Journal of Aerosol Medicine and Pulmonary Drug Delivery最新文献

Purpose: TRK-250 is a novel single-stranded oligonucleotide carrying a human Transforming growth factor-beta 1-targeting siRNA motif tethered by two proline linkers. Nonclinical studies have shown that TRK-250 may have potency to prevent the progression of pulmonary fibrosis. Herein, a phase I study was conducted to investigate the safety and pharmacokinetics (PKs) of TRK-250 in patients with idiopathic pulmonary fibrosis (IPF). Method: In the phase I study, 34 IPF patients were partially randomized to receive a placebo or TRK-250 in 4 single doses of 2, 10, 30, and 60 mg or multiple rising doses of 10, 30, and 60 mg once per week for 4 weeks by oral inhalation. For both the single- and multiple-dose studies, the primary endpoint was safety, and the secondary endpoint was PKs. Result: In all IPF patients who orally inhaled TRK-250, no significant drug-related adverse events (AEs) were observed. The AEs were mild or moderate, except for one severe case with acute exacerbation. One of the more common AEs was coughing. One patient discontinued treatment before the last dose because of coughing. There were no medically important findings related to safety endpoints based on clinical laboratory data (clinical chemistry, hematology, or urinalysis), vital signs data, electrocardiogram data, physical examination findings, pulse oximetry data, spirometry data, or diffusing capacity of the lung for carbon monoxide data. All the bioanalytical results of PKs in the blood were below the lower limit of quantification. Conclusions: Both the single and multiple doses of TRK-250 were safe and well tolerated in this first study done in IPF patients. Furthermore, TRK-250 was not detected in the systemic circulation following inhalation, indicating low or virtually nonexistent systemic exposure. This study is registered at ClinicalTrials.gov with identifier number NCT03727802.

Dry powder inhaler products have played an important role in the treatment and prevention of asthma and more recently chronic obstructive pulmonary disease. The considerations that go into formulation development to support these products cover a unique range of disciplines including analytical and physical chemistry, aerosol physics, device technology, process engineering and industrial design. An enormous research effort has been expended in the last half century to provide understanding of this complex dosage form. The guiding principles in considering the development of dry powder inhaler products encompass requirements for disease therapy, advantages and limitations of adopting certain technological approaches, and desirable features to facilitate patient use, which are all embodied in the target product profile.

Introduction: The management of severe hemoptysis mainly consists of invasive interventional procedures, including angiographic bronchial artery embolization, various endobronchial interventions, and sometimes surgery. However, there are limited effective noninvasive medical therapies available. The objective of this analysis was to evaluate the effectiveness and safety of nebulized tranexamic acid (TXA) administration compared with conventional management in patients with hemoptysis. Methods: This Institutional Review Board-approved, single-center, retrospective matched cohort study was performed from January 1, 2018 to March 31, 2021. Electronic health record data were used to identify all adult inpatients with hemoptysis (International Classification of Diseases, Tenth Revision, code R04.2). All patients who received ≥1 dose of nebulized TXA were matched with up to five controls based on available severity criteria (hemoptysis severity, need for mechanical ventilation, and sequential organ failure assessment score at the time of hemoptysis diagnosis) with coarsened exact matching. The primary outcome was the need for invasive interventions for the management of hemoptysis. Secondary outcomes included time to hemoptysis resolution, duration of mechanical ventilation, hemoptysis recurrence, and hospital length of stay. Results: A total of 14 patients were treated with nebulized TXA; they were matched with 58 controls. Patients were 59.7% male, had a median age of 65.5 years, with airway disease (36.1%) being the major etiology of hemoptysis. There was no difference in the number of patients who required an invasive intervention between the TXA (35.7%) versus control group (56.9%), p = 0.344. Additionally, no difference was found in the time to hemoptysis resolution (p = 0.050), duration on mechanical ventilation (p = 0.128), hemoptysis recurrence (p = 1.000), or hospital length of stay (p = 0.139). Conclusions: In patients with hemoptysis, nebulized TXA may be considered as a noninvasive option for the management of hemoptysis. However, a larger analysis is warranted to determine the impact of nebulized TXA on invasive interventions for management.

Dry powder inhalers (DPIs) are now widely prescribed and preferred by the majority of patients. These devices have many advantages over the traditional pressurized metered-dose inhaler (pMDI) but they do have disadvantages. The characteristics of the dose emitted from a DPI are affected by the inhalation manoeuvre used by a patient. Each patient is different and the severity of their lung disease varies from mild to very severe. This affects how they use an inhaler and so determines the type of dose they inhale. An understanding of the pharmaceutical science related to DPIs is important to appreciate the relevance of how patients inhale through these devices. Also, each type of DPI has its unique dose preparation routine, and thus it is essential to follow these recommended steps because errors at this stage may result in no dose being inhaled. All issues related to the inhalation manoeuvre and dose preparation are addressed in this chapter. The importance of the inhalation technique is highlighted with a realization of inhale technique training and checking. During routine patient management, devices should not be switched nor doses increased unless the patient has demonstrated that they can and do use their DPI.

Background: A distinctive pathological feature of idiopathic pulmonary fibrosis (IPF) is the aberrant accumulation of extracellular matrix components in the alveoli in abnormal remodeling and reconstruction following scarring of the alveolar structure. The current antifibrotic agents used for IPF therapy frequently result in systemic side effects because these agents are distributed, through the blood, to many different tissues after oral administration. In contrast to oral administration, the intrapulmonary administration of aerosolized drugs is believed to be an efficient method for their direct delivery to the focus sites in the lungs. However, how fibrotic lesions alter the distribution of aerosolized drugs following intrapulmonary administration remains largely unknown. In this study, we evaluate the intrapulmonary distribution characteristics of aerosolized model compounds in mice with bleomycin-induced pulmonary fibrosis through imaging the organs and alveoli. Methods: Aerosolized model compounds were administered to mice with bleomycin-induced pulmonary fibrosis using a Liquid MicroSprayer^®. The intrapulmonary distribution characteristics of aerosolized model compounds were evaluated through several imaging techniques, including noninvasive lung imaging using X-ray computed tomography, ex vivo imaging using zoom fluorescence microscopy, frozen tissue section observation, and three-dimensional imaging with tissue-clearing treatment using confocal laser microscopy. Results: In fibrotic lungs, the aerosolized model compounds were heterogeneously distributed. In observations of frozen tissue sections, model compounds were observed only in the fibrotic foci near airless spaces called honeycombs. In three-dimensional imaging of cleared tissue from fibrotic lungs, the area of the model compound in the alveolar space was smaller than in healthy lungs. Conclusion: The intrapulmonary deposition of extracellular matrix associated with pulmonary fibrosis limits the intrapulmonary distribution of aerosolized drugs. The development of delivery systems for antifibrotic agents to improve the distribution characteristics in fibrotic foci is necessary for effective IPF therapy.

Introduction: Inhaled antimuscarinics are a cornerstone of the management of chronic obstructive pulmonary disease. This article details a series of five pharmacokinetic (PK) studies comparing a generic tiotropium dry powder inhaler (DPI) to Spiriva HandiHaler, the realistic in vitro methods used to support those studies, and the related in vitro-in vivo correlations (IVIVCs). Methods: All five PK studies were of open-label, single-dose, crossover design with test and reference treatments administered to healthy subjects. Following unexpected results in the first three PK studies, a realistic impactor method was developed comprising an Oropharyngeal Consortium (OPC) mouth-throat and simulated inspiratory profiles in conjunction with a Next Generation Impactor (NGI). Mass fractions and the in vitro whole lung dose were estimated for the test product and Spiriva^® HandiHaler^® using this method, and IVIVCs derived. Results: Bioequivalence could not be demonstrated for C_max in the first three PK studies (test/reference ratios ranging from 83.1% to 131.8%), although was observed for AUC_t. Reanalysis of the corresponding biobatches with the realistic NGI method revealed in vitro ratios aligned with these PK data (in contrast to the compendial NGI data) and thus inadvertent selection of "mismatched" biobatches. Two further PK studies were undertaken, supported by the realistic NGI method. With the comparison of test and reference products similarly positioned within their respective product performance distributions, bioequivalence was confirmed in both studies. IVIVCs based on mass fractions as per the realistic NGI method were robust and highly predictive of PK outcomes. Conclusions: The test tiotropium DPI and Spiriva HandiHaler were bioequivalent when equitable biobatch comparisons, based on realistic NGI testing, were performed. The observations from this program support the utility of realistic test methods for inhaled product development.