Comparison of the Pharmacokinetics of Salmeterol and Fluticasone Propionate 50/100 µg Delivered in Combination as a Dry Powder Via a Capsule-Based Inhaler and a Multi-Dose Inhaler.

BACKGROUND AND OBJECTIVES: The Rotacaps(®)/Rotahaler(®) system is a single unit dose inhaler being developed to deliver inhaled salmeterol/fluticasone propionate combination (SFC) as an alternative treatment option to the metered dose inhaler and the multi-dose dry powder inhaler, Diskus(®). The aim of this study was to compare the systemic exposure of SFC 50/100 µg following delivery via the Rotacaps(®)/Rotahaler(®) and the Diskus(®). METHODS: This was an open-label, randomized, cross-over, repeat-dose (3.5 days of twice-daily dosing) study comparing salmeterol and fluticasone propionate systemic exposure following inhaled SFC 50/100 µg delivered via the Rotacaps(®)/Rotahaler(®) and Diskus(®), in healthy subjects. Pharmacokinetic sampling was conducted over 12 h post-dose on the last day of each treatment. Pharmacokinetic samples were analysed using solid phase extraction followed by high performance liquid chromatography/tandem mass spectrometry. Co-primary endpoints were fluticasone propionate area under the concentration-time curve over the dosing interval (AUC0-τ ) and salmeterol maximum plasma concentration (C max) on the last day of treatment. RESULTS: Following SFC 50/100 µg Rotacaps(®)/Rotahaler(®), fluticasone propionate and salmeterol systemic exposures were comparable with Diskus(®) in terms of both AUC0-τ [geometric mean ratio (GMR) with 90 % confidence interval (CI) of Rotahaler(®)/Diskus(®) for fluticasone propionate: 0.98 (0.91, 1.06) and salmeterol: 1.04 (0.99, 1.10)] and C max [GMR (90 % CI) for fluticasone propionate: 1.04 (0.94, 1.15) and salmeterol: 0.97 (0.87, 1.08)], meeting the pre-defined criteria for comparability (upper limit of the 90 % CI for the GMRs (Rotahaler(®)/Diskus(®)) ≤1.25]. SFC delivered from both inhalers was well tolerated. CONCLUSIONS: SFC 50/100 µg Rotacaps(®)/Rotahaler(®) showed comparable fluticasone propionate and salmeterol systemic exposure to Diskus(®) for all pharmacokinetic endpoints with GMR and both upper and lower limits of 90 % CIs within conventional acceptance criteria for bioequivalence (0.8, 1.25), sufficient for considering progression of the Rotacaps(®)/Rotahaler(®) product for further clinical development.

Pharmacokinetics of fluticasone propionate and salmeterol delivered as a combination dry powder via a capsule-based inhaler and a multi-dose inhaler.

AIM: To compare salmeterol (SALM) and fluticasone propionate (FP) systemic exposure following inhaled salmeterol/fluticasone propionate combination (SFC) from a unit-dose capsule-based inhaler (Rotacaps(®)/Rotahaler(®)) and a multi-dose dry powder inhaler (Diskus(®)) in healthy volunteers. METHODS: An open-label, randomised, repeat-dose, cross-over, adaptive design study (n = 36 in each part) evaluated SFC 50/250 µg and SFC 50/100 µg in Rotacaps used with two types of Rotahaler inhalers (airflow resistance similar to (S) and lower than (L) Diskus) versus the Diskus. Primary endpoints were area under the concentration-time curve over the dosing interval [AUC0-τ] and maximum plasma concentration [Cmax]. RESULTS: SFC 50/250 µg Rotacaps/Rotahaler (S) showed 1.2-1.9-fold greater FP and SALM systemic exposure compared with Diskus. FP and SALM systemic exposure were comparable to DISKUS following SFC 50/250 µg Rotacaps/Rotahaler (L) (90% CI of ratio of Rotahaler to DISKUS within 0.8-1.25) for salmeterol (AUC0-τ and Cmax) and FP (AUC0-τ). Following SFC 50/100 µg Rotacaps/Rotahaler (L), FP and SALM systemic exposures were 1.2-1.4 fold higher in terms of FP (AUC0-τ and Cmax) and salmeterol (Cmax) compared with Diskus. SFC at both doses and via both inhalers was well tolerated. CONCLUSIONS: SFC 50/250 µg Rotacaps/Rotahaler (L) showed comparable systemic exposure to Diskus in terms of FP AUC and SALM AUC and Cmax. These results merit further progression of SFC 50/250 µg Rotacaps/Rotahaler (L) to phase 3 clinical evaluation in asthma and COPD patients. The lack of pharmacokinetic comparability between the inhalers for SFC 50/100 µg requires further evaluation.

Pharmacokinetics and pharmacodynamics of fluticasone propionate and salmeterol delivered as a combination dry powder from a capsule-based inhaler and a multidose inhaler in asthma and COPD patients.

BACKGROUND: The object of this study was to assess whether a capsule-based and multidose dry powder inhaler containing salmeterol (as xinafoate salt) 50 µg plus fluticasone propionate (FP) 250 µg [combination (SFC 50/250)] could be equivalent in terms of in vivo drug delivery and systemic exposure. METHODS: This was a randomized, double-blind, double-dummy, replicate treatment design comparative bioavailability study of SFC 50/250 delivered in a capsule-based inhaler (Rotahaler®) and a multidose dry powder inhaler (Diskus®). Subjects with asthma or chronic obstructive pulmonary (COPD) disease (n=60) were randomized to receive twice-daily SFC 50/250 via a Rotahaler and via Diskus each for two 10-day treatment periods (GlaxoSmithKline Protocol ASR114334). RESULTS: For FP and salmeterol, the in vitro aerodynamic particle size profiles were within±15% of Diskus for the fine particle mass (FPM) and emitted dose (ED) using the Andersen Cascade Impactor, and ED, mass median aerodynamic diameter, and geometric standard deviation using the New Generation Impactor (NGI). This was also the case for FP but not salmeterol for FPM and fine particle dose using the NGI. For the combined asthma and COPD subjects, the plasma AUC and Cmax for FP and salmeterol were higher for Rotahaler:Rotahaler/Diskus geometric mean ratios (90% confidence intervals) for FP AUC0-τ of 1.52 (1.37-1.67) and Cmax of 1.94 (1.75-2.10) and salmeterol AUC0-τ of 1.15 (1.09-1.21) and Cmax of 1.56 (1.42-1.67). Corresponding values for the primary pharmacodynamic endpoint, weighted mean (0-12 hr) serum cortisol, were 0.928 (0.886-0.971). Inhaled FP/salmeterol via both inhalers was well-tolerated. One serious adverse event, considered possibly related to study medication, resulted in subject withdrawal from the study. CONCLUSIONS: The in vitro tests and systemic pharmacodynamic endpoints revealed no major differences between the two inhalers, but lacked predictive power and sensitivity to guide in vivo drug delivery performance and systemic exposure. Based on pharmacokinetic endpoints, the inhalers were not considered bioequivalent in terms of systemic exposure. Further studies to refine the Rotahaler performance are ongoing.

Aerosol dispersion of respirable particles in narrow size distributions produced by jet-milling and spray-drying techniques.

PURPOSE: To examine the effect of particle size and morphology on aerosol dispersion using jet-milled and spray-dried mannitol particles in narrow size distributions within the respirable range. METHODS: Particle size and morphology were examined by laser diffraction and scanning electron microscopy, respectively. Aerosol dispersion was examined using a cascade impactor with a preseparator operating at a flow rate of 60 L/min, using two inhaler devices: Rotahaler (low-resistance device) and Inhalator (high-resistance device). Powder flow was examined using static and dynamic methods (Carr's compressibility index and vibrating spatula, respectively). RESULTS: Narrow size distributions of jet-milled and spray-dried particles were produced (d50% = 1.4 to 10.3 microm, GSD = 1.8 to 2.1, and d50% = 1.6 to 7.5 microm; GSD = 1.5 to 1.9, respectively). All particles were highly crystalline. Differences in particle shape were observed between jet-milled and spray-dried particles. Higher fine particle fraction (FPF) and relative fine particle fraction (FPFrel) (greater aerosol dispersion) and lower geometric standard deviation (GSD) (less variation) were obtained using particles with d50% between 2 and 5 microm. Higher mass median aerodynamic diameter were obtained with larger d50%. Spray-dried particles produced greater aerosol dispersion compared with jet-milled particles. Greater aerosol dispersion was obtained using the Inhalator than the Rotahaler. CONCLUSIONS: Small changes in the particle size within the 1-10-microm range produced a major impact in the aerosol dispersion of jet-milled and spray-dried particles. Even in these narrow size ranges, aggregation plays an important role in aerosol dispersion.

Aerosol dispersion of respirable particles in narrow size distributions using drug-alone and lactose-blend formulations.

PURPOSE: To examine the effect of formulation type on the aerosolization of respirable particles in narrow size distributions. METHODS: Aerosol dispersion of two formulation types (drug alone and 2% w/w drug-lactose blends) containing micronized or spray-dried fluticasone propionate (FP) particles (d50% = 1.3 to 9.6 microm, GSD = 1.8 to 2.2) were examined using cascade impaction at 60 l/min with low and high resistance inhaler devices: Rotahaler and Inhalator, respectively. RESULTS: The aerosol dispersion of FP particles was significantly affected by the particle size, particle type, inhaler device, and formulation type. Interactions were observed between all factors. Generally, greater powder entrainment was obtained with smaller d50%. Higher emitted doses were obtained from drug-alone formulations of spray-dried FP particles and lactose blends of micronized FP particles. Greater aerosol dispersion of spray-dried FP particles was obtained using lactose-blend formulations with d50% around 4 microm. Greater aerosol dispersion of micronized FP particles was obtained using formulations of drug alone. Larger d50% produced larger mass median aerodynamic diameters. CONCLUSIONS: Small changes in the particle size within the 1-10-microm range exerted a major influence on aerosol dispersion of jet-milled and spray-dried FP particles using drug-alone and lactose-blend formulations.

Influence of physico-chemical carrier properties on the in vitro aerosol deposition from interactive mixtures.

Interactive mixtures were prepared containing 5% (w/w) salbutamol sulfate using various lactose carrier systems, including sieved fractions and blended mixtures of coarse and fine particles. The solid state and powder properties of the lactose carriers were examined by laser diffraction, differential scanning calorimetry, thermogravimetric analysis, powder X-ray diffraction, vapor sorption gravimetry, rotating drum and atomic force microscopy. The in vitro aerosol deposition was determined using a twin-stage impinger with a Rotahaler at an airflow rate of 60l/min. The fine particle fraction (FPF) of salbutamol sulfate was determined using a validated HPLC assay. All samples were highly crystalline with minimal moisture sorption and the major phase in all samples was alpha-lactose monohydrate. Significant differences in FPF were observed using the various carrier systems. FPF increased with decreasing carrier d(50%) (r(2)=0.919) and increasing proportion of fine carrier particles (below 5 microm) (r(2)=0.841). Carriers consisting of very large proportions of fine particles showed low FPF and did not fit the correlation. The presence of coarse carrier particle fractions was essential to achieve maximum FPF, which occurred when about 10% of fine carrier particles were present in the mixture. Dispersion characteristics may be related to the degree of drug aggregation on the carrier surface.

Particle interactions involved in aerosol dispersion of ternary interactive mixtures.

PURPOSE: To investigate the mechanism of action of ternary components within dry powder aerosols. METHODS: Ternary interactive mixtures were prepared containing salbutamol sulphate (SS), coarse lactose carriers and either micronized lactose (ML) or micronized glucose (MG). In vitro drug and excipient aerosol deposition was performed using a twin-stage impinger (TSI) at 60 L/min with a Rotahaler device. Adhesional properties of the lactose carrier were examined using an atomic force microscope (AFM) colloidal probe technique. RESULT: The fine particle fraction (FPF) from ternary mixtures were dependent upon carrier type (p < 0.001), ternary concentration (p < 0.001) and ternary component type (p < 0.05). Ternary mixtures produced higher FPF than binary mixtures, except those containing Superfine (SF), which was attributed to the high proportion of intrinsic fine carrier particles. The higher FPF obtained from ternary mixtures was independent of the mixing order (p = 0.08). Increased adhesion force was observed on the carrier surface following the addition of ternary components (p < 0.001). CONCLUSION: The results confirm that ternary components increase aerosol deposition of powder mixtures. Some results were not entirely consistent with the saturation of active site theory and a hypothesis involving competitive and multilayer adhesion was proposed and requires further testing.