Advancing Lamotrigine Therapy: Piezoelectric Atomized Cloud Drying-Developed Microparticles in Lyophilized Orally Disintegrating Tablets with Characterization and PBPK Simulation for Enhanced Dissolution, Rapid Absorption, and Faster Onset of Action

Abstract

Epilepsy, a prevalent neurological disorder, is predominantly managed by antiepileptic drugs (AEDs) like lamotrigine. Despite its clinical efficacy, its slow dissolution rate delays therapeutic onset, necessitating improved formulation strategies. This study introduces a novel compression-free lamotrigine formulation using lyophilized orally disintegrating tablets (ODTs) containing microparticles developed through Piezoelectric Atomized Cloud Drying (PACD). The PACD-generated microparticles significantly enhanced lamotrigine’s aqueous solubility (from 0.17 mg/mL to 2.62 mg/mL with PVP K30) and demonstrated > 90% drug release within 10 min, addressing lamotrigine’s dissolution limitations. DSC and PXRD studies confirm the amorphization of lamotrigine that contributed to improvement in the solubility and dissolution rate. Microparticles with significantly smaller size (D90 = 1.851 μm, Mean Size (SD) = 1.098 ± 0.563 μm and PDI = 0.262) are also responsible for this solubility improvement. The optimized lamotrigine microparticle-loaded lyophilized orally disintegrating tablet (LMP-LODT) evaluated for physicochemical properties, disintegration, and in-vitro dissolution, showing rapid drug release and excellent patient-friendly attributes. Furthermore, Physiology-Based Pharmacokinetic (PBPK) simulations using PK-Sim^® predicted a reduced Tmax (0.66 h) indicating faster absorption and earlier attainment of therapeutic levels. In conclusion, combining PACD-engineered amorphous microparticles with lyophilized ODT technology effectively improved lamotrigine’s solubility, dissolution, and pharmacokinetic profile. This formulation approach offers a promising alternative to conventional lamotrigine tablets by enabling faster therapeutic onset, improved patient compliance, and potentially reduced dose-dependent adverse effects.