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Formoterol fumarate dihydrate (FFD) is a long-acting β2 agonist, while Fluticasone propionate (FP) is a synthetic glucocorticoid receptor agonist. Both are used to manage chronic asthma and chronic obstructive pulmonary disease. The objective of this work is the quantitative analysis of the two drugs concurrently in their pure raw powder and medication dosage form, synthetic laboratory mixtures by three simple, precise, sensitive, and accurate spectrophotometric techniques operating on ratio spectra with the advantages of low-cost, high sensitivity, and no previous separation. Method (I) is based on the ratio subtraction method, which allows FP to be determined without the interference of FFD at its λmax of 236 nm. Method (II) is the first derivative of the ratio spectra, which enabled the measurement of peak amplitude of D1 spectra at 233.2 nm for FP and 301.0 nm for FFD. Method (III) is the ratio difference spectrophotometry, where the difference in values between (214.4 and 236.0 nm) was calculated for the determination of FP; and the difference of peak amplitudes at 270.0 and 290.0 nm for the estimation of FFD. The linearity of the calibration curve considered the range of concentrations of 2.0–12.0 and 2.5–25.0 µg/mL for FFD and FP, respectively. The accuracy and precision of the three achieved methods have been assayed to verify their validation according to ICH guidelines. They were 100.1 ± 1.3, 101.5 ± 0.5, and 101.2 ± 1.2 for FP, and 99.2 ± 1.6 and 100 ± 2 related to FFD. Regarding precision, the relative standard deviation was not more than 1.5%. The specificity of the three methods was estimated through their determination in various synthetic laboratory mixes. Additionally, the obtained results by the suggested procedures are compared statistically to those obtained by the reported HPLC technique. Another statistical comparison was done using a one-way ANOVA test; all of them showed no discernible differences. The three methods are specific, simple, and do not require sophisticated instruments. They can be employed in quality control laboratories for routine assays of two drugs in pure raw powder, synthetic laboratory-prepared mixes, and medication dosage forms quantitatively, and have been successfully utilized and validated. [ABSTRACT FROM AUTHOR]

Summary: Dry powder inhalers (DPIs) have been well established and recognized for the delivery to the lungs. It provides better drug stability, less irritable, easy to use with deep penetration of drugs in the lungs. Budesonide (BDS) and formoterol fumarate dihydrate (FFD) indicated in pulmonary diseases. The main aim of the study is to evaluate BDS, FFD and their marketed DPIs product in Pakistan were compare in quality and performance with the reference product. The particle size distribution and aerodynamic characterization were analyzed by laser diffraction and multi stage liquid impinger, respectively. The particle density and delivered dose uniformity were also determined. HPLC was also used for the qualitative and quantitative estimation of BDS and FFD along with its marketed products. Laser diffraction particle size analyzer revealed Dv50 53.27 to 56.34 µm having surface area 1815 to 2304 cm3/g. The percentages of emitted dose (%ED) and fine particle fraction (%FPF) was found 98.19 to 99.23% and 31.57 to 34.87%, respectively. The mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) were calculated 2.62 to 2.89 µm and 1.99 to 2.54, correspondingly. The quantitative assay of BDS and FFD in all the commercial DPIs and reference product were well within the pharmacopeial limit i.e. 97.26 to 101.36%. The average of ten units results of delivered dose uniformity for BSD and FFD were also found in the range i.e. 97.97 to 103.19% and 98.48 to 104.41 %, respectively. The results of evaluation of parameters of DPIs like Dv50, %ED, %FPF, MMAD, GSD has shown compliance with the pharmacopeial standards. It is concluded that the all DPIs of BDS/FFD marketed in Pakistan has revealed conformance with the standard of pharmacopoeia and meet the requirements of drug regulatory authority of Pakistan. [ABSTRACT FROM AUTHOR]

This study aimed to design and characterize an inhalable dry powder of mometasone furoate monohydrate (MFM) combined with the formoterol fumarate dihydrate (FFD). Homogenization in water and spray drying processes were used to prepare the dry powders for inhalation. The physicochemical characteristics of the dry powders were evaluated by differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FT-IR), X-ray diffractometry (XRD) and scanning electron microscopy (SEM). The particle size distribution, content uniformity, solid behavior and aerodynamic properties of DPI were also determined. After the micronization process, the particle sizes of the raw materials significantly decreased. SEM images implied that FFD covered the MFM surface during the spray drying step, and uniform particles were produced. X-ray and DSC results demonstrated that MFM did not show any change in crystal structure after homogenization and spray drying processes. DSC analysis of DPI formulation exhibited that the same melting point of MFM was observed when the drugs were spray dried. FT-IR spectra exhibited the characteristic peaks for MFM in DPI formulation. Content uniformity results showed that the developed production method is suitable for manufacturing uniform formulations. According to angle of repose, Hausner ratio and Carr's index results, DPI formulation has preferable flow properties. In addition, emitted dose, mass median aerodynamic diameter, fine particle fraction showed that the DPI formulation could ensure drug delivery to the alveoli. This study showed that the combination of homogenization and spray drying methods is suitable to obtain a DPI formulation containing MFM and FFD with a particle size less than 5 µm to reach alveoli. [ABSTRACT FROM AUTHOR]

Background: The Phase III PINNACLE studies assessed the efficacy and safety of glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI), a dual long-acting bronchodilator for chronic obstructive pulmonary disease (COPD). Here we present a pre-specified pooled analysis of PINNACLE-1, PINNACLE-2, and PINNACLE-4.Methods: PINNACLE-1, -2, and -4 were multicenter, double-blind, randomized controlled trials that enrolled patients with moderate-to-very severe COPD, with no requirement for exacerbation history or a high symptom burden. Patients received GFF MDI 18/9.6 μg, glycopyrrolate (GP) MDI 18 μg, formoterol fumarate (FF) MDI 9.6 μg, or placebo MDI, twice-daily for 24 weeks. The primary endpoint of the pooled analysis was the change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV1) at week 24. Secondary endpoints included COPD exacerbations and clinically important deterioration (CID). Adverse events were also assessed.Results: The pooled intent-to-treat population included 4983 patients; of these, 61.9% had a COPD assessment test (CAT) score ≥15, and 25.0% had experienced ≥1 moderate/severe exacerbation in the past year. At week 24, GFF MDI improved morning pre-dose trough FEV1 versus GP MDI (least squares mean [LSM] difference [95% confidence interval (CI)]: 59 mL [43, 75]), FF MDI (65 mL [48, 81]), and placebo MDI (146 mL [125, 166]); all p < 0.0001. GFF MDI reduced the risk of a moderate/severe exacerbation by 18% (p = 0.0168), 15% (p = 0.0628), and 28% (p = 0.0012) compared with GP MDI, FF MDI, and placebo MDI, respectively. In general, exacerbation risk reduction with GFF MDI versus comparators was greater in subgroups of symptomatic patients (CAT ≥15) and those who had an exacerbation history, than in the pooled intent-to-treat population. The risk of CID was also lower with GFF MDI versus GP MDI (23% decrease), FF MDI (17%), and placebo MDI (49%); all p < 0.0001. All treatments were well tolerated, with no unexpected safety signals.Conclusions: This pooled analysis of the PINNACLE studies demonstrated that GFF MDI improved lung function and reduced the risk of exacerbations compared with monocomponents and placebo in patients with COPD. Exacerbation reductions with GFF MDI versus comparators were generally greater in patients with higher symptom burden and those with exacerbation history.Trial Registration: ClinicalTrials.gov NCT01854645, NCT01854658, and NCT02343458. Registered 13 May 2013 (NCT01854645, NCT01854658) and 6 January 2015 (NCT02343458). [ABSTRACT FROM AUTHOR]

Lack of coordination between the beginning of the inhalation and device triggering is one of the most frequent errors reported in connection with the use of pMDI devices. Earlier results suggested a significant loss in lung deposition as a consequence of late actuation. However, most of our knowledge on the effect of poor synchronization is based on earlier works on CFC devices emitting large particles with high initial velocities. The aim of this study was to apply numerical techniques to analyse the effect of late device actuation on the lung dose of a HFA pMDI drug emitting high fraction of extrafine particles used in current asthma and COPD therapy. A computational fluid and particle dynamics model was combined with stochastic whole lung model to quantify the amount of drug depositing in the extrathoracic airways and in the lungs. High speed camera measurements were also performed to characterize the emitted spray plume. Our results have shown that for the studied pMDI drug late actuation leads to reasonable loss in terms of lung dose, unless it happens in the second half of the inhalation period. Device actuation at the middle of the inhalation caused less than 25% lung dose reduction relative to the value characterizing perfect coordination, if the inhalation time was between 2 and 5 s and inhalation flow rate between 30 and 150 L/min. This dose loss is lower than the previously known values of CFC devices and further support the practice of triggering the device shortly after the beginning of the inhalation instead of forcing a perfect synchronization and risking mishandling and poor drug deposition. [ABSTRACT FROM AUTHOR]

The budesonide/glycopyrronium/formoterol fumarate dihydrate metered dose inhaler (BGF MDI) is an inhaled corticosteroid/long-acting muscarinic antagonist/long-acting β 2 -agonist fixed-dose combination formulated with innovative co-suspension delivery technology that is in clinical development for the treatment of chronic obstructive pulmonary disease (COPD). This randomized, Phase I, single-dose, six-treatment, four-period, crossover study (NCT01980615) examined the pharmacokinetic (PK) and safety profile of three doses of BGF MDI (320/14.4/10 μg [equivalent to budesonide/glycopyrrolate/formoterol fumarate 320/18/9.6 μg], 160/14.4/10 μg and 80/14.4/10 μg), two doses of a budesonide/formoterol fumarate dihydrate fixed-dose combination (BUD/FORM MDI 320/9 μg and 160/9 μg; not using co-suspension delivery technology) and a glycopyrronium/formoterol fumarate dihydrate co-suspension delivery technology MDI (GFF MDI 14.4/10 μg) in healthy volunteers (18–45 years of age). PK parameters included area under the plasma concentration–time curve from 0 to 12 h (AUC 0–12 ), AUC up to the last measurable concentration (AUC 0–t ), maximum plasma concentration (C max ) and time to maximum plasma concentration (t max ). Safety was monitored throughout the study. Of 84 subjects randomized, 76 completed the study. BGF MDI 320/14.4/10 μg was bioequivalent to BUD/FORM MDI 320/9 μg for budesonide for C max , AUC 0–12 and AUC 0–t (primary objective). Dose proportionality was observed for the budesonide component between BGF MDI 80/14.4/10 μg and BGF MDI 160/14.4/10 μg, and between BGF MDI 160/14.4/10 μg and BGF MDI 320/14.4/10 μg. Systemic exposure to glycopyrronium and formoterol after BGF MDI 320/14.4/10 μg treatment was similar to GFF MDI 14.4/10 μg. The rate of adverse events was 3.7–17.9% across treatments without any serious adverse events. In conclusion, BGF MDI 320/14.4/10 μg had a similar budesonide PK profile to BUD/FORM MDI 320/9 μg. No PK drug–drug interactions were observed when budesonide was added to glycopyrronium and formoterol fumarate dihydrate. These data support the use of budesonide 320 μg and 160 μg in future clinical trials of BGF MDI in COPD. [ABSTRACT FROM AUTHOR]

This gamma scintigraphy imaging study was the first to assess pulmonary and extrathoracic deposition and regional lung deposition patterns of a radiolabelled long-acting muscarinic antagonist/long-acting β 2 -agonist fixed-dose combination glycopyrronium/formoterol fumarate dihydrate (GFF) 14.4/10 μg (equivalent to glycopyrrolate/formoterol fumarate 18/9.6 μg), delivered by pressurized metered dose inhaler (pMDI) using novel co-suspension delivery technology. In this Phase I, randomized, single-centre, single-blind, single-dose, two-treatment, crossover, placebo-controlled study (PT003020), 10 healthy male adults received two actuations of GFF pMDI (7.2/5.0 μg per actuation) and placebo pMDI (containing phospholipid-based porous particles without active pharmaceutical ingredient), both radiolabelled with 99m Tc, up to 5 MBq per actuation. Gamma scintigraphy images of lungs, stomach, head and neck were recorded. In addition, images of the actuators after use, collected mouth washings and exhalation filters were acquired. On average, 38.4% of the emitted dose of radiolabelled GFF pMDI, and 32.8% of radiolabelled placebo pMDI, was deposited in the lungs. The percentage emitted dose detected in the oropharyngeal and stomach regions was 61.4% and 66.9% for radiolabelled GFF pMDI and placebo pMDI, respectively. For both treatments, ≤ 0.25% of the emitted dose was detected in the exhalation filter. The normalized outer/inner ratio was 0.57 and 0.59 for radiolabelled GFF pMDI and placebo pMDI, respectively, and the standardized central/peripheral ratio was 1.85 and 1.94 respectively, indicating delivery of both co-suspension delivery technology formulations throughout the airways. There were no new or unexpected safety findings. In conclusion, both formulations were efficiently and uniformly deposited in the lungs with similar regional deposition patterns, oropharyngeal and stomach deposition, exhalation fraction and actuator-recovered dose. [ABSTRACT FROM AUTHOR]

In this study rapid, simple, accurate and sensitive spectrophotometric method has been developed for the determination of formoterol fumarate dihydrate in bulk and dosage forms. The method is based on the formation of yellow coloured ion pair complex due to the reaction of formoterol fumarate dihydrate (FF) and methyl orange (MO) at pH 4. Ion pair complex has a maximum absorption at 428 nm in chloroform and a linear calibration over the range of 4-20 µg/ mL. The slope of the calibration curve was 0.0433, limit of detection was 0.22 µg/mL and limit of quantification was 0.66 µg/mL. The proposed method has been applied to the assay of formoterol fumarate dihydrate commercially available capsules. There was no significiant difference between the results obtained by proposed and reference methods in view of accuracy and reproducibility. No interference was observed from common excipients. [ABSTRACT FROM AUTHOR]

• FFD could significantly inhibit EV-A71 replication in human neuronal cells by interfering the early stages of viral replication cycle. • FFD treatment exhibited the anti-apoptotic and anti-autophagy activities triggered by EV-A71 infected neuronal cells. To investigate antiviral activity, anti-apoptosis and anti-autophagy associated with antiviral effect of repurposing formoterol fumarate dihydrate (FFD) against enterovirus A71 (EV-A71) infection in human neuroblastoma cells. In vitro antiviral effects of FFD against EV-A71 infection were examined in human neuroblastoma SK-N-SH cells. The impacts on EV-A71 replication were evaluated by progeny virus production, viral RNA synthesis, and viral protein expression. The target of action of FFD against EV-A71 was determined from the effective stage by time-of-addition assay. Moreover, the anti-apoptosis and anti-autophagy activities associated with antiviral effect were observed by detection of apoptosis- and autophagy-related proteins. FFD significantly inhibited EV-A71 replication in neuronal cells through interfering the early stages of replication cycle which might be the steps during uncoating to viral protein synthesis. Additionally, FFD culminated in reducing of EV-A71-induced apoptosis and autophagy with caspase-3-cleaved form and LC3-II expression levels showed markedly decreased while increasing of Bcl-2 and mTOR expression levels. These might indicate the neuroprotective effect of FFD on EV-A71-induced apoptosis and autophagy. Preliminary mode of action studies showed that repurposing FFD significantly inhibited EV-A71 replication at early stage of viral replication and exhibited anti-apoptosis and anti-autophagy activities in neuronal cells. These findings may provide an opportunity, via drug repurposing of FFD, for a candidate antiviral drug against EV-A71 infection. [ABSTRACT FROM AUTHOR]

Objectives The formulation of multi-drug pressurised metered dose inhalers (pMDIs) opens up exciting therapeutic opportunities for the treatment of asthma and chronic obstructive pulmonary disease (COPD). We have investigated the formulation of a solution-based triple therapy pMDI containing ipratropium, formoterol, budesonide and ethanol as co-solvent. Methods This system was characterised for in-vitro performance and compared with marketed pMDIs (Atrovent and Symbicort). Key findings No significant difference was found in the stage deposition of each drug from the triple therapy formulation, suggesting that the droplets contained a fixed ratio of the three components used. Stage deposition of formoterol and budesonide from the suspension-based marketed Symbicort were significantly different, suggesting that the two drugs were deposited as separate entities. Calculation of the mass median aerodynamic diameter (MMAD) of each formulation suggested Atrovent (ipratropium, MMAD = 0.9 ± 0.0 µm) to have a small particle size, similar to the triple therapy formulation. Atrovent, like the triple therapy formulation was solution based and it contained ethanol as a co-solvent (triple therapy formulation, MMAD = 1.3 ± 0.0 µm). Conclusions This study demonstrated the feasibility of formulating a solution-based pMDI containing a triple therapy with identical deposition pattern for the treatment of several respiratory diseases where multi-drug cell targeting is required. [ABSTRACT FROM AUTHOR]