Development of a Novel Oral Cavity Compartmental Absorption and Transit Model for Sublingual Administration: Illustration with Zolpidem

Abstract

Abstract. Intraoral (IO) delivery is an alternative administration route to deliver a drug substance via the mouth that provides several advantages over conventional oral dosage forms. The purpose of this work was to develop and evaluate a novel, physiologically based oral cavity model for projection and mechanistic analysis of the clinical pharmacokinetics of intraoral formulations. The GastroPlus™ Oral Cavity Compartmental Absorption and Transit (OCCAT™) model was used to simulate the plasma concentration versus time profiles and the fraction and rate of intraoral drug transit/absorption for Intermezzo® sublingual tablets (zolpidem tartrate). The model was evaluated by the goodness-of-fit between simulated and observed concentrations and the deviation of key PK parameters (e.g., C max , T max , and AUC). In addition, a sensitivity analysis was conducted to demonstrate the interplay and impact of key modeling parameters on the fraction absorbed via oral mucosa (F a_IO ). The OCCAT™ model captured the observed pharmacokinetics for Intermezzo® sublingual tablets (R 2 >0.9). The predicted deviations (%) for C max , AUC 0-inf , AUC 0-20 min , and T max were 5.7, 28.0, 11.8, and 28.6%, respectively, indicating good prediction accuracy. The model also estimated~18% of total drug was absorbed via the IO route. Furthermore, the sensitivity analysis indicated that the F a_IO was not only associated with drug diffusivity and unbound fraction in epithelium tissue (f ut ) but also depended on the physicochemical properties of compounds for IO delivery (e.g., solubility and logD pH=7.4 ). The novel physiologically based IO absorption OCCAT™ model showed satisfactory performance and will be helpful to guide development of future intraoral formulations.KEY WORDS: diffusivity; intraoral delivery; oral cavity compartmental absorption and transit (OCCAT™) model; unbound fraction in epithelium tissue; zolpidem.

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“…The pH value in the oral cavity for healthy humans was found to be ~6.3-7.4, 43,44 while it decreased to weak acid condition for patients who suffered from oral C. albicans. In this research, in vitro release profile of AmB/MPP micelles and redissolved micelles (lyophilized powder redissolved in water) in different mediums (pH 5.8 and 6.8 and 0.5% SDS aqueous solution) was investigated ( Figure 3).…”

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“…The estimated zolpidem absorption via the oral mucosa was about 18% (Xia et al, 2015). In addition, the validation of the OCCAT model was also conducted for other intraoral drug delivery systems, such as sublingual solution (verapamil), and sublingual tablets (propranolol, asenapine, and nicotine) (Xia et al, 2015). The simulated oral transmucosal absorption portion was comparable with the observed data, except nicotine, a small molecule of low lipophilicity and high solubility, which was underestimated (Xia et al, 2015).…”

“…The results showed that the OCCAT model well captured the observed pharmacokinetics of zolpidem (R 2 > 0.9). The estimated zolpidem absorption via the oral mucosa was about 18% (Xia et al, 2015). In addition, the validation of the OCCAT model was also conducted for other intraoral drug delivery systems, such as sublingual solution (verapamil), and sublingual tablets (propranolol, asenapine, and nicotine) (Xia et al, 2015).…”

“…The Oral Cavity Compartment Absorption and Transit (OCCAT) model divided the oral cavity into six physiological compartments: buccal, gingival, palate, top of the tongue, bottom of the tongue, and mouth floor, which accounts for drug dissolution in saliva, diffusion through the oral mucosa, and drug absorption into the systemic circulation (Xia et al, 2015). The parameters involved in the intraoral modeling settings, such as fraction unbound in oral tissue (F u-t ), and oral mucosa diffusivity (D iff-t ), were estimated using GastroPlus™.…”

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“…ACAT also considers the gastrointestinal tract as nine subsections, each with unique physicochemical properties, such as pH, allowed solubility, particle size, and permeability [93]. Novel developments have included other absorption routes other than the GI, which have been recently included in commercially available software, such as oral absorption for the development of sublingual zolpidem tablets [94]. The absorption constant (K a , expressed in terms of h −1 min −1 ), or also called first-order absorption rate constant (to not be confounded with pKa), is employed in most of the aforementioned models and is determined as a result from the changes in mass of absorbable drug over time at the site of administration.…”