Salmeterol Research Articles

Predicting the Fine Particle Fraction of Dry Powder Inhalers Using Artificial Neural Networks

Dry powder inhalers are increasingly popular for delivering drugs to the lungs for the treatment of respiratory diseases, but are complex products with multivariate performance determinants. Heuristic product development guided by in vitro aerosol performance testing is a costly and time-consuming process. This study investigated the feasibility of using artificial neural networks (ANNs) to predict fine particle fraction (FPF) based on formulation device variables. Thirty-one ANN architectures were evaluated for their ability to predict experimentally determined FPF for a self-consistent dataset containing salmeterol xinafoate and salbutamol sulfate dry powder inhalers (237 experimental observations). Principal component analysis was used to identify inputs that significantly affected FPF. Orthogonal arrays (OAs) were used to design ANN architectures, optimized using the Taguchi method. The primary OA ANN r2 values ranged between 0.46 and 0.90 and the secondary OA increased the r2 values (0.53-0.93). The optimum ANN (9-4-1 architecture, average r2 0.92 ± 0.02) included active pharmaceutical ingredient, formulation, and device inputs identified by principal component analysis, which reflected the recognized importance and interdependency of these factors for orally inhaled product performance. The Taguchi method was effective at identifying successful architecture with the potential for development as a useful generic inhaler ANN model, although this would require much larger datasets and more variable inputs.

N-Desmethylclozapine, Fluoxetine, and Salmeterol Inhibit Postentry Stages of the Dengue Virus Life Cycle.

Around 10,000 people die each year due to severe dengue disease, and two-thirds of the world population lives in a region where dengue disease is endemic. There has been remarkable progress in dengue virus vaccine development; however, there are no licensed antivirals for dengue disease, and none appear to be in clinical trials. We took the approach of repositioning approved drugs for anti-dengue virus activity by screening a library of pharmacologically active compounds. We identified N-desmethylclozapine, fluoxetine hydrochloride, and salmeterol xinafoate as dengue virus inhibitors based on reductions in the numbers of infected cells and viral titers. Dengue virus RNA levels were diminished in inhibitor-treated cells, and this effect was specific to dengue virus, as other flaviviruses, such as Japanese encephalitis virus and West Nile virus, or other RNA viruses, such as respiratory syncytial virus and rotavirus, were not affected by these inhibitors. All three inhibitors specifically inhibited dengue virus replication with 50% inhibitory concentrations (IC50s) in the high-nanomolar range. Estimation of negative-strand RNA intermediates and time-of-addition experiments indicated that inhibition was occurring at a postentry stage, most probably at the initiation of viral RNA replication. Finally, we show that inhibition is most likely due to the modulation of the endolysosomal pathway and induction of autophagy.

Preventive effect of salmeterol xinafoate and fluticasone propionate aerosol on radiation pneumonia in local advanced non-small cell lung cancer: a clinical study

Objective To observe the preventive effect of salmeterol xinafoate and fluticasone propionate aerosol on radiation pneumonia in patients with local advanced non-small cell lung cancer (NSCLC) after radiotherapy. Methods Sixty-four patients with local advanced NSCLC were randomly divided into the study group and the control group. Both groups were treated with intensity modulated radiation therapy treatment and routine interventions. Salmeterol xinafoate and fluticasone propionate aerosol were given to the study group from the first day of radiation therapy at both the morning and evening time. Clinical symptoms, chest CT, Karnofsky score and tumor necrosis factor-α (TNF-α) levels in the two groups were analyzed at the time before radiotherapy and three months after radiotherapy. Results The radiation pneumonia incidence of the study group was lower than that of the control group[21.9 %(7/32) vs 46.9 %(15/32)]. The plasma TNF-α content after radiotherapy of the study group was lower than that of the control group [(9.18±3.45) ng/ml vs (13.38 ± 2.75) ng/ml]. Moreover, the Karnofsky score of the study group was higher than that of the control group [(81.67 ± 7.18) scores vs (75.00± 6.74) scores]. The differences between the two groups were statistically significant(all P<0.05). Conclusion Salmeterol xinafoate and fluticasone propionate aerosol can reduce the radiation incidence of the patients with local advanced NSCLC, improve patients’ quality of life after radiotherapy and prevent the radiation pneumonia. Key words: Salmeterol xinafoate and fluticasone propionate aerosol; Radiotherapy, intensity-modulated; Radiation pneumonitis; Carcinoma, non-small-cell lung

Effects of aerosol tiotropium and salmeterol/fluticasone propionate aerosol on lung function in patients with COPD and related indicators

Objective To analyze the effects of salmeterol/fluticasone propionate aerosols fluticasone propionate and salmeterol joint tiotropium aerosol on pulmonary function and exercise tolerance in patients with chronic obstructive pulmonary disease (COPD), and to provide a theoretical basis for clinical treatment. Methods 119 COPD patients were selected in this study.They were randomly divided into 65 cases of seretide group and 54 cases of combined treatment group.Before treatment, three months after treatment and six months after treatment, the pulmonary function and 6MWD were measured in all patients. Results After 3 months, 6 months of treatment, the FEV1, FEV1/FVC, FVC, 6MWD of the combined treatment group had significant differences compared with before treatment(ta=-5.89, tb=-6.88, te=-8.46, tf=-8.86, ti=-10.74, tj=-8.52, tm=-9.37, tn=-13.04, all P<0.05). After 3 months, 6 months of treatment, the FEV1, FEV1/FVC, FVC, 6MWD in the control group had significant differences compared with before treatment (tc=-4.29, td=-7.19, tg=-6.16, th=-11.40, tk=-11.69, tl=-7.43, to=-11.71, tp=-10.53, all P<0.05). After 3 months of treatment, the differences of FEV1, FEV1/FVC, FVC between two groups were significant (tv=2.69, tq=6.74, tr=2.91, all P<0.05). In the control group, the FEV1, FEV1/FVC, FVC after 6 months of treatment had significant differences compared with after 3 months of treatment(ts=-2.50, tt=-9.46, tu=-1.65, all P<0.05). Conclusion Seretide and tiotropium aerosol aerosol can better improve lung function in patients with COPD and exercise tolerance, but the result of using two drugs to improve the patients' lung function was significantly better than seretide alone. Key words: Pulmonary disease, chronic obstructive; Pulmonary function; Tiotropium bromide aerosol; Salmeterol/fluticasone aerosol

Impact of jet-milling and wet-polishing size reduction technologies on inhalation API particle properties

The main goal of this work is to investigate the physical and chemical properties of fluticasone propionate (FP), mometasone furoate (MF) and salmeterol xinafoate (SX) after being size-reduced by jet-milling (JM) and wet-polishing (WP) technologies. FP, MF and SX crystals were size-reduced by JM and WP until a volumetric median particle size (Dv50) of 2μm. Additionally, FP particles were also produced by WP to target a Dv50 of 3μm. The micronized APIs were analyzed by laser diffraction, scanning electron microscopy, modulated differential scanning calorimetry, X-ray powder diffraction, Karl-Fischer, dynamic vapour sorption, mercury intrusion, Brunauer-Emmet-Teller adsorption method and by gas chromatography. The FP and MF powders size-reduced by JM presented a higher specific surface area (SSA), rugosity, porosity and water content and lower skeletal density, bulk density and solvents content when compared to the WP powders. On the other hand, SX by JM powders presented lower SSA, rugosity and porosity and higher densities compared to the WP powders. FP size-reduced by WP to a Dv50 of 2 and 3μm showed identical physicochemical properties. The JM and WP technologies produced FP, MF and SX powders with a similar PSD suitable for inhalation delivery but with distinct physicochemical properties that were technology dependent. These singular attributes may impact the interfacial properties and therefore the final drug product behavior, indicating that additional characterization of micronized API might be recommended for establishing meaningful and performance-oriented specifications.

Preliminary Assessment of Tc-Salmeterol Xinafoate as a Potential Bone Imaging Agent

Sameterol xinafoate is a selective β2-adrenoceptor agonist used in the treatment of some lung diseases and play a vital role in the regulation of bone mass and bone turnover. 99mTc-salmeterol was formulated for the development of a novel potential diagnostic bone imaging agent with excellent biological properties. Factors influencing the labeling yield such as salmeterol xinafoate amount, pH of the reaction medium, reducing agent amount and the reaction time were studied in details. 99mTc-salmeterol was obtained with a high radiochemical yield of 94.6±0.5% and in vitro stability of 6 h when 0.5 mg of salmeterol was mixed with 10 mg NaBH4 at pH 9 and a reaction time 30 min. The biological distribution showed that 99mTc-salmeterol was highly concentrated in the bone (36.5 ± 2%ID/organ) at 30 min post injection. The bone uptake of 99mTc-salmeterol was remained high (29.3 ± 2ID/organ) for a time up to 2h post injection. The results revealed that 99mTc-salmeterol could solve the 99mTc-phosphonate drawbacks and could be used as a bone imaging agent.

Fluticasone plus Salmeterol vs. Fluticasone Alone for Patients with Asthma

In a 2006 industry-sponsored safety study conducted in >26,000 asthma patients, the long-acting β-agonist (LABA) salmeterol (Serevent) — when given in its own inhaler and not as a fixed-dose combination with inhaled corticosteroids — was associated with more asthma-related deaths than was placebo (NEJM JW Gen Med Mar 1 2006 and Chest 2006; 129:15). About half of study participants used inhaled corticosteroids outside the study, but the study was not designed to evaluate whether concomitant use of inhaled corticosteroids protected …

Corticosteroid modulation of immunoglobulin expression and B-cell function in COPD.

We investigated changes in gene expression that occur in chronic obstructive pulmonary disease (COPD) after corticosteroid treatment and sought to identify the mechanisms that regulate these changes. Biopsy samples were taken from patients with COPD (Global Initiative for Chronic Obstructive Lung Disease stage I to II) before and after treatment with fluticasone propionate (FP)/salmeterol (SM) (50/500, 4 wk). Gene expression was measured by microarray and was confirmed by real-time reverse transcription-quantitative PCR (RT-qPCR). The effect of FP on IgG expression and B-cell proliferation in the presence of oxidative stress was also studied. FP/SM significantly increased the expression of 180 genes while repressing 343 genes. The top 5 down-regulated genes were associated with immunoglobulin production, whereas the immunomodulatory FK506 binding protein (FK506BP) was up-regulated. Genes including IL6, IL8, and TBET-encoding TBX21 were unaffected. FP reduced IgG protein and mRNA expression and proliferation of human B cells through the dephosphorylation of ERK-1/2 via increased DUSP1 (dual-specificity protein phosphatase 1) expression. Consistent with in vivo data, oxidative stress did not prevent FP-induced suppression of IgG expression in human B cells in vitro Changes in expression were validated by RT-qPCR and by gene set enrichment analysis in distinct COPD cohorts. FP may reduce the adaptive immune response in COPD and may be more effective in patients with an increased B-cell/antibody response indicated by high autoantibody titers.-Lee, J., Machin, M., Russell, K. E., Pavlidis, S., Zhu, J., Barnes, P. J., Chung, K. F., Adcock, I. M., Durham, A. L. Corticosteroid modulation of immunoglobulin expression and B-cell function in COPD.

Austri, a Large Randomized Study in Adolescents and Adults with Asthma, Assessing the Safety and Efficacy of Salmeterol in Combination with Fluticasone Propionate Compared to Fluticasone Propionate Alone

Previous studies have shown an excess of serious asthma-related outcomes, including death, in subjects taking Long Acting Beta Agonists (LABAs). This study was designed to examine the risks and/or benefits of LABA therapy when added to an ICS in a combination inhaler in patients with asthma. A global, randomized, double-blind, parallel group study of asthmatic subjects ≥12 years; treated with salmeterol (SAL) and fluticasone propionate (FP) in combination (FSC) or FP alone for 26 weeks. The primary endpoint was time to first serious asthma-related event, the composite of death, intubation or hospitalization. To declare non-inferiority the hazard ratio of subjects with a serious asthma-related event with FSC compared to FP was <2.0 based on the upper bound of the 95% confidence interval (CI) on the estimate of the hazard ratio. The secondary endpoint was time to first asthma exacerbation requiring OCS. Of 11,751 subjects randomized, 67 subjects experienced 74 serious asthma-related events with 34 and 33 subjects treated with FSC and FP, respectively. The FSC/FP hazard ratio was 1.029 (0.638-1.662) for time to first serious asthma-related event. Non-inferiority was achieved. There were no asthma-related deaths and 2 asthma-related intubations (both on FP). The FSC/FP hazard ratio for time to first asthma exacerbation was 0.787 (0.698-0.888). There was no evidence of an increased risk of serious asthma-related events when SAL was used in a combination product with FP compared to FP. There was a significant reduction in risk of asthma exacerbations for FSC compared to FP alone.

Analysis of effect of salmeterol, fluticasone propionate combined with tiotropium bromide in the treatment of elderly patients with chronic obstructive pulmonary disease

Objective To evaluate the clinical curative effect of salmeterol, fluticasone propionate combined with tiotropium bromide in the treatment of elderly patients with chronic obstructive pulmonary disease (COPD), thus to provide reference for the clinical treatment. Methods 76 patients with moderate and severe COPD were randomly divided into observation group and control group, 38 cases in each group.The control group on the basis of COPD conventional treatment, received salmeterol, fluticasone propionate inhalation therapy.The observation group was treated with the treatment of the control group and treated with the inhalation of tiotropium bromide.The lung function tests, C reactive protein and T lymphocyte subsets were compared between the two groups before and after treatment. Results After treatment, FEV1, FEV1/FVC, FEV1% in the two groups were significantly higher than before treatment (t=4.25, 4.43, 3.98, 4.12, 4.26, 4.07, all P<0.05).After treatment, FEV1, FEV1/FVC, expected value for FEV1% in the observation group were (2.45±0.35)L/s, (63.91±7.42)%, (47.29±7.52), which were significantly higher than those of control group (t=3.68, 4.03, 4.18, all P<0.05).After treatment, C reactive protein, CD8+ in the two groups were significantly lower than those before treatment, while CD4+, CD4+/CD8+ were significantly higher than those before treatment (t=4.45, 3.99, 5.13, 3.86, 4.13, 4.59, 3.89, 4.03, all P<0.05).After treatment, C-reactive protein, CD+ 8 of the observation group were (10.38±3.12)mg/L, (22.47±2.13)%, which were significantly lower than the control group, and CD4+ (31.62±4.22)%, CD4+/CD8+ (1.43±0.20) were significantly higher than control group (t=4.46, 4.17, 3.92, 4.72, all P<0.05). Conclusion Salmeterol, fluticasone propionate combined with tiotropium bromide in the treatment of elderly patients with COPD can significantly improve the patients' lung function, reduce the inflammation reaction, improve the patients' immune function, alleviate the patients' disease. Key words: Pulmonary disease, chronic obstructive; Salmeterol; Fluticasone propionate; Tiotropium bromide; Aged

Blood eosinophils and inhaled corticosteroid/long-acting β-2 agonist efficacy in COPD

ObjectiveWe performed a review of studies of fluticasone propionate (FP)/salmeterol (SAL) (combination inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA)) in patients with COPD, which measured baseline (pretreatment) blood eosinophil levels, to test...

Bioassay of salmeterol in children using methacholine challenge with impulse oscillometry.

Bronchoprovocation with methacholine (MC) is the most sensitive method of determining bioequivalence of inhaled bronchodilators. FEV1 is used to determine the endpoint, but many children cannot perform spirometry reproducibly. The purpose of this study was to determine whether MC, using impulse oscillometry (IOS) as the endpoint, can differentiate between two doses of salmeterol (SM). This was a single-blind, randomized study of 10 subjects with mild stable asthma, ages 4-11 years. None were taking a long-acting β-agonist but most were on low-dose inhaled corticosteroid. On one study day, MC was performed 1 hr after one inhalation from each of two separate Advair 100/50 Diskus (100 μg salmeterol treatment). On a second day, MC was performed after one inhalation from Advair Diskus and one inhalation from Flovent Diskus 100 (50 μg salmeterol treatment). The provocative concentration of methacholine causing a 40% increase in total airway resistance (PC40 R5 ) was calculated. The reduction in R5 (bronchodilator effect) was 15.5% and 18.4% for 50 and 100 μg, respectively (NS). After MC (bronchoprotective effect), the geometric mean (95%CI) PC40 R5 (mg/ml) was 2.4 (1.3-4.4) during screening, 22.9 (8.5-61.6) after 50 μg SM and 47.0 (25.2-87.8) after 100 μg SM (P = 0.051 for 50 vs. 100 using a linear mixed effects model). No adverse effects were observed. MC with IOS endpoint will be a useful method for determining bioequivalence of a generic inhaler in children. Seventy-two subjects will be required to achieve 80% power to assess bioequivalence of SM. Pediatr Pulmonol. 2016;51:570-575. © 2015 Wiley Periodicals, Inc.

Crystal structure of salmeterol xinafoate form I (Serevent®Diskus®), (C25H37NO4)(C11H8O3)

The crystal structure of salmeterol xinafoate has been solved and refined using synchrotron X-ray powder diffraction data, and optimized using density functional techniques. Salmeterol xinafoate crystallizes in space group P−1 (#2) with a = 9.173 89(13), b = 9.483 79(14), c = 21.3666(4) Å, α = 82.2646(13), β = 85.2531(12), γ = 62.1565(11)°, V = 1628.37(5) Å3, and Z = 2. Key to the structure solution was linking the two fragments by a Li atom along the expected N–H···O hydrogen bond. The salmeterol cation and xinafoate anion are linked by N–H···O and O–H···O hydrogen bonds, interactions which cause the salmeterol to adjust its conformation. The hydrogen bonds result in complex chains along the b-axis. The powder pattern is included in the Powder Diffraction File™ as entry 00-065-1430.

Interaction of Formulation and Device Factors Determine the In Vitro Performance of Salbutamol Sulphate Dry Powders for Inhalation

A variety of capsule-based dry powder inhalers were used to evaluate formulation-device interaction. The in vitro deposition of salbutamol sulphate (SS) was compared directly to published data for salmeterol xinafoate (SX). A 3(2) factorial design was used to assess the effect of SS formulations with three blends of different grade coarse lactose supplemented with different levels of fine lactose. These formulations were tested for homogeneity and evaluated for their in vitro deposition using Aeroliser, Handihaler and Rotahaler devices. The performance of the SS-lactose formulations differed across the grade of lactose and amount of fine lactose used compared to the same powder compositions blended with SX. SX had a greater fine particle fraction than SS for most of the comparable formulations, probably because of the different cohesiveness of the drugs. A head-to-head comparison of 'matched' SX and SS formulations when aerosolised from the same three devices demonstrated that formulation-device interactions are as critical in determining the in vitro deposition of drug-lactose blends as the identity of the active pharmaceutical ingredient. This work has revealed the limitations of the interpretative value of published in vitro performance data generated with a single device (even at equivalent aerosolisation force), when designing formulations for a different device.

Clinical curative effect of salmeterol fluticasone in asthma therapy and its influence on lung function and serum CRP

Objective To investigate the clinical curative effect of salmeterol fluticasone asthma and its influence on lung function, serum CRP. Methods 202 cases of asthma patients were divided into the observation group and control group, with 101 cases in each group. The control group patients simply give fluticasone propionate inhalation therapy, the observation group patients were given salmeterol fluticasone inhalation therapy. Before and after treatment in patients with two groups of curative effect and treatment of pulmonary function, the change of serum CRP were compared. Results The total effective rate of the observation group was 92.1%,which was higher than the control group(78.2%)obviously, the difference was statistically significant (χ2=3.842,P<0.05). After treatment, the forced vital capacity(FVC), forced expiratory volume in first second(FEV1)and the maximum peak expiratory flow(PEF)of the observation group were respectively(84.11± 16.25)%,(96.34±19.65)%and(93.14±17.85)%,and the control group were respectively(74.31±14.27)%,(84.36±20.31)%and(83.52±19.89)%,each group was obviously improved than before treatment, and the observation group improvement were better than the control group,the difference was statistically significant(t=3.425,2.573,2.895,all P<0.05).After treatment,the CRP of the observation group was(18.94± 3.46)mg/L, and the control group was(10.34±1.97)mg/L, each group was obviously improved than before treatment, and the observation group improvement was better than the control group,the difference was statistically significant(t=2.874,P<0.05). Conclusion Salmeterol fluticasone inhaled asthma can significantly improve the clinical curative effect to improve the patient's lung function and serum CRP level,and is safe and reliable.It is worth widely application in the clinical practice. Key words: Salmeterol fluticasone; Asthma; Lung function; C reaction protein

Mathematical approach for understanding deagglomeration behaviour of drug powder in formulations with coarse carrier

Deagglomeration of cohesive particles in combination with coarse carrier is a key requirement for inhaled formulations. The aim of the project was to propose a mathematical approach to understand aerosolization behaviour of micronized particles alone and in formulation with carriers. Salbutamol sulphate and salmeterol xinafoate were blended separately with fine lactose (ratio 1:4) and fine and coarse lactose (1:4:63.5). Laser diffraction was employed to characterize the powder median particle size. The deagglomeration of micronized materials followed an asymptotic monoexponential relationship. When the coarse lactose was added, the relationship fitted a bi-exponential equation showing an easily and a poorly dispersed fraction. Using model hydrophobic and hydrophilic APIs, this study has demonstrated the utility of an analytical approach that can parameterize deagglomeration behaviour of carrier-free and carrier-based inhalation formulations. The analytical approach provides the ability to systematically study the effect of material, formulation and processing factors on deagglomeration behaviour.

Population pharmacokinetics of fluticasone propionate/salmeterol using two different dry powder inhalers

The combination of fluticasone propionate (FLP) and salmeterol (SAL) is often used in clinical practice for the treatment of pulmonary disorders. The purpose of this study was to explore the pharmacokinetics (PK) of inhaled FLP and SAL, after concomitant administration, in healthy male and female subjects using two dry powder inhalers. Plasma concentration (C)–time (t) data were obtained from a single dose, two-sequence, two-period, crossover (2×2) bioequivalence (BE) study. Activated charcoal was co-administered in order to prohibit absorption from the gastrointestinal tract. A number of 60 subjects were recruited, while 57 of them completed the study and were included in the PK analysis. Initially, PK parameters of FLP and SAL were estimated using the classic non-compartmental methods. Subsequently, BE assessment was applied to the estimated PK parameters of the two dry powder inhalers. Special focus was placed on the population PK analysis of the C–t data, which were pooled together. ‘Treatment’ (i.e., test or reference) and ‘period’ of the BE study were considered as covariates. A variety of structural and residual error models were tested to find the one which best described the plasma C–t data of FLP and SAL. Demographic data were also evaluated for their impact on the PK parameters. Several goodness-of-fit criteria were utilized. The non-compartmental PK estimates of this study were in agreement with previously reported values. The population PK analysis showed that FLP data were described by a two-compartment model with first-order absorption and elimination kinetics. Body weight was found to affect significantly absorption rate constant, inter-compartmental clearance, and volume of distribution of the peripheral compartment. As body weight increases, the values of these PK parameters also rise. For SAL, the best results were obtained when a two-compartment disposition model was used assuming very rapid absorption kinetics (like intravenous bolus) and first-order elimination kinetics. Gender was found to be a significant covariate on clearance, with men exhibiting higher clearance than women.

Abstracts from The Aerosol Society Drug Delivery to the Lungs 25Edinburgh International Conference Centre Edinburgh, Scotland, UK December 10–12, 2014

Abstracts from The Aerosol Society Drug Delivery to the Lungs 25Edinburgh International Conference Centre Edinburgh, Scotland, UK December 10–12, 2014

Formulation of a novel fixed dose combination of salmeterol xinafoate and mometasone furoate for inhaled drug delivery

Co-administration of an inhaled corticosteroid and long acting beta agonist for chronic obstructive pulmonary disease has reduced mortality compared to either drug alone. This combination reduces exacerbations, hospitalization, emergency department visits and health care costs. A novel fixed-dose combination of the long acting beta-2 agonist salmeterol xinafoate (SX) and the corticosteroid mometasone furoate (MF) were prepared in a composite particle formulation as brittle matrix powder (BMP) and investigated for suitability as an inhaled combination product. In this study, BMP fixed dose combinations of SX and MF with or without stabilizing excipients (lactose, mannitol, glycine and trehalose) were prepared and characterized with respect to their thermal properties, morphology, aerodynamic performance and physical stability. BMP combination formulations of SX and MF exhibited improved aerodynamic properties when delivered by dry powder inhalation as compared to the micronized blends of the same substances. Aerodynamic evaluation was carried out by next generation pharmaceutical impactor (NGI) with a marketed DPI device. Results demonstrated that co-deposition occurred when SX and MF were formulated together as composite particles in a BMP, while physical blends resulted in inconsistent deposition and dose uniformity. As a result of the bottom-up particle engineering approach, combination BMP formulations allow for dual API composite formulations to be dispersed as aerosolized particles. Aerosolized BMP combination formulations resulted in delivered dose uniformity and co-deposition of each API. Further, an excipient-free formulation, BMP SXMF, delivered approximately 50% of the loaded dose in the respirable range and demonstrated stability at ambient conditions for 6months. Single dose 24-h pharmacokinetic studies in rats demonstrated that lung tissue deposition and blood circulation (AUC0–24h) of two APIs were higher for the BMP combination group exhibiting a significantly higher lung concentration of drugs than for the crystalline physical blend. While high system drug levels are generally undesirable in lung targeted therapies, high blood levels in this rodent study could be indicative of increased pulmonary tissue exposure using BMP formulations.

High shear mixing of lactose and salmeterol xinafoate dry powder blends: Biopharmaceutic and aerodynamic performances

This work aimed to investigate the effect of a high shear mixer on the biopharmaceutics and aerodynamic performances of salmeterol xinafoate/lactose blends for inhalation. The influence of mixing energy during blending on powder bulk properties, aerosolisation and in vitro dissolution rate of drug was studied. There was a clear dependence of the blends bulk characteristics on the mixing rate and time that affected the emitted dose. The fine particle dose or respirable fraction of salmeterol xinafoate was favored by the mixing intensity leading to the disaggregation of the drug particles. An important dependence of the extra-fine drug particles on the mixing conditions was determined. The effective dispersion on the carrier particles of the salmeterol xinafoate improved the dissolution rate of the drug from the blend. This was due to the drug particle size distribution in the blend. When the fine particle dose of different blends was dissolved, no differences among the dissolution rates were observed.