Use of PBPK Modeling to Evaluate the Performance of Dissolv It, a Biorelevant Dissolution Assay for Orally Inhaled Drug Products

The dissolution of inhaled drug particles in the lungs is a challenge to model using biorelevant methods in terms of: (i) collecting a respirable emitted aerosol fraction and dose, (ii) presenting this to a small volume of medium that is representative of lung lining fluid, and (iii) measuring the low concentrations of drug released. We report developments in methodology for each of these steps and utilise mechanistic in silico modelling to evaluate the in vitro dissolution profiles in the context of plasma concentration-time profiles. The PreciseInhale® aerosol delivery system was used to deliver Flixotide aerosol particles to DissolvIt® apparatus for measurement of dissolution. Different media were used in the DissolvIt chamber to investigate their effect on dissolution profiles, these were: (i) 1.5% polyethylene oxide with 0.4% L-alphaphosphatidyl choline, (ii) Survanta®, and (iii) a synthetic simulated lung lining fluid (SLF) based on human lung fluid composition. For fluticasone proprionate (FP) quantification, solid phase extraction was used for sample preparation with LC-MS-MS analysis to provide an assay which was fit for purpose with a limit of quantification for FP of 312 pg/mL. FP concentration-time profiles in the flow-past perfusate were similar irrespective of the medium used in the DissolvIt chamber (~0.04-0.07%/min), but these were significantly lower than transfer of drug from air-to-perfusate in isolated perfused lungs (0.12%/min). This difference was attributed to the DissolvIt system representing slower dissolution in the central region of the lungs (which feature non-sink conditions) compared to the peripheral regions which are represented in the isolated lung preparation. Pharmacokinetic parameters (Cmax, Tmax and AUC0-∞) were estimated from the profiles for dissolution in the different lung fluid simulants and were predicted by the simulation within 2-fold of the values reported for inhaled FP (1000 µg dose) administered via Flixotide Evohaler® 250 μg strength inhaler in man. In conclusion, we report methods for performing biorelevant dissolution studies for orally inhaled products and illustrate how they can provide inputs parameters for physiologically based pharmacokinetic (PBPK) modelling of inhaled medicines

Siting conflicts between wind power and military aviation-Problems and potential solutions

The expansion of wind power in Sweden has brought increasing conflicts between the wind power industry and the interests of the military forces. This paper analyses the reasons for these perceived conflicts and suggests solutions for mitigating at least some of the problems. The analysis is based on literature studies, several semistructured interviews and workshops with stakeholders in Sweden, Denmark, Germany, Finland and Norway. Some of the problems originate from diverging views on how various societal interests should be weighed against each other, others from uncertainties in the planning and investment environment. The wind power industry has difficulties predicting whether a project will be rejected by the armed forces and believes that the armed forces often change their view on a specific project during the planning process. The Swedish armed forces, on their part, perceive the planning process to be hampered by low-quality, unsubstantiated applications, which sometimes block potentially available areas for more serious applicants. Better communication to improve mutual understanding between the stakeholders and more efficient information systems regarding existing and planned wind power plants would help reduce planning uncertainties in the short term. Better information on how wind power and military installations affect each other in a technical sense could also be important. Early identification of areas with little or no risk of conflict with military interests would help decrease the proportion of projects rejected by the military. In a more far-reaching reform, the wind power planning and permit system could be changed to one similar to the current Danish system, which provides a more important role for comprehensive spatial planning than granting of permits for single projects. (c) 2013 Elsevier Ltd. All rights reserved