Quality by Design in Pulmonary Drug Delivery: A Review on Dry Powder Inhaler Development, Nanotherapy Approaches, and Regulatory Considerations.

Dry powder inhalers (DPIs) are state-of-the-art pulmonary drug delivery systems. This article explores the transformative impact of nanotechnology on DPIs, emphasizing the Quality Target Product Profile (QTPP) with a focus on aerodynamic performance and particle characteristics. It navigates global regulatory frameworks, underscoring the need for safety and efficacy standards. Additionally, it highlights the emerging field of nanoparticulate dry powder inhalers, showcasing their potential to enhance targeted drug delivery in respiratory medicine. This concise overview is a valuable resource for researchers, physicians, and pharmaceutical developers, providing insights into the development and commercialization of advanced inhalation systems.

Comparisons between In-Check DIAL® and PF810® in evaluation and training inspiratory capacity for using dry powder inhalers.

BACKGROUND: Dry powder inhalers (DPIs) rely on both internal resistance and patients' inspiratory capacity for effective operation. Optimal inspiratory technique is crucial for DPI users. This study assessed the accuracy and repeatability of two available devices, PF810® and In-Check DIAL®, and analyzed their measurement errors and consistency in detecting inspiratory capacity. METHODS: The accuracy and repeatability of peak inspiratory flow (PIF) and forced inspiratory vital capacity (FIVC) against various internal resistances of the two devices were assessed using standard waveforms generated by a breathing simulator. The agreement of PIF measurements between the two devices in healthy volunteers and chronic obstructive pulmonary disease (COPD) patients was analyzed with the intraclass correlation coefficient and Bland-Altman graphical analysis. RESULTS: PF810® showed great accuracy and repeatability in measuring PIF, except for square waveforms at the lowest flow rate (20 L/min). In-Check DIAL® exhibited poor accuracy against high resistance levels. In scenarios with no resistance, In-Check DIAL® had significantly smaller measurement errors than PF810®, but larger errors against high resistance levels. The two devices showed excellent agreement (ICC > 0.80, P < 0.05), except for healthy volunteers against medium to high resistance (R3-R5) where the ICC was insignificant. Bland-Altman plots indicated small disagreements between the two devices for both healthy volunteers and COPD patients. CONCLUSIONS: In-Check DIAL® exhibited poor accuracy and larger measurement errors than PF810® when detecting PIFs against higher internal resistances. However, its good performance against lower internal resistances, along with its cost-effectiveness and convenience made it appropriate for primary care. PF810® showed good accuracy and repeatability and could detect additional parameters of inspiratory capacity beyond PIF, though required further studies to confirm its clinical benefits.

Building respirable powder architectures: utilizing polysaccharides for precise control of particle morphology for enhanced pulmonary drug delivery.

INTRODUCTION: Dry powder inhaler (DPI) formulations are gaining attention as universal formulations with applications in a diverse range of drug formulations. The practical application of DPIs to pulmonary drugs requires enhancing their delivery efficiency to the target sites for various treatment modalities. Previous reviews have not explored the relation between particle morphology and delivery to different pulmonary regions. This review introduces new approaches to improve targeted DPI delivery using novel particle design such as supraparticles and metal-organic frameworks based on cyclodextrin. AREAS COVERED: This review focuses on the design of DPI formulations using polysaccharides, promising excipients not yet approved by regulatory agencies. These excipients can be used to design various particle morphologies by controlling their physicochemical properties and manufacturing methods. EXPERT OPINION: Challenges associated with DPI formulations include poor access to the lungs and low delivery efficiency to target sites in the lung. The restricted applicability of typical excipients contributes to their limited use. However, new formulations based on polysaccharides are expected to establish a technological foundation for the development of DPIs capable of delivering modalities specific to different lung target sites, thereby enhancing drug delivery.

Cryomilled electrospun nanofiber mats containing d-mannitol exhibit suitable for aerosol delivery of proteins.

Dry powder inhalers (DPIs) are the first choice for inhalation drug development. However, some conventional DPI formulation processes require heating, which may damage high molecular weight drugs such as proteins and nucleic acids. In this study, we propose a novel DPI preparation process that avoids the use of heat. Dry powders were prepared by cryomilling nanofiber mats composed of polyvinyl alcohol, D(-)-mannitol (Man), and α-chymotrypsin (α-Chy) as the model drug using the electrospinning method. The addition of Man conferred high dispersibility and excellent in vitro aerosol performance to the nanofiber mat powder in a very short milling time (less than 0.5 min) as assessed using the Andersen cascade impactor. Powders were classified according to the degree of friability, and among these, nanofiber mats containing 15 % Man and milled for 0.25 min exhibited the highest aerosol performance. Nanofiber mats containing Man milled for less than 0.5 min also exhibited greater α-Chy enzymatic activity than a nebulized α-Chy solution. Furthermore, single inhalation induced no significant lung tissue damage as evidenced by lactate dehydrogenase activity assays of mouse bronchoalveolar lavage fluid. This novel DPI formulation process may facilitate the safe and efficient inhalational delivery of therapeutic proteins.

Inhalable solid lipid nanoparticles of levofloxacin for potential tuberculosis treatment.

Delivering novel antimycobacterial agents through the pulmonary route using nanoparticle-based systems shows promise for treating diseases like tuberculosis. However, creating dry powder inhaler (DPI) with suitable aerodynamic characteristics while preserving nanostructure integrity and maintaining bioactivity until the active ingredient travels deeply into the lungs is a difficult challenge. We developed DPI formulations containing levofloxacin-loaded solid lipid nanoparticles (SLNs) via spray-drying technique with tailored aerosolization characteristics for effective inhalation therapy. A range of biophysical techniques, including transmission electron microscopy, confocal microscopy, and scanning electron microscopy were used to measure the morphologies and sizes of the spray-dried microparticles that explored both the geometric and aerodynamic properties. Spray drying substantially reduced the particle sizes of the SLNs while preserving their nanostructural integrity and enhancing aerosol dispersion with efficient mucus penetration. Despite a slower uptake rate compared to plain SLNs, the polyethylene glycol modified formulations exhibited enhanced cellular uptake in both A549 and NR8383 cell lines. The percent viability of Mycobacterium bovis had dropped to nearly 0 % by day 5 for both types of SLNs. Interestingly, the levofloxacin-loaded SLNs demonstrated a lower minimum bactericidal concentration (0.25 µg/mL) compared with pure levofloxacin (1 µg/mL), which indicated the formulations have potential as effective treatments for tuberculosis.

High-loading cannabidiol powders for inhalation.

Limited attempts have been made previously to develop high-loading CBD inhalable powders, which are essential for high dose delivery. Therefore, this study aimed to develop and characterise inhalable powders with ≥ 95 % w/w CBD by wet ball milling. The effects of magnesium stearate (2 % and 5 %) and inhaler resistance (low-resistance and high-resistance RS01 inhalers) on aerosol performance were also compared. Wet ball milling produced CBD powders with > 50 % production yield. The milled particles showed irregular shapes. The powders were crystalline with minimal amorphous content, low residual solvent level (<1%), and low moisture sorption (<4%). Magnesium stearate improved both the emitted and fine particle fractions. The aerodynamic particle size distribution of the formulations differed between the low-resistance and high-resistance RS01 inhalers. The latter decreased throat deposition but increased inhaler retention. The dissolution profiles showed that all three formulations released CBD steadily and plateaued at 30 min. The best scenario was CBD with 5 % magnesium stearate dispersed from the high resistance RS01 inhaler, showing the highest FPF with the lowest throat deposition. This combination may be tested in vivo in the future to investigate its pharmacokinetic profile.

Influence of particle diameter on aerosolization performance and release of budesonide loaded mesoporous silica particles.

The potential of micron-sized amorphous mesoporous silica particles as a novel controlled release drug delivery system for pulmonary administration has been investigated. Mesoporous silica formulations were demonstrated to provide a narrower particle size distribution and (spherical) shape uniformity compared to commercial micronized formulations, which is critical for repeatable and targeted aerosol delivery to the lungs. The release profiles of a well-known pulmonary drug loaded into mesoporous particles of different mean particle diameters (2.4, 3.9 and 6.3 µm) were analysed after aerosolization in a modified Andersen Cascade Impactor. Systematic control of the release rate of drug loaded into the particles was demonstrated in simulated lung fluid by variation of the mean particle diameter, as well as an enhanced release compared to a commercial micronized formulation. The mesoporous silica formulations all demonstrated an increased release rate of the loaded drug and moreover, under aerosolization from a commercial, low-cost dry powder inhaler (DPI) device, the formulations showed excellent performance, with low retainment and commercially viable fine particle fractions (FPFs). In addition, the measured median mass aerodynamic diameter (MMAD) of the different formulations (2.8, 4.1 and 6.2 µm) was shown to be tuneable with particle size, which can be helpful for targeting different regions in the lung. Together these results demonstrate that mesoporous silica formulations offer a promising novel alternative to current dry powder formulations for pulmonary drug delivery.

Salbutamol Easyhaler provides non-inferior relief of methacholine induced bronchoconstriction in comparison to Ventoline Evohaler with spacer: A randomized trial.

BACKGROUND: Salbutamol is a cornerstone for relieving acute asthma symptoms, typically administered through a pressurized metered-dose inhaler (pMDI). Dry powder inhalers (DPIs) offer an alternative, but concerns exist whether DPIs provide an effective relief during an obstructive event. OBJECTIVE: We aimed to show non-inferiority of Salbutamol Easyhaler DPI compared to pMDI with spacer in treating methacholine-induced bronchoconstriction. Applicability of Budesonide-formoterol Easyhaler DPI as a reliever was also assessed. METHODS: This was a randomized, parallel-group trial in subjects sent to methacholine challenge (MC) test for asthma diagnostics. Participants with at least 20 % decrease in forced expiratory volume in 1 s (FEV1) were randomized to receive Salbutamol Easyhaler (2 × 200 µg), Ventoline Evohaler with spacer (4 × 100 µg) or Budesonide-formoterol Easyhaler (2 × 160/4.5 µg) as a reliever. The treatment was repeated if FEV1 did not recover to at least -10 % of baseline. RESULTS: 180 participants (69 % females, mean age 46 yrs [range 18-80], FEV1%pred 89.5 [62-142] %) completed the trial. Salbutamol Easyhaler was non-inferior to pMDI with spacer in acute relief of bronchoconstriction showing a -0.083 (95 % LCL -0.146) L FEV1 difference after the first dose and -0.032 (-0.071) L after the last dose. The differences in FEV1 between Budesonide-formoterol Easyhaler and Salbutamol pMDI with spacer were -0.163 (-0.225) L after the first and -0.092 (-0.131) L after the last dose. CONCLUSION: The study confirms non-inferiority of Salbutamol Easyhaler to Ventoline Evohaler with spacer in relieving acute bronchoconstriction, making Easyhaler a sustainable and safe reliever for MC test and supports its use during asthma attacks.

Polyvinyl alcohol-based capsule shells manufactured by injection molding as ready-to-use moisture barriers for the development of delivery systems.

In this work, feasibility of injection molding was demonstrated for manufacturing capsule shells. 600 µm-thick prototypes were successfully molded with pharmaceutical-grade low-viscosity polyvinyl alcohols (PVAs), possibly added with a range of different fillers. They showed reproducible weight and thickness (CV < 2 and 5, respectively), compliant behavior upon piercing (holes diameter analogous to the reference), tunable release performance (immediate and pulsatile), and moisture protection capability. To assess the latter, an on-line method relying on near infrared spectroscopy measurements was set-up and validated. Based on the data collected and considering the versatility IM would provide for product shape/thickness/composition, PVA-based molded shells could help widening the portfolio of ready-to-use capsules, representing an interesting alternative to those commercially available. Indeed, these capsules could be filled with various formulations, even those with stability issues, and intended either for oral administration or for pulmonary delivery via single-dose dry powder inhalers.

A Review on Micro and Nanoengineering in Powder-Based Pulmonary Drug Delivery.

Pulmonary delivery of drugs has emerged as a promising approach for the treatment of both lung and systemic diseases. Compared to other drug delivery routes, inhalation offers numerous advantages including high targeting, fewer side effects, and a huge surface area for drug absorption. However, the deposition of drugs in the lungs can be limited by lung defence mechanisms such as mucociliary and macrophages' clearance. Among the delivery devices, dry powder inhalers represent the optimal choice due to their stability, ease of use, and absence of propellants. In the last decades, several bottom-up techniques have emerged over traditional milling to produce inhalable powders. Among these techniques, the most employed ones are spray drying, supercritical fluid technology, spray freeze-drying, and thin film freezing. Inhalable dry powders can be constituted by micronized drugs attached to a coarse carrier (e.g., lactose) or drugs embedded into a micro- or nanoparticle. Particulate-based formulations are commonly composed of polymeric micro- and nanoparticles, liposomes, solid lipid nanoparticles, dendrimers, nanocrystals, extracellular vesicles, and inorganic nanoparticles. Moreover, engineered formulations including large porous particles, swellable microparticles, nano-in-microparticles, and effervescent nanoparticles have been developed. Particle engineering has also a crucial role in tuning the physical-chemical properties of both carrier-based and carrier-free inhalable powders. This approach can increase powder flowability, deposition, and targeting by customising particle surface features.

Safety, tolerability, and pharmacokinetics of a single orally inhaled dose of PUR3100, a dry powder formulation of dihydroergotamine versus intravenous dihydroergotamine: A Phase 1 randomized, double-blind study in healthy adults.

BACKGROUND: Intravenous dihydroergotamine (DHE) has well-established efficacy for the acute treatment of migraine, but its use is limited by the need for in-hospital administration and the nausea/vomiting associated with a high maximum plasma concentration (Cmax). Inhalation is an alternative to intravenous dosing. The surface area of the lung allows for rapid absorption of a self-administered dose. OBJECTIVE: This study evaluated the safety, tolerability, and systemic pharmacokinetics (PK) of a dry powder formulation (PUR3100) DHE when delivered via inhalation compared to intravenous delivery. METHODS: In this double-blind, double-dummy Phase 1 study, healthy volunteers (N = 26) were randomized (1:1:1:1) to one of four groups: orally inhaled placebo plus intravenous DHE 1.0 mg or orally inhaled PUR3100 (0.5, 1.0, or 1.5 mg) plus intravenous placebo. Blood samples were drawn pre-dose and at time points post-dose over 48 h. Standard PK and safety parameters were assessed and values for Cmax and area under plasma concentration time curve (AUC) were used to assess comparative exposures of PUR3100 versus intravenous DHE. RESULTS: All doses of PUR3100 were associated with a lower incidence of nausea (21% vs. 86%), vomiting (0% vs. 29%), and headache (16% vs. 57%) compared to intravenous DHE. The PK profile of PUR3100 versus intravenous DHE was characterized by a similar mean time to Cmax (5 vs. 5.5 min), with reduced AUC0-2h (1120-4320 vs. 6340), and a lower Cmax (3620-14,400 vs. 45,000). Compared to intravenous DHE 1.0 mg, the highest nominal PUR3100 dose (1.5 mg), which delivers a fine-particle dose of approximately 0.9 mg to the lungs, had a geometric mean ratio percentage (90% confidence interval [CI]) for Cmax of 32% [17.2, 59.6] and AUC0-inf of 93% (62.9, 138.5), the latter of which was not significantly different. CONCLUSIONS: Inhaled PUR3100 is associated with rapid systemic PK within the therapeutic window and an improved safety profile relative to intravenous DHE.

Dry powder inhalation containing muco-inert ciprofloxacin and colistin co-loaded liposomes for pulmonary P. Aeruginosa biofilm eradication.

Pseudomonas aeruginosa (PA), a predominant pathogen in lung infections, poses significant challenges due to its biofilm formation, which is the primary cause of chronic and recalcitrant pulmonary infections. Bacteria within these biofilms exhibit heightened resistance to antibiotics compared to their planktonic counterparts, and their secreted toxins exacerbate lung infections. Diverging from traditional antibacterial therapy for biofilm eradication, this study introduces a novel dry powder inhalation containing muco-inert ciprofloxacin and colistin co-encapsulated liposomes (Cipro-Col-Lips) prepared using ultrasonic spray freeze drying (USFD) technique. This USFD dry powder is designed to efficiently deliver muco-inert Cipro-Col-Lips to the lungs. Once deposited, the liposomes rapidly diffuse into the airway mucus, reaching the biofilm sites. The muco-inert Cipro-Col-Lips neutralize the biofilm-secreted toxins and simultaneously trigger the release of their therapeutic payload, exerting a synergistic antibiofilm effect. Our results demonstrated that the optimal USFD liposomal dry powder formulation exhibited satisfactory in vitro aerosol performance in terms of fine particle fraction (FPF) of 44.44 ± 0.78 %, mass median aerodynamic diameter (MMAD) of 4.27 ± 0.21 µm, and emitted dose (ED) of 99.31 ± 3.31 %. The muco-inert Cipro-Col-Lips effectively penetrate the airway mucus and accumulate at the biofilm site, neutralizing toxins and safeguarding lung cells. The triggered release of ciprofloxacin and colistin works synergistically to reduce the biofilm's antibiotic resistance, impede the development of antibiotic resistance, and eliminate 99.99 % of biofilm-embedded bacteria, including persister bacteria. Using a PA-beads induced biofilm-associated lung infection mouse model, the in vivo efficacy of this liposomal dry powder aerosol was tested, and the results demonstrated that this liposomal dry powder aerosol achieved a 99.7 % reduction in bacterial colonization, and significantly mitigated inflammation and pulmonary fibrosis. The USFD dry powder inhalation containing muco-inert Cipro-Col-Lips emerges as a promising therapeutic strategy for treating PA biofilm-associated lung infections.

Phase 1 Study of MK-5475, an Inhaled Soluble Guanylate Cyclase Stimulator, in Participants with Pulmonary Hypertension Associated with Chronic Obstructive Pulmonary Disease.

Purpose: This phase 1 study (NCT04370873) evaluated safety and pharmacokinetics/pharmacodynamics (PK/PD) of MK-5475 in participants with pulmonary hypertension associated with COPD (PH-COPD). Methods: Eligible participants were 40-80 years old with COPD (FEV1/FVC <0.7; FEV1 >30% predicted) and PH (mean pulmonary arterial pressure ≥25 mmHg). Participants were randomized 2:1 to MK-5475 or placebo via dry-powder inhaler once daily for 7 days in Part 1 (360 µg) or 28 days in Part 2 (380 µg). Safety was assessed by adverse events (AEs) and arterial blood oxygenation. Part-2 participants had pulmonary vascular resistance (PVR; primary PD endpoint) and pulmonary blood volume (PBV; secondary PD endpoint) measured at baseline and Day 28. A non-informative prior was used to calculate posterior probability (PP) that the between-group difference (MK-5475 - placebo) in mean percent reduction from baseline in PVR was less than -15%. Results: Nine participants were randomized in Part 1, and 14 participants in Part 2. Median age of participants (86.4% male) was 68.5 years (41-77 years); 95.5% had moderate-to-severe COPD. Incidences of AEs were comparable between MK-5475 and placebo: overall (5/14 [36%] versus 5/8 [63%]), drug-related (1/14 [7%] versus 2/8 [25%]), and serious (1/14 [7%] versus 1/8 [13%]). MK-5475 caused no meaningful changes in arterial blood oxygenation or PBV. MK-5475 versus placebo led to numerical improvements from baseline in PVR (-21.2% [95% CI: -35.4, -7.0] versus -5.4% [95% CI: -83.7, 72.9]), with between-group difference in PVR less than -15% and calculated PP of 51%. Conclusion: The favorable safety profile and numerical reductions in PVR observed support further clinical development of inhaled MK-5475 for PH-COPD treatment.

Real-Time Particle Emission Monitoring for the Non-Invasive Prediction of Lung Deposition via a Dry Powder Inhaler.

Although inhalation therapy represents a promising drug delivery route for the treatment of respiratory diseases, the real-time evaluation of lung drug deposition remains an area yet to be fully explored. To evaluate the utility of the photo reflection method (PRM) as a real-time non-invasive monitoring of pulmonary drug delivery, the relationship between particle emission signals measured by the PRM and in vitro inhalation performance was evaluated in this study. Symbicort® Turbuhaler® was used as a model dry powder inhaler. In vitro aerodynamic particle deposition was evaluated using a twin-stage liquid impinger (TSLI). Four different inhalation patterns were defined based on the slope of increased flow rate (4.9-9.8 L/s2) and peak flow rate (30 L/min and 60 L/min). The inhalation flow rate and particle emission profile were measured using an inhalation flow meter and a PRM drug release detector, respectively. The inhalation performance was characterized by output efficiency (OE, %) and stage 2 deposition of TSLI (an index of the deagglomerating efficiency, St2, %). The OE × St2 is defined as the amount delivered to the lungs. The particle emissions generated by four different inhalation patterns were completed within 0.4 s after the start of inhalation, and were observed as a sharper and larger peak under conditions of a higher flow increase rate. These were significantly correlated between the OE or OE × St2 and the photo reflection signal (p < 0.001). The particle emission signal by PRM could be a useful non-invasive real-time monitoring tool for dry powder inhalers.

Suboptimal peak inspiratory flow rate in dry-powder inhaler users for chronic obstructive pulmonary disease in Korea.

BACKGROUND: A suboptimal peak inspiratory flow rate (PIFR) in dry-powder inhaler (DPI) users can lead to insufficient therapeutic effects in the treatment of chronic obstructive pulmonary disease (COPD). However, few data on the prevalence of and factors associated with suboptimal PIFR in Korean patients with COPD are available. METHODS: We conducted a cross-sectional study of patients with COPD who had been using DPIs for more than three months. PIFR was measured using an In-Check DIAL G16 device. Suboptimal PIFR was defined as below the resistance-matched threshold. Multivariable logistic regression analysis was used to determine factors associated with suboptimal PIFR. RESULTS: Of 444 DPI users with COPD, the rate of suboptimal PIFR was 22.0 % (98/444). In a multivariable analysis, significant factors associated with suboptimal PIFR were age (adjusted odds ratio [aOR] = 1.06 by 1-year increase; 95 % confidence interval [CI] = 1.02-1.09), male sex (aOR = 0.28; 95 % CI = 0.11-0.73), body mass index (BMI) (aOR = 0.91 by 1 kg/m2 increase; 95 % CI = 0.85-0.99), post-bronchodilator forced vital capacity (FVC) %pred (aOR = 0.97 by 1%pred increase; 95 % CI = 0.95-0.99), and In-Check DIAL R2-type inhaler [medium-low resistance] use (aOR = 3.70 compared with R1-type inhalers [low resistance]; 95 % CI = 2.03-7.03). CONCLUSIONS: In Korea, more than one-fifth of DPI users with COPD had a suboptimal PIFR. The factors associated with suboptimal PIFR were age, female gender, low BMI, low FVC, and R2-type inhaler use. Therefore, clinicians should carefully evaluate the possibility of suboptimal PIFR when prescribing DPIs.

Effects of the deformation and size of the upper airway on the deposition of aerosols.

Aerosol drug delivery in the human airway is significantly affected by the morphology and size of the airway. This work developed a CFD-DEM model to simulate and analyze air flow and powder dynamics in combined inhaler-airway systems with different degrees of airway deformation (non-deformed, 50%, and 75% deformed) and sizes (adult, 0.80, and 0.62 scaled). The airways were generated based on a regular airway constructed from the MRI images through finite element method (for deformed airways) or scaling-down (for smaller airways). The airways were connected to Turbuhaler® through a connector. The results showed that under the same flow rate, the variation in the airway geometry and size had a minimum impact on the flow field and powder deposition in the device and the connector. However, deformation caused more particle deposition in the deformed region. Notably, the airway with 50% deformation had the most particles passing through the airway with the largest particle sizes due to its lower air velocity in the deformed area. Reducing airway size resulted in more powder deposition on the airway, particularly at the pharynx and mouth regions. This was because, with the same flow rate, the flow velocity in the smaller airway was higher, causing more particle-wall collisions in the mouth and pharynx regions. More importantly, the deposition efficiency in the 0.62-scaled airway was significantly higher than the other two airways, highlighting the importance of the different administration of aerosol drugs for young children.

Pharmacokinetic Models for Inhaled Fluticasone Propionate and Salmeterol Xinafoate to Quantify Batch-to-Batch Variability.

Advair Diskus is an essential treatment for asthma and chronic obstructive pulmonary disease. It is a dry powder inhaler with a combination of fluticasone propionate (FP) and salmeterol xinafoate (SX). However, the pharmacokinetics (PK) batch-to-batch variability of the reference-listed drug (RLD) hindered its generic product development. This work developed the PK models for inhaled FP and SX that could represent potential batch variability. Two batches each of the reference and the test product (R1, R2, T1, T2) of Advair Diskus (100 µg FP/50 µg SX inhalation) were administered to 60 healthy subjects in a 4-period, 4-sequence crossover study. The failure of the bioequivalence (BE) between R1 and R2 confirmed the high between-batch variability of the RLD. Non-linear mixed effect modeling was used to estimate the population mean PK parameters for each batch. For FP, a 2-compartment model with a sequential dual zero-order absorption best described the PK profile. For SX, a 2-compartment model with a first-order absorption model best fit the data. Both models were able to capture the plasma concentration, the maximum concentration, and the total exposure (AUCinf) adequately for each batch, which could be used to simulate the BE study in the future. In vitro properties were also measured for each batch, and the batch with a higher fraction of the fine particle (diameter < 1 µm, < 2 µm) had a higher AUCinf. This positive correlation for both FP and SX could potentially assist the batch selection for the PK BE study.

The carbon footprint of as-needed budesonide/formoterol in mild asthma: a post hoc analysis.

INTRODUCTION: The use of pressurised metered-dose inhalers (pMDIs) and asthma exacerbations necessitating healthcare reviews contribute substantially to the global carbon footprint of healthcare. It is possible that a reduction in carbon footprint could be achieved by switching patients with mild asthma from salbutamol pMDI reliever-based therapy to inhaled corticosteroid-formoterol dry powder inhaler (DPI) reliever therapy, as recommended by the Global Initiative for Asthma. METHODS: This post hoc analysis included all 668 adult participants in the Novel START trial, who were randomised 1:1:1 to treatment with as-needed budesonide/formoterol DPI, as-needed salbutamol pMDI or maintenance budesonide DPI plus as-needed salbutamol pMDI. The primary outcome was carbon footprint of asthma management, expressed as kilograms of carbon dioxide equivalent emissions (kgCO2e) per person-year. Secondary outcomes explored the effect of baseline symptom control and adherence (maintenance budesonide DPI arm only) on carbon footprint. RESULTS: As-needed budesonide/formoterol DPI was associated with 95.8% and 93.6% lower carbon footprint compared with as-needed salbutamol pMDI (least-squares mean 1.1 versus 26.2 kgCO2e; difference -25.0, 95% CI -29.7 to -20.4; p<0.001) and maintenance budesonide DPI plus as-needed salbutamol pMDI (least-squares mean 1.1 versus 17.3 kgCO2e; difference -16.2, 95% CI -20.9 to -11.6; p<0.001), respectively. There was no statistically significant evidence that treatment differences in carbon footprint depended on baseline symptom control or adherence in the maintenance budesonide DPI arm. CONCLUSIONS: The as-needed budesonide/formoterol DPI treatment option was associated with a markedly lower carbon footprint than as-needed salbutamol pMDI and maintenance budesonide DPI plus as-needed salbutamol pMDI.

Optimal Inhalation Profile of Pressurized Metered Dry Powder Inhaler Using a Valved Holding Chamber: A Dynamic Analysis.

Background: The combined use of a pressurized metered-dose inhaler and valved holding chamber (pMDI+VHC) is recommended to improve efficiency and safety; however, aerosol release is likely to vary with the inhalation maneuver. This in vitro study investigated the aerodynamic characteristics and aerosol release features of pMDI+VHC (Aerochamber, Trudell Medical International). Methods: The static and dynamic changes in the airway resistance (Raw) during inhalation (withdrawal) through pMDI+VHC were measured. Subsequently, the aerosol released from pMDI+VHC was measured using simplified laser photometry during withdrawal with either fast ramp-up then steady or slow ramp-up followed by gradual decrement at different intensities and times to peak flow (TPWF). Results: Raw increased linearly with changes in the withdrawal flow (WF) rate between 10 and 50 L/min. The slope was steep in the low WF range (<50 L/min) and became milder in the higher range. The aerosol mass tended to increase with an increase in the peak WF (PWF) of slow ramp-up profile. When three different WF increment slopes (TPWF: 0.4, 1.4, and 2.4 seconds) were compared, the released aerosol mass tended to decrease, and the aerosol release time was prolonged at longer TPWF. When the PWF was increased, the aerosol release time became shorter, and the withdrawn volume required for 95% aerosol release became larger; however, it did not exceed 0.4 L at suitable TPWF (0.4 seconds). Conclusion: Raw analysis suggests that inhalation at 30-50 L/min is suitable for pMDI+VHC in this setting. Rapid (TPWF, 0.4 seconds) inhalation, but not necessarily long (maximum 2.0 seconds) and deep (but larger than 0.55 L), is also recommended. Practically, direct inhalation to be weaker than usual breathing, as fast as possible, and far less than 2.0 seconds.

Developing Dry Powder Inhaler Formulations.

This section aims to provide a concise and contemporary technical perspective and reference resource covering dry powder inhaler (DPI) formulations. While DPI products are currently the leading inhaled products in terms of sales value, a number of confounding perspectives are presented to illustrate why they are considered surprisingly, and often frustratingly, poorly understood on a fundamental scientific level, and most challenging to design from first principles. At the core of this issue is the immense complexity of fine cohesive powder systems. This review emphasizes that the difficulty of successful DPI product development should not be underestimated and is best achieved with a well-coordinated team who respect the challenges and who work in parallel on device and formulation and with an appreciation of the handling environment faced by the patient. The general different DPI formulation types, which have evolved to address the challenges of aerosolizing fine cohesive drug-containing particles to create consistent and effective DPI products, are described. This section reviews the range of particle engineering processes that may produce micron-sized drug-containing particles and their subsequent assembly as either carrier-based or carrier-free compositions. The creation of such formulations is then discussed in the context of the material, bulk, interfacial and ultimately drug-delivery properties that are considered to affect formulation performance. A brief conclusion then considers the future DPI product choices, notably the issue of technology versus affordability in the evolving inhaler market.