In Vitro, Pharmacokinetic, Pharmacodynamic, and Safety Comparisons of Single and Combined Administration of Tiotropium and Salmeterol in COPD Patients Using Different Dry Powder Inhalers.

In vitro Andersen cascade impactor-sized mass (ISM) and aerodynamic fine particle mass (FPM) <5 µm for tiotropium and salmeterol combined in a novel inhalation powder formulation containing 7.5 µg tiotropium/25 µg salmeterol (TSHH) were similar (within ±15%) to reference products containing 18 µg of tiotropium (Spiriva® HandiHaler®) (TioHH) and 50 µg of salmeterol (Serevent® Diskus®) (SalD). The pharmacokinetics (PK), pharmacodynamics, safety, and tolerability of the novel fixed-dose TSHH formulation administered once daily was compared with the single-agent therapies TioHH (once daily [qd]) and SalD (twice daily [bid]) and with the jointly administered combination of TioHH (qd) plus SalD (bid) in a randomized, 22-week, open-label, four-way crossover study in 50 patients with chronic obstructive pulmonary disease (COPD). For tiotropium, TSHH and TioHH were bioequivalent based on mean steady-state plasma area under the plasma concentration-time curves (AUC), while the urinary excretion amount was higher for TSHH and not bioequivalent to TioHH. Tiotropium peak plasma concentrations at steady state (C max,ss) were 40% higher with TSHH. For salmeterol, substantial differences were observed in plasma AUCs and Cmax,ss. No significant differences in 8-h forced expiratory volume in 1 s or forced vital capacity were detected for the TSHH (qd) against the combination of TioHH (qd) with SalD (bid). Maintenance therapy with tiotropium plus salmeterol as TSHH or as the jointly administered reference products is superior to either agent alone, safe, and well tolerated in COPD patients. In vitro results were not predictive of clinical PK findings for both tiotropium and salmeterol for the TSHH dry powder inhaler product.

Force control and powder dispersibility of spray dried particles for inhalation.

This study aims towards a deeper understanding of the correlation between particle morphology, cohesion forces, and aerosol performance of spray dried powders for inhalation. Therefore, forces affecting cohesion and dispersion are considered and some novel contact models are introduced to explain the improved powder dispersibility of corrugated particles. Particles with different degrees of corrugation are prepared by spray drying and characterized. Powder dispersibility is measured by positioning a dry powder inhaler in front of the laser diffraction device. The particle sizes of all powders are in the range of x(50) = 2.11 +/- 0.15 microm. The ratio of mass specific surface area S(m) to volume specific surface area S(V) rises from 0.54 cm(3)/g (spherical particles) to 0.83 cm(3)/g (most corrugation). The fine particle fraction (FPF) rises significantly with increasing corrugation at 24 L/min which can be explained by a distinct difference in powder dispersibility. From theoretical models a reduction in cohesion up to 90% can be estimated for corrugated particles compared to spherical particles. Advantages in powder dispersibility can be expected for particles having a lower density and smaller radius of curvature in the contact zone. Both characteristics are given in case of corrugated particles and can be optimized to a certain degree of corrugation.

Assessing the re-crystallization behaviour of amorphous lactose using the RH-perfusion cell.

Many different reports have studied the crystallization behaviour of lactose, e.g., by exposing samples of amorphous lactose to different relative humidity at constant temperatures. However, only few reports are available investigating the formation of alpha-lactose monohydrate and beta-lactose during re-crystallization. Applying the static ampoule method in the microcalorimeter, the enthalpies of amorphous lactose were reported to be constantly 32 and 48 J/g, respectively, considering the mutarotation of lactose at 25 degrees C and 58% RH, 75% RH and 100% RH. In this study, an alternative microcalorimetric technique, the relative humidity-perfusion cell (RH-perfusion cell) was chosen. The RH-perfusion cell is able to deliver a constant and controlled flow of humidified air to the sample. Investigated compounds were purely amorphous lactose and different powder mixtures of lactose. They consisted of alpha-lactose monohydrate (Pharmatose 325M), beta-lactose (Pharmatose DCL21) or a combination (1:1) thereof as carriers, and different concentrations of amorphous lactose. The determination of the enthalpy of desorption of the just re-crystallization lactose by the RH-perfusion cell was used to discriminate whether the monohydrate or the anhydrous form of lactose was produced. Differences in the re-crystallization behaviour of lactose at 25 degrees C and 58-100% RH were found. At 60-80% RH purely amorphous lactose showed a high heat of desorption which can be attributed to a very high content of formed beta-lactose. Powder mixtures containing high contents of amorphous lactose (8% and 15%, respectively) blended with alpha-lactose monohydrate as a carrier resulted in similar results at the same RH ranges. The high amount of beta-lactose can be due to the equilibrium anomeric composition. Whereas powder mixtures containing beta-lactose as a carrier and amorphous lactose in a concentration of 1%, 8% and 15%, respectively, formed less beta-lactose than the mixtures containing alpha-lactose monohydrate as a carrier. At a relative humidity of 90% none of the powder mixtures showed desorption as to the fact that in all cases only alpha-lactose monohydrate was formed at the surface of the re-crystallized lactose. Furthermore, mixtures of alpha-lactose monohydrate and beta-lactose (1:1) and 8% amorphous lactose were investigated. An increase in formed alpha-lactose monohydrate by increasing RH was found. To consolidate the results, the same mixtures were re-crystallized at different RH in desiccators and subsequently investigated in the solution calorimeter. The results of the pre-mix were confirmed by the solution calorimeter. In summary, purely amorphous lactose and mixtures containing alpha-lactose monohydrate as a carrier show different re-crystallization behaviour compared to mixtures containing beta-lactose as a carrier.