Journal of Aerosol Medicine and Pulmonary Drug Delivery最新文献

Background: Dry powders offer the potential to increase stability and reduce cold-chain requirements associated with the distribution of vaccines and other thermally sensitive products. The Alberta Idealized Nasal Inlet (AINI) is a representative geometry for in vitro characterization of nasal products that may prove useful in examining intranasal delivery of powders. Methods: Spray-dried trehalose powders were loaded at 10, 20, and 40 mg doses into active single-dose devices. Primary particle sizes (∼D_v50 = 10 µm for powder A and 25 µm for powder B), and sizes dispersed by devices, were evaluated using laser diffraction. The interior of the AINI was coated with a glycerol-surfactant mixture to mitigate particle bounce, and flow rates of 7.5 or 15 L/min were drawn through the AINI. Deposition of trehalose powder was determined in the four regions of the AINI (vestibule, turbinates, olfactory, and nasopharynx), a downstream preseparator, and an absolute filter (representing in vitro lung deposition) using liquid chromatography coupled with mass spectrometry. Results: Coating the AINI was effective in mitigating particle bounce for both trehalose powders. No difference in regional nasal deposition was observed when testing at a flow rate of 7.5 versus 15 L/min. A high fraction of both powders penetrated past the vestibule and deposited in the turbinates and nasopharynx for all loaded doses. For powder A, a non-negligible fraction of the recovered dose (up to 7%) is deposited on the filter, representing potential lung exposure. Conversely, a negligible fraction of the total recovered dose was deposited on the filter for powder B. Conclusion: Powders with a larger primary particle size showed reduced penetration through the nasal airways while maintaining high turbinate deposition. Optimized spray-dried powders offer the potential to target delivery to the peripheral nasal airways based on powder particle size while reducing lung exposure.

Approved drug products may be subject to change(s) for a variety of reasons. The changes may include, but are not limited to, increase in batch size, alteration of the drug product constituent(s), improvement in the manufacturing process, and shift in manufacturing sites. The extent of pharmaceutical testing and the regulatory pathway for timely implementation of any change in the approved product and/or process depends upon the nature and extent of change. The U.S. Food and Drug Administration (FDA) has published guidelines that outline its expectations for the Scale-Up and Postapproval Changes (SUPAC) in the solid oral immediate and modified release (MR) products, and semisolid formulations. However, to date, no such guidelines have been issued to address SUPAC in the orally inhaled drug products (OIDPs), and this article represents a seminal contribution in this direction. It is hoped that it will inspire contributions from the relevant multidisciplinary experts from the pharmaceutical industry and the agency in accomplishing formal regulatory guidelines relevant to the OIDP SUPAC. The OIDPs are complex drug-device combination products. Therefore, a conceptualization of SUPAC guidelines for these products warrants consideration of contributions of effect of change(s) in individual components (drug substance, formulation, device) as well as a compound effect that a single or multiple changes may have on product performance, and its safety and efficacy. This article provides a discussion of scientific aspects and regulatory bases relevant to the development of SUPAC for OIDPs, and it attempts to outline considerations that may be applicable in addressing issues related to the OIDP SUPAC in the context of human drugs. The authors' statements should not be viewed as recommendations from any regulatory agency, as the applicable guidelines would be determined on case-by-case evaluation by the relevant authorities.

Background: Aerosol delivery may be enhanced by utilizing an inspiration-synchronized nebulization mode, where nebulization occurs only during inspiration. This study aimed to compare aerosol delivery of albuterol via a prototype of an inspiration-synchronized vibrating mesh nebulizer (VMN) versus continuous VMN during invasive mechanical ventilation. Methods: A critical care ventilator equipped with a heated-wire circuit to deliver adult parameters was attached to an endotracheal tube (ETT), a collection filter, and a test lung. The nebulizer was placed at the humidifier's inlet, inspiratory limb at the Y-piece, and between the Y-piece and ETT. Conventional VMNs producing standard size aerosol particles (Solo; Aerogen Ltd) were compared with prototype small-particle VMNs (Aerogen Pharma) in both inspiration-synchronization and continuous modes. In each run, 1 mL of albuterol (2.5 mg) was used (n = 5). The drug was eluted from the collection filter and assayed with UV spectrophotometry (276 nm). Results: The inhaled dose with inspiration-synchronization mode was 1.4 to 3.6 times that with the continuous mode, regardless of nebulizer positions (all p < 0.001). The small-particle VMN delivered an 8%-69% greater inhaled dose than the conventional VMN (Solo), regardless of the nebulizer placement or aerosol generation mode (all p < 0.001). The highest inhaled dose (50%-60%) with the inspiration-synchronized VMN was observed when it was placed at the ETT (all p < 0.001), whereas the continuous VMN performed better when positioned near the humidifier, with an inhaled dose of 21%-37% (p < 0.001). Conclusion: The inspiration-synchronized VMN delivered a greater inhaled dose than continuous VMN, irrespective of nebulizer placement. The prototype VMN producing smaller aerosol particles resulted in a greater inhaled dose than the conventional VMN (Solo), regardless of placement or aerosol generation modes. The inspiration-synchronized VMN achieved the highest delivery when placed close to the airway, whereas the continuous VMN delivered the most when positioned near the ventilator.

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. [Figure: see text].

Background: It remains challenging to quantify lung pharmacokinetics (PK) of a drug administered and targeted to act in the lung. Exhaled breath particles (PEx), which are generated when collapsed distal airways reopen during inhalation, offer a noninvasive way to access undiluted epithelial lining fluid (ELF). Therefore, it was the aim of this study to investigate whether PK data can be derived from PEx. Methods: Six healthy volunteers received either an inhaled dose (400 μg) or an oral dose (8 mg) of salbutamol in a randomized, crossover design with 7-day washout between treatments. PEx were collected before and at nine time points after dosing (0-315 minutes [min]). Following each 15 min PEx sampling period, nasosorption and plasma samples were collected. Salbutamol was quantified by liquid chromatography-mass spectrometry. Results: After oral delivery and inhalation, salbutamol PK profiles could be obtained for plasma and nasal samples. In PEx samples, a PK profile could be obtained in 5 of 6 participants after inhalation, but the salbutamol concentration was often at or below detection limit after oral intake. After inhaled administration we found higher salbutamol concentrations in PEx as compared with nasal and plasma samples. Conclusion: This study provides proof of principle that PEx samples can be used to quantify drug levels in ELF.

Background: Asthma controller medications can be delivered via pressurized metered dose inhaler (pMDI) or dry powder inhaler (DPI) devices. Objective: This study aimed to evaluate the frequency of exacerbations and satisfaction rate with device use in asthmatics using pMDIs or DPIs. Methods: A multicenter, cross-sectional study was conducted in adults who used pMDIs or DPIs with correct inhaler technique and good adherence for asthma treatment. Demographic and asthma-related characteristics of the subjects and data regarding device satisfaction were collected through a face-to-face interview in the outpatient clinic. Rates of pMDI and DPI users and the data were compared between the two groups. Results: The study included 338 patients (mean age: 48.6 ± 14.5 years, 253 [74.9%] women). Among participants, 96 (28.4%) were using pMDI and 242 (71.6%) were using DPI. The age of patients using pMDI were significantly lower compared with DPI users. No significant difference was observed in terms of device satisfaction and clinical outcomes of asthma between pMDI and DPI users with good inhaler technique and good adherence. Conclusion: More asthmatics use DPIs, however, pMDIs are used in younger asthmatic patients. No significant difference in terms of device satisfaction and clinical outcomes of asthma was observed between pMDI and DPI users.

In contemporary times, there has been a rise in the utilization of dry powder inhalers (DPIs) in the management of pulmonary and systemic diseases. These devices underwent a swift advancement in terms of both the equipment utilized and the formulation process. In this review, the carrier physicochemical characteristics that influence DPI performance are discussed, focusing its shape, morphology, size distribution, texture, aerodynamic diameter, density, moisture, adhesive and detachment forces between particles, fine carrier particles, and dry powder aerosolization. To promote the deposition of the active principal ingredient deep within the pulmonary system, advancements have been made in enhancing these factors and surface properties through the application of novel technologies that encompass particle engineering. So far, the most used carrier is lactose showing some advantages and disadvantages, but other substances and systems are being studied with the intention of replacing it. The final objective of this review is to analyze the physicochemical and mechanical characteristics of the different carriers or new delivery systems used in DPI formulations, whether already on the market or still under investigation.

Background: Small airways disease (SAD) in severe asthma (SA) is associated with high disease burden. Effective treatment of SAD could improve disease control. Reduced end-expiratory flows (forced expiratory flow [FEF]_25-75 and FEF₇₅) are considered sensitive indicators of SAD. Inhaled medication should be delivered to the smaller peripheral airways to treat SAD effectively. Aerosol deposition is affected by structural airway changes. Little is known about the effect of SAD on aerosol delivery to the smaller peripheral airways. Functional respiratory imaging (FRI) is a validated technique using 3D reconstructed chest computed tomography (CT) and computational fluid dynamics to predict aerosol deposition in the airways. Aim: This study aims to compare central and peripheral (= small airways) deposition between children with SA and SAD and children with SA without SAD, with different inhaler devices and inhalation profiles. Methods: FRI was used to predict the deposition of beclomethasone/formoterol dry powder inhaler (DPI), beclomethasone/formoterol pressurized metered dose inhaler with valved holding chamber (pMDI/VHC), and salbutamol pMDI/VHC for different device-specific inhalation profiles in chest-CT of 20 children with SA (10 with and 10 without SAD). SAD was defined as FEF_25-75 and FEF₇₅ z-score < -1.645 and forced vital capacity (FVC) z-score > -1.645. No SAD was defined as forced expiratory volume (FEV)₁, FEF_25-75, FEF₇₅, and FVC z-score > -1.645. The intrathoracic, central, and peripheral airways depositions were determined. Primary outcome was difference in central-to-peripheral (C:P) deposition ratio between children with SAD and without SAD. Results: Central deposition was significantly higher (∼3.5%) and peripheral deposition was lower (2.9%) for all inhaler devices and inhalation profiles in children with SAD compared with children without SAD. As a result C:P ratios were significantly higher for all inhaler devices and inhalation profiles, except for beclomethasone administered through DPI (p = .073), in children with SAD compared with children without SAD. Conclusion: Children with SA and SAD have higher C:P ratios, that is, higher central and lower peripheral aerosol deposition, than children without SAD. The intrathoracic, central, and peripheral deposition of beclomethasone/formoterol using DPI was lower than using pMDI/VHC.

Introduction: In normal subjects, during tidal breathing, aerosols deposit by settling in small airways. With obstructive lung disease (OLD), collapse of airways during expiration causes turbulence and increased deposition in central airways. High-flow nasal cannula (HFNC) therapy, washing out dead space, may affect deposition mechanisms and drug delivery. This study compared aerosol deposition and airway responsiveness in OLD after traditional and HFNC nebulization therapy. Methods: Twelve subjects with moderate to severe OLD participated in a two-day study. Spirometry was measured pre- and post-aerosol inhalation. On Day 1 (D1) subjects tidally inhaled radiolabeled albuterol (^99mTc DTPA) by mouth via AeroTech II, (Biodex. Shirley, NY). Day 2 (D2) inhalation was via HFNC using i-AIRE (InspiRx, Inc. Somerset, NJ). The HFNC system (60 L/m) was infused by syringe pump at 50 mL/h. D2 lung deposition was monitored in real time by gamma camera to match D1. Pre and post heart rate, O₂ sat, and nasopharyngeal deposition (NP) were measured. Mechanistic contributions were modeled using multiple linear regression (MLR) of deposition rate (DR µg/m) as a function of breathing frequency, airway geometry (FEV₁), and parenchymal integrity (DLCO). Results: Albuterol lung depositions were matched (p = 0.13) with D1 central/peripheral (sC/P) ratios 1.99 ± 0.98. Following HFNC, peripheral deposition increased (31% ± 33%, sC/P = 1.51 ± 0.43, p = 0.01). D2/D1% change FVC increased by 16.1 ± 16.7% (p = 0.003). NP deposition averaged 333% of lung. Heart rate and O₂ sat were unaffected (p = 0.31, p = 0.63 respectively). DR analysis was markedly different between D1 (R² = 0.82) and D2 (R² = 0.12). Conclusion: In subjects with OLD, HFNC nebulization at 60 L/min was well tolerated and increased peripheral drug delivery. Spirometry significantly improved. Systemic effects were undetected indicating limited nasal absorption. MLR demonstrated that different mechanisms of deposition govern traditional vs HFNC aerosol delivery. Breath-enhanced nebulization via HFNC may provide controllable and effective aerosol therapy in OLD.

The respiratory tract with its vast surface area and very thin air-blood tissue barrier presents an extremely large interface for potential interaction with xenobiotics such as inhaled pathogens or medicaments. To protect its large and vulnerable surface, the lung is populated with several different types of immune cells. Pulmonary epithelial cells, macrophages and dendritic cells are key players in shaping the innate and adaptive immune response. Due to their localization, they represent a frontline of cell populations that are among the first to come in contact with inhaled xenobiotics. Furthermore, depending on the lung compartment they populate, these cells show a large variety in morphology, phenotype, and function. These unique characteristics make those cell populations ideal targets for specific immunomodulators that are designed for inhalation. Depending on cell population or lung compartment targeting, a specific immune response may be triggered or modulated. The purpose of a potent carrier for pulmonary immunomodulation is, first, to efficiently target a specific immunocompetent cell and, second, to affect its role in generating an immune response. Immunomodulation may occur at different levels of immune cell-antigen interaction, i.e. antigen uptake, trafficking, processing and presentation. Inhalation of nanosized carriers for drugs or vaccines shows great potential for both prophylactic and therapeutic approaches in order to modulate immune responses locally or systemically, due to the specific deposition and targeting properties of nanoparticles. Immune responses triggered by nanosized particles may be either immunostimulatory or immunosuppressive and depending on the specific purpose, stimulation or suppression may either be desired or unwanted. Meticulous analysis of immunomodulatory potential, pharmacologic and toxicologic testing of inhalable nanocarriers is required in order to find novel and optimal approaches for prophylaxis and therapy of pulmonary diseases. The design and characterization of such nanoparticles requires well-coordinated interdisciplinary research among engineers, biologists and clinicians.