Pulmonary Drug Delivery Research Articles

Pirfenidone microcrystals for pulmonary delivery: Regulation of the precipitation behavior in the supercooled droplet.

Pirfenidone (PFD) is one of the first-line drugs for treating idiopathic pulmonary fibrosis, while directly delivering PFD to lung showed better efficiency. However, PFD is a non-glass former and easily precipitates into larger-sized crystals that are undesirable for pulmonary delivery. Hence, the fabrication of PFD particles with pulmonary delivery efficiency remains challenging. Herein, a series of particles were prepared by spray freeze drying a PFD and leucine mixed solution. The sub-ambient behavior of the mixed solution was evaluated via a differential scanning calorimeter. The effects of the PFD/leucine mass ratio and freezing temperature on the particle morphology, size, crystal polymorphism, molecular structure and in vitro aerosol performance were investigated. Shortening the lifetime of the droplet and adding proper amounts of leucine are the keys to decreasing the PFD crystal size and improving its dispersity. The optimal sample is SF-80D-P95L5-2, with high FPF and eFPF values of∼65.97% and∼27.86%, and owing to its high drug loading (95%), the FPD and eFPD are extremely high at∼6.27mg and∼2.65mg, respectively, equivalent to∼6.27mg and∼2.65mg PFD deposited in the lungs and alveoli, respectively, when 10mg dry powder is inhaled. This work provides a potential strategy for tuning the precipitation behavior of PFD microcrystals with high pulmonary drug delivery efficiency.

Evaporation Dynamics and Dosimetry Methods in Numerically Assessing MDI Performance in Pulmonary Drug Delivery

Evaporation Dynamics and Dosimetry Methods in Numerically Assessing MDI Performance in Pulmonary Drug Delivery

Aerosol Fluorescent Labeling via Probe Molecule Volatilization.

The physicochemical properties of aerosols, including hygroscopicity, phase state, pH, and viscosity, influence important processes ranging from virus transmission and pulmonary drug delivery to atmospheric light scattering and chemical reactivity. Despite their importance, measurements of these key properties in aerosols remain experimentally challenging due to small particle sizes and low mass densities in air. Fluorescence probe spectroscopy is one of the only analytical techniques that is capable of experimentally determining these properties in situ in a nondestructive and minimally perturbative manner. However, the application of fluorescence probe spectroscopy to important classes of aerosols including exhaled respiratory and ambient atmospheric aerosols has been limited due to a typical reliance on premixing the probe molecule with particle constituents prior to particle generation, which is not always possible. Here, a method for aerosol fluorescent labeling based on probe molecule volatilization is developed. The method is first applied to label model polyethylene glycol (PEG) aerosols with two different polarity-sensitive probes, Nile red and Prodan. The similarity of the relative humidity-dependent fluorescent emission of each probe between prelabeled and volatilized-probe PEG particles validated the methodology. A preliminary application of the technique to indicate the hygroscopicity of artificial saliva respiratory particles and model atmospheric secondary organic aerosol particles is demonstrated. The methodology developed here paves the way for future studies applying powerful fluorescent probe-based analytical techniques to study exhaled or natural aerosols for which fluorescent prelabeling is not possible.

Biopolymeric Inhalable Dry Powders for Pulmonary Drug Delivery

Natural and synthetic biopolymers are gaining popularity in the development of inhaled drug formulations. Their highly tunable properties and ability to sustain drug release allow for the incorporation of attributes not achieved in dry powder inhaler formulations composed only of micronized drugs, standard excipients, and/or carriers. There are multiple physiological barriers to the penetration of inhaled drugs to the epithelial surface, such as the periciliary layer mucus mesh, pulmonary macrophages, and inflammation and mucus compositional changes resulting from respiratory diseases. Biopolymers may facilitate transport to the epithelial surface despite such barriers. A variety of categories of biopolymers have been assessed for their potential in inhaled drug formulations throughout the research literature, ranging from natural biopolymers (e.g., chitosan, alginate, hyaluronic acid) to those synthesized in a laboratory setting (e.g., polycaprolactone, poly(lactic-co-glycolic acid)) with varying structures and compositions. To date, no biopolymers have been approved as a commercial dry powder inhaler product. However, advances may be possible in the treatment of respiratory diseases and infections upon further investigation and evaluation. Herein, this review will provide a thorough foundation of reported research utilizing biopolymers in dry powder inhaler formulations. Furthermore, insight and considerations for the future development of dry powder formulations will be proposed.

Cell Membrane Hybrid Liposome-Targeted Delivery of the Heat Shock Protein 90 C-Terminal Inhibitor for the Treatment of Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) represents a grave challenge as it is characterized by high fatality rates and irreversible progression without effective clinical interventions available at present. Previous studies have demonstrated that inhibition of heat shock protein 90 (HSP90) by an N-terminal inhibitor disrupts its interaction with TGFβRII, leading to the instability of TGFβRII, thus blocking the role of transforming growth factor-β1 (TGF-β1), which could potentially ameliorate IPF symptoms. However, given that the broad spectrum of HSP90 N-terminal inhibitors may lead to unanticipated side effects, we hypothesize that C-terminal inhibitors of HSP90 can interfere with TGFβRII while minimizing adverse reactions. In this study, silybin, a C-terminal inhibitor of HSP90, was separated into monomers, and silybin A was screened for its superior efficacy against TGFβRII. To facilitate targeted therapy for treating IPF, a cell membrane hybrid liposome loaded with silybin A (Cm-A-Lip) was developed to deliver silybin A to lung fibroblasts through pulmonary drug delivery. A bleomycin-induced IPF mouse model was used to evaluate the efficacy of Cm-A-Lip. By examination of lung hydroxyproline content, wet weight, histology, and inflammatory factor expression, the results showed that pulmonary delivery of Cm-A-Lip could increase the drug retention time in lung tissue compared with intravenous injection. Furthermore, Cm-A-Lip exhibited superior antifibrotic activity relative to conventional liposmomes loaded with silybin A (A-Lip) while concurrently mitigating systemic inflammatory responses associated with silybin A administration, thus enhancing the overall safety profile.

Advances in Aerogels Formulations for Pulmonary Targeted Delivery of Therapeutic Agents: Safety, Efficacy and Regulatory Aspects.

Aerogels are the 3D network of organic, inorganic, composite, layered, or hybrid-type materials that are used to increase the solubility of Class 1 (low solubility and high permeability) and Class 4 (poor solubility and low permeability) molecules. This approach improves systemic drug absorption due to the alveoli's broad surface area, thin epithelial layer, and high vascularization. Local therapies are more effective and have fewer side effects than systemic distribution because inhalation treatment targets the specific location and raises drug concentration in the lungs. The present manuscript aims to explore various aspects of aerogel formulations for pulmonary targeted delivery of active pharmaceutical agents. The manuscript also discusses the safety, efficacy, and regulatory aspects of aerogel formulations. According to projections, the global respiratory drug market is growing 4-6% annually, with short-term development potential. The proliferation of literature on pulmonary medicine delivery, especially in recent years, shows increased interest. Aerogels come in various technologies and compositions, but any aerogel used in a biological system must be constructed of a material that is biocompatible and, ideally, biodegradable. Aerogels are made via "supercritical processing". After many liquid phase iterations using organic solvents, supercritical extraction, and drying are performed. Moreover, the sol-gel polymerization process makes inorganic aerogels from TMOS or TEOS, the less hazardous silane. The resulting aerogels were shown to be mostly loaded with pharmaceutically active chemicals, such as furosemide-sodium, penbutolol-hemisulfate, and methylprednisolone. For biotechnology, pharmaceutical sciences, biosensors, and diagnostics, these aerogels have mostly been researched. Although aerogels are made of many different materials and methods, any aerogel utilized in a biological system needs to be made of a substance that is both biocompatible and, preferably, biodegradable. In conclusion, aerogel-based pulmonary drug delivery systems can be used in biomedicine and non-biomedicine applications for improved sustainability, mechanical properties, biodegradability, and biocompatibility. This covers scaffolds, aerogels, and nanoparticles. Furthermore, biopolymers have been described, including cellulose nanocrystals (CNC) and MXenes. A safety regulatory database is necessary to offer direction on the commercialization potential of aerogelbased formulations. After that, enormous efforts are discovered to be performed to synthesize an effective aerogel, particularly to shorten the drying period, which ultimately modifies the efficacy. As a result, there is an urgent need to enhance the performance going forward.

Rosalind Franklin Society Proudly Announces the 2023 Award Recipient for Journal of Aerosol Medicine and Pulmonary Drug Delivery.

Rosalind Franklin Society Proudly Announces the 2023 Award Recipient for Journal of Aerosol Medicine and Pulmonary Drug Delivery.

Preparations, Applications, Patents, and Marketed Formulations of Nanoemulsions - A Comprehensive Review.

Nanoemulsions have emerged as versatile colloidal dispersions with promising applications in various fields, including pharmaceuticals, food, and cosmetics. These nano-sized emulsions, stabilized by surfactants, offer unique advantages such as enhanced ingredient penetration efficacy and versatile dosage forms. This article provides an extensive overview of nanoemulsions, covering their composition, methods of preparation, and applications in drug delivery, the food industry, and cosmetics. Various high-energy and low-energy methods for nanoemulsion preparation are discussed, along with their advantages and limitations. Additionally, the article highlights the potential of nanoemulsions in improving drug bioavailability, stability, and therapeutic efficacy, especially in oral, topical, parenteral, intranasal, ocular, and pulmonary drug delivery. Furthermore, nanoemulsions are explored as carriers for encapsulating flavoring agents, nutraceuticals, and natural preservatives in the food industry, as well as their use in cosmetic formulations. Current clinical trials involving nanoemulsions and recent patents in the field are also summarized, providing insights into ongoing research and development efforts. Lastly, a selection of marketed nanoemulsion formulations is presented, showcasing their practical applications and commercial availability. Overall, nanoemulsions hold great promise as effective delivery systems with broad applications across various industries.

Evaluating drug distribution in rat lung by mass spectrometry imaging after dry powder insufflation: Comparison of jet-milling, spray-drying, and thin film freezing

Uniform drug distribution within lungs is crucial for effective treatment of lung diseases when delivered via the pulmonary route. Imaging techniques such as gamma scintigraphy, positron emission tomography, and single-photon emission computed tomography, and others, have limitations, including the need for tagging, product reformulation, and in vitro validation. Mass Spectrometry Imaging (MSI) overcomes these drawbacks by visualizing drug distribution within lungs without tagging. In this study, voriconazole dry powder formulations for inhalation were prepared by three different methods: jet-milling, spray-drying, and thin film freezing (TFF). MSI was used to differentiate voriconazole distribution in rat lung after dry powder insufflation. The TFF-processed voriconazole powder, consisting of brittle, easily shearable nanoaggregates, exhibited the most homogeneous distribution in lung tissue, with the lowest airway-to-lung voriconazole deposition ratio (1.27), followed by spray-dried (1.76) and jet-milled (2.73). This enhanced distribution is attributed to the smaller particle size after disaggregation and rapid movements on the liquid surface. The results suggest that TFF dry powders for inhalation can enhance treatment efficiency and reduce toxicity for lung diseases, further supporting TFF as a promising method to formulate powder for pulmonary drug delivery.

The Role of Pulmonary Drug Delivery in Modern Therapeutics: An Overview.

The pulmonary drug delivery system is a promising and evolving technology in which the prescribed medicine is breathed through the lungs, and subsequently, it enters the circulation via the alveolar epithelium. This category of pulmonary drug delivery system is an appealing and non-invasive administration method. Pulmonary drug delivery is most commonly utilized to treat airway problems by providing locally active medicines directly to their site of action. The dose required to have a pharmacological effect is reduced when medicines are delivered directly to their site of action. In addition to locally acting medications, the pulmonary route can be utilized to deliver compounds with systemic effects, such as in the case of insulin inhalation therapy for systemic absorption. Particle size, bioavailability, device compatibility, and other aspects must be addressed, including the formulation of drugs into an acceptable dosage for inhalation with sufficient stability. This formulation must also be used in conjunction with a suitable inhaler device that produces an aerosol with a particle or droplet size that assures deposition in the required targeted area of the pulmonary system. Recent advancements in pulmonary drug delivery include the development of targeted nanoparticles and inhalable biologics, which enhance drug absorption and efficacy while minimizing systemic side effects. Future directions focus on personalized medicine approaches and advanced inhalation technologies, although limitations such as variable patient adherence and the need for precise dosing continue to pose challenges.

Development of a Formulation and In Vitro Evaluation of a Pulmonary Drug Delivery System for a Novel Janus Kinase (JAK) Inhibitor, CPL409116.

The pursuit of targeted therapies for cytokine-dependent diseases has led to the discovery of Janus kinase (JAK) inhibitors, a promising class of drugs. Among them, CPL409116, a selective dual JAK and rho-associated protein kinase inhibitor (ROCK), has demonstrated potential for treating conditions such as pulmonary fibrosis exacerbated by the COVID-19 pandemic. This study investigated the feasibility of delivering CPL409116 via inhalation, with the aim of minimizing the systemic adverse effects associated with oral administration. Two micronization methods, jet milling and spray drying, were assessed for CPL409116, with spray drying chosen for its ability to produce an amorphous form of the compound. Moreover, parameters such as the mixing energy, drug load, and force control agent significantly influenced the fine particle fraction (FPF), a critical parameter for pulmonary drug delivery. This study provides insights into optimizing the formulation parameters to enhance the delivery efficiency of CPL409116 to the lungs, offering potential for improved therapeutic outcomes in cytokine-dependent pulmonary diseases.

Progress in Utilizing Chitosan-Based Nanoparticles for Pulmonary Drug Administration

The escalating prevalence of respiratory ailments poses a significant global public health challenge, ranking among the primary causes of mortality worldwide. Notably, diseases such as asthma, chronic obstructive pulmonary disease, pneumonia, cystic fibrosis, and lung cancer, alongside the emergence of respiratory diseases, notably those induced by the coronavirus family, have contributed substantially to global fatalities in the past two decades. Consequently, numerous studies have been undertaken to enhance the effectiveness of therapeutic interventions against these diseases, with a particular emphasis on nanomedicine-driven pulmonary drug delivery. As a result, the development of nanocarriers has emerged as a promising avenue to surmount the constraints associated with traditional therapies, aiming to elevate drug bioavailability at the intended site while minimizing undesired side effects. Within this domain, nanoparticles fashioned from chitosan (CS) exhibit distinct advantages over alternative nanocarriers owing to the inherent biological properties of chitosan, including its anti-inflammatory, antimicrobial, and mucoadhesive attributes. Furthermore, CS nanoparticles have demonstrated the potential to augment drug stability, extend the duration of action, refine drug targeting, regulate drug release kinetics, optimize the dissolution of poorly soluble drugs, and enhance the cell membrane permeability of hydrophobic drugs. These unique properties position CS nanoparticles as a promising candidate for optimizing drug performance following pulmonary administration. Consequently, this review endeavors to elucidate the potential of chitosan nanoparticles in the realm of pulmonary drug delivery, shedding light on how their intrinsic biological characteristics can ameliorate the treatment landscape of pulmonary diseases. Emphasis is placed on delineating the synergistic interplay between chitosan nanoparticles and the encapsulated drug, thereby offering insights into the prospective advancements in treating respiratory ailments.

Cross-Linked Thiolated Hydroxypropil-β-Cyclodextrin for Pulmonary Drug Delivery.

The effectiveness of cross-linked HP-β-CD-SH nanoparticles (HP-β-CD-SH-NP) was compared to transient nanoaggregates in enhancing the activity of dexamethasone (DMS) and olive leaf extracts (OLE). DMS, a poorly soluble drug commonly used in lung treatments, and OLE, known for its antioxidant properties, were chosen. Drug-loaded HP-β-CD-SH-NP were prepared and nebulized onto a lung epithelial Air-Liquid Interface (ALI) model, assessing drug permeation and activity. HP-β-CD-SH with 25% thiolation was synthesized via microwave reaction, forming 150 nm nanoaggregates and stabilized 400 nm HP-β-CD-SH-NP. All carriers showed good complexing ability with DMS and OLE and were biocompatible in the lung ALI model. HP-β-CD-SH promoted DMS absorption, while stabilized HP-β-CD-SH-NP protected against oxidative stress. HP-β-CD-SH is promising for lung delivery, especially as stabilized nanoaggregates, offering versatile administration for labile molecules like natural extracts.

Multiscale Modeling of Respiratory Transport Phenomena and Intersubject Variability

Our understanding of respiratory flow phenomena has been consolidated over decades with the exploration of in vitro and in silico canonical models that underscore the multiscale fluid mechanics spanning the vast airway complex. In recent years, there has been growing recognition of the significant intersubject variability characterizing the human lung morphometry that modulates underlying canonical flows across subjects. Despite outstanding challenges in modeling and validation approaches, exemplified foremost in capturing chronic respiratory diseases, the field is swiftly moving toward hybrid in silico whole-lung simulations that combine various model classes to resolve airflow and aerosol transport spanning the entire respiratory tract over cumulative breathing cycles. In the years to come, the prospect of accessible, community-curated datasets, in conjunction with the use of machine learning tools, could pave the way for in silico population-based studies to uncover unrecognized trends at the population level and deliver new respiratory diagnostic and pulmonary drug delivery endpoints.

Imaging Identifies Superior Inflammation Targeting of M1 Macrophages for Cryo-Shocked Cell Pulmonary Drug Delivery to Treat Acute Lung Injury.

In the realm of combating acute lung injury (ALI) induced by a myriad of triggers including sepsis, pneumonia, aspiration, trauma, and pancreatitis, macrophages emerge as crucial players. However, traditional treatments such as systemic administration of glucocorticoids come with the baggage of severe side effects, curtailing their utility. Enter an innovative solution: a biomimetic drug delivery system fashioned from cryo-shocked macrophages, tailored for pulmonary drug delivery. Positron emission tomography (PET) imaging has shed light on the remarkable targeting abilities of live M1 macrophages, showcasing their unparalleled efficacy in homing in on local inflammatory foci when contrasted with naive, M1, and M2 macrophages. Building upon this foundation, liquid nitrogen-treated (LNT) M1 macrophages are developed, engineered to preserve their inflammation-targeting prowess while sidestepping the release of pro-inflammatory cytokines. This breakthrough allows for the delivery of glucocorticoids directly to inflamed lung tissues, efficiently quelling inflammation and mitigating pulmonary edema while drastically reducing systemic drug exposure. Inspired by the effectiveness of live M1 macrophages, the potential of glucocorticoid-loaded LNT M1 macrophages are harnessed, utilizing them as a stealthy "Trojan horse" in the battle against pneumonia-induced ALI. This innovative approach holds promise as a safe and potent treatment avenue for acute lung injury.

Nano-Medicine for Treatment of Tuberculosis, Promising Approaches Against Antimicrobial Resistance.

Even though the number of effective anti-tuberculosis or anti-mycobacterial agents is increasing, a large number of patients experience severe side effects as a result of these drugs. This hurts the patients' well-being and quality of life. Tumor cells that survive treatment modalities can become chemotherapy resistant at the molecular level. Furthermore, negative effects on normal cells occur concurrently. Strategies that minimize the negative effects on normal cells while efficiently targeting infected cells are required. Nanotherapies, according to recent research, may be one option in this direction. The present study differs from previously published review studies as it concentrates on examining the most recently developed nanoparticles for anti-mycobacterial purposes. Such novel approaches have the potential to reduce harmful side effects and improve patients' health prognoses.Current paper provides a comprehensive analysis of recent advances in nanotherapy systems for the pulmonary delivery of anti-tuberculous drugs. In addition, to low-priced and convenient alternatives for pulmonary delivery, different types of NPs for oral and topical application were also deliberated and summarized in this review.

Inhalable drug-loaded silk fibroin carriers for pulmonary drug delivery.

The design and development of engineered micro and nano-carriers offering superior therapeutic performance compared to traditional delivery forms, are crucial in pharmaceutical research. Aerosolization and inhalation of carriers with improved solubility/stability of insoluble drugs, has huge potential for targeted drug delivery (DD) in various pulmonary diseases. Indeed, dedicated carriers must meet specific dimensional rules for proper lung delivery. Particles between 2-10 μm in size are normally deposited in the tracheobronchial region, while particles of 0.5-2 μm may be properly deposited in the alveoli. In this work, we report the development of inhalable nanostructured carries made of a 'green' bio-inspired polymer from aqueous solutions, i.e. silk fibroin (SF), efficiently loaded with a hydrophobic drug, i.e. the thyroid hormone levothyroxine (L-T4), a drug for the treatment of idiopathic pulmonary fibrosis. The aim is to optimize a standard method for the synthesis of SF-based nanocarriers with controlled size and shape, where a fine control of their geometrical properties is aimed at efficiently controlling the pulmonary DD. L-T4 loaded SF particles were synthesized through a one-pot co-precipitation method. Optimized systems were determined by varying the chemo-physical parameters during the synthesis. Ethylenediaminetetraacetic acid (EDTA) was used to remove CaCO3 cores. The proposed synthesis routes have led to two SF structures, whose structural heterogeneity and nanostructured morphology have been demonstrated using fluorescence microscopy, DLS, SEM and EDX. Two systems with varying shape and size have been obtained: (i) a flat disk-like SF structure with an irregular surface and an in-plane length of about 1-2 μm; (ii) solid SF nanospheres, obtained using ethylene glycol as additive, showing two size populations (main diameters of 0.5 μm and 1.7 μm). Solid nanospherical systems, in particular, show a tendency to arrange into agglomerates that, when loosely bound into smaller particles, can facilitate the delivery at the alveoli. Both formulations exhibited similar drug loading efficiencies, evaluated by HPLC analysis. However, SF nanospheres showed greater in vitro drug release after 24 hours. The demonstrated control over the characteristics imparted to the proposed DD systems may be critical to select the most suitable size/shape to achieve high rates of delivery to the appropriate lung compartment.

Anticancer drug delivery: Investigating the impacts of viscosity on lipid-based formulations for pulmonary targeting

Pulmonary drug delivery via aerosolization is a non-intrusive method for achieving localized and systemic effects. The aim of this study was to establish the impact of viscosity as a novel aspect (i.e., low, medium and high) using various lipid-based formulations (including liposomes (F1-F3), transfersomes (F4-F6), micelles (F7-F9) and nanostructured lipid carriers (NLCs; F10-F12)) as well as to investigate their impact on in-vitro nebulization performance using Trans-resveratrol (TRES) as a model anticancer drug. Based on the physicochemical properties, micelles (F7-F9) elicited the smallest particle size (12–174 nm); additionally, all formulations tested exhibited high entrapment efficiency (>89 %). Through measurement using capillary viscometers, NLC formulations exhibited the highest viscosity (3.35–10.04 m2/sec). Upon using a rotational rheometer, formulations exhibited shear-thinning (non-Newtonian) behaviour. Air jet and vibrating mesh nebulizers were subsequently employed to assess nebulization performance using an in-vitro model. Higher viscosity formulations elicited a prolonged nebulization time. The vibrating mesh nebulizer exhibited significantly higher emitted dose (ED), fine particle fraction (FPF) and fine particle dose (FPD) (up to 97 %, 90 % and 64 µg). Moreover, the in-vitro release of TRES was higher at pH 5, demonstrating an alignment of the release profile with the Korsmeyer-Peppas model. Thus, formulations with higher viscosity paired with a vibrating mesh nebulizer were an ideal combination for delivering and targeting peripheral lungs.

Immobilised artificial membrane liquid chromatography vs liposome electrokinetic capillary chromatography: Suitability in drug/bio membrane partitioning studies and effectiveness in the assessment of the passage of drugs through the respiratory mucosa

This study pioneers a comparison of the application of biomimetic techniques, immobilised artificial membrane liquid chromatography (IAM LC) and liposome electrokinetic capillary chromatography (LEKC), for the prediction of pulmonary drug permeability. The pulmonary absorption profiles of 26 structurally unrelated drug-like molecules were evaluated using their IAM hydrophobicity index (CHI IAM) measured in IAM LC, and the logarithm of distribution constants (log KLEKC) derived from the LEKC experiments. Lipophilicity (phospholipids) parameters obtained from IAM LC and most LEKC analyses were linearly related to the n-octanol/water partitioning coefficients of the neutral forms (i.e., log Po/w values) to a moderate extent. However, the relationship with distribution coefficients at the experimental pH (7.4) (i.e., log D7.4) were weaker overall for IAM LC data and sigmoidal for some liposome compositions (phosphatidyl choline (PC): phosphatidyl inositol (PI) 85:15 mol% and 90:10 mol%) and concentrations (4 mM) in LEKC. This suggests that phospholipid partitioning supports both hydrophobic and electrostatic interactions occurring between ionised drugs and charged phospholipid moieties. The latter interactions are original when compared to those taking place in the more established n-octanol/water partitioning systems.A stronger correlation (R2 > 0.65) was identified between the LEKC retention parameters, and the experimental apparent lung permeability (i.e., log Papp values) as opposed to the values obtained by IAM LC. Therefore, LEKC offers unprecedented advantages over IAM LC in simulating cell membrane partitioning processes in the pulmonary delivery of drugs. Although LEKC has the advantage of more effectively simulating the electrostatic and hydrophobic forces in drug/pulmonary membrane interactions in vitro, the technique is unsuitable for analysing highly hydrophilic neutral or anionic compounds at the experimental pH. Conversely, IAM LC is useful for analysing compounds spanning a wider range of lipophilicity. Its simpler and more robust implementation, and propensity for high-throughput automation make it a favourable choice for researchers in drug development and pharmacological studies.

Effect of airway wall motion on particle deposition and delivery in the neonatal trachea

Modeling pulmonary drug delivery in the airway using computational fluid dynamics (CFD) simulations tracks drug particles throughout the airway, providing valuable information on the deposition location of inhaled drugs. However, most studies simulate particle transport within static airway models that do not incorporate physiological airway motion; this choice limits accuracy since airway motion directly affects particle transport and deposition, notably in newborns with airway abnormalities such as tracheomalacia. The objective of this study is to determine the effect of airway motion on drug delivery in neonates with and without airway disease. For this study, two control subjects without any airway disease and three subjects with tracheomalacia (dynamic tracheal narrowing) were enrolled. Each subject was imaged at approximately 40-weeks post-menstrual age using magnetic resonance imaging (MRI). MRI data were retrospectively reconstructed to obtain static airway images gated to different time points of the breath (i.e., end expiration and end inspiration) and an image representing combined data from all timepoints (ungated). Virtual airway surfaces (pharynx to main bronchi) were made from each MR image. A moving airway surface was created from surface registration of these surfaces and used as the boundary for a CFD simulation of one inhalation, along with subject-specific inspiratory flow waveforms. To assess the effect of airway wall motion on particle deposition, static-walled simulations, based on the airway surfaces at end inspiration, end expiration, and the ungated airway surface, were also performed using the same flow boundary conditions. Particle transport (particles diameter range 0.5–15 μm) was compared between the simulations during the inhalation. Airway surface motion affected particle transport into the small airways by 65% on average (0.5–5 μm– 22%, 5-15 μm– 86%) compared to static-walled simulations, while comparison between static end expiration and other static-walled simulations using geometries acquired during different phases of breathing differed by more than 500% on average (0.5–5 μm– 45%, 5-15 μm– 741%). For particle deposition, airway surface motion affected by 43% on average (0.5–5 μm– 86%, 5-15 μm– 21%) compared to static-walled simulations and comparison between static end expiration and other static-walled simulations differed by 47% on average (0.5–5 μm– 58%, 5-15 μm– 41%). Differences between dynamic and static deposition results and between static simulations from different timepoints occurred in patients with and without airway disease. This study suggests the importance of using airway wall motion in CFD simulations to model aerosolized drug delivery in the airway. If a CFD simulation is limited to only a static airway image without physiological motion, particle deposition mapping may yield markedly inaccurate results, potentially resulting in higher or lower drug dosing than intended.