A Biopredictive In Vitro Comparison of Oral Locally Acting Mesalazine Formulations by a Novel Dissolution Model for Assessing Intraluminal Drug Release in Individual Subjects

Abstract

Drug release and availability at the site of action are the major factors determining the clinical response for locally-acting gastrointestinal (GI) drug products. The present work focused on the prediction of site and extent of in vivo mesalazine release after oral administration to a variety of subjects using individualized in vitro drug release experiments. First, experiments mimicking GI passages in average adult subjects were performed. Then, results from a study screening fasted in vivo pH and transit profiles in individual subjects were translated into a novel in vitro dissolution model enabling to mimic individual GI pH-profiles and transit times with physiologically relevant dissolution media. A selection of monolithic and multiparticulate mesalazine formulations with pH-dependent and pH-independent drug release was screened with the novel dissolution model. Results of the study indicate that dosage form performance can be significantly different in individual subjects and highlight the importance of addressing individual physiological parameters relevant to intraluminal drug release when the aim is to predict the in vivo performance of locally-acting mesalazine formulations in individual patients. The novel in vitro dissolution approach thus represents a valuable tool for both improving individual oral therapy with locally-acting GI drug products and assessing bioequivalence of these formulations.

In Vitro Methodologies for Evaluating Colon-Targeted Pharmaceutical Products and Industry Perspectives for Their Applications

“…The automated system produced a slower onset of dissolution in Hanks buffer compared to the USP phosphate buffer, applying the same pH gradient manually (by adding sodium hydroxide) [111]. Likewise, the in vitro dissolution of monolithic mesalazine locally acting colonic delivery products was delayed in CarbSIF (pH gradient handled by the automated system) compared to phosphate with the same gradient, revealing differences in the in vivo performance between Salofalk ® and Claversal ® coated tablets [88]. The ability to replicate pH gradients during dissolution can be very valuable to assess the robustness of drug products in different scenarios where intestinal pH and transit may change significantly.…”

“…A more comprehensive analysis of transit variability effects was performed by Karkossa and Klein, who studied the in vitro dissolution of different mesalazine products in a multistage system using CarbSIF media [88]. They optimized transit time vs. pH gradient to account for different physiological scenarios previously observed (Figure 3, Karkossa et al) [4].…”

pH‑dependent vs. constant release of mesalazine in the treatment of ulcerative colitis: Do drug delivery concepts determine therapeutic efficacy? (Review)

“…Of the tested constant release formulation (Pentasa ® ) 50% was lost in the initial phase in an acidic ‘stomach-like’ environment, in contrast to the pH-triggered release variants ( 27 ). This notable effect however, was not confirmed by Karkossa and Klein ( 28 ) in their comprehensive and carefully designed in vitro comparison of different 5-ASA dosage forms. The chosen bicarbonate-based intestinal medium more accurately reflected physiological conditions, and their simulations of gastrointestinal transition were based on reliable in vivo measurements of pH and transit times.…”

In vitro and human pharmacoscintigraphic evaluation of an oral 5-ASA delivery system for colonic release

“…Fluid samples were withdrawn continually for spectrophotometrical assay (λ=244 nm) at fixed time points and subsequently reintroduced into the vessel. Release tests (n=3) were carried out under sink conditions, here meant as those at which the concentration of the drug was <20% of its solubility in phosphate buffer pH 6.8 at 37 °C (~3.5 g/l) (Karkossa and Klein, 2018).…”