Binary lipid system-based granules with undissolved drug crystals enhance oral bioavailability by preventing degradation and improving permeability.

Conventional oral drug delivery systems, such as lipid-based formulations and nanoparticles, require drugs to fully dissolve in excipients to improve solubility and bioavailability. However, many drugs, including olmesartan medoxomil (OLM), an ester prodrug for hypertension, have low solubility in water, lipids, and surfactants, resulting in low drug loading (e.g. 1 ∼ 2 % drug loading) and formulation challenges. Premature degradation of ester prodrugs is also a major factor contributing to the low bioavailability of prodrugs. This study developed OLM lipid-solid granules (LSG) by coating OLM crystals with a binary lipid system (BLS) composed of one lipid and one water-soluble surfactant only. The OLM granules achieved 10 % drug loading and increased relative bioavailability to 625 %, surpassing all previously reported formulations containing dissolved OLM. Extensive in vitro studies, including two-step dissolution and Caco-2 cell assays with and without esterase, demonstrated that OLM LSG protected OLM from esterase-mediated hydrolysis and enhanced drug uptake and permeability. Pharmacokinetics and tissue distribution confirmed enhanced small intestine absorption. This novel approach introduces a transformative concept of coating drug crystals with a BLS in solid granules to enhance oral absorption and eliminates the need to dissolve drugs in excipients. It represents a fundamental shift in the use of lipids and surfactants, offering a promising platform for delivering prodrugs with low solubility and susceptibility to hydrolysis.