Search

(1) Background: As genomic testing is becoming a part of the mainstream oncology practice, it is vital to ensure that our patients fully understand the implications of these tests. This study aimed to compare the attitudes and expectations of cancer patients with those of their physicians regarding the role of biomarker testing in clinical decision making. (2) Methods: Two separate, complimentary, self-administered questionnaires for patients with cancer and their physicians, respectively, were collected in Calgary, Alberta, Canada. Out of 117, 113 completed patient surveys were included in the statistical analysis, constituting a 96.4% response rate. These surveys were subsequently matched with those of their corresponding oncologists to determine the concordance rates. (3) Results: Overall, patients demonstrated a good understanding of general cancer biology (80.0%) and diagnostic processes (90.0%) associated with precision oncology. Most patients wanted their tumours to be tested to guide treatment, and the oncologists broadly shared these views (concordance 65.1%). However, there were discrepancies between the knowledge and expectations regarding the applications of test results on actual diagnosis and prognosis between patients and their oncologists (concordance 26.1% and 36.0%, respectively). While only 28.0% of patients thought they had enough knowledge to make informed decisions, the majority (68.0%) said they needed more information. (4) Conclusion: Our study shows that patients and cancer physicians do not always agree with the roles and applications of genomic tests, which could lead to misplaced expectations and poor health outcomes. More research is needed to devise strategies to improve education and communication to align these expectations and improve the quality of clinical decision making.

Particles and droplets produced from pharmaceutical inhaler devices are naturally charged. Previous in silico and in vitro studies have shown that the levels of these electrostatic charges may pote...

Cisplatin and gemcitabine (CisGem) are standard chemotherapy for advanced biliary tract cancer (BTC). The MEK inhibitor selumetinib showed synergy with gemcitabine when administered sequentially in BTC. This randomised Phase 2 trial aimed to assess the efficacy of sequential or continuous selumetinib with CisGem.Patients with advanced BTC received CisGem; arm A included selumetinib every day, arm B: selumetinib, days 1-5, 8-19 each cycle. Arm C received CisGem alone. Selumetinib was dosed at 75 mg BID but amended to 50 mg BID due to toxicity.In all, 51 participants were evaluable for response. No significant difference was seen in mean change in tumour size at 10 weeks between arms A and C (-7.8% vs -12.8%, P = 0.54) or arms B and C (-15% vs -12.8%, P = 0.78). There was no difference in median progression-free survival (6.0, 7.0, 6.3 months, P 0.95) or overall survival (11.7, 11.7, 12.8 months, P = 0.70) for arms A, B and C, respectively. More participants experienced grade 3-4 toxicities in selumetinib-containing arms. More participants in arm A required chemotherapy dose reductions (P = 0.01) with lower chemotherapy dose intensity during the first 10 weeks.Adding sequential or continuous selumetinib to CisGem failed to improve efficacy and increased toxicity in patients with advanced BTC.

biBackground:/i/bIvermectin has received worldwide attention as a potential COVID-19 treatment after showing antiviral activity against SARS-CoV-2iin vitro./iHowever, the pharmacokinetic limitations associated with oral administration have been postulated as limiting factors to its bioavailability and efficacy. These limitations can be overcome by targeted delivery to the lungs. In this study, inhalable dry powders of ivermectin and lactose crystals were prepared and characterized for the potential treatment of COVID-19.biMethods:/i/bIvermectin was co-spray dried with lactose monohydrate crystals and conditioned by storage at two different relative humidity points (43% and 58% RH) for a week. Theiin vitro/idispersion performance of the stored powders was examined using a medium-high resistance Osmohaler connecting to a next-generation impactor at 60 L/min flow rate. The solid-state characteristics including particle size distribution and morphology, crystallinity, and moisture sorption profiles of raw and spray-dried ivermectin samples were assessed by laser diffraction, scanning electron microscopy, Raman spectroscopy, X-ray powder diffraction, thermogravimetric analysis, differential scanning calorimetry, and dynamic vapor sorption.biResults:/i/bAll the freshly spray-dried formulation (T0) and the conditioned samples could achieve the anticipated therapeutic dose with fine particle dose of 300 μg, FPFsubrecovered/subof 70%, and FPFsubemitted/subof 83%. In addition, the formulations showed a similar volume median diameter of 4.3 μm and span of 1.9. The spray-dried formulations were stable even after conditioning and exposing to different RH points as ivermectin remained amorphous with predominantly crystalline lactose.biConclusion:/i/bAn inhalable and stable dry powder of ivermectin and lactose crystals was successfully formulated. This powder inhaler ivermectin candidate therapy appears to be able to deliver doses that could be safe and effective to treat the SARS-COV-2 infection. Further development of this therapy is warranted.

This article contributes to the substantial body of publications on South African jazz with information on jazz performance and performers in New Brighton, a township adjacent to Port Elizabeth noted for its vibrant jazz scene and outstanding jazz musicians. The article covers several decades from the heyday of swing bands in the 1940s–50s through the 1960s–70s when New Brighton’s premier jazz combo, the Soul Jazzmen, were at the height of their artistry. The role of swing bands in New Brighton and surrounding communities as the training ground for members of the Soul Jazzmen and other local musicians of note is discussed, as well as how the Soul Jazzmen in turn were tutors for musicians of the next generation who became widely recognized artists, composers and arrangers. This is followed by a focus on the Soul Jazzmen and compositions by its members that protested against the apartheid regime in the 1960s–70s. The article is informed by historic photographs, newspaper clippings and information from oral history interviews that richly document how jazz was performed in service of the anti-apartheid struggle in New Brighton.

In order to better understand powder dispersion in dry powder inhaler (DPI) devices, a new powder disperser was designed, which uses flow modifiers to alter powder fluidization behavior so as to physically replicate various flow conditions observed in a range of commercial DPIs. The influence of these modifiers on the performance of the DPI was analyzed for flowrates progressing from laminar (15 L/min) to transitional (30 L/min), and finally turbulent flow regimes (60 L/min) in the device. The aerosol performance of the disperser was measured using a Next Generation Impactor. For flowrate in the laminar regime, powder evacuation from the disperser was generally insufficient (85% when the device was operated in the turbulent flow regime. In contrast, the highest fine particle fraction (FPF) and lowest throat deposition were achieved when operating in the transitional flow regime. The FPF could be increased further by applying flow modifications such as narrowing the air passage before the powder pocket, inducing localized turbulence (by a grid) near the powder pocket, and by changing the loading position of the powder. Flow modifiers had the most noticeable effect under a laminar flow regime, however, the device operated most efficiently under a transitional flow regime.

The coronavirus disease 2019 (COVID-19) is an unprecedented pandemic that has severely impacted global public health and the economy. Hydroxychloroquine administered orally to COVID-19 patients was ineffective, but its antiviral and anti-inflammatory actions were observed in vitro. The lack of efficacy in vivo could be due to the inefficiency of the oral route in attaining high drug concentration in the lungs. Delivering hydroxychloroquine by inhalation may be a promising alternative for direct targeting with minimal systemic exposure. This paper reports on the characterisation of isotonic, pH-neutral hydroxychloroquine sulphate (HCQS) solutions for nebulisation for COVID-19. They can be prepared, sterilised, and nebulised for testing as an investigational new drug for treating this infection. The 20, 50, and 100 mg/mL HCQS solutions were stable for at least 15 days without refrigeration when stored in darkness. They were atomised from Aerogen Solo Ultra vibrating mesh nebulisers (1 mL of each of the three concentrations and, in addition, 1.5 mL of 100 mg/mL) to form droplets having a median volumetric diameter of 4.3–5.2 µm, with about 50–60% of the aerosol by volume &lt, 5 µm. The aerosol droplet size decreased (from 4.95 to 4.34 µm) with increasing drug concentration (from 20 to 100 mg/mL). As the drug concentration and liquid volume increased, the nebulisation duration increased from 3 to 11 min. The emitted doses ranged from 9.1 to 75.9 mg, depending on the concentration and volume nebulised. The HCQS solutions appear suitable for preclinical and clinical studies for potential COVID-19 treatment.

Polymeric nanoparticles have been widely investigated as a controlled release drug delivery platform for the treatment of tuberculosis (TB). These nanoparticles are readily internalised into macrophages and leads to high intracellular drug concentration. In this study two anti-TB drugs, amikacin and moxifloxacin were encapsulated into PLGA nanoparticles. The novelty of this work includes: (1) the efficient encapsulation of two hydrophilic second-line anti-TB drugs, and (2) intra-macrophage delivery of this combination potentially for rapid treatment of multi-drug resistant TB (MDR-TB). Two water-oil-water (w/o/w) emulsion strategies were employed in this study to produce: (1) alginate coated PLGA nanoparticles, and (2) alginate entrapped PLGA nanoparticles. The average particle size and polydispersity index (PDI) of the alginate coated PLGA nanoparticles were found to be unfavourably high with values of 640 ± 32 nm and 0.63 ± 0.09, respectively. In contrast, the alginate entrapped PLGA nanoparticles were within the desired particle size range of 312–365 nm and the PDI was 0.14– 0.31, and therefore were chosen for subsequent studies. Alginate entrapped nanoparticles exhibited an entrapment of moxifloxacin in the range of 10.1–18.7 μg/mg and an entrapment of amikacin in the range of 15–17.4 μg/mg. On the contrary, non-modified PLGA nanoparticles exhibited a significantly less amikacin loading of 6.2 μg/mg polymer and 4.2 μg/mg of moxifloxacin. The release of alginate modified PLGA nanoparticles showed slower release in comparison with the non-modified PLGA nanoparticles. The alginate entrapped PLGA nanoparticles did not show significant difference from the alginate coated PLGA nanoparticles in the release pattern. To study the macrophage uptake efficiency, both formulations of the alginate entrapped nanoparticle; non-calcium formulation and calcium, and alginate coated PLGA nanoparticles (that includes no calcium) formulation was loaded with coumarin-6 as a marker, seeded to THP-1 derived macrophages infected with Mycobacterium tuberculosis (H37Ra), and examined by confocal microscopy. Both formulations of alginate entrapped particles (calcium and non-calcium) were readily internalised into the macrophages and highly concentrated in the perinuclear region, and the non-calcium alginate entrapped formulation showed a maximum internalisation. Furthermore, the anti-mycobacterial activity of the dually entrapped drug-loaded particles (moxifloxacin and amikacin) was evaluated using M. tuberculosis-infected macrophages, which revealed an enhanced inhibition of viable bacterial count compared to single drug loaded nanoparticle formulations, and untreated cells. The dually entrapped nanoparticles showed bacterial viability of 0.6% relative to the untreated group, compared to 6.49% for amikacin alone nanoparticles and 3.27% for moxifloxacin alone nanoparticles. In conclusion, the amikacin-moxifloxacin alginate entrapped PLGA nanoparticles are promising for further in vivo studies.

Introduction Oncogenic KRAS mutations are absent in 10% of patients with pancreatic ductal adenocarcinoma (PDAC) and may represent a subgroup of PDAC with therapy options beyond standard-of-care chemotherapy. While distinct gene fusions have been implicated in KRAS wildtype (wt) PDAC, other traits unique to KRAS wt PDAC remain unexplored. Methods Patients with treatment-naive metastatic PDAC (n=63) received matched tumor/normal whole-genome and RNA sequencing and clinical follow-up as part of the PanGen trial (NCT02869802). Clinical data and mutation, gene fusion and copy alteration frequency was compared between KRAS wt (n=9) and mutant (n=54) groups. Metastatic colorectal adenocarcinoma and cholangiocarcinoma samples from the POG trial (NCT02155621) were incorporated for sequencing-based comparison. Results KRAS wt tumors showed lower frequency of TP53 SNV/indels (p=0.01) and distinct amplifications affecting chr1q genes NR5A2 (p=9.0e-4), MPC2 (p=0.002) and MCL1 (p=0.02) and chr8q gene SQLE (p=0.02). Oncogenic fusions involving NRG1, FGFR2, NTRK2 or BRAF were unique to KRAS wt tumors (67% of samples; p=1e-6). KRAS wt tumors showed expression patterns indicative of cholangiocytes and, when clustered alongside other tumor types, formed a distinct cluster with cholangiocarcinoma samples. Conclusion These data provide the first identification of distinct chr1q/chr8q amplification events unique to KRAS wt PDAC while highlighting novel and striking molecular similarities to cholangiocarcinoma. Taken together, results of the PanGen trial generate new hypotheses relevant to therapeutic targeting of KRAS wt PDAC and rationale towards incorporating KRAS mutation status as part of routine clinical testing in PDAC. Citation Format: James Topham, Erica Tsang, Joanna Karasinska, Andrew Metcalfe, Hassan Ali, Steve Kalloger, Veronika Csizmok, Laura Williamson, Emma Titmuss, Hui-Li Wong, Richard Moore, Andrew Mungall, Jonathan Loree, Oliver Bathe, Patricia Tang, Rachel Goodwin, Janessa Laskin, Marco Marra, Steven Jones, David Schaeffer, Daniel Renouf. Analysis of KRAS wildtype pancreatic ductal adenocarcinoma reveals mutation and expression-based similarities to cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB129.

Tobramycin (TOB) and clarithromycin (CLA) can potentially be used synergistically for the treatment of respiratory infections caused by Pseudomonas aeruginosa (P. aeruginosa) in cystic fibrosis (CF) patients. This study aimed to develop a novel combination proliposome formulation (TOB/CLA-CPROLips) containing both hydrophilic TOB and hydrophobic CLA via a core-carrier approach. The combination proliposomes were produced by spray drying a suspension comprising spray-driedmannitol (SD-MAN, 0.45%) and spray-dried tobramycin (SD-TOB, 0.05%) particles suspended in an ethanolic lipid solution of CLA (0.05%). The lipid layer coated on the surface of the dry proliposome particles conferred moisture protection and sustained drug release properties in comparison to the pure drugs. The optimized TOB/CLA-CPROLips formulation was stable after 3 months of storage at 60% relative humidity (RH) and 25 °C. The combination drug proliposomes showed a synergistic antimicrobial activity against planktonic cells and biofilm cultures of P. aeruginosa. In conclusion, the core-carrier method coupled with spray-drying provided a novel approach for the preparation of combination antibiotics proliposomes.

Inhaled drugs are routinely used for the treatment of respiratory-supported patients. To date, pressurized metered dose inhalers and nebulizers are the two platforms routinely employed in the clinical setting. The scarce utilization of the dry powder inhaler (DPI) platform is partly due to the lack of in vivo data that proves optimal delivery and drug efficacy are achievable. Additionally, fitting a DPI in-line to the respiratory circuit is not as straightforward as with the other aerosol delivery platforms. Importantly, there is a common misconception that the warm and humidified inspiratory air in respiratory supports, even for a short exposure, will deteriorate powder formulation compromising its delivery and efficacy. However, some recent studies have dispelled this myth, showing successful delivery of dry powders through the humidified circuit of respiratory supports. Compared with other aerosol delivery devices, the use of DPIs during respiratory supports possesses unique advantages such as rapid delivery and high dose. In this review, we presented in vitro studies showing various setups employing commercial DPIs and effects of ventilator parameters on the aerosol delivery. Inclusion of novel DPIs was also made to illustrate characteristics of an ideal inhaler that would give high lung dose with low powder deposition loss in tracheal tubes and respiratory circuits. Clinical trials are urgently needed to confirm the benefits of administration of dry powders in ventilated patients, thus enabling translation of powder delivery into practice.

The aim of this study was to investigate the ability of L-leucine (LL) in preventing moisture-induced deterioration in the in vitro aerosolization performance of spray-dried (SD) salbutamol sulfate (SS). Increasing mass fraction of LL (5-80%) were co-spray dried with SS, and the physicochemical properties of the powders were characterized by laser diffraction, X-ray powder diffraction (XRD) and dynamic vapour sorption (DVS). Furthermore, the surface morphology and chemistry of fine particles was analyzed by scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS). The in vitro aerosolization performance of powders stored at different relative humidity (RH) was evaluated by a next generation impactor (NGI). The SD SS powders were moderately hygroscopic and amorphous, of which the uptake of moisture upon storage caused a drop in the aerosolization performance. The results showed that 40% (w/w) LL was sufficient to eliminate the effect of moisture on the aerosolization performance at 60% RH. The formulation containing 40% (w/w) LL also maximized the aerosolization performance of SD SS powders (stored in desiccator) with the emitted fraction being 90.0±1.8%, and the fine particle fraction based on the recovered dose (FPFrecovered) and emitted dose (FPFemitted) being 78.0±3.7% and 86.6±2.9%, respectively. The underlying mechanisms were that the crystalline LL increased the degree of particle surface corrugation, and reduced particle fusion and cohesiveness to facilitate dispersion. However, there is still a great challenge to prevent the moisture-induced deterioration in the aerosolization performance at 75% RH due to the recrystallization of SD SS. In conclusion, LL is a potential excipient for reducing moisture-induced deterioration in the aerosolization performance of SD amorphous powders, but still has drawbacks in preventing the recrystallization-induced deterioration.

Background: Aerosol delivery through a nasal high flow (NHF) system is attractive for clinicians as it allows for simultaneous administration of oxygen and inhalable drugs. However, delivering a fine particle fraction (FPF, particle wt. fraction < 5.0 μm) of drugs into the lungs has been very challenging, with highest value of only 8%. Here, we aim to develop an efficient nose-to-lung delivery system capable of delivering improved quantities (FPF > 16%) of dry powder aerosols to the lungs via an NHF system. Methods: We evaluated the FPF of spray-dried mannitol with leucine with a next generation impactor connected to a nasopharyngeal outlet of an adult nasal airway replica. In addition, we investigated the influence of different dispersion (20-30 L/min) and inspiratory (20-40 L/min) flow rates, on FPF. Results: We found an FPF of 32% with dispersion flow rate at 25 L/min and inspiratory flow rate at 40 L/min. The lowest FPF (21%) obtained was at the dispersion flow rate at 30 L/min and inspiratory flow rate at 30 L/min. A higher inspiratory flow rate was generally associated with a higher FPF. The nasal cannula accounted for most loss of aerosols. Conclusions: In conclusion, delivering a third of inhalable powder to the lungs is possible in vitro through an NHF system using a low dispersion airflow and a highly dispersible powder. Our results may lay the foundation for clinical evaluation of powder aerosol delivery to the lungs during NHF therapy in humans.

Knowledge that enables the accurate simulation of drug deposition in the human upper airway is necessary to develop robust platforms for efficient drug delivery by inhalation devices. The human upper airway is deformable during inhalation but how it could affect the deposition of inhaled drugs is unknown. We aimed to determine whether pharyngeal deformation at the soft palate level would have any significant effects on throat deposition, in vitro lung dose and fine particle fraction. In this study, dry mannitol powders were delivered to the next-generation cascade impactor (NGI) through the United States Pharmacopeia (USP) throat, and a realistic upper airway cast (RUPAC) at flow rates of 40, 60 and 80 L min−1. Deformation of the upper airway at 25%, 50%, and 75% in the lateral and antero-posterior directions were experimentally simulated in the RUPAC. Throat deposition (p = 0.04) is significantly affected when the upper airway deforms laterally but not antero-posteriorly.

L-Leucine (LL) has been widely used to enhance the dispersion performance of powders for inhalation. LL can also protect powders against moisture, but this effect is much less studied. The aim of this study was to investigate whether LL could prevent moisture-induced deterioration in in vitro aerosolization performances of highly hygroscopic spray-dried powders. Disodium cromoglycate (DSCG) was chosen as a model drug and different amounts of LL (2-40% w/w) were added to the formulation, with the aim to explore the relationship between powder dispersion, moisture protection and physicochemical properties of the powders. The powder formulations were prepared by spray drying of aqueous solutions containing known concentrations of DSCG and LL. The particle sizes were measured by laser diffraction. The physicochemical properties of fine particles were characterized by X-ray powder diffraction (XRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and dynamic vapor sorption (DVS). The surface morphology and chemistry of fine particles were analyzed by scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), and time-of-flight secondary ion mass spectrometry (ToF-SIMS). In vitro aerosolization performances were evaluated by a next generation impactor (NGI) after the powders were stored at 60% or 75% relative humidity (RH), and 25 degrees C for 24 h. Spray-dried (SD) DSCG powders were amorphous and absorbed 30-45% (w/w) water at 70-80% RH, resulting in deterioration in the aerosolization performance of the powders. LL did not decrease the water uptake of DSCG powders, but it could significantly reduce the effect of moisture on aerosolization performances. This is due to enrichment of crystalline LL on the surface of the composite particles. The effect was directly related to the percentage of LL coverage on the surface of particles. Formulations having 61-73% (molar percent) of LL on the particle surface (which correspond to 10-20% (w/w) of LL in the bulk powders) could minimize moisture-induced deterioration in the aerosol performance. In conclusion, particle surface coverage of LL can offer short-term protection against moisture on dispersion of hygroscopic powders Refereed/Peer-reviewed

Conventional nebulisation has the disadvantages of low aerosol output rate and potential damage to macromolecules due to high shear (jet nebulisation) or cavitation (ultrasonic nebulisation). HYDRA (HYbriD Resonant Acoustics) technology has been shown to overcome these problems by using a hybrid combination of surface and bulk sound waves to generate the aerosol droplets. We report the first in vivo human lung deposition study on such droplets. Twelve healthy adult subjects inhaled saline aerosols radiolabelled with technetium-99 m complexed with diethylene triamine penta-acetic acid (99mTc-DTPA). The distribution of the aerosolised droplets in the lungs was imaged by single photon emission computed tomography combined with low dose computed tomography (SPECT/CT). The volume median diameter and geometric standard deviation of the droplets were 1.32 ± 0.027 µm and 2.06 ± 0.040, respectively. The mean delivery efficiency from the nebuliser into the body was 51.2%. About 89.1 ± 4.3% and 2.3 ± 1.4% of the inhaled radiolabelled dose deposited in the lungs and oropharynx, respectively. The deposition was symmetrical and diffusive between the two lungs, with a mean penetration index of 0.82. Thus, the prototype HYDRA nebuliser showed excellent in vivo aerosol deposition performance, demonstrating its potential to be further developed for clinical applications.

The present study was conducted to harness spray drying technology as a novel method of producing Ciprofloxacin nanocrystals inside liposomes (CNL) for inhalation delivery. Liposomal ciprofloxacin dispersions were spray dried with sucrose as a lyoprotectant in different mass ratios (0.5:1, 1:1 and 2:1 sucrose to lipids), along with 2% w/w magnesium stearate and 5% w/w isoleucine as aerosolization enhancers. Spray drying conditions were: inlet air temperature 50 °C, outlet air temperature 33-35 °C, atomizer rate 742 L/h and aspirator 35 m3/h. After spray drying, the formation of ciprofloxacin nanocrystals inside the liposomes was confirmed by cryo- transmission electron microscopy. The physiochemical characteristics of the spray dried powder (particle size, morphology, crystallinity, moisture content, drug encapsulation efficiency (EE), in vitro aerosolization performance and drug release) were determined. The EE of the liposomes was found to vary between 44 and 87% w/w as the sucrose content was increased from 25 to 57% w/w. The powders contained partially crystalline particles with a volume median diameter of ~ 1 μm. The powders had low water content (~2 % wt.) and were stable at high relative humidity. Aerosol delivery using the Osmohaler® inhaler at a flow rate of 100 L/min produced an aerosol fine particle fraction (% wt. < 5 μm) of 58 - 64%. The formulation with the highest sucrose content (2:1 w/w sucrose to lipid) demonstrated extended ciprofloxacin release from liposomes (80% released within 7 hours) in comparison to the original liquid formulation (80% released within 2 hours). In conclusion, a stable and inhalable CNL powder with controlled drug release was successfully prepared by spray drying.

Background Nebulised antibiotics are frequently used for the prevention or treatment of ventilator-associated pneumonia. Many factors may influence pulmonary drug concentrations with inaccurate dosing schedules potentially leading to therapeutic failure and/or the emergence of antibiotic resistance. We describe a research pathway for studying the pharmacokinetics of a nebulised antibiotic during mechanical ventilation using in vitro methods and ovine models, using tobramycin as the study antibiotic. Methods In vitro studies using a laser diffractometer and a bacterial-viral filter were used to measure the effect of the type and size of tracheal tubes and antibiotic concentration on the particle size distribution of the tobramycin 400 mg (4 ml; 100 mg/ml) and 160 mg (4 ml, 40 mg/ml) aerosol and nebulised mass delivered. To compare the regional drug distribution in the lung of two routes (intravenous and nebulised) of drug administration of tobramycin 400 mg, technetium-99m-labelled tobramycin 400 mg with planar nuclear medicine imaging was used in a mechanically ventilated ovine model. To measure tobramycin concentrations by intravenous and nebulised tobramycin 400 mg (4 ml, 100 mg/ml) administration in the lung interstitial space (ISF) fluid and blood of mechanically ventilated sheep, the microdialysis technique was used over an 8-h duration. Results Tobramycin 100 mg/ml achieved a higher lung dose (121.3 mg) compared to 40 mg/ml (41.3 mg) solution. The imaging study with labelled tobramycin indicated that nebulised tobramycin distributed more extensively into each lung zone of the mechanically ventilated sheep than intravenous administration. A higher lung ISF peak concentration of tobramycin was observed with nebulised tobramycin (40.8 mg/l) compared to intravenous route (19.0 mg/l). Conclusions The research methods appear promising to describe lung pharmacokinetics for formulations intended for nebulisation during mechanical ventilation. These methods need further validation in an experimental pneumonia model to be able to contribute toward optimising dosing regimens to inform clinical trials and/or clinical use.

We aimed to obtain fundamental information for potential pulmonary delivery of powder aerosols using a clinically-approved nasal high-flow system (AIRVO), with spray-dried mannitol (SD-Man) being a model powder. Compressed air exiting the AIRVO at set 'dispersion' air flow rates dispersed SD-Man loaded in an Osmohaler® into a human nasal airway replica (NAR) coupled downstream to a Next Generation Impactor (NGI) running at specific 'inspiratory' flow rates. Increasing the dispersion flow rate from 30 to 60L/min increased powder deposition in the NAR from 50 to 70% of the emitted dose, while decreased the NGI deposition from 50 to 30% of the emitted dose. The inspiratory flow rate did not affect powder deposition in the NAR and NGI. In contrast, as the inspiratory flow rate was increased from 15 to 40L/min, powder recovery, emitted fraction, and fine particle fraction below 5μm (as aerosol performance indices) were increased from 90, 30 and 5% to 97, 45 and 8% of the loaded dose, respectively. The dispersion flow rate did not change the performance indices. Importantly, heating and humidification of dispersion airflow, loaded doses, and nasal cannula sizes did not greatly affect the aerosol characteristics.

Novel inhaled therapeutics including antibiotics, vaccines and anti-hypertensives, have led to innovations in designing suitable delivery systems. These emerging design technologies are in urgent demand to ensure high aerosolisation performance, consistent efficacy and satisfactory patient adherence. Recent vibrating-mesh and software technologies have resulted in nebulisers that have remarkably accurate dosing and portability. Alternatively, dry powder inhalers (DPIs) have become highly favourable for delivering high-dose and single-dose drugs with the aid of advanced particle engineering. In contrast, innovations are needed to overcome the technical constrains in drug-propellant incompatibility and delivering high-dose drugs with pressurised metered dose inhalers (pMDIs). This review discusses recent and emerging trends in pulmonary drug delivery systems.

The routine of loading multiple capsules for delivery of high-dose antibiotics is time consuming, which may reduce patient adherence to inhaled treatment. To overcome this limitation, an investigation was carried out using four modified versions of the Aerolizer® that accommodate a size 0 capsule for delivery of high payload formulations. In some prototypes, four piercing pins of 0.6 mm each were replaced with a single centrally located 1.2-mm pin and one-third reduced air inlet of the original design. The performance of these inhalers was evaluated using spray-dried antibiotic powders with distinct morphologies: spherical particles with a highly corrugated surface (colistin and tobramycin) and needle-like particles (rifapentine). The inhalers were tested at capsule loadings of 50 mg (colistin), 30 mg (rifapentine) and 100 mg (tobramycin) using a multistage liquid impinger (MSLI) operating at 60 L/min. The device with a single pin and reduced air inlet showed a superior performance than the other prototypes in dispersing colistin and rifapentine powders, with a fine particle fraction (FPF wt%

The design of a dry powder inhaler device has significant influence on aerosol performance; however, such influence may be different between the drug-only and carrier-based formulations. The present study aims to examine the potential difference on the dispersion between these distinct types of formulations, using Aerolizer(®) as a model inhaler with the original or modified (cross-grid) designs. A coupled CFD-discrete element method analysis was employed to determine the flow characteristics and particle impaction. Micronized salbutamol sulphate as a drug-only formulation and three lactose carrier-based formulations with various drug-to-carrier weight ratios 1:5, 1:10 and 1:100 were used. The in vitro aerosolization performance was assessed by a next-generation impactor operating at 100 L/min. Using the original device, FPFloaded was reduced from 47.5 ± 3.8% for the drug-only formulation to 31.8 ± 0.7%, 32.1 ± 0.7% and 12.9 ± 1.0% for the 1:5, 1:10 and 1:100 formulations, respectively. With the cross-grid design, powder-mouthpiece impaction was increased, which caused not only powder deagglomeration but also significant drug retention (doubling or more) in the mouthpiece, and the net result is a significant decrease in FPFloaded to 36.8 ± 1.2%, 20.9 ± 2.6% and 21.9 ± 1.5% for the drug-only, 1:5 and 1:10 formulations, respectively. In contrast, the FPFloaded of the 1:100 formulation remained the same at 12.1 ± 1.3%, indicating the increased mouthpiece drug retention was compensated by increased drug detachment from carriers caused by increased powder-mouthpiece impaction. In conclusion, this study has elucidated different effects and the mechanism on the aerosolization of varied dry powder inhaler formulations due to the grid design.

In this study, lactose crystalline powder was produced to improve its stability. The effect of micronised crystalline lactose on a dry powder inhalation formulation was investigated. Supercritical carbon dioxide (scCO 2 ) modified with menthol was used for the conditioning of spray-dried amorphous lactose and salbutamol sulphate to generate micro-spherical crystalline powders. The optimum processing conditions, which include: menthol concentration, temperature and processing time, were determined by experimental design to produce crystalline and a desired particle size. The average particle size of spray-dried amorphous lactose decreased from 8.15 ± 0.28 μm to 7.60 ± 0.10 μm after conditioning with modified CO 2 at 150 bar and 50 °C for a period of 5 h. The SEM results shows that these particles kept their micro-spherical shape, however, the particle surface became rough due to crystallisation. This particle size reduction was most likely due to increasing surface roughness, which decreased agglomeration between particles. The blend of this fine powder and coarse crystalline lactose enhanced salbutamol sulphate inhalation performance. The emitted fine particle fraction of salbutamol sulphate was enhanced to 40 ± 0.3% compare to the samples that contained only coarse lactose (38.2 ± 0.6%) or conditioned lactose (24.6 ± 0.4%).

We hypothesize that the USP induction port may de-agglomerate carrier-free powder emitting from dry powder inhalers (DPIs).Aerosols emitting from a range of DPIs (Spinhaler®, Turbuhaler® and Osmohaler™) and induction ports (USP throat, straight tube, Alberta idealized mouth-throat geometry (AG)) were sized by laser diffraction. Total drug recovery was obtained by HPLC and fine particle fraction computed. Air flow patterns were simulated using Computational Fluid Dynamics (CFD).The straight tube did not de-agglomerate emitted powder. However, the USP throat and AG further de-agglomerated powders from the Spinhaler, but not the Turbuhaler and Osmohaler. While budesonide powder deposited similarly in all induction ports, deposition was significantly higher in the AG for both DSCG and mannitol. CFD revealed agglomerates impacting on the USP throat with higher localized velocity compared with the straight tube. CFD further showed a more complex flow pattern with high-velocity air jets in the AG, which explains the higher FPF for DSCG and the lower FPF for mannitol using the AG.The USP throat further de-agglomerated the emitted powder from the DPI when it did not sufficiently disperse the powder. Other tools such as laser diffraction may be used for cross-examining to avoid artifacts in the results.

Preventing obesity could be done by lowering plasma TAG that inhibits adipogenesis. Oat and mushroom beta-glucans in the diet has been reported to lower plasma lipid; however the data focusing on their effects on TAG and obesity are insufficient. In the present study, lowering plasma triacylglycerol, fat deposition, body weight gain (BWG) in rats fed a high fat diet (HFD) was evaluated. Rats in the control group were given HFD only and rats in the treatment group fed HFD enriched with 0.2%, 0.6% and 1.8% (wt:wt) beta-glucan from oats (LD-O, MD-O, HD-O) or mushroom (LD-M, MD-M, HD-M). After 6 weeks dietary intervention, the rats fed HD-M showed significantly lower plasma TAG, total fat mass, white adipose tissue, inguinal fat and BWG level more than HD-O treated rats (p < 0.05). The underlying mechanism in lowering plasma TAG, fat pad masses and BWG in HD-M was increasing ratio of fat faecal to faecal weight which was significantly higher than HD-O (p < 0.05). This study demonstrated that the preventing obesity via lowering plasma TAG and fat deposition was different depending on beta-glucan origin, either from oats and Shiitake mushroom.

The aim of this study was to develop a method for converting an amorphous drug to a crystalline form to enhance its stability and inhalation performance. Spray-dried amorphous salbutamol sulphate powder was conditioned with supercritical carbon dioxide (scCO 2 ) modified with menthol. The effect of menthol concentration, pressure, temperature and time on the characteristics of the resulting salbutamol sulphate powder was investigated. Pure scCO 2 had no effect on the physical properties of amorphous salbutamol sulphate; however, scCO 2 modified with menthol at 150 bar and 50 °C was efficient in converting amorphous drug to crystalline form after 12 h of conditioning. The average particle size of powders decreased slightly after the conditioning process because of reducing agglomeration between particles by increasing surface roughness. Emitted dose measured by the fine particle fraction (FPF emitted ) of amorphous salbutamol sulphate was enhanced from 32% to 43% after conditioning with scCO 2 + menthol and its water uptake was significantly decreased. This study demonstrates the potential of scCO 2 + menthol for converting amorphous forms of powders to crystalline, while preserving the particle size.

Two instruments, namely the Aerosizer LD and the Particle Size Distribution Analyser (PSDA) 3603, were used to measure aerodynamic diameters of spray dried bovine serum albumin (BSA) particles with different surface corrugation ( D S ). The measured aerodynamic diameters were compared with the values calculated using the theoretical model previously developed by our group. The model-calculated aerodynamic diameters have been shown to agree with the measured values for corrugated and less cohesive BSA particles with D S varying between 2.18 and 2.41. For smoother and more cohesive BSA particles with D S of 2.06 the measured and calculated values differed by 27% (compared to the value measured by PSDA 3603) and 115% (compare to the value measured by Aerosizer). This variation resulted from the difficulty to completely disperse the more cohesive particles during measurement. Hence, the model can be used to estimate aerodynamic diameter in situations when direct measurement fails due to unavailability of equipment, limitations or difficulty in dispersing powders into their individual particles in the aerosol.

Commercial dry powder dispersers needed in conjunction with particle size measurement equipment are usually quite expensive (of the order of thousands of dollars). We have found that a simple vacuum generator can be used as a cost-effective disperser (US$50). Comparison with other commercial dispersers, small scale powder disperser (SSPD) model 3433 (TSI, Shoreview, USA) and Scirocco dry powder disperser (Malvern, Worcs, UK), showed that our disperser worked as efficiently as these expensive dispersers. Crystalline mannitol (less than 1% moisture content) and amorphous BSA (8.5–9.2% moisture content) smooth spherical particles were used to test the dispersion capability of the unit. Smooth spherical particles were chosen because they are more cohesive than corrugated particles due to increased contact points. Therefore, sufficient dispersions of other less cohesive particles should be able to be achieved using the optimum conditions reported here. The effects of air pressure, sample weight, and nozzle size of the disperser were investigated. Comparison of the particle size distributions between wet and dry measurements were used to determine the dispersion efficiency. Quantitative comparisons were made using the values of D ( v ,0.5) and span. The best dispersion was found using a 1.00 mm nozzle and the maximum percentage differences in D ( v ,0.5) and span are 23% and 19%, respectively, with more than 200 mg mannitol powder dispersed with pressures of 50, 70, 90 psi. Using BSA powders, the maximum percentage differences of D ( v ,0.5) and span are 37% and 25%, respectively. As was the case for the commercial devices, the dispersion of BSA particles could not be improved even when the pressure of the compressed air was increased.

Atomic force microscopy (AFM) was used to evaluate the particle adhesion and surface morphology of engineered particles for dry powder inhaler (DPI) respiratory therapy to gain a greater understanding of interparticle forces and the aerosolisation process. A series of spherical model drug particles of bovine serum albumin (BSA) was prepared with different degrees of surface corrugation. The particles were evaluated in terms of particle size (laser diffraction) and microscopic morphology (scanning electron microscopy). Conventional tapping mode AFM was used to evaluate the nanoscopic morphology and derive specific roughness parameters, while AFM colloid probe microscopy was used to directly measure the interaction of functionalised probes. The physical characterisation and AFM measurements were evaluated in terms of in vitro aerosolisation performance, using a conventional Rotahaler((R)) DPI and multistage liquid impinger. A direct relationship between the root mean square roughness, particle adhesion and in vitro aerosol performance (measured as fine particle fraction, FPF) was observed suggesting that as the degree of corrugation increased, particle adhesion was reduced which, resulted in a concomitant increase in FPF. This study demonstrates that AFM may be used to predict the aerosolisation performance micron sized particles for inhalation based on their morphological properties.

Fine sodium chloride particles are of pharmaceutical interest in aerosol delivery for diagnosis of asthma and bronchial related disorders. In this paper, stable NaCl particles with size ranging from approximately 1μm to sub-micron range were achieved by sonocrystallisation. The effects of sonocrystallisation temperature, ultrasonic power output and salt concentration were investigated in the ranges of 5–35∘C, 22–60 W and 8–34 g/100 g water, respectively, under a fixed ultrasonic frequency of 20 kHz. Size and morphology characterisation of particles were undertaken using laser diffraction and scanning electron microscopy. Optimally prepared particles were spray dried followed by in vitro impaction test for inhalation efficiency determination using an Aeroliser®. Optimal conditions of temperature (

The current study aimed to examine the pharmaceutical applications of the focused-ion-beam (FIB) in the inhalation aerosol field, particularly to particle porosity determination (i.e. percentage of particles having a porous interior). The interior of various spray dried particles (bovine serum albumin (BSA) with different degrees of surface corrugation, mannitol, disodium cromoglycate and sodium chloride) was investigated via FIB milling at customized conditions, followed by viewing under a high resolution field-emission scanning electron microscope. Two sets of ten particles for each sample were examined. For the spray-dried BSA particles, a decrease in particle porosity (from 50 to 0%) was observed with increasing particle surface corrugation. Spray-dried mannitol, disodium cromoglycate and sodium chloride particles were determined to be 90–100%, 0–10% and 0% porous, respectively. The porosity in the BSA and mannitol particles thus should be considered for the aerodynamic behaviour of these particles. The FIB technology represents a novel approach useful for probing the interior of particles linking to the aerosol properties of the powder. Suitable milling protocols have been developed which can be adapted to study other similar particles.

The US pharmacopeia (USP) and Alberta throats were recently reported to cause further de-agglomeration of carrier-free powders emitted from some dry powder inhalers (DPIs). This study assessed if they have similar influences on commercially available carrier-based DPIs. A straight tube, a USP throat, and an Alberta throat (non-coated and coated) were used for cascade impaction testing. Aerosol fine particle fraction (FPF ≤ 5 μm) was computed to evaluate throat-induced de-agglomeration. Computational fluid dynamics are employed to simulate airflow patterns and particle trajectories inside the USP and Alberta throats. For all tested products, no significant differences in the in vitro aerosol performance were observed between the USP throat and the straight tube. Using fine lactose carriers (10 μm), Symbicort(®) and Oxis(™) showed minimal impaction inside the Alberta throat and resulted in similar FPF among all induction ports. For products using coarse lactose carriers (10 μm), impaction frequency and energy inside the Alberta throat were significant. Further de-agglomeration was noted inside the non-coated Alberta throat for Seretide(®) and Spiriva(®), but agglomerates emitted from Relenza(®), Ventolin(®), and Foradil(®) did not further break up into smaller fractions. The coated Alberta throat considerably reduced the FPF values of these products due to the high throat retention, but they generally agreed better with the in vivo data. In conclusion, depending on the powder formulation (including carrier particle size), the inhaler, and the induction port, further de-agglomeration could happen ex-inhaler and create differences in the in vitro measurements.

A fatal incident was reported when a mechanical ventilated patient received nebulization of a reconstituted RelenzaThis is a bench study demonstrating the feasibility of a delivery system to introduce dry powder of Relenza to intubated patients. A dry powder inhaler placed within a delivery chamber was actuated by compressing a ventilation bag to disperse powder into a tracheal tube. The performance of two inhalers, a DiskhalerThe efficiency of Osmohaler in delivering Relenza to the distal end [delivered dose=30.2±0.2% and fine particle fraction (FPF)=14.5±1.7%] was significantly higher than the Diskhaler (delivered dose=18.1±4.7% and FPF=3.4±2.1%). While no differences in the delivered dose and FPF were observed between the tracheostomy and endotracheal tubes of the same internal diameter, a larger endotracheal tube (9.0 mm internal diameter) gave a 6% higher FPF compared with the smaller counterpart (7.0 mm internal diameter).The dry powder delivery system has been demonstrated to be capable of delivering Relenza formulation to the distal end of tracheal tubes with a reasonable delivered dose and FPF. It would be necessary for further investigation into incorporating the proposed powder delivery system within a mechanical ventilator, as well as animal and clinical studies to prove its applicability to deliver zanamivir dry powder to ventilated influenza patients in the intensive care setting.

Currently bronchial provocation testing (BPT) using mannitol powder cannot be performed in children under 6 years. A primary reason is it is challenging for children at this age to generate a consistent inspiratory effort to inhale mannitol efficiently from a dry powder inhaler. A prototype system, which does not require any inhalation training from the pediatric subject, is reported here. It uses an external source of compressed air to disperse mannitol powder into a commercial holding chamber. Then the subject uses tidal breathing to inhale the aerosol.The setup consists of a commercially available powder disperser and Volumatic™ holding chamber. Taguchi experimental design was used to identify the effect of dispersion parameters (flow rate of compressed air, time compressed air is applied, mass of powder, and the time between dispersion and inhalation) on the fine particle dose (FPD). The prototype was tested in vitro using a USP throat connected to a next generation impactor. The aerosols from the holding chamber were drawn at 10 L/min. A scaling factor for estimating the provoking dose to induce a 15% reduction in forced expiratory volume in 1 second (FEV1) (PD15) was calculated using anatomical dimensions of the human respiratory tract at various ages combined with known dosing values from the adult BPT.Consistent and doubling FPDs were successfully generated based on the Taguchi experimental design. The FPD was reliable over a range of 0.8 (±0.09) mg to 14 (±0.94) mg. The calculated PD15 for children aged 1-6 years ranged from 7.1-30 mg. The FPDs generated from the proposed set up are lower than the calculated PD15 and therefore are not expected to cause sudden bronchoconstriction.A prototype aerosol delivery system has been developed that is consistently able to deliver doubling doses suitable for bronchial provocation testing in young children.

The use of aerosolized hypertonic saline (4.5% NaCl) as an osmotic agent for bronchial provocation tests to identify people with asthma is problematic due to the inconvenience in administration using ultrasonic nebulizers. Delivery using dry powder inhalers is an attractive solution but production of inhalable powders of NaCl is challenging because of physical stability issues. In this study, dry powders of NaCl were prepared using an ultrasound-mediated precipitation process followed by spray drying. The resulting particles (mass median diameter, 2.12 ± 0.35 μm) showed the typical cubic crystal habit of NaCl and were confirmed to be crystalline by X-ray powder diffraction. Dispersion of the particles by dry powder inhalers (Inhalator, Dinkihaler, and Aeroliser) showed aerosol performance (fine particle fraction, 18, 35, and 36%, respectively) suitable for the bronchoprovocation test. The present method can thus be a promising alternative for preparing dry powder NaCl aerosols for inhalation delivery.

This work demonstrates a simple means of predicting aerodynamic diameter of particles having fractal surfaces. A number of drag coefficient expressions were employed for the calculation of aerodynamic diameter. A set of model objects having surface fractal dimensions varying from 2.00 to 2.55 was constructed, from which all the parameters required to compute shape and surface roughness factors can be obtained. Drag coefficients ( C D ) formulated by Ro and Neethling, Haider and Levenspiel, Thompson and Clark, Ganser, and Tran-Cong et al. were shown to perform similarly within the specified criteria. The aerodynamic diameters calculated follow the expected trend of decreasing diameter with increasing surface roughness. Comparisons with literature data show that the C D expressions by Ro and Neethling, Haider and Levenspiel, and Ganser, on average, agree to within 17–23% of the measured values.

Sedimentation is one of the simplest and cheapest methods used for the removal of particulate matter from wastewater. However, the method is only viable for large particles and hence pollutants need to be flocculated to form large aggregates, normally behaving as fractals. Knowledge of the structure of fractal aggregates and their settling behaviour are crucial for optimisation of the sedimentation process. The structure of fractal aggregates can be readily measured using methods such as light scattering. However, the characteristics of the settling behaviour of fractal aggregates are not well understood since these aggregates do not behave as spheres with constant density. The settling behaviour of fractal aggregates depends on various aspects, such as the porosity, size, and buoyant density. The models used in this paper to predict settling velocity of fractal aggregates show that aggregates with particles packed closely together settle more easily than open flocs of particles when the size of aggregates exceeds the transition radius, RT. RT exists due to porosity of the flocs. When the sizes of the flocs are smaller than RT, the passage of fluid through the interior of the aggregates allows the reduction of the drag coefficient, which further results in faster settling of loose aggregates compared to compact aggregates. However, when flocs are bigger than the RT, gravity plays a more important role, which allows compact aggregates to settle faster than loose aggregates. This result suggests that by controlling aggregation processes to ensure aggregates have compact structure and are bigger than RT, sedimentation could be further utilised in pollution control processes. Additionally, the usage of coagulant can be greatly reduced since less coagulant is needed to produce compact aggregates.

This paper presents the problems encountered and methods undertaken in the design and construction of equipment for measuring the particle size and settling velocity of flocs. The paper reviews existing settling columns and the development of an experimental system suitable for such measurements. The equipment consisted of a rectangular glass column (1.5 m high, 1.5 cm deep and 3 cm wide) filled with water, into which flocs were introduced at the top and their size and settling velocity measured. This column was housed in a cylindrical aluminium vessel temperature controlled by air, using a fan-forced heat exchanger which was in turn temperature controlled by a water bath. Both the air column and all air lines were insulated. Air was fan forced into the aluminium vessel at the top and bottom to achieve an internal temperature of 25 °C, thus eliminating any convection currents caused by temperature variations. The image-capturing equipment consisted of a CCD camera, with illumination provided by a stroboscope fitted with a polarizing and a red filter to achieve optimum contrast. All the equipment was mounted on a heavy aluminium-skirted base fitted with 50 squash balls to eliminate any vibration causing disturbance to the settling column and associated optics. The signal from the CCD camera was fed into a video recorder and analysed by image analysis software (WiT) on a standard computer. The magnification range for the optical system was 1300 times, capable of measuring in the range of 2-240 µm. The maximum settling velocity that can be measured is 0.225 m s-1. The field of view was 240 µm by 180 µm.