Enhancing Oral Absorption of an Ester Prodrug by Coating Drug Crystals with Binary Lipid Systems and Evaluating the Influence of Compositions.

Background/Objectives: Prodrug strategies are a vital aspect of drug development, with ester prodrugs particularly notable for modifying parent drug properties through ester functional groups to enhance oral absorption. However, ester prodrugs are prone to hydrolysis by water and enzymes, making stability in the gastrointestinal (GI) tract prior to absorption a key challenge. Few formulation strategies effectively address this degradation issue. We recently introduced binary lipid systems (BLS), comprising a lipid and a water-soluble surfactant only that form stable microemulsions. This study aimed to explore the application of BLS for enhancing the oral absorption of ester prodrugs by coating drug crystals with BLS in solid granules and study the impact of the compositions of BLS on oral absorption. Methods: Olmesartan medoxomil (OLM), a methyl ester prodrug of olmesartan (OL), was selected as a model drug. Various lipids were combined with TPGS to form BLS and used to prepare OLM solid granules containing OLM crystals. Results: Among the tested formulations, OLM MCM-TPGS granules significantly enhanced drug release and protected OLM from enzyme-mediated degradation in two-step dissolution studies with esterase. Pharmacokinetic and tissue distribution studies in rats confirmed that OLM MCM-TPGS granules improved oral absorption by 145% and increased tissue uptake compared to OLM powder. Conclusions: This approach overcomes solubility limitations when using lipids and surfactants as excipients, enabling high drug loading in solid dosage forms and expanding the utility of lipids and surfactants for water-insoluble drugs. This novel formulation strategy holds great potential for enhancing oral absorption of ester prodrugs, representing a significant advancement in formulation technologies and offering more effective and versatile drug delivery solutions.