Journal of Aerosol Medicine and Pulmonary Drug Delivery最新文献

Objective: This study aimed to compare the pharmacokinetics and tissue distribution of aerosolized pegylated interferon α-2b (PEG IFNα-2b) with standard interferon α-2b (IFNα-2b) in an animal model, paving the way for further investigation into their pharmacodynamics. Methods: Fifty-six Sprague Dawley rats were divided into 14 groups receiving either PEG IFNα-2b or standard IFNα-2b via aerosolized inhalation into the lower respiratory tract. Each group received a single dose of consistent concentration and volume. Pharmacokinetic parameters such as C_max, T_max, t_1/2, AUC_(0-t), and MRT_(0-t) were evaluated through blood samples and tissue dissection at specified time intervals post-administration. Results: Analysis revealed significantly higher AUC_(0-t) and MRT_(0-t) in the lungs, trachea, and bronchi of the PEG IFNα-2b group compared to the standard IFNα-2b group (p < 0.05), with minimal systemic exposure. Conclusion: Aerosolized PEG IFNα-2b demonstrated increased drug exposure and retention in the lower respiratory tract compared to standard IFNα-2b, suggesting potential therapeutic advantages such as reduced dosing frequency. Further studies are warranted to explore enhanced clinical outcomes.

Background: Drug resistant tuberculosis is a major public health concern, since the causative agent Mycobacterium tuberculosis is resistant to the most effective drugs against tuberculosis treatment ie., rifampicin and isoniazid. Globally, it accounts 4.6 percent of the patients with tuberculosis, but in some low socioeconomic areas this proportion exceeds to 25 percent. The treatment of drug resistant tuberculosis is prolonged (9-12 months) and often have less favorable outcome with novel as well as recently repurposed drugs administered by conventional routes. Materials and Methods: Clinically, these repurposed drugs have shown several major concerns including low penetration of the drugs to the pulmonary region, emergence of resistant forms, first pass effects, drug-drug interactions, food effects, and serious side effects upon administration by conventional route of administration. Although, several antimicrobial agents have been either approved or are under investigation at different stages of clinical trials and in pre-clinical studies via inhalation route for the treatment of respiratory infections, inhalable formulation for the treatment of drug resistant tuberculosis is most untouched aspect of drug delivery to validate clinically. Only a single dry powder inhalation formulation of capreomycin is able to reach the milestone, ie., phase I for the treatment of drug resistant tuberculosis. Results: Administering inhalable formulations of repurposed drugs as adjuvant in the treatment of drug resistant tuberculosis could mitigate several concerns by targeting drugs directly in the vicinity of bacilli. Conclusion: This review focuses on the limitations and major concerns observed during clinical trials of repurposed drugs (host directed or bactericidal drugs) administered conventionally for the treatment of drug resistant tuberculosis. The outcomes and the concerns of these clinical trials rationalized the need of repurposing formulation which could be administered by inhalation route as adjunctive treatment of drug resistant tuberculosis.

Background: This study advanced the preclinical development of a new dry powder aerosol synthetic lung surfactant (SLS) product for neonatal respiratory distress syndrome (RDS) by integrating a multiple-actuation device and scalable spray-dried formulation, evaluating physicochemical and in vitro aerosol performance, and then comparing biological efficacy with the current clinical standard of high-volume liquid bolus instillation. Methods: A new high-dose air-jet dry powder inhaler was developed that was characterized by a variable-volume aerosolization chamber (D3 device) with the goal of unifying aerosol quality and emitted dose (ED) over multiple actuations. The SLS excipient enhanced growth dry powder formulation was advanced through production on a scalable nozzle-based spray dryer system (Mini Spray Dryer; MSD2 formulation). Physicochemical characterization of the formulation was performed along with in vitro aerosol testing of the new D3-MSD2 device and formulation combination. The optimized D3-MSD2 aerosol therapy was then evaluated in a rabbit model of severe RDS. Results: The new D3-MSD2 combination produced a small-particle aerosol with high fine particle fraction (FPF_{<5 µm} = 87.9%; FPF_{<2.5 µm} = 61.6%) and percent ED (77.4% of loaded). Additional in vitro testing highlighted consistent particle size (D_v50 = 1.6 µm) and ED across multiple actuations. In the animal model experiments, a total device-loaded formulation mass of 60 mg (delivered as 2x30 mg) produced a total phospholipid (PL) dose of 24 mg-PL/kg and a device ED of 18 mg-PL/kg compared with the 200 mg-PL/kg clinical dose of Curosurf liquid. In vivo response rate for the D3-MSD2 aerosol therapy was considerably more rapid with arterial oxygenation recovering 5-12 times faster than for liquid Curosurf. Biological response for the D3-MSD2 aerosol therapy was also superior with 2-fold improvement in final lung compliance compared with liquid Curosurf. Conclusions: The new D3-MSD2 aerosol therapy was found to be superior to clinical-practice liquid bolus instillation in the critical areas of required dose (order-of-magnitude reduction), delivery time, biological response rate, and efficacy.

Background: Several studies have demonstrated the benefit of inhaled corticosteroids (ICS) before COVID-19 illness in reducing hospitalization time and reducing viral entrance to lung cells. This study explores the risk of severe COVID-19 illness among patients who had purchased ICS. Methods: In a retrospective study, adult patients with COVID-19 before the emergence of the Omicron variant were included. The severity, hospitalization rates, and mortality due to COVID-19 among patients who purchased and did not purchase ICS during the 6 months before the illness were compared. Results: Of the 44,866 COVID-19 patients, 2359 (5.3%) were hospitalized. Information regarding the severity of hospitalization was available for 2259 patients. Of these, 602 (27%) were classified as having severe disease and 510 (22%) died. Patients with higher socioeconomic status (SES) had less hospitalization rates but significantly higher risk for severe COVID-19 and a higher mortality rate. In a multivariate analysis, a significantly higher risk for hospitalization was found only for patients who purchased ICS when no respiratory disease was recorded (odds ratio 1.53,95% confidence interval: 1.15-2.01), relative to those who did not purchase ICS. Conclusions: Patients with unrecorded respiratory disease who purchased ICS are at higher risk for hospitalization due to COVID-19; therefore, rigorous attempts should be made to better characterize their illness. Higher SES was associated with more severe COVID-19 and higher mortality rates and these patients should have early hospitalization.

Backgroud: A key attribute in selecting an oral inhaler device for chronic obstructive pulmonary disease (COPD) and asthma is its ability to dispense a high degree of pulmonary deposition of the drug at low inspiratory flows. Methods: In this study, the lung deposition of extrafine formulations of beclomethasone dipropionate (BDP) and formoterol fumarate (FF) (pressurized metered-dose inhaler [pMDI] and dry powder inhaler [DPI], NEXThaler) was compared with that of nonextrafine formulations of fluticasone/salmeterol (FP/SAL) Diskus DPI and budesonide/formoterol (BUD/FF) Turbuhaler DPI in 10 patients. Diskus intrathoracic (peripheral and central) lung deposition was estimated at low inhalation flow rates (30 and 40 L/min) via validated functional respiratory imaging (FRI) and computational fluid dynamics (CFD) methods. Results: The BDP/FF NEXThaler and BDP/FF pMDI had the highest median percentages of intrathoracic deposition, with consistent mean values of approximately 50% and 40%, respectively. The median percentage of peripheral deposition from extrafine inhalers was above 30% with BDP/FF NEXThaler and pMDI, 5% or less with the FP/SAL Diskus at both flow rates, and ranged between 12% and 22% with the BUD/FF Turbuhaler DPI at flow rates of 30 and 40 L/min, respectively. Conclusions: Extrafine BDP/FF using NEXThaler and pMDI resulted in greater peripheral deposition of both the inhaled corticosteroid and long-acting beta-agonists moieties than the nonextrafine FP/SAL Discus and BUD/FF DPIs did.

Spacers, primarily valved holding chambers (VHCs), are widely used to overcome some of the problems associated with the use of pressurized metered-dose inhalers (pMDIs). These include the difficulty experienced by patients in trying to coordinate the initiation of inhalation with the actuation of the pMDI. High oropharyngeal deposition of drug, which may result in both local and systemic side effects, is also a problem. Although the variability in output from pMDIs under optimized conditions in the laboratory is low, the variability when used in clinical practice is likely to increase considerably. Hence, the dose introduced into a holding chamber may vary significantly depending on the way in which the pMDI canister is handled before it is actuated. Several studies have shown that various design factors can influence the dose delivered from a holding chamber. These include spacer volume, shape, valve design, using multiple actuations, delay between actuation and inhalation, and construction material, which affects the level of electrostatic charge accumulating on the spacer surfaces. Several spacers which are made from low or anti-static materials are now available. Recommendations for optimal use of spacers, including inhalation techniques are outlined in this chapter, and vary according to patient age and inhalation coordination capability. Efficiency of drug delivery and lung deposition are also dependent on pMDI drug formulation and the patient's anatomical and physiological characteristics.

Background: N-acetylcysteine (NAC) is a classical mucolytic agent that, in addition to its mucolytic activity, also exhibits antioxidant activity. This could be beneficial in treating chronic inflammatory airway diseases, including asthma. Background: We evaluated the ability of NAC to modulate airway defense mechanisms, airway reactivity, inflammation, and remodeling after 10 days of administration [20 and 60 mg/(kg·d)] in an experimental guinea pig model of allergic inflammation. Methods: The concentrations of inflammatory cytokines (interleukins: IL-4, IL-5, IL-10, IL-12, and IL-13), granulocyte macrophage-colony stimulating factor (GM-CSF), interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α) were measured in bronchoalveolar lavage fluid using a multiplex detection method. The concentration of remodeling marker transforming growth factor beta-1 (TGF-β1) was measured in lung homogenates using enzyme-linked immunosorbent assay. In vivo, changes in specific airway resistance and number of cough efforts were determined. Tracheal smooth muscle reactivity was evaluated in vitro. Ciliary beat frequency (CBF) indicated mucociliary clearance. Results: A 10-day administration of NAC at a higher dosage led to a significant decrease in the regulatory cytokines IL-4, IL-5, and GM-CSF. NAC, in both dosing schedules, decreased the levels of TGF-β1. NAC at a higher dosage reduced the number of chemically induced cough reflexes and CBF. NAC did not affect airway hyperreactivity parameters. Conclusion: NAC is a multifactorial drug, and under our experimental conditions of allergic inflammation, it showed positive effects on the levels of regulatory cytokines and growth factors, which probably led to a reduction in the intensity of airway defense mechanisms.

Background: Extrathoracic deposition is a large source of in vivo variability in dosing for pressurized metered dose inhaler (pMDI) aerosols. A majority of previous studies have focused on only total extrathoracic deposition for pMDIs. The present work evaluates regional deposition within the extrathoracic region to better understand the impact of actuator orifice diameter and inhalation flow rate on extrathoracic deposition of a suspension pMDI formulation of epinephrine. Methods: Regional deposition of a commercially available HFA (hydrofluoroalkane) suspension pMDI formulation of epinephrine was evaluated using plastic and metal versions of the newly developed sectioned Alberta Idealized Throat (s-AIT), divided into analogs of the oral cavity, the pharynx/larynx, and the upper trachea. Influences of actuator orifice diameter and inhaler insertion angle on regional extrathoracic deposition were evaluated in the plastic s-AIT at a 30 L/min flow rate, followed by additional testing in the metal s-AIT to evaluate effects across a range of flow rates (from 10 to 100 L/min). Results: Actuator orifice was found to strongly influence regional extrathoracic deposition of a commercially available epinephrine HFA suspension pMDI aerosol, with smaller actuator orifices yielding reduced oral cavity deposition and increased distal-filter (in vitro lung) deposition in both the plastic and metal s-AIT. Inhalation flow rate was found to strongly influence deposition in the metal s-AIT, with higher flow rates associated with reduced oral cavity deposition, increased pharynx/larynx deposition, and increased upper trachea deposition. Smaller orifices showed less variability in results as a function of inhaler insertion angle. Conclusions: Actuator orifice diameter (spanning 0.22-0.42 mm) can strongly influence regional deposition of an HFA epinephrine suspension pMDI aerosol within the extrathoracic region. Smaller actuator orifices may provide reduced oral cavity deposition and increased delivery to the lungs. Smaller actuator orifices may also reduce variability in extrathoracic deposition that is associated with patient use aspects such as inhaler insertion angle.

Several inhaled proteins and peptides have been developed to treat indications in the respiratory tract or systemically with varying degrees of success. This section will summarize the preclinical and clinical studies for inhaled Pulmozyme® (recombinant human deoxyribonuclease, rhDNase), insulin, human growth hormone (hGH), cyclosporine, alpha-1 antitrypsin, measles vaccine, and anti-immunoglobulin E (IgE). For Pulmozyme® (rhDNase), monkeys had positive serum antibody titers to rhDNase and allergic/hypersensitivity (type I) lung lesions in response to foreign protein likely due to differences in homology between monkey and human DNases. However, in patients, the levels of rhDNase antibodies were low and of no consequence. For inhaled insulin in rats, dogs and monkeys, there were no adverse effects related to insulin or excipients. In clinical trials, over 13,000 patients were safely treated with inhaled insulin for an average of 1 year. Some patients had higher antibody levels than comparators, but these antibodies did not decrease the effectiveness, safety or tolerability of inhaled insulin over time and/or affect clinical outcomes. Inhaled hGH had no adverse effects in monkeys, healthy volunteers or pediatric patients, but its absorption from the lungs was too low (<5%) in pediatric patients to be successful as a medical product. Inhaled cyclosporine had no unexpected systemic toxicity or clinically limiting findings in the respiratory tract in rat and dogs; it also had promising Phase 2 clinical data but failed in Phase 3. Inhaled alpha-1 antitrypsin also failed in a recent Phase 2/3 trial. A liquid inhaled measles vaccine was safe, well tolerated and produced an appropriate immune response in Phase 2/3 studies for children ages 10-35 months, but not younger. A dry powder inhaled vaccine in monkeys had no adverse effects and produced an immune response; Phase 1 trials are underway. Inhaled anti-IgE was well tolerated in monkeys and asthma patients, but systemic delivery had superior results in patients.