Integration of artificial neural network and physiologically based biopharmaceutic models in the development of sustained-release formulations.

Model-informed drug development is an important area recognized by regulatory authorities and is gaining increasing interest from the generic drug industry. Physiologically based biopharmaceutics modeling (PBBM) is a valuable tool to support drug development and bioequivalence assessments. This study aimed to utilize an artificial neural network (ANN) with a multilayer perceptron (MLP) model to develop a sustained-release matrix tablet of metformin HCl 500 mg, and to test the likelihood of the prototype formulation being bioequivalent to Glucophage® XR, using PBBM modeling and virtual bioequivalence (vBE). The ANN with MLP model was used to simultaneously optimize 735 formulations to determine the optimal formulation for Glucophage® XR release. The optimized formulation was evaluated and compared to Glucophage® XR using PBBM modeling and vBE. The optimized formulation consisted of 228 mg of hydroxypropyl methylcellulose (HPMC) and 151 mg of PVP, and exhibited an observed release rate of 42% at 1 h, 47% at 2 h, 55% at 4 h, and 58% at 8 h. The PBBM modeling was effective in assessing the bioequivalence of two formulations of metformin, and the vBE evaluation demonstrated the utility and relevance of translational modeling for bioequivalence assessments. The study demonstrated the effectiveness of using PBBM modeling and model-informed drug development methodologies, such as ANN and MLP, to optimize drug formulations and evaluate bioequivalence. These tools can be utilized by the generic drug industry to support drug development and biopharmaceutics assessments.

Synergy between surfactants and mucoadhesive polymers enhances the transbuccal permeation of local anesthetics from freeze-dried tablets.

We report on the advance of freeze-dried mucoadhesive orodispersible tablets (ODTs) loaded with prilocaine (PRC) and lidocaine (LDC) hydrochlorides, aiming to promote noninvasive buccal anesthesia. The influences of combining biocompatible polymers (pullulan and HPMC K100 LV) and a blend of surfactants (oleic acid, polysorbate 80 and propylene glycol) acting as chemical enhancers on the permeation of such drugs through the esophageal porcine epithelium and in vitro mucoadhesion were investigated. The ODTs were also characterized in terms of average weight, thickness, pH, drug content, in vitro release, thermal behavior and scanning electronic microscopy. A dissolution test showed fast drug release within one hour. The drug release data for all ODTs fitted first order. No significant influence of the type of mucoadhesive polymer on release was observed, while the drug release from ODTs decreased in the presence of chemical enhancers. For the ODT containing pullulan the drug release mechanism was anomalous transport, whist for all others it was case-II transport. A remarkable synergic effect between pullulan and chemical enhancers on the permeation flux, lag time, and permeability coefficient of both drugs, but mainly for PRC was observed. Pullulan together with permeation enhancers also substantially improved the work of mucoadhesion as compared to HPMC. In contrast, HPMC improved drug retention in the epithelium. The novel drug delivery platform achieved by combining a freeze-drying technique, mucoadhesive biocompatible polymers, and chemical permeation enhancers displayed an effective strategy for the transbuccal delivery of PRC and LDC that can be used to improve needle-free buccal anesthesia.