Journal of Aerosol Medicine and Pulmonary Drug Delivery最新文献

Background: Dry powder inhalers (DPIs) are passive devices, which rely on a patient's inspiratory effort for drug dispersion and delivery. The aim of this study was to assess how acute bronchoconstriction affects the ability to use Easyhaler DPI in adults. Methods: This study was conducted as part of a parallel-group clinical trial assessing use of Salbutamol Easyhaler, Budesonide-formoterol Easyhaler and salbutamol pMDI with spacer during a methacholine challenge (MC) test. The inhalations through both Easyhaler variants, the inhaler for the single active substance product (EH-mono) and the inhaler for the combination product (EH-combi), were recorded at baseline and during bronchoconstriction. Peak inspiratory flow (PIF), flow rate acceleration and inhalation volume after PIF were compared to the criteria for successful inhalation. Results: The study population consisted of 120 adult subjects indicated for MC as a diagnostic test for asthma, with 60 subjects in both Easyhaler arms. With EH-combi 98.3% and 91.4% passed the criteria (PIF ≥30 L/min, inhalation acceleration ≥0.7 L/s², and inhalation volume ≥500 mL after PIF) for successful inhalation at baseline and during bronchoconstriction, respectively. With EH-mono, success rates were 95.0% and 88.1% at baseline and during bronchoconstriction, respectively. The most common reason for not passing the criteria was slow inhalation acceleration. Aside from two subjects using EH-mono during bronchoconstriction, all subjects were able to generate PIF ≥ 30 L/min. Conclusions: During an acute obstructive event, the vast majority of patients have no difficulty in achieving sufficient PIF, inhalation acceleration, and volume after PIF when using an Easyhaler DPI.

Background: A fixed combination of formoterol, glycopyrrolate, and beclomethasone dipropionate is approved in some geographic areas as pressurized metered dose inhaler (pMDI) formulation for the treatment of asthma and chronic obstructive pulmonary disease. Current pMDIs use hydrofluoroalkanes (HFAs) as a propellant, such as 1,1,1,2-tetrafluoroethane (HFA134a), that have a high global warming potential (GWP), but their use is being progressively lowered to reduce impact on climate. One option to reduce the carbon footprint of the pMDI products while preserving pMDIs as a therapeutic option is reformulating the current pMDIs using low GWP propellants, such as 1,1-difluoroethane (HFA152a). Nevertheless, pharmaceutical, clinical, and regulatory challenges need to be considered when reformulating a pMDI. A nonclinical study in rodents has been performed to support the formulation work and optimize the design of the bioequivalence study in humans. Methods: A fixed combination of formoterol, glycopyrrolate, and beclomethasone dipropionate (BDP) as pMDI with the two propellants HFA134a or HFA152a was administered by inhalation to Sprague-Dawley rats, using inhalation tower, to assess the impact of the propellant on the PK profile of the active components. After administration, serial blood samples were taken from each rat, and plasma aliquots were analyzed by HPLC-MS/MS. Results: Inhalation administration to rats of the fixed triple combination as pMDI showed similar PK profile for formoterol, glycopyrrolate, and BDP with the two propellants. Exposure parameters C_max and AUC_last of the three active ingredients were compared, showing no statistically significant differences in the systemic exposure between the two treatment groups. Higher interanimal variability was observed for the metabolite beclomethasone 17-monopropionate, likely due to individual differences in the metabolite generation. Conclusions: Considering these data, it was possible to conclude that replacing propellant HFA134a with HFA152a in a newly developed formulation had no significant impact on the plasmatic PK profile of formoterol, glycopyrrolate, and BDP in rats after inhalation administration using inhalation towers.

The chlorofluorocarbons (CFCs) that were used as propellants in early pressurized metered-dose inhalers (pMDIs) had substantial ozone-depleting potential. Following the Montreal Protocol in 1987, the manufacture of a range of ozone-depleting substances, including CFCs, was gradually phased out, which required the propellants used in pMDIs to be replaced. Current pMDIs use hydrofluoroalkanes (HFAs) as propellants, such as 1,1,1,2-tetrafluoroethane (HFA-134a). Although these HFAs have no ozone-depleting potential, they have a high global warming potential (GWP), and consequently, their use is being phased down. One option for the discontinuation of HFA use in inhalers would be to discontinue all pMDIs, switching patients to dry powder inhalers (DPIs). However, a switch from pMDIs to DPIs may not be a clinically appropriate option for some patients; furthermore, the full lifecycle carbon footprint and the overall environmental impact of different inhalers should be considered. An alternative is therefore to reformulate the current HFA pMDIs to use low-GWP propellants, such as 1,1-difluoroethane (HFA-152a). This article summarizes the various steps and challenges associated with this change, illustrated using data from the inhaled triple combination of beclomethasone dipropionate, formoterol fumarate, and glycopyrronium bromide, a complex formulation of three molecules in a solution that contains liquid-phase propellant.

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.

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.

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: 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.