Inhaled Edoxaban dry powder inhaler formulations: Development, characterization and their effects on the coagulopathy associated with COVID-19 infection.
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ABSTRACT:
SUBMITTER: Rashid MA
PROVIDER: S-EPMC8463814 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:This study aims at developing and characterizing the puerarin dry powder inhaler (DPI) formulations for pulmonary delivery. The inhalable particles size (<2 μm) was accomplished by micronization and its morphology was examined by scanning electron microscopy (SEM). The puerarin-excipient interaction in powder mixtures was analyzed by using Fourier transform infrared spectroscopy (FTIR), Raman confocal microscopy, X-Ray powder Diffraction (XRD), and differential scanning calorimetry (DSC) methods. Using a Twin stage impinger (TSI), the in-vitro aerosolization of the powder formulations was carried out at a flow rate of 60 L/min and the drug was quantified by employing a validated HPLC method. No significant interactions between the drug and the excipients were observed in the powder formulations. The fine particle fraction (FPF) of the drug alone was 4.2% which has increased five to six-fold for the formulations with aerosolization enhancers. Formulation containing lactose as large carriers produced 32.7% FPF, which further increased with the addition of dispersibility enhancers, leucine and magnesium stearate (40.8% and 41.2%, respectively). The Raman and FTIR techniques are very useful tool for understanding structural integrity and stability of the puerarin in the powder formulations. The puerarin was found to be compatible with the excipients used and the developed DPI formulation may be considered as an efficient formulation for pulmonary delivery for the management of various diseases at a very low dose.
| S-EPMC8043385 | biostudies-literature
Project description:Spray drying is a particle engineering technique used to manufacture respirable pharmaceutical powders that are suitable for delivery to the deep lung. It is amenable to processing both small molecules and biologic actives, including proteins. In this work, a simultaneous spray-drying process, termed simul-spray, is described; the process involves two different active pharmaceutical ingredient (API) solutions that are simultaneously atomized through separate nozzles into a single-spray dryer. Collected by a single cyclone, simul-spray produces a uniform mixture of two different active particles in a single-unit operation. While combination therapies for dry powder inhalers containing milled small molecule API are commercially approved, limited options exist for preparing combination treatments that contain both small molecule APIs and biotherapeutic molecules. Simul-spray drying is also ideal for actives which cannot withstand a milling-based particle engineering process, or which require a high dose that is incompatible with a carrier-based formulation. Three combination case studies are demonstrated here, in which bevacizumab is paired with erlotinib, cisplatin, or paclitaxel in a dry powder inhaler formulation. These model systems were chosen for their potential relevance to the local treatment of lung cancer. The resulting formulations preserved the biologic activity of the antibody, achieved target drug concentration, and had aerosol properties suitable for pulmonary delivery.
| S-EPMC9227944 | biostudies-literature
Project description:This study aimed to gain an in-depth understanding of the pulmonary fate of three experimental fluticasone propionate (FP) dry powder inhaler formulations which differed in mass median aerodynamic diameters (MMAD; A-4.5 µm, B-3.8 µm and C-3.7 µm; total single dose: 500 µg). Systemic disposition parameter estimates were obtained from published pharmacokinetic data after intravenous dosing to improve robustness. A biphasic pulmonary absorption model, with mucociliary clearance from the slower absorption compartment, and three systemic disposition compartments was most suitable. Rapid absorption, presumably from peripheral lung, had half-lives of 6.9 to 14.6 min. The peripherally deposited dose (12.6 µg) was significantly smaller for formulation A-4.5 µm than for the other formulations (38.7 and 39.3 µg for B-3.8 µm and C-3.7 µm). The slow absorption half-lives ranged from 6.86 to 9.13 h and were presumably associated with more central lung regions, where mucociliary clearance removed approximately half of the centrally deposited dose. Simulation-estimation studies showed that a biphasic absorption model could be reliably identified and that parameter estimates were unbiased and reasonably precise. Bioequivalence assessment of population pharmacokinetics derived central and peripheral lung doses suggested that formulation A-4.5 µm lacked bioequivalence compared to the other formulations both for central and peripheral doses. In contrast, the other fomulations were bioequivalent. Overall, population pharmacokinetics holds promise to provide important insights into the pulmonary fate of inhalation drugs, which are not available from non-compartmental analysis. This supports the assessment of the pulmonary bioequivalence of fluticasone propionate inhaled formulations through pharmacokinetic approaches, and may be helpful for discussions on evaluating alternatives to clinical endpoint studies.
| S-EPMC10686290 | biostudies-literature
Project description:Background: Wixela Inhub is a generic version of Advair Diskus recently approved by the U.S. Food and Drug Administration. The Inhub inhaler delivers fluticasone propionate (FP)/salmeterol in a dry powder formulation. The goals of our studies were to demonstrate that the Inhub inhaler can be used by representative end users and confirm the robustness of the Inhub inhaler. Methods: Study 1: A nondosing usability assessment, the device orientation study, confirmed that intended users (represented by patients diagnosed with asthma or chronic obstructive pulmonary disease [COPD] who were naive to dry powder inhalers and current Advair Diskus users) could use the Inhub inhaler safely and effectively. Subjects were provided with an Inhub inhaler in commercial packaging, including instructions for use, and were asked to undertake three dose simulations using the inhaler. Subjects were encouraged to interact with this new drug delivery device as they would at home. Subjects were not provided with training on the use of the device. Subjects were observed interacting with the Inhub inhaler, and those who currently use Diskus were also observed interacting with the Diskus to determine whether their mental model of the use of Diskus impacted their interaction with the Inhub device, this assessment was not a primary outcome of the study. Study 2: This is an open-label clinical study to confirm the robustness of the Inhub inhaler after at home patient use. Subjects diagnosed with asthma or COPD were provided Inhub inhaler training and subsequently self-administered 3 weeks of twice daily doses of Wixela Inhub 250 μg FP/50 μg salmeterol in the home environment. The Inhub inhalers were returned to the investigator after ∼3 weeks of outpatient use for in vitro tests on the drug remaining in each inhaler. Results: Study 1 enrolled 110 subjects, and all completed the study. Most subjects (100/110) held the Inhub inhaler in the correct orientation and of those who did not, 9 still achieved a peak inhalation flow rate of ≥30 L/min and a total inhaled volume of ≥1 L, thus meeting the requirements of the study success criteria. In Study 2, 111 pediatric, adult, and elderly subjects with asthma or COPD received the study drug. After ∼3 weeks of outpatient use of the Inhub inhaler by subjects, comprehensive in vitro testing demonstrated that the FP and salmeterol pharmaceutical performance in the Inhub inhaler was preserved. Conclusions: The majority of subjects demonstrated safe and effective use of the Inhub inhaler. In vitro testing and inspections confirmed the robustness of the Inhub inhaler after outpatient use. Clinical trial registration number: NCT02474017.
| S-EPMC8060712 | biostudies-literature
Project description:BackgroundThree 52-week studies in COPD have assessed the efficacy and safety of single-inhaler extrafine formulation triple therapy combining beclomethasone dipropionate (BDP), formoterol fumarate (FF) and glycopyrronium (G) delivered via pressurized metered-dose inhaler (pMDI). BDP/FF/G is now being developed for delivery via multi-dose dry-powder inhaler (DPI; NEXThaler). This study aimed to demonstrate non-inferiority of BDP/FF/G DPI vs pMDI for lung function.MethodsMulticenter, randomized, double-blind, double-dummy, active-controlled, three-way cross-over study in patients with COPD and post-bronchodilator forced expiratory volume in 1 second (FEV1) 30-80% predicted. Patients received BDP/FF/G 100/6/10µg via DPI and pMDI, and BDP/FF 100/6µg via pMDI, all two inhalations twice daily for four weeks, with treatments separated by two-week washout. The two co-primary objectives were to demonstrate non-inferiority between the two BDP/FF/G formulations for FEV1 area under the curve between 0 and 12 hours post-dose (AUC0-12h) normalized by time and trough FEV1 at 24 hours, both on Day 28. EudraCT 2017-004405-41.ResultsOf 449 patients screened, 366 were randomized, with 342 (93.4%) completing all three treatment periods. The primary objectives were met, with changes from baseline in FEV1 AUC0-12h and trough FEV1 on Day 28 similar for the two BDP/FF/G formulations, and the confidence intervals for the difference lying entirely within the pre-specified non-inferiority criterion (-50mL): -20 (-35, -6) mL and 3 (-15, 20) mL for AUC0-12h and trough FEV1, respectively. BDP/FF/G pMDI and DPI were statistically superior to BDP/FF for these endpoints (p<0.001). A similar proportion of patients experienced adverse events with each treatment (15.5%, 18.7% and 15.4% with BDP/FF/G DPI and pMDI, and BDP/FF, respectively); the majority were mild or moderate, with few related to treatment.ConclusionExtrafine BDP/FF/G DPI and pMDI demonstrated similar efficacy and safety in patients with COPD, supporting the DPI formulation as a valid alternative.
| S-EPMC7814657 | biostudies-literature
Project description:Two main types of devices are used to facilitate the administration of inhaled corticosteroid (ICS) and long-acting β-agonist (LABA) in combination, dry powder inhalers (DPIs) and pressurized metered-dose inhalers (pMDIs). There are few reports comparing the effects of the two devices, and it is unknown which should be recommended for asthma patients with given sets of characteristics. In the current study, the beneficial effects and side effects associated with DPIs and pMDIs were compared, and the question of which device should be recommended for asthma patients was investigated. A prospective, randomized, crossover, comparative study in adult outpatients with asthma was conducted using salmeterol/fluticasone propionate combination (SFC) 50 μg/250 μg, one inhalation of Adoair® 250 Diskus® twice daily or two inhalations of Adoair® 125 Aerosol twice daily, for 8 weeks. Questionnaires, exhaled nitric oxide (FeNO) tests and pulmonary function tests were administered after the use of each device for 8 weeks, and the results derived from each device were compared. Sixty-eight subjects were included in the final analysis. There were no significant differences between quality-of-life scores, FeNO, spirometry test results and forced oscillation results. With regard to patient preferences, 57.4% preferred the Adoair® Aerosol and 35.3% preferred the Adoair® Diskus®, as determined via the comparative evaluation questionnaire. Although DPI prescription accounts for the predominant market share of combined ICS/LABA in Japan, patients preferred a pMDI device to a DPI device. Compared to DPIs, pMDIs may be the preferential choice for patients with asthma.
| S-EPMC8241158 | biostudies-literature
Project description:Correct inhalation technique is essential for effective use of dry powder inhalers (DPIs), as their effectiveness largely depends on the patient's inhalation manoeuvre. Children are an especially challenging target population for DPI development due to the large variability in understanding and inspiratory capacities. We previously performed a study in which we determined the prerequisites for a paediatric DPI in a mostly healthy paediatric population, for which we used an empty test inhaler with variable internal airflow resistance and mouthpiece. In the current study we investigated what specifications are required for a DPI for children with cystic fibrosis (CF), for which we expanded on our previous findings. We recorded flow profiles of 35 children with CF (aged 4.7-14.7 years) at three airflow resistances (0.031-0.045 kPa0.5.min.L-1) from which various inspiratory parameters were computed. Obstructions in the mouth during inhalation were recorded with a sinuscope. All children were able to perform a correct inhalation manoeuvre, although video analysis showed that children did not place the inhaler correctly in the mouth in 17% of the cases. No effect was found of medium to high airflow resistance on total inhaled volume, which implies that the whole resistance range tested is suitable for children with CF aged 4-14 years. No effect could be established of either mouthpiece design or airflow resistance on the occurrence of obstructions in the mouth cavity. This study confirms our previous conclusion that the development of DPIs specifically for children is highly desired. Such a paediatric DPI should function well at 0.5 L inhaled volume and a peak inspiratory flow rate of 20 to 30 L/min, depending on the internal airflow resistance. This resistance can be increased up to 0.045 kPa0.5.min.L-1 (medium-high) to reduce oropharyngeal deposition. A higher resistance may be less favourable due to its compromising effect on PIF and thereby on the energy available for powder dispersion.
| S-EPMC5553717 | biostudies-literature
Project description:Lower respiratory tract infections (LRTIs) are one of the fatal diseases of the lungs that have severe impacts on public health and the global economy. The currently available antibiotics administered orally for the treatment of LRTIs need high doses with frequent administration and cause dose-related adverse effects. To overcome this problem, we investigated the development of ciprofloxacin (CIP) loaded poly(2-ethyl-2-oxazoline) (PEtOx) nanoparticles (NPs) for potential pulmonary delivery from dry powder inhaler (DPI) formulations against LRTIs. NPs were prepared using a straightforward co-assembly reaction carried out by the intermolecular hydrogen bonding among PEtOx, tannic acid (TA), and CIP. The prepared NPs were characterized by scanning electron microscopy (SEM), dynamic light scattering (DLS), Fourier transform infrared spectroscopy (FTIR), powder X-ray diffraction analysis (PXRD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). The CIP was determined by validated HPLC and UV spectrophotometry methods. The CIP loading into the PEtOx was between 21-67% and increased loading was observed with the increasing concentration of CIP. The NP sizes of PEtOx with or without drug loading were between 196-350 nm and increased with increasing drug loading. The in vitro CIP release showed the maximum cumulative release of about 78% in 168 h with a burst release of 50% in the first 12 h. The kinetics of CIP release from NPs followed non-Fickian or anomalous transport thus suggesting the drug release was regulated by both diffusion and polymer degradation. The in vitro aerosolization study carried out using a Twin Stage Impinger (TSI) at 60 L/min air flow showed the fine particle fraction (FPF) between 34.4% and 40.8%. The FPF was increased with increased drug loading. The outcome of this study revealed the potential of the polymer PEtOx as a carrier for developing CIP-loaded PEtOx NPs as DPI formulation for pulmonary delivery against LRTIs.
| S-EPMC8699692 | biostudies-literature
Project description:Age appropriateness is a major concern of pulmonary delivery devices, in particular of dry powder inhalers (DPIs), since their performance strongly depends on the inspiratory flow manoeuvre of the patient. Previous research on the use of DPIs by children focused mostly on specific DPIs or single inspiratory parameters. In this study, we investigated the requirements for a paediatric DPI more broadly using an instrumented test inhaler. Our primary aim was to assess the impact of airflow resistance on children's inspiratory flow profiles. Additionally, we investigated children's preferences for airflow resistance and mouthpiece design and how these relate to what may be most suitable for them. We tested 98 children (aged 4.7-12.6 years), of whom 91 were able to perform one or more correct inhalations through the test inhaler. We recorded flow profiles at five airflow resistances ranging from 0.025 to 0.055 kPa0.5.min.L-1 and computed various inspiratory flow parameters from these recordings. A sinuscope was used to observe any obstructions in the oral cavity during inhalation. 256 flow profiles were included for analysis. We found that both airflow resistance and the children's characteristics affect the inspiratory parameters. Our data suggest that a medium-high resistance is both suitable for and well appreciated by children aged 5-12 years. High incidences (up to 90%) of obstructions were found, which may restrict the use of DPIs by children. However, an oblong mouthpiece that was preferred the most appeared to positively affect the passageway through the oral cavity. To accommodate children from the age of 5 years onwards, a DPI should deliver a sufficiently high fine particle dose within an inhaled volume of 0.5 L and at a peak inspiratory flow rate of 25-40 L.min-1. We recommend taking these requirements into account for future paediatric inhaler development.
| S-EPMC4047113 | biostudies-other
Project description:In this work, heat stable dry powders of oxytocin (OT) suitable for delivery by oral inhalation were prepared. The OT dry powders were prepared by spray drying using excipients chosen to promote OT stability including trehalose, isoleucine, polyvinylpyrrolidone, citrate (sodium citrate and citric acid), and zinc salts (zinc chloride and zinc citrate). Characterization by laser diffraction indicated that the OT dry powders had a median particle size of 2 μm, making them suitable for delivery by inhalation. Aerodynamic performance upon discharge from proprietary dry powder inhalers was evaluated by Andersen cascade impaction (ACI) and in an anatomically correct airway (ACA) model, and confirmed that the powders had excellent aerodynamic performance, with respirable fractions up to 77% (ACI, 30 L/min). Physicochemical characterization demonstrated that the powders were amorphous (X-ray diffraction) with high glass transition temperature (modulated differential scanning calorimetry, MDSC), suggesting the potential for stabilization of the OT in a glassy amorphous matrix. OT assay and impurity profile were conducted by reverse phase HPLC and liquid chromatography-mass spectrometry (LC-MS) after storage up to 32 weeks at 40°C/75%RH. Analysis demonstrated that OT dry powders containing a mixture of citrate and zinc salts retained more than 90% of initial assay after 32 weeks storage and showed significant reduction in dimers and trisulfide formation (up to threefold reduction compared to control).
| S-EPMC4666249 | biostudies-literature