Search Results (270)

Background/Objectives: The development of dry powder formulations for pulmonary delivery of therapeutic antibodies requires careful stabilization strategies to preserve protein integrity during spray-drying and long-term storage. This study investigates the impact of various sugar-derivatives, a polyol (D-mannitol), a disaccharide (D-sucrose) and a polysaccharide (dextran 10 kDa), used individually or in combination, on the physical stability of bovine polyclonal immunoglobulin G (pAb) in dry powders for inhalation (DPIs). Methods: A design of experiments (DoE) approach was employed to evaluate the effects of these excipients on residual moisture (RM), low-order aggregates (LOA) and high-order aggregates (HOA), immediately after spray-drying (T0) and after 10 months of storage at room temperature in a desiccator (T10). Results: All DPIs exhibited a high amorphous content and a favorable glass transition temperature, with RM decreasing over time. The combination of D-mannitol and dextran 10 kDA (DPI-MD) demonstrated the most effective stabilization, minimizing LOA and HOA formation at T0 and T10. Although the ternary mixture, including D-sucrose (DPI-MSD) exhibited higher process stability, it was less stable over time in comparison to the binary mixture. The aerodynamic performance of these carrier-free DPIs, assessed via laser diffraction (% ˂ 5 µm), were between 51 ± 3 (DPI-MD) and 67 ± 4 (DPI MSD) and a Next Generation Impactor, confirmed that formulation produced aerosol with suitable size distribution and fine particle fractions (FPFn upt to 71 ± 5% for DPI-MSD), for deep pulmonary deposition. Conclusions: These findings highlight the importance of combining excipients with complementary physical properties to achieve robust protein stabilization. The DPI-MD emerged as the most promising candidate for pAb lung delivery, balancing protein integrity, powder stability, and aerodynamic efficiency. Full article

Background/Objectives: Cannabidiol (CBD) has emerged as a potential therapeutic agent for respiratory disorders, including asthma and chronic obstructive pulmonary disease. However, its clinical translation via pulmonary delivery is limited by poor aqueous solubility, chemical instability, and low local bioavailability. This study aimed to develop and optimize a sodium stearate (NaSt)-based spray-dried dry powder inhaler (DPI) formulation to enhance the aerosol performance, dissolution, and storage stability of CBD. Methods: CBD microparticles were prepared by spray drying using NaSt as the primary excipient. The feed preparation method, spray-drying parameters, and CBD:NaSt ratios were systematically optimized. The resulting powders were evaluated for aerodynamic properties using cascade impaction, dissolution behavior in simulated lung fluid, solid-state characteristics, and accelerated stability under stress conditions. Results: The optimized formulation, SD-4, a spray-dried CBD:NaSt formulation prepared at a 20:80 weight ratio using Process B, demonstrated excellent aerosolization performance, with a fine particle fraction (FPF) exceeding 50% and a mass median aerodynamic diameter (MMAD) of 5.08 ± 0.1 μm. Dissolution testing revealed more than a three-fold increase in drug release compared with raw CBD, attributed to amorphous dispersion within the NaSt matrix and surfactant-induced micellization. Accelerated stability studies confirmed improved retention of the amorphous state and drug content, while antioxidant incorporation further reduced oxidative degradation. Conclusions: The NaSt-based spray-dried formulation significantly improved aerosol deposition efficiency, dissolution rate, and physicochemical stability of CBD. This formulation strategy may provide a promising platform for pulmonary delivery of poorly water-soluble compounds. Full article

Background: Inhaled therapy is the mainstay of asthma management, yet many patients are prescribed pressurized metered-dose inhalers (pMDIs) with valved holding chambers (VHCs) based on a presumed low inspiratory capacity, often without objective measurement. The USE-DPI study aimed to determine how many of these patients can generate sufficient peak inspiratory flow (PIF) to use a dry powder inhaler (DPI). Methods: This multicenter, observational, cross-sectional study included 346 patients with asthma treated with pMDI and VHC. PIF was measured using the In-Check Dial at two resistance settings (R2 and R4). The primary outcome was the proportion of patients achieving PIF ≥ 30 L/min. Results: Almost all patients reached the 30 L/min threshold (99.4% at R2 and 98.7% at R4). Using a higher threshold of 60 L/min (R2), 76.1% met this criterion. Lower PIF (<60 L/min) was associated with older age, reduced lung function (FEV1 ≤ 80% predicted), and poorer asthma control. No significant variables were associated with failure to reach 30 L/min. Conclusions: Most patients using pMDI with VHC can generate sufficient inspiratory flow for medium- to high-resistance DPIs. Objective PIF assessment may help guide inhaler selection, although its clinical impact requires further study. Full article

This review summarizes innovative co-formulation strategies for non-marketed dry powder inhalers (DPIs), enabling the simultaneous pulmonary delivery of multiple active pharmaceutical ingredients (APIs). Key approaches include co-amorphous systems (COAMS) and co-crystals, which combine two APIs into a single particle, improving aerodynamic properties, solubility, dissolution, and patient compliance while reducing manufacturing complexity. Core–shell microparticles, produced via spray drying, allow spatial separation and controlled release of APIs, minimizing drug–drug interactions and enabling tailored pharmacokinetics. Co-spray drying of dual APIs can yield particles with superior aerosolization and stability, though examples remain limited. Nanoparticle-based systems offer enhanced lung deposition and cellular uptake but face challenges in device compatibility, scalability, and regulatory approval. Each technology presents unique advantages and limitations regarding manufacturability, dose flexibility, and clinical translation. This review also highlights advances in in vitro toxicity testing, including air–liquid interface cultures, organoids, lung-on-chip models, and precision-cut lung slices, which are increasingly important as alternatives to animal studies. The importance of using an aerosol exposure system for the testing is highlighted. Ultimately, the choice of co-formulation platform should balance scientific innovation with practical considerations of manufacturing and regulatory requirements to maximize therapeutic benefit and commercial viability for future DPI combination products. Full article

Background/Objectives: Accurate determination of active pharmaceutical ingredient (API) particle size within dry powder inhaler (DPI) formulations is essential for ensuring effective pulmonary delivery but remains analytically challenging due to low API content and micronized particle size. Methods: In this study, scanning electron microscopy (SEM) coupled with energy-dispersive X-ray microanalysis (EDX) was used to directly identify and calculate the API particle size within several different commercial DPI products fit for purpose under regulatory constraints. The method exploits unique elemental markers inherent to each API, enabling reliable discrimination from excipients without prior sample modification or API extraction. Results: Large-area SEM–EDX mapping was used to localize API particles, followed by high-magnification imaging and confirmatory spot microanalysis. Particle sizes were manually measured for at least 50 API particles per formulation using image analysis software, and particle size distribution parameters were calculated from equivalent spherical diameters. Conclusions: The methodology was successfully applied to Spiriva^®, Anoro^® Ellipta, and Relvar^® Ellipta inhalation powders, revealing micronized APIs with distinct morphological features and verifying systematic application across products. Cross-validation against laser diffraction measurements of pure APIs demonstrated statistical equivalence, confirming the robustness and analytical utility of the proposed method for particle size assessment in DPI formulations. Full article

Inhaled Treprostinil is the primary treatment of pulmonary hypertension related to interstitial lung disease (PH-ILD). Despite treatment effectiveness in clinical trials, the real-world safety and tolerability of this therapy remains unclear. We conducted a multicenter, retrospective review of adults with PH-ILD who were prescribed inhaled treprostinil. We assessed clinical outcomes, 6 min walk distance (6MWD) and changes in natriuretic peptides (BNP, NT-proBNP), as well as medication tolerance. Eighty-three patients met the inclusion criteria. The 6MWD data was collected but a limited number of patients had results within close proximity to initiation of inhalational treprostinil with only seven patients having assessments within the 3 months prior to initiation as well as 3 months post therapy. Limited 6MWD data is likely due, in part, to coinciding with the COVID pandemic, limiting face-to-face interactions and exercise testing. The majority of our subjects, 63%, had an absolute improvement in their BNP level, over a mean duration of 170 days. However, no significant difference was detected between baseline and follow-up natriuretic peptide levels. Adherence was assessed and the majority (77%) of patients remained on therapy at the time of censoring, with three-quarters (75%) meeting the target dose. Of the 15 patients intolerant to nebulized treprostinil who were transitioned to a dry powder inhaler, the majority (87%) were able to tolerate the other formulation. The medication was well-tolerated with a large percentage of patients remaining on therapy indefinitely and reaching the targeted therapeutic dose. Full article

Background/Objectives: Reproducible evaluation of aerosol dispersibility remains a key challenge in the development of dry powder inhalers (DPIs), where small variations in particle cohesion, morphology, or device resistance can lead to large differences in aerodynamic performance. In passive DPIs, the forces required for powder fluidization and aerosolization arise from the interaction of patient inspiratory airflow with device geometry and must overcome strong interparticle cohesive forces to enable effective lung delivery. Cascade impaction is the gold standard for determining aerodynamic particle size distribution (APSD), but its low throughput and experimental burden limit its utility for systematic formulation and device screening. Prior studies have explored laser diffraction-based particle sizing under varying dispersion energies as indirect metrics of powder dispersibility. Here, we extend this approach by introducing a mathematically rigorous, distribution-based framework that applies the first-order Wasserstein distance (Earth Mover’s Distance) to quantify relative dispersibility with respect to a material-specific maximally dispersed reference state. Methods: Mannitol, trehalose, and inulin were spray-dried under matched conditions to generate model dry powders. Particle size distributions were measured by laser diffraction (Sympatec HELOS/R) using both a RODOS dry dispersion module to define a maximally dispersed reference state and an INHALER module to generate aerosols under clinically relevant dispersion conditions spanning multiple device resistances and pressure drops. For each condition, the Wasserstein-1 distance (W₁) was computed between cumulative volume-based size distributions obtained under reference and inhaler-based dispersion. Cascade impaction was used as an orthogonal method to characterize aerodynamic performance under a representative dispersion condition. Results: W₁ captured formulation-, device-, and flow-dependent differences in dispersibility that were not readily separable by visual inspection of particle size distributions alone. Crystalline mannitol exhibited the largest and most flow-rate-dependent W₁ values, whereas amorphous trehalose and polymeric inulin showed smaller W₁ values with distinct, non-monotonic pressure responses that depended on device resistance. W₁ qualitatively aligned with cascade impaction metrics, exhibiting a positive association with mass median aerodynamic diameter and an inverse association with fine particle fraction, while also demonstrating that efficient dose emission can occur despite incomplete deagglomeration. Conclusions: This study establishes the Wasserstein distance as a physically interpretable, formulation-agnostic metric for quantifying aerosol dispersibility relative to a material-specific reference state. This framework enables systematic comparison of dispersion efficiency across devices and operating conditions using standard laser diffraction data and provides a reproducible basis for mechanistic optimization of DPI formulations and inhaler designs. Full article

Background/Objectives: Carrier-based dry powder inhaler (DPI) formulations remain the predominant platform for respiratory drug delivery. However, integrated development frameworks that align upstream particle engineering with downstream manufacturing are underdeveloped. This study aimed to develop a comprehensive Quality-by-Design (QbD) strategy that systematically connects jet milling, formulation design, and blending scale-up for carrier-based DPI products containing micronized crystalline active pharmaceutical ingredient (API). Methods: Phenytoin was selected as a model API to investigate process–formulation–performance relationships. Jet milling parameters were optimized to generate three distinct API particle size distributions while monitoring solid-state integrity. A design of experiments (DoE) evaluated the impact of API particle size and lactose fines level on aerodynamic performance (fine particle fraction, FPF) and powder processability (flowability, compressibility). High-shear and low-shear blending techniques were compared, and a novel V-shell blending scale-up methodology was developed based on maintaining particle fall velocity and total strain across multiple scales (one-, two-, and eight-quart). Results: Optimized jet milling produced inhalation grade API particles with controlled amorphous content localized to high-energy processes. DoE analysis identified a design space in which API Dv90 of 2.9–4.5 µm and coarse lactose <96% maximized both aerosolization and blend flowability. Low-shear blending achieved superior lung delivery (FPF 62.6 ± 1.7%) compared with high-shear micing (50.1 ± 1.5%). The particle-velocity-based scale up strategy produced statistically equivalent FPF and ED across all scales (p < 0.01), with content uniformity (RSD ≤ 5%) and variability comparable to commercial DPIs. Conclusions: This integrated QbD framework demonstrates that the co-optimization of particle size engineering, formulation composition, and blending dynamics is essential for achieving robust and scalable DPI products. The approach offers a material-sparing, efficient pathway from API characterization through commercial scale manufacturing and is broadly applicable to respiratory drug development. Full article

Background/Objectives: Tuberculosis (TB) remains a major global health threat. Current administration methods for anti-TB drugs, including oral or intravenous, suffer from systemic side effects, low lung distribution, and poor patient compliance. Dry powder inhalers (DPIs) offer a promising alternative. This study investigates the aerodynamic performance of co-spray-dried DPIs containing rifampin or pyrazinamide and amino acids by using machine learning. Methods: Firstly, 72 formulations were prepared by varying drug-amino acid combinations, molar ratios, and spray-drying parameters. Subsequently, the aerodynamic performance of all 72 formulations was evaluated using a Next Generation Impactor, and the solid-state characterizations of optimal DPIs were carried out. Finally, four machine learning (ML) models were successfully developed and were utilized to predict the fine particle dose (FPD), FPF, MMAD, and geometric standard deviation (GSD) of DPIs based on the high-quality in-house data above. Results: Key results showed that the aerodynamic performance of DPIs was highly dependent on the specific drug-amino acid combination, with rifampin-L-lysine acetate and pyrazinamide-L-leucine formulations achieving the highest fine particle fraction (FPF, 73.37%, 87.74%) and optimal mass median aerodynamic diameter (MMAD, 2.59 µm, 1.88 µm). Notably, XGBoost (v3.1.3) exhibited the best predictive performance, with R² values ranging from 0.894 to 0.991 in the testing set for the four prediction tasks. Meanwhile, SHapley Additive exPlanations (v0.50.0) was used for model interpretability analysis. The molecular weights and LogP of the drug and amino acid were identified as two of the most important features affecting the prediction of FPD, FPF, MMAD, and GSD. Conclusions: This work demonstrates the feasibility of ML in accelerating the development of inhalable spray-dried anti-TB drugs by enabling the prediction of DPI formulations. Full article

Lower respiratory tract infections caused by Pseudomonas aeruginosa are a global concern. Patients with chronic lung diseases such as cystic fibrosis and non-cystic fibrosis bronchiectasis often do not receive adequate antibiotic delivery through conventional routes. P. aeruginosa employs several mechanisms, including biofilm formation and efflux pumps to limit the accumulation of bactericidal drug concentrations. Direct drug delivery to the lung epithelial lining fluid can increase antibiotic concentration and reduce treatment failure rates. This review discusses current research and developments in inhaled antibiotic formulations for treating P. aeruginosa infections. Recent studies on particle engineering for the dry powder inhalers of antibiotics emphasized three fundamental principles of development: micro, nano, and nano-in-microparticles. Carrier-free microparticles showed potential for high-dose delivery but suffered from poor aerosolization, which could be improved through a drug–drug combination. Amino acids in a co-spray-dried system improved powders’ aerodynamics and reduced moisture sensitivity while incorporating the chitosan/poly(lactic-co-glycolic acid) (PLGA)-modified release of the drug. Nano-in-microsystems, embedding lipid carriers, showed improved antibiofilm activity and controlled release. We also highlight emerging biologics, including antibacterial proteins/peptides, vaccines, bacteriophages, and probiotics. Research on antibiotics and biologics for inhalation suggests excellent safety profiles and encouraging efficacy for some formulations, including antimicrobial peptides and bacteriophage formulations. Further research on novel molecules and synergistic biologic combinations, supported by comprehensive animal lung safety investigations, will be required in future developments. Full article

Background/Objectives: This study developed a macitentan (MAC)–tadalafil (TAD) dry powder inhalation preparation using suspension-based spray drying to enhance pulmonary delivery and reduce systemic exposure to oral combination therapy in patients with pulmonary arterial hypertension (PAH). Methods: MAC–TAD composite powders were prepared by physically mixing or spray-drying aqueous ethanol suspensions at various MAC:TAD ratios. The lead M2-T8 was co-spray-dried with 5, 25, or 50% (w/w) L-leucine. Results: Spray-dried formulations exhibited narrower and more uniform particle size distributions (Dv50 2–6 µm; Dv90~10 µm) and higher emitted dose values than the physical mixtures. In the M2-T8 spray-dried formulation, TAD exhibited an elevated fine particle dose (FPD) (3073.45 ± 1312.30 μg), demonstrating improved aerosolization relative to the physical mixture, even outperforming the TAD-higher M1-T9 formulation (2896.83 ± 531.38 μg), suggesting that favorable interparticle adhesive interactions were developed during co-drying. The incorporation of 25% L-leucine produced the greatest improvement in dispersibility, increasing the FPD by ~31% for MAC and 17% for TAD, whereas excessive L-leucine (50%) reduced the aerosol performance. Powder X-ray diffraction and differential scanning calorimetry confirmed the retention of the MAC and TAD crystallinities, with L-leucine remaining either amorphous or partially crystalline. Conclusions: Suspension-based spray drying yielded MAC–TAD composite formulations with improved uniformity and aerosol performance. The optimized 2:8 formulation containing 25% L-leucine demonstrated the most efficient pulmonary deposition, supporting its potential as an inhaled combination therapy for the treatment of PAH. Full article

Background/Objective: Osimertinib (OSI) is a third-generation tyrosine kinase inhibitor approved for non-small cell lung cancer (NSCLC) therapy. OSI is administered orally; this route limits the amount of OSI reaching the tumor in the lungs and is associated with serious systemic toxicity. This study aimed to develop a dry powder inhalable formulation to provide tumor-targeted delivery and minimize systemic toxicity. To the best of our knowledge, this is the first study to prepare and evaluate a dry powder inhalation formulation of OSI. Methods: Chitosan-coated PLGA nanoparticles (PLGA-C NPs) encapsulating OSI were prepared using a single emulsion-solvent evaporation technique. PLGA-C NPs were assembled into respirable nanocomposite microparticles (NCMPs) via spray drying with L-leucine as a carrier. PLGA-C NPs were characterized for particle size, zeta-potential, encapsulation efficiency, and in vitro efficacy in A-549 cell line. NCMPs were evaluated for solid-state properties, aerosolization performance, stability and in vitro release. Results: PLGA-C NPs exhibited a particle size of 145.18 ± 3.0 nm, high encapsulation efficiency and a positive zeta potential. In vitro studies demonstrated a 3.6-fold reduction in IC50 compared to free OSI, superior antimigratory effects and enhanced cell cycle arrest. Solid-state characterization of NCMPs demonstrated drug encapsulation in the polymer without chemical interaction. NCMPs exhibited excellent aerosolization (mass median aerodynamic diameter of 1.09 ± 0.23 μm, fine particle fraction of 73.48 ± 8.6%) and sustained drug release (61.76 ± 3.9% at 24 h). Stability studies confirmed the physicochemical stability integrity. Conclusions: These findings suggest that this novel dry powder inhalable OSI formulation may improve therapeutic outcomes while reducing systemic toxicity. Full article

Background: Self-amplifying mRNA (sa-mRNA) represents a promising platform for vaccines and gene therapies, offering sustained protein expression at low doses through self-replication. For vaccines targeting respiratory pathogens, pulmonary delivery of sa-mRNA lipid nanoparticles (LNPs) is particularly advantageous, enabling direct delivery to the infection site and induction of mucosal immunity. Objective: In this study, we evaluated the stability of sa-mRNA–LNPs under refrigerated and frozen conditions and developed a dry powder formulation suitable for inhalation, produced by freeze-drying followed by cryomilling with leucine. Methods: sa-mRNA–LNPs formulated in HEPES buffer with 20% (w/v) sucrose were stored for up to 8 weeks as liquid or freeze-dried samples at various temperatures (−80 °C, −20 °C, 4 °C, and 20 °C). Biological stability was assessed by transfection efficiency in HeLa cells, while physical stability was characterized by encapsulation efficiency, zeta potential, particle size, and polydispersity index. Results: Liquid formulations remained stable for at least 8 weeks at −80 °C and −20 °C but rapidly lost stability at 4 °C and 20 °C. Freeze-drying effectively preserved sa-mRNA–LNP functionality and structural integrity for up to 8 weeks at 4 °C, with only minor structural changes. Subsequent cryomilling in the presence of 4 wt-% leucine produced a respirable dry powder while retaining approximately 60% of the original sa-mRNA–LNP functionality. Although cryomilling induced some structural alterations, the remaining functional fraction remained stable during storage. The resulting powders displayed favorable aerosol performance for deep lung delivery, as demonstrated by cascade impaction (MMAD = 4.13 ± 0.26 µm). Conclusions: In conclusion, freeze-drying effectively preserved sa-mRNA–LNP integrity at 4 °C, whereas cryomilling with leucine produced a respirable dry powder suitable for pulmonary delivery, providing a foundation for globally accessible, needle-free sa-mRNA vaccines against respiratory diseases. Full article

In this article, a systematic review and analysis of the present literature is conducted, regarding the excipients present in dry powder inhaler formulations. Until now, there has been no list of excipients recorded, specifically for DPIs, with the number of approved excipients for pulmonary delivery being restricted, despite their choice as a pivotal step for the formulating process. Understanding the DPI formulations, physicochemical characteristics, efficiency, and release profiles, demonstrated in detail here, could contribute to their application in future studies and be a useful research tool in the choice of excipients in the field of inhalation technology and specifically DPIs. Full article

Pulmonary drug delivery represents a promising approach in the treatment of respiratory diseases, allowing for passive targeting and enhanced drug efficacy. Background/Objectives: The aim of the present study was to develop inhalable dry powders from lyophilized sildenafil citrate (SC)-loaded liposomes made from phosphatidylcholine and either cholesterol (CH) or resveratrol (RSV). Methods: Liposomes were prepared via a pH gradient method to increase drug entrapment efficiency and drug loading, and then the liposomes were lyophilized using different proportions of ethanol, mannitol, and lactose as excipients. The resulting dry cakes were converted into powders and evaluated for aerodynamic performance using a custom-designed air-blowing device. Notably, this is the first time that resveratrol has been used as a substitute for cholesterol in SC-loaded liposomes. Results: Our results demonstrate that RSV is a suitable liposome bilayer component and improves drug loading. Our findings prove that lyophilized cakes containing liposomes produce a dry powder that is suitable for aerosolization with potential application to pulmonary delivery of sildenafil citrate. The results suggest that RSV represents a potential alternative to traditional cholesterol-based liposomal formulations. Conclusions: This work presents a novel strategy for the pulmonary delivery of sildenafil, using biocompatible and FDA-approved mannitol and lactose for this administration route. Full article