- Pages:89–100
- Published Online:14 April 2023
https://doi.org/10.1089/jamp.2022.0056
- Pages:101–111
- Published Online:12 May 2023
https://doi.org/10.1089/jamp.2022.0036
Review Articles
- Pages:112–126
- Published Online:20 April 2023
https://doi.org/10.1089/jamp.2022.0058
- Pages:127–143
- Published Online:15 May 2023
https://doi.org/10.1089/jamp.2022.0049
Invited Review Article
- Pages:144–151
- Published Online:13 June 2023
https://doi.org/10.1089/jamp.2023.29089.sb
Abstracts
- Pages:A-1–A-39
- Published Online:24 May 2023
https://doi.org/10.1089/jamp.2023.ab01.abstracts
Abstracts: Drug Delivery to the Lungs 33
01. DRUG DELIVERY OVER THE LAST 100 YEARS...AND THE FUTURE
Federico Lavorini, MD, PhD
Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, Florence, 50134, Italy
Summary: Inhalation therapy is one of the oldest approaches to the therapy of diseases of the respiratory tract. It is well recognised today that the most effective and safe means of treating the lungs is to deliver drugs directly to the airways. Surprisingly, the delivery of therapeutic aerosols has a rich history dating back more than 2000 years to ayurvedic medicine in India. In the late 18th and in the 19th century, earthenware inhalers were popular for the inhalation of air drawn through infusions of plants and other ingredients. Atomizers and nebulizers were developed in the mid‐1800s in France and were thought to be an outgrowth of the perfume industry as well as a response to the fashion of inhaling thermal waters. The marketing of the first pressurized metered‐dose inhaler for epinephrine and isoproterenol, by Riker Laboratories in 1956, was a milestone in the development of inhaled drugs. The first dry powder inhaler (DPI) was developed in the mid‐19th century, but DPIs did not gain market prominence until the 1990s. The signing of the Montreal Protocol in 1987 led to a surge in innovation that resulted in the diversification of inhaler technologies with significantly enhanced delivery efficiency, including modern pMDIs, dry powder inhalers, and nebuliser systems. There is also great interest in tailoring particle size and deliver to treat specific areas of the respiratory tract. One challenge that has been present since antiquity still exists, however, and that is ensuring that the patient has access to the medication and understands how to use it effectively. patient compliance will likely lead to market acceptance of smart inhalers. However, the desire for high‐tech inhalers will be countered by the increasing healthcare cost pressures and will likely ensure that MDI and DPI therapies remain important components of therapeutic aerosol delivery.
02. CHANGE IS IN THE AIR ‐ THE NEW PRESSURIZED METERED‐DOSE INHALER PROPELLANTS
John N Pritchard1
1Inspiring Strategies, Leicester, LE6 0AF, UK
Summary: Climate change is increasingly at the forefront of public and political discussions. The fact that the hydrofluorocarbons (HFCs) currently used as propellants in pressurized metered‐dose inhalers (pMDIs) have relatively high global warming potential (GWP) has led to their usage becoming increasingly subject to legislation. Recent acceleration of the overall phase down of HFCs, notably in the European Union and in California, could put the availability of affordable pMDI medication at risk towards the end of this decade. At the same time, it is likely that the cost of bulk HFC‐134a and ‐227 propellants will rise substantially over the next few years as other industrial uses decline, and quota mechanisms further impact on availability. Taken together, this could lead to a shortage of affordable reliever medication, even if new exemptions for medical uses were to be introduced.
Three companies have stated publicly that they are actively developing lower‐GWP pMDIs. However, only one is a major supplier of rescue medication, which accounts for more than 60% of all emissions from pMDIs. Whilst targeting first launches in 2025, these timelines are at risk if the health authorities require full clinical development programmes to be completed for a change of the propellant, when there are no other substantial changes in the formulation The pharmaceutical industry needs to respond with lower‐GWP alternatives whilst at the same time, regulators need to work with the industry to expedite the approval of such new products if essential patient medication is not to be put at risk in the Western world.
03. IN‐SILICO PREDICTION OF PMDI PERFORMANCE WITH LOW‐GWP PROPELLANTS HFA‐152A AND HFO‐1234ZE(E)
Daniel Duke1, Lingzhe Rao1, Nirmal Marasini2, Hui Xin Ong2, David Schmidt3, Benjamin Myatt4, Phil Cocks4 & Paul Young2
1Laboratory for Turbulence Research in Aerospace & Combustion (LTRAC), Department of Mechanical & Aerospace Engineering, Monash University, Clayton, 3800, Australia
2Respiratory Technology, Woolcock Institute of Medical Research, Glebe, Sydney, NSW 2037, Australia
3University of Massachusetts‐Amherst, Amherst, MA 01003, United States of America
4Kindeva Drug delivery, Charnwood Campus, 10 Bakewell Road, Loughborough, United Kingdom, LE11 5RB
Summary: The transition to low greenhouse warming potential propellants for pressurised metered dose inhalers will necessarily require a redesign of the nozzle orifice to compensate for changes in physicochemical properties such as reduced vapour pressure, density, and increased saturation temperature. New propellants have reduced spray momentum, reduced flash‐evaporation, altered spray morphology resulting in larger primary droplet size at the orifice. Investigating these phenomena is challenging due to the large parameter space for orifice and actuator design and multiple propellant candidates that must be searched in order to find an optimal arrangement. A cost‐effective solution to this problem is the use of in silico models which can search the parameter space quickly by running dozens of detailed computational fluid dynamics simulations on hundreds to thousands of processors. We present the first results of a parametric study of the effect of orifice diameter and length for solution formulations with propellants HFA‐134a, HFA‐152 and HFO‐1234ze(E). The simulations are capable of capturing trends in near‐orifice spray structure and accurately predicting droplet size. We show that manipulation of the orifice geometry may be able to compensate for the differences between propellants.
04. CARBON FOOTPRINT IMPACT ON INHALERS
Christer Janson
Department of Medical Sciences: Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, Sweden
That inhalation therapy can harm the environment became apparent in the 1990s when pressurised metered dose inhalers (pMDI)s that used chlorofluorocarbons (CFC) had to be replaced because of the depleting effect of CFCs on atmospheric ozone. CFC‐containing pMDIs were replaced with dry powder inhalers (DPI), soft mist inhalers (SMI) and pMDIs that used HFCs as propellant. There were large differences between countries in how CFC‐ pMDIs were replaced, with DPI becoming the dominating type of device in Sweden while pMDIs dominated in the UK [1].
It was recently discovered that HFCs also were problematic from an environmental perspective as the ones used in pMDIs (HFA 134a and HFA 227ea) had a considerable global warming potential of 1300 to 3000 times larger than that of CO2. Consequently, the carbon footprint of treating asthma or COPD with pMDIs is approximately 20 times higher than giving a similar treatment using DPIs [2] or SMIs [3]. A retrospective analysis of a pragmatic trial indicated that it is possible to switch asthmatics from pMDI to DPI and thereby significantly reduce carbon footprints without losing asthma control [4].
05. EFFECT OF AIRWAY DISEASE ON DRUG DEPOSITION IN THE LUNG
Chantal Darquenne1
1University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093‐0623, USA
Summary: Drug inhalation is a mainstay in the management of respiratory diseases. Its success not only depends on the pharmacology of the drugs being inhaled but also on the site and extent of deposition in the respiratory tract. Such deposition is tightly related to the physical properties of the inhaled aerosols (shape, size, density, electrostatic charge) and to the characteristics of the subject (lung geometry and size, breathing pattern, disease state). The most relevant deposition mechanisms for pharmaceutical aerosols are inertial impaction, a velocity‐dependent mechanism, and gravitational sedimentation, a time‐dependent mechanism. Increasing airflow rates increase the efficiency of deposition by inertial impaction and decreases that by sedimentation while increasing tidal volumes allow particles to reach more distal regions of the lung, where deposition by sedimentation is likely to occur.
06. EVALUATION OF TUMOUR EXPOSURE FOLLOWING THE ADMINISTRATION OF AN INNOVATIVE CISPLATIN DRY POWDER FOR INHALATION AT DIFFERENT DOSE LEVELS AND REGIMENS
N. Wauthoz1, S. Chraibi1, T. Davenne1,2, P. Gérard2, R. Rosière1,2, K. Amighi1
1Unit of Pharmaceutics and Biopharmaceutics, Université libre de Bruxelles (ULB), boulevard du Triomphe, Campus plaine CP207, 1050 Brussels, Belgium – Nathalie.wauthoz@ulb.be
2InhaTarget Therapeutics, Rue Antoine de Saint Exupéry 2, 6041 Gosselies, Belgium
Summary:
Introduction: A cisplatin‐based dry powder for inhalation (CIS‐DPI‐50) was developed to be administered during the off‐cycles of conventional anticancer therapies to intensify tumour exposition to chemotherapy. The aim was to evaluate the exposure of lung tumour and organs to platinum after CIS‐DPI‐50 administration in lung tumour‐bearing mice.
Methods: Pharmacokinetic and biodistribution studies were conducted following different cisplatin dose levels and regimens in the LLC1‐Luc model.
Results: After a single administration of CIS‐DPI‐50 at 0.5 mg/kg, platinum concentrations in the lung tumour were immediately high and increased slowly until reaching Cmax 2h later (20 ± 17 ng/mg) before decreasing gradually. This led to an AUC0‐∞ of 10,683 ± 5,837 ng.min.mg‐1 in the lung tumour, which was nearly 10‐fold higher than the AUC0‐∞ in tumour‐free lungs (1,072 ± 825 ng.min.mg‐1). This trend was also observed at different dose levels and regimens within a week with platinum concentration in the lung tumour 2‐fold (with 0.5 mg/kg/day x 3 days), 4‐fold (with 0.5 mg/kg/day x 5 days) and up to 6‐ fold higher (with 1 mg/kg/day x 5 days) than in tumour‐free lungs. Moreover, it seemed that the higher the weekly dose was, the higher the concentration in the lung tumour, which tended to demonstrate a higher penetration within the lung tumour than in tumour‐free lungs due to a diffusion effect based on the gradient of concentration.
Conclusion: Single and repeated.
07. AEROSOLISED PHOSPHODIESTERASE 3 INHIBITOR ENOXIMONE IN THE TREATMENT OF COVID‐19 PNEUMONIA: IN VITRO EVALUATIONS SUPPORTING CLINICAL EVIDENCE
A. M. Piras1, B. Grassiri1, C. Migone1, Y. Zambito1, A. M. Healy2,3, C. Ehrhardt3, P. Roncucci4 and B. Ferro4
1Department of Pharmacy, University of Pisa, Pisa/56126, Italy
2SSPC, The Science Foundation Ireland Research Centre for Pharmaceuticals, Ireland
3School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland
4Departments of Anesthesia and Critical Care, Spedali Riuniti Livorno Estav Nordovest, Livorno/57121, Italy
Summary: Enoximone (ENOX) is a phosphodiesterase‐3 (PDE‐3) inhibitor, which is clinically applied in congestive heart failure, having vasodilating and positive inotropic activity. It is commercially available as an i.v. aqueous formulation (PERFAN®), containing ethanol and propylene glycerol as co‐solvents. The aim of this work is to support the encouraging clinical preliminary results observed with the off‐label pulmonary administration of PERFAN®, through the inhalation route, in patients affected by COVID‐19‐related acute respiratory distress syndrome (CARDS). PERFAN® aerosolisation was characterised in terms of delivered dose, aerodynamic droplet size distribution and applied to in vitro models dedicated to IVIV correlation. The results demonstrate that ENOX is capable of a local direct effect on human pulmonary epithelial cell line NCI‐H441, increasing intracellular cAMP levels and providing protection from oxidative stress. Furthermore, the delivered drug permeates across the in vitro monolayer model, suggesting good in vivo bioavailability to achieve a vasodilatory effect. It was also noted that the in vivo effect is due to about ∼30% of the delivered PERFAN® dose (50 mg), since ENOX precipitates rapidly in the nebuliser cup during the aerosolisation. However, the droplets produced on nebulisation have a MMAD of 5 μm and GSD of 2, indicating a favourable size and size distribution for deposition in the bronchi‐alveolar region. Beyond the beneficial exploitation of the off‐label PERFAN® administration, this research opens up future development of ENOX inhalable medicines.
08. TRANSLATION OF INHALED EXPOSURE THROUGHOUT DRUG DEVELOPMENT: A CASE‐STUDY ON HOW TO DE‐RISK FORMULATION DEVELOPMENT AND SECURE CLINICAL EXPOSURE
Rebecca Fransson1, Carolyn Stevensson2 & Ulrika Tehler1
1Advanced Drug Delivery, Pharmaceutical Science, R&D, AstraZeneca, 43183 Gothenburg, Sweden
2Early Product Development & Manufacturing, Pharmaceutical Science, R&D, AstraZeneca, 43183 Gothenburg, Sweden
Summary: Biopharmaceutics is a skill area residing within pharmaceutical sciences and relates the physicochemical properties of a drug in a dosage form to the pharmacology, toxicology, or clinical response observed after its administration. The major responsibility of a biopharmaceutics expert within the industrial setting is to ensure that the drug product reliably delivers the intended exposure in animal and clinical studies. Specialized inhalation biopharmaceutics focuses on drug delivery to, and sometimes, through the lungs. Inhaled drug delivery requires expert knowledge within several scientific disciplines, but the core technical skill areas for an inhaled biopharmaceutics researcher resides within the aerosol testing, dissolution and absorption area. Scientific understanding on how the formulation, the inhalation device and relevant physiology impacts the drug product performance is the mainstay of an inhaled biopharmaceutics representative assignment in the industrial setting.
09. DELIVERY DEVICE AND METHOD FOR AEROSOL PATHOGEN EXPOSURE AND INHALED THERAPEUTIC IN A MACAQUE MODEL
Justina Creppy1,2, Benoit Delache1, Maria Cabrera2, Georges Roseau3, Cécile Herate1, Thibaut Naninck1, Asma Berriche1, Quentin Sconosciuti1, Eléana Navarre1, Frederic Ducancel1 & Laurent Vecellio2,3
1CEA/IDMIT, Fontenay aux Roses, France
2CEPR, INSERM U1100, University of Tours, Tours, France
3PST‐A, University of Tours, Tours, France
Summary: The main objective of this study was to develop an inhalation delivery device for macaque allowing either pathogen and drug administration. Using an inhalation device close to human device, it will allow rapid transfer to clinical trial and will give a high level of confidence if human study is not possible. Aerosol deposition measurement in 3 macaques have been performed by gamma camera using five different nebulizers with a face mask: one standard jet nebulizer with a 0.4μm MMAD, one standard jet nebulizer with a 3.2μm MMAD, one standard jet nebulizer with a 13.9μm MMAD, one prototype of jet nebulizer with 3.9μm MMAD and a second prototype using mesh nebulizer with a 3.9μm MMAD. Results show a decrease of aerosol deposition variability when using prototypes in comparison with standard jet nebulizer (34% and 30% respectively for prototype 1 and 2 vs 54%, 61%, 75% for standard nebulizers). Mesh nebulizer has the higher efficiency in terms of total airways deposition (37% vs 2.5% in terms of nebulizer charge) and lung targeting. PET‐Scan measurement using prototype number 2 confirms its ability to target the whole macaque.
10. CONSTRUCTION OF A FULL AIRWAY VOLUME “TOTAL INHALABLE DEPOSITION IN AN ACTUATED LUNG” (TIDAL) MODEL FOR APPROXIMATING SPATIAL DEPOSITION UNDER BREATHING PROFILES
Ian R Woodward1 & Catherine A Fromen1
1University of Delaware, Department of Chemical and Biomolecular Engineering, 150 Academy St. Newark, DE 19808, USA
Summary: New preclinical experimental approaches are needed to measure the spatial deposition of inhaled aerosols and improve evaluation of orally inhaled and nasal drug products, leading to the development of new vaccines and therapeutics, as well as bioequivalent assessments of generic options. To address this, our lab has created a multiscale dynamic preclinical tool to spatial measure deposition as a function of patient‐specific breathing, anatomy, and disease state. Coined the “total inhalable deposition in an actuated lung” (TIDAL) model, this platform leverages advances in additive manufacturing to recreate spatial aerosol collection efficiencies across the five lung lobes. TIDAL represents an innovative life‐ size physical model built of moving, modular, plug‐and‐play components that faithfully recreates the essential physical phenomena occurring in both inhaled formulation and the lung. A full TIDAL model representing an adult male has been fabricated and used to assess spatial deposition under physiological breathing conditions. Five sealed elastic lobe units filled with latticed parts actuated to create independent airflow by expansion and contraction under cycles of compression and release within the sealed compartment. We have successfully achieved breathing profiles with asymmetric lobe involvement, tunable flow rates and volume exchange, and breath holds. Aerosols are introduced at the mouth inlet and following designated breathing cycles, deposition is quantified on the latticed parts following a wash. Differential lattice structures provide spatial collection, where finer lattices increase the local deposition to benchmark to clinical observations. Overall, this work demonstrates important proof‐of‐concept towards developing the preclinical TIDAL model.
11. CAN WE MAKE BETTER USE OF ROUTINE PHYSIOLOGICAL SIGNALS? USING MATHS TO IMPROVE THE SENSITIVITY OF DETECTING DRUG OR DISEASE‐INDUCED CHANGES
Manasi Nandi1, Miquel Serna Pascual1, Maria Volovaya1, Yujia Wu1, Rebecca D'Cruz2, Philip Aston3, Carolyn Lam1,4, Aileen Milne4, Mary McElroy4
1School and Cancer and Pharmaceutical Sciences, King's College London, Franklin Wilkins Building, 150 Stamford Street, London, U.K
2Department of Mathematics, Centre for Mathematical and Computational Biology, University of Surrey, Guildford Surrey U.K
3Lane Fox Respiratory Unit, Guys and St Thomas’ NHS Foundation Trust, London, U.K
4Discovery Pharmacology and Toxicology, Charles River, Edinburgh, U.K
Summary: Symmetric Projection Attractor Reconstruction (SPAR) is a newly developed mathematical technique. It quantifies the shape and variability changes of cyclic waveforms by using all the available digital data, most of which is typically discarded during conventional analysis. We demonstrate the additive value of this technique in more sensitively quantifying lung function changes in a preclinical lung fibrosis model and in patients with COPD.
12. A TEST OF THE SAME DOSE OF A FINE AND A COARSE AEROSOL IN DOG SURPRISINGLY INDICATED NEGLIGIBLE INTRANASAL FILTRATION
Mikael Brülls1, Steven Oag1 & Eva Lamm Bergström1
1AstraZeneca BioPharmaceuticals R&D, AstraZeneca R&D Gothenburg, Mölndal, SE‐431 83, Sweden
Summary: A novel inhalation exposure system was developed to increase the efficiency of pharmacokinetic (PK) evaluations of inhaled drugs in a large species such as the dog by enabling simultaneous administration of multiple drugs to the same animal in a single experiment, facilitating a direct comparison of the same lung dose of different drugs using the same blood samples, which can be considered to be a refinement measure from an animal research perspective.
When validating the system in vivo, which included a comparison of the same nebulized dose of a fine and coarse aerosol, no detectable difference in lung deposited dose was observed. We expected the aerosol droplet size to have an impact and were surprised by the results, which indicated negligible intranasal filtration.
The intentionally extremely poorly soluble drugs selected for this study were developed for local treatment of the lung via inhalation. The three drugs were known to have low oral bioavailability and expected to also have low nasal bioavailability, because it has been shown [1‐3] that drugs such as mometasone furoate, fluticasone propionate and fluticasone furoate have low nasal bioavailability (<1%) due to poor solubility. The solubilities of the selected drugs are as low or even lower than the mentioned drugs. It was thus expected that the systemic exposure would be derived primarily from pulmonary absorption. This facilitated the determination of the lung deposited dose by a PK assessment.
This finding disproves the assumption that a mouth tube is required in dog studies to eliminate the high filtration that is believed to occur during nasal inhalation. The option of using nasal breathing instead of a mouth tube in dog studies is less invasive and considered a refinement measure from an animal research perspective.
13. DEVELOPMENT OF AN IMMUNOGENIC SPRAY‐FREEZE‐DRIED POWDER VACCINE AGAINST SARS‐COV‐2
Harry W. Pan1, Jian‐Piao Cai2, Kwok‐Yung Yuen2, Jenny K.W. Lam1,3
1Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong
2Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong
3Department of Pharmaceutics, UCL School of Pharmacy, University College London
Summary: After more than two years of experience with SARS‐CoV‐2, a suite of vaccines has become available as part of the global efforts to contain the rapid spread and devastating impact of the pandemic. Like many other liquid vaccines, currently approved COVID‐19 vaccines are intramuscular injections. While this invasive route of administration has acquired strong evidence of efficacy, other delivery methods may be more advantageous. In the context of COVID‐19, mucosal immunity in the respiratory tract would be highly beneficial, given that is it typically the first point of viral entry. In this study, a dry powder vaccine based on the receptor‐binding domain (RBD) of the SARS‐CoV‐2 spike protein was developed for intranasal inhalation. Spray‐freeze‐drying with an ultrasonic nozzle was applied to produce porous particles adequate for aerosolisation to the nasal airway. The formulation was a mixture of the antigen, aluminium hydroxide gel as adjuvant, and 2‐hydroxypropyl‐beta‐cyclodextrin as cryoprotective and lyoprotective agent. The spray‐freeze‐dried powder was characterised in terms of particle size by laser diffraction and morphology by scanning electron microscopy. The median volume diameter of the spherical particles was approximately 38 μm, which is suitable for nasal deposition in humans. The antigen‐adjuvant binding efficiency measured by polyacrylamide gel electrophoresis was 68%, a reduction from 87% before drying. Preliminary in vivo assessment of the vaccine delivered via intratracheal administration induced remarkable immune responses in mice. Together, the results indicate that this solid‐state vaccine possesses physical characteristics appropriate for intranasal delivery and is a promising alternative to parenteral COVID‐19 vaccines.
14. NASAL POWDER DELIVERY – CHARACTERISATION OF THE INFLUENCE OF EXCIPIENTS ON DRUG ABSORPTION
Marie Trenkel & Regina Scherließ
Kiel University, Department of Pharmaceutics and Biopharmaceutics, Grasweg 9a, 24118 Kiel, Germany
Summary: The nasal physiology has high potential for systemic drug delivery, while at the same time the natural clearing mechanism poses a specific challenge. The formulation of nasal powders and the use of mucoadhesive excipients are possible strategies to overcome this hurdle. For a targeted selection of excipients, the knowledge of their influence in the process of drug absorption through the nasal mucosa is essential. For that purpose, the effects of two fillers (mannitol, microcrystalline cellulose) and three mucoadhesives (pectin, chitosan glutamate and hydroxypropyl cellulose) as excipients in nasal powder formulations with atenolol as model drug were investigated. We evaluated the ability of the formulations to prolong the nasal residence time of the drug by assessing their influence on the viscoelasticity of simulated nasal fluid. Undissolved drug particles increased the elasticity to an extent that slows down the mucociliary clearance. Characterisation of the dissolution and release of the drug on a wet surface in a Franz cell setup revealed a decrease in dissolution rate for formulations that contained insoluble or gelling excipients. This may be beneficial for drugs that show fast dissolution but low permeability, since undissolved or swollen particles, which slow mucociliary clearance, remain longer in the nasal cavity. In order to assess drug permeability, we used the nasal carcinoma cell line RPMI 2650 in an air‐liquid interface model. The separate evaluation of the dissolution and permeability processes is essential for the understanding of the influence of excipients in the nose and thus will enable an effective selection in product development.
15. GENERATION AND CHARACTERISATION OF AN ORGANOTYPIC CELL KNOCKOUT MODEL TO STUDY PULMONARY MRP1
Johannes A. Sake1, Lyubomyr Burtnyak2, Mohammed Ali Selo1,3, Severin Mairinger4,5, Henriette E. Dähnhardt1, Camelia Helbet1, Vincent P. Kelly2, Oliver Langer4,5, Carsten Ehrhardt1
1School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin, Ireland
2School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
3Faculty of Pharmacy, University of Kufa, AL‐Najaf, Iraq
4Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
5Department of Biomedical Imaging and Image‐guided Therapy, Medical University of Vienna, Vienna, Austria
Summary: We recently reported a contribution of multidrug resistance‐associated protein 1 (MRP1/ABCC1) to pulmonary drug absorption in vivo. To study pulmonary MRP1 function in vitro, an organotypic knockout model based on the human NCI‐H441 distal lung epithelial cell line was generated and characterised.
A CRISPR/Cas9 technique using the knock‐in/promoter trap method was employed. Pre‐assembled spCas9 protein/gRNA construct and repair template were delivered to NCI‐H441 cells by electroporation. Repair templates contained puromycin resistance and mCherry fluorescence genes. The successful knock‐in was evaluated by puromycin selection and mCherry detection via flow cytometry. In the thus generated clones ABCC1 gene and MRP1 protein expression were compared to wild‐type (WT) cells by real‐time polymerase chain reaction (qPCR) and immunoblot, respectively. Transporter activity was studied using 6‐bromo‐7‐methylpurine (BMP), a prodrug of the MRP1‐specific substrate S‐(6‐(7‐methylpurinyl))glutathione (MPG).
Initially, eight KO clones (M1–M8) were generated, of which only M1 and M2 showed significantly (p ≤ 0.001) reduced ABCC1 mRNA levels, while MRP1 protein was undetectable in all clones. Transport studies in M2 revealed significantly (p ≤ 0.001) reduced release of MPG compared to WT cells. The inhibitory effect was comparable to the MRP1 inhibitor MK‐571.
We successfully generated MRP1 KO clones, which can be used to study the potential influence of MRP1 on pulmonary drug disposition and physiology on mechanistic levels in vitro.
16. SIMULTANEOUS NASAL AND LUNG DELIVERY OF AN ANTIVIRAL METALLODRUG USING A DUAL TARGETING POWDER FORMULATION
Han Cong Seow1, Suyu Wang2, Hongzhe Sun2 & Jenny K.W. Lam1,3
1Department of Pharmacology and Pharmacy, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR
2Department of Chemistry, State Key Laboratory of Synthetic Chemistry, CAS‐HKU Joint Laboratory of Metallomics on Health and Environment, The University of Hong Kong, Pokfulam, Hong Kong SAR
3Department of Pharmaceutics, UCL School of Pharmacy, University College London, UK
Summary: In the fight against respiratory viral infections, new aerosol drug delivery strategies are developed to target the entire respiratory tract. As highly contagious and deadly viruses infect both the upper and lower respiratory tract, an antiviral therapy that can deliver to the target sites would be most effective. This study aimed to reformulate ranitidine bismuth citrate (RBC), an anti‐ulcer drug with broad‐spectrum coronavirus activity, as a dual particle size powder formulation that targets both the nasal cavity and deep lung by a single route of intranasal administration. Spray freeze drying (SFD) using appropriate atomising nozzles produces distinctly large (>10 μm) and small (<5 μm) particles for nasal and lung deposition, respectively. When dispersed from a nasal device, the aerosol performance of the powder was evaluated using the Next Generation Impactor (NGI) coupled with a glass expansion chamber. By blending two formulations with different particle sizes, a single powder formulation with bimodal size distribution and dual aerosol deposition characteristics was produced. The aerosol deposition profile can potentially be manipulated by varying the powder mixing ratio. Compared to orally administered unformulated RBC, intratracheal administration of a lower dose of SFD powder to mice resulted in significantly higher drug concentration in the lungs. Overall, a dual targeting powder formulation of RBC with customisable nasal and lung deposition profile was developed. This innovative formulation strategy may potentially be applied to deliver therapeutic agents to the human airways for respiratory diseases.
17. DEVELOPMENT OF INHALED PLATELET‐BASED THERAPY TO REPAIR DAMAGED LUNGS
Ziru Xu, Ben Forbes, Simon Pitchford & Magda Swedrowska
King's College London, Institute of Pharmaceutical Science, London SE1 9NH, UK
Summary: As the first defence line in the lungs, the epithelium can be damaged by infections, inflammation, toxic compounds, and trauma. It is critical to recover a healthy epithelial barrier after lung injury. Platelets produce many different types of growth factors which promote cell growth and tissue regeneration. The aim of this project was to investigate the regenerative role of platelet extract on lung alveolar epithelial cells and the potential for development into an inhaled medicine. To gain the extract, platelets were subjected to ultrasound sonication to release their cell contents. Cell proliferation assays using A549 cells showed that sonicated platelet extract enhanced alveolar epithelial cell growth in a time‐ and concentration‐ dependent manner. The extract also accelerated closure of a scratched wound on the monolayer of A549 cells. When nebulised with an Aerogen Pro® mesh nebuliser, the extract produced an aerosol with a fine particle fraction below 5 μm of ca. 50% and no loss of activity in bioassay. In conclusion, sonicated platelet extract was effective at promoting alveolar epithelial cell growth and can be nebulised to form a bioactive respirable aerosol.
18. WHAT HAPPENED TO NEBULISER INNOVATION?
Wilbur de Kruijf1
1Resyca, Colosseum 23, Enschede, the Netherlands. Resyca is a joint venture between Recipharm and Medspray
Summary: Nebuliser innovation is ongoing, often far away from the spotlights of the inhalation pharma industry. This paper lists some of the recent innovations in liquid inhalation systems during the last five years: From smaller and smarter vibrating mesh nebulisers to aerosol dispensers for mass vaccination via inhalation. The DDL lecture gives an overview of the physics of aerosol generation principles for existing nebulisers and addresses their limitations.
Existing drug device combination products based on jet, ultrasonic and vibrating mesh nebulisers generally only serve rather small patient groups. Soft mist inhalers (SMIs) are mass produced (in double digit millions) mechanical portable ‘nebulisers’ and are in use for large patient groups like COPD.
However, more fundamental liquid inhaler system innovation will be needed to enable the delivery of biologics to the lung, especially for diseases that affect large patient populations. The novel therapies will likely require milligrams of drug, not micrograms like current asthma drugs. The first generation SMIs can only handle relatively small doses, due to the physics of their aerosol generation process. Regular nebulisers enable large drug doses, but the filling and cleaning of these devices is a burden for the patient, devices are not pocket size and the cost per treatment is high when compared to DPIs, SMIs and pMDIs.
With the upcoming wave of biological treatments, the requirements for inhalation systems are changing. Treatments may follow totally new regimen, like a single 10‐day course. Handing out an electric nebuliser device to a large group of patients may not fit that well to the reimbursement of such a treatment. The author expects biologics to become a driver of liquid inhalation innovation in the coming five years.
19. AEROSOL DEPOSITION IN A MECHANICALLY VENTILATED EX VIVO PORCINE LUNG USING A VIBRATING MESH NEBULISER AND A PRESSURIZED METERED DOSE INHALER
Ronan MacLoughlin1, C Champigny2, J Montharu2, L Vecellio2, & E Dalloneau3
1Research and Development, Science and Emerging Technologies, Aerogen Limited, IDA Business Park, H91 HE94 Galway, Ireland
2Université de Tours, Plateforme Scientifique et Technique Animaleries (PST‐A), 37032, Tours, France
3Inhalation solutions, 37510, Tours, France
Summary:
Introduction: Despite its frequency of use aerosol delivery during mechanical ventilation of the anesthetised patient is not yet well described in humans. Porcine lungs are known to approximate the airway diameters, branching geometries and volumes of the human lung and ex‐vivo lung models have shown utility across several studies. Here, we applied scintigraphic imaging in an ex vivo porcine lung model in the characterisation of aerosol delivery performance of the vibrating mesh nebuliser (VMN) and pMDI during simulated adult mechanical ventilation.
Methods: Two groups of three lungs from Large White pigs were used (body weight 102‐126 kg). Ventilation parameters were fixed using volume control ventilation. Vt 800, I:E 1:2, BPM 15, PEEP 5cmH20. 5 mg/5 mL of salbutamol with 0.1mL of 99mTc‐DTPA (37mBq) was loaded into the VMN (Aeroneb Solo, Aerogen, Ireland). 10 puffs of 99mTc‐DTPA labelled salbutamol were delivered by the pMDI (Ventolin®, GSK, UK). Ventilator Circuit resistance was measured pre, during and post dosing to quantify any change.
Results: For both VMN and pMDI no change in ventilator circuit resistance was noted. Aerosol deposition obtained in the porcine lung was higher with VMN than pMDI (11.59 ± 1.25% vs 1.31 ± 0.46%).
Conclusion: The choice of aerosol drug delivery device has a significant bearing on the amount of drug delivered to the ventilated lung. These findings may be of use in the design and optimisation of clinical interventions but may also inform device selection criteria during pharmaceutical development of therapeutics indicated for use in mechanically ventilated patients.
20. A METHOD FOR EVALUATION OF AERODYNAMIC PARTICLE SIZE DISTRIBUTION OF NOVEL INHALABLE LIGHT EMITTING PARTICLES FOR PHOTODYNAMIC THERAPY – LIGHT4LUNGS
Chen Zheng, Cuong Tran, Simon Warren & Glyn Taylor
i2c Pharmaceutical Services, Cardiff Medicentre, Cardiff, CF14 4UJ, UK
Summary: Light4Lungs is a Horizon 2020 project to investigate a novel therapeutic approach for treatment of antimicrobial resistant (AMR) chronic lung infections. Inhalable light emitting particles (LEPs) that excite endogenous bacterial photosensitisers by photodynamic effect and thereby eliminate pathogenic bacteria were formulated for aerosol delivery. LEPs are composed of a metal oxide core, a transition metal dopant, and a surface coating. Excitation spectrum is in the UV range with the emission peak in the blue spectrum. For pharmaceutical formulation development a novel quantification method for LEPs, independent of light emitting properties, was developed using a turbidimeter. Turbidity measurements were used to investigate LEP suspension stability and to establish the relationship between LEP concentration and turbidity readings. Standardised suspension preparation methods involving sonication and the addition of surfactant were established in order to prepare stable suspensions of LEPs for aerosolisation using an air‐jet nebuliser. The physico‐chemical properties of LEPs, in particular the tendency for surface adhesion, resulted in significant retention of material within the nebuliser. Furthermore, accurate and reproducible recovery of LEPs from a standard Next Generation Impactor, was not possible. The use of a Viable Andersen Cascade Impactor resulted in efficient and accurate recovery and facilitated determination of aerosol characteristics. The fine particle fraction (% <5μm) was >65% with a mass median aerodynamic diameter of approximately 1μm. Work is ongoing to investigate suitability of alternative nebuliser technology e.g. vibrating mesh, in order to optimise delivery of LEPs.
21. NONCLINICAL SAFETY EVALUATION OF EXCIPIENTS FOR INHALATION DRUG PRODUCTS
Viktoria McDonald BSc (Hons), ERT, MRSB
AlbaTox Consulting Ltd.
Summary: Drug product development requires qualification of both the drug substance and all ingredients contained within the formulation including data on the local tolerance and systemic toxicity. Whilst many excipients are precedented as safe inactive ingredients for the inhaled route, use of a novel excipients necessitates the generation of safety data, which may be obtained from public domain or proprietary literature or by additional nonclinical (toxicology) testing. This presentation will discuss the nonclinical regulatory requirements and approaches for establishing safety data to qualify novel excipients for inhaled formulations.
22. ISOTHERMAL DRY PARTICLE COATING (IDPC) – DRY POWDER INHALER (DPI) FORMULATIONS BY DESIGN: CONTROLLED AND CONTROLLABLE MANUFACTURE OF FIXED DOSE COMBINATIONS
Jasdip S Koner1, Shital Lungare1, Amandip Gill1, Rhys Jones1, David A Wyatt1,2, & Afzal Mohammed2
1Aston Particle Technologies, Aston Triangle, Birmingham, B4 7ET, United Kingdom
2Aston University, Aston Triangle, Birmingham, B4 7ET, United Kingdom
Summary: The current gold standard treatments for asthma and Chronic Obstructive Pulmonary Disease (COPD) involve the use of fixed dose combinations of highly potent agents to reach a range of therapeutic pathways synergistically. To prepare such formulations the pharmaceutical industry predominantly employs traditional technologies, often high shear blenders, with little advancement in the manufacturing process over the last 30 years. Such techniques are stochastic and difficult to control whilst imparting undesirable stress through local frictional heating and triboelectrification of the constituent materials. A novel manufacturing technology isothermal Dry Particle Coating (iDPC) through its unique operating principle at low shear, delivers the benefits of a high shear blender and consequently has wide applicability to DPI formulation. This study delivers intimate control of the manufacturing process using a Quality by Design (QbD) approach to the development and manufacture of triple fixed dose combination DPI formulations. Wide manufacturing design spaces using three defined critical process parameters (CPPs) were generated for two different triple combination formulations. iDPC delivers consistently acceptable blend homogeneity and controlled fine particle fraction (FPF) for each of the active pharmaceutical ingredients (APIs) within the formulation. In addition, the study shows that by altering the process parameters, good aerosolisation performance can be achieved without the requirement of force control agents. In conclusion this study demonstrates that iDPC delivers a controlled and predictable manufacturing process for the development of fixed dose combination DPI formulations and presents a viable new alternative to the antiquated gold standard manufacturing processes currently used across the industry.
23. A NOVEL THERMOSENSITIVE IN SITU HYDROGEL FORMULATION FOR SUSTAINED INTRANASAL DRUG DELIVERY
Hanieh Gholizadeh1,2, Juhura G. Almazi3, Dina M. Silva3, Kate Barry2, Ali Fathi4, Simin Maleknia4, Paul Young1,3,5, Daniela Traini1,2, Hui Xin Ong1,2,3
1Respiratory Technology, The Woolcock Institute of Medical Research, Sydney, NSW 2037, Australia
2Macquarie Medical School, Faculty of Medicine, Health, and Human Sciences, Macquarie University, Sydney, NSW 2109, Australia
3Ab Initio Pharma Pty Ltd, Sydney, NSW, Australia
4Tetratherix Technology Pty Ltd, Sydney, NSW, Australia
5Department of Marketing, Business School, Macquarie University, Sydney, NSW 2109, Australia
Summary: In this study, a novel synthetic thermosensitive polymer, poly(N‐isopropylacrylamide)‐co‐(polylactide/2‐hydroxy methacrylate)‐co‐(oligo (ethylene glycol), denoted as TP, is presented as a promising drug carrier for sustained intranasal drug delivery. TP is in a liquid state at room temperature, enabling aerosolisation, while it undergoes a phase transition at the physiological temperature to form a hydrogel with a mucoadhesive characteristic that increases the nasal drug residence time, enhancing drug bioavailability. Solutions of TP with varying concentrations (50, 100, and 140 mg/mL) were prepared and found to have desirable spray characteristics and large coverage of the nasal cavity surface area when delivered as a nasal spray. Moreover, the in situ gel formation of TP at 140 mg/mL concentration (TP140) prevented nasal runoff and dripping to the nasopharynx. This is an ideal characteristic of this TP‐based formulation as it allows for efficient drug absorption and hence, treatment efficiency. The 98.9% encapsulation efficacy of TP140 for entrapment of ibuprofen (IBU) as a model drug and sustained IBU release from TP140 hydrogel during a 140‐hour study showed its suitability as a desirable platform for controlled nasal drug delivery. Furthermore, TP140 did not show any toxic effect on the nasal epithelial cells, suggesting its safety as an excipient in nasal formulations.
24. IN VITRO SCALING OF NEBULISED DOSES OF ETD001 FOR CLINICAL TRIALS IN PAEDIATRIC SUBJECTS WITH CYSTIC FIBROSIS
Eddie J French1, Samantha Heath3, Joanne Charlwood2, Paul Russell2 Kathy Woodward2 Niyati Prasad2 & Thomas Moody3
1TEKH Consulting Limited, Queen Street Deal CT13 6EY UK
2Enterprise Therapeutics Ltd., Sussex Innovation Centre, Falmer, Brighton, BN1 9SB, UK
3Intertek Melbourn, Saxon Way, Melbourn, Hertfordshire, SG8 6DN, United Kingdom
Summary: Early clinical trials are usually undertaken solely in an adult population. When designing clinical trials to include paediatric patients, the prospective clinical dose may need to be suitably adjusted to reduce the possibility of under or overdosing. Scaling of prospective inhaled clinical doses from an adult dose, based solely on relative body weight or body surface area does not account for the change in delivery efficiency of the formulation to paediatric populations compared to adults.
ETD001 is a novel inhaled ENaC (Epithelial sodium Channel) blocker being developed by Enterprise Therapeutics Ltd. to enhance mucociliary clearance in people with cystic fibrosis. ETD001 is currently in phase 2 clinical trials and clinical studies are being designed for the paediatric population in discussion and agreement with the regulators in Paediatric Investigational Plan (PIP). An in‐vitro assessment of relative dosing efficiency was undertaken for ETD001 solution delivered by a nebuliser.
The aerosol particle size distribution (aPSD) via Next Generation Impactor (NGI) using both USP and Alberta idealised throats and the delivered dose, using various paediatric breathing profiles with face masks on anatomical face models, were assessed using pharmacopeial methods. The testing demonstrated for infants there is a 4 fold reduction and for babies a 6.5 fold reduction in dose reaching the lungs from the same nominal dose.
In vitro studies using anatomically representative models and appropriate breathing cycles can significantly enhance the ability to scale doses for paediatric clinical studies with inhaled therapies by predicting the relative delivery efficiency from a nebuliser. These factors need to be taken into consideration when calculating clinical doses for paediatric subjects as scaling doses based solely on body weight could lead to significant underdosing.
25. BIOPHARMACEUTICS MEETS INHALED DRUG DELIVERY – INTRODUCING THE IBCS GRID
Jayne E. Hastedt1, Per Bäckman2 Antonio Cabal3, Andy Clark4, Carsten Ehrhardt5, Ben Forbes6, Anthony J. Hickey7, Guenther Hochhaus8, Wenlei Jiang9, Stavros Kassinos10, Philip Kuehl11, David Prime12, Yoen‐ Ju Son13, Simon Teague14, Ulrika Tehler15, & Jen Wylie16
1JDP Pharma Consulting, California, USA
2Emmace Consulting, Lund, Sweden
3Eisai, Woodcliff Lake, NJ, USA
4Aerogen Pharma, California, USA
5Trinity College Dublin, Dublin, Ireland
6King's College London, London, UK
7University of North Carolina, North Carolina, USA
8University of Florida, Florida, USA
9FDA Office of Generic Drugs, Maryland, USA
10University of Cyprus, Cyprus
11Lovelace Biomedical, New Mexico, USA
12Pulmonary Drug Delivery Consultant, Ware, UK
13Genentech, South San Francisco, CA, USA
14GlaxoSmithKline, Stevenage, UK
15AstraZeneca, Gothenburg, Sweden
16Merck & Co., Rahway, NJ USA
Summary: The delivery of an inhaled drug is influenced by several factors including its physicochemical properties, lung deposition and disposition. Each of these properties is influenced by underlying factors such as the formulation, the delivery device, and the physiology, anatomy and pulmonary function of the patient. The assessment of an inhalation‐based classification system (iBCS) has progressed since the concept was first introduced at an AAPS workshop in 2014 [i]. The principles of the proposed iBCS are based on those used for the classification of oral immediate release drugs (giBCS) and therefore are well established [ii]. On the other hand, the framework of the iBCS needs to be altered from that used in the giBCS providing a route‐specific framework encompassing the intricacies of pulmonary physiology. The premise for the proposed classification system is that it is desirable from a drug discovery, development, and regulatory perspective to anticipate the behavior of inhaled drugs. Our proposal is that a qualitative classification of a drug based on a classification system constructed from critical drug attributes will aid in understanding how to reduce the risk and overall complexity of inhaled drug product development, scale‐ up, and post‐approval changes.
26. POLYSACCHARIDES: IS THERE AN OPPORTUNITY FOR APPLICATION AS LUNG DELIVERY EXCIPIENTS?
Ana Grenha
Centre for Marine Sciences, Faculty of Sciences and Technology, Universidade do Algarve, Campus de Gambelas, 8005‐139 Faro, Portugal
Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia da Universidade de 7 Lisboa, Av. Prof. Gama Pinto, 1649‐003, Lisboa, Portugal
Summary: Dry powders and dry powder inhalers (DPI) are currently of the most used and investigated inhalable formulations and devices, respectively. The higher stability characteristic of solids, the lower environmental impact of DPIs, and the higher flexibility of dry powder formulations contribute to their popularity. Dry powder formulations typically involve the use of new excipients, which assume different roles that include the improvement of aerosolization properties or of formulation stability, the enhancement of targeting abilities, among others. Excipients approved for inhalation comprise a limited list. This prevents progresses in the area, as the current need for more targeted and effective therapies, implies the development of new technologies and sophisticated medicines, typically involving new excipients. From the range of excipients proposed by the literature, polysaccharides are of the most popular, not only because of their structural flexibility and low cost, but also due to the identification of functional abilities, such as targeting capacity. Our research group has proposed the use of polysaccharides in several lung delivery approaches. Some polysaccharides were used to actively target macrophages, owing to a chemical composition that favours the interaction with the cell surface receptors. In this lecture, results of the application of polysaccharides (locust bean gum and konjac glucomannan) as excipients of inhalable dry powders will be showcased, particularly exploring cell targeting abilities, exemplified by an application in inhalable tuberculosis therapy. The concerns regarding excipient safety for inhalation applications will be addressed and preliminary toxicological results subsequent to in vivo exposure presented.
27. THE FUTURE OF INNOVATION FOR HEALTHCARE
Magnus Björsne
AstraZeneca BioVentureHub AB
Summary: Pharma industry is in the midst of the perfect storm, pushed by technology while at the same time being pulled by both patients and payors. Future products will to a less extent be about medicines in isolation and we will increasingly see combinatorial innovation where different industry verticals jointly create new solutions for healthcare. As such, we as an industry need to pay more attention to “how to innovate” rather than zooming in on “what to innovate”. Bringing different tech areas together while at the same time merging cultures which all have different business logics require new type of innovation arenas.
AstraZeneca BioVentureHub was initiated 2015 with a purpose to create a new type of ecosystem where we bring together different industry verticals in the same physical environment. By deliberately mixing complementary technologies in a non‐competitive fashion, we have created an environment where domain expertise replaces dollars and where we promote a dare‐to‐share culture. By inviting SMEs in the areas of Tech, ICT, diagnostics and pharma we have created a model that encourages technology exploration and where curiosity drives science rather than monetary predictions. By definition, disruptive innovation is not easy to predict and BioVentureHub has introduced a complementary innovation system that predominantly address horizon 2 and horizon 3 type of innovation.
This presentation will describe AstraZeneca BioVentureHub, an new type of open innovation model where scale‐ up SMEs can access human capital and infrastructure residing within a large pharma organisation like AstraZeneca.
28. OVERCOMING BARRIERS IN DRUG DELIVERY TO THE LUNG, WHAT HAVE WE LEARNT AND WHERE ARE WE GOING?
Hugh D C Smyth1
1The University of Texas at Austin, 2401 University Ave., College of Pharmacy, Austin, Texas 78713, USA
Summary: Although the science and technology of inhaled products has advanced markedly over the past 20 years, our increased knowledge has also allowed us to uncover critical gaps. For many years, it seemed much of the scientists in this area were on a quest for improved efficiency and performance from inhaled devices and formulations. This focus on aerosol dispersion was addressed from many angles and led to the discovery of several technologies that have advanced our understanding of drug delivery to the lung. These discoveries have also now revealed new avenues for research that need to address important issues in the field. Importantly these include (1) understanding how small changes in formulations and delivery lead to significant changes in pharmacokinetics, thus potentially revealing the most critical parameters for aerosol dispersion (2) how new therapeutic modalities can fit in with the understanding built from the traditional inhaled potent small molecules widely studied, (3) and the development of technologies that minimize patient to patient and breath to breath variability. In this paper a synopsis of this work will be presented and the authors provide their vision on the future directions of this exciting field.
29. PHYSICOCHEMICAL AND AEROSOLIZATION PERFORMANCE STABILITY OF AN EXCIPIENT ENHANCED GROWTH (EEG) SYNTHETIC LUNG SURFACTANT POWDER FORMULATION
Mohammad A.M. Momin1, Connor Howe2, Worth Longest2 & Michael Hindle1
1Department of Pharmaceutics, Virginia Commonwealth University, Richmond, VA 23298, USA
2Department of Mechanical & Nuclear Engineering, Virginia Commonwealth University, Richmond, VA 23298, USA
Summary: Neonatal respiratory distress syndrome (NRDS) remains one of the single major causes of infant death. Surfactant replacement therapy (SRT) is the standard therapy for infants with NRDS. However, there are delivery issues associated with liquid bolus instillation which could be eliminated by aerosol delivery of the surfactant formulation. This study aims to characterize the stability of a novel synthetic lung surfactant excipient enhanced growth (EEG) powder formulation. The synthetic lung surfactant EEG powder aerosol formulation was prepared by spray drying a feed dispersion containing the phospholipid, dipalmitoylphosphatidylcholine (DPPC), a surfactant protein B mimic (B‐YL), hygroscopic excipients (mannitol and sodium chloride) and a dispersion enhancer (l‐leucine). Powders were packaged in hydroxypropyl methylcellulose (HPMC) capsules and stored in Aluminium‐Aluminium blister packs. The physicochemical properties and aerosol performance of the powders were characterized immediately following spray drying and after 3 months storage at 25±2°C, 5±2°C and −20±2°C. No significant differences were observed in the DPPC content of the powders after 3‐month storage at the three storage temperatures. The micrometer sized powder remained unchanged following storage at 5°C and −20°C, with a small increase in primary particle size observed at 25°C. There were no changes observed in the surface activity of the powder formulation following storage at 25°C and 5°C. Following 3 months storage, the emitted dose (>95%) from a novel dry powder inhaler (DPI) remained unchanged. There was a small decrease in in vitro lung deposition in a simulated neonatal airway model from ∼50% initially to ∼40% following storage under all conditions.
30. EFFECT OF INHALER PARAMETERS ON THE AEROSOL PERFORMANCE OF D‐LAK PEPTIDE/CAPREOMYCIN CO‐SPRAY DRIED POWDER FOR PULMONARY DELIVERY
Zitong Shao1, Shing Fung Chow1 and Jenny K.W. Lam1,2,*
1Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicines, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong SAR, China
2Department of Pharmaceutics, UCL School of Pharmacy, University College London, UK
Summary: D‐LAK120‐A peptide is a synthetic peptide with anti‐tuberculosis (TB) activity. Capreomycin is a second‐line antibiotic combating drug‐resistant Mycobacterium tuberculosis (Mtb). Previous study suggested that D‐LAK120‐A peptide could potentiate the efficacy of capreomycin when they are used in combination. In this study, a total of eight D‐LAK120‐A peptide/capreomycin co‐spray dried powder formulations were developed with different drug content and mass ratios. The aerosol performance of the combined powder formulations was first evaluated using the next generation impactors (NGI) with Breezhaler® at a flow rate of 90 L/min. All formulations had a similar emitted fraction (EF) of around 80% and fine particle fraction (FPF) of 40 ∼ 45%. The drug content and mass ratios between two anti‐ TB agents have no impact on the powder aerosol performance. The aerosol performance of formulation A1 (0.5% capreomycin and 2% D‐LAK120‐A (w/w)) was further evaluated using three different inhalers, namely Breezhaler®, High‐resistance Osmohaler® (HR‐Osmohaler®) and Handihaler® at different operation flowrates. This combined formulation showed flowrate‐dependent EF and FPF. The best powder dispersion was achieved with HR‐Osmohaler® operated at a flow rate of 50 L/min, with an EF of around 65% and the FPF of over 50%. This dispersion condition facilitates powder emission and simultaneously avoids excessive impaction on the throat, resulting in better particle distribution and higher FPF.
31. OPTIMIZATION OF MODIFIED POLY (GLYCEROL ADIPATE) NANOPARTICLES FOR PULMONARY DRUG DELIVERY
Ramy Said‐Elbahr1,2, Vincenzo Taresco3 , Giuseppe Mantovani1, Snow Stolnik1 & Cynthia Bosquillon1
1University of Nottingham, School of Pharmacy, University Park, Nottingham, NG7 2RD, United Kingdom
2Ain Shams University, Faculty of Pharmacy, African Union Organization St., Abbassia, Cairo, 11566, Egypt
3University of Nottingham, School of Chemistry, University Park, Nottingham, NG7 2RD, United Kingdom
Summary: Pulmonary drug delivery is largely used for the localized treatment of lung diseases but suffers from various limitations, some of which could be overcome by polymeric nanoparticles. Unfortunately, few polymers have been deemed compatible with the inhaled route. Poly (glycerol adipate) (PGA), a green enzyme‐synthesized biodegradable polymer, offers several advantages over traditional polymers for pulmonary drug delivery purposes. However, modification of its chemical structure is necessary to obtain solid polymers with a high glass transition temperature (Tg) and thus, enable the formulation of modified PGA nanoparticles into micron‐sized inhalable powders by spray‐drying. PGA was modified with N‐acetyl‐tryptophan (NAT) using a simple Steglich esterification reaction. The polymers obtained were thoroughly characterised to monitor the effect of NAT % substitution on their Tg values. The PGA polymers were formulated into nanoparticles by nanoprecipitation in presence of different surfactants and the nanoparticles were characterized using dynamic light scattering. PGA was successfully coupled to NAT to obtain solid powder polymers that demonstrated Tgvalues >40oC, with a positive correlation between Tg and NAT % substitution observed. The nanoparticle formulations showed hydrodynamic diameters <120 nm, narrow size distributions (PDI <0.2) and negative zeta potential values. Furthermore, they could be sterically stabilized by all the surfactants tested. Thus, modified PGA‐NAT nanoparticles are promising candidates for pulmonary delivery. However, future work is needed to confirm that PGA biodegradability and safety on lung cells are preserved upon its chemical modification.
32. INHALABLE NANOMEDICINE FOR TREATMENT OF PULMONARY TUBERCULOSIS
Khaled H. Alzahabi1, Theoni K. Georgiou2, Hisham Al‐Obaidi3, Brian D. Robertson4, Omar Usmani1, Alexandra E. Porter2 and Teresa D. Tetley1
1National Heart and Lung Institute, Imperial College London, London, UK
2Department of Materials and London Centre for Nanotechnology, Imperial College London, London, UK
3College of Pharmacy, University of Reading, Reading, UK
4MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, UK
Summary: Tuberculosis (TB) is currently treated using a cocktail of antituberculosis (anti‐TB) drugs for between 6 and 24 months. The systemic side effects and lack of compliance can lead to multidrug resistant TB (MDR‐TB). A faster, simpler more reliable therapy is urgently required to reduce both the drug dose and period of treatment, to improve patient compliance and reduce MDR‐TB. To this end, we have constructed an inhalable anti‐TB formulation to target Mycobacterium tuberculosis (M.tb) in the airways and in particular the deep lung. The aim was to assemble poly (lactic‐co‐glycolic acid) microparticles to carry silver nanoparticles (AgNPs) associated with rifampicin (RIF) in an aerosolised microparticle form to be delivered directly to the lungs by inhalation. The safety of the microparticles at the human alveolar respiratory gas‐liquid interface was determined using transformed primary human alveolar epithelial cells with type 1 cell‐like characteristics (TT1). The synthesised AgNPs were spherical, with a mean diameter of 15‐18 nm. A concentration ≤10 mg/ml of AgNPs in serum free medium did not cause TT1 cell death. PLGA microparticles containing AgNPs and RIF were generated using solvent evaporation method and fully characterised for their size, charge and AgNP/RIF content. The microparticle constructs were spherical with diameter less than 5 μm (median 1.35 μm). RIF and AgNPs were successfully encapsulated within the PLGA microparticles with an encapsulation percentage of 79% and 53% respectively. The next step is to assess the safety of this delivery system against M.tb alone and against M.tb‐infected models of TT1 epithelial cells and human lung macrophages.
33. ATRA‐LOADED NANOPARTICLES AS INHALABLE HOST‐DIRECTED IMMUNOTHERAPY FOR TUBERCULOSIS
Ahmad Z. Bahlool1,2,3, Sarinj Fattah1,2,4, Andrew O'Sullivan1,5, Brenton Cavanagh6, Ronan MacLoughlin1,5,7, Joseph Keane3, Mary P O'Sullivan3, Sally‐Ann Cryan1,2,4,8
1School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland (RCSI), 123 St Stephens Green, Dublin 2, D02 YN77, Dublin, Ireland
2Tissue Engineering Research Group, Royal College of Surgeons in Ireland (RCSI), 123 St Stephens Green, Dublin, Ireland
3Department of Clinical Medicine, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, The University of Dublin, Dublin 8, Ireland
4SFI Centre for Research in Medical Devices (CÚRAM), NUIG & RCSI, Dublin, Ireland
5Research and Development, Science and Emerging Technologies, Aerogen Ltd, Galway Business Park, Dangan, Galway, Ireland
6Cellular and Molecular Imaging Core, Royal College of Surgeons in Ireland RCSI, Dublin 2, Ireland
7School of Pharmacy and Pharmaceutical Sciences, Trinity College, D02 PN40 Dublin, Ireland
8SFI Advanced Materials and Bioengineering Research (AMBER) Centre, RCSI and Trinity College Dublin, Dublin, Ireland
Summary: Tuberculosis (TB) is the top bacterial infectious disease killer worldwide. The emergence of strains of multiple drug‐resistant tuberculosis (MDR‐TB) has pushed our available stock of anti‐TB agents to the limit of effectiveness. An adjunctive, host‐directed therapy (HDT) designed to act on the host, instead of the bacteria, could help address this issue. We successfully developed a host‐directed formulation for TB, using All Trans Retinoic Acid (ATRA)‐loaded PLGA nanoparticles. Confocal laser scanning microscopy (CLSM) showed efficient cellular delivery of ATRA‐loaded NPs into macrophages. Efficacy studies conducted in THP‐1 derived macrophages infected with the avirulent Mtb strain (H37Ra) have demonstrated a dose dependent reduction in mycobacterial growth as determined by the BACT/ALERT® liquid culture system. The formulation was integrated with a vibrating mesh nebulizer. Aerosol droplet size was characterized using laser diffraction and cascade impaction. The aerosol had a volumetric median diameter (VMD) of 4.09 μm and mass median aerodynamic diameter (MMAD) of 2.13 μm. 65.1% of the dose was inhaled in an adult breathing simulation which was generated using a breathing stimulator. A scalable nanomanufacturing approach was optimized using microfluidics mixing.
34. MICROENCAPSULATION OF MPEG‐PLGA NANOPARTICLES FOR POTENTIAL INHALABLE ANTICANCER THERAPY
Cláudia Viegas1,2*, João P. Lourenço3,4, Ana Grenha1,4 & Pedro Fonte1,2,4*
1Centro de Ciências do Mar (CCMAR), Universidade do Algarve, 8005‐139 Faro, Portugal
2IBB—Institute for Bioengineering and Biosciences, Department of Bioengineering, Instituto Superior Técnico, Universidade de Lisboa, 1049‐001 Lisboa, Portugal
3Centro de Química Estrutural (CQE), Instituto Superior Técnico, Universidade de Lisboa, 1049‐001 Lisboa, Portugal
4Faculdade de Ciências e Tecnologia, Universidade do Algarve, 8005‐139 Faro, Portugal
*Corresponding authors: viegas.claudiasofia@gmail.com, prfonte@ualg.pt
Summary: Lung cancer therapies are usually administered intravenously with low selectivity for tumor cells and severe side effects. Therapeutic antibodies are useful in treatment due to their higher specificity and bioactivity, and lower toxicity compared to small molecule drugs. Antibody encapsulation into nanoparticles for inhalable delivery is a promising strategy, which combines targeted and controlled drug delivery with the ability to protect antibody structure and bioactivity. Thus, the aim of this work was the development and optimization of mPEG‐PLGA nanoparticles formulated into dry powder by spray‐drying aimed at lung cancer treatment. The formulation development followed a Design‐of‐Experiment (DoE) approach to target the desired nanoparticle features. Between the tested surfactants, PVA and Tween 80®, the latter showed better colloidal stability for the nanocarriers. The optimized nanoparticles were produced with 150 mg mPEG‐PLGA and 1% Tween®80, showing the lowest particle size of ≈300 nm, polydispersity index (PdI) of 0.36 and negative zeta potential of ‐24 mV, considered suitable features for antibody encapsulation. The spray drying studies have demonstrated that D‐mannitol and L‐leucine were the best performing matrix excipients. Microparticles resulting from their combination, present in the spraying dispersion at concentrations of 2% and 1% (w/v), respectively, produced with spray‐drying yields up to 59%, showing low powder adhesion to the apparatus. Subsequent studies will involve the association of selected therapeutic antibodies, aimed at establishing an inhalable lung cancer therapy.
35. EVALUATION OF DIFFERENT POWDER CHARACTERIZATION TECHNIQUES FOR DPI PERFORMANCE IN CAPSULE‐BASED INHALERS
Salvatore Pillitteri1, Joana T. Pinto2, Sarah Zellnitz‐Neugebauer2, Aurélien Neveu1 & Filip Francqui1
1Granutools, Rue Jean Lambert Defrêne 107, Awans, 4340, Belgium
2Research Center Pharmaceutical Engineering GmbH, Inffeldgasse 13, 8010 Graz, Austria
Summary: We investigated the rheological properties of dry powder inhaler (DPI) formulations, composed of an adhesive mixture of salbutamol sulphate and different lactose grades, with tapped density and rotating drum methods. The results from these characterization methods were compared to the performance of the DPI, evaluated by the fine particle mass (FPM) released after aerosolization from a capsule‐based inhaler. We found that the dynamical measurement provided by the rotating cell could be more relevant to understand inhaler performance than quasi‐static ones. On the one hand, we observed that the classification that can be done with a quasi‐static measurement, i.e., with the tapped density measurement and the rotating drum at low speed, is completely different from the classification proposed by a dynamical measurement, performed with the drum at high rotating speed. This difference is due to rheological properties of the powders, such as shear‐thinning and shear‐thickening behaviours. On the other hand, the flow state undergone by the powder during aerosolization is dynamical in a capsule‐based inhaler since the powder is released by a pierced capsule that rotates to a speed up to 1000 rpm. These results highlight the relevance of dynamics measurement for DPI performance characterization and optimization.
36. DRY POWDER MICROPARTICLES WITH REDISPERSIBLE CLARITHROMYCIN NANOCRYSTALS FOR HIGH DOSE INHALATION
Anna Neustock & Regina Scherließ
Kiel University, Department of Pharmaceutics and Biopharmaceutics, Grasweg 9a, DE‐24118 Kiel
Summary: Pulmonary drug delivery is an established route of administration for local and also systemic therapy. Typically, dry powder inhalers are loaded with an interactive powder blend consisting of a carrier and a small amount of high potent drugs. By preparing “Trojan” microparticles (microparticles “hiding” many nanoparticles in their shell) composed of a hollow core and a shell out of more than 70 per cent drug nanocrystals plus a small amount of matrix material, it is possible to use active ingredients with higher therapeutic doses, such as antibiotics. In this study, Clarithromycin nanocrystals for Trojan particles were prepared by media milling in an HPMC solution. The influence of different additives aiding the redispersibility of dried nanosuspensions into the primal nanocrystals was investigated. The addition of pH 5 buffer led to a Z average of 400 nm instead of > 1000 nm without further additives.
37. OPTIMIZATION OF THE DEVELOPMENT OF INHALABLE EGCG NANO‐LIPOSOME AS A POTENTIAL TREATMENT FOR PULMONARY ARTERIAL HYPERTENSION BY IMPLEMENTATION OF DESIGN OF EXPERIMENTS APPROACH
Fatma Haddad1, Khaled Assi1, Talat Nasim1, and Rajendran Gopalan1
1School of Pharmacy and Medical Sciences, University of Bradford, Bradford, United Kingdom.
Summary: Epigallocatechin gallate (EGCG), the main ingredient in green tea, holds promise as a potential treatment for pulmonary arterial hypertension (PAH). However, EGCG has many drawbacks including stability issues, low bioavailability, and short half‐life. Therefore, research aimed to optimize the development of inhalable EGCG nano‐liposome formulation to overcome EGCG drawbacks. Using the Design expert software version‐13, the design of experiments (DOE) strategy was applied to study the impact of formulation compositions on the liposomal characteristics and to develop the optimum inhalable EGCG nano‐liposome formulation. Then it was characterized, and its aerodynamic behavior was identified utilizing the next‐generation impactor (NGI). The in vitro effect of the optimum EGCG nano‐liposome was determined using the reporter assay. The prepared optimum inhalable EGCG liposome has the following experimental characteristics: the average liposome size of 105 nm, polydispersity index (PDI) of 0.18, the zeta potential of −25.5 mV, encapsulation efficiency of 90.5%, and the PDI after three months of 0.19. All the actual results of these responses were in great agreement with the anticipated values by the model. Its aerodynamic properties were as follows: the mass median aerodynamic diameter (MMAD) was 4.41 μm, and the fine particle fraction (FPF) (<5μm) was 53.46%. The stability study has shown that the liposomal formulation of EGCG was stable for at least three months with an excellent encapsulation efficiency of more than 90%. The optimum nano‐liposome has also been shown to be stable after nebulization using the vibrating mesh nebulizer and has inhibited the reporter activity in a dose‐dependent manner.
38. THE FORGOTTEN MATERIAL: GELATIN‐BASED INHALABLE MICROCAPSULES FORMULATED BY A SIMPLE IONIC COMPLEX APPROACH AS A PLATFORM FOR CONTROLLED PULMONARY DRUG DELIVERY
Beatriz Behrend‐Keim1, Almendra Castro‐Muñoz1, Tania F. Bahamondez‐Canas1,2, & Daniel Moraga‐ Espinoza1,2
1Escuela de Química y Farmacia, Universidad de Valparaíso, Gran Bretaña 1093, Playa Ancha, Valparaíso, Región de Valparaíso 2340000, Chile
2Centro de Investigación Farmacopea Chilena, Universidad de Valparaíso, Gran Bretaña 1093, Playa Ancha, Valparaíso, Región de Valparaíso 2340000, Chile
Summary: Formulating pulmonary controlled‐release formulations is highly desirable when treating chronic diseases such as COPD and Asthma. However, a limited number of excipients are approved for inhalation. The following study presents a promising strategy that provides a matrix for controlling the release of anionic drugs using gelatin as the core of the encapsulation process for dry powder formulations. The ionic interaction between this biodegradable polymer and the drugs allows for controlling the diffusion rate of the drug while presenting swelling properties that could help to avoid macrophage patrolling and early clearance from the lung. Overall, the decrease in the drug release rate was minor, considering the expected. However, the time necessary to reach maximum concentration was three times higher compared to the drug without the presence of gelatin.
On the other hand, the particle swelling increases by tenfold in five minutes while presenting a good aerodynamic performance with 70 % of FPF. Even though these results are favorable, a more comprehensive study is required to understand the mechanism behind the ionic interaction between the polymer and the drug. However, this can be the start of developing a new generation of controlled‐ release formulations.
39. A COMPARISON OF DIFFERENT PARTICLE DEPOSITION METHODS ON DISSOLUTION USING TRANSWELL® SETUP
Abhimata Paramanandana1, Magda Swedrowska1 & Ben Forbes1
1Institute of Pharmaceutical Science, King's College London, Waterloo Road, London, SE1 8WA, United Kingdom
Summary: The study compared aerosolized particles collected using different deposition techniques by investigating the dissolution of Budesonide delivered by 400 μg Novolizer®. Drug was aerosolized using a flow of 60 L/min into an abbreviated and modified Andersen cascade impactor system and collected onto a GF/A glass microfiber using methods which favoured impaction or sedimentation. In the sedimentation method, the collection filters are placed in two different configuration levels: at the bottom of the hollow stage (Sedimentation‐1) and the end filter stage (Sedimentation‐2). A burst of airflow (0.4 ‐ 0.7 s) to carry particles into the hollow chamber was performed followed by a sedimentation time of 20 min between actuations. The dissolution setup was a 6‐well Transwell® system agitated at 60 rpm using an incubator shaker maintained at 37°C. Dissolution medium was 0.1% SDS in PBS with 2.35 mL and 0.1 mL as receptor and donor chamber volumes, respectively. Particle mass collected was between 25.6 ‐ 28.3 μg, 6 – 12.5 μg and 37.2 ‐ 48.5 μg for Impaction, Sedimentation‐1, and Sedimentation‐2, respectively. Scanning electron micrograph showed several aggregates were observed in , Sedimentation‐1 whereas denser particles were observed both in Impaction and Sedimentation‐2. Dissolution of all particle collection methods did not show significant differences.
40. SOLUTION‐BASED PRESSURIZED METERED DOSE INHALER FORMULATIONS USING HFA134A, HFA152A AND HFO1234ZE(E) PROPELLANTS: ANALYSIS OF SIZE, AEROSOLIZATION PERFORMANCE AND PARTICLE MORPHOLOGY
Nirmal Marasini1, Varsha Komalla1, Lingzhe Rao2, Daniel Duke2, Damon Honnery2, Stephen W. Stein3, Benjamin Myatt4, Phil Cocks4, Hui Xin Ong1,5, & Paul Young1,6
1Respiratory Technology, Woolcock Institute of Medical Research, Glebe, Sydney, NSW 2037, Australia
2Laboratory for Turbulence Research in Aerospace & Combustion (LTRAC), Department of Mechanical & Aerospace Engineering, Monash University, Melbourne, Australia
3Kindeva Drug delivery, 11200 Hudson Road, Woodbury, MN 55129
4Kindeva Drug Delivery, Charnwood Campus, 10 Bakewell Road, Loughborough, United Kingdom, LE11 5RB
5Macquarie Medical School, Faculty of Medicine, Healthy and Human Sciences, Macquarie University, Sydney, NSW 2109, Australia
6Department of Marketing, Macquarie Business school, Macquarie University, Sydney, NSW 2109, Australia
Summary: The transition of propellants from the traditional pressurised metered‐dose inhalers (pMDIs) to low global warming potential (GWP) propellants is challenging for the pharmaceutical industry. A better understanding of how these propellants impact the thermodynamic and physicochemical properties and aerosolization performance of a formulation is required. In this study, we investigate the impact of propellant type on the physicochemical and aerosol properties of a model solution‐based formulation containing 2 mg/mL dissolved drug and 8% w/w ethanol cosolvent. After five shots, all formulations had a consistent emitted dose, i.e. within 15% ex‐actuator variation of the 500 μg target dose. In general, laser diffraction particle size analysis showed that the formulations prepared with HFA152a produced a significantly larger volume‐based particle size distribution than formulations prepared using HFA134a and HFO1234ze(E). Andersen cascade impaction measurements of pMDIs revealed that aerosol aerodynamic particle size distributions were similar in terms of fine particle dose (167‐177 μg) regardless of the propellant, with the exception of MMAD [HFA134a‐0.8 μm, HFO1234ze (E)‐0.9 μm and HFA 152a ‐1.5 μm] and GSD [HFA134a‐ 2.3, HFO1234ze (E)‐2.6 and HFA 152a ‐1.8]. Morphological analysis of the ex‐actuator drug particles delivered from HFA134a and HFO1234ze(E) based pMDIs revealed the formation of spherical particles with smooth and irregular surfaces. In conclusion, the HFO1234ze(E) and HFA134a model solution pMDI formulations performed more similarly with respect to aerosol delivery than the HFA152a pMDI formulation.
41. SATURATED VAPOR PRESSURE OF HFA152A‐ETHANOL AND HFO1234ZE(E)‐ETHANOL BINARY MIXTURES
Swetha Vutlapalli1, Lingzhe Rao1, Ben Myatt2, Phil Cocks2, Paul Young3,4, Damon Honnery1, Daniel Duke1
1Laboratory for Turbulence Research in Aerospace and Combustion, Department of Mechanical and Aerospace Engineering, Monash University, Clayton, Victoria 3800, Australia
2Kindeva Drug Delivery, Charnwood Campus, 10 Bakewell Road, Loughborough, United Kingdom, LE11 5RB
3Respiratory Technology, Woolcock Institute of Medical Research, Glebe, Sydney, NSW 2037, Australia
4Department of Marketing, Macquarie Business school, Macquarie University, Sydney, NSW 2109, Australia
Summary: Hydrofluoroalkane propellants HFA134a and HFA227ea are being phased down under the Kigali amendment due to their high global warming potential. Propellants HFA152a and HFO1234ze(E) have been proposed as potential alternatives for pressurised metered dose inhalers (pMDIs). Knowledge of the fundamental thermodynamic properties of these alternative propellants is essential to predict and optimise device performance. The vapor pressure of low‐GWP propellant binary mixtures with ethanol for use in solution formulations are presently not available in the literature. In this paper, the saturated vapor pressures of HFA152a and HFO1234ze(E) have been measured using a constant‐volume technique. For temperatures below 45°C the relative deviations of vapor pressures of HFA152a and HFO1234ze(E) are below 5% and 3.5% as compared with REFPROP10.0, respectively. We show the vapor pressure dependency on ethanol cosolvent concentration for HFA152a and HFO1234ze(E) at a concentration of 8% w/w.
42. PRE‐FORMULATION SCREENING OF METERED DOSE INHALER USING MOLECULAR DYNAMIC SIMULATION APPROACH
Alaa Aldabet1, JohnMiller2, Somaieh Soltani3, Mohammad Haroun1, Marouf Alkhayer1, Wassim Abdelwahed4
1Faculty of Pharmacy, Tishreen University, Lattakia, Syria
2Enlighten Scientific LLC, NC, USA.
3faculty of pharmacy, Tabriz University of Medical Science , Tabriz, Iran.
4Faculty of Pharmacy, Aleppo University, Aleppo, Syria
Summary: More than 50 years since the first introduction of metered dose inhaler (MDI) by Riker laboratories. Development of MDI formulation was challenging due to the low solubility profile of most excipients in Hydro flouro Alkane (HFA) propellants and the limitation of generally recognized as safe (GRAS) excipients that was authorized to be delivered to the lung.
The main purpose of this study was to develop a new salbutamol sulfate (SS) MDI free off ethanol using PEG400(1%) w/w as suitable alternative co‐solvents to ethanol (10 %)w/w. PVP‐k30(0.001‐0.0001 %) w/w and Brij72(0.001‐0.005‐0.01 %) were used separately as suggested stabilizer. In silico molecular dynamic (MD) simulation was carried out to investigate the compatibility of new excipients with SS and PEG400 before adding the HFA134a. Differential scanning calorimeter (DSC) was also run to evaluate the compatibility between formulations components that passed the visual observation test. Content per actuation was also used to estimate the developing formulation at accelerated stability conditions (40°C/75%RH).(N=10)
MD simulation results demonstrated the compatibility of PVP‐k30(0.0001%) w/w with other formulation's components before adding HFA134a propellant( small or negative value for and Emix). MD simulation results were also confirmed by DSC thermograms which indicate the compatibility between PVP‐k30 based formulation due to a small change in endothermic maximum melting point compared with Brij 72 based formulation. Content per actuation of PVP‐k30(0.0001 %)w/w based formulation passed the accelerated stability test and there is a significant effect of stabilizer type and concentration on the emitted dose (p‐value < 0.05).
43. IN‐VITRO EVALUATION OF PMDI SPRAY DEVELOPMENT OF HFA134A, HFA152A AND HFO1234ZE(E)
Lingzhe Rao1, Anesu J Kusangaya1, Nirmal Marasini2, Hui Xin Ong2,3, Ben Myatt5, Phil Cocks5, Damon Honnery1, Paul Young2,4, Daniel J Duke1
1Laboratory for Turbulence Research in Aerospace and Combustion (LTRAC), Department of Mechanical and Aerospace Engineering, Monash University, Clayton Campus, Melbourne, VIC 3800, Australia
2Respiratory Technology, Woolcock Institute of Medical Research, Sydney, NSW 2037, Australia
3Macquarie Medical School, Faculty of Medicine, Healthy and Human Sciences, Macquarie University, Sydney, NSW 2109, Australia
4Department of Marketing, Macquarie Business School, Macquarie University, NSW 2109, Australia
5Kindeva Drug Delivery Limited, Charnwood Campus, 10 Bakewell Road, Loughborough, LE11 5RB, UK
Summary: To assist the transition to alternative low GWP pMDI propellants, the current study performed high‐ speed imaging and droplet sizing of the near‐orifice spray development of HFA‐152a and HFO‐1234ze(E) based formulations. Conventional HFA‐134a propellant was tested as the control. Placebo (pure HFA/HFO) and model solution (2 mg/mL drug dissolved in 8%w/w ethanol) formulations were measured, for each propellant. The results indicate larger droplets produced by HFA‐152a and HFO‐1234ze(E) based placebo formulations at the near‐orifice locations. HFA‐152a also showed a wider and denser spray profile as compared to that of HFA‐134a due to its low vapour pressure and density. The temporal spray development was also less stable and repeatable. HFO‐1234ze(E) showed a similar spray profile and a more stable spray development compared to that of HFA‐134a, however with reduced spray repeatability. The impact of changing propellants on spray development was reduced in model solution formulations. Both HFA‐152a and HFO1234‐ze(E) showed comparable spray profiles and measured droplet size to that of HFA‐134a. The issue of low spray stability and repeatability persists in solutions, particularly for HFA‐152a. These early results indicate that the transition to low GWP propellants is feasible, but further optimisation of the actuator design and formulation composition is needed.
44. ASSESSING THE ADAPTABILITY OF BENCH SCALE DRY POWDER TECHNOLOGY FOR FILLING OF AN PMDI CAN WITH A HIGH FILL WEIGHT API
Sheryl Johnson1, James Murray1, Johnathan Carr1, Marco Laackmann2, Daniel‐Jakub Wilhelm2, Tony Clark3, Cristino Ruano3
1Koura Global, Pool lane, Ince, Cheshire, CH2 4NU, UK
2Harro Höfliger, Helmholzstraße 4, 71573 Allmersbach i.T., Germany
3Pharmatec solutions ltd, Timberly, Gyfelia, Wrexham. LL13 0YH, UK
Summary: Due to the present tightening of environmental legislations governing medical propellants, there is more emphasis than ever on understanding the manufacturing steps required in handling of low global warming potential (GWP) propellants. This paper explores one such approach that aims to mitigate safety concerns at the formulation manufacturing stage, brought about by the flammability of the novel propellants. By first proving the adaptability of dry powder filling equipment in filling pMDI cans at the bench scale, the ability to separate the drug dosing and propellant filling stages can be assessed. The use of such technology to dispense a high fill weight API, resulted in data that met precision limits outlined (±10%). Optimised trial dosages all fell within 6% of the target weight with low RSD values of 1.7‐2.1%. The next step is to determine if formulations manufactured using this technique are of equivalent in‐vitro performance to those made using traditional bench filling techniques.
45. RADIOLABELLING OF LOW GWP PMDI FORMULATIONS FOR SCINTIGRAPHY
Simon J Warren1, Chen Zheng1, Aneta Obirek1, Rebecca Price‐Davies2 & Glyn Taylor1
1Cardiff Scintigraphics Ltd., Cardiff Medicentre, Cardiff, CF14 4UJ, UK
2Simbec Research Ltd., Merthyr Rd, Merthyr Tydfil, CF48 4DR, UK
Summary: Pressurised metered dose inhalers (pMDIs) use hydrofluorocarbon (HFC) propellants, some of which have noteworthy global warming potential (GWP). HFC uses are regulated and an international phase down has been implemented through the Kigali Amendment to the Montreal Protocol.
Some pharmaceutical companies have already stated their intention to transition to low GWP propellants, e.g. Chiesi (HFC 152a) and AstraZeneca (HFO 1234ze).
Marketing approvals for pMDIs with low GWP propellants will be dependent, in part, upon establishing bioequivalence with reference products. For locally acting medications gamma scintigraphy offers an accurate and fully quantifiable technique to conduct comprehensive in vivo characterisation of inhalers i.e. lung deposition/distribution, swallowed and exhaled fractions and the impact of patient factors.
To achieve these objectives radiolabelling methods for low GWP formulations must be developed. Trace amounts of Technetium‐99m (Tc‐99m) are incorporated into the formulations, without changing the pharmaceutical properties, so that the radiotracer acts as an accurate surrogate for the active pharmaceutical ingredients (APIs). Standard pharmacopoeial inertial impaction tests were conducted to characterise both the API and Tc‐99m aerosol properties.
Two model triple combination pMDI formulations, using the APIs in commercial HFA 134a products i.e. in Chiesi's Trimbow®(beclometasone/formoterol/glycopyrronium in solution) and AstraZeneca's Trixeo® (budesonide/formoterol/glycopyrronium in suspension) were produced using HFC 152a and HFO 1234ze respectively, then radiolabelled with Tc‐99m. Using acceptance criteria recommended for the validation of radiolabelled orally inhaled products (Devadason et al. 2012) the radiolabel was shown to be an accurate surrogate for the APIs in both formulation types.
46. PILOT SCALE MANUFACTURING APPROACH FOR NOVEL LOW‐GWP PROPELLANTS
Paul Dowdle1, John Crowder1, Ian Robinson1, Mark Hargreaves1, & Simon Bryan1
1Koura, Thornton Science Park, Pool Lane, Ince, CH2 4NU, Chester, UK
Summary: Koura is a global supplier of fluoroproducts, including the pressurised metered dose inhaler propellants Zephex®134a (P134a) and Zephex® 227ea (P227ea). As part of a transition towards the new generation of low Global Warming Potential (GWP) propellants such as Zephex® 152a (P152a), Koura has installed and qualified a compatible pilot scale manufacturing system at Thornton Science Park, UK. The facility is constructed and operated to consider the risks associated with filling of flammable gases and has already been used to manufacture multiple batches using the new propellants on behalf of several parties. The principles applied within the facility have also been used to define the requirements for larger scale operations at pilot, registration and commercial scale using the new low GWP propellants with planning and in some cases implementation for these facilities at an advanced stage.
47. PREDICTION OF THE AEROSOL PERFORMANCE OF ACTIVE SOLUTION AND SUSPENSION FORMULATION PMDIS USING A 1‐DIMENSIONAL THERMOFLUID‐MECHANIC MODEL
B.J.A. Thorne1, D.P.J. Cotton1, S.B. Kirton2, M. Knowles1, K.C. Lee3, D. Murnane2, A.I. Sapsford1, A.D. Wright1
1Recipharm, Bergen Way, King's Lynn, PE30 2JJ, U. K.
2University of Hertfordshire, College Lane, Hatfield, Hertfordshire, AL10 9AB
3University of East London, Docklands Campus, University Way, London, E16 2RD
Summary: A thermofluid mechanic model to predict the aerosol performance of pressurised metered dose inhalers (pMDIs) was developed and used to predict the droplet size distribution generated for a range of pMDI valve and actuator configurations. An experimental study was also conducted to measure the droplet size distributions of the same pMDI valve and actuator configurations using laser diffraction, and proof of principal next generation impactor (NGI) stage performance testing, to establish links between aerosol droplet and residual particle sizes. Experimental measurements were taken for both suspension and solution formulations of fluticasone propionate (FP) in R134a propellant, where solution formulations incorporated ethanol at 15% w/w. For both formulations, FP was present at a 0.07% concentration w/w. The suspension formulation results show good agreement between the simulation‐ derived droplet sizes and those obtained via laser diffraction. The simulation data follow the trend exhibited by the experimental data in terms of the effect of spray orifice diameter on droplet size. For the smaller orifice diameter case, the solution formulation simulation data agree very well with experimental results. However, a significant discrepancy is observed for the results obtained from the larger actuator orifice diameter case, indicating the significant effect of ethanol on the flashing properties of the formulation during spray generation.
48. CANDIDATE DEVICE SELECTION FOR PMDI IN‐VITRO ONLY BIOEQUIVALENCE FOCUSSING ON SPRAY PATTERN AND PLUME GEOMETRY ANALYSIS
Miles Jeanneret1, Michael Kurowski1, Joe Woodcock1 & Mervin Ramjeeawon1
1Intertek Melbourn, Saxon Way, Melbourn, Herts, SG8 6DN, UK
Summary: In‐Vitro only bioequivalence (IVBE) submissions for orally inhaled and nasal drug products (OINDP) have become an increased focus for the generic pharmaceutical industry in recent years. Spray pattern (SP) and plume geometry (PG) testing can be included as in‐vitro studies to facilitate a weight of evidence‐based approach to submission for a pMDI product. SP and PG are well‐established techniques for OINDP characterisation and are good indicators of spray performance and therefore the likely bioavailability of delivered drug product.
Two different commercially available pressurized metered dose inhalers (pMDIs) were selected to investigate performance ‐ these devices were a generic pMDI device and its’ reference listed drug (RLD). Three additional commercially available actuators were also investigated using the canister from the generic pMDI device to examine the impact of actuator selection on product performance. SP and PG were analysed for a full range of actuator/canister combinations along with force to actuate, plume duration and spray intensity. The change in actuator with identical canisters was seen to alter the spray characteristics such as for the SP area.
49. COMPARISON OF IN‐VITRO PERFORMANCE CHARACTERISTICS OF SALBUTAMOL PMDI WITH LOW GWP PROPELLANT (HFA‐152A) VS THE CURRENT PROPELLANT (HFA‐134A)
Ameet Sule1, Sunita Sule1, Tracey Mullington1, Arslan Khan1, Lauren Liddle1, Robert Bootle1
1H&T Presspart Inhalation Product Technology Centre, Whitebirk Industrial Estate, Blackburn BB1 5RF, UK
Summary: Pressurised metered dose inhalers (pMDIs) though complex systems, remain highly preferred drug delivery devices for the treatment of asthma and chronic obstructive pulmonary disease (COPD). Low GWP propellants are now being explored to reduce the carbon footprint of the pMDI. HFA‐152a and HFO‐1234ze are two current low GWP alternatives. Even after almost four decades, Salbutamol is still the most sought‐after short‐acting beta2‐adrenergic agonist as a reliever for Asthma. Along with the propellants, the container closures and formulation characteristics play an essential role in product development.
To understand the behaviour of Salbutamol API with HFA‐152a and HFA‐134a in a plasma‐treated canister, a series of in‐vitro tests were conducted at an initial time point and 12 months at ambient conditions. The test results indicated that HFA‐152a is a promising potential alternative to HFA‐134a as a low GWP propellant. The data generated shows a close match for fine particle dose between the two propellants with a p‐value of 0.903. Modifications to actuator geometries are to be considered to allow for the differences in the physical properties of the propellants. The delivered dose performance throughout canister life showed acceptable performance for each propellant at initial and 12‐month time points with no individual results exceeding ± 25% of the target dose. Due to the differences in density between the propellants, the difference in spray area is significant, with a p‐value of 0.000, with HFA‐152a generating a larger spray area and wider plume.
50. INVESTIGATING RULES OF DESIGN TO OPTIMISE PMDI PLUME PROPERTIES
Sebastian White1, Franck Rubiconi1, John Sendall1, Jeremy Baker1, Alim Thawer1, Fred Hamlin1 & Baudouin Géraud1
1Cambridge Consultants Ltd, 29 Science Park, Milton Road, Cambridge, CB4 0DW, UK
Summary: An experimental investigation into the relative impact of a pMDI's orifice diameter and sump volume on the resultant plume was conducted as an empirical approach to optimise nozzle design. Image processing of high‐speed videos and light scattering based particle size acquisition were implemented to quantify the relative impact of each geometric parameter. Five metrics were used to quantify performance: Delay, Optical Duration, plume Expansion Coefficient, Dv50 and plume Cone Angle. Quantitative comparison of correlation coefficients between measurements show that orifice diameter has a significantly greater impact on performance than the sump Volume.
51. ACCELERATED STABILITY STUDIES WITH PMDIS OF RESPITAB HFA‐152A PROPELLANT DISPERSIBLE SALBUTAMOL TABLETS
Rachael Kay, Aneta Obirek, Wiktoria Wegrzyn and Cuong Tran
i2c Pharmaceutical Services, Cardiff Medicentre, Cardiff, CF14 4UJ, UK
Summary: Transition to next‐generation low global warming potential propellants for production of pressurised metered dose (pMDIs) presents challenges with process equipment and adapting manufacturing environments to ensure safe working with propellants classified as flammable. Respitab®, with drug in tablet form dispensed directly into canisters and crimped, avoids the need for pressurised mixing vessels and manipulation of large volumes of propellant in staffed working environments. Thus, Respitab offers a unique approach to developing formulations in Next Generation propellants such as HFA‐152a.
A Respitab salbutamol sulphate (SS) dispersible tablet formulation was prepared in HFA‐152a and accelerated storage stability (6 months at 40°C/75% relative humidity) assessed. The product was manufactured in plain aluminium canisters and stored unprotected. Following storage, pMDI canisters were evaluated using Next Generation Impactor (NGI) aerosol characterisation.
Aerosol characterisation of SS dose content uniformity (DCU) and aerodynamic particle size distribution (APSD) showed minimal changes over 6 months storage. DCU showed metered dose of 10 canisters was within acceptable limits with all measurements within ±35% of target and 90% of results within ±25% of target. APSD showed good reproducibility between the 5 pMDIs tested. While some small but statistically significant differences in APSD patterns were observed during storage, fine particle fraction (FPF, % < 5μm) indicated efficient aerosol production, with mean FPF decreasing from 63% to 56%. In comparison with off the shelf Ventolin obtained via pharmacy wholesaler, the beginning of can life, no accelerated storage, performance of Respitab showed a mean FPF of 49% compared with 46% for Ventolin.
52. ACHIEVING CONSISTENT, USER INDEPENDENT, NASAL DOSE DELIVERY USING A SPRING DRIVEN DEVICE
S. Falloon1 & A. Gibbons1
1Recipharm, Bergen Way, King's Lynn, PE30 2JJ, U.K.
Summary: Unit dose nasal drug delivery devices are used to administer a variety of drugs to a broad range of patients, without the need for more invasive delivery methods or the assistance of a healthcare professional (HCP). Due to the large variation in user strength, dexterity and finger size, the device design should aim to minimise the impact of differing user interaction. The focus of this investigation was to assess the performance of a novel unit dose device, measuring Essential Performance Requirements (EPRs) as an indication of consistent drug delivery. The reference device (RD) was Imigran® – a marketed user driven nasal spray, containing sumatriptan – and the novel device was a Recipharm proprietary spring driven nasal spray, currently under development, filled with the same formulation to enable direct comparison. Metered Shot Weight (MSW) and Droplet Size distribution (DSD) were measured in user and laboratory studies under representative use conditions. Results showed that the spring driven devices consistently delivered a MSW within specification limits and with significantly less variation than the user driven devices during hand actuation (Mean: 98.5 mg, RSD: 1.19% vs Mean: 101.1, RSD: 8.15%). Similarly, droplet sizes remained within a narrow range for spring driven devices (RSD: 3.11‐10.44%). User driven devices appeared to be affected by actuation speed of the thumb (RSD: 26.73‐34.37%), unlike spring driven devices. This supports the hypothesis that a spring driven delivery system can provide a more consistent device performance.
53. DEVELOPMENT OF A MATHEMATICAL MODEL TO ESTIMATE DROPLET SIZE DISTRIBUTION OF A PRESSURISED METERED DOSE INHALER IN THE NEAR‐ORIFICE REGION
Hossain Chizari1, Barzin Gavtash1, Benjamin Myatt1, Weeratunge Malalasekera2 & Hendrik K Versteeg2
1Kindeva Drug Delivery, Derby Road, Loughborough, LE11 5SF, UK
2Wolfson School of Mech, Elec & Man Eng, Loughborough University, Loughborough, Leics, LE11 3TU, UK
Summary: In a pMDI a range of droplet sizes will be created. In previous models, the mean droplet size was calculated and compared with PDA data. In the current study, we estimate a droplet distribution from the proposed model. This will generate more understanding of how a pMDI works and pave the path to the full model for ACI/NGI in the future.
54. HFO‐1234ZE(E): PROPELLING TOWARDS CARBON NEUTRALITY
Erik Boldt1, Ryan Hulse1, Barbara Decaire1, Greg Smith1
1Honeywell International, 20 Peabody Street, Buffalo, NY 14210, USA
Summary: The effects of climate change have been becoming more apparent each year. Rising global temperatures are significantly affecting ecosystems, resulting in detrimental changes to human health and longevity. There has been a concerted effort to combat the many causes of anthropogenic climate change, including the reduction of carbon and greenhouse gas emissions. Although they only account for a small proportion of global emissions, less than 0.003%, pressurized metered dose inhalers use fluorinated gases with high global warming potentials, exceeding 1000 times that of carbon dioxide.
Industry leaders in respiratory therapy have taken note and begun a push to reduce their carbon emissions by phasing out these potent gases. However, with over 600 million people worldwide suffering from respiratory diseases, a large percentage rely on pressurized metered dose inhalers to manage their symptoms. Keeping these medications readily available while reducing environmental impact is of the utmost importance.
Hydrofluoroolefin‐1234ze(E) (HFO‐1234ze(E), brand name Solstice® Air, Honeywell) is currently under evaluation and has been adopted as an alternative propellant for pressurized metered dose inhalers. With a near‐zero global warming potential, it offers environmental, safety, and regulatory benefits without compromising on performance. HFO‐1234ze(E) has been shown to offer similar performance metrics and an excellent safety and tolerability profile in healthy volunteers in a clinical study sponsored by AstraZeneca.
55. DETERMINING MEASURED EXPERIMENTAL VALUES OF DENSITY TO AID FORMULATION DEVELOPMENT OF NEW ENVIRONMENTALLY FRIENDLY PROPELLANT MIXTURES WITH ETHANOL
Lauren Harrison1
1Kindeva Drug Delivery Limited, Derby Road, Loughborough, UK, LE11 5SF
Summary: Kindeva have been working on multiple projects with greener propellants, hydrofluoroolefin (HFO) 1234ze(E) and hydrofluoroalkane (HFA) 152a to assess their suitability to replace the current HFA 134a and HFA 227 as greener alternatives.
A key property of propellants to consider when formulating pressurised metered dosage inhalers (pMDIs) is density, due to its direct impact on characteristics of the formulation and calculations to determine exact quantities of each component required. When there are no additional excipients, the formulation density is the same as the liquid propellant density and this value is used when determining quantities of the formulation.
However, as additional excipients such as co‐solvents are added to the formulation the overall density of the formulation will change. Historically, this has been well characterised for HFA 134a and HFA 227, but with the change to greener propellants, these density values need to be determined experimentally.
Kindeva therefore assessed the effect of increasing levels of Ethanol on density of HFA 152a and HFO 1234ze(E) containing formulations to improve accuracy when formulating by measuring actual experimental values. See Table 1 below that shows the change in overall formulation density for HFA 152a as Ethanol % increases.
56. RAPID SCREENING PARTICLE SIZE ANALYSIS OF SOFT MIST AEROSOLIZATION DEVICES
Aurélien Martin1, Dylan Antoniak2, Adam Stuart2, Laura Urbano1 & Darragh Murnane1
1University of Hertfordshire, College Lane, Hatfield, AL10 9AB, UK
2Merxin Ltd, King's Lynn Innovation Centre, 1 Innovation Drive, King's Lynn, PE30 5BY, UK
Summary: Soft mist inhalers (SMI) generate a metered dose of a liquid formulation with an extra‐fine droplet size distribution. There is significant interest in the development of new SMI products, and this requires the availability of high throughput performance‐screening tools that meet the requirements of regulatory guidelines. The aim of this work was to develop a laser diffraction method which is suitable to assess the size distribution of the rapidly evaporating soft mist aerosols. The aerosol size distribution of a commercially available tiotropium inhalation solution SMI device (UK product licence number PL 14598/0084) was measured for the entire spray duration using a Malvern Panalytical Spraytec instrument and inhalation cell, operating at 30 and 90 L/min as well as at ambient (40‐60% RH) and high (98%) relative humidity (RH). When tested at 30 L/min over detectable time frame (when laser beam obscuration is above 2%), the spray duration was observed to increase from 1.5 ± 0.1 seconds at ambient RH to 3.2 ± 0.30 seconds at 98%. Measurements at 90 L/min could not detect any droplets when testing at ambient RH (40‐60% RH), preventing a size measurement. However, at 98% RH, the spray duration at 90 L/min was 2.1 ± 0.1 s. A beam steering correction was employed to account for the impact of humidity on the laser scattering signal detection caused by droplet evaporation and inlet air humidity. Aerosol size measurement was restricted to periods where laser beam obscuration was greater than 2%. With the developed method, a volume median diameter of 4.5 ± 0.1 μm was observed, which agrees with literature values.
57. UNDERSTANDING THE TRANSIENT FLOW BEHAVIOR OF ABBREVIATED IMPACTORS FOR TESTING OF DRY‐POWDER INHALERS
Hendrik K. Versteeg1, Daryl L. Roberts2, Andrew Cooper3 and Jolyon Mitchell4
1Wolfson School of Mechanical, Electrical & Manufacturing Engineering, Loughborough University, Loughborough, Leics, LE11 3TU, UK
2Applied Particle Principles LLC, 17347 Westham Estates Court, Hamilton, VA 20158, USA
3Kindeva Drug Delivery, Derby Road, Loughborough, LE11 5SF, UK
4Jolyon Mitchell Inhaler Consulting Services Inc., 1154 St. Anthony Road, London, N6H 2R1, Canada
Summary: We present the results of a computer model of the transient flow behavior of abbreviated impactors (AIM) during testing of dry‐powder inhalers. The principles of the model were established in a cross‐ industry study of full‐resolution Next Generation Impactors (NGI) and Andersen impactors (ACI). Here, we apply the model to abbreviated impactors that were examined experimentally in a preliminary study of the reduced NGI (rNGI), of the Fast Screening Impactor (FSI), and of the Fast Screening Andersen (FSA) impactor, reported in a companion abstract at this conference (Mitchell et al.). The flow rate rise times of the FSI and FSA predicted by the model were significantly shorter than those of the rNGI and full‐resolution impactors NGI and ACI, as expected, and in agreement with experimental results. The correlation between the system volume and flow rate rise time of AIM impactors was good, which suggests that the rise time is mainly associated with evacuation of air out of the impactor system to reduce the pressure by 4 kPa, which is the surrogate DPI resistance. The final nozzle stages and the MOC in the rNGI have high resistance but have only a modest effect because of the small volume between these components and the vacuum outlet. Some quantitative differences between model predictions and experimental results were found, particularly with the rNGI where the experimental results are sparse. The cause of these differences is at present unknown, and further experimental work is needed to develop a fuller understanding of these AIM systems.
58. FLOW RATE‐RISE TIME PROFILES FROM MODEL DRY POWDER INHALER (DPI) TESTING OF ABBREVIATED IMPACTOR SYSTEMS COMPARED WITH THEIR FULL RESOLUTION COUNTERPARTS: INITIAL EXPERIMENTAL DATA
Mitchell JP1, Roberts DL2, Versteeg H3, Cooper A4, Copley M5 & Greguletz R6
1Jolyon Mitchell Inhaler Consulting Services Inc., 1154 St. Anthony Road, London, N6H 2R1, Canada
2Applied Particle Principles LLC, 17347 Westham Estates Court, Hamilton, VA 20158, USA
3Mechanical and Manufacturing Engineering, Loughborough University, Loughborough, LE11 3TU, UK
4Kindeva Drug Delivery, Derby Road, Loughborough, LE11 5SF, UK
5Copley Scientific Ltd., Colwick Quays Business Park, Rd. No 2, Colwick, Nottingham NG4 2JY, UK
6Sofotec GmbH, a member of the AstraZeneca Group, Benzstraße 1‐3, Bad Homburg, D‐61352, Germany
Summary: We report the outcome of a European Pharmaceutical Aerosol Group study evaluating flow rate‐rise times for reduced Next Generation Impactor (rNGI), Fast‐Screening Impactor (FSI) and Fast‐Screening Andersen impactor (FSA) with surrogate low‐, medium‐ and high‐resistance DPIs. Time for the flow rate to reach 90% of target (t90) and flow acceleration rate (slopet20/t80) defined the profiles. Volumes of the abbreviated impactors were estimated (±10mL) and compared to published values for their counterpart parent impactors (rNGI and FSI to NGI; FSA to Andersen Cascade Impactor (ACI)). t90(n=3 replicates; mean±S.D.) for rNGI (system volume 1990 mL, participant D) for target flow rates of 30 and 60 L/min were 387±5 and 218±8 ms respectively, close to corresponding values of 400±7 and 219±6 ms for the NGI (2000mL). The slopet20/t80) values were 0.09±0.00 and 0.31±0.00L/min/ms at 30 and 60L/min for the rNGI, also similar to the NGI value. Values of t90(170±5; 76±2ms) and slopet20/t80(0.22±0.01; 0.96±0.01 L/min/ms) with the smaller FSI (1150 mL), were significantly different at 30 and 60 L/min respectively than those of the NGI. Data from Participant G contained similar divergences including tests at 90L/min (t9060±3ms (FSI); 185±6ms (NGI). When testing two FSAs (volume of 630mL) at 60 L/min, Participant J found almost identical t90 values (70±3; 71±2 ms), shorter than 60‐L/min values (151±3; 162±6 ms) for their two ACIs (larger volume, 1180 ml). Apparatus internal volume is an important determinant of flow rate‐rise time.
59. EXPERIMENTAL EVALUATIONS OF INTERNAL LOSSES IN ‘MILLER’ MIXING INLET USED TO ENABLE CONSTANT FLOW RATE TO A CASCADE IMPACTOR WHILST ALLOWING AN INHALER TO BE TESTED FOR EMITTED AEROSOL AERODYNAMIC PARTICLE SIZE DISTRIBUTION (APSD) WITH REALISTIC BREATHING PROFILES
Cooper A1, Slator L2, Mitchell JP3 & Svensson, M4
1Kindeva Drug Delivery, Derby Road, Loughborough, LE11 5SF, UK
2Philips, Chichester Business Park, City Fields Way, Tangmere, Chichester PO20 2FT, UK
3Jolyon Mitchell Inhaler Consulting Services Inc., 1154 St. Anthony Road, London, N6H 2R1, Canada
4Emmace Consulting AB, Scheelevägen 22, 223 63 Lund, Sweden
Summary: The ‘Miller’ design of mixing inlet enables a cascade impactor to operate at constant flow rate whilst the inhaler‐on‐test can be evaluated at varying flow rates. Two studies forming part of a cross‐industry assessment of mixing inlet internal losses are reported, the first evaluating continuous medication delivery of salbutamol via a nebulizer, the other examining bolus delivery of pMDI‐actuated beclomethasone dipropionate (BDP). The nebulizer was subjected to a standard adult breathing profile (inspiratory/expiratory ratio = 1:1; tidal volume = 500 ml; respiration frequency = 15/min; peak inspiratory flow rate = 24 L/min). The pMDI was sampled at 30 L/min without mixing inlet and then at 40, 60 and 90 L/min with 10, 30 and 60 L/min compressed air added to the side‐arm of the mixing inlet. In the nebulizer study, total mass recovered from a Next Generation Impactor (NGI) was 569.3 ± 82.2 μg. Average losses in the mixing inlet therefore represented 0.26% of the mass recovered from the impactor. In the pMDI study, total mass recovered from the NGI components was 78.1 ± 2.0 μg BDP/actuation, and the mass recovered from the mixing inlet interior surfaces was 0.6 ± 0.2 μg BDP/actuation for measurements at 40, 60 and 90 L/min. Internal losses within the ‘Miller’ mixing inlet are <1% of the total mass of medication sampled by the impactor, and, from the pMDI study, these losses did not change significantly when the flow rate was increased through the mixing inlet to the impactor from 40 to 90 L/min.
60. EVALUATING A VARIABLE VOLUME AND FLOW RESISTANCE COMPENSATOR FOR THE MATCHING OF FLOW RATE RISE‐TIME PROFILES BETWEEN FULL RESOLUTION AND ABBREVIATED IMPACTORS WHEN TESTING DRY POWDER INHALERS (DPIS)
Ben Bradley1 & Mark Copley1
1Copley Scientific Ltd, Colwick Quays Business Park, Road No 2, Nottingham, NG4 2JY, UK
Summary: Abbreviated Impactor Measurement (AIM) is a simple, robust alternative to full resolution aerodynamic particle size distribution (APSD) measurement with several perceived benefits for both R&D and QC applications. However, differences between the flow rate rise‐time profile of AIM and full resolution impactors are a recognised issue for use in dry powder inhaler (DPI) testing because of the dependence of DPI drug delivery on inspiratory flow rate rise‐time. A variable volume and flow resistance compensator (VRC) has been developed to address this issue and used to match the flow rate rise‐ time profiles of AIM apparatuses with their full resolution counterparts, using a commercial DPI device. Flow resistance and flow rate rise‐time were successfully matched for both the Andersen Cascade Impactor (ACI) and Next Generation Impactor (NGI). The results demonstrate the utility of the VRC for laboratories seeking to match flow rate rise‐time profiles and apply closely comparable test conditions when using AIM for DPI testing.
61. A METHOD FOR DETERMINATION OF THE AERODYNAMIC DROPLET SIZE OF NEBULISED COLISTIMETHATE SODIUM USING A NEXT GENERATION IMPACTOR WITH UHPLC‐UV DETECTION
Ian Carter1, Thomas Keogh1 & Tejas Parekh1
1PPD Clinical Research Services, Thermo Fisher Scientific, IDA Business Park, Garrycastle, Athlone, Ireland
Summary: Colistimethate sodium is used in the treatment of Chromic pulmonary bacterial infection. It is a sulfomethylated pro‐drug of colistin (primarily polymyxin E1 and E2), a poly cationic peptide produced by biosynthesis and is delivered via nebulisation of a reconstituted powder. In aqueous solutions the Colistimethate Sodium undergoes hydrolysis to produce colistin with a variety of partially sulfomethylated chains of varying molecular sizes and chain lengths. This makes chromatographic analysis challenging due to the number of and varying quantities of each polymyxin and the degree of sulfomethylation. Non chromatographic methodologies used for determination of the aerodynamic droplet size distribution of nebulised colistimethate sodium can be labour intensive involving manual measurements and calculations. Ultra‐high performance liquid chromatography (UHPLC) offers automated rapid analysis and processing of data, making this a more suitable technique for higher throughput testing, which is advantageous for aerodynamic droplet size determinations. Therefore, a UHPLC method has been developed that allows quantitation of the colistimethate sodium content delivered by the nebuliser directly against the un nebulised material from the same batch, which does not require integration of the full complex chromatogram, making the method suitable for routine determination of the aerodynamic size distribution and additionally the emitted dose.
62. MEASUREMENT OF THE SATURATED VAPOUR PRESSURE OF LOW‐GWP PROPELLANTS IN CONJUNCTION WITH ETHANOL
B.J.A. Thorne1, P. Allsop1, D.P.J. Cotton1, S.B. Kirton2, M. Knowles1, K.C. Lee3, D. Murnane2, A.I. Sapsford1
1Recipharm, Bergen Way, King's Lynn, PE30 2JJ, U. K.
2University of Hertfordshire, College Lane, Hatfield, Hertfordshire, AL10 9AB
3University of East London, Docklands Campus, University Way, London, E16 2RD
Summary: Measurements of the saturated vapour pressure (SVP) of low global warming potential (GWP) propellants, R152a and HFO1234ze(e), in conjunction with ethanol, at various concentrations, were conducted to investigate for possible deviation from Raoult's law. This law allows the vapour pressure of a volatile mixture to be predicted based upon the individual vapour pressures of the constituents and their respective mole fractions in the mixture. Knowledge of the vapour pressures of these mixtures is vital for simulating the aerosolisation process for pressurised metered dose inhalers (pMDIs) using thermofluid mechanic modelling, as the vapour pressure is one of the key driving forces for aerosolisation. Any deviation from Raoult's law would necessitate a full experimental study to map the vapour pressures of these mixtures as a function of ethanol fraction and temperature.
63. DEVELOPMENT OF DUAL AERODYNAMIC PARTICLE SIZERS METHOD TO UNDERSTAND AEROSOL PLUME DYNAMICS
Yiliang Lance Jiang1, Dan Hardy1, Mahmoud Ahmed1, Gareth Hardwell,2 Richard Friend2 and Jonathan P. Reid1
1University of Bristol, School of Chemistry, Cantock's Cl, Bristol, BS8 1TS, United Kingdom
2Chiesi Ltd., 1 Bath Road Industrial Estate, Bath Rd, Chippenham, SN14 0AB, United Kingdom
Summary: Hygroscopic growth can play a crucial role in determining the size of the therapeutic particle, and, hence, affect the deposition profile of that inhalable medication. Single‐particle levitation studies, such as comparative kinetic electrodynamic balance, tells us the hygroscopicity of a particle. However, in a therapeutic setting, the dynamics of a plume of aerosol are often more relevant. Therefore, a dual aerodynamic particle sizer method has been developed to measure the plume generated from the same actuation at two different relative humidity. A connector and two spacers were 3d‐printed to connect the inhaler and suppress transient fluctuations in particle counting, respectively. A Python programme has been developed to better visualize the data obtained from the two Aerodynamic Particle Sizer. OriginLab was used to estimate the size distribution of the plume. In this study, a low concentration of sodium chloride has been nebulized, with the study benefiting from an abundance of salt hygroscopicity literature already available. The aerosol thermodynamic model E‐AIM can be used to model the hygroscopic growth against the water activity curve of well‐characterized substances including sodium chloride, allowing us to compare our changes in plume size distribution. Preliminary measurements demonstrate that the plume in the drier relative humidity exhibits a smaller mean of size distribution compared to that of the more humid one. The experimental results agrees with the E‐AIM results. Further improvement and refinement is required both to the dual APS set up and to the programme to extract more accurate size distribution.
64. CHEMICAL IMAGING BY RAMAN SPECTROSCOPY: A POWERFUL ANALYTICAL TECHNIQUE FOR SURFACE MORPHOLOGY INVESTIGATION OF INHALED PRODUCTS
Lluis Pausas, Memory Jiri, Daniel Ross & Mridul Majumder
M2M Pharmaceuticals Ltd., The Gateway Building, 1 Collegiate Square, Thames Valley Science Park (TVSP) Reading RG2 9LH, UK
Summary: Pulmonary disorders are a growing healthcare problem that are expected to worsen as the population ages. Regular use of inhaled bronchodilators to prevent and relieve symptoms is the mainstay of many pulmonary disorders. Inhalers may contain drugs either alone or combined with other Active Pharmaceutical Ingredients (API), for example, the long‐acting beta 2‐agonist and corticosteroid inhaler, which is mainly used for exacerbated chronic obstructive pulmonary disease (COPD).
Particle interactions are of great importance where the dispersion of API particles from carrier particles is critical for lung deposition. Poor API homogeneity is undesirable since homogenous drug content is essential to achieve consistent emitted dose of the drug during inhalation. Moreover, not only must the force of adhesion be strong enough to maintain the blend homogeneity during manufacturing process, but it must also allow the detachment on inhalation to effectively deposit API into the deep lung. Thus, blending API with carrier is a critical stage that determines the blend homogeneity and is the first step towards obtaining the final quality of the powder blend. Raman spectroscopy and its powerful chemical imaging capability enables understanding of many of these key attributes for inhaled formulations.
In this study, two marketed inhaler products, used for the treatment of exacerbated COPD, were compared by chemical imaging using Raman spectroscopy.
65. ASSESSMENT OF MASS FRACTION LESS THAN 10 MICRON IN NASAL PRODUCTS ‐ METHOD CONSIDERATIONS
Niklas Baltz and Regina Scherließ
Department of Pharmaceutics and Biopharmaceutics, Kiel University, Grasweg 9a, 24118 Kiel, Germany
Summary: Nasal products may contain inhalable droplets or particles smaller than 10 microns. With rising interest in using the nasal application route for systemic treatment, e.g. for diseases of the central nervous system, the safety of the route needs to be further assessed. Those small droplets or particles may transport drugs and excipients to the lungs where their risk profile is unknown or negative. Hence, a fast and easy method for determining the mass fraction less than 10 micron is needed. Different setups were assessed using a commercially available and locally acting nasal spray for allergy treatment. Different impactors and inlets were tested. The Fast Screening Impactor provided the best results with a high recovery and low standard deviation. Further experiments with suspension, dry powder and nasal metered dose formulations will be conducted to optimise and validate the preferred method.
66. ASSESSMENT OF NASAL PRODUCTS – PROPOSING A NEW INLET
Niklas Baltz and Regina Scherließ
Department of Pharmaceutics and Biopharmaceutics, Kiel University, Grasweg 9a, 24118 Kiel, Germany
Summary: With increasing interest in intranasal applications, quality attributes of nasal medicines are gaining more interest. The Ph.Eur. requires nasal products, inter alia, to be tested for uniformity of delivered dose and EMA and FDA furthermore recommend the assessment of the sub 10 micron fraction. Yet, a suitable setup for both applications including an inlet is missing. This study presents considerations regarding the inlet design for the assessment of nasal products and proposes a newly developed inlet for discussion.
67. EVALUATION OF PERFORMANCE OF DRY POWDER INHALER FORMULATIONS BY LASER DIFFRACTION
Cintia Veiga1,3, Beatriz Fernandes2 & Luis Sousa1
1Analytical Development, R&D, Hovione Hovione FarmaCiência SA, Lumiar, 1649‐038, Portugal
2Inhalation and Advanced Drug Delivery, R&D, Hovione Hovione FarmaCiência SA, Lumiar, 1649‐038, Portugal
3Biochemistry Department, University of Lisboa, Alameda da Universidade, 1649‐004 Lisboa, Portugal
Summary: The work presented here describes an alternative approach to evaluate the inherent dispersibility of powders, by laser diffraction, to assess the performance of Dry Powder Inhaler (DPI) products and guide their formulation development at early stages. Laser diffraction has been previously used to characterize the dispersibility of respirable powders [1] and even to correlate the laser diffraction results with fine particle fraction obtained by cascade impaction [2]. However, the correlations that were found were greatly dependent on some method parameters, such as the dispersing pressure, and the most adequate parameters could not be selected prior to testing. This limitation constitutes a major drawback for implementing a tool to predict the aerodynamic performance of powder formulations. The laser diffraction approach presented here, involves analysing different DPI formulations, at different dispersing pressures, and determining the rate of de‐agglomeration as a function of pressure. The parameters, obtained from this methodology, were then correlated with the emitted dose and fine particle fraction values obtained from cascade impaction testing.
68. APPLICATION OF MICRO‐RAMAN SPECTROSCOPY FOR AUTOMATIC CHEMICAL IDENTIFICATION AND SIZE DISTRIBUTION MEASUREMENT OF API PARTICLES IN PHARMACEUTICAL SUSPENSIONS. THE CASE OF FLUTICASONE PROPIONATE IN SUSPENSION NASAL SPRAYS
Alexios Tsiligiannis1, Varvara Zoumpliou1, Argyro‐Nektaria Taouktsi1, Michail Lykouras2, Ioanna Chrisikou3, Christos Kontoyannis2,3 & Malvina Orkoula2
1Elpen Pharmaceuticals Co. Inc., 95, Marathonos avenue, Pikermi, 190 09, Greece
2Department of Pharmacy, University of Patras, University Campus, GR‐26504 Rio Achaias, Greece,
3Institute of Chemical Engineering Sciences, Foundation of Research and Technology‐Hellas (ICE‐HT/FORTH), GR‐26504 Platani Achaias, Greece
Summary: The current regulatory framework allows for the in vitro comparison of inhalation and nasal products, under specific restrictions and requirements. One of the most challenging prerequisites is the comparison focusing on component identification and particle size determination, in an automated, unbiased and valid manner. In this study, a method for the automatic chemical identification of suspensions’ constituents and simultaneous determination of their particle size distributions (PSD) has been proposed. A micro‐Raman spectrometer equipped with the ParticleFinderTM software was used to identify the suspended active pharmaceutical ingredient (API) and excipients particles in azelastine hydrochloride/fluticasone propionate nasal spray suspensions and to assess their size distribution. A “generic” nasal spray suspension has been developed as a therapeutic equivalent alternative to Dymista® nasal spray. Two batches of reference product differing in their shelf life and one batch of test product were tested and compared. No individual azelastine HCl particles were detected possibly due to API dissolution and potential precipitation as an extremely fine particle size distribution. Fluticasone propionate API and Avicel® CL‐611 excipient were clearly identified and their particle size distribution was assessed. The method was successful in identifying the intended attributes, as well as potential aging effects: in several expired formulations Fluticasone propionate particles exhibited aggregation tendency captured by the proposed technique.
69. APPLICATION OF SMARTTRACK® TOOLS TO THE INVESTIGATION OF AEROSOLIZATION AND PHYSICO‐CHEMICAL PROPERTIES OF VILANTEROL DRY POWDER INHALERS (DPIS)
Jared Hall1, Elisavet Dimosthenous1, Lucas Silva1, Gonçalo Farias1, David Gomez Lamarca2, Monica Capon Borrell2, Robert Price1, Jagdeep Shur1 & Irene Rossi1
1Nanopharm, An Aptar Pharma Company, Grange Road, Cwmbran, NP44 3WY, United Kingdom
2Inke S. A., Carrer Argent 1, Barcelona, 08755, Spain
Summary: The influence of aerosolization and physico‐chemical properties of vilanterol dry powder inhalers on the in vitrorelease rate (IVRR) was investigated, employing Nanopharm's SmartTrack®, a collection of tools, which can help in demonstrating bioequivalence. In a previous study, the discriminatory ability of in vitro release testing (IVRT) to highlight differences on particle size distribution of vilanterol batches was demonstrated. In this work, instead, we focused on understanding if the use of a different device and formulation composition could be distinguished by IVRT. A Relvar Ellipta®(GlaxoSmithKline, UK) was dissembled and the content of the strips loaded in size 3 capsules and aerosolized with RS01 (Plastiape S.p.A., IT). Relvar Ellipta® as it is was compared to an Ellipta device loaded with just a vilanterol strip, RS01 loaded with vilanterol formulation and the combination vilanterol/fluticasone furoate. Impactor sized mass (ISM) was collected with Nanopharm's Dissohale and analysed by morphological directed Raman spectroscopy (MDRS) and IVRT. MDRS showed morphological equivalence between the four samples analysed, as expected. However, IVRR was significantly different between devices used. The capsule‐ based device delivered a faster release rate, showing a high initial release and a quicker plateau of the ISM compared to the Ellipta device. This outcome was inversely correlated to the circular equivalent mean diameter obtained by MDRS which was significantly lower for ISM delivered by RS01 compared to the Ellipta. The discriminatory ability of IVRT was demonstrated, particularly in assessing the influence of device employed for aerosolization on the IVRR and ISM particle size.
70. STABILITY AND AEROSOL PERFORMANCE OF AN EXCIPIENT‐FREE DRY POWDER OF TIGECYCLINE FOR LOCAL DELIVERY IN LUNG INFECTIONS
Varsha Nair1, Hugh D.C Smyth1
1The University of Texas at Austin, 2409 University Avenue, Austin, 78705, USA
Summary: Tigecycline (TIG) is a broad‐spectrum antibiotic that is susceptible against a wide variety of bacteria. It is currently marketed as Tygacil®, an intravenous injection. However, TIG undergoes rapid degradation upon exposure to an aqueous environment and must be only reconstituted at the time of administration. Through this study, a dry micronization process, air jet milling, was utilized to reduce the TIG powders into a respirable particle size range. Neat micronized TIG was found to have enhanced aerosolization efficiency as well as stability as a dry powder for inhalation. The micronized powders were compared to the non‐micronized or unmilled powder to detect any degradation that may occur due to processing. The excipient free formulation also enables high dose delivery while maintaining a lower powder payload for the patients. Further, to ensure efficient delivery and storage of TIG, it was subjected to storage stability studies as per ICH guidelines. TIG powders remained stable upon storage at high temperatures and relative humidity for 6 months. Micronized TIG powders also had little to no propensity to absorb moisture thereby facilitating the storage stability of the powders further. Additionally, the micronized powders also maintained their aerosolization efficiency with no difference between Day 0 and the 6‐month time point at 25°C/60% RH and a slight difference at 40°C/75% RH. Thus, an excipient free, inhalable, high dose dry powder of TIG exhibiting promising storage stability was developed.
71. ENCAPSULATION OF CLOFAZIMINE IN MESOPOROUS SILICA AS A POTENTIAL DRY POWDER FORMULATION FOR TREATING TUBERCULOSIS
Jesús Enrique Campos Pacheco1,2, Azra Riaz1,2, Peter Falkman1,2, Adam Feiler3,4*, Mikael Ekström5, Georgia Pilkington3 & Sabrina Valetti1,2
1Biomedical Science, Faculty of Health and Society, Malmö University, 205 06 Malmö, Sweden
2Biofilms – Research Center for Biointerfaces (BRCB), Malmö University, 205 06 Malmö, Sweden
3Nanologica AB (publ), Forskargatan 20G, 151 36 Södertälje, Sweden
4Surface and Corrosion Science, KTH Royal Institute of Technology, SE‐100 44 Stockholm, Sweden
5Iconovo AB, Ideongatan 3A‐B, 223 70 Lund, Sweden
*Current affiliation Interrobang AB. Sweden
Summary: Over the past two decades, mesoporous silica particles (MSPs) have generated significant interest for the delivery of poorly soluble drugs for oral administration. However, only more recently has their use for drug delivery via inhalation been considered, harnessing the particles’ free flowing and aerodynamic properties towards delivery to the airways. The present study demonstrates the formulation of a dry powder composed of micron‐sized MSPs loaded with clofazimine (CLZ), a drug that has been shown to be effective for the treatment of multidrug‐resistant tuberculosis. Solid state analysis indicated that the drug was fully amorphous when confined in the nanometre pores (9‐10 nm) of the mesoporous structure, with a drug loading content around 8‐10% w/w. Under simulated lung fluid conditions, 50% of the encapsulated dose of CLZ was released in 2.5 h. The concentration of drug released from CLZ loaded MSPs was greater than the measured solubility of the crystalline drug. This observation was attributed to the increased solubility of CLZ in its amorphous form. The Aerodynamic Particle Size Distribution (APSD) of the CLZ loaded particles actuated from an ICOone®inhaler at 4 kPa showed a Fine Particle Fraction (<5 μm) of 48%. In vitro permeation studies of CLZ released from MSP were performed using a Calu‐3 monolayer. The results revealed that the encapsulated CLZ can permeate across epithelium cells, whilst retention in the cell monolayer was observed. The present study indicates that CLZ‐MSPs could have value as a potential inhaled formulation for pulmonary treatment of TB and warrants further investigation.
72. UNDERSTANDING THE EFFECT OF MIXING ON THE PERFORMANCE OF DRY POWDERS FOR INHALATION
Kyrre Thalberg1,2
1Emmace Consulting AB, Scheelevägen 22, S‐223 63 Lund, Sweden
2Department of Food Technology, Engineering and Nutrition, Lund University, Lund, Sweden
Summary: This study investigates the influence of the mixing process on the dispersibility of adhesive mixtures for inhalation in terms of the fine particle fraction, FPF, with focus on formulations comprising a ‘coating agent’, blended in a high shear mixer. For such systems, an increase in dispersibility as function of the mixing time, followed by a decrease at longer mixing times, is observed. It was found that the applied mixing energy, ME, calculated from carrier particle mass, the radius of the mixing bowl, mixing time and speed, is a key factor. Based on ME, the FPF behavior can be modeled mathematically and rate constants for the increasing and the decreasing part of the FPF curve can be obtained. Formulations without a coating agent blended in a high shear mixer can also be modelled based on ME. In this case, the resulting equation is an exponential decay function. The exact mechanisms behind the increasing and the decreasing parts of the FPF curve remains to be understood but it is hypothesized that the FPF increase is caused by smearing of coating agent onto the API particles. The absence of an increasing phase for formulations without a coating agent supports this hypothesis.
73. THE MATCH BETWEEN ADHESIVE MIXTURE FORMULATION AND DEVICE
Kyrre Thalberg1,2, Rasia Ahmadi1, Peter Elfman2 & Mårten Svensson2
1Department of Food Technology, Engineering and Nutrition, Lund University, Sweden
2Emmace Consulting AB, 223 63 Lund, Sweden
Summary: This work deals with the basic question of dry powder inhaler technology: is it the device or the formulation that determines the performance? To address the question, three reservoir type DPI products: Novopulmon Novolizer®, Giona Easyhaler® and DuoResp Spiromax®, were analyzed using the Next Generation Impactor, NGI. Thereafter, the devices were carefully opened and emptied, and formulations were switched between devices and analyzed. Finally, ‘prototype’ formulations containing 2.0% budesonide and carriers of different size were tested in the Novolizer and Easyhaler devices.
The inhalers equipped with a cyclone (Novolizer and Spiromax) provided markedly higher fine particle fractions, FPFs, than the one without (Easyhaler). The switch study showed that Novolizer gave a high FPF also for the Easyhaler formulation, while the Novolizer formulation yielded a very low FPF in the Easyhaler device. When filled into Easyhaler, all prototype formulations dispersed poorly, with significantly lower FPF values than the Easyhaler product. When applied in Novolizer, the FPF level was higher, although lower than for the original Novolizer. It can be concluded that devices with a cyclone give considerably higher FPF's than devices without, regardless of the formulation. Additionally, a trend of increasing FPF for smaller carrier particle size could be observed in the Easyhaler device.
74. SEGREGATION AND DISTRIBUTION OF DIFFERENT PARTICLE SIZES IN THE COMPONENTS OF A CAPSULE FILLING MACHINE BASED ON THE VACUUM DRUM FILLER FOR DPI APPLICATIONS
Isabel Gallego1,2, Thomas Brinz1 & Martin Sommerfeld2
1Syntegon Technology GmbH, Stuttgarter Str. 130, 71332 Waiblingen, Germany
2Institute of Process Engineering, Multiphase Flow Systems, Otto‐von‐Guericke‐University Magdeburg, Hoher Weg 7b, 06120 Halle (Saale), Germany
Summary: Capsule filling using a vacuum drum allows low dose filling of dry powder inhalation (DPI) formulations. Due to the low amount of powder dosage, accurate fill weight and uniform content of active pharmaceutical ingredient (API) in the capsules are critical. API is mixed with the excipients before entering the capsule filling machine, however, it is desired to investigate whether there is any segregation of the powder during the capsule filling process. The capsule filling machine is mainly composed of a feeding station, a powder chamber with a stirrer and a vacuum drum with bores. In this study, the segregation in the vacuum drum was investigated by using a tracer, as well as the influence of different types of stirrers in the powder chamber. A mixture of three lactose with different particle size was studied to analyse the behaviour of small and big particles in the filling process, by replacing either small or big particles with their respective tracer. To obtain the tracer, the lactose was dyed with a solution of methylene blue in ethanol in a fluidized bed, and its concentration was measured with UV‐ Vis spectroscopy. It was identified that the type of stirrer used in the powder chamber influences the segregation of particles of different sizes in the vacuum drum, showing statistically significant differences.
75. INVESTIGATION OF THE DISPERSIBILITY FOR SOFTPELLETS AND THE BENEFICIAL EFFECT OF ARTIFICIAL DISPERSING AIDS
Melvin Wostry and Regina Scherließ
Department of Pharmaceutics and Biopharmaceutics, Kiel University, Grasweg 9a, 24118 Kiel, Germany
Summary: In this study, the new approach utilizing softpellets as dry powder formulation for inhalation in combination with an inhaler containing a dispersing aid was investigated. The preparation of the softpellets was done by controlled agglomeration of micronised particles of lactose via vibration. While the micronised powders with a x50 value of 2.86 μm are suitable for inhalation into the deep lung, they are prone to uncontrolled cohesion and bad flowability behaviour. Contrary, the softpellets with an x50 value of 363.17 μm are round agglomerates with beneficial handling characteristics. The characterisation of dispersing behaviour was performed by laser diffraction using the HELOS with either the RODOS module for optimal dispersion or the INHALER module. With the RODOS micronised powder and softpellets showed an equivalent dispersing behaviour. Inhaled from the Cyclohaler, the softpellets showed a relative deagglomeration of 48.98% compared to the optimal dispersed micronised powder. The micronised powders in the inhaler created a relative deagglomeration of 41.21%. Therefore, the agglomeration into softpellets did not hinder the dispersibility. Additionally, the effect of dispersing aids for the generation of a fine aerosol was analysed. The dispersing aid was a 3D printed complex geometry with a diameter of 3 mm. It was placed in the mouthpiece of the inhaler. During inhalation, the dispersing aid was lifted with the airflow and due to the additional collision with the softpellets the relative deagglomeration of the softpellets was increased to 81.74%. It was proven that dispersing aids have a beneficial effect on the generation of fine particles from softpellets.
76. CAPSULE FILLING OF SPRAY DRIED POWDERS FOR INHALATION USING A DRUM FILLING TECHNOLOGY: FROM LAB TO PILOT SCALE
Rui Churro1, Carolina Lopes1, Maria Inês Lopes1,2, Susana Saldanha1 & João Pires1
1 Hovione FarmaCiência S.A., Estrada do Paço do Lumiar, Campus do Lumiar, Edifício R, 1649‐038 Lisboa, Portugal
2 Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049‐001, Lisboa, Portugal
Summary: Spray dried composite formulations are an attractive alternative for dry powder inhalers (DPIs) since these can be obtained in a semi‐continuous operation where it is possible to manipulate process parameters to tailor‐made particles with the desired properties for aerosolization. However, these powders typically have low density and poor flowability, creating operational challenges in downstream processes such as capsule filling. It is then important to characterize which are the main challenges in processing these materials both at lab and industrial scale. The current study aims at deeply understand process development across lab and pilot scale, of a capsule filling process of spray dried composite powders for pulmonary drug delivery, by means of drum technology. For that, capsule filling process performance was evaluated in terms of relative standard deviation (RSD) and aerodynamic performance, using both a lab‐ and a pilot‐scale process equipment train under different conditions. Formulation comprised trehalose dihydrate/L‐leucine (80:20 %w/w). The obtained results contribute for the choice of the most appropriate process parameters regarding drum‐based capsule filling for powders intended for inhalation and for the implementation of a suitable strategy for the upscaling of low dose DPI product using this technology.
77. ELUCIDATING THE MECHANISM OF THE EFFECTS OF CO‐JET‐MILLED L‐LEUCINE ON THE DISPERSIBILITY OF LEVODOPA DRY POWDER FOR INHALATION
Julia M.E. Berends1, Henderik W. Frijlink1, Floris Grasmeijer1,2
1Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Antonius Deusinglaan 1, Groningen, the Netherlands
2PureIMS B.V., Ceintuurbaan Noord 152, Roden, the Netherlands
Summary:Introduction – A common approach to enhance the dispersion of highly dosed dry powders for inhalation is to add force control agents, such as L‐leucine. In co‐spray‐dried formulations, L‐leucine enhances the dispersion by the formation of a shell surrounding the particles. However, the mechanism whereby L‐leucine exerts its dispersion‐enhancing effects in co‐jet‐milled formulations is unknown. This study aims to gain insight into this mechanism.
Methods – Pure levodopa and L‐leucine were micronized to an inhalable size range using a jet mill. Furthermore, levodopa was co‐jet‐milled with L‐leucine in contents of 0.5%, 2%, and 10%. Inhaler dispersion measurements were performed to analyse the performance of the formulations regarding dispersion efficiency and inhaler retention. Furthermore, the morphology of the formulations was assessed.
Results and discussion – Co‐jet‐milling of only 0.5% L‐leucine led to a marked increase in dispersibility and a reduction in inhaler retention compared to pure jet‐milled levodopa. The particles of the co‐jet‐ milled formulations exhibited a less smooth surface and appeared to be more edgy than particles of pure jet‐milled levodopa. Furthermore, the primary particle size distribution of the co‐jet‐milled formulations was smaller than that of pure jet‐milled levodopa. Additionally, the pure jet‐milled L‐leucine exhibited poor dispersion properties, including high inhaler retention. These results suggest that the mechanism behind the increased dispersibility arises from an interacting effect between L‐leucine and levodopa during co‐jet‐milling.
Conclusion – Co‐jet‐milled L‐leucine enhances the powder emission and dispersion of levodopa dry powder for inhalation. The underlying mechanism could possibly be attributed to an increased surface roughness of the co‐jet‐milled formulations, but other interacting effects may play a role as well.
78. COMPARISON OF THE LUNG DELIVERY OF A CISPLATIN DRY POWDER USING ENDOTRACHEAL ADMINISTRATION AND NOSE‐ONLY INHALATION IN RATS
Pauline Percier1, Tamara Davenne1,2,3, Ismaël Hennia1, Baptiste Mingers1, Karim Amighi2 and Rémi Rosière1,2
1InhaTarget Therapeutics, Rue Antoine de Saint Exupéry 2, 6041 Gosselies, Belgium
2Unit of Pharmaceutics and Biopharmaceutics, Université libre de Bruxelles (ULB), Brussels, Belgium
3Laboratory of Immunobiology, U‐CRI, Rue Adrienne Boland 10, 6041, Gosselies Belgium
Summary: Preclinical studies remain necessary for the development of inhaled therapies. The devices used for lung delivery of inhaled formulations to rodents can be classified as passive exposure devices (e.g., nose‐only exposure) or endotracheal devices. Endotracheal devices are used at early‐stage of development when a limited amount of drug formulation is available whereas nose‐only inhalation devices are used in more advanced non‐clinical stages such as in pivotal GLP studies. The preclinical development of a cisplatin dry powder for inhalation (CIS‐DPI) followed this approach with the use of both devices at different stages of preclinical development. In the present study, we compared the administration of CIS‐DPI using an endotracheal device and a nose‐only exposure system in rats. The two routes of administration resulted in different exposures to cisplatin, with higher exposure in the lungs and plasma following endotracheal administration at the same cisplatin dose. The upper airways (the nasal cavity in particular) were very sensitive to cisplatin and endotracheal route bypassed the upper airways, which led to higher overall tolerance to CIS‐DPI following endotracheal administration.
79. ENHANCED ENGINEERED FORMULATIONS IN DRY POWDER INHALERS FOR HIGH DOSE LUNG DELIVERY
Susana Saldanha1, Luís Sousa2 & Eunice Costa1
1Inhalation and Advanced Drug Delivery, R&D, Hovione FarmaCiência SA, Lumiar, 1649‐038, Portugal
2Analytical Development, R&D, Hovione FarmaCiência SA, Lumiar, 1649‐038, Portugal
Summary: The work reports the development of an enhanced inhalable pharmaceutical formulation for high dose delivery to the lungs that comprises spray dried cohesive composite particles physically blended with fluidizing particles. Formulations were tested in combination with the larger version of the marketed TwinCaps© single‐use dry powder inhaler: the TwinMax DPI (Hovione). Spray dried formulations are proven flexible platforms that can successfully deliver multiple active pharmaceutical ingredients, from small molecules to biologics, to the lung at relatively high dosages. However, optimized spray dried formulations are still challenging in terms of flow properties, requiring complex manufacturing processes and often the use of more complex devices, with multiple dispersion mechanisms, for successful aerosolization. Herein, an efficient aerodynamic performance of a model spray dried formulation is obtained by physically blending with an appropriate fluidizer, combining spray drying and blending, two unit operations, that are not usually combined. The testing in combination with a single‐use reservoir‐ based device, with minimum complexity, shows that this formulation provides a solution for delivering highly cohesive powders, such as spray dried powders, to the lungs by increasing the FPFED from 9.8% to 49% when comparing with neat composite particles. The combination of the single‐use device and the pharmaceutical composition embodies a dry powder inhaler platform that can be applied in a wide range of acute indications, more specifically in high drug load inhalable powders for respiratory intake.
80. ASSESSMENT OF THE REALISTIC PERFORMANCE OF A HIGH PAYLOAD DRY POWDER INHALER FOR THE DELIVERY OF BIOMOLECULES TO THE RESPIRATORY TRACT
Antonia Zapata del Baño1, Reanne Beaird1, Chloe Szeto1, Antoine Laut2, Jonathan Tournaire2, Eride Quarta3, William J Ganley1, Niall Doherty1, Robert Price1, Jagdeep Shur1 & Irene Rossi1
1Nanopharm Ltd, An Aptar Pharma Company, Franklin House, Grange Rd, Cwmbran NP44 3WY, United Kingdom
2Aptar Pharma, Route des Falaises, Le Vaudreuil 27100, France,
3University of Parma, Food and Drug Department, Parco Area delle Scienze 27/A, Parma 43123, Italy
Summary: Orbital™ is a unit dose dry powder inhaler (DPI) capable of delivering high doses to the lungs over several inhalations. The assessment of the realistic performance of Orbital™ as potential device platform for the delivery of high payload of biomolecules was performed. Most biological drugs are currently administered intravenously. Therefore, the delivery of these formulations to the lungs consist of a promising alternative with an enormous potential to treat several diseases, such as, diabetes, cystic fibrosis or asthma. A spray dried formulation comprising lysozyme was successfully manufactured and the lysozyme showed to be still active after the spray dried process. Even though Orbital™ device showed a lower emitted fraction, it was more efficient in delivering a higher dose to the lungs with a FPF of 68.57% in comparison to the 52.21% reported by RS01. Predicted regional deposition of the cumulative doses of lysozyme delivered by Orbital™showed high deposition to the deep lung (alveolar interstitial region) with lower extra‐thoracic fraction compared to RS01, demonstrating the higher de‐agglomeration efficiency of Orbital™. The lung dose achieved in a single breath with Orbital™already exceeds that of the RS01. The distribution of the lung dose across three consecutive breaths though Orbital™ (and RS01) showed the expected pattern of alveolar > tracheobronchial > bronchiolar, with the Orbital™ achieving nearly 50% alveolar dose on the second and third breaths. This device is able to deliver high doses and it is versatile enough to allow further optimization, particularly focused on improving drug emitted maintaining high respirability.
81. SIMULATION LUNG DISSOLUTION – FAST‐TRACKING DPI DEVELOPMENT
Beatriz Noriega‐Fernandes1,2, Maria Malmlöf3,4, Per Gerde3,4, M. Luisa Corvo2, Eunice Costa1
1Hovione Farmaciência S.A., R&D Inhalation & Advanced Drug Delivery, Estrada do Lumiar, Campus do Lumiar, Edifício R, 1649‐038 Lisbon, Portugal
2iMed.ULisboa, Faculdade de Farmácia, Universidade de Lisboa, Avenida Prof. Gama Pinto, Lisboa, 1649‐003, Portugal
3Inhalation Sciences, Hälsovägen 7‐9, 141 57, Huddinge, Sweden
4Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
Summary: The present abstract summarizes the development and validation work performed for a novel biorelevant collection and dissolution method for orally inhaled drug products (OIDP), in specific for dry powder inhaler (DPI) products. PreciseInhale® (Inhalation Sciences, IS) as a breath simulator for particle aerosolization and collection, and DissolvIt® (IS) as a biorelevant dissolution system were applied. The results showcase the base for decision making during equipment and method development – addition of a pre‐separator (PS) during the collection and analysis dissolution optimal concentration. Additionally, the methodology was applied for DPI formulation differentiation for Fluticasone Propionate (FP) and Salmeterol Xinafoate (SX), two active pharmaceutical ingredients (API) with different solubilities, testing particle engineering technologies and formulation strategies. The methodology showed to be suitable for formulation differentiation and ranking.
82. THE BARRIER‐FORMING ABILITIES OF A SODIUM HYALURONATE FORMULATION DELIVERED USING THE PILLHALER® DPI DEVICE FOR PROTECTION AGAINST URBAN DUST
Juhura G. Almazi1,3, Dina M. Silva3, Valentina Trotta4, Walter Fiore5, Hui X. Ong1,2,3 & Daniela Traini1,2
1Respiratory Technology, Woolcock Institute of Medical Research, Sydney, NSW 2037, Australia
2 Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, NSW 2109, Australia
3Ab Initio Pharma Pty Ltd, 63‐73 Missenden Road, Camperdown, NSW 2050, Australia.
4HollyCon Italy Pte Ltd srl, Via Danimarca 21, 20083 Gaggiano (MI), Italy.
5SOFAR Spa, Via Firenze, 40, 20060 Trezzano Rosa (MI), Italy
Summary: The pathogenesis of several bronchopulmonary diseases such as asthma, chronic obstructive pulmonary disease, acute respiratory distress syndrome and cystic fibrosis are linked to exposure to environmental pollutants such as dust, pollen, smoke, and pathogens. Thus, a comprehensive biological assessment of the protective barrier abilities against environmental pollutants (Urban Dust ‐ UD) of a formulation of sodium hyaluronate delivered to the upper respiratory tract via the monodose PillHaler® dry powder inhaler (DPI) device was performed. Using Calu‐3 cells it was demonstrated that the formulation, by forming a barrier layer, was able to prevent the direct contact of UD with the cells and in this way significantly reduced UD‐induced oxidative stress and protected the epithelium from UD‐induced inflammation. The protective barrier‐forming abilities of the sodium hyaluronate formulation have exciting implications for preventative mechanisms against exposure to environmental hazards and resulting cardiopulmonary diseases.
83. USING PRECISEINHALE® FOR CONTROLLED VOLUNTEER EXPOSURES WITH AEROSOLS EXTRACTED FROM CLINICAL INHALERS
Per Gerde1,2, Carl‐Olof Sjöberg1 Helen Bäckroos1 & Helena Litorp3,4
1Inhalation Sciences AB, Hälsovägen 7, Novum, 141 57 Huddinge, Sweden
2IMM, Karolinska Institutet, Nobels väg 13, 171 77 Stockholm, Sweden
3CTC Clinical Trial Consultants, Dag Hammarskjölds väg 10B, 752 37 Uppsala, Sweden
4Department of Global Public Health, Karolinska Institutet, 171 77 Stockholm, Sweden
Summary: The PreciseInhale® (PI) platform was used to extract clinical inhaler doses from the pressurized metered dose inhaler (pMDI) Evohaler Seretide forte, Fluticasone Propionate (FP) 250 μg, Salmeterol Xinafoate (SMX) 25 μg and then expose human volunteers by visually prompting controlled administration from the clinical exposure module of PI. Through 4 study arms the following two comparisons were made: I) The direct inhalation of one dose from the clinical inhaler, according to the label instructions, was compared to the same dose aspirated into the PI and inhaled by the volunteers, following prompted instructions. II) Six subdivided fractions of one dose from the Evohaler was inhaled and targeted to the peripheral lung and the central airways respectively, using the bolus breath hold method provided by the PI. Results show that, compared to direct inhalation from the inhaler, instead extracting the clinical inhaler dose into the PI and then controlling the exposure from the PI both increase the lung deposited dose of drug and the dosing precision. The peripheral lung bolus of FP had a 98% deposition upon inhalation compared to 58% deposition of the central airway bolus. FP had similar pharmacokinetics in both regions, whereas SMX had a significantly higher Cmax following exposure of the peripheral lung.
84. AN IN VITRO EXPOSURE PLATFORM FOR INVESTIGATING BACTERIAL AND EPITHELIAL CELL RESPONSES TO AEROSOLIZED PHAGE CHALLENGE.
Mathura Thirugnanasampanthar1,2, Michelle Feng1,3, Fereshteh Bayat1,4, Rod G Rhem5, Myrna B Dolovich1,5,6 & Zeinab Hosseinidoust1,2,4,7
1McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada
2Department of Chemical Engineering
3Department of Electrical Engineering
4School of Biomedical Engineering
5St. Joseph's Healthcare, Firestone Research Aerosol Laboratory, 50 Charlton Avenue East, Hamilton, ON, L8N 4A6, Canada
6Faculty of Health Sciences, Department of Medicine
7Michael DeGroote Institute for Infectious Disease Research
Summary:Pseudomonas aeruginosa (Pa) is a bacterial pathogen responsible for chronic respiratory infections in cystic fibrosis (CF) patients. Bacteriophages (also known as phages) are viruses which infect bacteria; phage therapy is the use of these natural predators to treat infections. Investigations with aerosolized phage are limited and primarily focus on proof‐of‐concept demonstrations with animal models. In vitro models are needed to conduct comprehensive, mechanistic research. We report the development of an in vitro platform for evaluating the response of Pa bacterial cells and Calu‐3 human airway epithelial cells to aerosolized Pseudomonas phage vB_Pae‐TbilisiM32. Phage aerosols were generated using a single jet Blaustein atomizer. Transwells containing Pa biofilms and air‐liquid interface cultures of Calu‐3 were separately exposed to aerosolized phage within a cascade impactor. Assays performed 24 hours later were used to determine the effect of airflow and phage treatments on Pa and Calu‐3 cells. XTT assay and Live/Dead staining were used to assess the metabolic activity and viability of bacterial cells, respectively. Significant reductions in metabolic activity and viability of Pa cells were observed after phage exposure, indicating phage‐mediated killing of bacterial cells has occurred. Fluorescein isothiocyanate‐conjugated dextran (FITC‐dextran) assay and Live/Dead staining were used to assess the barrier integrity and viability of Calu‐3 cells, respectively. The results show exposure to high‐velocity airflow and phage aerosols does not affect barrier integrity or viability of Calu‐3 cells. In summary, our platform can be used to assess bacterial and epithelial cell responses to aerosolized phage treatment.
85. PULMONARY DELIVERY OF SIRNA TARGETING EGFR AND PD‐L1 IN IN VIVOTRACEABLE NSCLC MODELS
Rico Chi Hang Man1,2, Susan Wai Sum Leung1, Jenny Ka Wing Lam1,3 & Gilbert O. Fruhwirth2
1 Laboratory of Macromolecular Drug Delivery, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong SAR
2 Imaging Therapies and Cancer Group, Comprehensive Cancer Centre, School of Cancer and Pharmaceutical Sciences, Teaching Department of Biochemistry, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom
3 Department of Pharmaceutics, UCL School of Pharmacy, University College London, London, United Kingdom
Summary: Non‐small cell lung cancer (NSCLC) is the leading cause of cancer mortality globally. NSCLC is frequently associated with an up‐regulation of epidermal growth factor receptor (EGFR) and programmed death‐ligand 1 (PD‐L1), where the former promotes tumour survival and the latter prevents cancer cells from immune detection. However, existing therapeutics, such as EGFR and PD‐1/PD‐L1 inhibitors or monoclonal antibodies are subject to drug resistance, poor response rate and tumour relapse, thereby limiting their efficacies. The development of an alternative therapeutic strategy for NSCLC is of the utmost urgency. Recently, small interfering RNA (siRNA) emerges as a novel anticancer therapeutic. It inhibits specific gene expression of proteins involved in tumorigenesis through RNA interference (RNAi). We aim to inhibit both EGFR and PD‐L1 expressions using siRNAs to enhance NSCLC treatment outcome. To track the tumour progression following siRNA treatments, we successfully engineered and characterised two in vivo traceable NSCLC cell models, which express either luciferase (for 2D bioluminescence imaging) or NIS‐TagRFP (for 3D radionuclide tomography). Furthermore, the expressions of EGFR and PD‐L1 were significantly reduced in human lung cancer cells mediated by synthetic PEG12‐KL4 peptide, which acts as an efficient siRNA delivery vector. More importantly, initial in vivo work demonstrated that the delivery of siRNA through intratracheal route was safe and effective in maximising siRNA concentration in the lungs. With the successfully validated in vivo traceable NSCLC lines, orthotopic NSCLC models will now serve to evaluate anti‐tumour effects of siRNA treatment on EGFR and PD‐L1 knockdown.
86. CHARACTERISING PROTEIN DPI FORMULATIONS: HOW AND WHY DOES THE DISSOLUTION BEHAVIOUR CHANGE?
Friederike Roth, Regina Scherließ
Department of Pharmaceutics and Biopharmaceutics, Kiel University, Grasweg 9a, Kiel, 24118, Germany
Summary: Treating lung diseases with high molecular protein drugs is still limited by their inability to penetrate well through the pulmonary tissue. Local pulmonary application facilitates treatment with these protein drugs. Furthermore, it would broaden the application possibilities of smaller proteins and peptides that are able to penetrate through the epithelium. The application via the lung is a suitable alternative to the commonly used parental application. To ensure the stability of the sensitive protein drugs during storage an inhalable dry powder formulation is a good option. The most suitable production method for protein DPI formulations is spray drying. This, however, comes with various stress factors for the protein and can thereby change the properties of the protein. This study focuses on observed changes in the dissolution behaviour. It aims to characterise these changes and to find a structural explanation. We used ovalbumin as a model protein and compared the commercial lyophilisate with ovalbumin spray‐ dried with two different spray‐drying nozzles: the two‐fluid nozzle and the ultrasonic nozzle. As a characterising method, we choose the Franz cell dissolution measurements. The obtained dissolution profiles show differences in dissolution velocity. Although a morphological explanation seems obvious, experimental observations indicate further changes. Further experiments to characterise these changes are ongoing It was not possible to find a structural explanation for these dissolution changes with the used methods. Neither XRPD measurements nor fluorescence emission spectra assay showed structural changes after spray drying. The search for a method to identify the structural explanation for the observed changes continues.
87. A FUNCTIONAL STUDY OF TUBING MATERIAL FOR THE SPRAY DRYING OF MRNA‐LIPOPLEXES
Jana Schembera1, Ricarda Leister2 and Regina Scherließ1
1Department of Pharmaceutics and Biopharmaceutics, Kiel University, Grasweg 9a, Kiel, 24118, Germany
2Meggle GmbH & Co. KG, Megglestr. 6‐12, Wasserburg am Inn, 83512, Germany
Summary: The overall goal of this project was to produce an inhalable dry powder platform for mRNA vaccination. In order to achieve this goal mRNA‐lipoplexes comprising mRNA and DOTAP:DOPE were developed, which shall be transferred to inhalable dry particles by spray drying. Compatibility experiments with mRNA‐lipoplexes have shown that mannitol or lactose could be suitable excipients with established use in inhalation. However, the first spray drying experiments revealed decreased transfection capabilities of the processed mRNA‐lipoplexes compared to the control. Thus, we focused on the spraying process itself to assess the influence of each individual step: the pumping of feed liquid through the tube, the atomisation and the drying itself. The tube was identified as a major obstacle as the lipoplexes adsorbed to the tubing, resulting in loss‐of‐function of the mRNA‐lipoplexes. Comparative studies identified materials suitable for the processing of DOTAP:DOPE mRNA‐lipoplexes.
88. REAL‐TIME IN‐SITU MONITORING OF AIR INTERFACE PSEUDOMONAS AERUGINOSA BIOFILMS GROWTH AND ITS ANTIBIOTIC SUSCEPTIBILITY USING A NOVEL DUAL‐CHAMBER MICROFLUIDIC DEVICE
Ye Zhang1,2, Hanieh Gholizadeh1,2, Paul Young2,4, Daniela Traini2,3, Shaokoon Cheng1, Hui Xin Ong2,3
1School of Engineering, Faculty of Science and Engineering, Macquarie University, Sydney, NSW, Australia
2Woolcock Institute of Medical Research, Sydney, NSW, Australia.
3Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia
4Department of Marketing, Macquarie Business School, Macquarie University, Sydney, NSW, Australia
Summary:Pseudomonas aeruginosa(P. aeruginosa) biofilm colonizing and growing in the human respiratory tract is a known cause of reduced antimicrobial response in several chronic respiratory diseases. Despite the plethora of research, most biofilm models are cultured on a solid‐liquid interface, and conventional biofilm characterization methods are usually destructive, time‐consuming, and cost‐ineffective. In this study, we developed a novel dual‐chamber microfluidic device integrated with advanced electrochemical microelectrodes consisting of conical carbon fibre electrodes for culturing biofilm at the air‐liquid interface (ALI). Using our novel chamber real‐time and in‐situ monitoring of biofilm's viability by detecting the excretion of pyocyanin (PYO) was also performed. Using this device, the growth of P. aeruginosa biofilms was monitored over 48 h, and its viability after 6 h exposure to 50, 400, and 1600 μg/mL of ciprofloxacin solutions via direct treatment (drug delivered into the apical chamber) and indirect treatment (drug delivered into the basal chamber) was measured and compared and electrochemical results verified with the colony‐forming unit (CFU) count method.
89. IN‐VITRO MODELLING OF THE LUNGS RESPONSE TO NANOPARTICULATES
Altin Kocinaj1, Laura Urbano1, Darragh Murnane1
1University of Hertfordshire, College Lane, Campus, Hatfield AL10 9AB
Summary: Nanoparticles are abundant in everyday life, with air pollution and consumer products leading to a growing number of concerns for potential health effects of inhaled exposure. There is no standalone alternative for animal toxicity studies, thus we sought to build a predictive cell culture model using high content imaging/analysis (HCA) and traditional viability assays. Human lung epithelial cells (NCI‐H441) were seeded for in a 96‐well plate and exposed to a panel of nanoparticles for 24 hours, for high content imaging. For the HCA, plated cells were given fluorescent labels which allowed both morphological assessment (such as cell area and diameter, membrane permeability and mitochondrial activity) and cell segmentation for the consequent analysis. Image acquisition was performed using an automated fluorescence imager (EVOS M7000) and was segmented and analysed using the accompanying Celleste program. Morphological differences can be seen and analysed using HCA, with the possible identification of subgroups of cells. There are differences in such parameters as cell area with ∼100% of cells exposed to 33ug/ml of copper oxide being below the median cell area of the control or lowest concentration used. Also, a flattening and spread of the 33ug/ml distribution indicating a larger population of cells compared to control with greater membrane permeability. These preliminary results indicate the possible use of HCA to define morphometric cell‐by‐cell changes and population subgroups that are not able to be elucidated by a single value from standard assays (such as Prestoblue – cell viability).
90. CORRELATION BETWEEN PATIENT HANDLING ERRORS AND IN‐VITROPERFORMANCE OF SPIRIVA® HANDIHALER®
Jetmir Xhema1, Line Tschiember1 & Yannick Baschung1
1OINDP analytical services, Solvias AG, Kaiseraugst, Switzerland
Summary: Success of inhalation therapy highly correlates with appropriate and reproducible doses delivered to the lungs, and correct inhaler technique are key for successful treatment outcome. Lack of treatment adherence, incorrect breathing techniques and misuse of inhalers by patients are some of the parameters that lead to uncertainties about lung deposition and can have a significant impact on the dose delivered and on the success of the treatment. Several studies exist in which the prevalence of human error for each type of inhaler and each category are described. However, the impact of these errors on the dose delivered to the patient and on the aerodynamic size distribution of the particles delivered by the inhaler remains unclear.
In the present study, various commonly reported patient handling errors were reproduced in‐vitro to identify their impact on the Emitted Dose (ED) and Aerodynamic Particle Size Distribution (APSD) performance of the device. We have highlighted that adapted in‐vitro measurements may help to better understand the importance and interactions between human handling errors and device performance, and that a particular emphasis should be placed on the training of patients against critical inhaler handling errors, as some of the in‐vitro reproduced errors have shown to lead to a drastic decrease of device performance, both on the Emitted Dose (ED) and on the Aerodynamic Particle Size Distribution (APSD) performance of the device, which can therefore significantly impact the success of the treatment.
91. PREVENTION OF LUNG INFLAMMATION BY ISOFLAVONE GENISTEIN
Susan W.S. Leung1, Pang Zhang1,2, Jenny K.W. Lam1 & Judith C.W. Mak1,3
1Department of Pharmacology and Pharmacy, University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong SAR, China
2Department of Pharmacy, Luohu People's Hospital, 47 Youyi Road, Luohu, Shenzhen, 518001, China
3Department of Medicine, University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong SAR, China
Summary: Genistein is a natural product present in the diet, and appears to possess many biological actions including anti‐inflammatory, anti‐oxidant, anti‐microbial, estrogenic/anti‐estrogenic and vasodilatory activities. As such, it is likely to be useful as a preventive/therapeutic agent against inflammatory responses in the lung caused by bacterial/viral infection. The present study aimed to determine the effects of genistein in the lung exposed to inflammatory insults. Male Sprague Dawley rats (eight‐week old) were administered with either genistein (10−2 g/kg) or its vehicle (methylcellulose, 0.5%) by oral gavage once every day for eight weeks, and with bacterial endotoxin lipopolysaccharides (LPS; 2×10−4 g/kg) or its vehicle (sterile saline) intratracheally using a microsprayer at day 28 and day 42 during genistein/vehicle treatment. Exposure to airborne LPS resulted in alveolar enlargement; this is associated with increased levels of inflammatory mediators [interleukin (IL)‐6, CINC‐1 (resemble to human IL‐8) and monocyte‐chemotactic protein‐1] in the bronchoalveolar lavage fluid, and of the oxidative stress marker malondialdehyde in the lung lysates. These effects of LPS were reduced in rats treated with genistein. Moreover, genistein prevented the LPS‐induced increased activity of the anti‐ oxidant enzyme catalase in the lungs. The present findings, therefore, demonstrated a protective effect of genistein against the induction of lung inflammation by airborne LPS. Taken into consideration of the multiple systemic biological actions, and the variable pharmacokinetic profile of orally‐administered genistein, the development of inhalable formulation or pulmonary delivery approaches is warranted in order for genistein to be useful as a preventive/therapeutic agent against lung inflammation.
92. INHALED CISPLATIN DRY POWDER COMBINED WITH ANTI‐PD1 INDUCES ANTI‐TUMOUR IMMUNE‐ RESPONSE IN LUNG CANCER
Tamara Davenne1,2,3, Pauline Lehebel1, Lionel Larbanoix4, Muriel Moser3, Oberdan Leo3, Etienne Meylan3, Nathalie Wauthoz2, Stanislas Goriely3, Karim Amighi2 and Rémi Rosière1,2
1InhaTarget Therapeutics, Rue Antoine de Saint Exupéry 2, 6041 Gosselies, Belgium
2Unit of Pharmaceutics and Biopharmaceutics, Université libre de Bruxelles (ULB), boulevard du triomphe, Campus plaine CP207, 1050 Brussels, Belgium
3Laboratory of Immunobiology, U‐CRI, Rue Adrienne Boland 10, 6041, Gosselies Belgium
4Center for Microscopy and Molecular Imaging (CMMI), Université de Mons, 6041 Gosselies, Belgium
Summary: Despite advances in targeted therapies and immunotherapy in non‐small cell lung cancer (NSCLC), intravenous chemotherapy, and its numerous side effects, remains the backbone of NSCLC treatment. Inhaled chemotherapy addresses the problem of systemic toxicities observed with intravenous administration and increased local concentrations. Dry powder cisplatin for inhalation (CIS‐DPI) was tested as a novel way to deliver cisplatin locally via the pulmonary route, to target lung tumours. CIS‐ DPI delivered by endotracheal administration demonstrated a dose dependent efficacy in the syngeneic orthotopic M109 lung carcinoma murine model. In addition, CIS‐DPI induced an upregulation of the immune checkpoint PD‐L1 on tumour cells, suggesting an additional benefit when combined with an immune checkpoint inhibitor. Indeed, the combination of CIS‐DPI with anti‐PD1 therapy significantly reduced tumour growth and prolonged survival compared to anti‐PD1 monotherapy. In the tumour, the combination treatment induced the most potent recruitment of conventional dendritic cells and of tumour infiltrating lymphocytes, showing the hallmarks of an anti‐tumour immune response. Altogether, our results show the efficient pulmonary delivery of CIS‐DPI exerting its direct cytotoxic effect on tumour, and its additional effect on the anti‐tumour immune response when combined with anti‐PD1 therapy. Thus, combining CIS‐DPI with anti‐PD1 is a promising strategy for improved lung cancer therapy.
93. A MONOCLONAL ANTI‐SARS‐COV‐2 IGG ADMINISTERED BY INTRAVENOUS OR NEBULIZATION ROUTE REDUCES VIRAL LOAD IN UPPER AND LOWER RESPIRATORY TRACT
Benoît Delache1*, Cécile Hérate1*, Paule Hermet2, Andres Männik2, Quentin Sconosciuti1, Francis Relouzat1, Asma Berriche1, Thibaut Nanninck1, Nathalie Deureuddre‐Bosquet1, Roger Le Grand1 and Mart Ustav Jr2
aUniversité Paris‐Saclay, Inserm, CEA, Center for Immunology of Viral, Auto‐immune, Hematological and Bacterial diseases (IMVA‐HB/IDMIT), Fontenay‐aux‐Roses & Le Kremlin‐Bicêtre, Paris, France
bIcosagen Cell Factory OÜ, Tartu, Estonia,
Summary: Icosagen developed an anti‐Sars‐COV‐2 neutralising monoclonal antibody (VH16VL104) effective in vitro against multiple variants of the virus including the Delta and Omicron variants of concern (VOC). We developed an optimized prototype for respiratory tract delivery customized for Non‐Human Primate (NHP) in spontaneous breathing by adapting a vibrating mesh nebulizer (VMN) from Aerogen (Aeroneb solo) to a facemask fitted with unidirectional valves. The effectiveness of the device has been confirmed by positron emission tomography coupled to X‐ray scan (PET‐CT) imaging after 18‐FDG nebulization on three macaques. The therapeutic efficacy of the nebulized (Neb) VH16VL104 was assessed in cynomolgus macaques 24 hours after exposure to a high dose (105 TCID50/animal by intranasal & tracheal route) of Sars‐COV2. We compared the nebulization route with intravenous (IV) bolus administration. The antibody treatment was administrated as a single dose of 25mg.kg−1. Nebulization administration results in antibody concentrations in broncho alveolar lavages (BAL) more than 10 times higher than the IV route 48 hours post‐treatment and a systemic passage resulting in serum concentrations 100 times lower than the IV route. The antibody is present in the blood of all animals for at least 28 days after administration. The VH16VL104 treatment efficacy on viral load measured in nasopharyngeal swabs and BALs was statistically significant regardless of the route of treatment administration. Our data suggest that mesh vibrating nebulization is of interest for patients requiring immediate strong antiviral effect in the lung. This route of administration, in complement to IV, could be used against other pathogens when a therapeutic pulmonary bolus is crucial.
94. EFFECTS OF SALINE NEBULISATION ON SARS‐COV2 SPREADING AND EXHALED BIO‐AEROSOL PARTICLES IN HOSPITALISED COVID‐19 PATIENTS
Francesca Buttini1, Leonardo Gori2, Fabio Morecchiato2, Andrea Bartolini2, Gian Maria Rossolini,2 Alessandro Bartoloni2, Jessica Mencarini2, Ruggero Bettini1 and Federico Lavorini2
1Food and Drug Department, University of Parma, Parco Area delle Scienze 27A, Parma, 43124, Italy
2Department of Experimental Medicine, University of Florence, Largo Brambilla 3, Florence, 50134, Italy
Summary: Nebulised therapy is the mainstay for treating obstructive airway diseases, but there is heightened particular concern about the potential risk for SARS‐CoV2 transmission during nebulisation in COVID‐19 patients. In 10 patients (6 females, mean age 63±4 yr) hospitalised for COVID‐19 we investigated the effects of 0.9% saline nebulisation on SARS‐CoV2 spreading. In 5 out of the 10 patients we also ascertained whether saline nebulisation changed the number of exhaled particles. Air samples were collected by using suction pumps equipped with 0.45μ PTFE filters and positioned around the patient's bed. Exhaled particles were quantified by using an optical particle counter. At baseline (i.e. before nebulisation) SARS‐CoV2 was detected more in the pumps close to the patient than in those far away.
In the pumps close to the patient, detection of SARS‐CoV2 was similar after saline nebulisation compared to baseline. In the pumps far from the patient saline nebulisation slightly but not significantly increased SARS‐CoV2 detection compared to baseline. Overall, no significant changes in the SARS‐ CoV2 detection was observed after saline nebulisation. At baseline, we found a large variability among patients in the exhaled particles emission, with 2 patients showing higher emission of particles than the remaining patients. Saline nebulisation induced a marked decrease in exhaled particles in the 2 patients who displayed high emission at baseline, whereas no changes was observed in the remaining. Of note, the patients who displayed high emission at baseline showed a reduction in the number of pumps positive for SARS‐CoV2 after saline nebulisation. This pilot study shows that saline nebulisation does not significantly change SARS‐CoV2 spreading. Thus, there is no compelling reason to alter aerosol delivery devices for patients with established nebuliser‐based regimens.
95. ASSESSMENT OF FUGITIVE AEROSOL EMISSION DURING ACTUATION OF A BREATH‐ACTUATED MESH NEBULISER
Edgar H. Cuevas Brun, Ciou‐Ting Wang, Yen‐Ting Chen, Jui‐Sui Chen & Yuan‐Ming Hsu
HCmed Innovations Co. Ltd., Rm. B, 10F., No.319, Sec.2, Dunhua S. Rd., Taipei City, 10669, Taiwan
Summary: Emission of fugitive aerosol has increasingly gained attention in the inhalation therapy field due to the risk it may pose to medical practitioners and bystanders that are in close proximity to patients receiving treatment with nebulisers. Existing data indicates that up to 50% of the aerosol generated with continuous output mode nebulisers could potentially end up as fugitive aerosol. As a result, several approaches have been introduced to mitigate this issue, one of them being breath actuation, which offers among the most effective solutions to reduce fugitive emission, while improving delivered dose. In this study, a breath‐actuated mesh nebuliser was used to assess fugitive aerosol emission by comparing a control setup against two other setups that included a suction source (30 L/min and 60L/min) to capture fugitive aerosol that could escape from the back ventholes of the nebuliser. The results revealed that while keeping a delivered dose close to 80%, the captured fugitive aerosol remained between 1.6 and 2.1%. The results also indicated that the aerodynamic design for the air flow path of the nebuliser had also contributed to the resistance of reverse air flow to a certain degree. The findings did not only support the expected outcomes of the nebuliser's breath‐actuated function, but also confirmed the generation of a desirable aerosol performance with droplets within the respirable range. Moreover, it is projected that studies of this nature could further encourage the development of inhalation treatments involving inhaled formulations that contain biologics and antibiotics.
96. TREATING INFLAMMATION IN RESPIRATORY DISEASES BY INHALED ARYL HYDROCARBON RECEPTOR LIGANDS AND ACTIVATORS
M. Puccetti1, M. Pariano2, D. Traini3, W. Paulina1, A. Schoubben1, M. Ricci1 & S. Giovagnoli1
1Department of Pharmaceutical Science, University of Perugia, Perugia, 06123, Italy
2Department of Medicine and Surgery, University of Perugia, Perugia, 06132, Italy
3Macquarie Medical School, Faculty of Medicine, Health, and Human Sciences, Macquarie University, Sydney, NSW 2109, & The Woolcock Institute of Medical Research, Sydney, NSW, 2031, Australia
Summary: Due to mechanical, chemical and immunological barriers to the respiratory tract, pulmonary drug delivery is complex and demands strategies and formulations that maximize airway selectivity. The association between inflammation and chronic disease is still under investigation and how to translate the body of knowledge into effective strategies for the prevention and treatment of pathologic inflammation is lagging. In this regard, in this study, a dry powder formulation acting on the xenobiotic aryl hydrocarbon receptor (AhR) to regulate lung function and inflammation is presented and in vivo pharmacological properties and toxicity are assessed. Targeting of AhR is of great medical and pharmaceutical interest for inhaled therapies targeting diseases in which immunopathology plays a pathogenetic role. However, despite the availability of several structurally diverse ligands of AhR, the bottleneck in targeting this receptor is its ubiquitous expression and its functional activity that is both contexts and ligand‐dependent. In this study, we provide a proof‐of‐concept demonstration of the druggability of AhR in lung inflammation via inhalable dry powders of either the tryptophan metabolite of microbial origin, indole‐3‐aldehyde, an AhR ligand, or of the recombinant form of the endogenous IL‐1 receptor antagonist (anakinra), an AhR modulator. Either immunomodulatory treatment resolved inflammation without compromising the ability of the immune system to respond to pathogens and with no signs of unwanted toxicities and off‐target effects.
97. ASSESSMENT OF AEROSOL DRUG DELIVERY TO SIMULATED ADULT AND PAEDIATRIC PATIENTS WITH VARYING LUNG DISEASES DURING MECHANICAL VENTILATION
Shane Raftery1, Marc Mac Giolla Eain1, Mary Joyce1, Andrew O'Sullivan1 & Ronan MacLoughlin1
1Aerogen Ltd., Galway Business Park, Dangan, Galway, H91HE941, Ireland
Summary: Mechanical ventilation, used in combination with nebulised therapeutics, plays an integral role in the management of patients with acute respiratory disease. Disease type and severity alters pulmonary function and therefore could potentially affect aerosol drug delivery. This study investigated different disease states and the potential effect of each on aerosol drug delivery during mechanical ventilation. Aerosol drug delivery using a vibrating mesh nebuliser was assessed in two different patient cohorts, adult and paediatric, with four different diseased lung states, and compared to a normal healthy lung profile, during simulated mechanical ventilation. Diseased lung breath patterns were provided by a breathing simulator. The mass of drug captured on a filter was determined using UV spectroscopy at 276nm. For both adult and paediatric simulated patients, there was a statistically significant difference in aerosol dose (%) delivered across all disease states assessed (p<0.05) with the largest dose delivered to the normal healthy lung (23.85 ± 1.16% for adults and 7.70 ± 0.36% for paediatrics). In comparing disease states, a significant difference was reported for the simulated adult disease states assessed (13.79 ±0 .73% for COPD; 8.82 ± 0.47% for ARDS) but not for paediatrics (5.91 ± 0.48% for asthma; 5.35 ± 0.29% for obstructive lung disease). It can be concluded that aerosol drug delivery can be affected by the condition of the patient and the severity of the disease.
98. PHARMACOKINETICS, SAFETY AND TOLERABILITY OF INHALED EPINEPHRINE FROM CYCLOPS™ IN HEALTHY VOLUNTEERS
Floris Grasmeijer1,2, Wouter Dijkstra1, Reinier Schwietert1 & Erik Frijlink2
1PureIMS B.V., Ceintuurbaan Noord 152, Roden, 9301 NZ, the Netherlands
2Department of Pharmaceutical Technology & Biopharmacy, University of Groningen, Antonius Deusinglaan 1, Groningen, 9713 AV, the Netherlands
Summary: Intramuscular administration of epinephrine by autoinjectors is prone to errors and associated with a high barrier to use. Epinephrine dry powder inhalation may offer a more convenient, low‐barrier alternative. Therefore, the pharmacokinetics, safety and tolerability of an epinephrine dry powder inhalation formulation administered with the single‐use inhaler Cyclops™ was determined in this phase I, ascending‐dose, placebo‐controlled crossover study. Inhaled epinephrine in nominal doses of 0.35, 0.65 and 1.3 mg was well tolerated by ten healthy volunteers as no cough or local irritation was observed and no systemic reactions occurred. The Tmax of inhaled epinephrine was 2 minutes versus 34 minutes following intramuscular administration of epinephrine with an autoinjector. The mean Cmax was four‐fold higher after inhalation of 1.3 mg of epinephrine than after 0.3 mg intramuscular epinephrine, whereas the mean total exposure in the first 30 min (AUC0‐30) was comparable. This study therefore demonstrates the potential of inhaled epinephrine as a first‐line treatment in the event of an emerging allergic reaction.
99. PULMONARY DELIVERY OF FAVIPIRAVIR FORMULATION USING SOFT‐MIST INHALER FOR COVID‐19
Ayca Yildiz‐Pekoz1, Ozlem Akbal‐Dagistan1, Hanan Fael1, Meltem Culha1, Aybige Erturk1,9, Nur Sena Basarir1, Gokben Sahin1,10, Mustafa Sevim2, Semiha Leyla Sen2, Mert Kaskal3, Muge Serhatli5, Gamze Cakirca5,6, Saban Tekin5,7, Lutfiye Mulazimoglu Durmusoglu8, Berrak Yegen2
1Istanbul University, Faculty of Pharmacy, Department of Pharmaceutical Technology, Istanbul, Türkiye
2Marmara University, School of Medicine, Basic Medical Sciences, Department of Physiology, Istanbul, Türkiye
3Marmara University, School of Medicine, Internal Medical Sciences, Department of Medical Pharmacology, Istanbul, Türkiye
4TUBITAK Marmara Research Center‐MRC, Life Sciences, Medical Biotechnology (Marmara Research Center (MRC), 41470, Gebze‐Kocaeli, Türkiye
5Molecular Biology and Genetics, Institute of Natural and Applied Sciences, Gebze Technical University, 41400, Gebze, Kocaeli, Türkiye
6University of Health Sciences, Hamidiye Faculty of Medicine, Department of Basic Medical Sciences, Medical Biology, Istanbul, Türkiye
7Marmara University, School of Medicine, Department of Infectious Diseases, Istanbul, Türkiye
8Istinye University, Faculty of Pharmacy, Department of Pharmaceutical Technology, Istanbul, Türkiye
9Trakya University, Faculty of Pharmacy, Department of Pharmaceutical Technology, Istanbul, Türkiye
Summary: Favipiravir, an RNA‐dependent RNA polymerase (RdRp) inhibitor, is one of the repurposed drugs that were used for patients in the COVID‐19 pandemic. Although favipiravir was shown to be effective against SARS‐CoV‐2 virus, the expected performance was not achieved in the clinic. This was mainly due to the poor accumulation of favipiravir in the lung tissue following conventional administration. For our study, we proposed a theory that favipiravir is an ideal candidate for pulmonary delivery and developed the first suitable oral inhalation formulation with a high reduction in the dosage using soft‐mist inhalers. Local lung targeting through inhalation of favipiravir is not only expected to overcome the low bioavailability of oral administration, but also aims to achieve a higher drug concentration in the lung tissues. Favipiravir pH‐solubility profile was constructed and the impact of cyclodextrin additives on its solubility was investigated through phase solubility diagram. Preclinical studies were carried out on both sexes of rats, showing significant local lung accumulation and safe oxidative stress parameters. Ex vivo studies were carried out with xCELLigence RTCA MP device and proved that an inhalation dose of 2 mg/ml of favipiravir to be an effective dose against COVID‐19 virus when given with soft‐mist inhalers. These studies are noteworthy in terms of developing an alternative dosage form to the product available in the market for treatment of diseases caused not only by SARS‐CoV‐2, but also other airborne viruses.
100. NOVEL HIGHLY EFFICIENT SYSTEM FOR BREATH‐TRIGGERED AEROSOL DELIVERY FOR PRETERM INFANTS USING NON‐ CONTACT BREATH CAPTURE
Felix C. Wiegandt1, Luisa K. Ermoneit1, Ulrich P. Froriep1 and Gerhard Pohlmann1
1Fraunhofer Institute for Toxicology and Experimental Medicine, Nikolai‐Fuchs‐Straße 1, 30625 Hannover, Germany
Summary: A major and costly disadvantage of inhalation therapy with continuous drug delivery to patients is its inefficiency, also often leading to ineffectiveness. Breath‐triggered drug release systems can highly improve efficiency. Preterm infants have especially challenging breathing patterns with breathing frequency up to 1 Hz, low tidal volume (4‐6 ml/kg) and short inspiration times (0.2‐0.4 s). There is currently no technology available enabling breath‐triggered drug release directly into the patient interface for (pre)term infants. The breathing pattern has to be detected in order to deliver an aerosolized drug in a breath‐triggered manner. For preterm infants, contact‐based sensors such as the Graseby capsule are usually employed. However, these have the drawback of being highly position‐ dependent and can irritate or, in the worst case, injure the sensitive skin of preterm infants. Therefore, we developed a system combining (1) a novel patient interface with (2) a non‐contact breath detection unit to enable breath‐triggered aerosol release in preterm infants.
As test substance saline solution was aerosolized with a mesh nebulizer and delivered to a preterm infant test bed via a standard interface (FlexitrunkTM) and our novel interface, respectively. For breath detection abdominal movement of preterm infants was recorded with a time‐of‐flight camera.
We achieved up to 2.5‐fold (non‐triggered) and 4‐fold (triggered) dose increase with the novel patient interface compared to the standard interface. Breathing patterns were reliably extracted from the abdominal movement data to generate trigger signals.
Thus, despite the extreme respiratory patterns of preterm infants, our system enables a very efficient breath‐triggered drug release.
101. INHALABLE N‐ACETYLCYSTEINE DRY POWDER FORMULATIONS AS POTENTIAL ADJUVANT TREATMENT FOR COVID‐19
Alessandra Rossi, Teresa Greco, Chiara Ogliari, Arianna Ferrari, Marianna Boraschi & Matteo Incerti
Department of Food and Drug, University of Parma, Parco Area delle Scienze 27/A, Parma, 43121, Italy
Summary: N‐acetylcysteine (NAC), a mucolytic drug with antioxidant and anti‐inflammatory properties, has been recently proposed as adjuvant in the treatment of SARS‐CoV‐2 infection. In this study spray‐dried powders of NAC for inhalation with 75% drug loading were prepared. NAC and the excipients were dissolved at acid pH and the solution was subjected to a spray drying process in close loop under nitrogen atmosphere. The effect of polyvinylpyrrolidone (PVP) or lactose in the spray dried powders and the variation of aspiration rate on the stability of NAC and powder aerosolization performance was investigated. The spray dried powders were characterized in terms of process yield, drug content, residual water content, particle size distribution, particle morphology and thermal behaviour. In vitro aerodynamic performance was evaluated using Fast Screening Impactor. The results showed that NAC was stable under nitrogen atmosphere during the spray drying process, as confirmed by the drug content values in the spray dried powders between 95% and 105%. The aspirator rate did not affect the overall properties of the spray dried powders. However, even if the lactose‐containing spray dried powders exhibited the lower value of residual water respect to those with PVP, the better aerosolization performance was observed with the spray dried powders containing PVP.
102. A DEVICE TO ADD CONNECTIVITY TO A PMDIS WITHOUT IMPACTING AEROSOL PERFORMANCE
William J. Ganley1, Lucas Silva1, Nuria Manzano1, Nicholas Wright1, Ronald Nocua2, Adam Shain2, Marcus Bates2
1Nanopharm Ltd, an Aptar Pharma Company, Franklin House, Grange Road, Cwmbran, NP44 3WY, United Kingdom
2Aptar Digital Health, Cygna House, Opal Drive, Milton Keynes, MK15 0DF, United Kingdom
Summary: The use of digital adherence and compliance monitoring tools have the potential to improve the management of chronic respiratory diseases by providing the possibility of interventions when health care professionals cannot be present. A key challenge in developing these technologies is introducing connectivity whilst ensuring that the performance of the underlying inhaler remains unaffected. In this study, the technical performance of Fostair® pressured metered dose inhaler (pMDI) was tested with and without the HeroTracker® Sense digital adherence and compliance add‐on device i. The results show that the dose, aerodynamic particle size distribution, aerosol plume characteristics and the dynamic resistance of the Fostair pMDI remained unchanged when the add‐on device was present. This demonstrates that the potential benefits of adding connectivity with the HeroTracker Sense can be realised without impacting underlying inhaler performance.
103. DESIGN AND EXPLORATION OF MODIFIED CYCLONE SEPARATOR FOR IMPROVED YIELD OF SPRAY‐DRIED CUBOSOMAL POWDER USING DESIGN OF EXPERIMENT
Akash Deep & Vikas Rana
Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala (Punjab), India
Summary: This research work aimed to study effect of cyclone design or dimensions on cyclone separator performance in bench‐top spray‐dryer for the production of spray‐dried cubosomal powder. The different cyclone separators were designed by modifying five geometrical parameters, i.e., length of cyclone body (Lb), length of cyclone cone (Lc), Height (H) and Width (W) of inlet section, and gas/air exit diameter (De) of standard cyclone separator. Further, the designed cyclones were evaluated using Lapple's equations, i.e., number of effective turns (Ne), inlet velocity of air (Vi), pressure drop (ΔP) and cut‐point diameter (dpc). The modified cyclone (type XVII) with highest Ne, Vi, ΔP and lowest dpc was selected for preparation of powder in comparison to standard cyclone (type I). Further, the Design of experiment was employed to evaluate the effect of formulation, process parameter and cyclone design (type I and XVII) on device removal efficiency (DRE), aerosolization efficiency (AE), fine particle fraction (FPF) and yield of cubosomal powder. Experimental results indicated that modified cyclone has significantly improved the yield of powder with insignificantly increasing the ΔP. The optimized spray‐ dried powder possesses sufficient geometrical standard diameter (dG) (3.9 ± 0.25 μm) & aerodynamic diameter (dA) (2.04 ± 0.15 μm) to deliver formulation to deeper lung tissues. It was found that modified cyclone was advantageous over standard one in increasing 1.8 folds yield with DRE, AE and FPF of 94.2%, 52.2%, and 63.8% respectively. Overall, this improvement in powder yield with desirable aerosolization properties will be beneficial in early‐stage research and development involving bench‐ top spray‐dryer.
104. A PERSONALIZED APPROACH TO RESPIRATORY DRUG DELIVERY: UMIST ®SPRAY TECHNOLOGY ELECTRICALLY CONTROLS AND ADJUSTS THE LOCATION OF DRUG DEPOSITION IN THE RESPIRATORY TRACT
Caitlin F Stewart, Paul Ravenhill, James Brown, Jon DeBohun, Richard Hoolahan, Tom Morris & Tom Podkolinkski
uMIST Technologies Ltd, The Nook, Kingsmill Industrial Estate, Cullompton. Devon. EX15 1BS
Summary: This work presents proof‐of‐concept evidence demonstrating the ability of the uMIST® spray platform to electrically control and adjust the location of drug deposition in the respiratory tract. A common bronchodilator, salbutamol sulphate, was selected to demonstrate the fine control of drug deposition in an artificial lung model. Salbutamol nebules were delivered using the spray technology set to deliver different mass median aerodynamic diameters (MMADs) of 5, 6 and 7‐μm and assessed by Next Generation Cascade (NGI). Results demonstrated the fine‐control of drug deposition with MMADs of 5.7, 6.5 and 7.1‐μm recorded respectively. A supplementary study conducted to assess potential treatment times, showed that flow rates of 72 mL/hr can be achieved whilst generating fine particles with narrow bandwidths (Dv.50, 5.81±0.54‐μm). These findings highlight the potential of uMIST® aimed to deliver optimal drug concentrations to the intended site of absorption, thereby limiting systemic toxicity, and improving therapeutic efficacy. Overall, these results support further development of uMIST® spray platform as a targeted delivery approach across a range of respiratory drug delivery platforms and applications.
105. NEW PILLHALER® DEVICE WITH HIGHER RESISTANCE FOR DRY POWDER FORMULATIONS
Valentina Trotta1, Juhura G. Almazi2, Hui X. Ong3, Huaxin Wu1, Qi Wu1 & Daniela Traini3
1HollyCon Italy Pte Ltd srl, via Danimarca 21, Gaggiano (MI), 20083, Italy
2Ab Initio Pharma, PTY, Ltd, 67‐73 Missenden Road, Camperdown, NSW, 2050, Sydney
3Macquarie Medical School Faculty of Medicine, Health and Human Sciences, Macquarie University, NSW 2109, & Woolcock Institute of Medical Research, Sydney, NSW 2031, Australia
Summary: Dry powder inhalers (DPIs) are widely used to administer treatments for respiratory diseases for which the device represents one of the central factors affecting therapy's success. The PillHaler® (HollyCon, Italy) is a single dose low resistance, disposable DPI for dry powder formulations. A new prototype device of the PillHaler® with higher resistance has been designed to increase the airflow resistance, enhancing the flexibility of this device to different types of formulations and its versatility for different treatments for lung diseases. To verify the device's aerosol performance, a model formulation blend, based on Fluticasone Propionate and lactose carrier, was used. Data showed that the new PillHaler® prototype with higher resistance can improve the aerosol deposition of a dry powder formulation. Moreover, this new prototype has shown to be efficient at a low flow rate setting as well. Collectively, the obtained data further highlights the importance of selecting optimal device resistance for the rationale design of inhalable formulations.
106. OPTIMIZING THE MAGNETIC FIELD MECHANISM OF A NOVEL DRY POWDER NEBULIZER FOR HIGH DOSE DELIVERY
Daniel Moraga‐Espinoza1,2, Amr Hefnawy3, Tania Bahamondez‐Canas1,2, Matt Reed4, Yun Li4, Hugh D. C. Smyth3, & Paul Atkins4
1Escuela de Química y Farmacia, Universidad de Valparaíso, Gran Bretaña 1093, Playa Ancha, Valparaíso, Región de Valparaíso 2340000, Chile
2Centro de Investigación Farmacopea Chilena, Universidad de Valparaíso, Gran Bretaña 1093, Playa Ancha, Valparaíso, Región de Valparaíso 2340000, Chile
3Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, The University of Texas at Austin, 2409 University Ave, Austin TX, 78712, USA
4Nob Hill Therapeutics, Albuquerque NM, USA
Summary: The novel DryNeb dry powder nebulizer works based on magnetic responsive elements (MREs) that can rotate and collide with each other in chaotic motion. Movement of the MREs is driven by an external magnet below the dosing chamber of the device that generates a magnetic field causing the MREs to collide and disperse the drug powder during the inhalation manoeuvre. The work reported in this study further explores optimization of delivery device whereby an external single‐phase coil was used to generate a magnetic field causing vertical motion of the MREs, promoting additional collisions with the mesh at the top of the drug dosing chamber. The mesh functions to prevent larger agglomerates from exiting the dosing chamber. It was hypothesized that increasing the collisions of the MREs on the mesh can enhance dispersion of the micronized drug and increase delivery efficiency from the device. The study followed a Box‐Behnken Design of Experiments (DoE) approach to determine the effect of applied magnetic field frequency of activation and power applied to the coil on drug delivery performance. A third variable, mesh pore size, was also evaluated. Within the bounds of the operating ranges studied, the study was intended to enable prediction of the most effective combination of magnetic field power, field frequency, and mesh size to produce and control delivery of higher Fine Particle Fractions (FPF) from these features of the dry powder nebulizer. Overall, only the mesh pore size had a significant effect on improving the Emitted Dose (ED) and the FPF from the device. The variables related to the single‐ phase coil did not demonstrate a significant impact on the device delivery performance. However, after completion of the study, issues were identified with the single‐phase coil function, which likely explains its limited influence on delivery performance. The elements of the study related to the single‐phase coil will be revisited when the coil is fully operational.
107. MODULATING THE FINE PARTICLE FRACTION, SURFACE AREA AND SURFACE ENERGY OF A HIGH DOSE FLUTICASONE PROPIONATE FORMULATION USING ISOTHERMAL DRY PARTICLE COATING (IDPC) TECHNOLOGY
Rhys Jones1, Jasdip S Koner1, Shital Lungare1, Amandip Gill1, Isobel Clark1,2, David Wyatt1,2 & Afzal Mohammed2
1Aston Particle Technologies, Aston Triangle, Birmingham, B4 7ET, United Kingdom
2Aston University, School of Life & Health Sciences, Birmingham, B4 7ET, United Kingdom
Summary: Isothermal Dry Particle Coating (DPC) technology is a proprietary powder blending/coating technology that can be utilised to manufacture a range of DPI formulations due to its controlled and predictable formulation pathway. This study reported here was conducted to assess how iDPC can modify fine particle fraction (FPF) performance, surface area and total surface energy of a high dose fluticasone propionate (FP) (50%w/w) formulation by simply adjusting Critical Process Parameters (CPPs). A single FP formulation was processed in a series of experiments in which the rotation speed of the chamber (centrifugal force), gas flow rate in the fluidising air blade and the process time was varied. Twenty‐ three formulations were manufactured and analysed for aerodynamic particle size distribution. Five formulations across the range of FPF were selected for surface area and total surface energy analysis using an inverse gas chromatography–surface energy analyser. The surface area of these formulations ranged from 4.58–7.33m2/g and the total surface energy range heterogeneity analysis varied from 17.01–22.14mJ/m2. The ability to modify these values show that it may be possible to prepare high dose formulations with a targeted FPF performance through control of the iDPC process parameters. This level of control in dry powder inhaler (DPI) formulation manufacturing would circumvent trial‐and‐ error practices used with existing technologies and improve the efficiency of DPI formulation development. Further research is ongoing to fully understand the effects of each of the three critical process parameters on the surface area and surface energy of DPI formulations and their FPF performance.
108. SOUNDCATCHER: ACOUSTIC EMISSION WITH MACHINE LEARNING FOR ROOT CAUSE ANALYSIS OF COMPLAINT DEVICES
Johanna Fredriksson1, Stina Sjödin1, Charlie Dempster1, Mats Josefson1, Ellinor Nilsson1, Gabriel Bjerner2, Roland Greguletz3, and Lars Karlsson1
1Inhalation Pharmaceutical Development, Pharmaceutical Technology & Development, Operations, AstraZeneca, Gothenburg, Sweden
2Technology Operations Science and Innovation, Pharmaceutical Technology & Development, Operations, AstraZeneca, Södertälje, Sweden
3Inhalation Pharmaceutical Development, Pharmaceutical Technology & Development, Operations, AstraZeneca, Bad Homburg, Germany
Summary: Acoustic Emission (AE) profiles, in combination with machine learning (ML) algorithms, have been shown to provide valuable quality related information for inhalation devices and formulations. Here, the technique applicability is extended to patient complaint analysis. A feasibility study was carried out using a dry powder inhaler (DPI) platform, designed to be highly resistant to powder clogging, as a model device. Test inhalers were mechanically manipulated to simulate patient failure modes associated with clogging. AE profiles from the manipulated devices were collected under a non‐destructive analysis by purging air through the devices with various flows without actuation while using an automated delivered dose analytical platform. The acquired AE data was analysed using different ML algorithms including orthogonal projections to latent structures (OPLS) and deep learning algorithms such as convolutional neural networks (CNN). Predictions were made on the position of particles glued on internal surfaces of the inhaler device as well as on the related amount of artificially applied powder residue. Using this approach, AE profiles from 123 inhalers showed an accuracy of above 85% when predicting residue level. At higher residue levels, the model could also distinguish between residue position with an accuracy of above 85%. Flow rate was also assessed in relation to model predictability. Based on these results, the models developed were applied on a set of 6 devices with unknown and challenging simulated residue levels, giving an accuracy of around 75%. The overall conclusion is that AE combined with ML is a non‐destructive analytical approach with the potential of providing valuable information when assessing the root cause for complaint sample returns. Long term, the hope is for the methodology to be evaluated on other device platforms to generalise the approach.
109. SOUNDCATCHER: ACOUSTIC EMISSION WITH MACHINE LEARNING FOR MONITORING OF MDI ADHERENCE AND DETECTION OF NON‐OPTIMAL ACTUATION PERFORMANCE
Ellinor Nilsson1, Mats Josefson2, Lisa Holmstén1, Patrik Andersson1, Lubomir Grandinarsky3, Matthew Ferriter4, and Lars Karlsson1
1Inhalation Pharmaceutical Development, Pharmaceutical Technology & Development, Operations, AstraZeneca, Gothenburg, Sweden
2Oral Product Development, Pharmaceutical Technology & Development, Operations, AstraZeneca, Gothenburg, Sweden
3Innovation Strategies & External Liaison, Pharmaceutical Technology and Development, AstraZeneca, Gothenburg, Sweden
4Inhalation Pharmaceutical Development, Pharmaceutical Technology & Development, Operations, AstraZeneca, Durham, USA
Summary: Acoustic Emission (AE) profiles, in combination with machine learning (ML) algorithms have been shown to provide valuable quality related information for inhalation devices and formulations. Here, the technique applicability is extended to patient adherence related monitoring. A feasibility study focusing on the attribute of non‐optimal or unexpected actuation performance was carried out using pMDIs as model devices. The approach was evaluated and in an experimental set‐up designed to mimic a domestic environment with a varying soundscape to properly challenge the algorithm, while using three different technical configurations to produce of non‐optimal/unexpected actuation performance. Using an image‐based ML model with Convolutional Neural Networks (CNN) it was possible to obtain highly accurate predictions, approximately 90%, of non‐optimal actuations.
110. A COMPUTATIONAL STUDY OF AEROSOL DROPLET FORMATION MECHANISM FOR PERSONALISED AIRWAY AND LUNG MANAGEMENT (PALM)
Abanoub Shenoda, Jason Brenker, Jackson Gum & Tuncay Alan
Monash University, Department of Mechanical and Aerospace Engineering, Melbourne VIC, 3800 Australia
Summary: Personalised Airway and Lung Management (PALM) is an acoustically actuated hand‐held inhaler that can produce aerosols with tuneable diameters. The device employs an array of microfabricated hydrophilic channels, which bound the liquid to be aerosolised in a well‐defined region. When the microfluidic chip is vibrated at high frequencies, capillary waves form within the liquid/ air interface and after a threshold amplitude is reached, those waves start to break up and eject droplets. Our experiments show that the formation of the droplets, as well as their size, can be accurately controlled on‐demand by dialling the actuation parameters. This has unique applications for personalised, effective pulmonary drug delivery to address specific patients’ needs. This paper presents a mathematical model and numerical simulations to explain the on‐demand control mechanism. A two‐ dimensional (2D) computational fluid dynamics (CFD) model is used to simulate the microfluidic component of the inhaler. Our results illustrate that the actuation frequency and amplitude strongly influence the onset of the droplet break‐up mechanism as well as the droplet size. The simulations agree well with a mathematical model relying on the damped Mathieu equation and the predicted amplitude for the onset of aerosolisation lies within the expected range.
111. USE OF ENGINEERING ANALYSIS AND SIMULATION TO GUIDE AND DE‐RISK MEDICAL DEVICE DEVELOPMENT
Chris Hurlstone1, Charlie Lowndes1, Stuart Abercrombie1
1Team Consulting Limited, Abbey Barns, Duxford Road, Ickleton, Cambridgeshire, CB10 1SX, UK
Summary: Recent advances in computing technology and analysis software have had significant impact on how quickly and efficiently performance simulation can be carried out. This paper describes three examples where the application of simulation tools has helped guide and de‐risk device development programmes.
On the rapid development of an emergency use ventilator, computational fluid dynamics (CFD) was used to assess risks relating to oxygen concentrations inside the device casework. In another example, the impact on key performance characteristics of an inhaler from small changes in geometry arising from manufacturing variability was modelled, also using CFD, to assist the setting of design specifications. In the third example, FEA was employed to ensure that deformation during manufacture of a custom foil blister pack did not exceed recommended limits, so as to minimise the risk of imperfections in finished parts. The case studies illustrate methods by which simulation and modelling can inform design decisions, in ways which do not necessarily require major commitments of time and resources.
112. TOWARDS A STANDARDISED DISSOLUTION METHODOLOGY FOR ORALLY INHALED DRUG PRODUCTS
Karin Somby1,2, Ivana Tomic2, Martin Hingle2 & Ben Forbes1
1King's College London, Stamford Street, London, SE1 9HN, UK
2Novartis Pharma AG, Fabrikstrasse 2, Novartis Campus, Basel, 4056, Switzerland
Summary: The role of dissolution in pulmonary drug delivery has received significant interest over the last decade, with intensifying research into dissolution methods for orally inhaled drug products (OIDPs). Proposers of an inhaled biopharmaceutical classification system (iBCS) argue for dissolution as a quality attribute of inhaled aerosol medicines that contain drugs with low aqueous solubility. OIDPs containing the corticosteroid fluticasone propionate (FP), e.g., Advair Diskus, fall into the category of products for which dissolution may play a significant role in product performance. The aim of this study was to take advantage of the learnings in the scientific literature and configure an in vitro aerosol deposition and dissolution system for inhaled dosage forms that is: (i) predictive of in vivo performance, and (ii) amenable to standardisation. Respirable fractions of Advair Diskus were collected using a Next Generation Impactor (NGI) and transferred to a Transwell® chamber in which dissolution conditions were selected based on simplicity, previously published literature and bio relevance. First, a Transwell® dissolution system was established with a dissolution medium containing phosphate buffer and 0.15% surfactant (SDS) which was benchmarked to the published solubility of FP in more representative epithelial lung lining fluids. The dissolution of different dosage strengths (100 μg, 250 μg, and 500 μg FP in Advair Diskus) were evaluated and found to differ with previously reported data potentially due to the aerosol collection and use of sink and non‐sink conditions. This work contributes to the development of systems with the potential to become standardised dissolution procedures for OIDPs.
113. USING FUNCTIONAL RESPIRATORY IMAGING (FRI) TO COMPARE PREDICTED AIRWAY DEPOSITION BETWEEN PRESSURIZED METERED DOSE INHALER (PMDI) WITH AEROCHAMBER PLUS FLOW‐VU ® VALVED HOLDING CHAMBER (VHC) AND TWO DRY POWDER INHALERS (DPIS) IN A COPD PATIENT
Suggett JA1, Sadafi H2 Mussche C3 & Mitchell JP4
1Trudell Medical International, 725 Baransway Drive, London, Ontario, N65 5G4, Canada
2FLUIDDA NV, Groeningenlei 132, 2550 Kontich Belgium
3FLUIDDA Inc., 228 East 45th Street, 9th Floor, Suite 9E, New York, NY 10017, USA
4Jolyon Mitchell Inhaler Consulting Services Inc., 1154 St. Anthony Rd., London, Ontario, N6H 2R1, Canada
Summary: Functional respiratory imaging (FRI) is a relatively recently developed in silico technique, whereby the regional lung deposition pattern can be predicted using 3‐dimensional respiratory tract models from multi‐slice computer tomographic scans of patients, following segmentation to extract patient‐specific airway and lung structures. We used FRI to compare predicted delivery of inhaled medication from a pMDI+VHC with two commonly prescribed mid‐resistance DPIs to an adult with COPD (GOLD stage‐ III), mimicking representative optimal and sub‐optimal inhalation profiles. The pMDI with antistatic AeroChamber* Plus Flow‐Vu* VHC delivered salbutamol (100μg/actuation) as model formulation inhaled at 30 (optimal) or 60 (sub‐optimal) L/min. This inhaler was compared with Symbicort* Turbohaler* DPI delivering 6μg formoterol fumarate/200μg budesonide inhaling at 30 (sub‐optimal) or 60 (optimal) L/min and Trelegy* Ellipta* DPI delivering fluticasone furoate (100μg); umeclidinium (62.5μg); vilanterol (25μg) inhaled at 30 (sub‐optimal) or 60 (optimal) L/min. Predicted extrathoracic deposition, representing dose delivered to the oropharynx was appreciably lower for the pMDI/VHC combination compared to the two DPIs. Predicted intrathoracic deposition, representing dose delivered to the lungs, for the pMDI/VHC combination was greater than corresponding values for either of the DPIs. Regional deposition to the lung periphery under optimum inhalation, based on central/peripheral (C/P) deposition ratio, was slightly higher for the pMDI/VHC combination than for either DPI. Efficiency of inhaled medication delivery to the lungs by pMDI/VHC when inhaling either optimally or sub‐optimally is likely to be greater than for either DPI.
114. THE EFFECT ON DELIVERED DOSE WHEN USING AND MISUSING NEBULISER FACE MASKS
Anna Gyllenstrand1, Ellinor Nilsson1 & Gunilla Petersson1
1AstraZeneca R&D Gothenburg, Pepparedsleden 1, Mölndal, 43183, Sweden
Summary: The effect on delivered dose when using nebuliser and face masks was studied for a range of nebulisers, face mask brands and patient simulation scenarios. It was found that the dose to a patient may vary substantially for the same drug product, depending on the combination of nebuliser, mask type and size, breathing pattern and user handling. The terbutaline dose varied for adult mask and adult breathing pattern between 332‐1361 μg and for children between 138‐801 μg. Adding a face mask reduced the patient dose by about 50%. Interestingly the dose increased more than two times when a small dead volume mask, intended for a younger patient, was used. The impact of simulated air leakages varied not only for different nebulisers and face masks, but also for different face model types used. It is clear that there is no mask fitting all face shapes, not even when the mask is of the intended age design. Face mask design, mask volume, breathing pattern and leakages were shown critical for the patient dose. Flexible mask materials seemed more efficient in maintaining the skin contact and hence more efficiently preventing leakages, also if the mask is somewhat moved during treatment.
115. DELIVERY OF ALBUTEROL SULPHATE SOFT MIST AEROSOLS USING A MICRO SPRAY NOZZLE PLATE TECHNOLOGY BASED PULMOSPRAY™
Lei Mao, Nischal Pant, Tashara Ross, Ben Rinne & Donald Ellis
Recipharm Laboratories Inc, 511 Davis Drive, Morrisville, NC, 27560, USA
Summary: The goal of this study is to demonstrate delivery performance and efficiency of an albuterol sulphate solution (2 mg/mL) from a Resyca Pulmospray™ based on a silicon micro spray nozzle plate technology. In the study, delivered dose, aerodynamic and geometric size distribution of the aerosols are measured using dose collector, Next Generation Impactor (NGI) and Spraytec. The device effectively delivers aerosols of inhalable size with a good delivery efficiency, i.e. more percentage delivery when actuation is synchronized with inhalation to avoid the exhaling phases in the breathing cycles. This is advantageous for patients dependant on ventilation in a clinical setting. In addition, impact from the testing flow rate on the aerodynamic and geometric size distribution was investigated. The results show a decrease in aerosol size when the test flow rate increased. An equivalent aerodynamic and geometric particle size distribution of 5.554 μm and 5.863 μm were observed when tested at 15 L/min. This was not observed at 30 L/min where the geometric particle size (3.512 μm) was smaller than the aerodynamic particle size (4.386 μm). This suggested that physical changes to the droplets, e.g. possible shrinking of the droplets leading to smaller geometric size, might have occurred at the higher test flow rate. This supports industry's practice of testing nebulizers at a low flow rate of 15 L/min.
116. PERFORMANCE VARIABILITY OF COMMERCIAL JET NEBULISER SYSTEMS MEASURED WITH EUROPEAN STANDARD AND ITS CLINICAL IMPLICATION
Fischer R1, Jain A K2, Jukic F2 & Ledermüller R1
1PARI GmbH, Moosstraße 3, Starnberg, 82319, Germany
2PARI Pharma GmbH, Lochhamer Schlag 21, Gräfelfing, 82166, Germany
Summary: There are many inhalers on the market with considerably different performances. The aim of this in vitro study was to evaluate the aerosol delivery efficiency of 15 commercially available jet nebuliser systems and to discuss the clinical implications of the differences in their performance. For the determination of aerosol parameters like Mass Median Aerodynamic Diameter (MMAD), Respirable Fraction (RF), Aerosol Output (AO) and Aerosol Output Rate (AOR), the new version of the European standard DIN EN ISO 27427:2020 was used, which allows an objective comparison of the parameters that manufactures are required to comply with. Respirable Dose (RD = RF x AO) and Respirable Drug Delivery Rate (RDDR = RF x AOR) representing the rate of the drug mass which can be theoretically deposited intrabronchially per time unit. The PARI BOY Junior and the PARI COMPACT2 have the highest RD and RDDR, surpassing the Aponorm Compact plus and the BRM‐085II in terms of RDDR by a factor of about 3 each. RDDR (calculated from aerosol parameters measured according to the European standard [12]) differs significantly between commercially available jet nebuliser systems. Therefore, it is important that physicians consider RDDR to ensure that patients receive clinically effective doses. RDDR is an objective, quality parameter for the efficiency of a nebuliser. To achieve the best possible therapeutic effect and avoid insufficient drug dosage a jet nebuliser system with a high RDDR should be selected. Taking this into account, nebuliser therapy offers a reliable treatment option especially for young children and the elderly due to its ease of application.
117. INSPIRATORY PROFILES FROM VOLUNTEER ADULTS WHO HAVE READ THE PATIENT INSTRUCTIONS FOR USE FOR TWO PASSIVE DRY POWDER INHALERS (DPIS) COMPARED WITH THOSE FROM A PRESSURIZED METERED DOSE INHALER WITH VALVED HOLDING CHAMBER (PMDI+VHC)
Mark W Nagel1, Cathy Doyle1, Rubina Ali1, Jason A Suggett1 & Jolyon P Mitchell2
1Trudell Medical International, 725 Baransway Drive, London, Ontario, N65 5G4, Canada
2Jolyon Mitchell Inhaler Consulting Services Inc., 1154 St. Anthony Rd., London, Ontario, N6H 2R1, Canada
Summary: We recorded inhalation waveforms by pneumotachometer (SpiroQuant‐H flow sensor, connected to a data recorder) from adult healthy volunteers with basic training in placebo inhaler use. We measured inhaled volume per inspiration (Vi) and peak inspiratory flow rate (PIFR) to explore natural variability within male (M) and female (F) volunteers. Before using each inhaler, the volunteers were asked to read the instructions‐for‐use. For the pMDI/AeroChamber* Plus VHC‐breath‐hold option, the volunteer exhaled then pressed the inhaler once at the beginning of a slow inhalation, then inhaled slowly and deeply through the chamber until a full breath had been taken followed by a breath‐hold lasting 5 to 10 seconds. For the Turbuhaler* and Ellipta* DPIs, each volunteer inhaled strongly and deeply. Values of both parameters (mean ± SD) varied widely between both sexes for all inhaler types (Vi: pMDI/VHC M=2334 ± 1465 mL; F=1425 ± 803 mL: Turbuhaler* DPI M=2879 ± 948 mL; F=1870 ± 881 mL: Ellipta* DPI M=2796 ± 859 mL; F=1873 ± 669mL); (PIFR: pMDI/VHC M=47 ± 27 L/min; F=34 ± 18 L/min: Turbuhaler* DPI M=86 ± 24 L/min; F=85 ± 17 L/min: Ellipta* DPI M=90 ± 2 9 L/min; F=85 ± 26 L/min). This variability masked sex‐based differences. Vi for the males using the Turbuhaler* DPIs were comparable to the females (2‐way t‐test, p=0.13, but corresponding values for the males using the Ellipta* DPI were significantly larger (p=0.008). PIFR for the same comparison were similar (p⋟0.66). Sex‐based differences in either parameter for the VHC configuration were insignificant (p=0.083).
118. MODEL OF THE PULMONARY VENTILATION AND EFFECTS OF AIRWAYS PROPERTIES ON DRUG DELIVERY TO THE LUNGS
Karla Sanchez1, Mark Allen1, Brian Chang2, Rosie Earl1 & Kim Parker3
1Cambridge Design Partnership, Church Road, Toft, Cambridge CB23 2RF, UK
2Cambridge Design Partnership, 801 West Morgan Street, Suite 120, Raleigh, NC 27603, USA
3Department of Bioengineering, Imperial College London, UK
Summary: A model of the lungs is presented focusing on the mechanical properties of the airways and their effect on the tracheobronchial and alveolar regions. Difficulties in breathing can result in poor particle deposition of drugs in the lungs and therefore poor patient outcome. The model explores the expected behaviour of these properties in young healthy controls vs ageing and pathological conditions e.g., Chronic Obstructive Pulmonary Disorder (COPD). The aim of the model is to provide an inexpensive tool for assessment of physiological parameters of airways and as an aid in design of devices that deliver drugs to the lungs. This is achieved using a fractal model which analyses all generations of the lung simultaneously, considering the stiffness of airways tissue and the interaction with transmural pressure to allow physical property changes to the lung to be assessed quickly. The model highlights that a decrease in lung compliance and input pressure, decreases the respiratory volume. The model also indicates airway opening size and transmural flux are sensitive to transmural pressure and the diffusivity at the alveolar region. These insights have significant implications to how we treat respiratory pathologies depending on the mechanical effects of age and disease. Future iterations of this model aim to include parameters such as air velocity, mucus viscosity and gas exchange to allow further interrogation to help understand and improve drug deposition characteristics.
119. NEBULISATION OF SUSPENSION FORMULATIONS
Christian Witte1, Elijah Nazarzadeh1, John Pritchard1, Julien Reboud2 & Jonathan M. Cooper2
1Acu‐Flow Limited, Advanced Research Centre, 11 Church Street, Glasgow, G11 6EW, United Kingdom
2University of Glasgow, Advanced Research Centre, 11 Church Street, City, G11 6EW, United Kingdom
Summary: Suspension formulations for inhalation therapy can have the benefit of prolonged retention time in the lung and may allow controlled release of the drugs to treat lung disorders. However, delivery of suspensions is often complicated due to incompatibility of the inhaler system with suspension particle size (e.g. Mesh nebulisers) or unwanted particle interactions as the result of the aerosolisation mechanism (Ultrasound nebulisers). In this study the nebulisation of suspension formulations using a surface acoustic wave (SAW) device with liquid confining microstructure was investigated. We demonstrated the nebulisation of monodisperse suspensions with particle sizes from 4.8 μm to 0.1 μm and identified key factors that when adjusted improve aerosolisation. We found that particle dispersity is influenced by acoustic energy transmission into the liquid dispensing system and liquid confining microstructure. Acoustic cavity effects drive particle aggregation for larger particles. This resulted in poor delivery of suspensions into the Andersen Cascade Impactor. Controlled liquid introduction of suspension formulations to the SAW transducer improved the delivery of larger particles by 250%.
120. IN VITRO INVESTIGATION OF INHALATION DELIVERY OF NEBULIZED LIPOSOMES
Ondrej Misik1, Jana Szabova2, Filip Mravec2 & Frantisek Lizal1
1Faculty of Mechanical Engineering, Brno University of Technology, Technicka 2896/2, Brno, 616 69, Czech Republic
2Faculty of Chemistry, Brno University of Technology, Purkynova 464, Brno, 612 00, Czech Republic
Summary: Inhalation therapy is a promising way of drug delivery, but the suitable carrier system plays an important role in its effectiveness. The inhalation administration of two nebulized liposomal systems was investigated in this study. The first system contained dipalmitoylfosfatidylcholine (DPPC), polyethylene glycol (PEG) bonded to dipalmitoylphosphoethanolamine (DPPE), and cholesterol (Chol). The second one consisted of DPPC, phosphatidic acid (PA), and Chol. These systems were nebulized by 2 air‐jet nebulizers (AJN): Pari LC Sprint, and Pari LC Sprint Star. The stability during nebulization was assessed for both systems and both nebulizers. Aerodynamic Particle Size Distribution (APSD) of nebulized aerosols was measured. According to the results of the stability and APSD (MMADLC_Sprint_Star 7.39 ± 0.24 μm; MMADLC_Sprint 9.79 ± 0.41 μm), the air‐jet nebulizer PARI LC Sprint Star and DPPC‐ PA‐Chol liposomal system were selected as the most promising choice among the tested cases. This combination was used for the investigation of the in vitro inhalation drug delivery. For this purpose, realistic replicas of upper airways and trachea were used and the liposomal vesicles were labeled with fluorescent dye to enable the local deposition evaluation. The nebulized system was inhaled into the airways model with a steady flow rate of 20 l/min and a realistic breathing pattern of a normal tidal breathing regime. In the case of inhalation at a fixed flow rate, more than 90 % of the aerosol mass penetrated below the trachea segment. In the case of the realistic breathing pattern, around 70 % of aerosol mass reached the region below the trachea.
121. DEVELOPMENT CHALLENGES FOR HYBRID APPLICATIONS OF DPIS. COULD IVIVC TOOLS PREDICT IN VIVO CONDITIONS? A CASE STUDY WITH ELPENHALER DEVICE
Stavroula Rozou1, Ergina Pentafragka1, Magdalene Kalovidouri1
1ELPEN Pharm.Co.Inc., 95 Marathonos Ave., Pikermi, 19009, Greece
Summary: It is a common practice to combine various techniques in the effort to predict the clinical outcome of OIDPs. An official regulatory framework is not yet available, but efforts are made to unscramble the fate of the drugs in the respiratory tract. Prediction can be more risky when it comes to comparison of inhalers with different geometries and aerodynamic performance. This being the case, the development and comparison of DPI products are challenged with the use of two different versions of Elpenhaler devices that have entirely different principle of use from the reference product (blisters vs capsules). The challenge was the prediction of clinical similarity of these products by combining in vitro methodologies with computational models. In vitro results were partially indicative but not reliable of the clinical outcome. Anatomic models and patient simulated flow rates were proved to be more accurate as per the information provided and gave more close results to the actual bioequivalence outcome. Nevertheless, the biggest uncertainty remains the actual users and all their associated individualities. To this end, very good knowledge of the inhalers performance, adequate user training and very close monitoring of the clinical study could increase the probability of a successful outcome.
122. NANOCELLE® NASAL SPRAY: FORMULATION DEVELOPMENT AND BIOLOGICAL CHARACTERISATION OF INSULIN NANOMICELLE
Chun Yuen Jerry Wong1, Tomas Andersen2, Michelle Quezada2, Julie Suman3, Luis Vitetta2,4, Hui Xin Ong1,5 & Daniela Traini1,5
1Woolcock Institute of Medical Research, Sydney, NSW, 2037, Australia
2Research Department, Medlab Clinical, Sydney, NSW, 2015, Australia
3Aptar Pharma, Congers, 10920, NY, United States
4Faculty of Medicine and Health, University of Sydney, Sydney, Australia
5Faculty of Medicine and Health Sciences, Macquarie Medical School, Macquarie University, Sydney, Australia
Summary: The present study developed an insulin nano‐sized drug delivery system to be delivered to the nasal cavity using a proprietary carrier technology (Nanocelle®, MedLab). The main objective was to evaluate the physicochemical properties and permeation efficacy of the insulin Nanocelle on RPMI‐2650 human nasal epithelial cells. The stability of the developed formulation was analysed in terms of particle size, polydispersity index and zeta potential. The use of Nanocelle to encapsulate insulin did not elicit any toxicity in RPMI‐2650 nasal cells. Nanocelle allowed direct drug permeation through the nasal epithelial cells, with approximately 44.93 ± 3.33 % of drug permeated in the first 0.5 hours. This preliminary study demonstrated how insulin Nanocelle could be used therapeutically to deliver proteins via the intranasal route as a non‐invasive prophylactic strategy for cognitive deficits and blood glucose control.
123. GALLIUM SIDEROPHORES FOR THE TREATMENT OF ASPERGILLUS FUMIGATUS LUNG INFECTIONS
B. Grassiri1,2, M.E. Piatek3,4, L. More O'Ferrall3,5, J.A. Sake2, G. Batoni6, C. Ehrhardt2, D.M. Griffith3,5, K. Kavanagh3,4, A.M. Piras1, A.M. Healy2,3
1University of Pisa, Department of Pharmacy, 56126 Pisa, Italy
2School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland
3SSPC, The Science Foundation Ireland Research Centre for Pharmaceuticals, Ireland
4Department of Biology, Maynooth University, Maynooth, Ireland
5Department of Chemistry, Royal College of Surgeons in Ireland, Dublin 2, Ireland
6Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy
Summary: Fungal lung infections are a serious threat, especially for immunocompromised patients. The metal gallium can disrupt iron metabolism in bacteria. Indeed, gallium salts have been reported to be valuable tools for the treatment of P. aeruginosa infections in cystic fibrosis patients. Recently the antifungal effect of gallium nitrate has been demonstrated against Aspergillus fumigatus. The aim of this project was to assess inhaled formulations of gallium salts or siderophore complexes that can be efficiently delivered to the lungs and act on the fungal infection. The synthesis of gallium maltolate (GaM), gallium citrate (GaC) and three novel siderophore Ga complexes (GaS1, GaS2 and GaS3) was undertaken. Microbiological testing of all synthesised compounds was carried out to evaluate their toxicity on A. fumigatus and a cytotoxicity screening on NCI‐H441 was performed to evaluate the safety of the compounds with respect to inhaled administration. None of the tested compounds were toxic to NCI‐ H441 cells at any of the concentrations and time points tested. The siderophore complexes were more effective against A. fumigatus compared to the other salts. GaS1 showed fungicidal properties at 0.5 mg/mL and was selected as the lead compound.
DPI formulations of GaS1 were prepared by spray‐drying with L‐leucine and in vitro deposition characteristics of prepared powders indicated good potential for efficient pulmonary delivery. Ultimately, the anti‐fungal activity of a formulated inhalable product will be tested on an in vitro infection lung model.
124. INHALABLE CYCLOSPORINE POWDER FOR THE PREVENTION OF PULMONARY REJECTION AND THE TREATMENT OF COVID‐19
Davide D'Angelo1, Eride Quarta1, Martina Brandolini2, Vittorio Sambri2, Lisa Flammini1, Simona Bertoni1, Fabio Sonvico1 & Francesca Buttini1
1Department of Pharmacy, University of Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy
2Microbiology Unit, The Great Romagna Area Hub Laboratory, 47522 Pievesestina, Cesena, Italy
Summary: The work describes the formulation of a powder for inhalation containing Cyclosporine_A (CsA), a peptide with low water solubility. The formulation was designed to reduce the dose of CsA to be administered following lung transplantation and potentially against SARS‐CoV‐2 replication and in the containment of the inflammatory process associated with Covid‐19.
The powder was obtained through a spray drying process and mannitol was chosen as bulk excipient to improve the respirability and solubility of the CsA. Dissolution, studied using RespicellTM apparatus, showed a faster profile for the spray‐dried powder compared to the raw material. The CsA powder was found to be highly respirable (MMAD of 1.38 μm and FPF 83.3%). In vitro analysis on A549 and THP‐1 cell lines did not indicate any cytotoxic effect and the anti‐inflammatory effect was maintained even after the spray drying process. This study also highlights the efficacy of cyclosporine against the omicron BA.1 variant of SARS‐CoV‐2, opening the possibility of using this formulation with a low dose in the treatment of Covid 19.
125. DEVELOPMENT AND ACTIVITY TESTING OF SPRAY DRIED PHOSPHORYLATED HEXAACYL DISACCHARIDE FOR NASAL ADMINISTRATION
Jasmine Ahad1, Jack Sorrell1, Laura Mason1, Kristine Storey2 & Joe Ninosky2
1Upperton Pharma Solutions, Albert Einstein Centre, Nottingham Science and Technology Park, Nottingham, NG7 2TN, United Kingdom
2Revelation Biosciences Inc., 11011 Torreyana Road, Suite 102, San Diego, CA 92121, United States
Summary: Derived from the lipopolysaccharide fraction of the cell walls within Gram negative bacteria, Phosphorylated Hexaacyl Disaccharide (PHAD) activates Toll‐like receptor 4 (TLR4) leading to the production of cytokines, activation of CD4+ and CD8+ T cells, and the activation of the adaptive immune response. This has potential applications for the prevention and/or treatment of respiratory viral infection and allergies, and so a product for nasal administration is targeted. However, PHAD is poorly soluble in aqueous formulations, and may incur stability issues due to hydrolysis. Thus, investigations were conducted to produce a dry powder PHAD formulation (2:49:49 %w/w/w PHAD:Hydroxypropyl‐β‐Cyclodextrin:Trehalose) by spray drying to increase long‐term stability and improve aqueous solubility. The optimum feed solution preparation process to generate micellar PHAD for spray drying has been investigated. Reconstitution of the resultant powder formulations at 0.6 mg/mL PHAD in water found that decreasing the concentration of PHAD within the spray drying feed solution resulted in improved reconstitution of the spray dried PHAD formulation, with faster dissolution and reduced solution turbidity observed. In addition, micelle diameter distributions by dynamic light scattering (DLS) showed a trend towards uniformity as the feed solution concentration was reduced. As a result, it was identified that a concentration of 0.5 mg/mL PHAD in the initial spray drying feed solution balanced spray drying efficiency and quality of micelles when reconstituted. Spray dried PHAD also maintained similar biological activity to unprocessed PHAD in solution. The spray dried PHAD will be further investigated as a stable form of PHAD that can be administered intranasally, either as a reconstituted solution or as a powder.
126. INVESTIGATING THE IMPACT OF DEVICE POSITIONING ON THE NASAL REGIONAL DEPOSITION
Gonçalo Farias, Manon Sautreuil, Charles Cazzola, Gerallt Williams & Julie Suman
Aptar Pharma, Route des Falaises, Le Vaudreuil, 27100, France
Summary: Novel therapeutic applications are currently being considered for nasal drug delivery. To optimise nasal drug products, the targeted regional deposition has become a key factor in product development. For this purpose realistic in vitronasal cast models have been developed. Likewise, human factors are becoming increasingly important in the development of drug‐device combination products with aspects such as device insertion angle/depth and their impact in regional deposition in the sites of absorption, and whether these pose concerns for efficacy and safety if performed incorrectly or not at all, requiring careful consideration.
The impact of the position of a customised unit dose nasal product in the nasal regional deposition, by varying the insertion angle and depth, was evaluated on a validated male nasal cast model (Aeronose™). During this study, a significant impact of both insertion angle and depth was witnessed. Lower angles (30°C) and higher insertion depths (15 mm) resulted in a higher deposition in the posterior region of the nasal cast (turbinates and olfactory region). Fixing the position of a nasal product allows a lower variability of the in vitro test for device/formulation screening purposes, but may also have to be considered for in vivo studies and real‐life use due to safety and efficacy concerns.
127. DEVELOPING METHODS FOR AUTOMATED DELIVERED DOSE UNIFORMITY (DDU) TESTING FOR NASAL SPRAYS
Adam Smith & Mark Copley
Copley Scientific Ltd, Colwick Quays Business Park, Road No 2, Nottingham, NG4 2JY, UK
Summary: Studies were carried out to assess strategies for automating delivered dose uniformity (DDU) testing for nasal sprays. DDU was determined by two alternative methods. With the first a novel accessory was used to ensure complete dose collection in a vertical/near vertical orientation and subsequent chemical assay, as required for regulatory nasal spray testing. This method was trialled using two commercially available suspension‐based formulations Beclometasone Dipropionate (BDP) and Fluticasone Propionate (FP) and in each case excellent drug recovery and high repeatability was observed; 99 ± 4% and 96 ± 5% relative to label dose, respectively. The second method was based on the measurement of shot weight, by difference, an alternative compendial method for solution‐based formulations. Water was used as a placebo formulation and again, excellent repeatability was observed; an RSD of between 0.45% and 0.8% over 150 deliveries, in each of 5 runs. The shot weight method was also used for ‘Number of deliveries per container testing’. Testing was highly efficient, taking ∼100 mins with no manual intervention required post set‐up, a substantial gain in analyst time. Together, the results illustrate how DDU test set‐ups for nasal sprays can be implemented to achieve high productivity and high repeatability.
128. LOCUST BEAN GUM MICROPARTICLES AS CARRIERS FOR LUNG DELIVERY OF BACTERIAL LYSATES
Joana Pinto‐da‐Silva1#, Joana Cruz1,2# & Ana Grenha1,2
1Centre for Marine Sciences, Universidade do Algarve, Campus de Gambelas, Faro, 8005‐139, Portugal
2Faculdade de Ciências e Tecnologia, Universidade do Algarve, Campus Gambelas, Faro, 8005‐139, Portugal
#equally contributing authors
Summary: Bacterial lysates (BL) are used as immunomodulators to prevent respiratory infections, being typically administered orally, which limits their potential to generate strong mucosal immunity in the lung. This work consists in repurposing bacterial lysates for immunisation against respiratory infections, proposing immunisation via inhalation to mitigate efficacy issues associated with conventional oral delivery. The main aim is to reach the mid‐lung region and the smaller airways and generate a local immune response, along with a systemic effect. Used as model, a commercial formulation of BL was converted into inhalable microparticles (MP) by spray‐drying, associating locust bean gum (LBG). LBG is a galactomannan which mannose units are expected to mediate specific targeting of lung resident antigen presenting cells through interaction with mannose surface receptors. BL‐loaded MP were successfully produced with varied LBG/BL mass ratios and the effective association of BL was confirmed. Aerodynamic evaluation of the MP revealed mass median aerodynamic diameters (MMAD) with potential to reach the lung (< 5 μm) for optimised formulations. An evaluation of the effect of MP in alveolar epithelial (A549) cells suggested dose‐dependent toxicity, which requires attention. Overall, the data obtained so far are encouraging for pursuing the evaluation of LBG MP as carriers of bacterial lysates to the lung aimed at the prevention of respiratory diseases.
129. IN VITRO CHARACTERISATION OF A NASAL SPRAY COMPRISING AN EXTREMELY POTENT HUMAN MONOCLONAL ANTIBODY
Irene Rossi1, Manuele Biazzo2, Christian Duchow2, Jagdeep Shur1, Antonia Zapata del Baño1, Chloe Szeto1, Jlenia Brunetti3, Luisa Bracci3, Ida Paciello4, Emanuele Andreano4 & Rino Rappuoli4,5
1Nanopharm Ltd, An Aptar Pharma Company, Grange Road, Cwmbran NP44 3WY, United Kingdom
2The BioArte Limited, Valletta Road, Mosta, MST 9012, Malta
3MedBiotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Via Aldo Moro 2, Siena 53100, Italy
4Monoclonal Antibody Discovery (MAD) Lab, Fondazione Toscana Life Sciences, Siena 53100, Italy
5Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena 53100, Italy
Summary: MAD0004J08 was identified between 453 neutralising antibodies (mAb) from 14 COVID‐19 recovered patients as the most potent against SARS‐CoV‐2. A single dose of MAD0004J08 administered intramuscularly (i.m.) showed to induce extremely high serum neutralisation titres against SARS‐CoV‐2 and its variants of concern. Inhaled air is primarily routed through the nose, representing the principal port of entry for the virus. For this reason, interest in nasal delivery has increased, especially to deliver mAbs. The aim of this study was to re‐design MAD0004J08 formulation used for i.m. administration to exploit nasal delivery. A chitosan/polysorbate formulation platform already applied to another immunoglobulin was employed in combination with Aptar CPS preservative‐free nasal pump. A suitable formulation for nasal delivery was obtained, as indicated by pH (6.24) and osmolality (303 mOsm/kg) measured. Formulation process did not impact the size or percentage of the dimeric fraction of the mAb. Droplet size distribution (Dv50 > 50 μm) reported a likely deposition of the formulation in the anterior‐middle region of the nose, whereas the chitosan positive charge ensures mucoadhesion and, therefore, will help obtaining a prolonged presence of MAD0004J08. Viscosity of the final nasal formulation (3.3 cP) showed to influence spray pattern and plume geometry. Finally, a reproducible dose of 816.25 μg of MAD0004J08 was delivered with Aptar CPS preservative‐free nasal pump. Binding and neutralisation activity before and after spraying was maintained, highlighting the suitability of this platform for nasal delivery of monoclonal antibodies.
130. DIRECT PARTICLE SIZE DISTRIBUTION MEASUREMENT OF AN ACTIVE INGREDIENT SUSPENDED IN PRESSURISED METERED DOSE INHALERS AND PARAMETERS, WHICH INFLUENCE MIGRATION RATE
Cristina Rey Blanes1, Luca Serratore1, Katie Reichwald1, William J Ganley1, Jose Ferrao2, Marie‐Laure Vicenty2, Guillaume Lemahieu3, Matthias Sentis3, Giovanni Brambilla3, Robert Price1, Jagdeep Shur1 and Irene Rossi1
1Nanopharm, An Aptar Pharma Company, Grange Road, Cwmbran, NP44 3WY, United Kingdom
2Aptar Pharma, Route des Falaises, Le Vaudreuil, 27100, France
3Formulaction, 3‐5 Rue Paule Raymondis, Toulouse, 31200, France
Summary: pMDIs make up 70% of inhalers used in the United Kingdom. In the transition from HFA 134a and HFA 227ea to low‐GWP propellants, the understanding of the propellants’ properties is important for a successful re‐formulation of life‐saving medications, such as salbutamol MDI, in greener propellants. We have already explored propellant properties and API solubility, particle aerosolisation, electrostatic charge, deposition and distribution, which are highly valuable when making key decisions around formulation and device development. In this study, we looked into the evaluation of the direct measurement of migration rate and particle size distribution (PSD) of an API suspended in traditional and low‐GWP propellants. APIs with different PSD were employed and their average diameters obtained from the PSD measured in line by static multiple light scattering were compared with the raw PSD measured by laser light scattering (un‐processed > milled > micronised API) utilising the wet cell accessory and scanning electron microscopy. No correlation was found for PSD and migration rate for HFA 125a, however a correlation was found for HFA 134a and HFO 1234ze with the micronised API showing the slowest sedimentation. Finally, it was found that propellant density, raw API PSD, and PSD of suspension significantly affected the migration rate in such formulated systems. Particularly, migration rate influences the aerodynamic particle size distribution and drug delivered. Therefore, being able to contemporary measure PSD and migration rate of API suspended in MDI can facilitate the re‐formulation of current pMDIs in low‐GWP propellants and the development of bioequivalent products.
131. FORMULATION AND CHARACTERISATION OF LIPOSOMES LOADED WITH A MODEL SMALL NUCLEIC ACID FOR NASAL DELIVERY
Cristina Rey Blanes1 & Reanne Beaird1, Mira Buhecha1, Eleni Axioti1, William Terrell1, Nektaria Karavas2, Mohammad Isreb3, Robert Price1, Jagdeep Shur1 & Irene Rossi1
1Nanopharm, An Aptar Pharma Company, Grange Road, Cwmbran, NP44 3WY, United Kingdom
2Aptar Pharma, Congers, New York, 10920, United States
3University of Bradford, Faculty of Life Sciences, School of Pharmacy and Medical Sciences, Richmond Road, Bradford, BD7 1DP, United Kingdom
Summary: Nucleic acid delivery for vaccination and other applications (i.e. anti‐cancer therapy, cystic fibrosis) has currently attracted a lot of interest. However, nucleic acids can be susceptible to degradation and present some challenges, requiring an effective delivery platform. Liposomes have been used as a delivery system to entrap hydrophilic and hydrophobic drugs and nucleic acids preventing degradation, increasing absorption, allowing for a sustained release and acting as multifunctional vaccine adjuvant‐delivery system. In this study, a liposomal suspension loaded with a model small deoxyribonucleic acid (DNA) was successfully developed and characterised for nasal delivery. Empty and DNA loaded liposomes were successfully manufactured and formulated for nasal delivery. pH (∼ 6) and osmolality (∼ 300 mOsm/kg) of the resulting formulations were suitable for the nose. Droplet size distribution of the spray emitted from Aptar CPS nasal pump was in the range for nasal deposition (30‐120 μm), even though much closer to the upper limit. A potential reduction of the amount of the trimethyl chitosan (TMC) may help in obtaining smaller droplets, which will potentially increase the deposition at the target region (i.e. NALT and turbinates). Hydrodynamic diameter was larger for the DNA loaded liposomes (600 nm) than for empty ones, perhaps due to DNA conjugation or absorption to the external liposomal structure and/or DNA induced liposome‐liposome fusion. The formulation's positive charge determined by the presence of TMC, possibly covering liposomes surface, can allow to ionic interaction with the negatively charged mucin. Finally, liposomal structure and size was preserved after spraying as confirmed by dynamic light scattering and delivered drug assessment.
132. THE RELEVANCE OF NON‐STANDARDISED IN VITRO NASAL CAST MODELS IN PRODUCT DEVELOPMENT
Lucas Silva1, Nathalie Hauchard2, Nuria Manzano1 & Gonçalo Farias2
1Nanopharm Ltd, Franklin House, Grange Road, Cwmbran, NP44 3WY, UK
2Aptar Pharma, Route des Falaises, Le Vaudreuil, 27100, France
Summary: More realistic in vitro tools are being explored to facilitate product development by providing a better link between in vitro studies and in vivo outcomes. Standardisation is usually seen as a major challenge for these novel tools.
In this study, the nasal regional deposition of two distinct nasal products (liquid and powder) was evaluated in two different nasal cast models: one sophisticated model validated in vivo (Aeronose™) and one idealised model (AINI). Both nasal casts were able to track differences in regional deposition of two products with comparable results in anterior and posterior deposition. Nonetheless, a different deposition on the olfactory region was observed, possibly related to differences in adhesion of the powder to the nasal cast. Standardisation of realistic in vitro tools might be useful from a quality control perspective particularly by using idealised models. However, it might not be required during product development, where sophisticated and complete geometry models that can be built to be representative of certain target populations could be used as long as those models are validated with in vivo studies.
Author Index
- Pages:A-40–A-43
- Published Online:24 May 2023
https://doi.org/10.1089/jamp.2023.ab01.index.abstracts
