Suitable ex vivo models are required as predictive tools of oromucosal permeability between in vitro characterizations and in vivo studies in order to support the development of novel intraoral formulations. To counter a lack of clinical relevance and observed method heterogenicity, a standardized, controlled and physiologically relevant ex vivo permeation model was established. This model combined the Kerski diffusion cell, process automation, novel assays for tissue integrity and viability, and sensitive LC-MS/MS analysis. The study aimed to assess the effectiveness of the permeation model in the sublingual formulation development of cyclobenzaprine, a promising agent for the treatment of psychological disorders. A 4.68-fold enhancement was achieved through permeation model-led focused formulation development. Here, findings from the preformulation with regard to pH and microenvironment-modulating excipients proved supportive. Moreover, monitoring of drug metabolism during transmucosal permeation was incorporated into the model. In addition, it was feasible to assess the impact of dosage form alterations under stress conditions, with the detection of a 33.85% lower permeation due to salt disproportionation. Integrating the coherent processes of disintegration, dissolution, permeation, and metabolization within a physiological study design, the model enabled successful formulation development for cyclobenzaprine sublingual tablets and targeted development of patient-oriented drugs for the oral cavity.
IntroductionHeart failure is well investigated in adults, but data in children is lacking. To overcome this shortage of reliable data, appropriate bioanalytical assays are required.ObjectivesDevelopment and validation of a bioanalytical assay for the determination of aldosterone concentrations in small sample volumes applicable to clinical studies under Good Clinical Laboratory Practice.MethodsAn immunoassay was developed based on a commercially available enzyme-linked immunosorbent assay and validated according to current bioanalytical guidelines of the European Medicines Agency (EMA) and U.S. Food and Drug Administration (FDA).ResultsThe assay (range 31.3–1000 pg/mL [86.9–2775 pmol/L]) is characterized by a between-run accuracy from − 3.8% to − 0.8% and a between-run imprecision ranging from 4.9% to 8.9% (coefficient of variation). For within-run accuracy, the relative error was between − 11.1% and + 9.0%, while within-run imprecision ranged from 1.2% to 11.8% (CV). For parallelism and dilutional linearity, the relative error of back-calculated concentrations varied from − 14.1% to + 8.4% and from − 7.4% to + 10.5%, respectively.ConclusionsThe immunoassay is compliant with the bioanalytical guidelines of the EMA and FDA and allows accurate and precise aldosterone determinations. As the assay can run low-volume samples of 40 μL, it is especially valuable for pediatric investigations.
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