Oxidative stress is instrumental in the pathogenesis and progression of chronic obstructive pulmonary disease (COPD). Novel therapeutic strategies that target macrophages, based on the use of antioxidant compounds, could be explored to improve corticosteroids responses in COPD patients. In this study, inhalable microparticles containing budesonide (BD) and resveratrol (RES) were prepared and characterized. This approach was undertaken to develop a multi-drug inhalable formulation with anti-oxidant and anti-inflammatory activities for treatment of chronic lung diseases. The inhalable microparticles containing different ratio of BD and RES were prepared by spray drying. The physico-chemical properties of the formulations were characterized in terms of surface morphology, particle size, physical and thermal stability. Additionally, in vitro aerosol performances of these formulations were evaluated with the multi-stage liquid impinger (MSLI) at 60 and 90 l/min, respectively. The cytotoxicity effect of the formulations was evaluated using rat alveolar macrophages. The biological responses of alveolar macrophages in terms of cytokine expressions, nitric oxide (NO) production and free radical scavenging activities were also tested. The co-spray dried (Co-SD) microparticles of all formulations exhibited morphologies appropriate for inhalation administration. Analysis of the deposition profiles showed an increase in aerosol performance proportional to BD concentration. Cell viability assay demonstrated that alveolar macrophages could tolerate a wide range of RES and BD concentrations. In addition, RES and BD were able to decrease the levels of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) in lipopolysaccharide (LPS) induced alveolar macrophages. 
This study has successfully established the manufacture of Co-SD formulations of RES and BD with morphology and aerosol properties suitable for inhalation drug delivery, negligible in vitro toxicity and enhanced efficacy to control inflammation and oxidative stress in LPS-induced alveolar macrophages. 

Purpose: To discuss the challenges and opportunities for dry powder nasal medications and to put this in to perspective by evaluating and characterizing the performance of the Teijin- bechlomethasone diproprionate dry powder nasal inhaler; providing a baseline for future nasal products development. 
Methods: The aerosol properties of the formulation and product performance of Teijin powder intranasal spray were assessed, with a particular focus on particle size distribution (laser diffraction), powder formulation composition (confocal Raman microscope) and aerosol performance data (British Pharmacopoeia Apparatus E cascade impactor, aerosol laser diffraction).
Results: Teijin Rhinocort® (beclometasone dipropionate, BDP) dry powder spray formulation is a simple blend of one active ingredient, BDP with hydroxypropylcellulose (HPC) carrier particles and a smaller quantity of lubricants (stearic acid and magnesium stearate). The properties of the blend are mainly those of the carrier (Dv50 = 98 ± 1.3 μm). Almost the totality of the capsule fill weight (96.5 %) was emitted with 8 actuations of the device. Using the pharmacopeia suggested nasal chamber deposition apparatus attached to an Apparatus E impactor. The BDP main site of deposition was found to be in the nasal expansion chamber (90.2 ± 4.78 %), while 4.64 ± 1.38 % of the BDP emitted dose was deposited on Stage 1 of the Apparatus E.
Conclusions: The Teijin powder nasal device is a simple and robust device to deliver pharmaceutical powder to the nasal cavity, thus highlighting the robustness of intranasal powder delivery systems. The large number of actuations needed to deliver the total dose (eight) should be taken in consideration when compared to aqueous sprays (usually 2 actuations), since this will impact on patient compliance and consequently therapeutic efficacy of the formulation.

Purpose: Typical methods to study pMDI sprays employ particle sizing or visible light diagnostics, which suffer in regions of high spray density. X-ray techniques can be applied to pharmaceutical sprays to obtain information unattainable by conventional particle sizing and light-based techniques.

Methods: We present a technique for obtaining quantitative measurements of spray density in pMDI sprays. A monochromatic focused X-ray beam was used to perform quantitative radiography measurements in the near-nozzle region and plume of HFA- propelled sprays.

Results: Measurements were obtained with a temporal resolution of 0.184 ms and spatial resolution of 5 um. Steady flow conditions were reached after around 30 ms for the formulations examined with the spray device used. Spray evolution was affected by the inclusion of ethanol in the formulation and unaffected by the inclusion of 0.1% drug by weight. Estimation of the nozzle exit density showed that vapour is likely to dominate the flow leaving the inhaler nozzle during steady flow.

Conclusions: Quantitative measurements in pMDI sprays allow the determination of nozzle exit conditions that are difficult to obtain experimentally by other means. Measurements of these nozzle exit conditions can improve understanding of the atomization mechanisms responsible for pMDI spray droplet and particle formation.

Purpose: 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.
Methods: 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.
Results: 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.
Conclusions: 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.

Biofilm tolerance has become a serious clinical concern in the treatment of nosocomial pneumonia owing to the resistance to various antibiotics. There is an urgent need to develop alternative antimicrobial agents or combination drug therapies that are effective via different mechanisms. Silver nanoparticles (AgNPs) have been developed as anti-biofilm agent for the treatment of infections associated with the use of mechanical ventilations, such as endotracheal intubation. Meanwhile curcumin, a phenolic plant extract, has displayed natural anti-biofilm properties through the inhibition of bacterial quorum sensing systems. The aim of this study was to investigate the possible synergistic/additive interactions of AgNPs and curcumin nanoparticles (Cur-NPs) against both Gram-negative (Pseudomonas aeruginosa) and Gram-positive (Staphylococcus aureus) microorganisms. Combination of AgNP sand Cur-NPs (termed as Cur-SNPs) at 100 μg/mL disrupted 50% of established bacterial biofilms (formed on microtiter plates). However, further increase in the concentration of Cu-SNPs failed to effectively eliminate the biofilms. To achieve the same effect, at least 500 μg/mL of Cur-NP alone was needed. Scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM) revealed that combination therapy (Cur-SNPs) was the most potent to eradicate pre-formed biofilm compared to mono-drug therapy. These agents are also non-toxic to healthy human bronchial epithelial cells (BEAS2B).

Introduction: During the last few decades, cell-based therapies have shown great potential to treat patients with lung diseases [1]. It has been proposed that the administration of cells into an injured lung could be considered as a therapeutic method to repair and replace lost lung tissue [2, 3]. Using this method, transplanted cells with the ability to proliferate and differentiate into alveolar cells, have been suggested as a therapeutic strategy. Cell-based therapy aims to perform structural repair (engraftment of cells) and have an immunomodulation effect to treat the diseased lung. The ability to enhance endogenous stem cells to regenerate lung tissue is key for the treatment of a multitude of fatal lung diseases, such as idiopathic pulmonary fibrosis (IPF). Originally cell-based therapies were thought as ‘the ultimate strategy’ for regenerating diseased lung, but these kinds of therapies have shown to be more complex than specific molecular targeted therapy. Due to the challenges facing cell-based therapy, achieving success to find a safe and efficient strategy for IPF treatment has been slow.
Areas covered: In this review, the latest investigations using various types of cells for IPF therapy has been presented. The cells studied for cell-based therapies in IPF are lung alveolar epithelial cells, lung resident stem cells and exogenous adult stem cells such as MSCs derived from bone and adipose. Moreover, recent clinical trials in this field are also listed.
Expert opinion: After many years of investigation, the use of cell-based therapies to treat IPF is still at the experimental phase. Problems include bioethical issues, safety of cell transplantation, routes of delivery and the dose and timing of administration. Further investigations are necessary to establish the best strategy for using cell-based therapies effectively for the treatment of IPF.

Purpose: Drug concentration measurements in MDI sprays are typically performed using particle filtration or laser scattering. These techniques are ineffective in proximity to the nozzle, making it difficult to determine how factors such as nozzle design will affect the precipitation of co-solvent droplets in solution-based MDIs, and the final particle distribution.
Methods: In optical measurements, scattering from the constituents is difficult to separate. We present a novel technique to directly measure drug distribution. A focused x-ray beam was used to stimulate x-ray fluorescence from the bromine in a solution containing 85% HFA, 15% ethanol co-solvent, and 1 ug/uL IPBr.
Results: Instantaneous concentration measurements were obtained with 1ms temporal resolution and 5um spatial resolution, providing information in a region that is inaccessible to many other diagnostics. The drug remains homogeneously mixed over time, but was found to be higher at the centerline than at the periphery. This may have implications for oropharyngeal deposition in vivo.
Conclusions: Measurements in the dynamic, turbulent region of MDIs allow us to understand the physical links between formulation, inspiration, and geometry on final particle size and distribution. This will ultimately lead to a better understanding of how MDI design can be improved to enhance respirable fraction.

Background: Fifteen percent of Australians with intellectual disability (ID) are reported to have asthma. People with ID are at risk of poor health knowledge due to deficits in intellectual and adaptive functioning, but their medication knowledge has largely been ignored in research to date.
Objective: To explore the level of understanding of asthma medication use of people with ID who self-administer their inhaled medications, in order to inform future educational support. Setting the research was conducted in NSW, Australia, at the participants’ homes, the point of health care access, or the offices of relevant support organisations.
Method: In this qualitative study face-to-face interviews were conducted with people with ID using a semi-structured interview guide. The interviews were recorded, transcribed and thematically analysed. Main outcome Identification of barriers to asthma medication self-management by people with ID.
Results: Seventeen people with ID who self-administer their asthma medications were interviewed. Factors influencing their asthma medication knowledge and use included understanding of their illness and the need for medication; aspects of self-management and autonomy versus dependence. This sample of people with ID had a good understanding of the importance of using their inhaled asthma medications, as well as asthma triggers, and the difference between use of preventer and reliever medications. Both enablers and barriers to asthma medication self-management were identified in the domains of managing attacks, adherence, knowledge of side effects and sources of information on correct use of inhalers. The level of autonomy for medication use varied, with motivation to self-manage asthma influenced by the level of support that was practically available to individual participants.
Conclusion: This research investigated aspects of asthma medication self-management of people with ID. Based on the barriers identified, pharmacists should promote use of spacers and written asthma action plans as well as counsel people with ID about how to recognise and minimise side effects of asthma medications. Specific strategies for pharmacists when educating people with ID and their caregivers include active listening to determine understanding of concepts, exercising care with language, and working with the person’s known routines to maximise adherence with preventer medications.

Objective: To develop and characterise a highly respirable dry powder inhalable formulation of voriconazole (VRZ)  
Methods: Powders were prepared by spray drying aqueous/alcohol solutions. Formulations were characterised in terms of particle size, morphology, thermal, moisture responses and aerosolisation performance. Optimised powder was deposited onto air-interface Calu-3 model to assess their uptake across Calu-3 lung epithelia. Optimised formulation was evaluated for stability (drug content and aerosol performance) for 3 months. Additionally, Calu-3 cell viability, lung bioavailability and tissue distribution of optimised formulation were evaluated. 
Results: Particle size and aerosol performance of dry powder containing 80% w/w VRZ and 20% w/w leucine was appropriate for inhalation therapy. Optimised formulation showed irregular morphology, crystalline nature, low moisture sensitivity and was stable for 3 months at room temperature. Leucine did not alter the transport kinetics of VRZ, as evaluated by air-interface Calu-3 model. Formulation was non-cytotoxic to pulmonary epithelial cells. Moreover, lung bioavailability and tissue distribution studies in murine model clearly showed that VRZ dry powder inhalable formulation has potential to enhance therapeutic efficacy at the pulmonary infection site whilst minimising systemic exposure and related toxicity.
Conclusion: This study support the potential of inhaled dry powder VRZ for the treatment of fungal infections.

The aerosol particle size distributions of solution based pressurised metered dose inhalers containing 15%w/w ethanol and different quantities of non-volatile component (NVC) (drug and glycerol) were evaluated at 25°C and 55°C, using a custom-built heating rig that pre-heated air prior to aerosolisation. Particle size distributions were assessed using an Anderson cascade impactor and mass‐weighted cumulative aerodynamic diameter distributions were compared to a theoretical model that predicts the final size distribution, based on initial droplet size, vapour pressure of the formulation containing HFA 134a and percent NVC. In general, the mass median aerodynamic diameter was proportional to NVC1/3 , with experimental particle size distributions following theoretical values. However, when comparing theoretical vs. experimental data over the range of mass weighted cumulative aerodynamic diameter distributions between 10 and 90%, the 55°C experimental measurements more closely fitted the theoretical equation when compared to 25 °C. This was attributed to incomplete drying of some of the larger initial droplets prior to impaction. Additionally, post induction port measurements of volumetric size distribution using laser diffraction, showed a reduction in median particle diameter at 55 °C, compared to 25 °C and a change from bi-modal to mono modal distribution, indicating complex drying kinetics under ambient conditions. 

Theophylline (TP) is a very well established orally or intravenously delivered anti asthma 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 associate 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 the lipophilicity of the formulation.

A DPI formulation of TP was developed that was shown to be suitable for inhalation.

Ever since the success of developing inhalable insulin, drug delivery via pulmonary administration has become an attractive route to treat chronic diseases. Pulmonary delivery system for nanotechnology is a relatively new concept especially when applicable to lung cancer therapy. Nano-based systems such as liposome, polymeric nanoparticles or micelles are strategically designed to enhance the therapeutic index of anti-cancer drugs through improvement of their bioavailability, stability and residency at targeted lung regions. Along with these benefits, nano-based systems also provide additional diagnostic advantages during lung cancer treatment, including imaging, screening and drug tracking. Nevertheless, delivery of nano-based drugs via pulmonary administration for lung cancer therapy is still in its infancy and numerous challenges are expected. Pharmacology, immunology, toxicology and large-scale manufacturing (stability and activity of drugs) are some aspects in nanotechnology that should be taken into consideration for the development of inhalable nano-based chemotherapeutic drugs. This review will focus on the current inhalable nano-based drugs for lung cancer treatment.

Purpose: The surface charge of nanoparticles is an important factor that controls efficiency and cellular uptake. The aim of this study was to investigate curcumin nanoparticles (Cur-NPs) with different surface charges, in terms of toxicity, internalization, anti-inflammatory and anti-oxidant activities towards alveolar macrophages cells.

Methods: The surface charge of curcumin nanoparticles (positive, negative and neutral), with an average diameter of 30 nm, were synthesized and characterized. Polyvinyl-alcohol, polyvinylpyrrolidone and dextran were used as coatings to confer negative, positive and neutral charges. The synthesized Cur-NPs were evaluated for particle size, encapsulation efficiency, surface charge, qualitative and quantitative cellular uptakes , anti-oxidant and anti-inflammatory activities.

Results: Positively charged nanoparticles showed higher cytotoxicity effects compared to negative and neutral particles. The same trend was observed in antioxidant activity, which included radical scavenging and nitric oxide production. In addition, the anti- inflammatory activity (interleukin-1β, IL-6 and TNF-α) depleted in the order: positive>negative>neutral. The void neutral-, positively- and negatively-charged nanoparticles did not show any cytotoxic effects.

Conclusion: The difference in activity for different surface charges of Cur-NPs may be due to the internalization rate of the particles by alveolar macrophages. Intracellular uptake measurements demonstrated that Cur-NPs with positive surface charges possessed the strongest interaction with alveolar macrophages.

A methodology for studying the deagglomeration performance and emptying behaviour of micronised mannitol powder from two commercial capsule-based dry powder inhalers (DPIs), the low (LR) and high resistance (HR) RS01®, is presented. Mathematical modeling played a key role in the interpretation of the powder release behaviour from these two DPI systems. Non-linear regression models were used to estimate the rate constants for emptying of mannitol powder, which were characterized from the aerosol obscuration versus time profiles obtained from laser diffraction particle sizing data. The effects of device resistance and associated pressure drops, sampling flow rate, rates of powder emptying and the presence of a capsule on the dispersion characteristics were studied. The presence of a capsule significantly improved the aerosolisation performance of mannitol powder from both inhalers, which may be due to the extended powder-air-device interactions within the device. It is important to consider the stochastic nature of movement and physical state of the capsule when assessing the aerosolisation mechanisms and dispersion performance from these complex delivery systems. The methodology set out in this study has the capacity to provide a greater level of detail in the study of aerosol plume characteristics from capsule-based DPIs.

Purpose: The aim of this study is to evaluate the biological effects of Calu-3 epithelial cells in response to the delivery of simvastatin (SV) via solution pressurized metered dose inhaler (pMDI).

Methods: SV pMDI was aerosolised onto Calu-3 air-interface epithelial cells using a modified glass twin stage impinger. The transport of SV across Calu-3 cells, mucus production, inflammatory cytokines production i.e. interleukin (IL) 6, 8 and tumour necrosis factor alpha (TNF- α) and oxidative stress from Calu-3 cells following treatment with SV pMDI was investigated and compared to untreated cells.

Results: It was found that SV had the ability to penetrate into the respiratory epithelium and convert into its active SV hydroxy acid (SVA) metabolite. Furthermore, the amount of mucus produced was significantly reduced when SV was deposited on Calu-3 compared to untreated cells. Additionally, SV delivered by pMDI reduces production of IL-6, 8 and TNF-α from Calu-3 following stimulation with lipopolysaccharide (LPS). SV also showed equivalent antioxidant property to vitamin E.

Conclusions: Treatment with SV solution pMDI formulation on Calu-3 cells reduces mucus production, inflammatory cytokines and oxidative stress. This formulation could potentially be used clinically as muco-inhibitory and anti-inflammatory therapy for treatment of chronic lung diseases.

Aim of this study was to investigate the changes in transport and effectiveness of salbutamol sulphate (SAL) and budesonide (BD) following stimulation with transforming growth factor-β (TGF-β) in mono- and co-culture models of bronchial and alveolar epithelium. Primary bronchial and alveolar epithelial cells, air interface grown on filters either as mono- cultures or in co- culture with airway smooth muscle cells or alveolar macrophages, respectively, were stimulated with TGF-β. The biological response was modulated by depositing aerosolized SAL on bronchial and BD on 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 co- culture models, transport of SAL and BD were affected in cultures from some of the patients (6 out of 10 for bronchial and 2 out of 4 for alveolar cells). The bronchial co-culture showed a better responsiveness to SAL in terms of cAMP release than the monoculture. In contrast, difference between alveolar mono- and co- cultures 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, co-culture models are more potent to measure such effects than mono-cultures.

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 5 μm, 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 ± 0.1 μm, respectively when assessed with an Andersen cascade impactor (ACI) at 60 l/min. The cytotoxicity results of spray-dried resveratrol on Calu-3 revealed that the cells could tolerate high concentration of resveratrol (up to 160 μM). 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.

Objective: This aim of this study was to assess inhaler technique of people with intellectual disability (ID), and evaluate the effectiveness of teaching with respect to their individual ability to adopt correct technique. Methods: Seventeen people with ID were recruited through existing networks of general practitioners and disability support organisations. Inhaler technique was assessed using validated checklists and placebo devices, followed by provision of individualised training. The educational interaction between participant and researcher was captured via video recording and analysed qualitatively. Results: Seventeen people with ID participated; females comprised 65%. At baseline, no participants correctly used any device. Pressurised metered dose inhalers, with or without accessory devices, were the most poorly used devices. Inhalation steps were poorly performed across all devices. Following training, the proportions of assessed participants that were able to master inhaler technique were 100% of Accuhaler users, 40% of Turbuhaler users, 25% of pressurised metered dose inhaler users and 0% of Handihaler users. Barriers identified included poor comprehension of breathing processes, the lack of attentiveness and poor dexterity. Facilitators for educator delivery of inhaler technique education included the use of analogies and being patient. Conclusions: This is the first study to examine inhaler technique mastery in people with ID. Results show that with education that addresses the unique patient barriers inherent in this group, some individuals can be trained to mastery. Structured modules of inhaler technique training tailored for people with ID, but which can be individualised, are recommended.

The present research aimed to develop and characterise a sustained release dry powder inhalable formulation of voriconazole (VRZ) for invasive pulmonary aspergillosis. The developed formulations were studied for their in vitro release profile, aerosol and physico-chemical properties as well as interactions with lung epithelia in terms of toxicity and transport/uptake. VRZ and VRZ loaded poly lactide microparticles (VLM) were prepared by aqueous/organic co-solvent and organic spray drying respectively. Powders were characterised using laser diffraction, differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), dynamic vapor sorption (DVS) and electron microscopy. Aerosol performance was evaluated using an RS01 dry powder inhaler and in vitro cascade impaction. Uptake across Calu-3 lung epithelia was studied, using aerosol deposition of the powder onto cells cultured in an air interface configuration, and compared to dissolution using a conventional dialysis membrane. Additionally, toxicity of VRZ and VLM and the potential impact of transmembrane proteins on uptake were investigated. The particle size and the aerosol performance of spray dried VRZ and VLM were suitable for inhalation purposes. VRZ exhibited a median volume diameter of 4.52 ± 0.07 µm while VLM 2.40 ± 0.05 µm. Spray dried VRZ was crystalline and VLM amorphous as evaluated by DSC and XRPD and both powders exhibited low moisture sorption between 0 and 90% RH (<1.2% w/w) by DVS. The fine particle fraction (% aerosol < 5 µm) for the VRZ was 20.86 ± 1.98 % while the VLM showed significantly improved performance (p<0.01) with an FPF of 43.56 ± 0.13 %. Both VRZ and VLM were not cytotoxic over a VRZ concentration range of 1.2 nM to 30 µM and the VLM particles exhibited a sustained release over 48 hours after being deposited on the Calu-3 cell line or via conventional dialysis-based dissolution measurements. Lastly, VRZ exhibited polarized transport across epithelia with basal to apical transport being slower than apical to basal. Influx and efflux transports may also play a role as transport was altered in the presence of a number of inhibitors. This study has established an inhalable and sustained release powder of VRZ for targeting invasive pulmonary aspergillosis.

Purpose: An inhalable dry powder formulation of Tranexamic acid (TA) was developed and tested in a novel high-dose Orbital® multi-breath inhaler. The formulation was specifically intended for the treatment of pulmonary haemorrhage and wound healing associated with haemoptysis.

Methods: Inhalable TA particles were prepared by spray drying and the powder characterised using laser diffraction, electron microscopy, thermal analysis, moisture sorption and X-ray powder diffraction. The aerosol performance was evaluated using cascade impaction and inline laser diffraction and interaction with epithelia cells and wound healing capacity investigated using a Calu-3 air interface model.

Results: The spray dried TA particles were crystalline and spherical with a D0.5 of 3.35 μm. The powders were stable and had limited moisture sorption (0.307% w/w at 90% RH). The Orbital device delivered ca. 38 mg powder per ‘inhalation’ at 60 l.min-1 across four sequential shots with an overall fine particle fraction (≤6.4 µm) of 59.3 ± 3.5 % based on the emitted mass of ca. 150 mg. The TA particles were well tolerated by Calu-3 bronchial epithelia cells across a wide range of doses (from 1nM to 10 nM) and no increase in inflammatory mediators was observed after deposition of the particles (a decrease in of IL-1β, IL-8 and INFγ was observed). Time lapse microscopy of a damaged confluent epithelia indicated that wound closure was significantly greater in TA treated cells compared to control.

Conclusion: A stable, high performance aerosol of TA has been developed in a multi-breath DPI device that can be used for the treatment of pulmonary lesions and haemoptysis.