Green approaches for the development of highly bioavailable oral drug delivery systems

Poor oral bioavailability of APIs is a significant cause of drug failure in clinical development. Consequently, designing and developing effective oral formulations remains one of the primary challenges for the pharmaceutical industry. During my Ph.D. research, I explored new strategies involving the application of liquid eutectic mixtures, specifically NaDES and TheDES, to enhance the oral bioavailability of drugs with poor solubility and/or low gastrointestinal permeability. In Case Study I, various NaDES formulations were investigated to understand the mechanisms responsible for enhancing the solubility of poorly water-soluble APIs. NMR studies revealed the formation of an API-NaDES supramolecular assembly, characterized by a balanced network of hydrogen bonds and hydrophobic interactions. Hard gelatin capsules filled with NaDES maintained their structural integrity for six months. Then, the behavior of NaDES composed of choline chloride and malic acid, loaded with BCS Class II drugs with varying physicochemical properties, was evaluated upon dilution with gastrointestinal fluids (Case Study II). The results demonstrated that NaDES not only enhanced the solubility of these drugs but also formed supersaturated solutions, which potentially could drive in vitro drug absorption. In vitro permeability studies supported the findings from the in vitro dilution tests. As a further step (Case Study III), benznidazole, a BCS class IV drug used for the treatment of Chagas disease in pediatric patients, was selected and loaded in different eutectogel formulations. After their oral administration to rats, drug bioavailability increases by 2.6-fold. The correlation between the in vitro release profile and the in vivo results is noteworthy. Finally, various TheDES formulations were screened in Case Study IV. The most promising formulation, based on proline and ketoprofen, was found unsuitable for oral delivery but showed interesting results for cutaneous administration. Overall, eutectic mixtures represent sustainable and versatile drug delivery platforms to improve the oral bioavailability of poorly soluble/permeable drugs.