocontinue. The device is designed in the shape of a toy an-

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imal, this way the child can associate the device with ahelping friend, which it trusts and has no fear of.

We have assessed in-vitro the output of two MDIsthrough the new spacer. Applying spontaneous BPs,which were recorded in earlier studies, output was 50 �45%. Using the novel spacer device output variability wasreduced to 34,2�8,5% for 2,8�m particles and 35,6 � 5,6%for 3,8�m particles.

This abstract is funded by: Inamed GmbH

P-113DEVELOPMENT AND APPLICATION OF A 3-

DIMENSIONAL ALVEOLAR CELL MODEL FORTESTING AEROSOLS DIRECTLY AT THE

LIQUID/AIR-INTERFACE.

HF Krug1*, S Diabaté1, K Kern1, R Wottrich2, SMülhopt3, HR Paur3 and JM Wörle-Knirsch1

1. Forschungszentrum Karlsruhe, Institute of Toxicologyand Genetics, PO Box 76021 Karlsruhe, Germany

2. Cytopharm GmbH, PO Box 06120 Halle, Germany3. Forschungszentrum Karlsruhe, Institute of Technical

Chemistry, PO Box 76021 Karlsruhe, Germany

The biological effects of aerosols as well as the toxicityof nanoparticles (NP) can be tested in vitro only veryhardly. Therefore, we developed a totally new 3-dimen-sional cell model that represents the alveolar situation inthe lung. We used different synthetic membranes onwhich epithelial and endothelial cells were seeded onboth sides. Additionally, macrophages can be plated ontop of the epithelial cells. To receive constant conditionsover a longer period of time established human as wellas rat cell lines were used for all experiments. The twomodels are appropriate to detect interspecies variationsof the particle effects on the cellular level. The establishedcell systems fulfil all criteria that are necessary for toxi-cological studies. The seeded cell lines are viable over along period of time even at the air/liquid interface on topof the synthetic membrane. Microscopic analysis of par-ticle-exposed cells demonstrated clearly the uptake of NPnot only by macrophages but also by the epithelial cells.Moreover, by electron microscopy we observed transportfrom the upper to the lower compartment and an uptakeby the endothelial cells as well. Furthermore, we analyseda different level of cytokine production on both sides ofthe membrane after particle exposure: a higher IL-8 re-lease above and a higher IL-6 release below! This modelwill be used to recognise hazards at workplaces in anearly stage of nanomaterial technology. Thus, after stan-dardization it can contribute to the development of ef-fective control strategies which focus on those particles orparticle parameters which are most relevant for toxicity.

This work was in different parts supported by grantsof BWPLUS (BWB20013 and BWC21018), DFG (CFN E1.3)and BfR (WK1-1328-182)

P-114MUCOCILIARY CLEARANCE IS IMPAIRED

THROUGHOUT THE FIRST YEAR AFTER LUNGTRANSPLANTATION AND THE DEGREE OFIMPAIRMENT CORRELATES WITH TIME TO

FIRST INFECTION.

*Laube BL, PhD, Karmazyn YJ, MS, Orens JB, MD andMogayzel PJ, Jr, MD, PhD

The Johns Hopkins University School of Medicine,Baltimore, Maryland 21212, USA.

Purpose: Mucociliary clearance (MCC) is a major lungdefense mechanism against infection, which is a significantcause of morbidity and mortality after lung transplantation.This study quantified MCC in 7 patients at 1–5, 6 and 12months after transplantation. Results were compared toMCC measured in 4 healthy subjects. Patients were moni-tored for the development of infections, during the sametime-period. Methods: To measure MCC, patients inhaled99mtechnetium sulfur-colloid aerosol and underwentgamma camera lung imaging for 76 minutes thereafter. Re-sults: 1–5 months after transplantation, MCC was signifi-cantly reduced compared to healthy subjects, averaging(�standard deviation) 8.90 � 7.27% and 16.90 � 7.73%, re-spectively (p � 0.05). MCC did not improve significantlyat 6 months or 12 months, averaging 5.96 � 4.62% (n � 6)and 8.53 � 5.90% (n � 4), respectively. During the year,mean MCC ranged from 3.01% to 20.15% (n � 7) and thedegree of impairment was significantly correlated with in-fection, such that patients with lower percent clearance be-came infected earlier (p � 0.05). Conclusions: These resultsindicate that MCC is impaired as early as 1 month afterlung transplantation and does not improve significantlythroughout the first year. In addition, lung transplant pa-tients with lower percent MCC appear to be at greater riskfor early onset of infection. Funding: Johns Hopkins Com-prehensive Transplant Center

P-115AIR POLLUTION AND RESPIRATORY

PATHOLOGY: COMMUNICATION IMPACT ON THE AIR

S Lacour, V Leblond, M De Monte, S Le Guellec and P Diot

INSERM U.618, IFR 135, Faculté de Médecine, Tours, France.

Ozone concentrations in the air above 110 �g/m3 canhave harmful effects on health when they last. This situ-ation corresponds to a “basic” pollution more frequentthan the “peaks of pollution” which entail informationmessages. Indeed, the health threshold value is fixed bythe World Health Organization at 110 �g/m3 ozone in theair during 8 hours.

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The network of research in public health “PAPRICA”gathers various partners of the Region Centre, France,concerned by air pollution and its impact on health. Wehave for principal objective the estimation of the impacton health of a prevention strategy by information aboutbasic pollution.

We set up a modelling software making it possible toforesee one day in advance the crossing of the health thresh-old value for ozone and a strategy of prior information ofserious chronic respiratory deficients so that they can adapttheir behavior and protect themselves against ozone expo-sure. We made two comparable groups of patients. Half ofthem were equipped with a cellular phone to forecast of anexceeding of the threshold the next day. The other half didnot receive this information.

Preliminary results show that patients who receivedalarm messages have a better feeling of their health andtheir quality of life.

Funding: ADEME, PHRC, ANTADIR, Region Centre,ARAIR

P-116SUB-MICRON CHARACTERISATION OF

INHALERS

Brambilla G1, Church T2, Lee D2, *Lewis D2, Meakin B2

1Chiesi Farmaceutici SpA, Parma 43100, Italy.2Vectura Group plc, Chippenham, SN14 6FH, UK.

Recent publications have highlighted the importance ofultrafine (0.1–0.3�m particles) inhaled drug delivery.This study presents the characterisation of sub-micronparticle size distributions using a Micro-Orifice UniformDeposit Impactor (MOUDI) which is able to characterisedrug delivery from inhalers down to an aerodynamic di-ameter of 0.06�m.

Characterisation of two pMDI systems using theMOUDI was found to be comparable to that of the An-dersen Cascade Impactor (ACI). The sub-micron (1�m)fraction of the delivered dose characterised by theMOUDI for each pMDI system was 33.0 � 1.8% and70.4 � 0.3% compared to 27.6 � 1.6% and 66.0 � 1.1%from the ACI respectively.

Regarding the characterisation of a DPI system, althoughthe delivered dose and fine particle dose (5�m aerody-namic diameter) were comparable to that obtained whenusing an ACI and Next Generation Impactor (NGI), the de-gree of submicron drug dispersion was not; the sub-micron(1�m) fraction of the delivered dose as measured by theMOUDI was 19.9 � 2.3% compared to just 4.9 � 0.9% and8.2 � 0.2% from the ACI and NGI respectively.

The MOUDI is able to characterise the drug deliveryfrom inhalers down to an aerodynamic diameter of0.06�m, and may prove to be a more useful tool than theACI or NGI for characterising the ability of a dry powderinhaler/formulation to generate drug particles potentiallycapable of deep lung penetration.

P-117A SETUP FOR FIELD STUDIES OF TOTAL

DEPOSITION OF POLYDISPERSE AEROSOL INTHE HUMAN AIRWAYS

J Löndahl1*, J Pagels2, J Zhou, M Bohgard2

and E Swietlicki1.

1. Nuclear Physics, Lund Institute of Technology, SE-22100, Lund, Sweden

2. Aerosol Technology, Lund Institute of Technology, SE-221 00, Lund, Sweden

Measurements done on respiratory deposition hasmainly been performed using monodisperse hydropho-bic aerosols on a limited number of test persons in labo-ratories.

A method has been developed to measure respiratorydeposition of polydisperse fine- and ultrafine aerosol par-ticles in different environments. A human test subject in-hales sample aerosol from a tank made of stainless steel.The exhaled air is collected in another tank that is heatedto 38°C to prevent condensation. Size resolved particleconcentrations in the two containers are obtained with anSMPS system and the respiratory deposition is calculatedby comparing the two size distributions. A computer pro-gram has been developed that records the breathing pat-tern, control automatic valves and sensors, operates theSMPS and calculates the respiratory deposition.

The particle losses in the system are low; 10–15% for 20nm particles and 2–4% for particles in the sizes 80–350nm. A maximum concentration of about 150 000 parti-cles/cm3 is possible before coagulation constitutes a prob-lem. The time needed for a measurement is approximately10–60 minutes depending on the number concentrationand size-distribution of the inhaled aerosol.

Preliminary experiments made indicate a good agree-ment with the deposition pattern expected from estab-lished models.

This work is supported by the Swedish Research Coun-cil for Environment, Agrigultural Sciences and SpatialPlanning (FORMAS) and the Swedish EnvironmentalProtection Agency

P-118IMPROVING PREDICTION OF AEROSOL

DEPOSITION IN AN IDEALIZED MOUTH USINGLARGE EDDY SIMULATION

Matida, E. A.2, Finlay, W. H.1*, Breuer, M.3and Lange, C. F.1.

1. Department of Mechanical Engineering, University ofAlberta, Edmonton, Canada

2. Mechanical & Aerospace Engineering, CarletonUniversity, Ottawa, Canada

3. Institute of Fluid Mechanics, University of Erlangen-Nurenberg, Erlangen, Germany

Aiming at deagglomeration of particles, DPIs (dry pow-der inhalers) normally have very complex outlet flows (in-

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cluding swirling flows, grid turbulence, jets and imping-ing jets1) and small outlet diameters (up to 10 mm), whichundesirably will increase particle deposition in the mouthcavity. Some insight into the above mentioned particle de-position in the mouth could be made using LES (LargeEddy Simulation). The monodisperse aerosol depositionof particles in an idealized mouth with a small inlet di-ameter (3.0 mm) is investigated. The continuous phaseflow is solved using a Smagorinsky subgrid scale modelat a steady inhalation flow rate of 32.2 L/min. Using aLagrangian approach, hundreds of individual particleswith 2.5 micrometers (density of 912 kg/m^3) are re-leased in the computational flow domain and particle de-position is determined. Once adequate temporal and spa-tial resolutions are applied, the total particle depositionresults in an idealized mouth are in relatively good agree-ment when compared with measured data obtained inseparate experiments, showing considerable improve-ment over the standard RANS/EIM (Reynolds AveragedNavier-Stokes / Eddy Interaction Model) approach.

References

1. Finlay, W. H. (2001). The Mechanics of Inhaled Phar-maceutical Aerosols: An Introduction. Academic Press.

P-119COMPARISON OF THREE VALVED HOLDING

CHAMBERS FOR THE DELIVERY OFFLUTICASONE PROPIONATE TO AN INFANT

FACE MODEL

Emily Louca1*, Kitty Leung1, Allan Coates1, Jolyon Mitchell2, Mark Nagel2

1Division of Respiratory Medicine, Hospital for SickChildren, Toronto, Ontario 2Trudell Medical International,

London, Ontario, Canada

This study compared drug delivery efficiency of threevalved holding chambers (VHC) with facemasks. The Ae-roChamber Max™ made of electrostatic dissipative ma-terial was compared with two non-conducting VHCs, theOptiChamber® Advantage and ProChamber™. The Op-tiChamber® Advantage and ProChamber™ were washedwith a mild ionic detergent and dripped dried to mini-mize electrostatic charge. The AeroChamber Max™ wastested “out of the package” and after wash, rinse and dry-ing. A realistic infant face model with an electrostatic fil-ter in the oral cavity (ADAM) was connected to a breathsimulator set for a standard waveform for a small child.Facemask fit was demonstrated by agreement of simula-tor settings with inspiratory flow measurements from aflow pneumotachograph connected to the system. Ran-domized and blinded studies were performed using anHFA-fluticasone propionate MDI (2 � 125�g/dose), andfilters were assayed using high-pressure liquid chro-matography (HPLC). Drug delivery efficiency expressed

as a percentage of the total dose of fluticasone propionate(250�g) for the AeroChamber Max™ “out-of-the-pack-age” was 22.0(0.9)% (mean (95% CI)) and 20.5(1.3)% whenpre-washed/rinsed. Results for the ProChamber™ andOptiChamber® Advantage were 10.4(1.9)% and 7.8(1.9)%respectively. Improved delivery of medication via VHCsmade from electrostatic charge dissipative materialsshould be considered when choosing appropriate dosesfor small children.

Analytical services provided by Trudell Medical Inter-national

P-120SIZE-SELECTIVE AEROSOL NUMBER SAMPLER

C.C. Chen, Y.M. Weng, W.Y. Lin, S.H. Huang,and Y.M. Kuo

The aerosol number concentration has been shown toserve as a better surrogate for aerosol mass concentration,because it yields a better correlation between exposureand disease for population exposure to ambient air. Onthe other hand, aerosol deposition in the respiratory tractstrongly depends on the aerosol size. Therefore, a size-se-lective aerosol number sampler is essential in order to ac-curately assess the extent of the health hazard of fine par-ticulates.

Different porosities of polyurethane foam filters weretested for aerosol penetration. Among the parameters op-erated in this work were (a) foam porosity (ppi), (b) fil-ter thickness, (c) face velocity, and (d) packing density ofthe filter foams. Di-octyl phthalate was used as the testagent. A constant output atomizer and an ultrasonic at-omizing nozzle were used to generate polydisperse sub-micrometer- and micrometer-sized particles, respectively.Aerosol concentrations and size distributions upstreamand downstream of the filter foams were monitored byusing a scanning mobility particle sizer (for particlessmaller than 0.7 �m) and an aerodynamic particle sizer(for particles larger than 0.7 �m). The aerosol output wasneutralized by a radioactive source. A lognormal-distrib-ution curve with a mode of 0.25 �m and a GSD of 6.2 wasset as the primary target curve simulating the light-workICRP deposition model.

The results showed that the most penetrating size (alsoreferred to as collection minimum) of the filter foams de-creased upon increasing the foam porosity, packing den-sity and face velocity. In this work, the highest foamporosity and packing density we could acquire were 100ppi and 0.2, respectively. By adjusting the face velocity,the most penetrating size was able to move to 0.25 �m,which happened to be the most penetrating size for ICRPlight-work criterion. The whole aerosol penetration curvecould further fit to the modified ICRP curve by adjustingthe filter thickness. There are numerous ways to matchthe ICRP definition. This size-selective sampler becomeseven more versatile if the auxiliary detector and vacuumsystem can operate under different flow rates to simulatedifferent workload.

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