Use of PBPK Modeling To Evaluate the Performance of DissolvIt, a Biorelevant Dissolution Assay for Orally Inhaled Drug Products

Abstract

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 utilize mechanistic in silico modeling 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% poly(ethylene 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 that 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 nonsink conditions) compared to the peripheral regions that 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) modeling of inhaled medicines.

Manipulation of Spray-Drying Conditions to Develop an Inhalable Ivermectin Dry Powder

“…It is probably due to the saturation of the 50 μL dissolution medium by the drug tested for dissolution. A similar trend was also observed by Hassoun et al for a poorly water-soluble drug, fluticasone propionate, when tested using the DissolvIt system [ 69 ]. This is an interesting behavior for dissolution in a low volume of dissolution medium simulating lung conditions as opposed to dissolution study using large volumes of dissolution medium for orally administered drugs.…”

RespiCellTM: An Innovative Dissolution Apparatus for Inhaled Products

“…The benefits of this system are the simulation of the air-blood interface of the deep lung and the possibility of observing in real time the dissolution of the particles through a microscope. Recently, fluticasone propionate dissolution data obtained by this system were translated by in silico model pharmacokinetics parameters and found to be within 2-fold of the values reported for inhaled fluticasone in humans [21]. However, the limitations of the system are its complex configuration and high cost, as well as the collection of most of the aerosolised powder without a cut-off in the respirable particle size distribution range.…”

Optimization of the Transwell® System for Assessing the Dissolution Behavior of Orally Inhaled Drug Products through In Vitro and In Silico Approaches

“…We continued using a 0.4 µm pore size to ensure that undissolved micronized particles were unlikely to enter the receptor compartment. The polycarbonate membrane was selected rather than the polyester membrane because of the higher pore density (i.e., 25 times higher) [ 16 ].…”

“…Published approaches have utilized a range of dose collection and dissolution methodologies [ 5 , 6 ]. Suggested dissolution systems ranged from conventional USP dissolution apparatuses (e.g., USP II or V [ 7 , 8 ], and IV [ 9 , 10 ]), to fluid-limited diffusion-based approaches (e.g., Franz cell [ 11 ] and Transwell ® [ 12 , 13 , 14 ]), and Dissolv It [ 15 , 16 ], with a range of particle collection methods used for sample preparation [ 17 , 18 , 19 , 20 ].…”