Dr Mehra Haghi graduated with a Doctor of Pharmacy degree from Azad University of Tehran (2007). She received her PhD in Pharmaceutical Sciences from the Faculty of Pharmacy, University of Sydney in 2012 in the area of applied respiratory cell biology.
She was then employed as postdoctoral research scientist at the university of Sydney (2012-2013) and later at The Woolcock Institute of Medical Research (2013-2014) where she was appointed as Honorary Associate Lecturer in the Discipline of Pharmacology, Sydney Medical School, University of Sydney.
In 2014 she joined the Faculty of Pharmacy at the University of Technology, Sydney as lecturer in Pharmaceutics. Dr Haghi was awarded the Alexander von Humboldt fellowship to pursue her research in the area of applied respiratory cell biology at the Department of Drug Delivery, Helmholtz-Institute for Pharmaceutical Research (HIPS) in Saarbrücken, Germany during the second semester of 2014 and 2015.
She has authored more than 20 peer reviewed papers and conference proceedings involving international collaborators, from academia and industry: University of Groningen (Netherlands), Chiesi Ltd. and King’s College London (UK), University of Parma and University of Ferrara (Italy) and was selected as invited speaker and contributed oral presentations at SutEN (Sydney University tissue Engineering Network) in 2010, The Bosch Young Investigators 2012, Respiratory Drug Delivery Europe 2013 and seminars at The Woolcock Institute of Medical Research in 2012, Faculty of Pharmacy- University of Parma (Italy), Helmholz Research Institute (Germany), TSANZ (Thoracic Society of Australia & New Zealand) (NSW) Branch - Annual Scientific Meeting 2013 and TSANZSRS annual scientific meeting 2014.
Dr haghi has acted as reviewer for a number of research journals in the field of pharmaceutical sciences (Int. J. Pharm., Eur. J. Pharm. Biopharm., J. Pharm. Sci. etc.).
Can supervise: YES
Dr Mehra Haghi’s research interests have been devoted to understanding and treatment of respiratory diseases encompassing epithelial cell biology, molecular pharmacology, respiratory technology and the development of representative in vitro models that mimic healthy and diseased lung tissue. Specifically her team focus on understanding the complex mechanisms that occur when inhaled micro-particles are deposited at the lung epithelia; with a view to create new and more effective approaches to treat a range of respiratory diseases.
McAlinden, KD, Deshpande, DA, Ghavami, S, Xenaki, D, Sohal, SS, Oliver, BG, Haghi, M & Sharma, P 2019, 'Autophagy Activation in Asthma Airways Remodeling.', American Journal of Respiratory Cell and Molecular Biology.View/Download from: UTS OPUS or Publisher's site
Current asthma therapies fail to target airway remodeling which correlates with asthma severity driving disease progression that ultimately leads to loss of lung function. Macroautophagy (here after autophagy) is a fundamental cell recycling mechanism in all eukaryotic cells; emerging evidence suggests that it is dysregulated in asthma. We investigated the interrelationship between autophagy and airway remodeling and assessed preclinical efficacy of a known autophagy inhibitor in murine models of asthma. Human asthmatic and non-asthmatic lung tissues were histologically evaluated and were immuno-stained for key autophagy markers. The percent area of positive staining was quantified in the epithelium and airway smooth muscle (ASM) bundles using ImageJ software. Furthermore, autophagy inhibitor chloroquine (CQ) was tested (i.n.) in prophylactic (3-week) and treatment (5-week) models of allergic asthma in mice. Human asthmatic tissues showed greater tissue inflammation and demonstrated hallmark features of airway remodeling displaying thickened epithelium (p<0.001) and reticular basement membrane (p<0.0001), greater lamina propria depth (p<0.005), and increase in ASM bundles (p<0.001) with higher expression of Beclin1 (p<0.01) and ATG5 (p<0.05) along with reduced p62 (p<0.05) compared to non-asthmatic controls. Beclin1 expression was significantly higher in asthmatic epithelium and ciliated cells (p<0.05) suggesting potential role of ciliophagy in asthma. Murine asthma models demonstrated effective preclinical efficacy (reduced key features of allergic asthma: airway inflammation, AHR and airway remodeling) of autophagy inhibitor CQ. Our data demonstrates cell-context dependent, and selective activation of autophagy in structural cells in asthma. Further, this pathway can be effectively targeted to ameliorate airway remodeling in asthma.
Haghi, M, Windhab, N, Hartwig, B, Young, PM & Traini, D 2019, 'Human Stimulus Factor Is a Promising Peptide for Delivery of Therapeutics.', Journal of Pharmaceutical Sciences.View/Download from: Publisher's site
Fluticasone propionate uptake in the presence of a proprietary cell-penetrating peptide (human stimulus factor, [HSF]) based on the N-terminal domain of lactoferrin was studied, alone and in combination with salmeterol, using an air interface Calu-3 epithelial model. The HSF enhanced uptake and transport of fluticasone propionate across the epithelial barrier when alone and in presence of salmeterol. This was attributed to transcellular-mediated uptake. This HSF is a promising peptide for delivery of therapeutics where enhanced epithelial penetrating is required.
Faiz, A, Weckmann, M, Tasena, H, Vermeulen, CJ, Van den Berge, M, Ten Hacken, NHT, Halayko, AJ, Ward, JPT, Lee, TH, Tjin, G, Black, JL, Haghi, M, Xu, C-J, King, GG, Farah, CS, Oliver, BG, Heijink, IH & Burgess, JK 2018, 'Profiling of healthy and asthmatic airway smooth muscle cells following interleukin-1β treatment: a novel role for CCL20 in chronic mucus hypersecretion.', European Respiratory Journal, vol. 52, no. 2, pp. 1-12.View/Download from: UTS OPUS or Publisher's site
Chronic mucus hypersecretion (CMH) contributes to the morbidity and mortality of asthma, and remains uncontrolled by current therapies in the subset of patients with severe, steroid-resistant disease. Altered cross-talk between airway epithelium and airway smooth muscle cells (ASMCs), driven by pro-inflammatory cytokines such as interleukin (IL)-1β, provides a potential mechanism that influences CMH. This study investigated mechanisms underlying CMH by comparing IL-1β-induced gene expression profiles between asthma and control-derived ASMCs and the subsequent paracrine influence on airway epithelial mucus production in vitroIL-1β-treated ASMCs from asthmatic patients and healthy donors were profiled using microarray analysis and ELISA. Air-liquid interface (ALI)-cultured CALU-3 and primary airway epithelial cells were treated with identified candidates and mucus production assessed.The IL-1β-induced CCL20 expression and protein release was increased in ASMCs from moderate compared with mild asthmatic patients and healthy controls. IL-1β induced lower MIR146A expression in asthma-derived ASMCs compared with controls. Decreased MIR146A expression was validated in vivo in bronchial biopsies from 16 asthmatic patients versus 39 healthy donors. miR-146a-5p overexpression abrogated CCL20 release in ASMCs. CCL20 treatment of ALI-cultured CALU-3 and primary airway epithelial cells induced mucus production, while CCL20 levels in sputum were associated with increased levels of CMH in asthmatic patients.Elevated CCL20 production by ASMCs, possibly resulting from dysregulated expression of the anti-inflammatory miR-146a-5p, may contribute to enhanced mucus production in asthma.
Haghi, M, Young, PM & Traini, D 2018, 'A Simple and Rapid Method for Deposition and Measurement of Drug Transport Across Air Interface Respiratory Epithelia.', AAPS PharmSciTech, vol. 19, no. 7, pp. 3272-3276.View/Download from: UTS OPUS or Publisher's site
The purpose of this study was to present a novel and simple drug deposition method to evaluate drug transport of aerosol microparticles across airway epithelial cells. Microparticles containing ciprofloxacin HCl (Cip) and doxycycline (Dox), alone or in a 50:50% w/w ratio, were spray dried and suspended using 2H, 3H-perfluoropentane, model propellant. The suspension was then used to assess deposition, and transport of these drug microparticles across sub-bronchial epithelial Calu-3 cells was also studied. In comparison with other methods of depositing microparticles, this proposed method, using drug suspended in HPFP, provides control over the amount of drugs applied on the surface of the cells. Therefore, cell permeability studies could be conducted with considerably smaller and more reproducible doses, without the physicochemical characteristics of the drugs being compromised or the use of modified pharmacopeia impactors. The suspension of microparticles in HPFP as presented in this study has provided a non-toxic, simple, and reproducible novel method to deliver and study the permeability of specific quantity of drugs across respiratory epithelial cells in vitro.
Kota, A, Deshpande, D, Haghi, M, Oliver, B & Sharma, P 2017, 'Autophagy and airway fibrosis: Is there a link?', F1000 Research, vol. 6, no. 409, pp. 1-10.View/Download from: UTS OPUS or Publisher's site
In the past decade, an emerging process named 'autophagy' has generated intense interest in many chronic lung diseases. Tissue remodeling and fibrosis is a common feature of many airway diseases, and current therapies do not prevent or reverse these structural changes. Autophagy has evolved as a conserved process for bulk degradation and recycling of cytoplasmic components to maintain basal cellular homeostasis and healthy organelle populations in the cell. Furthermore, autophagy serves as a cell survival mechanism and can also be induced by chemical and physical stress to the cell. Accumulating evidence demonstrates that autophagy plays an essential role in vital cellular processes, including tissue remodeling. This review will discuss some of the recent advancements made in understanding the role of this fundamental process in airway fibrosis with emphasis on airway remodeling, and how autophagy can be exploited as a target for airway remodeling in asthma and chronic obstructive pulmonary disease.
Arora, S, Kappl, M, Haghi, M, Young, PM, Traini, D & Jain, S 2016, 'An investigation of surface properties, local elastic modulus and interaction with simulated pulmonary surfactant of surface modified inhalable voriconazole dry powders using atomic force microscopy', RSC Advances, vol. 6, no. 31, pp. 25789-25798.View/Download from: UTS OPUS or Publisher's site
© The Royal Society of Chemistry 2016. l-Leucine is used as the most common force control agent used in the inhaled dry powder formulations. In this study, the effect of l-leucine on the surface morphology, surface energy and the Young's modulus of the composite spray dried particles was studied. In addition, how l-leucine modifies the interaction of particles with a simulated pulmonary surfactant is also studied. Voriconazole (VRZ) was spray dried with different concentrations of l-leucine from hydroalcoholic solutions. Formulations were found to possess irregular morphology. Surface concentration of l-leucine was increased with increasing feed concentration and plateaued at about 20% w/w l-leucine. Atomic force microscopy (AFM) coupled with drug colloid probe enabled meas urement of cohesion forces between the prepared formulations and found cohesion to be reduced significantly (p < 0.05) with the increase of l-leucine concentration. Peak Force Tapping enabled characterization of nanomechanical properties (elasticity and deformation) of formulations. Co-spray drying l-leucine with VRZ does not seem to have any influence on the Young's modulus of the formulations. Lastly, AFM revealed that the surface chemistry of the drug particle and pulmonary surfactant, as well as the contact geometry of the interacting surfaces, plays an important role in determining nature and extent of interaction between inhaled drug particles and pulmonary surfactant.
Arora, S, Haghi, M, Young, PM, Kappl, M, Traini, D & Jain, S 2016, 'Highly respirable dry powder inhalable formulation of voriconazole with enhanced pulmonary bioavailability', EXPERT OPINION ON DRUG DELIVERY, vol. 13, no. 2, pp. 183-193.View/Download from: Publisher's site
Stigliani, M, Haghi, M, Russo, P, Young, PM & Traini, D 2016, 'Antibiotic transport across bronchial epithelial cells: Effects of molecular weight, LogP and apparent permeability.', European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences, vol. 83, pp. 45-51.View/Download from: UTS OPUS or Publisher's site
The first step in developing a new inhalable formulation for the treatment of respiratory diseases is to understand the mechanisms involved in the absorption of drugs after lung deposition. This information could be important for the treatment of bacterial infection in the lung, where low permeability would probably be beneficial, or a systemic infection, where high permeability would be desirable. The goal of this study was to evaluate the transport of several antibiotics (ciprofloxacin, azithromycin, moxifloxacin, rifampicin, doxycycline and tobramycin) across human bronchial airway epithelium and to study the influence of molecular weight and LogP on the apparent permeability.The experiments were conducted using Calu-3 cells seeded in the apical compartment of 24-well Transwell® inserts. The antibiotics transport was measured in both apical to basolateral (A-B) and basolateral to apical (B-A) directions and the apparent permeability of each antibiotic was calculated.The A-B transport of ciprofloxacin and rifampicin was independent of the initial concentration in the donor compartment, suggesting the involvement of active transporters in their absorption. Moxifloxacin, doxycycline, azithromycin and tobramycin presented a low absorptive permeation in the A-B direction, indicating that these substances could be substrate for efflux pumps. Generally, all antibiotics studied showed low permeabilities in the B-A direction.These findings suggest that the inhalation route would be favorable for delivering these specific antibiotics for the treatment of respiratory infection, compared with present oral or intravenous administration.
Haghi, M, Saadat, A, Zhu, B, Colombo, G, King, G, Young, PM & Traini, D 2015, 'Immunomodulatory Effects of a Low-Dose Clarithromycin-Based Macrolide Solution Pressurised Metered Dose Inhaler', PHARMACEUTICAL RESEARCH, vol. 32, no. 6, pp. 2144-2153.View/Download from: Publisher's site
Haghi, M, Traini, D, Wood, LG, Oliver, B, Young, PM & Chrzanowski, W 2015, 'A 'soft spot' for drug transport: modulation of cell stiffness using fatty acids and its impact on drug transport in lung model', JOURNAL OF MATERIALS CHEMISTRY B, vol. 3, no. 13, pp. 2583-2589.View/Download from: UTS OPUS or Publisher's site
Haghi, M, van den Oetelaar, W, Moir, LM, Zhu, B, Phillips, G, Crapper, J, Young, PM & Traini, D 2015, 'Inhalable tranexamic acid for haemoptysis treatment', EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, vol. 93, pp. 311-319.View/Download from: UTS OPUS or Publisher's site
Arora, S, Haghi, M, Loo, C-Y, Traini, D, Young, PM & Jain, S 2015, 'Development of an Inhaled Controlled Release Voriconazole Dry Powder Formulation for the Treatment of Respiratory Fungal Infection', MOLECULAR PHARMACEUTICS, vol. 12, no. 6, pp. 2001-2009.View/Download from: UTS OPUS or Publisher's site
Zhu, B, Haghi, M, Goud, M, Young, P & Traini, D 2015, 'The formulation of a pressurized metered dose inhaler containing theophylline for inhalation.', European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences, vol. 76, pp. 68-72.View/Download from: UTS OPUS or Publisher's site
BACKGROUND: Theophylline (TP) is a bronchodilator used orally to treat chronic obstructive pulmonary disease (COPD) that has been associated with multiple side effects, tempering its present use. This study aims to improve COPD treatment by creating a low-dose pressurized metered dose inhaler (pMDI) inhalable formulation of TP. METHODS: Aerosol performance was assessed using Andersen Cascade Impaction (ACI). Solubility of TP in HFA 134/ethanol mixture was measured and morphology of the particles analyzed with a scanning electron microscope (SEM). Calu-3 cell viability, epithelial cell transport and inflammatory-response assays were conducted to study the impact of the formulation on lung epithelial cells. RESULTS: The mass deposition profile of the formulation showed an emitted dose of 250.04±14.48μg per 5 actuations, achieving the designed nominal dose (50μg/dose). SEM showed that the emitted particles were hollow with spherical morphology. Approximately 98% of TP was transported across Calu-3 epithelial cells and the concentration of interleukin-8 secreted from Calu-3 cells following stimulation with tissue necrosis factor-α (TNF-α) resulted in significantly lower level of interleukin-8 released from the cells pre-treated with TP (1.92±0.77ng·ml(-1) TP treated vs. 8.83±2.05ng·ml(-1) TNF-α stimulated, respectively). CONCLUSIONS: The solution pMDI formulation of TP developed in present study was shown to be suitable for inhalation and demonstrated anti-inflammatory effects at low doses in Calu-3 cell model.
Trotta, V, Lee, WH, Loo, CY, Haghi, M, Young, P, Scalia, S & Traini, D 2015, 'In vitro biological activity of resveratrol using a novel inhalable resveratrol spray-dried formulation.', International journal of pharmaceutics.View/Download from: UTS OPUS or Publisher's site
The aim of the study was to prepare inhalable resveratrol by spray drying for the treatment of chronic obstructive pulmonary disease (COPD). Resveratrol, with a spherical morphology and particle diameter less than 5μm, was successfully manufactured. Fine particle fraction (FPF) and mass median aerodynamic diameter (MMAD) of spray-dried resveratrol was 39.9±1.1% and 3.7±0.1μm, respectively when assessed with an Andersen cascade impactor (ACI) at 60l/min. The cytotoxicity results of spray-dried resveratrol on Calu-3 revealed that the cells could tolerate high concentration of resveratrol (up to 160μM). In addition, in transport experiments using Snapwells, it was observed that more than 80% of the deposited dry powder was transported across the Calu-3 cells to the basal chamber within four hours. The expression of interleukin-8 (IL-8) from Calu-3 induced with tumor necrosis factor alpha (TNF-α), transforming growth factor beta (TGF-β1) and lipopolysaccharide (LPS) were significantly reduced after treatment with spray-dried resveratrol. The antioxidant assay (radical scavenging activity and nitric oxide production) showed spray-dried resveratrol to possess an equivalent antioxidant property as compared to vitamin C. Results presented in this investigation suggested that resveratrol could potentially be developed as a dry powder for inhalation for the treatment of inflammatory lung diseases like COPD.
Haghi, M, Hittinger, M, Zeng, Q, Oliver, BG, Traini, D, Young, P, Huwer, H, Schneider-Daum, N & Lehr, CM 2015, 'Mono- and Cocultures of Bronchial and Alveolar Epithelial Cells Respond Differently to Proinflammatory Stimuli and Their Modulation by Salbutamol and Budesonide.', Molecular Pharmacology, vol. 12, no. 8, pp. 2625-2632.View/Download from: UTS OPUS or Publisher's site
The aim of this study was to investigate the changes in transport and effectiveness of salbutamol sulfate (SAL) and budesonide (BD) following stimulation with transforming growth factor-β (TGF-β) in mono- and coculture models of bronchial and alveolar epithelium. Primary bronchial and alveolar epithelial cells, grown at air interface on filters, either as monocultures or in coculture with airway smooth muscle cells or alveolar macrophages, respectively, were stimulated with TGF-β. The biological response was modulated by depositing aerosolized SAL and BD on bronchial and alveolar models, respectively. Barrier integrity, permeability to fluorescein-Na, transport of the deposited drug, and the pharmacological response to SAL (cAMP and IL-8 levels) or BD (IL-6 and -8 levels) were measured. While stimulation with TGF-β did not have any significant effect on the transepithelial electrical resistance and permeability to fluorescein-Na in mono- and coculture models, transport of SAL and BD were affected in cultures from some of the patients (6 out of 12 for bronchial and 2 out of 4 for alveolar cells). The bronchial coculture showed a better responsiveness to SAL in terms of cAMP release than the monoculture. In contrast, the difference between alveolar mono- and cocultures to TGF-β mediated interleukin release and its modulation by BD was less pronounced. Our data point to intrinsic differences in the transport of, and responsiveness to, SAL and BD when epithelial cell cultures originate from different patients. Moreover, if the biological responses (e.g., IL-8, cAMP) involve communication between different cell types, coculture models are more relevant to measure such effects than monocultures.
Zhu, B, Haghi, M, Nguyen, A, Goud, M, Yeung, S, Young, PM & Traini, D 2015, 'Delivery of theophylline as dry powder for inhalation', Asian Journal of Pharmaceutical Sciences, vol. 10, no. 6, pp. 520-527.View/Download from: Publisher's site
© 2015 The Authors. Theophylline (TP) is a very well established orally or intravenously delivered antiasthma drug with many beneficial effects. This study aims to improve asthma treatment by creating a dry powder inhalable (DPI) formulation of TP to be delivered directly to the lung, avoiding the side effects associated with conventional oral delivery. The DPI TP formulation was investigated for its physico-chemical characteristics using scanning electron microscopy, laser diffraction, thermal analysis and dynamic vapour sorption. Furthermore, aerosol performance was assessed using the Multi Stage Liquid Impinger (MSLI). In addition, a Calu-3 cell transport assay was conducted in vitro using a modified ACI to study the impact of the DPI formulation on lung epithelial cells. Results showed DPI TP to be physico-chemically stable and of an aerodynamic size suitable for lung delivery. The aerosolisation performance analysis showed the TP DPI formulation to have a fine particle fraction of 29.70 ± 2.59% (P < 0.05) for the TP formulation containing 1.0% (w/w) sodium stearate, the most efficient for aerosolisation. Regarding the deposition of TP DPI on Calu-3 cells using the modified ACI, results demonstrated that 56.14 ± 7.62% of the total TP deposited (13.07 ± 1.69 μg) was transported across the Calu-3 monolayer over 180 min following deposition, while 37.05 ± 12.62% of the deposited TP was retained in the cells. This could be due to the presence of sodium stearate in the current formulation that increased its lipophilicity. A DPI formulation of TP was developed that was shown to be suitable for inhalation.
Saadat, A, Zhu, B, Haghi, M, King, G, Colombo, G, Young, PM & Traini, D 2014, 'The formulation, chemical and physical characterisation of clarithromycin-based macrolide solution pressurised metered dose inhaler.', Journal of Pharmacy and Pharmacology, vol. 66, no. 5, pp. 639-645.View/Download from: UTS OPUS or Publisher's site
OBJECTIVES: The formulation of a clarithromycin (CLA) pressurised metered dose inhalers (pMDIs) solution formulation opens up exciting therapeutic opportunities for the treatment of inflammation in chronic obstructive lung diseases. In this study, we have formulated and tested a low dose macrolide formulation of CLA for treatment of inflammation and studied its physicochemical and aerosol properties. METHODS: The system was characterised for in-vitro aerosol performance using an Andersen cascade impactor. Short-term chemical and physical stability was assessed by dose content uniformity over a range of temperatures. Standard physicochemical characteristics were also investigated using scanning electron microscopy, thermo analysis and laser diffraction techniques. KEY FINDINGS: The formulation had a relatively high fine particle fraction (47%) and produced a particle size distribution suitable for inhalation drug delivery. Particles had an irregular morphology and were predominately amorphous. Furthermore, the short-term stability showed the formulation to be stable from 4 to 37°C. CONCLUSIONS: This study demonstrated the feasibility of formulating a solution-based pMDI containing CLA for the treatment of lung inflammatory diseases.
Haghi, M, Ong, HX, Traini, D & Young, P 2014, 'Across the pulmonary epithelial barrier: Integration of physicochemical properties and human cell models to study pulmonary drug formulations.', Pharmacology and Therapeutics, vol. 144, no. 3, pp. 235-252.View/Download from: UTS OPUS or Publisher's site
During the process of inhalable formulation development a deep knowledge of the physicochemical characteristics of the drug and formulation components and the biological properties of the airways is necessary. For example, the solubility and lipophilicity of a drug may affect therapeutic efficacy by changing the residence time of the microparticles at the airway surface. Furthermore, the properties of microparticles, such as shape, size and density, as well as the diseases of the respiratory tract, delivery device and inhalation manoeuvre will have an impact on where these microparticles are deposited. The airway epithelium is involved in the pathogenesis and treatment of respiratory diseases. Epithelial cells are directly exposed to the environment and respond to xenobiotics. In some cases, they are the site of action for drug molecules or the drug molecules might need to be transported across the epithelium to arrive at the site of action. The drug particles deposited on the respiratory epithelia have to interact with the mucus lining, dissolve and get transported through this layer. Despite advances in in vitro testing of respiratory epithelial permeability, there is little known about how and where drugs are absorbed at a cellular level and how long they reside in the lung. Therefore, pulmonary permeability assessment of drugs may provide insights that will allow formulations to be developed with optimised therapeutic outcomes. This review focuses on the integration of these physicochemical characteristics with the biological factors to provide a better understanding of the fate of microparticles after deposition on the epithelial cells.
Haghi, M, Traini, D & Young, P 2014, 'In Vitro Cell Integrated Impactor Deposition Methodology for the Study of Aerodynamically Relevant Size Fractions from Commercial Pressurised Metered Dose Inhalers', PHARMACEUTICAL RESEARCH, vol. 31, no. 7, pp. 1779-1787.View/Download from: UTS OPUS or Publisher's site
Lewis, DA, Young, P, Buttini, F, Church, T, Colombo, P, Forbes, B, Haghi, M, Johnson, R, O'Shea, H, Salama, R & Traini, D 2014, 'Towards the bioequivalence of pressurised metered dose inhalers 1: Design and characterisation of aerodynamically equivalent beclomethasone dipropionate inhalers with and without glycerol as a non-volatile excipient', European Journal of Pharmaceutics and Biopharmaceutics, vol. 86, no. 1, pp. 31-37.View/Download from: UTS OPUS or Publisher's site
A series of semi-empirical equations were utilised to design two solution based pressurised metered dose inhaler (pMDI) formulations, with equivalent aerosol performance but different physicochemical properties. Both inhaler formulations contained the drug, beclomethasone dipropionate (BDP), a volatile mixture of ethanol co-solvent and propellant (hydrofluoroalkane-HFA). However, one formulation was designed such that the emitted aerosol particles contained BDP and glycerol, a common inhalation particle modifying excipient, in a 1:1 mass ratio. By modifying the formulation parameters, including actuator orifice, HFA and metering volumes, it was possible to produce two formulations (glycerol-free and glycerol-containing) which had identical mass median aerodynamic diameters (2.4 μm ± 0.1 and 2.5 μm ± 0.2), fine particle dose (⩽5 μm; 66 μg ± 6 and 68 μg ± 2) and fine particle fractions (28% ± 2% and 30% ± 1%), respectively. These observations demonstrate that it is possible to engineer formulations that generate aerosol particles with very different compositions to have similar emitted dose and in vitro deposition profiles, thus making them equivalent in terms of aerosol performance. Analysis of the physicochemical properties of each formulation identified significant differences in terms of morphology, thermal properties and drug dissolution of emitted particles. The particles produced from both formulations were amorphous; however, the formulation containing glycerol generated particles with a porous structure, while the glycerol-free formulation generated particles with a primarily spherical morphology. Furthermore, the glycerol-containing particles had a significantly lower dissolution rate (7.8% ± 2.1%, over 180 min) compared to the glycerol-free particles (58.0% ± 2.9%, over 60 min) when measured using a Franz diffusion cell. It is hypothesised that the presence of glycerol in the emitted aerosol particles altered solubility and drug transport, which may have...
Saadat, A, Haghi, M, Zhu, B, King, G, Colombo, G, Young, P & Traini, D 2014, 'THE FORMULATION OF A NOVEL MACROLIDE SOLUTION PRESSURISED METERED DOSE INHALER: THE USE OF CLARITHROMYCIN AS AN ANTI-INFLAMMATORY FOR BRONCHIECTASIS THERAPY', JOURNAL OF AEROSOL MEDICINE AND PULMONARY DRUG DELIVERY, vol. 27, no. 4, pp. A3-A3.
Zeng, Q, Haghi, M, Rimmer, J, Black, J, Shi, J, Oliver, B & Ge, Q 2014, 'THE TRANSPORT OF SALBUTAMOL SULFATE THROUGH CALU-3 AND DIFFERENTIATED HUMAN BRONCHIAL EPITHELIAL CELL', Respirology, vol. 19, pp. 63-63.
Trotta, V, Haghi, M, Lee, W-H, Scalia, S, Young, PM & Traini, D 2014, 'RESVERATROL, A NOVEL SPRAY DRIED INHALATION POWDER FOR COMPLEMENTARY THERAPY IN THE TREATMENT OF COPD', Journal of Aerosol Medicine and Pulmonary Drug Delivery, vol. 27, no. 6, pp. A8-A9.
Haghi, M, Bebawy, M, Colombo, P, forbes, B, Lewis, D, Salama, R, Traini, D & Young, P 2014, 'Towards the bioequivalence of pressurised metered dose inhalers 2. Aerodynamically equivalent particles (with and without glycerol) exhibit different biopharmaceutical profiles in vitro', European Journal of Pharmaceutics and Biopharmaceutics, vol. Online.View/Download from: UTS OPUS or Publisher's site
Two solution-based pressurised metered dose inhaler (pMDI) formulations were prepared such that they delivered aerosols with identical mass median aerodynamic diameters, but contained either beclomethasone dipropionate (BDP) alone (glycerol-free formulation) or BDP and glycerol in a 1:1 mass ratio (glycerol-containing formulation). The two formulations were deposited onto Calu-3 respiratory epithelial cell layers cultured at an air interface. Equivalent drug mass (~1000ng or ~2000ng of the formulation) or equivalent particle number (1000ng of BDP in the glycerol-containing versus 2000ng of BDP in the glycerol-free formulation) were deposited as aerosolised particles on the air interfaced surface of the cell layers. The transfer rate of BDP across the cell layer after deposition of the glycerol-free particles was proportional to the mass deposited. In comparison, the transfer of BDP from the glycerol-containing formulation was independent of the mass deposited, suggesting that the release of BDP is modified in the presence of glycerol. The rate of BDP transfer (and the extent of metabolism) over 2h was faster when delivered in glycerol-free particles, 465.01ng±95.12ng of the total drug (20.99±4.29%; BDP plus active metabolite) transported across the cell layer, compared to 116.17ng±3.07ng (6.07±0.16%) when the equivalent mass of BDP was deposited in glycerol-containing particles. These observations suggest that the presence of glycerol in the maturated aerosol particles may influence the disposition of BDP in the lungs.
Scalia, S, Haghi, M, Losi, V, Trotta, V, Young, PM & Traini, D 2013, 'Quercetin solid lipid microparticles: A flavonoid for inhalation lung delivery', EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 49, no. 2, pp. 278-285.View/Download from: UTS OPUS or Publisher's site
Mamlouk, M, Young, P, Bebawy, M, Haghi, M, Mamlouk, S, Mulay, V & Traini, D 2013, 'Salbutamol Sulfate Absorption Across Calu-3 Bronchial Epithelia Cell Monolayer is Inhibited in the Presence of Common Anionic NSAIDs', Journal Of Asthma, vol. 50, no. 4, pp. 334-341.View/Download from: UTS OPUS or Publisher's site
The aim of this study was to characterize the permeability kinetics of salbutamol sulfate, a commonly used ß2-agonist in the treatment of asthma exacerbation, across Calu-3 respiratory epithelial cell monolayers in the presence of non-steroidal anti-inflammatory drugs (NSAIDs), as they have been implicated to be able to modulate organic cation transporters (OCTs). Methods. Calu-3 cell monolayers were grown in a liquid covered culture (LCC) configuration on 0.33 cm2 Transwell polyester cell culture supports. Monolayers, cultured between 11 and 14 days were evaluated for epithelial resistance, tight junction integrity, and expression of OCT using Western blot analysis. The transport of salbutamol across the monolayer was studied as a function of concentration. Directional transport was investigated by assessing apical-basal (a-b) and basal-apical (b-a) directions. The influence of a non-specific OCT inhibitor (tetraethylammonium, TEA) and three NSAIDs (aspirin, ibuprofen, and indomethacin) on the uptake of salbutamol was studied. Results. The flux of salbutamol sulfate increased with increasing concentration before reaching a plateau, suggesting the involvement of a transport-mediated uptake mechanism. Western blot analysis detected the presence of OCT1-3 and N1 and N2 sub-types, suggesting the presence of functioning transporters. The apparent permeability (Papp) of 0.1 mM salbutamol across the epithelial monolayer displayed directional transport in the a-b direction which was inhibited by ~70% in the presence of TEA, suggesting OCT-mediated uptake. Likewise, the uptake of 0.1 mM salbutamol was decreased in the presence of all the three NSAIDs, supporting a mechanism whereby NSAIDs inhibit absorption of salbutamol across the bronchial epithelium via effects on the OCT transporters. Conclusion. This study demonstrates that NSAIDs influence the uptake kinetics of salbutamol in an in vitro Calu-3 cell system.
Marin, L, Traini, D, Bebawy, M, Colombo, P, Buttini, F, Haghi, M, Ong, HX & Young, P 2013, 'Multiple dosing of simvastatin inhibits airway mucus production of epithelial cells: Implications in the treatment of chronic obstructive airway pathologies', European Journal of Pharmaceutics and Biopharmaceutics, vol. 84, no. 3, pp. 566-572.View/Download from: UTS OPUS or Publisher's site
Background Chronic obstructive pulmonary disease (COPD) is characterised by mucus hyper-production. This pathology, together with other inflammatory contributions, leads to airway obstruction and breathing complications. Newer therapeutic approaches are of increased interest, including the use of HMG-CoA reductase inhibitors. Retrospective studies have shown that statins are effective in reducing patient mortality and blood cytokines levels. These findings suggest statins may also provide a new therapeutic approach in COPD treatment. Purpose The aim of the present work was to study the transport of simvastatin (SV) across Calu-3 epithelial cells and to investigate its pharmacological action with respect to reduction in mucus production. Methods Calu-3 cells were grown under liquid covered culture (LCC) conditions for transport studies in order to demonstrate the ability of SV to transport across the monolayer. For mucus detection, cells were grown under air interface culture (AIC) conditions. Samples collected for microscope analysis were stained with alcian blue; images of the stained cell surface were acquired and the mucus was quantified as the RGBB ratio.
haghi, M, Traini, D, Postma, DS, Bebawy, M & Young, PM 2013, 'Fluticasone uptake across Calu-3 cells is mediated by salmeterol when deposited as a combination powder inhale', Respirology, vol. 18, no. 8, pp. 1197-1201.View/Download from: UTS OPUS or Publisher's site
BACKGROUND AND OBJECTIVE: We assessed whether co-deposition of a long-acting ß2 -agonist and a corticosteroid affects their respective transport rates across epithelial cells. METHODS: Drug particles were deposited on the air-interface culture of Calu-3 cells using a twin-stage impinger. We compared the transport rate of salmeterol and fluticasone across the epithelial cells using commercially available formulations (Serevent, Flixotide and Seretide). The transepithelial resistance of Calu-3 cells was measured before and after each deposition to monitor epithelial resistance. RESULTS: The codeposition of salmeterol and fluticasone had no significant effect on transport of salmeterol through the cell layer. In contrast, the rate of fluticasone propionate transport in presence of salmeterol xinofoate was significantly lower (0.53 ± 0.20%) compared with the single fluticasone formulation (2.36 ± 0.97%). Furthermore, the resistance of the epithelial cells was significantly increased after salmeterol deposition from both single and combination products. CONCLUSIONS: Our data demonstrate that salmeterol may decrease the permeability of epithelial cells, resulting in slower fluticasone transport across Calu-3 epithelial monolayers. The subsequent increased residence time of fluticasone in the airways could prolong its anti-inflammatory effects.
Haghi, M, Salama, R, Traini, D, Bebawy, M & Young, P 2012, 'Modification of disodium cromoglycate passage across lung epithelium in vitro via incorporation into polymeric microparticles', The AAPS Journal, vol. 14, no. 1, pp. 79-86.View/Download from: UTS OPUS or Publisher's site
Two microparticle systems containing disodium cromoglycate (DSCG) alone or with polyvinyl alcohol (DSCG/PVA) were produced via spray drying and compared in terms of their physicochemical characteristics, aerosol performance and drug uptake across a pulmonary epithelial cell line (Calu-3), cultured under air interface conditions. The particle size distribution of DSCG and DSCG/PVA were similar, of spherical geometry, amorphous and suitable for inhalation purposes. Aerosolisation studies using a modified twin-stage impinger showed the DSCG/PVA to have greater aerosol performance than that of DSCG alone. Aerosol particles of DSCG and DSCG/PVA were deposited onto the surface of the Calu-3 air interface epithelium monolayer and the drug uptake from apical to basal directions measured over time. Drug uptake was measured across a range of doses to allow comparison of equivalent drug and powder mass deposition. Analysis of the data indicated that the percentage cumulative drug uptake was independent of the mass of powder deposited, but dependent on the formulation. Specifically, with the formulation containing DSCG, the diffusion rate was observed to change with respect to time (indicative of a concentration-dependent diffusion process), whilst DSCG/PVA showed a time-independent drug uptake (suggesting a zero-order depot release).
Haghi, M, Traini, D, Bebawy, M & Paul, YM 2012, 'Deposition, Diffusion and Transport Mechanism of Dry Powder Microparticulate Salbutamol, at the Respiratory Epithelia', Molecular Pharmaceutics, vol. 9, no. 6, pp. 1717-1726.View/Download from: UTS OPUS or Publisher's site
The deposition, dissolution and transport of salbutamol base (SB) and salbutamol sulfate (SS) inhalation powders were investigated using the Calu-3 air interface cell culture model and Franz diffusion cell. Drug uptake by cells was studied with respect to deposited dose, drug solubility and hydrophobicity. Furthermore, the role of active transport via organic cationic transporters (OCTs) was studied. SB and SS were processed to have similar diameters (3.09 ± 0.06 µm and 3.07 ± 0.03 µm, respectively) and were crystalline in nature. Analysis of drug wetting, dissolution and diffusion using a conventional in vitro Franz cell (incorporating a cell culture support Transwell polyester membrane) showed diffusion of SB to be slower than that of SS (98.57 ± 4.23 µg after 4 h for SB compared to 98.57 ± 4.01 µg after 15 min for SS). Such observations suggest dissolution to be the rate-limiting step. In comparison, the percentage transfer rate using the air interface Calu-3 cell model suggested SB transport to be significantly faster than SS transport (92.02 ± 4.47 µg of SB compared to 63.76 ± 8.84 µg of SS transported over 4 h), indicating that passive diffusion through the cell plays a role in transport. Furthermore, analysis of SB and SS transport, over a range of deposited doses, suggested the transport rate in the Franz diffusion cell to be limited by wetting of the particle and dissolution into the medium.
Haghi, M, Traini, D, Jaiswal, R, Gong, J & Bebawy, M 2010, 'Time- and passage-dependent characteristics of a Calu-3 respiratory epithelial cell model', Drug Development And Industrial Pharmacy, vol. 36, no. 10, pp. 1207-1214.View/Download from: UTS OPUS or Publisher's site
Background: Although Standard Protocols For The Study Of Drug Delivery In The Upper Airways Using The Sub-Bronchial Epithelial Cell Line Calu-3 Model, Particularly That Of The Air-Liquid Interface Configuration, Are Readily Available, The Model Remains U
Sharma, P, McAlinden, K, Oliver, B & Haghi, M 2018, 'Autophagy Is Selectively Activated and Correlated with Airway Remodeling in Asthma', American Journal of Respiratory and Critical Care Medicine, American Thoracic Society, American Thoracic Society, San Diego.View/Download from: UTS OPUS
Rationale: Asthma affects more than 330 million people worldwide and poses a huge economic burden on the healthcare system. Current anti-asthma therapies provide symptomatic relief but fail to target airway remodeling which drives disease progression and loss of lung function with time. Macroautophagy (autophagy) is a fundamental process that occurs in all eukaryotic cells and can be referred to as the cell recycling mechanism. Emerging evidence suggest that autophagy is dysregulated in asthma and can modulate pro-fibrotic signaling in asthma. Autophagy modulation may be a novel effective therapy for unmanageable asthma. The aim of this study was to explore the role of autophagy in asthma by investigating the interrelationship between autophagy markers and features of airway remodeling in large airways obtained from asthmatics (n=6) and non-asthmatics (n=8). Methods: Selected asthmatic tissue with hallmark features of airway remodeling (correlates with severe disease) and non-asthmatics were immuno-stained for autophagy markers; Beclin1, ATG5, and p62. The percent area of positive staining was quantified in the epithelium and airway smooth muscle (ASM) using ImageJ software. Features of airway remodeling were also measured in the large airways of patients using H&E and Masson's Trichrome staining. Results: Asthmatic airways in comparison with non-asthmatic airways displayed greater epithelium (p<0.01), and reticular basement membrane thickness (p<0.0001) with greater lamina propria depth (p<0.0001), and increased ASM bundles (p<0.005). Overall they displayed hallmark features of airway remodeling. In the ASM bundles, expression of ATG5 was significantly higher (p<0.05), while there was a trend for increased expression of Beclin-1 (p=0.08) and reduced expression of p62 (p=0.18) in asthmatics when compared with non-asthmatics. We found no difference in the expression profile of autophagy markers in the epithelium of asthmatics vs non-asthmatics. Interestingly, in a...
Zeng, QX, Haghi, M, Rimmer, J, Black, J, Shi, J, Oliver, BG & Ge, Q 2014, 'An Investigation Into Salbutamol Sulfate Dry Powder Transport Across Calu-3 And Differentiated Human Bronchial Epithelial Cells', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, AMER THORACIC SOC.View/Download from: UTS OPUS
Stigliani, M., Haghi, M., Russo, P., Young, P. & Traini, D. 2014, 'Evaluation of Antibiotic Transepithelial Transport Across Calu-3 Human Airway Cells', Respiratory Drug Delivery 2014, Respiratory Drug Delivery, Davis Healthcare Int.
Haghi, M., Traini, D., Lewis, D.A., Forbes, B., Colombo, P. & Young, P.M. 2014, 'Effect of Particle Size and Excipients on the Uptake of Beclomethasone Dipropionate-Pressurized Metered Dose Inhalers After Deposition on Calu-3 Respiratory Epithelia', Respiratory Drug Delivery 2014, Respiratory Drug Delivery, Davis Healthcare Int, Puerto Rico.View/Download from: UTS OPUS
Haghi, M., Traini, D., Bebawy, M. & Young, P. 2013, 'Uptake of Salmeterol Xinafoate and Fluticasone Propionate from Single and Combination Dry Powder Inhalers After Deposition on Calu-3 Respiratory Epithelia.', Respiratory Drug Delivery Europe 2013, Respiratory Drug Delivery, Berlin, Germany, pp. 445-448.
Haghi, M, Traini, D, Bebawy, M & Young, P 2011, 'Comparison of albuterol sulphate and base dry powder particulate deposition using the Calu-3 lung epithelial model', RDD Europe 2011, Respiratory Drug Delivery, Virginia Commonwealth University, Germany, pp. 519-522.View/Download from: UTS OPUS
To effectively predict the fate of formulated inhalation compounds delivered to the lung, a model of the airway epithelium should reflect drug permeability and transport characteristics in vivo. Most cell-based system established for this purpose, study drug transport using wet models and thus do not necessarily represent in vivo conditions. Recently, air-interface models have been established that increase the relevance of in vitro transport studies to the in vivo state. The aim of our study was to elucidate the dissolution and diffusion process of deposited dry drug particulates (albuterol) after aerosolization onto the epithelial surface and compare these to conventional in vitro `glass models. Two forms of albuterol were investigated (albuterol base and albuterol sulphate), to evaluate the effects of lipophilicity and aqueous solubility on the mechanism of transport.
Haghi, M, Young, P, Traini, D & Bebawy, M 2010, 'Characterization of P-gp Expression and Function vs. Time and Passage in the Calu-3 Air-Interface Model for Drug Delivery to the Lung', Proceedings of Respiratory Drug Delivery 2010, Respiratory Drug Delivery 2010, Davis Healthcare Int', Orlando, Florida, pp. 875-878.View/Download from: UTS OPUS
Calu-3, a sub-bronchial epithelial cell line, cultured at the air-interfaced, has been shown to be a very reliable model for the in vitro investigation of inhalation drug delivery to the upper airways. It has been found to be superior with respect to morphology and function when compared to the liquid covered culture model (1, 2), but the Calu-3 air-interface model has not been fully investigated for P-glycoprotein (P-gp) expression (3, 4) a parameter that could influence predicted drug delivery in the lung. P-gp is a plasma membrane drug transporter, actively involved in `carrying a wide range of structurally and functionally unrelated drugs out of cells (5). P-gp has been shown to interact with some drugs routinely used in respiratory therapy (1). Another factor that may affect drug transport across the epithelium is the presence of mucus; which, in healthy lungs, aids mucociliary clearance of deposited particulate matter, acts as an antibacterial substance and prevents loss of excessive fluid from the airway due to evaporation (6). The aim of this investigation was to characterize mucus secretion and cell surface P-gp expression and function in the Calu-3 air-interface model.