Formulation, Process Optimization, and in Vitro–in Vivo Evaluation of Buccal Effervescent Tablets of BCS Class II and Class IV Drugs: Asenapine Maleate and Telmisartan Cilexetil

Abstract

Conventional oral drug delivery is inadequate for drugs with extensive first-pass hepatic metabolism or poor gastrointestinal solubility and permeability. This study aimed to design, formulate, and comprehensively evaluate BETs of asenapine maleate (ASM; BCS Class II) and telmisartan cilexetil (TC; BCS Class IV) as candidate drugs for which oral bioavailability is critically limited. Preformulation studies (pH-dependent solubility, physicochemical characterization, FTIR and DSC drug-excipient compatibility) were performed for both drugs. Placebo effervescent granules were manufactured by RMG and FBP and characterized by SEM, particle size, compressibility, and flow. A 3 3 full factorial DoE (Design Expert® v9.0.4) with sodium bicarbonate (X₁), citric acid anhydrous (X₂), and tartaric acid (X₃) as factors optimized for disintegration time (R₁) and microenvironmental pH (R₂). Optimized formulations were evaluated for in vitro dissolution, in vitro buccal permeation through freshly excised goat mucosa using Franz diffusion cells, buccal mucosal irritation (histopathology), in vivo pharmacokinetics in New Zealand White rabbits, and 12-month ICH accelerated stability. FBP produced spherical, uniform granules (447–516 μm; Carr's index 12.10±0.32%; moisture 0.13%) superior to RMG in all quality attributes. The optimized ASM-BET (Batch F17; pH 4.5±0.2; DT 5.14±0.12 min) released 91.38±4.6% drug at 14 min, versus 68.12±4.9% for the marketed comparator (ASENAPT-5®), representing a 34% improvement. Permeation flux was 2.18-fold greater than the reference. The optimized TC-BET (Batch F2; pH 6.86; DT 6.7±2.3 min) demonstrated similarly enhanced dissolution and permeation. Buccal mucosal histopathology confirmed absence of irritation. In vivo pharmacokinetic studies in rabbits showed relative bioavailability of 147.2% (ASM-BET) and 142.8% (TC-BET) versus respective reference formulations, with significantly elevated AUC and Cₘₐₓ.