Paul M Young

Woolcock Institute of Medical Research, Sydney, New South Wales, Australia

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Publications (116)342.02 Total impact

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    ABSTRACT: Previous studies have suggested that particle-particle impaction may influence aerosolisation properties in carrier-based dry powder inhalers, through transfer of kinetic energy from large carriers to surface-deposited active drug. The importance of particle-particle collision has yet to be compared against other mechanisms that could lead to drug liberation, such as particle-wall impaction and turbulence. In particular, particle-particle collisions are difficult to model in silico due to computationalrestrictions. This study investigated the effects of dry powder inhaler particle-particle collisions in vitro using an established carrier-drug model dry powder inhalation formulation. Spherical polystyrene beads of median size 82.80 µmwere chosen as a model carrier as they were of uniform size, shape, surface area, density, porosity and hardness and thus eliminated potential variables that would have conflicted with the study. This model carrier was geometrically blended with micronised salbutamol sulphate(loaded blend).The correlation between the mass of loaded blend (5 - 40 mg) in the Rotahaler® DPI device and resulting fine particle fraction(FPF) was examined at a constant flow rate of 60 L.min-1. In a second experiment, the mass of loaded blend was kept constant and a variable amount of blank carrier particles were added to the Rotahaler® device to ascertain if additional "blank" carrier particles affected the final FPF.The efficiency of aerosolisation remained constant withvarying amounts of blank carrier particles as determined by the fine particle fraction of the emitted dose (FPFED)andfine particle fraction of the loadeddose (FPFLD). No statistical difference in FPFED and FPFLD values were observed for increasing masses of blank carrier. In addition, no statistical difference in FPFED and FPFLD between the two experiments was obtained. These observations suggest that particle-particle collisions are not a driving mechanism responsible for de-aggregation of drug from carrier-based systems.
    Current Drug Delivery 08/2014;
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    ABSTRACT: Endotracheal intubation is commonly associated with hospital-acquired infections as the intubation device acts as reservoir for bacterial colonization in the lungs. To reduce the incidence of bacterial colonization on the tubes, hydrogel coatings loaded with antimicrobial agents are gaining popularity. The aim of this study was to incorporate silver nanoparticles (AgNPs) into polyvinyl alcohol (PVA) to form stable hydrogels. Embedding AgNPs into PVA resulted in a decreased elongation at break and an increased tensile strength compared to PVA alone. The Ag release profile varied as a function of the degree of hydrolysis of PVA: the higher degree of hydrolysis demonstrated a lower release rate. Fourier infrared transform spectroscopy demonstrated that AgNPs interacted exclusively with the -OH groups of PVA. AgNP-loaded PVA was non-toxic against human normal bronchial epithelial cells while effective against the attachment of Pseudomonas aeruginosa and Staphylococcus aureus with a greater effect on P. aeruginosa.
    Biofouling 06/2014; · 3.40 Impact Factor
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    ABSTRACT: Non-volatile agents such as glycerol are being introduced into solution-based pMDI formulations in order to control mean precipitant droplet size. To assess their biopharmaceutical efficacy, both microscopic and macroscopic characteristics of the plume must be known, including the effects of external factors such as the flow generated by the patient's inhalation. We test the hypothesis that the macroscopic properties (e.g. spray geometry) of a pMDI spray can be predicted using a self-similarity model, avoiding the need for repeated testing.
    Pharmaceutical research. 06/2014;
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    ABSTRACT: Introduction: Natural compounds are emerging as effective agents for the treatment of malignant diseases. Curcumin (diferuloylmethane), the active constituent of turmeric extract, has gained significant interest as a plant-based compound with anti-cancer properties. Curcumin is physiologically very well tolerated, with negligible systemic toxicity observed even after high oral doses administration. Despite curcumin's superior properties as an anti-cancer agent its applications are limited due to its low solubility and physico-chemical stability, rapid systemic clearance and low cellular uptake. Areas covered: This review focuses on the development of curcumin nano-particle formulation to improve its therapeutic index through enhanced cellular uptake, localization to targeted areas and improved bioavailability. The feasibility of nano-formulation in delivering curcumin and the limitations and challenges in designing and administrating the nano-sized curcumin particles are also covered in this review. Expert opinion: Nanotechnology is a promising tool to enhance efficacy and delivery of drugs. In this context, formulation of curcumin as nano-sized particles could reduce the required therapeutic dosages and subsequently reduced its cell toxicity. These nanoparticles are capable to provide local delivery of curcumin targeted to specific areas and thereby preventing systemic clearance. In addition, using specific coating, better pharmacokinetic and internalization of nano-curcumin could be achieved. However, the potential toxicity of nano-carriers for curcumin delivery is an important issue, which should be taken into account in curcumin nano-formulation.
    Expert Opinion on Drug Delivery 05/2014; · 4.87 Impact Factor
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    ABSTRACT: Abstract A series of co-engineered macrolide-mannitol particles were successfully prepared using azithromycin (AZ) as a model drug. The formulation was designed to target local inflammation and bacterial colonization, via the macrolide component, while the mannitol acted as mucolytic and taste-masking agent. The engineered particles were evaluated in terms of their physico-chemical properties and aerosol performance when delivered via a novel high-payload dry powder Orbital(™) inhaler device that operates via multiple inhalation manoeuvres. All formulations prepared were of suitable size for inhalation drug delivery and contained a mixture of amorphous AZ with crystalline mannitol. A co-spray dried formulation containing 200 mg of 50:50 w/w AZ: mannitol had 57.6% ± 7.6% delivery efficiency with a fine particle fraction (≤6.8 µm) of the emitted aerosol cloud being 80.4% ± 1.1%, with minimal throat deposition (5.3 ± 0.9%). Subsequently, it can be concluded that the use of this device in combination with the co-engineered macrolide-mannitol therapy may provide a means of treating bronchiectasis.
    Drug Development and Industrial Pharmacy 05/2014; · 1.54 Impact Factor
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    ABSTRACT: Simvastatin (SV), a drug of the statin class currently used orally as an anti-cholesterolemic via 10 the inhibition of the 3-hydroxy-3-methyl-glutaryl-Coenzyme A (HMG-CoA) reductase, has been found 11 not only to reduce cholesterol but also to have several other pharmacological actions that might be 12 beneficial in airway inflammatory diseases. Currently, there is no inhalable formulation that could deliver 13 SV to the lungs. In this study, a pressurised metered-dose inhaler (pMDI) solution formulation of SV was 14 manufactured, with ethanol as a co-solvent, and its aerosol performance and physio-chemical properties 15 investigated. A pMDI solution formulation containing SV and 6%w/w ethanol was prepared. This 16 formulation was assessed visually for SV solubility. Furthermore, the aerosols performance (using 17 Andersen Cascade impactor at 28.3 L/min) and active ingredient chemical stability up to 6 months at 18 different storage temperatures, 4 and 25°C, were also evaluated. The physico-chemical properties of the 19 SV solution pMDI were also characterised by differential scanning calorimetry (DSC), thermogravimetric 20 analyses (TGA) and laser diffraction. The aerosol particles, determined using scanning electron micros-21 copy (SEM), presented a smooth surface morphology and were spherical in shape. The aerosol produced 22 had a fine particle fraction of 30.77±2.44% and a particle size distribution suitable for inhalation drug 23 delivery. Furthermore, the short-term chemical stability showed the formulation to be stable at 4°C for up 24 to 6 months, whilst at 25°C, the formulation was stable up to 3 months. In this study, a respirable and stable 25 SV solution pMDI formulation for inhalation has been presented that could potentially be used clinically 26 as an anti-inflammatory therapy for the treatment of several lung diseases. 27 28 KEY WORDS: lung inflammation; pMDI; pressurised metered dose inhaler; simvastatin. 29 30 INTRODUCTION 31 Statins (HMG-CoA reductase inhibitors) are widely used 32 as cholesterol-lowering drugs (1). These compounds inhibit 33 the activity of 3-hydroxy-3-methyl-glutaryl-CoA (HMG-34 CoA) reductase enzyme, which catalyses the rate-limiting step 35 in mevalonate biosynthesis, a key intermediate in cholesterol 36 metabolism. Studies have recently described other possible 37 roles for statins as immuno-modulatory and anti-inflammatory 38 compounds, suggesting a protective mechanism of action (2– 39 5). Clinical studies have also shown that statins have been 40 found to be effective in decreasing cardiac events in persons 41 with average cholesterol levels and reduce inflammatory 42 markers (6–8). Furthermore, in vitro, animal and human stud-43 ies have found statin to have anti-inflammatory and mucolytic 44 actions (9–14). 45 Observational studies, via both retrospective and pro-46 spective analysis, have shown that statins may be useful in 47 reducing mortality rates in patients with chronic obstructive 48 pulmonary disease (COPD) (15–18). Furthermore, it has been 49 observed that, in a murine model of allergic asthma, statins 50 had an immune-modulatory effect through several different 51 anti-inflammatory pathways that still require further elucida-52 tion (19). In general, statins beneficial effects cannot entirely 53 be attributed to reduction of lipid levels (20,21). ABBREVIATIONS: ACI, Andersen Cascade Impactor; COPD, Chronic obstructive pulmonary disease; °C/min, Temperature degree per minute; DUSA, Dose uniformity apparatus; DSC, Differential scanning calorimetry; Dv 0.1 , 10% of the volume distribution is below this value; Dv 0.5 , The volume median diameter is the diameter where 50% of the distribution is above and 50% is below; Dv 0.9 , 90% of the volume distribution is below this value/0 # 2014 American Association of Pharmaceutical Scientists JrnlID 12249_ArtID 127_Proof# 1 -30/04/2014
    AAPS PharmSciTech 05/2014; 15(4):956. · 1.58 Impact Factor
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    ABSTRACT: Recent murine studies found that rifapentine, dosed daily, at least halved tuberculosis treatment times compared with standard rifampicin and isoniazid-containing regimens. However, in humans, an inhalable form of rifapentine may be necessary to considerably shorten treatment duration because of the physiological barriers associated with oral therapy. The current study compares two inhalable rifapentine dry powders-a novel pure crystalline form and an amorphous form-by a series of in vitro tests. The crystalline and amorphous powders had a mass median aerodynamic size of 1.68 ± 0.03 and 1.92 ± 0.01 μm, respectively, associated with a fine particle fraction of 83.2 ± 1.2% and 68.8 ± 2.1%, respectively. A quinone degradation product was identified in the amorphous powder stored for 1 month, whereas the crystalline form remained chemically stable after storage at both 0% and 60% relative humidity, 25°C, for at least 3 months. Solubilized rifapentine was well tolerated by pulmonary tissue and macrophage cells up to approximately 50 μM. The accumulation of rifapentine within alveolar macrophage cells was significantly higher than for rifampicin, indicating enhanced delivery to infected macrophages. The novel inhalable crystalline form of rifapentine is suitable for targeted treatment of tuberculosis infection and may radically shorten treatment duration. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.
    Journal of Pharmaceutical Sciences 03/2014; · 3.13 Impact Factor
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    ABSTRACT: This study focuses on the co-engineering of salbutamol sulphate (SS), a common bronchodilator, and mannitol (MA), a mucolytic, as a potential combination therapy for mucus hypersecretion. This combination was chosen to have a synergic effect on the airways: the SS will act on the β2-receptor for relaxation of smooth muscle and enhancement of ciliary beat frequency, whilst mannitol will improve the fluidity of mucus, consequently enhancing its clearance from the lung. A series of co-spray-dried samples, containing therapeutically relevant doses of SS and MA, were prepared. The physico-chemical characteristics of the formulations were evaluated in terms of size distribution, morphology, thermal and moisture response and aerosol performance. Additionally, the formulations were evaluated for their effects on cell viability and transport across air interface Calu-3 bronchial epithelial cells, contractibility effects on bronchial smooth muscle cells and cilia beat activity using ciliated nasal epithelial cells in vitro. The formulations demonstrated size distributions and aerosol performance suitable for inhalation therapy. Transport studies revealed that the MA component of the formulation enhanced penetration of SS across the complex mucus layer and the lung epithelia cells. Furthermore, the formulation in the ratios of SS 10(-6) and MA 10(-3) M gave a significant increase in cilia beat frequency whilst simultaneously preventing smooth muscle contraction associated with mannitol administration. These studies have established that co-spray dried combination formulations of MA and SS can be successfully prepared with limited toxicity, good aerosol performance and the ability to increase ciliary beat frequency for improving the mucociliary clearance in patients suffering from hyper-secretory diseases, whilst simultaneously acting on the underlying smooth muscle.
    The AAPS Journal 01/2014; · 4.39 Impact Factor
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    ABSTRACT: Objectives: This study focuses on the development of a dry powder inhaler (DPI) formulation of simvastatin (SV), a common anti-cholesterol prodrug, which could potentially be used for its anti-inflammatory effects and its ability to reduce mucus production as therapy for respiratory diseases. Methods: Micronised SV samples were prepared by dry jet-milling. The longterm chemical stability and physicochemical properties of the formulations were characterised in terms of particles size, morphology, thermal and moisture responses. Furthermore, in vitro aerosol depositions were performed. The formulation was evaluated for cell viability and its effect on cilia beat activity, using ciliated nasal epithelial cells in vitro. The formulation transport across an established air interface Calu-3 bronchial epithelial cells and its ability to reduce mucus secretion was also investigated. Results: The particle size of the SV formulation and its aerosol performance were appropriate for inhalation therapy. Moreover, the formulation was found to be non-toxic to pulmonary epithelia cells and cilia beat activity up to a concentration of 10-6 M. Transport studies revealed that SV has the ability to penetrate into airway epithelial cells and is converted into its active SV hydroxy acid metabolite. Single dose of SV DPI also decreased mucus production after 4 days of dosing. Conclusion: This therapy could potentially be used for the local treatment of diseases like chronic obstructive pulmonary disease or cystic fibrosis, where hyper mucus production and inflammation are present.
    Expert Opinion on Drug Delivery 01/2014; · 4.87 Impact Factor
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    ABSTRACT: 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. 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. 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. This study demonstrated the feasibility of formulating a solution-based pMDI containing CLA for the treatment of lung inflammatory diseases.
    The Journal of pharmacy and pharmacology. 12/2013;
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    ABSTRACT: The purpose of this work was to evaluate gas perfusion isothermal calorimetry (ITC) as a method to characterize the physicochemical changes of active pharmaceutical ingredients (APIs) intended to be formulated in pressurised metered dose inhalers (pMDIs) after exposure to a model propellant. Spray dried samples of beclomethasone dipropionate (BDP) and salbutamol sulphate (SS) were exposed to controlled quantities of 2H,3H-decafluoropentane (HPFP) to determine whether ITC could be used as a suitable analytical method for gathering data on the behavioural properties of the powders in real time. The crystallization kinetics of BDP and the physiochemical properties of SS were successfully characterized using ITC and supported by a variety of other analytical techniques. Correlations between real and model propellant systems were also established using hydrofluoroalkane (HFA-227) propellant. In summary, ITC was found to be suitable for gathering data on the crystallization kinetics of BDP and SS. In a wider context, this work will have implications on the use of ITC for stability testing of APIs in HFA-based pMDIs.
    International Journal of Pharmaceutics 12/2013; · 3.99 Impact Factor
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    ABSTRACT: To investigate the influence of different actuator materials and nozzle designs on the electrostatic charge properties of a series of solution metered dose inhaler (pMDI) aerosols. Actuators were manufactured with flat and cone nozzle designs using five different materials from the triboelectric series (Nylon, Polyethylene terephthalate, Polyethylene-High density, Polypropylene copolymer and Polytetrafluoroethylene). The electrostatic charge profiles of pMDI containing beclomethasone dipropionate (BDP) as model drug in HFA-134a propellant, with different concentrations of ethanol were studied. Electrostatic measurements were taken using a modified electrical low-pressure impactor (ELPI) and the deposited drug mass assayed chemically using HPLC. The charge profiles of HFA 134a alone have shown strong electronegativity with all actuator materials and nozzle designs, at an average of -1531.34 pC ± 377.34. The presence of co-solvent ethanol significantly reduced the negative charge magnitude. BDP reduced the suppressing effect of ethanol on the negative charging of the propellant. For all tested formulations, the flat nozzle design showed no significant differences in net charge between different actuator materials, whereas the charge profiles of cone designs followed the triboelectric series. The electrostatic charging profiles from a solution pMDI containing BDP and ethanol can be significantly influenced by the actuator material, nozzle design and formulation components. Ethanol concentration appears to have the most significant impact. Furthermore, BDP interactions with ethanol and HFA have an influence on the electrostatic charge of aerosols. By choosing different combinations of actuator materials and orifice design, the fine particle fractions of formulations can be altered.
    Pharmaceutical Research 12/2013; · 4.74 Impact Factor
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    ABSTRACT: The potential for rifapentine-containing oral therapeutic regimens to significantly shorten the current six-month anti-tubercular treatment regimen is confounded by high plasma protein binding of rifapentine. Inhaled aerosol delivery of rifapentine, a more potent anti-tubercular antibiotic drug, in combination with other first-line antibiotics may overcome this limitation to deliver a high drug dose at the pulmonary site of infection. A formulation consisting of rifapentine, moxifloxacin and pyrazinamide, with and without leucine, was prepared by spray-drying. This formulation was assessed for its physico-chemical properties, in vitro aerosol performance and antimicrobial activity. The antibiotic powders, with and without leucine, had similar median aerodynamic diameters of 2.58 ± 0.08 μm and 2.51 ± 0.06 μm, with a relatively high fine particle fraction of 55.5 ± 1.9% and 63.6 ± 2.0%, respectively. Although the powders were mostly amorphous, some crystalline peaks associated with the δ polymorph for the spray-dried crystalline pyrazinamide were identified. Stabilisation of the powder with 10% w/w leucine and protection from moisture ingress was found to be necessary to prevent overt crystallisation of pyrazinamide after long-term storage. In vitro biological assays indicated antimicrobial activity was retained after spray-drying. Murine pharmacokinetic studies are currently underway.
    Pharmaceutical Research 11/2013; · 4.74 Impact Factor
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    ABSTRACT: The aerosol performance of budesonide solution-based pressurized metered-dose inhalers (HFA 134a), with various amounts of ethanol (5-30%, w/w) as co-solvents, was evaluated using impaction and laser diffraction techniques. With the increase of ethanol concentration in a formulation, the mass median aerodynamic diameter was increased and the fine particle fraction showed a significant decline. Although data obtained from laser diffraction oversized that of the impaction measurements, good correlations were established between the two sets of data. Particles emitted from all the five formulations in this study were amorphous, with two different types of morphology - the majority had a smooth surface with a solid core and the others were internally porous with coral-like surface morphology. The addition of ethanol in the formulation decreased the percentage of such irregular-shape particles from 52% to 2.5% approximately, when the ethanol concentration was increased from 5% to 30%, respectively. A hypothesis regarding the possible particle formation mechanisms was also established. Due to the difference of droplet composition from the designed formulation during the atomization process, the two types of particle may have gone through distinct drying processes: both droplets will have a very short period of co-evaporation, droplets with less ethanol may be dried during such period; while the droplets containing more ethanol will undergo an extra condensation stage before the final particle formation.
    Drug Development and Industrial Pharmacy 11/2013; 39(11):1625-1637. · 1.54 Impact Factor
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    ABSTRACT: Background and objectiveWe assessed whether co-deposition of a long-acting β2-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. ResultsThe 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.
    Respirology 11/2013; 18(8). · 2.78 Impact Factor
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    ABSTRACT: Abstract A critical problem associated with poor water-soluble drugs is their low and variable bioavailability, which is derived from the slow dissolution and erratic absorption. Nano-formulation has been identified as one approach to enhance the rate and extent of drug absorption for compounds that demonstrate limited water solubility. This study aimed to investigate the physico-chemical variables that affect the manufacture, dissolution and consequent bioavailability of wet-milled clarithromycin (CLA) nanoparticles, a macrolide antibiotic. CLA nanoparticles were prepared using wet milling method followed by freeze-drying. Different stabilizer systems, consisting of surfactants and polymers alone or their combinations were studied to determine the optimum conditions for producing nano-sized CLA particles. In vitro characterizations of the CLA nanoparticles were performed using dynamic light scattering, X-ray powder diffraction, differential scanning calorimetry and dissolution efficiency test. Results showed that in general the wet milling process did not modify the crystallinity of the CLA nanoparticles. The poloxamers and polyvinyl alcohol (PVA) stabilizers resulted in nanoparticles with the smallest particle size and best dissolution rates. Furthermore, poloxamers F68 and F127, and PVA stabilizers demonstrated the best performance in increasing dissolution efficacy.
    Pharmaceutical Development and Technology 10/2013; · 1.33 Impact Factor
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    ABSTRACT: Abstract Purpose: A new approach to delivering high doses of dry powder medicaments to the lung is presented. The Orbital(®) dry powder device is designed to deliver high doses of drugs to the respiratory tract in a single dosing unit, via multiple inhalation maneuvers, overcoming the need to prime or insert multiple capsules. Methods: The Orbital was tested in its prototype configuration and compared with a conventional RS01 capsule device. Three formulations were evaluated: 200 mg of spray-dried ciprofloxacin formulation for respiratory infection, 200 mg of spray-dried mannitol formulation for mucus clearance, and 100, 200, and 400 mg of co-spray-dried 1:8 formulations containing ciprofloxacin and mannitol as combination therapy. The systems were evaluated in terms of physicochemical properties and tested using a multistage liquid impinger at 60 L/min. Emptying rates were evaluated, and the aerosolization performance compared with 10 capsules used sequentially in the RS01. Results and Discussion: The systems were different in terms of morphology, thermal response, moisture sorption, and stability; however, they had similar sizes when measured by laser diffraction, making them suitable for comparison in the Orbital and RS01 devices. The aerosolization performance from the Orbital device and RS01 was dependent on the formulation type; however, the fine particle fraction (FPF) produced by the Orbital device was higher than that by the RS01. The FPFs for ciprofloxacin, mannitol, and co-spray-dried formulation were 67.1±1.8, 47.1±2.2, and 42.0±1.8, respectively. For the Orbital, 90% of the loaded dose was delivered within 10 inhalation maneuvers, with the profile being dependent on the formulation type. Conclusion: The Orbital provides a means of delivering high doses of medicine to the respiratory tract through multiple breath maneuvers after a single actuation. This approach will allow the delivery of a wide range of high-payload formulations (>100 mg) for the treatment of a variety of lung disorders. To date, no such passive device exists that meets these crucial criteria.
    Journal of Aerosol Medicine and Pulmonary Drug Delivery 09/2013; · 2.89 Impact Factor
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    ABSTRACT: The aim of the present study was to develop controlled release inhalable lipid microparticles (LMs) loaded with the antioxidant flavonoid, quercetin and to investigate the interaction of these microparticles with A549 pulmonary alveolar epithelial cells. The LMs were produced using different lipidic materials and surfactants, by melt emulsification followed by a sonication step. The most efficient modulation of the in vitro release of quercetin was achieved by the LMs prepared with tristearin and hydrogenated phosphatidylcholine, which were used for subsequent studies. These LMs exhibited a quercetin loading of 11.8±0.3%, and a volume median diameter, determined by laser diffraction, of 4.1±0.2μm. Moreover, their mass median aerodynamic diameter (4.82±0.15μm) and fine particle fraction (27.2±3.9%), as measured by multi-stage liquid impinger, were suitable for pulmonary delivery. Quercetin was found to be highly unstable (complete decomposition within 6-h incubation) in Ham's F-12 medium used for A549 cell culture. Degradation was markedly reduced (16.4% of the initial quercetin content still present after 24-h incubation) after encapsulation in the lipid particle system. Viability studies performed by lactate dehydrogenase assay, demonstrated that quercetin LMs showed no significant cytotoxicity on the A549 cells, over the concentration 0.1-5μM. The uptake of quercetin by the A549 lung alveolar cells was also investigated. After 4-h incubation, the accumulation of quercetin in the A549 cells was significantly higher (2.3-fold increase) for the microparticle entrapped flavonoid when compare to non-encapsulated quercetin. The enhanced intracellular delivery of quercetin achieved by the LMs is likely due to the flavonoid stabilization after encapsulation.
    Colloids and surfaces B: Biointerfaces 08/2013; 112C:322-329. · 4.28 Impact Factor
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    ABSTRACT: Liposomal ciprofloxacin formulations have been developed with the aim of enhancing lung residence time, thereby reducing the burden of inhaled antimicrobial therapy which requires multiple daily due to rapid absorptive clearance of antibiotics from the lungs. However, there is a lack of a predictive methodology available to assess controlled release inhalation delivery systems and their effect on drug disposition. In this study three ciprofloxacin formulations were evaluated: a liposomal formulation, a solution formulation and a 1:1 combination of the two (mixture formulation). Different methodologies were utilised to study the release profiles of ciprofloxacin from these formulations: (i) membrane diffusion, (ii) air-interface Calu-3 cells, and (iii) isolated perfused rat lungs. The data from these models were compared to the performance of the formulations in vivo. The solution formulation provided the highest rate of absorptive transport followed by the mixture formulation, with the liposomal formulation providing substantially slower drug release. The rank-order of drug release/transport from the different formulations was consistent across the in vitro and ex-vivo methods, and this was predictive of the profiles in vivo. The use of complimentary in vitro and ex-vivo methodologies provided a robust analysis of formulation behavior, including mechanistic insights, and predicted in vivo pharmacokinetics.
    European journal of pharmaceutics and biopharmaceutics: official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V 07/2013; · 3.15 Impact Factor
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    ABSTRACT: Inhalation of antibiotics and mucolytics are the most important combination of inhaled drugs for chronic obstructive lung diseases and have become a standard part of treatment. However, it is yet to be determined whether the administration of a mucolytic has an effect on the transport rate of antibiotics across the airway epithelial cells. Consequently, the aim of this study was to investigate the effects of inhalation dry powder, specifically mannitol, on ciprofloxacin transport using Calu-3 air interface cell model. Transport studies of ciprofloxacin HCl were performed using different configurations including single spray-dried ciprofloxacin alone, co-spray dried ciprofloxacin with mannitol and deposition of mannitol prior to ciprofloxacin deposition. To understand the mechanism of transport and interactions between the drugs, pH measurements of apical surface liquid and further transport studies were performed with ciprofloxacin base, with and without the presence of ion channel/transport inhibitors such as disodium cromoglycate and furosemide. Mannitol was found to delay absorption of ciprofloxacin HCl through the increase in ASL volume and subsequent reduction in pH. Conversely, ciprofloxacin base had a higher transport rate after mannitol deposition. This study clearly demonstrates that the deposition of mannitol prior to ciprofloxacin on the air-interface Calu-3 cell model has an effect on its transport rate. This was also dependent on the salt form of the drug and the timing and sequence of formulations administered.
    Molecular Pharmaceutics 06/2013; · 4.57 Impact Factor

Publication Stats

872 Citations
342.02 Total Impact Points


  • 2012–2014
    • Woolcock Institute of Medical Research
      Sydney, New South Wales, Australia
  • 2013
    • Shahid Beheshti University of Medical Sciences
      • Department of Pharmaceutics
      Tehrān, Ostan-e Tehran, Iran
  • 2009–2013
    • Universita degli studi di Ferrara
      • Department of Chemical and Pharmaceutical Sciences
      Ferrara, Emilia-Romagna, Italy
  • 2005–2013
    • University of Sydney
      • Faculty of Pharmacy
      Sydney, New South Wales, Australia
  • 2011–2012
    • Monash University (Australia)
      • • Faculty of Pharmacy and Pharmaceutical Sciences
      • • Monash Institute of Pharmaceutical Sciences
      Melbourne, Victoria, Australia
  • 2009–2011
    • Università degli studi di Parma
      • Department of Pharmacy
      Parma, Emilia-Romagna, Italy
  • 2003–2009
    • University of Bath
      • Department of Pharmacy and Pharmacology
      Bath, ENG, United Kingdom