Formulation Development of Sublingual Cyclobenzaprine Tablets Empowered by Standardized and Physiologically Relevant Ex Vivo Permeation Studies

Abstract

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.

Oral Mucosa Models to Evaluate Drug Permeability

“…In the conclusions, the authors state that future studies are necessary to optimize in vitro salivary flow simulation to develop a more suitable in vitro permeation model. Recently, a new permeation model was indeed proposed and validated by Majid et al [ 31 , 80 ]. The authors utilized a novel automatized vertical Kerski diffusion chamber (see Figure 1 Panel D) with a total volume of 12 mL and with controlled environmental conditions.…”

“…Sample preparation was performed automatically by the HTS PAL autosampler using Chronos XT software. Cell proliferation and cytotoxicity were evaluated by appropriate kits (Cell Counting Kit-8) [ 31 , 80 ].…”

“…The authors concluded that their results are aligned with the physiological–clinical conditions of therapeutic doses. The automation of the procedure represents a significant improvement in the standardization of permeability testing [ 31 , 80 ].…”

“…Based on the scientific literature mentioned above, it can be concluded that ex vivo models are optimal for both the analysis of drug permeability and for reducing the number of in vivo experiments; however, due to atherogenicity related to tissue origin and preparation, these models cannot completely replace in vivo tests, even if more recent publications are making progress in standardizing and automating many experimental procedures [ 31 , 72 , 80 ].…”