Dry Powder Inhaler Research Articles

A randomized crossover study assessing critical errors, preferences, and ease of use of two multidose powder inhalers

ABSTRACT Background The effectiveness of inhaled medications in asthma and COPD is significantly impacted by inhalation errors. Feedback mechanisms, built into the design of the inhaler might reduce the number of critical errors. This study compares critical errors, preferences, and ease of use of two dry powder inhalers, the Nexthaler and the Turbuhaler. Research design and methods In this multi-center, prospective, randomized, open-label, cross-over study, the proportions of asthma and COPD patients making critical errors were compared between the Nexthaler and Turbuhaler after 4 weeks of clinical use, after having been trained in the correct use of both inhalers. Results 90 and 49 patients with asthma and COPD, respectively were assessed. No significant difference was found in the number of critical errors between the two inhalers (3 with Nexthaler and 5 with Turbuhaler). However, more patients preferred the Nexthaler (57.6%) over the Turbuhaler (34.5%) (p = 0.006), while 7.9% stated no preference. Conclusions The study found no significant differences in critical error rate between the Nexthaler and Turbuhaler but the Nexthaler was preferred over the Turbuhaler. This study highlights the importance of dedicating sufficient time to instructing patients in correct inhalation technique, which can lead to long-term retention of the inhalation technique. Trial Registration The trial is registered at International Clinical Trials Registry Platform. Trial number NL-OMON55778.

Sustainability and choice of inhaled treatment for obstructive pulmonary diseases

Inhaled treatments are essential for obstructive lung diseases such as asthma and chronic obstructive pulmonary disease (COPD). However, pressurized metered-dose inhalers (pMDI) use propellant gases, contributing to greenhouse gas (GHG) emissions and thereby to climate change. The use of dry powder inhalers (DPI) or soft mist inhalers (SMI) when clinically appropriate is a way to reduce these emissions. It is essential to confirm the diagnosis, promote adherence and therapeutic education, and support effective recycling policies and the development of less polluting treatments. In any case, the right inhaler is the one that suits the patient, is used correctly, and stabilizes of the respiratory condition.

Comprehensive In Vitro and In Silico Aerodynamic Analysis of High-Dose Ibuprofen- and Mannitol-Containing Dry Powder Inhalers for the Treatment of Cystic Fibrosis

Background: Cystic fibrosis is a hereditary disease, which causes the accumulation of dense mucus in the lungs accompanied by frequent local inflammation. The non-steroidal anti-inflammatory drug ibuprofen (IBU) and the mucolytic mannitol (MAN) can treat these symptoms. Compared to per os administration, a lower dose of these drugs is sufficient to achieve the desired effect by delivering them in a pulmonary manner. However, it is still a challenge to administer high drug doses to the lungs. We aim to develop two inhaled powder formulations, a single-drug product of MAN and a combined formulation containing IBU and MAN. Methods: MAN was dissolved in an aqueous solution of Poloxamer-188 (POL). In the case of the combined formulation, a suspension was first prepared in a planetary mill via wet milling in POL medium. After the addition of leucine (LEU), the formulations were spray-dried. The prepared DPI samples were analyzed by using laser diffraction, scanning electron microscopy, powder X-ray diffraction, differential scanning calorimetry, density tests, in vitro aerodynamic studies (Andersen Cascade Impactor, Spraytec® device), in vitro dissolution tests in artificial lung fluid, and in silico tests with stochastic lung model. Results: The DPIs showed suitability for inhalation with low-density spherical particles of appropriate size. The LEU-containing systems were characterized by high lung deposition and adequate aerodynamic diameter. The amorphization during the procedures resulted in rapid drug release. Conclusions: We have successfully produced a single-drug formulation and an innovative combination formulation, which could provide complex treatment for patients with cystic fibrosis to improve their quality of life.

An approach to reduce inhaler errors using Donabedian's triad

Inhaler errors inversely affect the outcome of respiratory diseases. Inhaler devices, such as the metered-dose inhalers (MDI) and dry powder inhalers (DPI), are commonly used in treating respiratory diseases like asthma and chronic obstructive pulmonary disease (COPD), and incorrect use of these devices can result in suboptimal treatment outcomes, increased probabilities of hospitalizations or admissions, and poorer quality of life. Patient related factors to inhaler errors include age, cognitive and physical abilities, education, language barriers, and preferences. Device-related factors such as inhaler design and operational complexity can also lead to errors. Finally, factors related to healthcare professionals (HCP) such as competency, level of knowledge in disease and inhaler device and availability to educate patients, can play a role in inhaler error. Quality management is a potential solution to this problem. Quality improvement strategies towards addressing inhaler misuse can increase patient satisfaction and improve patient outcomes. Donabedian's triad, which includes structure, process, and outcome can be utilized in developing a framework for reducing inhaler errors. Institutional solutions are more towards the structural and process changes in the triad, such as HCP training, checklists on training efficacy, provision of action plans, and availability of staff to educate and train patients. Patient-centered solutions focus more on process and outcome domains, such as improvement in lung functions, patient education, re-assessment and re-education of inhaler techniques, and adherence to treatment regimen. By focusing on structural and process domains, the quality of care can be enhanced, resulting in improved outcomes.

Pharmaceutical, Clinical, and Regulatory Challenges of Reformulating Pressurized Metered-Dose Inhalers to Reduce Their Environmental Impact.

The chlorofluorocarbons (CFCs) that were used as propellants in early pressurized metered-dose inhalers (pMDIs) had substantial ozone-depleting potential. Following the Montreal Protocol in 1987, the manufacture of a range of ozone-depleting substances, including CFCs, was gradually phased out, which required the propellants used in pMDIs to be replaced. Current pMDIs use hydrofluoroalkanes (HFAs) as propellants, such as 1,1,1,2-tetrafluoroethane (HFA-134a). Although these HFAs have no ozone-depleting potential, they have a high global warming potential (GWP), and consequently, their use is being phased down. One option for the discontinuation of HFA use in inhalers would be to discontinue all pMDIs, switching patients to dry powder inhalers (DPIs). However, a switch from pMDIs to DPIs may not be a clinically appropriate option for some patients; furthermore, the full lifecycle carbon footprint and the overall environmental impact of different inhalers should be considered. An alternative is therefore to reformulate the current HFA pMDIs to use low-GWP propellants, such as 1,1-difluoroethane (HFA-152a). This article summarizes the various steps and challenges associated with this change, illustrated using data from the inhaled triple combination of beclomethasone dipropionate, formoterol fumarate, and glycopyrronium bromide, a complex formulation of three molecules in a solution that contains liquid-phase propellant.

Design and Evaluation of Dry Powder Inhalation Formulation for Pulmonary Delivery of Docetaxel: A Novel Approach in Non-Small Cell Lung Cancer

Design and Evaluation of Dry Powder Inhalation Formulation for Pulmonary Delivery of Docetaxel: A Novel Approach in Non-Small Cell Lung Cancer

Effect of lubricants type and particle size on the rheological properties and aerosolization behavior of dry powder inhalers

A commonly used strategy to improve aerosolization behavior of carrier-based dry powder inhalers (DPIs) is the addition of magnesium stearate as a lubricant, yet it may also negatively affect properties of DPIs. Thus, the aim of this study was to find lubricants that could be used as alternatives of magnesium stearate and meanwhile verify the applicability of using powder rheological properties to predict the performance of different lubricants in DPIs. Here, using fluticasone propionate as a model drug, LH200 as the carrier, influence of lubricants type and particle size, including magnesium stearate, sodium stearate, Leucine, sodium stearate fumarate, Compritol® 888 ATO, and Compritol® HD5 ATO, on the physicochemical properties, powder rheology and aerosolization behavior of the DPI formulations was characterized. Further, the relationship between powder rheological parameters and in-vitro drug deposition parameter, fine particle fraction (FPF), were explored, and the contribution of powder flowability and adhesion was evaluated using principal component analysis (PCA). The results showed that magnesium stearate, sodium stearate and smaller sized leucine significantly reduced the basic flowability energy, aeration energy and Permeability of the DPI formulations, leading to improved aerosolization behavior. A robust linear correlation was established between rheological parameters and FPF. PCA showed that in lubricants containing formulations, the contribution of flowability (74.69%) was greater than that of adhesion (25.31%). In conclusion, sodium stearate and smaller particle size Leucine can be considered as substitutes of magnesium stearate in DPI formulations.

Fast onset of thrombolytic effect of efficiently inhalable spray-dried rivaroxaban powder formulations

Pulmonary embolism is a critical medical condition and can lead to cardiovascular arrest or death if left untreated. Pulmonary delivery of an anti-coagulant therapeutic could provide a locally limited and efficient therapy, moreover combined with a potentially fast onset of the therapeutic effect that is demanded in emergency situations. Rivaroxaban (riva) was formulated as an inhalable dry powder that can be administered directly to the lungs in order to reach high local drug doses. Particles obtained spray drying dichloromethane-methanol mixtures yielded an aerodynamic diameter of about or smaller than 5 µm and were found to reach an emitted fine particle fraction (FPFEF) of at least 60 %. Pulmonary administration to rats using a dry powder insufflator revealed a nearly immediate therapeutic onset confirmed by the anticoagulant effects after 5 min in the plasma, followed by a plateau over the next 4 h. Such rivaroxaban particles were further formulated in binary blends using different lactose carriers (Inhalac® 70/251/400). These interactive blends resulted in high emitted fractions of at least 87 %, and furthermore, the highest fine particle fraction − total dose (FPFTD) (60 %) of all tested formulations was achieved by using Inhalac® 400 as a carrier. The data strongly suggest a significant therapeutic potential of a rivaroxaban dry powder formulation, combining fast onset and a plateau of plasma concentrations turning it into a potential first aid therapeutic.

Dry powder inhaler deposition in the larynx and the risk of steroid inhaler laryngitis: a computational fluid dynamics study

Dry Powder Inhalers (DPIs) are a mainstay in the treatment of obstructive respiratory diseases, including asthma and chronic obstructive pulmonary disease (COPD). Deposition of inhaled corticosteroids in the larynx elicits local side effects, potentially leading to steroid inhaler laryngitis. The objective of this study was to estimate the dose of DPIs that are deposited in the larynx relative to other regions of the respiratory tract using computational fluid dynamics (CFD). An anatomically accurate model of the airways (mouth to main bronchi) was constructed based on medical imaging of a healthy adult. Respiratory airflow and particle transport were simulated for constant inhalation rates of 30, 45, and 60 L/min. Two turbulence models were compared, namely the large eddy simulation (LES) and the models. DPIs were assumed to generate an aerosol cloud with a log-normal particle size distribution characterized by the mass median aerodynamic diameter () and geometric standard deviation (). We compared two commercial DPIs, namely DPI 1 had a large particle size ( = 50 μm, ) and DPI 2 had a small particle size ( = 2 μm, ). The laryngeal dose was 1.6-to-3.8-fold higher than the bronchial dose for DPI 1, while the laryngeal and bronchial doses (units of mass per unit surface area) were similar for DPI 2 for both turbulence models and all inhalation rates. The choice of turbulence model had little impact on the total extrathoracic deposition, but a significant impact on regional doses, with the LES model predicting higher larynx-to-bronchi relative doses than the model. Our prediction that the larynx is a hotspot for DPI deposition is consistent with the observation of laryngeal side effects in DPI users. Importantly, our simulations suggest that DPIs with larger particles ( = 50 μm) may increase the risk of steroid inhaler laryngitis.

Posaconazole nanocrystals dry powder inhalers for the local treatment of invasive pulmonary aspergillosis.

Invasive pulmonary aspergillosis poses a significant threat to immunocompromised patients, characterized by high mortality rates. Posaconazole (PSZ), a second-generation triazole antifungal, exhibits broad-spectrum activity but suffers from limited pulmonary concentrations and notable systemic side effects when administered orally or intravenously. This study focuses on optimizing PSZ nanocrystals-agglomerated particles for dry powder inhalers (DPIs) to enhance solubility, dissolution rates, and pulmonary deposition, ultimately improving therapeutic efficacy while minimizing systemic adverse effects. We employed wet medium milling and spray-drying techniques to formulate PSZ nanocrystals-agglomerated DPIs. Various stabilizers including HPMC, HPC, Soluplus, and PVPK30, were systematically evaluated to optimize physicochemical properties. Aerosolization performance was assessed using the Next Generation Impactor, while antifungal efficacy was evaluated through in vitro and in vivo studies The optimized PSZ DPIs demonstrated significant enhancements in solubility and dissolution rates, with a fine particle fraction (FPF) of 78.58 ± 3.21 %, ensuring optimal lung delivery. In vitro experiments revealed potent effects with minimal cytotoxicity to lung cells. In vivo studies indicated that the optimized formulation achieved a Cmax/AUC0→∞ ratio in lung tissues that was 27.32 and 6.76-fold higher than that of the oral suspension, highlighting increased local drug concentrations. This approach presents a scalable, cost-effective strategy for the pulmonary delivery of PSZ, ensuring high drug loading and promising clinical outcomes in treating pulmonary fungal infections.

Formulation and evaluation of carrier-based dry powders containing budesonide and arformoterol for inhalation therapy

Asthma and Chronic Obstructive Pulmonary Disease (COPD) are major global health concerns, with inhalation therapy being a primary treatment method. Dry powder inhalers (DPIs) often face challenges related to particle aggregation, which can diminish drug delivery efficiency. This study investigates particle aggregation and aims to optimize the cohesion–adhesion balance to improve inhalation efficiency. Advanced techniques like atomic force microscopy and Raman imaging were used to analyze particle interactions, focusing on lactose ratios, particle morphology, and drug-drug interactions. The therapeutic efficacy of optimized formulations containing budesonide (BUD) and Arformoterol (AFT) was assessed using an asthma model, showing significant improvements in sRAW, neutrophil count, and tidal volume compared to the positive control, with p-values below 0.01. AFT exhibited comparable efficacy to Formoterol at half the dose. Additionally, pharmacokinetic studies demonstrated similar in vivo behavior between the drugs, confirming the therapeutic advantage of AFT, with p-values for AUC0−t and Cmax of .646 and .153, respectively. The fine particle fractions for AFT and BUD were 39.4% and 50.6%, respectively, indicating improved drug delivery efficiency and potential for better clinical outcomes in asthma and COPD patients.

Prioritising Patients and Planet: Advocating for Change in Respiratory Care

The global burden of respiratory diseases, particularly asthma and chronic obstructive pulmonary disease (COPD), continues unabated. Suboptimal management places a significant strain on both patients and urgent or emergency care services. With an ageing population in many countries, the demand for these services is set to increase further. At the same time, healthcare systems are striving to reduce their carbon footprint and achieve net zero emissions, as the healthcare sector is a significant contributor to carbon emissions worldwide. Although these two goals may appear contradictory, they need not be in conflict. This article reviews an industry-sponsored symposium held at the European Respiratory Society (ERS) Congress 2024 in Vienna, Austria, in September 2024. The session addressed the urgent need to change the delivery model for respiratory healthcare in response to the increasing prevalence of respiratory diseases and the challenges posed by climate change. Co-chair John Hurst, Professor of Respiratory Medicine at University College London (UCL), UK, underscored the importance of innovative solutions for managing respiratory diseases and highlighted the challenges faced by healthcare decision-makers. This was further elaborated on by Omar Usmani, Professor of Respiratory Medicine at Imperial College London, UK, who emphasised the importance of clinical choice. He stated that inhaled medicines, which form the cornerstone of treatment, should not be considered interchangeable. He also discussed ongoing efforts to maintain access to essential medicines by developing novel next-generation propellants (NGP) for pressurised metered-dose inhaler (pMDI) devices, which will reduce their carbon footprint to levels comparable with dry powder inhalers (DPI). Additionally, he described the European Chemicals Agency (ECHA) proposal to restrict a broad range of chemicals classed as per- and polyfluoroalkyl substances (PFAS). This precautionary measure would affect both current propellants in pMDIs and the transition to NGPs, with global implications for inhaled medicines. Erika Penz, Associate Professor of Respirology, Critical Care, and Sleep Medicine at the University of Saskatchewan, Canada, noted that suboptimal management of respiratory disease is associated with a disproportionately high burden on both patients and the environment. The forthcoming availability of pMDI medicines with NGPs alone will not resolve this larger issue. As every healthcare interaction carries a carbon footprint, which increases with the intensity of treatment, the implementation of guidelines into clinical practice would improve patient outcomes and reduce the demand on healthcare services and the associated carbon emissions. Co-chair Helen Reddel, Clinical Professor and Research Leader at the Woolcock Institute of Medical Research, Australia, concluded by re-emphasising the urgent need to implement guidelines immediately for the benefit of both patients and the environment.

Evaluation of asthma control after reinforcement of proper inhaler techniques in a tertiary care center in northern India.

Asthma is an obstructive lung disease with high prevalence. Symptom control in asthma remains poor despite significant advancements in treatment guidelines and inhalational devices. This is often attributed to inadequate patient adherence to the inhaler technique and insufficient education on its long-term use. Through this study, we aimed to assess the impact of reinforcement of proper inhaler technique on asthma symptom control and quality of life. A prospective cohort of 400 asthma patients using dry powder inhalers and metered dose inhalers was recruited in the outpatient clinic of our hospital. At the time of recruitment, the correctness of inhaler technique usage was assessed, and the pre-test Inhaler Technique Score (ITS) was recorded for each patient. Then, a ten-step inhalation technique was taught through demonstration, and the post-test ITS score was recorded again. This was done for each patient at monthly intervals for 3 months. Along with it, two tailored questionnaires, the Asthma Control Test (ACT) and Asthma Quality of Life Questionnaire (AQLQ), were administered at each visit to assess disease control and quality of life. Significant enhancements in inhalation technique were noted from the first to the third visit using the ten-step inhalation usage scores, which improved from 6.91 to 9.87 (out of 10) (p<0.001), paralleled by ACT score increases from 17.06 to 19.37 (out of 25) (p<0.001) from visits one to two, and from 19.37 to 20.52 (out of 25) (p<0.001) from visits two to three, signifying improvement in symptom control. Quality of life similarly improved from 4.45 to 5.12 to 5.45 (out of 7) (p<0.001) across the three visits as assessed by AQLQ. In conclusion, promoting proper inhaler technique through structured education programs is crucial for optimizing long-term asthma management and enhancing patients' quality of life.

Revolutionizing Influenza Treatment: A Deep Dive into Targeted Drug Delivery Systems.

Influenza, a highly transmissible respiratory infection caused by influenza viruses A and B, poses a persistent threat to global public health due to its high mutation rate, ability to develop resistance to existing antiviral drugs, and capacity for rapid spread. Current treatment options, including four main classes of antiviral agents-adamantanes, neuraminidase inhibitors, RNA-dependent RNA polymerase inhibitors, and polymerase acidic endonuclease inhibitors- are limited by the emergence of drug-resistant viral strains, non-specific drug distribution, and adverse side effects. Moreover, the effectiveness of traditional vaccines is often compromised by antigenic drift and shift, necessitating the development of alternative therapeutic strategies. This review comprehensively explores the potential of novel targeted drug delivery systems to address these limitations and improve influenza management. Nanotechnology-based platforms, including lipid-based, polymer-based, inorganic, and hybrid nanoparticles, offer enhanced drug delivery through improved bioavailability, targeted action, and controlled release, thus minimizing systemic toxicity and optimizing therapeutic outcomes. Inhalation delivery systems such as dry powder inhalers (DPIs), nebulizers, and nanotechnology-based inhalation formulations provide direct delivery of antiviral agents to the respiratory tract, ensuring rapid onset of action with reduced systemic side effects. Transdermal delivery methods, including microneedle patches and hydrogel-based systems, offer non-invasive alternatives that enhance patient compliance and allow for sustained drug release. Furthermore, this review discusses recent innovations, such as responsive drug delivery systems and multifunctional nanoparticles capable of simultaneous delivery of multiple therapeutic agents, representing a significant advancement in the fight against influenza. These novel approaches promise improved targeting and efficacy and enable personalized treatment strategies, enhancing patient outcomes in both seasonal flu and pandemic scenarios. Integrating these advanced drug delivery systems into clinical practice could revolutionize the management of influenza, offering a promising pathway toward more effective and safer therapies.

Inhalable cyclodextrin metal-organic framework dry powder enhanced direct pulmonary delivery of paclitaxel for the treatment of lung cancer

Inhalation dry powders are in great demand for the treatment of lung diseases due to their unique advantages such as excellent direct delivery, rapid onset of action, and reduced systemic side effects. Herein, this work highlights the successful development of an inhalable paclitaxel dry powder, which is facilely constructed through the optimization of the formulation between chemotherapy components (paclitaxel) and a metal-organic framework (MOF) carrier (γ-cyclodextrin and KOH). Moderate pore and particle size distribution, as well as low hygroscopicity endow the dry powder with excellent loading efficiency and resistance to degradation. All ingredients and their interactions confer favorable emptying rates, flowability, and pulmonary deposition, as well as direct lung drug delivery and release. These attractive characteristics enable the dry powder to effectively enhance cytotoxicity, improve pharmacokinetics, promote lung accumulation, and reduce the side effects of paclitaxel. Thus, this paclitaxel dry powder may open a new avenue for the inhalation treatment of diseases, greatly advancing its clinical application.

Inhaler personalisation based on peak inspiratory flow (PIF) among dry powder inhaler users: a pilot randomised control trial (RCT) in COPD.

Dry powder inhalers (DPIs) are commonly used among patients with Chronic Obstructive Pulmonary Disease (COPD). These inhalers are breath-actuated, and require patients to generate sufficient peak inspiratory flow (PIF) to disaggregate the drug powder into respirable fine particles and deliver it to the lower airway tracts. Inhaler personalisation based on PIF among DPI users has not been studied in Malaysia, thus we conducted the present pilot study to determine the feasibility of conducting such research among COPD patients. This was an open-label pilot randomised control trial, conducted from June 2021-January 2022 at the respiratory clinic of Hospital Canselor Tuanku Muhriz, Universiti Kebangsaan Malaysia. Measurement of PIF was performed with In-Check DIAL G16 among adult COPD patients treated with DPI and had suboptimal PIF. Eligible subjects were randomised using block randomisation into two groups, either the interventional group or the control group. Twenty-two COPD patients fulfilled the study criteria and were randomised to intervention (n = 11) and control (n = 11) groups. For the interventional group, there were statistically significant improvements between baseline and at 12 weeks for both FEV1 and CAT scores. The mean (% predicted) FEV1 were 54.6 ± 20.4% and 56.6 ± 19.8% (p = 0.026), pre-and post-intervention. The mean CAT score at baseline was 24.4 ± 5.8 and reduced to 19.6 ± 4.4 at 12 weeks (p = 0.012). For the control group, the mean (% predicted) FEV1 at baseline was 58.0 ± 21.9% and 56.5 ± 20.7% at 12 weeks, with no statistical significance difference (p = 0.143). However, there was a statistically significant difference in CAT scores at baseline and 12 weeks, with a mean of 26.5 ± 6.1 and 23.3 ± 5.6, respectively (p = 0.010). The findings from the present pilot RCT highlighted that inhaler personalisation based on PIF among COPD patients was feasible and practical.

In Vitro Analysis of Aerodynamic Properties and Co-Deposition of a Fixed-Dose Combination of Fluticasone Furoate, Umeclidinium Bromide, and Vilanterol Trifenatate.

Effective airway delivery of a fixed-dose combination of triple-aerosolized inhaled corticosteroid (ICS)/long-acting beta agonist (LABA)/long-acting muscarinic antagonist (LAMA) is likely to positively affect therapeutic responses predicted in patients with asthma and chronic obstructive pulmonary disease. This study aimed to conduct in vitro fluticasone furoate, vilanterol trifenatate, and umeclidinium bromide depositions in a Next Generation Impactor. The aerodynamic properties of these inhaled medications influence the spatial distribution and drug abundance, particularly in the smaller airways, to reverse or alleviate disease pathology. The Next Generation Impactor was used to demonstrate the aerodynamic particle size distributions of fluticasone furoate, vilanterol trifenatate, and umeclidinium bromide delivered from a dry powder inhaler at different flow rates across all stages of the impactors. This in vitro study analyzed the distribution pattern of individual drug components to simulate mono-component deposition and co-deposition in the official model in the United States Pharmacopeia. An Andersen cascade impactor together with scanning electron microscope-energy-dispersive X-ray was employed to observe the drug deposition on each stage of the impactor. We found that the distribution pattern of each component at the same cascade level was comparable, and the aerosol particles of the three drugs reached the in vitro representation of the lower airway compartment. The specified flow rates generated the desired fine particle fraction, fine particle dose, and mass median aerodynamic diameter. Our results also demonstrated visualized deposition patterns of the delivered drugs from different stages of the cascade impactor that may predict deposition as it occurs in vivo. Spatial distribution and abundance of ICS/LABA/LAMA in the same cascade levels were closely comparable, and the aerosol particles were able to reach the small aerosol-sized cascades at the lower levels to some extent.

Comparative Preclinical Pharmacokinetics and Disposition of Favipiravir Following Pulmonary and Oral Administration as Potential Adjunct Therapy Against Airborne RNA Viruses.

Favipiravir is administered orally, even against airborne RNA viruses, in a loading-dose/maintenance dose regimen. We investigated whether-(a) pulmonary delivery of favipiravir would generate high concentrations in the luminal side of the respiratory tract; and (b) avoiding first-pass metabolism by the liver by inhaled drug would generate comparable pharmacokinetics (PK) with doses significantly smaller than the oral maintenance dose. A dry powder inhalation (DPI) of favipiravir formulated by mixing with Inhalac 400® was prepared and characterized. Inhalations of ~ 120µg dose strength, with or without a prior oral loading dose were administered to mice. Comparator mice received human-equivalent oral doses (3mg). Three mice per sampling time point were sacrificed and favipiravir concentrations in the blood plasma, bronchio-alveolar lavage fluid (BALF) and lung tissue homogenate determined by HPLC. One-compartment PK modeling of concentration-time data indicated that the area under the curve (AUC0-24h) generated in the BALF recovered from mice receiving inhalations of ~ 1/25th of the oral dose subsequent to an oral loading dose was 86.72 ± 4.48µg⋅mL-1⋅h. This was consistently higher than the AUC observed in the BALF of orally-dosed mice (56.71 ± 53.89µgmL-1⋅h). In blood serum, the respective values of AUC were 321.55 ± 124.91 and 354.71 ± 99.60µg⋅mL-1⋅h. Pulmonary delivery of significantly smaller doses of favipiravir generates meaningful drug disposition and pharmacokinetics at the site of respiratory viral infections. We provide the rationale for designing a self-administered, non-invasive, low-cost, targeted drug delivery system against airborne RNA virus infection.

Advanced Spray-Dried Inhalable Microparticles/Nanoparticles of an Innovative Mitophagy Activator for Targeted Lung Delivery: Design, Comprehensive Characterization, Human Lung Cell Culture, and In Vitro Aerosol Dispersion Performance.

Urolithin A (UA) has demonstrated the ability to stimulate mitophagy and enhance mitochondrial and cellular health in skeletal muscles in humans after oral administration. It is hypothesized that targeted delivery of UA as inhaled dry powders to the lungs will enhance mitochondrial health through mitochondrial biogenesis. This study aimed to engineer inhalable excipient-free powders of UA as dry powder inhalers (DPIs) for targeted pulmonary delivery. The particles were designed by particle engineering from dilute organic solutions of UA using the state-of-the-art spray drying technology in a closed mode. Comprehensive physicochemical characterization and advanced microscopy techniques were conducted to examine phase behavior, molecular properties, and particle properties, which are necessary for the rational design of advanced pulmonary inhalation aerosols. Molecular fingerprinting was conducted by using attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy and Raman spectroscopy. Chemical imaging and mapping were conducted using confocal Raman microscopy (CRM) and IR microscopy. The advanced spray-dried (SD) excipient-free powders were successfully produced at different spraying pump feed rates and exhibited favorable molecular and particle properties. The excipient-free SD powders exhibited outstanding in vitro aerosol dispersion performance with an FDI-approved human DPI device (Neohaler) and correlated with the spray drying pump rate. In vitro, cell viability of various human pulmonary cells from different lung regions demonstrated biocompatibility and safety at different doses of UA. The transepithelial electrical resistance (TEER) assay shows that UA maintains cell membrane integrity and barrier tightness, indicating its potential for safe and effective localized drug delivery without long-term adverse effects. These results demonstrated that UA has favorable physicochemical and in vitro properties for inhalation and can be successfully engineered into excipient-free inhalable microparticles/nanoparticles as DPIs.

Environmental impact of pressurised metered dose inhalers versus dry powder and soft mist inhalers at a tertiary Melbourne hospital.

The carbon footprint of devices to deliver inhaled respiratory medications has come into focus as climate change has been identified as a worldwide emergency. Metered dose inhalers (MDIs) contain hydrofluorocarbons that have significant global warming potential compared to dry powder inhalers (DPIs) and soft mist inhalers (SMIs), which do not use a propellant gas. A 12-month pharmacy inpatient dispensing audit demonstrated that inpatient MDI use significantly outweighed that of DPIs and SMIs and accounted for approximately 99% of inhaler-related greenhouse gas emissions at our hospital.