The impact of formulation design on the oral bioavailability of omega-3 polyunsaturated fatty acids

Omega-3 polyunsaturated fatty acids (n-3 PUFA) are essential dietary supplements with widespread health benefits. However, achieving therapeutic n-3 PUFA levels in systemic circulation represents a significant dosing challenge, complicated by a complex interaction between different physiological and chemical factors. Recently, significant efforts have been directed towards creating "bio-accessible" n-3 PUFA formulations that overcome this dosing challenge by enabling increased oral absorption across the small intestine. However, the impact of varying physiochemical formulation properties on n-3 PUFA bioavailability remains poorly understood and requires further investigation. This review explores the impact of formulation design, including self-emulsifying systems, micro- and nano-emulsions, chewable gels, and microencapsulation, on n-3 PUFA pharmacokinetics, considering both clinical and preclinical investigations. Key challenges in developing highly bioavailable n-3 PUFA formulations and quantifying their absorption, biodistribution and metabolism are discussed. Finally, recent progress in developing next-generation n-3 PUFA formulations, including solid lipid nanoparticles and nanostructured lipid carriers, and their targeting through innovative lipid structuring approaches will be addressed. The oral bioavailability of n-3 PUFA is ultimately influenced by multiple design factors related to each formulation strategy, underscoring the need for a systematic formulation approach that involves comprehensive testing of candidate formulation under simulated gastrointestinal conditions.