Self-nanonizing gelatin oleyl conjugate solid dispersions for enhanced solubility and permeability of tetrabenazine

The oral delivery of tetrabenazine (TBZ), a weakly basic drug, is markedly affected by its poor permeability and solubility, particularly under neutral pH conditions. This study aimed to design self-nanonizing solid dispersions (SDs) using a fattigated gelatin-oleic acid conjugate (GOC) to achieve a synergistic enhancement of the solubility and permeability of TBZ. Successful conjugation of amphiphilic GOC through N-acylation was confirmed using Fourier transform-infrared and proton nuclear magnetic resonance spectroscopies. Binary GOC-based SDs prepared by spray drying could encapsulate the drug into self-assembled nanoparticles, forming approximately 130 nm above critical micellar concentration (0.887 mg/mL) and enabling enhanced drug release of 62.38 ± 1.14% for 120 min with minimized drug precipitation in aqueous media. Furthermore, ternary SDs incorporating fumaric acid (Fu) as a microenvironmental pH (pHm) modifier showed the highest improvement of dissolution rate and permeability, achieving a 9-fold increased release of 85.32 ± 2.76% within 120 min and a 2.4-fold increase in transmembrane permeability compared to pure TBZ. Reduced crystallinity and increased affinity through hydrogen-bonded molecular dispersion of TBZ into the hydrophobic oleyl cores of GOC and the formation of an amorphous drug-Fu electrostatic complex are also crucial, boosting encapsulation efficiency and dissolution rates by producing approximately 170 nm-sized nanoparticles. Collectively, the current self-nanonizing SD system resolved the solubility and permeability issues associated with TBZ to improve oral drug treatment.