Formoterol Research Articles

Greenness assessment of a molecularly imprinted polymeric sensor based on a bio-inspired polymer

Methyldopa, a synthesized dopamine substitute with phenolic, amine, and carboxylic groups, was used to create a selective molecular imprinted polymer (MIP) for detecting formoterol fumarate dihydrate (FFD), a long-acting beta2-agonist for asthma and COPD. The bio-inspired polymer (MD) was electro-grafted onto a pencil graphite electrode (PGE) using cyclic voltammetry in a phosphate buffer (pH 6.5). An indirect method involving a redox probe (ferrocyanide/ferricyanide) and differential pulse voltammetry measured FFD binding to the MIP’s 3D cavities. The sensor showed a linear response range from 1 × 10⁻⁹ M to 2 × 10⁻¹⁰ M, with a detection limit of 1.7 × 10⁻¹¹ M. The polymethyldopa (PMD) and FFD interaction was assessed by UV spectroscopy, and the method was validated per ICH guidelines. Green analytical approaches, including RGB and GAPI, were also implemented. The goal was to use advances in molecularly imprinted polymers to develop a more precise and selective electrochemical sensor for FFD quantification.

Effects of inhaled beclometasone dipropionate/formoterol fumarate/glycopyrronium vs. beclometasone dipropionate/formoterol fumarate and placebo on lung hyperinflation and exercise endurance in chronic obstructive pulmonary disease: a randomised controlled trial

BackgroundThe single-inhaler triple combination of beclometasone dipropionate, formoterol fumarate, and glycopyrronium (BDP/FF/G) is available for maintenance therapy of chronic obstructive pulmonary disease (COPD). Cardinal features of COPD are lung hyperinflation and reduced exercise capacity. TRIFORCE aimed to evaluate the effect of BDP/FF/G on lung hyperinflation and exercise capacity in patients with COPD.MethodsThis double-blind, randomised, active- and placebo-controlled, crossover study recruited adults with COPD aged ≥ 40 years, who were hyperinflated and symptomatic, and were receiving mono- or dual inhaled maintenance COPD therapy. In the three treatment periods, patients were randomised to receive BDP/FF/G, BDP/FF, or placebo, each for 3 weeks, with a 7–10-day washout between treatment periods. Assessments included slow inspiratory spirometry (for resting inspiratory capacity [IC]) and constant work-rate cycle ergometry (for dynamic IC and exercise endurance time). The primary objective was to compare BDP/FF/G and BDP/FF vs. placebo for resting IC at Week 3. Key secondary objectives were to compare BDP/FF/G and BDP/FF vs. placebo for dynamic IC and exercise endurance time during constant work rate cycle ergometry at Week 3.ResultsOf 106 patients randomised, 95 completed the study. Resting IC adjusted mean differences vs. placebo were 315 and 223 mL for BDP/FF/G and BDP/FF, respectively (p < 0.001 for both). Adjusted mean differences vs. placebo for the key secondary endpoints were: 245 mL for dynamic IC (p < 0.001) and 69.2 s for exercise endurance time (nominal p < 0.001) with BDP/FF/G, and 96 mL (p = 0.053) and 70.1 s (nominal p < 0.001) with BDP/FF. Differences between BDP/FF/G and BDP/FF for resting and dynamic IC were 92 and 149 mL (p < 0.01 for both). All three treatments were generally well tolerated, with 27.3%, 25.3% and 19.0% of patients reporting adverse events with BDP/FF/G, BDP/FF and placebo, respectively, all mild or moderate.ConclusionsIn patients with COPD, BDP/FF/G provided significant and clinically relevant improvements vs. placebo and BDP/FF in static and dynamic hyperinflation, with an improvement vs. placebo in exercise endurance.Trial registrationClinicalTrials.gov (NCT05097014), registered 27th October 2021.

Choice of therapy for patients who do not achieve control over bronchial asthma on basic therapy with medium doses of inhaled glucocorticosteroids/long-acting β2-agonists. Resolution of the Expert Council

Recently, new drugs for the treatment of bronchial asthma (BA) have been registered in the Russian Federation: fixed triple combinations, which include inhaled corticosteroids (ICS), long-acting β2-agonists (LABA) and anticholinergics, high-dose combinations of beclomethasone dipropionate (BDP) and formoterol (FORM) in the form of an extrafine metered-dose aerosol, which allows prescribing 800 mcg of extrafine BDP and 24 mcg of FORM per day.The aim of publishing the resolution of the Expert Council “Choice of therapy for patients who do not achieve control over bronchial asthma on basic therapy with medium doses of inhaled corticosteroids/long-acting β2-agonists” was to compare possible ways of therapy optimization and propose criteria for choosing therapeutic alternatives based on the individual clinical and phenotypic characteristics.Conclusion. If a patient does not achieve asthma control (or had asthma exacerbations over the past year) with alternative therapy at step 4, it is advisable to switch to a maintenance and relief therapy (MART) regimen with fixed combination of inhaled corticosteroids/formoterol and with medium doses of ICS in the maintenance part of the regimen. In patients with poor control on alternative therapy with a medium dose of ICS, it is advisable to consider increasing the dose of ICS as part of an ICS/LABA combination or as part of a triple combination instead of switching to MART. Switching to a medium- or high-dose triple combination is especially useful for patients with fixed obstruction and when bronchial asthma is combined with chronic obstructive pulmonary disease. In patients who require high-dose therapy, it is advisable to consider prescribing high doses of ICS using an extrafine combination of BDP/FORM (400/12 mcg in the morning and evening). If MART with a medium dose of ICS does not prevent exacerbations, provide normal spirometry results and/or good control of symptoms, MART in combination with an anticholinergic drug should be used at step 5. If triple therapy or high doses of ICS/LABA are insufficiently effective, biological therapy should be considered.

7726 Central Adrenal Insufficiency From Inhaled Mometasone Manifesting As Growth Deceleration

Abstract Disclosure: S. Gurnurkar: None. F.I. Cooper: None. Introduction: While long courses and/or high-doses of oral steroids have been found to cause adrenal suppression and resultant insufficiency, inhaled corticosteroids from asthma management typically do not affect cortisol production. However, in this case, we describe a patient who presented with 3 years of growth deceleration and was found to have adrenal suppression from her inhaled corticosteroid/long-acting beta agonist, Dulera (mometasone furoate and formoterol fumarate). Case Presentation: An 11-year-old female with history of moderate persistent asthma presented to our endocrinology department with growth deceleration and resultant short stature. The parent noted that the child started to decelerate in height percentiles from the 50th percentile at age 8 to the 6th percentile at age 11. BMI gradually rose from the 85th to 95th percentiles. The parent noted that the child started having worsening asthma symptoms around the start of the growth deceleration, requiring a handful of oral steroid courses and the addition of daily inhaled corticosteroid, Dulera. She had remained on the Dulera for the previous three years, with her asthma under good control. She also took cetirizine daily and albuterol as needed. The last course of oral steroids was three months prior to her first endocrinology visit. The patient’s mid-parental target height was at the 50th percentile and she denied fatigue, headache, or abdominal pain. Family history was negative for endocrine conditions and short stature. Puberty began at age 10. Further workup was recommended. A bone age was concordant with chronologic age. Initial labs including a TSH, free T4, IGF-1, IGFBP-3, CBC, ESR, and CMP were within normal limits. A growth hormone stimulation test with arginine and clonidine was performed. Growth hormone peak was 11 ng/mL, but, interestingly, cortisol resulted as &amp;lt;1.0 ug/dl throughout the test. Due to concerns of adrenal insufficiency, she underwent a high dose ACTH stimulation test. Initial ACTH was 6.3 pg/mL (ref 6-48 pg/mL) and cortisol remained at &amp;lt;1.0 ug/dl at 0, 30, and 60 mins. She was diagnosed with central adrenal insufficiency and prescribed 11 mg/m2 BSA/day of hydrocortisone divided three times daily, with stress dosing and emergency hydrocortisone injection instructions. Conclusion: The existing literature suggests that Dulera (mometasone furoate and formoterol fumarate) does not significantly influence adrenal function nor growth velocity. However, we present the case of a child with 3 years of inhaled Dulera use and significant central adrenal insufficiency. This case report is the first of its kind to detail decreased adrenal function with Dulera in particular. Presentation: 6/2/2024

FLUTICASONE FUROATE AND VILANTEROL (FF/VI) VERSUS FLUTICASONE PROPRIONATE AND FORMOTEROL (FP/FM) AS MAINTENANCE THERAPY IN STABLE ASTHMATIC PATIENTS- A COMPARATIVE STUDY

Background: Fluticasone furoate (FF) is a novel long-acting inhaled corticosteroid (ICS). Vilanterol (VI) is a long‐acting beta2‐agonist (LABA) that binds to the beta2‐adrenoceptor on the airway smooth muscle, producing bronchodilation. The corticosteroid fluticasone propionate (FP)and the long-acting β₂-adrenoceptor agonist (LABA) formoterol fumarate (FM) have been combined in a single, pressurized, metered-dose, aerosol inhaler for the maintenance treatment of patients aged ≥12 years with persistent asthma.This study evaluated the efficacy and safety of Fluticasone furoate 100 mcgandVilanterol 6 mcg versus Fluticasone proprionate 250 mcg and Formoterol 25 mcg for 12 weeks in patients with persistent asthma as maintenance therapy. Methods and Materials: A hospital based comparative study was conducted among stable asthmatic patients attended to Santhiram Medical College and General Hospital, Nandyal during January 2024 to June 2024(6months) by using convenient sampling method with sample size 60. Study tool was pre-designed, pre-tested, asthma control questionnaire5 (ACQ5),asthma control test (ACT) and Ask 12 adherence barrier survey. Results: Among 60 patients, 30 patients (Group1) were given Fluticasone furoate and Vilanterol and another 30 patients (Group 2) were given Fluticasone proprionate and Formoterol. All the patients (both the treatment groups) completed the 12 weeks treatment period. Improvements from baseline in 0- to 24-h wmFEV1 were observed with both FF/VI (376 mL) and FP/FM (353 mL) the adjusted mean treatment difference was not statistically significant. There were no differences between 0- to 4-h serial wmFEV1, asthma control test, ACQ5 and Ask 12 adherence barrier survey. There was no difference in reported exacerbations between treatments. Adverse events reported in the present study were not significant. Both treatments were well tolerated. Conclusion: The present study shows that the efficacy of once daily Fluticasone furoate and Vilanterol was not inferior as compared to the efficacy of twice daily Fluticasone proprionate and Formoterol as maintenance therapy in stable asthmatic patients. Howevertreatment with once daily FF/VI has the advantage of forgetfulness and inconvenience of inhalation.Henceonce daily FF/VI can be also useful for stable asthmatic patients as maintenance therapy as FF/VI DPI treatment.

Integration of mucus and its impact within in vitro setups for inhaled drugs and formulations: Identifying the limits of simple vs. complex methodologies when studying drug dissolution and permeability

Traditionally, developing inhaled drug formulations relied on trial and error, yet recent technological advancements have deepened the understanding of ‘inhalation biopharmaceutics’ i.e. the processes that occur to influence the rate and extent of drug exposure in the lungs. This knowledge has led to the development of new in vitro models that predict the in vivo behavior of drugs, facilitating the enhancement of existing formulation and the development of novel ones. Our prior research examined how simulated lung fluid (SLF) affects the solubility of inhaled drugs. Building on this, we aimed to explore drug dissolution and permeability in lung mucosa models containing mucus. Thus, the permeation of four active pharmaceutical ingredients (APIs), salbutamol sulphate (SS), tiotropium bromide (TioBr), formoterol fumarate (FF) and budesonide (BUD), was assayed in porcine mucus covered Calu-3 cell layers, cultivated at an air liquid interface (ALI) or submerged in a liquid covered (LC) culture system. Further analysis on BUD and FF involved their transport in a mucus-covered PAMPA system. Finally, their dissolution post-aerosolization from Symbicort® was compared using ‘simple’ Transwell and complex DissolvIt® apparatuses, alone or in presence of porcine mucus or polymer-lipid mucus simulant. The presence of porcine mucus impacted both permeability and dissolution of inhaled drugs. For instance, permeability of SS was reduced by a factor of ten in the Calu-3 ALI model while the permeability of BUD was reduced by factor of two in LC and ALI setups. The comparison of dissolution methodologies indicated that drug dissolution performance was highly dependent on the setup, observing decreased release efficiency and higher variability in Transwell system compared to DissolvIt®. Overall, results demonstrate that relatively simple methodologies can be used to discriminate between formulations in early phase drug product development. However, for more advanced stages complex methods are required. Crucially, it was clear that the impact of mucus and selection of its composition in in vitro testing of dissolution and permeability should not be neglected when developing drugs and formulations intended for inhalation.

Advances in inhaler therapy for asthma and chronic obstructive pulmonary disease: a comprehensive review of Fostair™ and Trimbow™.

The management of asthma and chronic obstructive pulmonary disease (COPD) poses considerable challenges due to the intricate nature of these respiratory conditions. Fostair™ and Trimbow™, two pressurized metered dose inhalers, have emerged as noteworthy therapeutic options for treating both asthma and COPD. Fostair combines an inhaled corticosteroid, specifically beclometasone dipropionate, with a long-acting beta2-agonist, formoterol fumarate dihydrate, offering a dual-action approach to mitigate airway inflammation and bronchoconstriction. Conversely, Trimbow integrates a tri-particulate formulation consisting of beclometasone dipropionate, formoterol fumarate dihydrate, and glycopyrronium bromide, providing a comprehensive strategy to target the pathophysiology of COPD and asthma. Recent clinical trials have underscored Trimbow's superior efficacy compared with Fostair, particularly in terms of reducing exacerbation rates and enhancing lung function. However, despite their therapeutic promise, both inhalers encounter challenges, including limited generalizability of study findings and a disparity between in vitro and human trial results. This literature review offers an in-depth analysis of Fostair and Trimbow, delving into their mechanisms of action, clinical applications, and outcomes in human studies for asthma and COPD. Additionally, the review discusses the role of combination therapy in managing respiratory diseases and underscores the necessity for further research to address existing knowledge gaps and optimize therapeutic outcomes.

Development and Validation of a Viable and User-Friendly Spectrophotometric Analytical Method for Estimation of Assay of Formoterol and Beclomethasone in Metered Dose Inhaler Formulation

The primary aim of this research endeavor is to innovate a viable and user-friendly UV spectroscopic approach for quantifying formoterol and beclomethasone within metered dose inhalers (MDIs). These formulations, amalgamating Beclomethasone Dipropionate (BDP) and Formoterol Fumarate (FF), are extensively employed in managing bronchial asthma and chronic obstructive pulmonary diseases. Although analytical techniques already exist for assessing formoterol and beclomethasone in combination dry powder inhalers, this study concentrates on devising and validating a UV spectrophotometric method for simultaneously quantifying formoterol fumarate and Anhydrous Beclomethasone Dipropionate in Pressurized Metered Dose Inhalers (pMDIs). The estimation is performed at a wavelength of 240 nm for Beclomethasone Dipropionate and 216 nm for Formoterol Fumarate. Both drugs demonstrate satisfactory linearity within the concentration range of 10-30 μg/ml for BDP and 0.3 to 0.9 μg/ml for FF at wavelengths of 240 nm (r^2=0.999) and 216 nm (r^2=0.999), respectively. The Beer-Lambert law is adhered to within the concentration range of 10-30 μg/ml for BDP and 0.3-0.9 μg/ml for FF. The proposed methods are subjected to validation following ICH guidelines to assess accuracy, method precision, specificity, among other parameters. As a result, the proposed method can be effectively employed for the simultaneous determination of Beclomethasone Dipropionate and Formoterol Fumarate in routine analytical applications, offering a rapid and reliable solution for pharmaceutical analysis in the field.

Efficacy and safety of Once-Daily Vilanterol/Fluticasone furoate MDI in persistent asthma: Phase 3 OD-INHALE Study

Introduction Once-daily inhalers have been shown to improve adherence leading to lesser discontinuation compared to twice- or thrice-daily inhalers in management of asthma. Combination of Vilanterol and Fluticasone Furoate (VI/FF) is approved for management of asthma and COPD and is available as a dry powder inhaler. Pressurized-Metered Dose Inhalers (pMDIs) offer ease-of-use and therapy alternatives for patients with low inspiratory flow. This study assessed the efficacy and safety of a new once-daily pMDI containing VI/FF in individuals diagnosed with persistent asthma. Methods This phase 3, double-blind, randomized controlled study assessed the non-inferiority of VI/FF (12.5 mcg/50 mcg & 12.5 mcg/100 mcg; 2 puffs once-daily) over Formoterol Fumarate and Fluticasone Propionate (FOR/FP, 6 mcg/125 mcg & 6 mcg/250 mcg; 2 puffs twice-daily) in patients with persistent asthma. Primary outcome was change from baseline in trough FEV1 at the end of study (12 weeks). Adverse events and number of exacerbations were used to evaluate safety. Results A total of 330 patients were randomized into VI/FF (165) and FOR/FP (165). Trough FEV1 significantly improved in both the groups at week 12, with a mean difference (VI/FF minus FOR/FP) being 54.75 mL (95% CI, 8.42–101.08 mL, p = 0.02). The low dose VI/FF had similar efficacy to that of low dose FOR/FP and high dose VI/FF had similar efficacy to high dose FOR/FP. No serious adverse events were reported during the study. Conclusion Once daily VI/FF pMDI was non-inferior to twice daily FOR/FP pMDI in patients with persistent asthma.

Compatibility study of formoterol fumarate-lactose dry powder inhalation formulations: Spray drying, physical mixture and commercial DPIs

Formoterol fumarate (FF) is a long-acting beta-adrenergic receptor agonist that is administered as a dry powder inhaler (DPI) for chronic respiratory conditions. In most DPI formulations, the drug substance and the carrier are the two major components. Lactose is the most common carrier, which can undergo a Maillard reaction in the presence of primary and secondary amines. FF contains a secondary amine. Since the potential for Maillard reaction in DPI formulations has not been investigated yet, this study aims to investigate any potential reaction between lactose and FF. The formulations were prepared using a tubular mixer and spray drying techniques. FF and lactose were blended using a tubular mixer (TM FF-Lac). In the spray drying method, FF and lactose were dissolved in distilled water: MeOH and then spray dried (SD FF-Lac). The samples were stored at both ambient conditions and elevated temperature and humidity (40 °C ± 2, 75% ± 5 RH), and subsequently analyzed to identify any signs of incompatibilities. Differential scanning calorimetry (DSC), field emission scanning electron microscopy (FE-SEM), X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), thin-layer chromatography (TLC), high-performance liquid chromatography (HPLC), and liquid chromatography-mass spectrometry (LC-MS-MS) were employed for sample analysis. The in vitro aerosolization performance was evaluated using a next-generation impactor (NGI). The results showed that the colour of the DPI formulations changed from white to brown after storage at elevated temperature and humidity. Although the SD FF-Lac had better aerosolization properties, it was more vulnerable to degradation due to its amorphous nature. The FF-lactose adduct was formed in all samples. Interestingly, adduct compounds were also detectable before the storage for stability and stress tests. Incompatibility was confirmed by HPLC-PDA analysis. The mass spectra revealed the m/z of the adduct compound and confirmed the Millard reaction. Browning occurred in the prepared DPI formulations following storage at elevated temperature and humidity. Moreover, adduct compounds were also found in DPI formulations kept at ambient conditions and commercial DPI. Overall, mass spectroscopy was capable of detecting the incompatibility.

Budesonide/Formoterol or Budesonide/Albuterol as Anti-Inflammatory Reliever Therapy for Asthma

Over use of reliever as short acting beta-agonist (SABA) and associated underuse of controller as inhaled corticosteroid (ICS) administered via separate inhalers results in worse asthma outcomes . Such discordance can be obviated by combining both controller and reliever in the same inhaler. So called anti-inflammatory reliever (AIR) therapy comprises the use of a single inhaler containing an ICS such as budesonide (BUD) in conjunction with a reliever as either albuterol (ALB) or formoterol (FORM) ,to be used on demand with variable dosing driven by asthma symptoms in a flexible patient centred regimen. Global guidelines now support the use of BUD-ALB as AIR therapy to reduce exacerbations , either on its own in mild asthma or in conjunction with fixed dose maintenance ICS-long acting beta-agonist (LABA) in moderate to severe asthma . Using BUD-FORM on its own allows patients to seamlessly move in an intuitive flexible fashion between AIR or maintenance and reliever therapy (MART) , by stepping up and down the dosing escalator across a spectrum of asthma severities . Head to head clinical studies are indicated to compare BUD-FORM versus BUD-ALB as AIR in mild asthma ,and also BUD-FORM as MART versus BUD-ALB as AIR plus maintenance ICS-LABA in moderate to severe asthma. Patients should be encouraged to make an informed decision in conjunction with their health care professional regarding the best therapeutic option tailored to their individual needs , which in turn is likely to result in long term compliance and associated optimal asthma control.

Formoterol reduces muscle wasting in mice undergoing doxorubicin chemotherapy.

Even though doxorubicin (DOX) chemotherapy promotes intense muscle wasting, this drug is still widely used in clinical practice due to its remarkable efficiency in managing cancer. On the other hand, intense muscle loss during the oncological treatment is considered a bad prognosis for the disease's evolution and the patient's quality of life. In this sense, strategies that can counteract the muscle wasting induced by DOX are essential. In this study, we evaluated the effectiveness of formoterol (FOR), a β2-adrenoceptor agonist, in managing muscle wasting caused by DOX. To evaluate the effect of FOR on DOX-induced muscle wasting, mice were treated with DOX (2.5 mg/kg b.w., i.p. administration, twice a week), associated or not to FOR treatment (1 mg/kg b.w., s.c. administration, daily). Control mice received vehicle solution. A combination of FOR treatment with DOX protected against the loss of body weight (p<0.05), muscle mass (p<0.001), and grip force (p<0.001) promoted by chemotherapy. FOR also attenuated muscle wasting (p<0.01) in tumor-bearing mice on chemotherapy. The potential mechanism by which FOR prevented further DOX-induced muscle wasting occurred by regulating Akt/FoxO3a signaling and gene expression of atrogenes in skeletal muscle. Collectively, our results suggest that FOR can be used as a pharmacological strategy for managing muscle wasting induced by DOX. This study provides new insights into the potential therapeutic use of FOR to improve the overall wellbeing of cancer patients undergoing DOX chemotherapy.

Assessment of Critical Quality Attributes of Budesonide and Formoterol Fumarate Dihydrate in Dry Powder Inhalers Marketed in Pakistan

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 and#181;m 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 and#181;m 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.

Determination of Formoterol Fumarate in Pharmaceutical Formulations by Voltammetric Technique using a Novel Methyl Orange Layered Sensor

Determination of Formoterol Fumarate in Pharmaceutical Formulations by Voltammetric Technique using a Novel Methyl Orange Layered Sensor

Simultaneous UPLC Assay for Oxitropium Bromide and Formoterol Fumarate Dihydrate in Pressurized Metered Dose Inhaler Products for Chronic Obstructive Pulmonary Disease.

Oxitropium bromide (OB) and formoterol fumarate dihydrate (FFD) are inhaler molecules that are widely used in the treatment of chronic lung diseases. The goal of this work was to create a reversed phase-ultra performance liquid chromatography (RP-UPLC) technique for assay and identification of OB and FFD, as well as identification and estimate of its associated compounds in pressurized metered dose inhaler product (pMDI). Separation of oxitropium and formoterol peaks were enhanced on a C18 (50 × 2.1 mm × 1.7 μm) UPLC column with ethylene-bridged-hybrid technology, The mobile phase consists of buffer (0.07 M KH2PO4) and acetonitrile (80:20, v/v). The detector wavelength of 210 nm, flow rate of pump 0.6 mL/min, and oven temperature for column were set at 25°C. The injection volume was 10 μL. The method run time was 2 min. The mobile phase was used as the solvent. Retention times (RTs) were 0.5 min for OB and 1.0 min for FFD. The assay analysis was linear range for all analytes within the range for concentrations 0.03-14.8 µg/mL of OB, 0.01-0.88 µg/mL of FFD. LOD values and LOQ values 0.009 and 0.026 µg/mL for OB and 0.003 and 0.009 µg/mL for FFD, respectively. Recoveries were obtained at 96.3% for OB and 97.2% for FFD. Precisions values were (as RSD, %) ≤1.5%. With the UPLC method developed and validated according to the current ICH guidelines, it is possible to simultaneously detect OB and FFD of assay analysis in pMDI products accurately, precisely and selectively, independent of the matrix effect. The present method is the first method in the literature based on the UPLC method for this purpose. The UPLC method is a time-saving method, it provides a faster and cheaper technique than the high performance liquid chromatography (HPLC) method.

Evaluation of the antioxidant and anti-inflammatory effect of sublingual glutathione on COPD patients.

Glutathione (GSH) is a potent antioxidant and anti-inflammatory, proven effective in reducing treatment duration, prescribed doses, and hospitalization for several diseases. This study assessed the therapeutic response of chronic obstructive pulmonary disease (COPD) patients by measuring oxidative superoxide dismutase (SOD3), glutathione peroxidase 1 (GPX1), and inflammatory biomarkers such as tumor necrosis factor-alpha (TNF-α) and Interleukin-8 (IL-8) after sublingual administration of glutathione supplements. A cohort of 50 COPD individuals was involved and divided into two groups of 25 each. The first group received conventional therapy involving the administration of formoterol fumarate (12 µg inhaler) twice daily. The second group received the conventional treatment alongside sublingual glutathione (300 mg twice daily) for two months. The levels of serum IL-8, TNF-α, SOD3, and GPX1 were assessed before therapy, as well as at one and two months after treatment, in both cohorts. Both groups exhibited a notable reduction in the inflammatory mediators IL-8 and TNF-α when compared to their respective pre-treatment levels (P value <0.05). However, it is worth noting that the observed difference between the groups was not statistically significant (P value >0.05). The levels of SOD3 and GPX1 exhibited a substantial rise in both groups; however, they were found to be greater in group 2 compared to group 1 (P value >0.05). The administration of glutathione resulted in enhanced levels of antioxidant biomarkers among individuals diagnosed with COPD, accompanied by a minor and statistically insignificant decrease in the levels of the anti-inflammatory mediators IL-8 and TNF-alpha.

Simultaneous Quantification of Mometasone Furoate and Formoterol Fumarate in Bulk and Formulations by RP-HPLC Method

A simple and robust reversed-phase high pressure liquid chromatographic method was developed and validated for the quantification of Mometasone and Formoterol in bulk and fixed dosage forms. The column utilized for study was Inertsil C18, ODS was chosen for good peak shape. Ambient temperature was found to be suitable for the nature of drug solution. The mobile phase was streamlined with a ratio of 35:65 Methanol: Water was optimized for symmetrical peaks and good resolution. The flow rate was streamlined at 1.0 ml/min because of good peak area, satisfactory retention time and good resolution. Common λ-max was found to be at 278 nm and Injection volume was 20 µl which gave a good peak area. The percentage recovery was found to be 98.0-101.50 was linear and precise over the same range. Both system and method precision was found to be accurate and well within the acceptable limits. Detection limit was found to be 0.25 Mometasone and 0.34 for Formoterol. The analytical method was found linearity over the range of 20-80 ppm of the target concentration for both the drugs. The LOD and LOQ values for Mometasone, was observed to be 0.25 and 0.77 and for Formoterol was in the range of 0.34 and 1.05 consecutively. The analytical method passed both intermediate precision and robustness tests. On both cases, relative standard deviation was well satisfactory. The validation experiments met ICH standards. It inferred the method found to be simple, accurate, precise and linear. The method was found to be having suitable application in routine laboratory analysis with high degree of accuracy and precision.

Polysorbate 80 surface modified SLNs of formoterol suppress SNCA gene and mitochondrial oxidative stress in mice model of Parkinson’s disease

The present study hypothesises that the selective brain β2 receptor activation through β2-adrenoreceptor agonist (β2ARA), Formoterol (FMT), suppresses SNCA gene expression, a pathological hallmark of Parkinson’s disease (PD) in brain. Further, it is also hypothesized that brain targeted delivery of Formoterol via polysorbate-80 surface modified solid lipid nanoparticles of Formoterol (FMT-SLNs-PS80) can improve its stability, therapeutic efficacy and avoid/reduce peripheral off-target side effects. FMT-SLNs-PS80 was prepared by solvent injection method, the formulation was optimized by using Box–Behnken design and characterized by measuring drug content, entrapment efficacy, particle size, zeta potentials and poly dispersibility. The FMT-SLNs-PS80, significantly decreases the SNCA expression, mitochondrial membrane damage and rotenone induced changes in oxidative (SOD, CAT, GSH and ROS) stress markers in SH-SY5Y cell lines. The ex vivo permeation study of the formulation using everted chicken ileum exhibited a steady state flux. The pharmacokinetic and tissue distribution studies of the formulation in rats showed a significant improvement in the kinetic parameters when compared to naïve FMT, further the formulation also improved the brain bioavailability of FMT. The anti-Parkinson’s efficacy studies of the formulation in mice showed a significant neuroprotection against rotenone-induced changes in behavioural and biochemical parameters. Further, the histopathological analysis of mice brain confirms a significant neuroprotective benefit. The present study successfully establishes the brain targeted delivery and anti-Parkinson’s therapeutic efficacy of FMT-SLNs-PS80.

Formoterol Exerts Anti-Cancer Effects Modulating Oxidative Stress and Epithelial-Mesenchymal Transition Processes in Cigarette Smoke Extract Exposed Lung Adenocarcinoma Cells.

Lung cancer frequently affects patients with Chronic Obstructive Pulmonary Disease (COPD). Cigarette smoke (CS) fosters cancer progression by increasing oxidative stress and by modulating epithelial-mesenchymal transition (EMT) processes in cancer cells. Formoterol (FO), a long-acting β2-agonist widely used for the treatment of COPD, exerts antioxidant activities. This study explored in a lung adenocarcinoma cell line (A549) whether FO counteracted the effects of cigarette smoke extract (CSE) relative to oxidative stress, inflammation, EMT processes, and cell migration and proliferation. A549 was stimulated with CSE and FO, ROS were evaluated by flow-cytometry and by nanostructured electrochemical sensor, EMT markers were evaluated by flow-cytometry and Real-Time PCR, IL-8 was evaluated by ELISA, cell migration was assessed by scratch and phalloidin test, and cell proliferation was assessed by clonogenic assay. CSE significantly increased the production of ROS, IL-8 release, cell migration and proliferation, and SNAIL1 expression but significantly decreased E-cadherin expression. FO reverted all these phenomena in CSE-stimulated A549 cells. The present study provides intriguing evidence that FO may exert anti-cancer effects by reverting oxidative stress, inflammation, and EMT markers induced by CS. These findings must be validated in future clinical studies to support FO as a valuable add-on treatment for lung cancer management.

Comparison of extrafine beclomethasone dipropionate/formoterol fumarate dry powder inhaler and pressurized metered-dose inhaler in Chinese patients with asthma: the FORTUNE study

Objective When selecting inhaled therapies, it is important to consider both the active molecules and the device. Extrafine formulation beclomethasone dipropionate plus formoterol fumarate (BDP/FF) has been available for some years delivered via pressurized metered-dose inhaler (pMDI). More recently, a breath-activated, multi-dose dry-powder inhaler (DPI), the NEXThaler, has been approved. The current study aimed to demonstrate the non-inferiority of BDP/FF delivered via the DPI vs. via the pMDI, in Chinese adults with asthma. Methods After a four-week run-in period, when all patients received BDP/FF pMDI 100/6 µg, two inhalations twice daily (BID), patients were randomized equally to BDP/FF pMDI or DPI, both 100/6 µg, two inhalations BID for 12 weeks. The primary objective was to demonstrate non-inferiority of BDP/FF DPI vs. BDP/FF pMDI in terms of average pre-dose morning peak expiratory flow (PEF) over the entire treatment period. Results Of 252 and 242 patients in the DPI and pMDI groups, respectively, 88.5% and 88.8% completed the study. The primary objective was met, with no statistically significant difference between the treatments in average pre-dose morning PEF, and with the lower limit of the 95% CI above the −15 L/min non-inferiority margin (adjusted mean difference: 5.25 L/min [95% CI: −0.56, 11.06]). Adverse events were reported by 48.4% and 49.6% patients in the DPI and pMDI groups, respectively, most mild or moderate. Conclusions The NEXThaler DPI is a similarly effective device to the pMDI for the administration of BDP/FF in adults, so extending the options available for the management of asthma.