Salmeterol Research Articles

Novel Fluticasone Propionate and Salmeterol Fixed-Dose Combination Nano-Encapsulated Particles Using Polyamide Based on L-Lysine.

One of the key challenges in developing a dry powder inhaler (DPI) of an inhalable potent fixed-dose combination (FDC) is the ability of the formulation to generate an effective and reproducible aerosol able to reach the lower parts of the lungs. Herein, a one-step approach is presented to expedite the synthesis of nanoaggregates made from a biocompatible and biodegradable polyamide based on L-lysine amino acid employing market-leading active pharmaceutical ingredients (fluticasone propionate (FP) and salmeterol xinafoate (SAL)) for the management of asthma. The nanoaggregates were synthesized using interfacial polycondensation that produced nanocapsules with an average particle size of 226.7 ± 35.3 nm and zeta potential of −30.6 ± 4.2 mV. Differential scanning calorimetric analysis and x-ray diffraction, as well as scanning electron microscopy of the produced FDC, revealed the ability of the produced nanocapsules to encapsulate the two actives and display the best aerodynamic performance. The FDC nanocapsules displayed 88.5% and 98.5% of the emitted dose for FP and SAL, respectively. The fine particle fraction of the nominated dose was superior to the marketed product (Seretide Diskus®, Brentford, United Kingdom). The in-vitro release study showed an extended drug release profile. Our findings suggest that nanoaggregates using polyamides based on L-lysine and interfacial polycondensation can serve as a good platform for pulmonary drug delivery of FDC systems.

Smart spectrophotometric approach for the simultaneous determination of anti-asthma drugs in inhalation spray using least squares support vector machine and net analyte signal

In this study, easy, fast, inexpensive, and accurate spectrophotometric technique with the help of least square support vector machine (LS-SVM) and net analyte signal (NAS) as chemometrics approaches were developed for the simultaneous determination of salmeterol (SMT) and fluticasone (FLU) in mixtures and anti-asthma inhalation spray. The related parameters of the LS-SVM model (sigma and gamma) were optimized and root mean square error (RMSE) were obtained 0.3075 and 0.4553 for SMT and FLU, respectively. Limit of detection (LOD) and limit of quantification (LOQ) dedicated to the calibration plot of the NAS method were 1.434, 1.089 μg mL−1 and 4.584, 3.399 μg mL−1 for SMT and FLU, respectively. The optimum number of components was evaluated by the minimum predicted residual error sum of squares (PRESS) value, which achieved 1.7738 and 1.0636 for SMT and FLU, respectively. Also, the mean recovery value of test set related to the 25 binary mixtures was 98.45% and 98.98% for SMT and FLU, respectively. Analysis of variance (ANOVA) test represented no significant difference significant between high-performance liquid chromatography (HPLC) (reference technique) and chemometrics methods. The LS-SVM and NAS can be a good alternative to expensive methods such as chromatography in the quality control section of different industries.

Incidence of Oral Candidiasis in Patients with Asthma Using Inhaled Corticosteroids by Various Inhaler Devices

Objective: The aim of this study was to do the comparison of the incidence of oral candidiasis in individuals with inhaled corticosteroids by Rota caps via Revolizer and metered dose inhalers via spacer. Place and Duration: This Cross-sectional study was held in the Pulmonology department of Gulab Devi Hospital, Lahore for six-months duration from March 2021 to August 2021. Methods: Patients with asthma who were referred to chest clinics and used MDI inhaled corticosteroid with spacer or Rota cap with Revolizer for minimum two-months were alienated into 2 groups. The A Group included patients using metered dose inhalers with spacer and inhaled steroids and group B patients using Rota cps with Revolizer. The treating physician examined all patients for oropharyngeal candidiasis, and a thorough throat examination in patients was done who reported dysphonia or throat ache. Results: Of 120 patients (group A: 60 and group B: 60) who participated in the analysis, 72 (60%) were female and 48 (40%) were male. Their ages fluctuated from 15 to 75 (mean 43.2). 89 patients (74.2%) were encompassed in the analysis with moderate asthma and severe asthma was noted in 31 patients (25.8%). 39 patients (32.5%) described throat ache; 81 patients (67.5%) did not have such symptoms. The oral candidiasis incidence was noted in 18 (15%) in group B patients who used Rotacaps encompassing 6mcg and Formeterol Fumerate 400 mcg Budesonide and 12 (10%) in group A patients using MDI containing Salmeterol xinafoate 25 and Fluticasone propionate 250 mcg with spacer device. It was advanced in B group patients than A group (p <0.05). The oral candidiasis incidence in individuals over 50 years was also higher than patients under 50 years. Conclusion: This analysis exhibited a high proportion of oral candidiasis among individuals using Rota caps containing formoterol and Budesonide by Revolizer in comparison to metered dose inhalers with spacer. Keywords: Oral candidiasis; Asthma; Inhaled corticosteroids

Medication Cost-Savings and Utilization of Generic Inhaled Corticosteroid (ICS) and Long-Acting Beta-Agonist (LABA) Drug Products in the USA.

BackgroundIn the USA, drug costs associated with the inhaled corticosteroid (ICS) and long acting β agonist (LABA) combination products have been increasing since 2001. In January 2019, the first generic ICS/LABA drug product was approved by the U.S. Food and Drug Administration.MethodsWe investigated retrospectively the effects of the first approved generic ICS/LABA drug from 2019 to 2020 on the wholesale cost-savings and prescription dispensing using the IQVIA data system in the USA.ResultsThe marketing of the first generic for fluticasone propionate and salmeterol xinafoate dry powder inhaler was associated with $941 million in drug cost-savings during the first year for this class of medications. Although the brand-name drug manufacturer concurrently introduced its authorized generic, these cost-savings were driven by the averaged unit cost of the approved generic at $115, compared to $169 for the authorized generic and $334 for the branded product. Generic initiation and substitution with the first generic were, respectively, higher compared to those with authorized generics; however, overall dispensing of the first generic was lower than that of its branded product. As in the case of budesonide and formoterol fumarate dry powder inhaler, marketing of authorized generics alone was not associated with any noticeable change in sales or prescription cost-saving.ConclusionWe estimated that more than 20% of prescription cost-saving was achieved for the ICS/LABA dry powder inhalers in the first year following the introduction of the first approved generic, even though generic utilization remained lower than that of the branded counterpart.

An Efficient, Novel Synthetic Route to (R)-Salmeterol Xinafoate and Facile Synthetic Protocols for Preparation of its Process Related Potential Impurities

In present work, an effective, innovative enantioselective synthetic strategy for the synthesis of salmeterol xinafoate and its probable process-related impurities was reported. Seven pharmacopeia specified impurities were synthesized and confirmed by FT-IR, mass, 1H & 13C NMR spectroscopy. With respect to the corresponding retention factors, these contaminants were validated using the available RP-HPLC method. These compounds can be used as a reference standard for the active pharmaceutical ingredient manufactures and research organizations.

Allergic bronchopulmonary aspergillosis with chest pain as atypical symptoms

A 43-year-old man with a 1-month history of chest pain was admitted to West China Hospital (Chengdu, China) without cough, fever, or viscous sputum. He had a 36-year history of asthma, treated with inhaled 50 μg salmeterol xinafoate and 250 μg fluticasone propionate (Seretide; GlaxoSmithKline, Brentford, UK), without relapsing for nearly a year. A CT scan showed multiple mucus plugs (figure A). Blood tests showed the peripheral eosinophil count was 1380 cells per uL (normal range, 20–520 cells per uL), the total IgE concentration was 1640 IU/mL (normal range, 5–150 IU/mL), and the results from an Xpert MTB/RIF test, a galactomannan antigen, and a 1,3-β-D glucan antigen test were negative. No sputum pathogenic test was done as the patient had no sputum. According to the Asano criteria, these results suggested a diagnosis of allergic bronchopulmonary aspergillosis. 2 days after admission, a painless fibrobronchoscopy examination was done to obtain mucus plugs for mycology and histopathology tests. Mucus and mucus plugs were detected in the bilateral pulmonary bronchi by bronchoscopy (figure B). Galactomannan antigen test, microscopy, and fungal culture results were negative, but metagenomics next-generation sequencing (mNGS) testing of bronchial lavage and puncture tissue of the endobronchial membrane rapidly detected Aspergillus fumigatus. 4 days after admission, the concentration of specific IgE for filamentous fungi in the blood was 5·67 IU/mL. A pathological test of the puncture tissue of the endobronchial membrane showed infiltration of eosinophils and fungal mycelia and Charcot–Leyden crystals. Thus, the diagnosis was allergic bronchopulmonary aspergillosis and the treatment was intravenous voriconazole (0·4 g twice daily on day 1, then 0·2 g twice daily for 4 days). 8 days after admission, the chest pain eased after therapy. The patient was discharged and the treatment plan switched to oral voriconazole (0·2 g twice daily for 1 month) and prednisone (40 mg once daily for 2 weeks, then 30 mg once daily for 1 week, and 25 mg once daily for another week) for continued treatment. 1 month after being discharged from hospital, the patient received a CT scan review, showing the multiple mucus plugs had almost disappeared (figure C).

Optimization of two charge transfer reactions for colorimetric determination of two beta 2 agonist drugs, salmeterol xinafoate and salbutamol, in pharmaceutical and biological samples

Beta 2 agonists are well known for their use in the treatment of asthma and COPD however in the last few years new indications of beta 2 agonist appeared like reduction of local fats and treatment of preterm labour which required the formulation of new dosage forms and administration strategies. The new developments require accurate, economic and feasible methods the determination of these drugs to facilitate testing the newly introduced dosage forms and to study the pharmacokinetics and pharmacodynamics regarding the modern uses. In this study two rapid, sensitive and economic colorimetric methods for the determination of salmeterol xinafoate and salbutamol in pharmaceutical dosage forms and spiked plasma were developed and validated. The developed methods depends on the optimized reaction of the studied drugs with two charge transfer reagents, 2,3-dochloro-5,6-dicyano-1,4-benzoquonone (DDQ) and chloranilic acid (CA) to produce coloured complexes measured at 460 and 529 nm for DDQ and CA respectively. The developed methods showed high accuracy of 99.52 ± 1.108, 101.03 ± 0.389, 100.04 ± 1.520 and 100.3 ± 0.951 for salmetrol xinafoate and salbutamol with DDQ and CA respectively. The proposed methods were successfully used for the determination of the studied drugs in their dosage forms and spiked plasma with high accuracy and precision and the results were compared to reported methods.

Determination of the enantiomers of salmeterol xinafoate in salmeterol fluticasone powder inhalant by chiral nonaqueous capillary electrophoresis

昔萘酸沙美特罗是目前治疗哮喘夜间发作和哮喘维持治疗的理想药物之一,它在临床上以外消旋体形式给药。昔萘酸沙美特罗的两个对映体在药理活性和毒理作用等方面差异较大,建立昔萘酸沙美特罗对映体的手性分离分析方法对提高手性药物质量、保证临床用药安全有效具有重要意义。该文以L(+)-酒石酸-硼酸络合酸为手性选择剂,建立了测定沙美特罗替卡松粉吸入剂中昔萘酸沙美特罗对映体含量的非水毛细管电泳法。实验考察了L(+)-酒石酸浓度、硼酸浓度和表观pH(apparent pH, pH* )对手性分离效果的影响。优化的缓冲溶液为:含120.0 mmol/L L(+)-酒石酸和120.0 mmol/L硼酸的甲醇溶液,pH* 为0.93;其他实验条件为:未涂层弹性熔融石英毛细管(内径50.0 μm,总长度64.5 cm,有效长度55.5 cm),重力进样17.5 cm×10.0 s,检测波长225 nm,室温,工作电压20.0 kV。在优化的实验条件下,昔萘酸沙美特罗的两个对映体在18.0 min内获得了2.18的分离度;在27.5~800.0 mg/L质量浓度范围内,与峰面积呈现良好的线性关系,相关系数(r)大于0.9990;检出限和定量限分别为7.5和25.0 mg/L;加标回收率为98.1%~101.9%,相对标准偏差为1.2%~1.9%。随机购买市面上出售的沙美特罗替卡松粉吸入剂,对其昔萘酸沙美特罗对映体的含量进行了分析检测。结果显示,昔萘酸沙美特罗对映体1和对映体2的标示量百分含量均为98.7%, RSD分别为2.5%和2.7%。该方法操作简便易行,结果准确可靠,消耗低,可用于市售沙美特罗替卡松粉吸入剂中昔萘酸沙美特罗对映体的含量测定。

Synthesis and characterization of double molecular imprinted nanoparticles and investigation to adsorption of respiratory drugs

ABSTRACT In this study, novel double molecular imprinted nanoparticles (DMIP nanoparticles) with multi-functional monomers were prepared for adsorption of salmeterol xinafoate (SAM) and fluticasone propionate (FLU) drugs. For this purpose, SAM and FLU imprinted poly (2-hydroxyethyl methacrylate-N-methacryloyl-(L)-alanine-N-methacryloyl-(L)-histidine) [p(HEMA-MAAL-MAH)] nanoparticles were synthesized by surfactant-free emulsion polymerization method. After the characterization, adsorption conditions were optimized, and the adsorption kinetics parameters were also calculated. In the selectivity experiments, budesonide (BS) and formoterol fumarate (FF) drugs were used as competitive drugs. These novel development DMIP nanoparticles have the potential for use in many different areas, for purposes such as drug release, separation, and purification.

Rational design of salmeterol xinafoate imprinted polymer through computational method: Functional monomer and crosslinker selection

AbstractA molecular imprinted polymer (MIP) was computationally designed and synthesized for the selective extraction of salmeterol xinafoate (SLX) from human serum. In this study, semi‐empirical PM3 calculations were used to find a suitable functional monomer (FM), the ratio of template (T) to FM, and types of crosslinkers. MIPs were synthesized with 2‐hydroxyethyl methacrylate (HEMA) with T:FM mol ratios of 1:6 and 1:4 and ethylene glycol dimethacrylate (EGDMA) or trimethylolpropane trimethacrylate (TRIM) as a crosslinker. On the basis of computational and experimental results, HEMA and TRIM in the mol ratio 1:6 of T‐FM (MIP3) were found to be the best choices of FM and crosslinker, respectively. These polymers were then used as a selective sorbent to develop a molecularly imprinted solid‐phase extraction procedure followed by high performance liquid chromatography with UV detection for the determination of SLX in serum. The extraction ability of MIP3 was excellent with a recovery of 92.17% ± 2.66% of SLX in spiked serum, and 91.15% ± 1.12% when SLX was spiked as a mixture with another analogous structure. By comparing the performance of the synthesized sorbent with a C‐18 cartridge with a recovery of 79.11% ± 2.96%, it was determined that MIP had better performance over the latter. On the basis of these results, the imprinted receptor MIPs, especially MIP 3, can be applied for the direct extraction of SLX in clinical analysis.

Investigation of spectrophotometric simultaneous absorption of Salmeterol and Fluticasone in Seroflo spray by continuous wavelet transform and radial basis function neural network methods

In this research, the simultaneous absorption of Salmeterol (SAL) and Fluticasone (FLU) in Seroflo spray was investigated using a spectrophotometric device via employing continuous wavelet transform (CWT) and radial basis function neural network (RBF-NN) methods. Root mean square error (RMSE) related to the RBF model was obtained 3.17 × 10-13 and 1.41 × 10-13 for SAL and FLU, respectively. Limit of detection (LOD) and limit of quantification (LOQ) corresponding to the CWT method were 0.004, 0.280 μg/mL, and 0.431, 0.479 μg/mL for SAL and FLU, respectively. Root mean square error (RMSE) of SAL and FLU was obtained 3.17 × 10-13 and 1.41 × 10-13, respectively in RBF-NN method. In the end, the results obtained from all methods were compared with the high-performance liquid chromatography (HPLC) as a reference method. According to the one-way analysis of variance with a 95% confidence level, there is no significant difference between the proposed techniques and HPLC. Therefore, chemometrics methods are sufficiently accurate, as the reference method for the analysis of drugs. The suggested methods are simple, fast, and cheap. Also, there is no need for pre-preparation steps. These methods can be used for quality control laboratories in the pharmaceutical industry.

Fuzzy inference system and adaptive neuro-fuzzy inference system approaches based on spectrophotometry method for the simultaneous determination of salmeterol and fluticasone in binary mixture of pharmaceutical formulation

In this study, spectrophotometry as a simple, cost-effective, and rapid technique was proposed along with fuzzy inference system (FIS) and adaptive neuro-fuzzy inference system (ANFIS) as chemometrics methods for the simultaneous determination of Salmeterol (SMT) and Fluticasone (FLU) in mixtures and anti-asthma spray formulation. Mean recoveries of SMT and FLU were obtained 101.58%, 95.73% and 100.17%, 99.89% for FIS and ANFIS, respectively. Furthermore, root mean square error (RMSE) related to the FIS and ANFIS were 0.4201, 0.7047 and 0.2172, 0.4563 for SMT and FLU, respectively. Analysis of variance (ANOVA) test was performed to compare the spectrophotometry and high-performance liquid chromatography (HPLC) to confirm the absence of significant differences between the two methods. The proposed method can be useful for simultaneous analysis of drugs compared to the reference method (HPLC) without the need initial preparation steps of the sample.

METHOD DEVELOPMENT AND VALIDATION OF THE CHROMATOGRAPHIC ANALYSIS OF FLUTICASONE PROPIONATE AND SALMETEROL XINAFOATE COMBINATION IN SOLUTIONS AND HUMAN PLASMA USING HPLC WITH UV DETECTION

Objective: A simple, Rapid, and sensitive HPLC method utilizing UV detection was developed and validated for the simultaneous estimation of Fluticasone propionate (FP) and Salmeterol xinafoate (SX) in solutions and in vitro human plasma.
 Methods: Chromatographic analysis was done on SUPELCO® RP-C18 column (150 x 4.6 mm, 5 μm particle size) with an isocratic mobile phase composed of methanol, acetonitrile, and water (50:20:30, v/v) mixture while flow rate was set to 1 ml/min. Detection with UV at maximum absorbance wavelength (ʎmax) values of 236 and 252 for FP and SX, respectively. Spiked plasma samples were liquid-liquid extracted by diethyl ether and reconstituted using methanol.
 Results: Method was accurate and precise over a linear (R2>0.995) range of (0.067-100 µg/ml) and (0.0333-50 µg/ml) for FP and SX, respectively. LOD/lOQ values were 0.13/0.6 and 0.06/0.3 µg/ml for FP and SX, respectively.
 The developed method was successfully applied for the analysis of FP and SX in spiked human plasma samples. The method is considered to be accurate and precise over a linear (R2>0.9969) range of (6.67-66.67 µg/ml) and (3.33-33.3 µg/ml) for FP and SX, respectively. Extraction efficiency was approved by recovery values of (94.98–102.46 %) and (96.54–102.62 %) for FP and SX, respectively.
 Conclusion: This validated method revealed simple and cheap extraction procedures and detectors, non-buffered mobile phase, and short retention times with excellent resolution.

PRS10 Economic Evaluation of Umeclidinium/Vilanterol Versus Umeclidinium or Salmeterol in a UK COPD Population at Low Risk of Exacerbations Using the GALAXY Model

The 24-week EMAX trial in symptomatic patients with chronic obstructive pulmonary disease (COPD) and low exacerbation risk not receiving inhaled corticosteroids demonstrated clinical benefits of once-daily umeclidinium/vilanterol (UMEC/VI) 62.5/25 mcg versus once-daily UMEC 62.5 mcg and twice-daily salmeterol (SAL) 50 mcg. This post hoc analysis assessed cost-effectiveness of UMEC/VI versus UMEC or SAL from a UK payer perspective in patients with COPD and no exacerbation history in the EMAX trial. The validated GALAXY risk equation model was populated with EMAX patient characteristics, treatment effects, rescue medication use data, and 2020 UK costs. Treatment effects included forced expiratory volume in 1 second (FEV1) and St George’s Respiratory Questionnaire (SGRQ); no treatment effect was included for exacerbations. Model outputs included estimated exacerbation rates, survival, costs, life years (LYs), and quality-adjusted LYs (QALYs); incremental cost-effectiveness ratio (ICER) was calculated for cost per QALY gained. The base case used a 10-year time horizon, excluded treatment discontinuation, and discounted future costs and QALYs by 3.5% annually. Sensitivity and scenario analyses assessed robustness of model results. Despite greater incremental drug costs, UMEC/VI was the dominant treatment versus UMEC and SAL, providing an additional 0.090 LYs (95% CI: 0.035, 0.158) and 0.055 QALYs (-0.059, 0.168) with cost savings of £690 (-£1306, -£231) versus UMEC, and 0.174 LYs (0.076, 0.286) and 0.204 QALYs (0.079, 0.326) with cost savings of £1336 (-£2032, -£1006) versus SAL. In scenario and sensitivity analyses, ICERs for UMEC/VI versus UMEC were sensitive to time horizon (5 years: ICER=£4) and SGRQ treatment effect (upper CI: ICER=£12,337), while UMEC/VI was consistently dominant versus SAL. Based on model predictions from a UK NHS perspective, symptomatic patients with COPD and no exacerbation history receiving UMEC/VI are expected to have better outcomes (QALYs and survival) at lower costs versus UMEC and SAL. FUNDING: GSK (study 209845; EMAX study 201749/NCT03034915).

Simple spectrophotometric method for simultaneous determination of salmeterol and fluticasone as anti-asthma drugs in inhalation spray based on artificial neural network and support vector regression

In this study, the application of artificial neural network (ANN) and support vector regression (SVR) methods with spectrophotometry approach was assessed for the simultaneous determination of salmeterol (SMT) and fluticasone (FLU) in synthetic mixtures and inhalation anti-asthma spray. Levenberg–Marquardt (LM) and gradient descent with adaptive learning rate backpropagation (GDA) were applied as training algorithms of feedforward neural network (FFNN). According to the results of mean square error (MSE), the LM algorithm had better ability than GDA for the prediction. Root mean square error (RMSE) of the LM algorithm related to the training, validation, and test sets were 0.168, 0.238, 0.192 and 0.275, 0.360, 0.331 for SMT and FLU, respectively. Also, the mean recovery of these sets was obtained between 99.11% and 102.39% for both components. Optimum parameter values of SVR model were found with minimum RMSE of 0.1068 and 0.1443 for SMT and FLU, respectively. In addition, the mean recovery of test set was achieved 100.91% and 100.46% for SMT and FLU, respectively. The analysis results of anti-asthma spray were compared with high-performance liquid chromatography (HPLC) as a reference technique. No significant difference was observed between these methods using one-way analysis of variance (ANOVA).

Green spectrofluorimetric determination of salmeterol xinafoate in its pure forms, medicinal commercial formula, and human plasma: Application for stability studies.

A natural, accurate, extremely rapid, and precise spectrofluorometric method has been developed and validated for determination of salmeterol (SAL) xinafoate in its medicinal commercial form and spiked human plasma. The native SAL fluorescence has been measured at 415 nm (after 340 nm as excitation) in distilled water. Different factors affecting the native fluorescence consistency of SAL were surveyed and optimized. The suggested procedure was capable of SAL determination over concentrations ranging 200-2000 ng.mL-1 with excellent correlation coefficient of 0.9995. The limits of detection and quantification were estimated as 44.44 ng mL-1 and 134.66 ng mL-1 , respectively. The method has good accuracy and precision. The green spectrofluorometric method was used for determination of SAL in its commercial preparations and the results were in accordance with other reported methods regarding accuracy and precision. Moreover, the proposed procedure was enforced for stability indicating assay of SAL and for SAL determination in spiked human plasma. Nearly no cost, high sensitivity, and wide application make the proposed method ideally suited for analysis of SAL in quality control laboratories.

A generic fluticasone propionate and salmeterol dry powder inhaler: Evidence of usability, function, and robustness.

Background: A generic combination of fluticasone propionate and salmeterol xinafoate inhalation powder in a premetered, multidose, nonreusable inhaler was recently approved. Objective: To assess the performance of the generic device. Methods: Findings from three studies with regard to device usability, function, and robustness were reviewed. Results: In a study to assess device function in patients and healthy volunteers, the generic device was successfully used by patients with asthma and chronic obstructive pulmonary disease who were either dry powder inhaler users or dry powder inhaler-naive, even though they were not trained beyond being provided the instructions for use. In a study to measure inhaled flow rates generated by patients and healthy volunteers, the generic device consistently simulated the delivery of a full dose of drug, even to patients with severe respiratory disease and reduced inspiratory flow rates. Although the generic device had a slightly higher airflow resistance, this study demonstrated that this difference did not result in any clinically meaningful differences in terms of drug delivery. Pressure drop, a key parameter that drives the fluidization and aerosolization of the powder dose, was found to be comparable between the devices. In an open-label study, the generic device met all U.S. Food and Drug Administration specifications for device robustness after 21.5 days of twice-daily dosing via oral inhalation among 111 participants with asthma or chronic obstructive pulmonary disease. All inhalers tested demonstrated conformity with a pharmacopeia with respect to key quality parameters (assay, delivered dose uniformity, aerodynamic size distribution). There was no evidence of chemical degradation of the active ingredients, nor of microbial or water ingress into the powder, as a result of inhaler use.

Airway Epithelial Lining Fluid and Plasma Pharmacokinetics of Inhaled Fluticasone Propionate and Salmeterol Xinafoate in Mechanically Ventilated Pigs.

Background: The lower respiratory tract of the landrace pig has close anatomical and physiological similarities with that of the human, and hence, for inhalation studies this species is well suited for biopharmaceutical research. Methods: The objective of this study was to evaluate pharmacokinetics in pigs following one dose of Diskus™ Seretide™ forte device, labeled 500/50 fluticasone propionate (FP) and salmeterol xinafoate (SX), respectively. The PreciseInhale™ (PI) instrument was used to actuate the inhaler for in vitro testing and aerosol dosing to pigs. In vitro, the aerosol was characterized with a cascade impactor with respect to mass median aerodynamic diameter, geometric standard deviation, and fine particle dose. In vivo, dry powder inhalation exposure was delivered as a short bolus dose, to anesthetized and mechanically ventilated landrace pigs. In addition to plasma PK, PK assessment of airway epithelial lining fluid (ELF) was used in this study. ELF of the depth of three to fourth airway generation of the right lung was accessed using standard bronchoscopy and a synthetic absorptive matrix. Results and Conclusions: Dry powder inhalation exposures with good consistency and well characterized aerosols to the pig lung were achieved by the use of the PreciseInhale™ instrument. Drug concentrations of ELF for both FP and SX were demonstrated to be four to five orders of magnitude higher than its corresponding systemic plasma drug concentrations. Clinical PK following inhalation of the same dose was used as benchmark, and the clinical study did demonstrate similar plasma PK profiles and drug exposures of both FP and SX as the current pig study. Two factors explain the close similarity of PK (1) similiar physiology between species and (2) the consistency of dosing to animals. To conclude, our study demonstrated the utility and translational potential of conducting PK studies in pigs in the development of inhaled pharmaceuticals.

Systematic review and Meta-analysis on efficacy and safety of Liujunzi Decoction combined with Western medicine for stable chronic obstructive pulmonary disease

To systematically review the efficacy and safety of Liujunzi Decoction combined with Western medicine in the treatment of stable chronic obstructive pulmonary disease(COPD). Three English databases and four Chinese databases were systematically searched from the database establishment to April 1, 2020. We screened randomized controlled trial(RCT) according to the pre-determined inclusion and exclusion criteria, then extracted data. Methodological quality of included studies was assessed with Cochrane bias risk evaluation tool. Data were analyzed by using RevMan 5.3. A total of 401 articles were retrieved and finally 17 RCTs were included in this study, involving 1 447 patients, and the overall quality of the included studies was not high. Meta-analysis showed that, in reducing traditional Chinese medicine symptom score, Liujunzi Decoction combined with conventional Western medicine or Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation was superior to conventional Western medicine or Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation alone. In reducing the grade of modified medical research council(mMRC), Liujunzi Decoction combined with Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation was superior to Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation alone. In reducing COPD assessment test(CAT) score, Liujunzi Decoction combined with conventional Western medicine was superior to conventional Western medicine alone. In delaying the decline of forced expiratory volume in one second(FEV_1) or % in the expected value, Liujunzi Decoction combined with conventional Western medicine or Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation was superior to conventional Western medicine or Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation alone. In delaying the decline of ratio of FEV_1 to forced vital capacity(FEV_1/FVC), Liujunzi Decoction combined with conventional Western medicine was superior to conventional Western medicine alone, but there was no statistical difference between Liujunzi Decoction combined with Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation and Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation alone. In reducing acute exacerbation rate, there was no statistical difference between Liujunzi Decoction combined with Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation and Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation alone. On the other outcome measures of Liujunzi Decoction combined with other Western medicine, Meta-analysis could not be conducted and conclusions due to the inclusion of only one study. In terms of the occurrence of adverse reactions, some studies did not mention, so the safety of Liujunzi Decoction combined with Wes-tern medicine could not be determined in this paper. Due to the limitations of the quality and quantity of inclu-ded studies, the efficacy of Liujunzi Decoction combined with Western medicine for COPD still needs more high-quality studies for confirmation, and its safety needs to be further verified.

Systematic review and Meta-analysis on efficacy and safety of Buzhong Yiqi Decoction for stable chronic obstructive pulmonary disease

To systematically review the efficacy and safety of Buzhong Yiqi Decoction in the treatment of stable chronic obstructive pulmonary disease(COPD) at the stable stage. Three English databases and four Chinese databases were systematically searched from the database establishment to August 1, 2020. Randomized controlled trials(RCTs) were screened according to the pre-determined inclusion and exclusion criteria, and then the data were extracted. Methodological quality of the included studies was assessed based on Cochrane bias risk tool, and RevMan 5.3 was used for data analysis. A total of 389 articles were retrieved and finally 18 RCTs were included in this study, involving 1 566 patients, and the overall quality of the included studies was not high. Meta-analysis showed that, in terms of improving 6-minute walk distance(6 MWD), and delaying the decline of forced expiratory volume in one second(FEV_1) or its % in the expected value as well as the decline in ratio of FEV_1 to forced vital capacity(FVC), Buzhong Yiqi Decoction alone or in combination with conventional Western medicine was superior to conventional therapy Western medicine alone. Subgroup analysis showed that, in terms of reducing traditional Chinese medicine symptom scores, Buzhong Yiqi Decoction combined with conventional treatment was superior to conventional treatment. In terms of reducing the grade of modified medical research council(mMRC), Buzhong Yiqi Decoction combined with conventional treatment was superior to conventional treatment. In terms of improving 6 MWD, Buzhong Yiqi Decoction combined with conventional treatment or Tiotropium Bromide Powder for Inhalation was superior to conventional treatment alone or Tiotropium Bromide Powder for Inhalation alone. In terms of delaying the decline of FEV_1 or its % in the expected value, Buzhong Yiqi Decoction combined with conventional treatment or Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation or Tiotropium Bromide Powder for Inhalation was superior to conventional treatment or Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation or Tiotropium Bromide Powder for Inhalation alone, and Buzhong Yiqi Decoction alone was superior to Theophylline alone. In terms of delaying the decline in FEV_1/FVC, Buzhong Yiqi Decoction combined with conventional treatment was superior to conventional treatment, and Buzhong Yiqi Decoction alone was superior to Theophylline alone. Meta-analysis of other outcome measures was not available and no conclusion can be drawn due to the inclusion of only one study. As some studies did not mention the adverse reactions, no safety comments can be made for Buzhong Yiqi Decoction alone or combined with conventional Western medicine. Due to the limitations of the quality and quantity of included studies, the conclusions of this research should be treated with caution. The efficacy of Buzhong Yiqi Decoction for stable COPD still needs more high-quality studies for confirmation, and its safety needs to be further verified.