Abstract
ObjectiveThe aim of the present study was to investigate the absorption routes as well as the potential application of the oral transmucosal delivery of risperidone orodispersible film (ODF) using physiologically based pharmacokinetic modeling.MethodsThe pharmacokinetic study after intragastric (i.g.), supralingual, and sublingual administration of risperidone ODF was conducted in Beagle dogs. Then a mechanic absorption model which combined Oral Cavity Compartment Absorption and Transit (OCCAT) model with Advanced Compartment Absorption and Transit (ACAT) model for predicting the absorption routes of risperidone ODF in vivo was constructed using GastroPlus™. A sensitivity analysis was performed to investigate the impact of oral residence time on the in vivo absorption of risperidone ODF. Based on the fraction of intraoral absorption, the potential of the oral transmucosal delivery of risperidone were predicted.ResultsThere were no statistical differences in the AUC0–t (P = 0.4327), AUC0-∞ (P = 0.3278), Cmax (P = 0.0531), and Tmax (P = 0.2775) values among i.g., supralingual, and sublingual administration of risperidone ODF in Beagle dogs. The predicted absorption percentage via oral mucosa at oral residence time of 2 min, 5 min, and 10 min was 7.0%, 11.4%, and 19.5%, respectively. No obvious difference was observed for the bioavailability of risperidone ODF within 10 min of oral residence time. The PBPK absorption model for risperidone could be simplified to include ACAT model solely. ConclusionThe main absorption route for risperidone ODF was the gastrointestine. The absorption percentage via oral mucosa was almost negligible due to the physicochemical properties of risperidone although ODF dissolved completely in the oral cavity of Beagle dogs within 2 min.
Highlights
Orodispersible films (ODFs) are single or multilayer sheets of water-soluble polymer materials (Madhav et al, 2009; Hoffmann et al, 2011; Lam et al, 2014; Krampe et al, 2016; Foo et al, 2018)
Risperidone ODF was prepared by solvent casting method (Foo et al, 2018).Weighted amount of risperidone was dispersed in purified water at ambient temperature under constant stirring
The ODF all achieved a complete release of its risperidone contents in different medium within 2 min
Summary
Orodispersible films (ODFs) are single or multilayer sheets of water-soluble polymer materials (Madhav et al, 2009; Hoffmann et al, 2011; Lam et al, 2014; Krampe et al, 2016; Foo et al, 2018). Owing to the characteristic of fast wetting, ODFs may adhere to the oral mucosa site and dissolve rapidly, so they cannot be spat out They are very suitable for special patients such as pediatric, geriatric, and psychiatric patients. Risperidone has been widely used for acute and chronic schizophrenia (Huang et al, 1993; Mannens et al, 1993; Gong et al, 2015; Narayan et al, 2016) It can alleviate the symptoms of schizophrenia and improve the social and personal performance (Huang et al, 1993; de Leon et al, 2010). The oral bioavailability of risperidone is about 70% and the pre-systemic metabolism yields the active metabolite of 9-hydroxy (9-OH) risperidone via cytochrome P450 2D6, 3A4, and 3A5 (Huang et al, 1993; de Leon et al, 2010; Shimizu et al, 2017)
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