Indacaterol Research Articles

A dual methodology employing ion-pair chromatography and built-in UV spectrophotometry for quantifying recently approved combination of mometasone and indacaterol in a novel combined metered dose inhaler: assessing the greenness, carbon footprint, blueness, and whiteness

Developing analytical techniques that align with green and sustainable chemistry principles is crucial in today's scientific landscape. This work introduces two innovative approaches for the simultaneous quantification of indacaterol (IND) and mometasone (MOM), a recently approved combination therapy for chronic obstructive pulmonary disease. These methods—rapid isocratic ion pair chromatography (IPC) and UV–visible spectrophotometry—demonstrate improved environmental sustainability, cost-effectiveness, and versatility compared to existing techniques. The optimized 4-min IPC method achieved excellent resolution (retention times 2.18 ± 0.1 min for IND and 3.95 ± 0.1 min for MOM), peak symmetry, and sensitivity. It utilizes a low-cost ion pair mobile phase of acetonitrile and acidified water containing 0.025% sodium dodecyl sulfate (50:50% v/v), making it suitable for laboratories with standard chromatographic instruments. The spectrophotometric approach offers two procedures: first derivative and ratio derivative methods. These serve as simplified, low-cost alternatives for resource-limited laboratories without access to advanced instruments. Both techniques feature simplified protocols that minimize extraction and fractionation steps. Comprehensive validation confirmed outstanding accuracy (98–102%) and precision (%2 <). Sustainability assessments using ComplexGAPI, AGREE, carbon footprint, BAGI, and RGB12 tools demonstrated enhanced environmental performance compared to existing methods. The IPC and spectrophotometry methods achieved greenness scores of 0.81 and 0.85, respectively, surpassing the 0.63–0.67 range of reported techniques. Additionally, they showed lower carbon footprints of 0.035 and 0.022 kg CO2 equivalent emissions per sample, compared to 0.079–0.092 kg for conventional procedures. The application of novel "blueness" and "whiteness" concepts using BAGI and RGB12 algorithms further confirmed superior sustainability, with scores of 87.5 & 90 for blueness and 88.1 & 89.8 for whiteness. Successfully applied to quantify IND and MOM in combined capsules, this work provides a model for eco-friendly pharmaceutical analysis that maintains high analytical reliability while improving sustainability metrics.

Whiteness and greenness appraisal approaches for quantitative determination of recently approved combination of indacaterol and mometasone via utilization of nuclear magnetic resonance technique

Quantitative proton nuclear magnetic resonance (1H-qNMR) is currently being used in a variety of applications in many disciplines due to the great privileges. Economical and minimal solvent system volume is utilized; no sample labelling or pre-treatment is necessary. Furthermore, no sample destruction is occurred. The all aforementioned benefits are contributed to its suitability for employment in pharmaceutical companies and quality control laboratories. Starting from this significance, a simple, quick, and sustainable method was developed for the determination of indacaterol (IND) and mometasone (MOM) in the raw material and newly approved pharmaceutical dosage form Atectura Breezhaler®. The developed approach involved the utility of pyridoxine (PYR) as an internal standard (IS) and DMSO-d6 as the suitable deuterated solvent for the analysis. The quantitative peaks of IND (doublet at 8.247 and 8.254 ppm) and MOM (singlet at 1.014 ppm) were obviously disengaged from the IS peak; which was singlet peak at 8.082 ppm. The developed methodology was perfectly linear over concentration range of 0.05–5.00 and 0.001–1.00 mg/mL for IND and MOM, respectively. The developed protocol was applied successfully for the determination of IND and MOM mixtures, including capsule-based inhaler dosage form with % recovery of 100.15% and 97.98% for IND and MOM, respectively. Also, the greenness and whiteness (GAPI, AGREE and RGB-algorithm approaches) of the evolved method were evaluated in order to assess its impacts on the ecosystem. The method was proved to possess ecofriendly properties without any expected harmful effects on the environment.

Rapid enantiomeric separation of indacaterol by electrokinetic chromatography

The first chiral methodology enabling the separation of indacaterol enantiomers was developed in this work by cyclodextrin-electrokinetic chromatography. Indacaterol (IND) is a chiral drug marketed as a pure enantiomer. Then, the separation and quantification of each enantiomer is of great importance for the quality control of pharmaceutical formulations. After selecting the most suitable chiral selector and background electrolyte, two Box-Behnken designs were achieved to optimize the electrophoretic conditions using two different approaches to shorten analysis times: i) decreasing the capillary length, or ii) performing a short-end injection. Indacaterol enantiomers were separated in less than 5 min with a resolution value of 3.6 under the optimal separation conditions: 0.7% (m/v) carboxymethyl-α-cyclodextrin in 50 mM sodium formate buffer (pH 4.0) and using a short-end injection. Then, the analytical characteristics of the method were evaluated and LODs of 0.05 mg/L for S-IND and 0.04 mg/L for R-IND were achieved. Also, the method allowed the detection of a 0.1% enantiomeric impurity (S-IND) in the R-IND-based pharmaceutical formulations. The developed method was applied to the analysis of two pharmaceutical formulations. Percentages of 97 ± 3% and 103 ± 6% of R-IND with respect to the labeled amounts were found.

Determination of indacaterol at the surface of the boron-doped diamond electrode in inhaler capsules by using square-wave voltammetry

This research paper presents an electroanalytical investigation using the voltammetric method to quantify indacaterol maleate (IND) employing an unmodified boron-doped diamond (BDD) electrode. IND exhibited a distinct, irreversible oxidation peak at approximately + 1.06V (vs. Ag/AgCl) in a 0.1 mol L-1 phosphate buffer solution (PBS) with a pH of 2.5, as demonstrated by cyclic voltammetry (CV). A hypothetical mechanism for the electro-oxidation of IND was suggested based on data gathered from CV investigations. The square wave-adsorptive stripping voltammetric technique achieved acceptable linearity in PBS (pH 2.5) at approximately +0.90 V. The methodology demonstrated linearity within the concentration range of 1.0 to 30.0 ?g mL-1 (equivalent to 1.97x10-6-5.89x10-5 mol L-1) and yielded a limit of detection (LOD) of 0.22 ?g mL-1 (equivalent to 4.33x10-7 mol L-1). The proposed method's applicability was assessed through the sensing of IND in drug formulations.

Mixing energy as an adjustment tool for aerodynamic behaviour of an inhaled product: In-vitro and in-vivo effects

This paper describes the development of a fixed dose dry powder combination of indacaterol maleate (Inda) and glycopyrronium bromide (Glyco) in Easyhaler® inhaler for a comparative pharmacokinetic (PK) study, as well as the outcome of such a study. The development aim was to produce formulations with three different in vitro dispersibility profiles for both Inda and Glyco. This so-called ‘rake’ approach allows for quantitation of the candidate formulations relative to the reference product Ultibro® Breezhaler® in terms of the key PK parameters.Three formulations (A, B and C) were produced based on the mixing energy concept. For both APIs, formulation A (lowest mixing energy) displayed the highest fine particle fractions and formulation C (highest mixing energy) the lowest. GMP manufacturing confirmed the performance of the three formulations.The candidate formulations were tested against the reference product in a single dose PK study in healthy volunteers. Clear differences in Inda plasma concentration profiles were observed between the treatments when administered concomitantly with charcoal, with Easyhaler A showing the highest Cmax value and Easyhaler C the lowest. Easyhaler B was bioequivalent to Ultibro Breezhaler with regard to the primary PK parameters of Inda, Cmax and AUC72h. For Glyco, Easyhaler formulations A, B and C provided lower peak concentrations than Ultibro Breezhaler. For AUC72h of Glyco, Easyhaler B was bioequivalent to the reference product. Additional measures for adjustment of formulation performance can be foreseen, whose effects can be predicted based on mixing energy theory.

Eco-friendly micellar HPLC approach for assessment of two anti-asthmatic breezhalers; Application of central composite design

Short-term breathing problems are brought on by asthma, a chronic lung disease. Mometasone furoate (MOF) and Indacaterol (IDT), are co-formulated alone or with Glycopyrronium (GLY) in the form of inhalation powder to control the symptoms of asthma. A novel green hybrid micellar liquid chromatographic method was developed to analyze the three mentioned medications. Contrary to routine analysis, Quality by Design methodology was applied to maximize the resolution with the fewest number of trials. Fractional factorial design was used to study the impact of three significant variables: sodium dodecyl sulphate (SDS) concentration, methanol %, and the mobile phase pH. Separation of the analytes was optimized by central composite design using a mobile phase consists of (191.49 mM) SDS and (10.00 mM) potassium dihydrogen phosphate buffer: methanol (77.50: 22.50 v/v), pH 3.00 on a reversed phase C18 column, within eight minutes. The flow rate was 1.2 mL/min, with 20 µL injection volume, and UV detection at 210 nm. Green Analytical Procedure Index, and Analytical Greenness Calculator were used for the method’s greenness evaluation, and it was deemed to be an effective green methodology. The developed approach was effectively applied for quantitative determination of the three drugs in bulk powder and two pharmaceutical dosage forms. International Conference of Harmonization requirements were adhered to when validating the approach. Under optimized conditions, calibration curves of the studied drugs were linear over the concentration range of (10.00 – 100.00 µg/mL) with high accuracy results and correlation coefficients of 0.9997 for MOF, 0.9996 for IDT and 0.9996 for GLY. Additionally, a precise approach has been demonstrated by the intra- and inter-day coefficients of variation ≤ 2%. The LOD and LOQ were (2.39 μg/mL) and (7.25 μg/mL) for MOF, (2.67 μg/mL) and (8.08 μg/mL) for IDT, and (2.80 μg/mL) and (8.48 μg/mL) for GLY, respectively.

Method Development and Validation of Indacaterol Maleate By RP-HPLC In Bulk and Pharmaceutical Dosage Form

Method Development and Validation of Indacaterol Maleate By RP-HPLC In Bulk and Pharmaceutical Dosage Form

Comparison of Clinical Outcomes Among Different Fixed-Dose Combinations of Long-Acting Muscarinic Antagonists and Long-Acting β2-Agonists in Patients With COPD

Researchers have yet to obtain conclusive evidence differentiating among fixed-dose combinations (FDCs) of long-acting muscarinic antagonists (LAMAs) and long-acting β2-agonists (LABAs) for COPD in terms of real-world clinical outcomes. What are the differences between available LAMA/LABA FDCs in the risk of acute exacerbation (AE) and cardiovascular events? This retrospective cohort study based on a national insurance claims database included patients with COPD≥ 40 years of age who were newly prescribed glycopyrronium (GLY)/indacaterol (IND), umeclidinium (UMEC)/vilanterol (VI), or tiotropium (TIO)/olodaterol (OLO) FDC between January 1, 2015, and June 30, 2019. Propensity score matching and Cox regression models were used to compare outcomes of AE and cardiovascular events associated with LAMA/LABA FDC treatment. Among the 44,498 patients identified and included, 15,586 received GLY/IND, 20,460 received UMEC/VI, and 8,452 received TIO/OLO. Baseline characteristics were well balanced after 1:1 matching of UMEC/VI and GLY/IND, 2:1 matching of UMEC/VI and TIO/OLO, and 2:1 matching of GLY/IND and TIO/OLO. Risk of severe AE was lower among patients treated with UMEC/VI or GLY/IND than among those who received TIO/OLO (UMEC/VI vsTIO/OLO: 17.85 vs29.32 per 100 person-years; hazard ratio, 0.76; 95%CI, 0.68-0.84; GLY/IND vsTIO/OLO: 15.54 vs25.53 per 100 person-years; hazard ratio, 0.77; 95%CI, 0.67-0.88). In addition, GLY/IND users tended to have a lower risk of cardiovascular events than TIO/OLO users, but the difference dissipated when restricting follow up to a shorter duration. Our results revealed that the risk of severe AE was lower among patients with COPD receiving UMEC/VI or GLY/IND than among those receiving TIO/OLO, whereas the incidence of cardiovascular events was similar across groups but was slightly lower in GLY/IND users when compared with TIO/OLO users. Further research will be required to confirm these findings.

Optimization of Long-Acting Bronchodilator Dose Ratios Using Isolated Guinea Pig Tracheal Rings for Synergistic Combination Therapy in Asthma and COPD

The co-administration of a long-acting β2-agonist (LABA), and a long-acting muscarinic antagonist (LAMA), has been shown to be beneficial in the management of non-communicable chronic respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD). The resulting relaxation of the airways can be synergistically enhanced, reducing symptoms and optimizing lung function. This provides an insight into more effective treatments. In this study, the LABAs formoterol fumarate dihydrate (FOR) and indacaterol maleate (IND) were each associated with tiotropium bromide monohydrate (TIO) to assess their synergistic potential. This was done using an appropriate ex vivo model of isolated perfused guinea pig tracheal rings, and pharmacological models of drug interaction. Among the dose ratios studied for both types of combination, a higher synergistic potential was highlighted for FOR/TIO 2:1 (w/w). This was done through three steps by using multiple additions of drugs to the organ baths based on a non-constant dose ratio and then on a constant dose ratio, and by a single addition to the organ baths of specific amounts of drugs. In this way, the synergistic improvement of the relaxant effect on the airways was confirmed, providing a basis for improving therapeutic approaches in asthma and COPD. The synergy found at this dose ratio should now be confirmed on a preclinical model of asthma and COPD by assessing lung function.

Optimization and Application of an Efficient and Stable Inhalation Exposure System for Rodents.

Inhalation is a promising and challenging method in pharmaceutical and biological science research. A stable environment is critical in dynamic inhalation administration. However, the establishment of a stable inhalation system is very challenging. Indacaterol glycopyrronium bromide inhalation powder (IM/GP mixed powder) is composed of indacaterol maleate and glycopyrronium bromide powder to treat chronic obstructive pulmonary disease (COPD). The aim of this study is to build suitable inhalation conditions and then to evaluate the pulmonary safety of this drug in Sprague-Dawley(SD) rats. In the research, through the coordination of the atomization flow, air pump flow, and scraper speed, aerosols were stabilized at 200 ± 20% mg/m3, and then rats were nose-only administered with the IM/GP mixed powder, Ultibro, and lactose-magnesium stearate mixed powder at 2.6 mg/kg/day for 14 days and 14 days of recovery period, respectively. After exposure, hematology, inflammatory cytokines in rats bronchoalveolar lavage fluid (BALF) and serum, histopathological examination were performed. Results showed that the stability of powder aerosols can be realized under the atomization generation flow: 10 L/min, sampling flow: 2 L/min, system pumping capacity: 10 L/min and powder scraper speed: 8-10 L/min, and there were no significant adverse effects on body weight, clinic signs, hematology, and pathology in rats. Overall, the results suggested that the IM/GP mixed powder inhalation at the dose of 2.6 mg/kg/d can be reached when the aerosol concentration is within the range of 200 ± 20% mg/m3, and there were no pulmonary toxicity effects in rats.

Real-world Safety and Efficacy of Indacaterol Maleate in Patients with Chronic Obstructive Pulmonary Disease: Evidence from the Long-term Post-marketing Surveillance in Japan.

Objective Evidence concerning the safety and efficacy of indacaterol maleate in a real-life setting is limited. The objective of this post-marketing surveillance was to evaluate the real-life safety and efficacy of indacaterol maleate in Japanese patients with chronic obstructive pulmonary disease (COPD). Methods This was a 52-week post-marketing surveillance conducted between April 2012 and December 2018. The safety endpoints included the incidence of adverse events (AEs), serious adverse events (SAEs), and adverse drug reactions (ADRs). The efficacy endpoints included the physician-reported global evaluation of treatment effectiveness (GETE), change from baseline in the COPD assessment test (CAT) results, forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and %FEV1 following 4, 12, 26, and 52 weeks of indacaterol administration. Results Of the 1,846 enrolled patients, 1,726 were included in the safety and efficacy analyses. The mean age of the patients was 72.5 years old. Cough, pneumonia and COPD worsening were the most common AEs reported, while pneumonia (1.04%) was the most common SAE, and cough (1.68%) was the most common ADR. GETE showed that 69.70% of patients achieved an excellent/good/moderate response following indacaterol treatment. The CAT score decreased, and lung function parameters (FVC, FEV1 and %FEV1) improved across all the COPD stages following treatment with indacaterol. Conclusion Indacaterol showed a favorable safety and tolerability profile in Japanese patients with COPD without new safety signals observed in real-life settings. These findings demonstrated that indacaterol is an effective maintenance treatment in real-life practice for Japanese patients with COPD.

A simple and economic chromatographic method for simultaneous determination of six bronchodilator drugs in pharmaceutical dosage forms

Chronic obstructive pulmonary disease is a major cause of morbidity and mortality worldwide. Combining an inhaled anticholinergic and a β2-agonist are a convenient way of delivering treatment, obtaining better lung function and improved symptoms. We aimed to develop and validate a reliable HPLC method for the simultaneous determination of the anticholinergics; ipratropium bromide, glycopyrronium bromide and tiotropium bromide in addition to the β2-agonists; bambuterol hydrochloride, formoterol fumarate and indacaterol maleate. The chromatographic separation was achieved on a Phenomenex Luna phenyl-hexyl (250 × 4.6 mm i.d., 5 μm) column and a mobile phase composed of 0.2% phosphoric acid (pH 3.0)/methanol/acetonitrile (66:12:22, v/v/v). The analysis was performed at a flow rate of 1 mL/min with UV detection at 210 nm. Method validation showed that calibration curves were linear within the range from 0.5 to 30.0 μg/mL with a correlation coefficient > 0.998. Intraday and interday precision and accuracy evaluated by relative standard deviation were lower than 2%. The limits of detection were in the ranges of 0.037–0.152 μg/mL. The developed method which is rapid, sensitive and highly efficient was applied for the analysis of the six bronchodilators in single and combined formulations saving money, solvents and chemicals. In addition, the environmental impact of the proposed method was evaluated using a suitable analytical Eco-Scale.

Pharmacokinetics of indacaterol, glycopyrronium and mometasone furoate following once-daily inhalation as a combination in healthy subjects

Indacaterol (IND), is co-formulated with glycopyrronium (GLY), and mometasone furoate (MF) as a once-daily (o.d.) inhaled fixed-dose combination (IND/GLY/MF) delivered via the Breezhaler® device for maintenance treatment of asthma. We evaluated the steady state plasma pharmacokinetics (PK) of IND, GLY and MF following inhalation of IND/GLY/MF or as monotherapies.This was a randomized, open-label, four-way crossover study. Subjects received IND/GLY/MF 150/50/160 μg (high-dose), IND 150 μg, GLY 50 μg or MF 190 μg (in vitro fine particle mass comparable to 160 μg MF in IND/GLY/MF) via the Breezhaler® device, o.d. for 14 days in each period, with a washout of at least 7 days. PK was characterized on Day 14, up to 24 h post-dose.In total, 36 healthy subjects were randomized. For IND, the geometric mean ratios (90% CI) for AUC0-24h,ss and Cmax,ss were 0.922 (0.878, 0.969) and 1.02 (0.967, 1.08), respectively for the IND/GLY/MF versus IND monotherapy comparison. For GLY, the geometric mean ratios (90% CI) for AUC0-24h,ss and Cmax,ss were 0.986 (0.944, 1.03) and 1.21 (1.09, 1.34), respectively for the IND/GLY/MF versus GLY comparison. For MF, the geometric mean ratios (90% CI) for AUC0-24h,ss and Cmax,ss were 1.16 (1.09, 1.24) and 1.17 (1.09, 1.25), respectively for IND/GLY/MF versus MF comparison. Similar systemic exposure was noted for IND/GLY/MF versus monotherapy for all three mono-components, indicating a lack of PK interaction. Multiple inhaled doses of IND, GLY and MF were safe and well tolerated, when administered alone or in combination.There was no clinically relevant pharmacokinetic interaction between IND, GLY and MF when administered as IND/GLY/MF.

Lung function, pharmacokinetics, and tolerability of inhaled indacaterol maleate and acetate in asthma patients

BackgroundIndacaterol maleate delivered with the Breezhaler® inhalation device is a long-acting β2-agonist approved for chronic obstructive pulmonary disease. In the development of a once daily, inhaled fixed dose combination (FDC) of indacaterol, glycopyrronium bromide (a long-acting muscarinic antagonist), and mometasone furoate (an inhaled corticosteroid [ICS]) for the treatment of patients with asthma, the acetate salt of indacaterol is used instead of the maleate salt. Here, we investigated the lung function, pharmacokinetics (PK) and safety of indacaterol maleate 150 μg once daily (o.d.) and indacaterol acetate 150 μg o.d. in comparison with placebo.MethodsThis was a randomised, double-blind, three-period crossover study (ClinicalTrials.gov identifier, NCT03257995) in patients with asthma on background ICS therapy. Patients with percent predicted pre-bronchodilator forced expiratory volume per second (FEV1) ≥50% and ≤ 90% were included in the study. Patients received indacaterol maleate 150 μg o.d., indacaterol acetate 150 μg o.d., or placebo on top of stable background ICS in randomised sequence. Trough FEV1 was assessed after 14 days of treatment. PK of indacaterol salts were assessed at steady state after 14 days of treatment; peak expiratory flow (PEF) rate and rescue medication use were collected with a combined PEF-meter/electronic diary throughout the study.ResultsOf the 54 adult patients (median age of 48 years), 51 patients completed the study. Both indacaterol salts demonstrated statistically significant improvements in trough FEV1 of 186 mL (maleate) and 146 mL (acetate) compared with placebo (both P < 0.001). FEV1 AUC0-4h improved by 248 mL (maleate) and 245 mL (acetate), and PEF by 33 L/min (maleate) and 30.8 L/min (acetate) versus placebo. Systemic exposure of indacaterol (AUC0-24h,ss and Cmax,ss on Day 14) was comparable after administration of both salt forms. Both salt forms demonstrated a good safety profile and were well tolerated, with a difference in the reporting frequency of AEs of coughing (maleate, 23.5%; acetate, 0%).ConclusionsIn patients with asthma, indacaterol maleate and acetate elicited comparable and significant improvements in lung function compared with placebo and achieved comparable systemic exposure. Both indacaterol salts were safe and well tolerated.Trial registrationClinicalTrials.gov NCT03257995 June 06, 2017

Exploring the potential influence of drug charge on downstream deposition behaviour of DPI powders.

Dry powder inhaler (DPI) development is limited by the time- and labor-consuming in vitro lung deposition test. It's highly desirable to find an easy tool for DPI formulation screening. Dynamic powder rheological properties seem to present many advantages, however, the adoptability needs to be verified. Drug charge is an important parameter especially for DPI formulation design but how it affects the process of pulmonary drug delivery is unavailable. Therefore, the objective of this study is to explore the influence of drug charge on DPI powders, further testing the potentials of powder properties for downstream deposition behavior prediction. Taking five differently charged drugs as model, influence of drug charge on uniformity, rheological and aerodynamic properties of the mixtures were investigated systemically. It was found that mometasone furoate with near neutral charge presented better content homogeneity, while significantly decreased recovery was noted for charged drugs, such as positively charged drug (salbutamol sulphate and indacaterol maleate) mixtures and negatively charged drug (budesonide and fluticasone propionate) mixtures. Moreover, drug charge also influenced flowability and cohesion of their admixture with lactose. As for the downstream deposition, neutral drugs presented higher fine particle fraction (FPF), followed by positively charged drugs and negatively charged drugs. Good correlations between basic flowability energy, aeration energy, Permeability and FPF were established irrespective of different drugs. Principal component analysis results suggested flowability had a greater influence on FPF when mixtures were less cohesive. In conclusion, this study demonstrated drug charge can influence physicochemical, rheological and aerodynamic properties of the admixture, and DPIs' dynamic properties could be used as potential tools to predict downstream deposition with good accuracy.

Bioequivalence studies of inhaled indacaterol maleate in healthy Chinese volunteers under gastrointestinal non-blocking or blocking with concomitant charcoal administration

BackgroundIndacaterol is one of the long-acting beta2-adrenergic agonists, referred as first-line monotherapy for Chronic obstructive pulmonary disease since 2011. Generic products are encouraged to benefit the large COPD patients in China, in which can provide more choices association with reduced cost and improve the quality of patient life. ObjectiveThe three-part study consists of two independent cohorts of thirty-six subjects, aimed to evaluate the bioequivalence (BE) of two indacaterol formulations in gastrointestinal (GI) absorption charcoal-block or non-block conditions. One pilot study performed in six healthy subjects to determine the blocking effect of a new charcoal-based regimen on GI absorption after orally inhalation of indacaterol. MethodsTwo BE studies were conducted with a randomized, open-label, 2-period crossover design in two independent 36-healthy-subject cohorts, equivalence in systemic and lung deposition was assessed after inhalation of a single dose of 150 μg indacaterol (test or reference formulation) alone or concomitant administration of charcoal. The charcoal-based regimen was improved by optimizing the dose and number of doses, and its blocking efficacy against GI absorption was assessed in a pilot study. Six healthy subjects received 9 g charcoal 10 min before, immediately after and 2 h after indacaterol (3 g/100 ml water × 3 times). Blood collected at predetermined time points up to 72 h. Plasma indacaterol concentrations were determined using HPLC-MS/MS. Pharmacokinetics parameters were calculated with non-compartment analysis. Equivalences were concluded if the 90% confidence interval (CI) for test: reference of Cmax and AUC0-t fell within the limits of 0.8–1.25. ResultsIndacaterol was undetectable in plasma samples in pilot study. The T/R ratio of the geometric mean Cmax and AUC0-t was 109.9% (90% CI, 106.1–113.8%) and 104.8% (90% CI, 101.5–108.1%) for charcoal-block subjects and 105.4% (90% CI, 99.8% ~ 111.3%), and 101.0% (90% CI, 97.7%–104.4%) for non-block subjects. No serious adverse events were reported. ConclusionsThe results showed that 150 μg indacaterol (+/− 9 g charcoal) was well tolerated in all subjects. The two formulations are bioequivalent in terms of the rate and absorption both in charcoal-block and non-block conditions. The improved charcoal-based regimen demonstrated to be effective and fully blockade of GI absorption of indacaterol.

Development and Validation of a Stability-Indicating Chromatographic Method for the Determination of Indacaterol Maleate with Glycopyrronium Bromide in Mixture

Introduction: (COPD) Chronic Obstructive Pulmonary Disease is a partially reversible and treatable lung disease, characterized by progressive limitation of airflow. It is one of the main causes of mortality and morbidity worldwide. Methods: An easy, precise and selective reversed-phase liquid chromatographic method, with stabilityindicating assay was established and validated for the determination of indacaterol maleate and glycopyrronium bromide in the mixture. In addition, a forced degradation study was performed for indacaterol maleate, comprised of hydrolysis by acid and base, degradation by oxidation and heat, and photo-degradation. Separation and forced degradation were done by isocratic elution using a reversed phase phenyl column and (methanol: phosphate buffer) at ratio (65:35, v/v) with 3.5 pH buffer as an eluent at 1 mL min-1 as a flow rate. Quantitation was accomplished using a UV detector at 210 nm. Results: The method showed good separation of glycopyrronium bromide, indacaterol maleate and its degradation products. Accuracy, linearity, and precision were acceptable over 10-160 µg mL-1 and 10- 80 µg mL-1 concentration range for indacaterol maleate and glycopyrronium bromide, respectively. Conclusion: The proposed method does not require any previously done separation steps, making it applicable for the analysis of the drugs under investigation in their pharmaceutically marketed preparations.

TiO2 nanoparticles and ionic liquid platform for selective electrochemical determination of indacaterol in pharmaceutical formulations and human fluids: application to content uniformity

The present work described the first voltammetric sensor for the estimation of indacaterol (IND) in the presence of its co-formulated drug glycopyrronium bromide. Indacaterol (IND) is used to treat chronic obstructive pulmonary disease, which is a major cause of morbidity and mortality worldwide so the quick analysis of minor concentrations of this drug is very important. Titanium(IV) oxide nanoparticles (TiO2-NPs) and the ionic liquid (IL) n-hexyl-3-methylimidazolium hexafluorophosphate were used for the new formulated carbon paste electrode. Other factors, such as the pH of the solution, the TiO2-NP concentration and the scan rate, were also optimized using cyclic voltammetry. Scanning electron microscopy, chronoamperometry and electrochemical impedance spectroscopy were utilized for determination of the character of the electrochemical sensor. Moreover, the electrochemical redox mechanism of IND at the proposed sensor was studied. Under the optimum conditions, the proposed TiO2-NP–IL–MCPE showed good linearity over a concentration range of 2.00 nM–200.00 mM using square wave voltammetry. The LOD was found to be 500 pM, indicating excellent sensitivity. Satisfactory recoveries of IND from pharmaceutical formulations, content uniformity tests and human plasma and urine were achieved, clearly revealing that the new sensor can be used in the clinical analysis of IND and in quality control laboratories.

Bronchodilators for hyperinflation in COPD associated with biomass smoke: clinical trial.

IntroductionThe efficacy of long-acting bronchodilators for COPD associated with biomass (BE-COPD) has not been properly evaluated.ObjectiveTo determine the acute effect of indacaterol (IND) 150 μg q.d and tiotropium (TIO) 18 μg q.d. on lung hyperinflation, walking distance (WD) and dyspnea during the six-minute walking test (6MWT) in moderate BE-COPD at 30, 60 and 240 mins post-drug administration.DesignRandomized, controlled, open-level, crossover noninferiority clinical trial. Forty-two women with BE-COPD were randomly assigned to a bronchodilator sequence: IND–TIO or vice versa.ResultsThere were statistically significant changes over time in inspiratory capacity (IC) (p<0.0001), FEV1 (p<0.0001) and FVC (p<0.0001) when IND was used. When TIO was administered, an increase over all time periods was observed only for FEV1 (p<0.0001) and FVC (p<0.0001), whereas for IC an increase was observed only at 30 mins and 24 hrs after TIO administration. We did not find clinically significant increases in WD and dyspnea after the administration of both bronchodilators.ConclusionBoth IND and TIO showed significant and fast onset improvement in hyperinflation. Therefore, either of them may be recommended as a first line of treatment for COPD associated with BE-COPD.

Validated ion pair chromatographic method for simultaneous determination and in vitro dissolution studies of indacaterol and glycopyrronium from inhaled capsule dosage form

A rapid, and highly sensitive analytical method were developed for the simultaneous determination of indacaterol maleate (IND) and glycopyrronium bromide (GLY) in their inhaler capsules. Valid ion-pairing chromatographic (IPC) method was performed for separation of GLY in presence of IND using C18 column and mobile phase consisting of acetonitrile: acidified deionized water (60:40% v/v) containing 0.02% sodium dodecyl sulfate (SDS) adjusted to pH 3.0 using OPA (orthophosphoric acid) isocratically eluted at 2.0 mL/min. Quantitation was achieved with UV detection at 210 nm. Cyproheptadine was used as an internal standard. The retention times were 1.9 and 2.5 min for IND, and GLY, respectively. For the IPC method, the calibration graphs were linear in the range of 0.66–66.0 μg/mL for IND and 0.3–30.0 μg/mL for GLY. The proposed method are rapid, reproducible (R.S.D. <2.0%) and achieves satisfactory resolution between IND and GLY (resolution factor = 4.23). The mean recoveries of the analytes in their inhaler capsule were satisfactory. It was applied successfully to in vitro dissolution testing using Franz diffusion cell and extended to a content uniformity test consistent with the United States Pharmacopoeia (USP) guidelines and were found to be precise and accurate for the capsules studied with acceptance value of 4.53 and 1.39 for IND and GLY, respectively.