Transverse comparison of mannitol content in marketed drug products: Implication for no-effect dose of sugar alcohols on oral drug absorption

Some of pharmaceutical excipients are known to affect oral drug absorption via various mechanisms. Among diverse excipients, sugar alcohols (e.g. mannitol and sorbitol) are regarded as critical excipients that significantly alter drug absorption by osmotic effect. This recognition is based on the previous findings that several grams of sugar alcohols exhibited clear impact on the bioavailability/bioequivalence of certain drugs. However, commonly administered oral drug products contain less amount of sugar alcohol, thus, such a significant impact on drug absorption is questionable. The purpose of this research was to retrospectively estimate the no-effect dose of mannitol that may not affect oral absorption of BCS class I and III drugs. Mannitol content in marketed oral drug products (16 active pharmaceutical ingredients, 132 drug products) was quantified by means of reverse engineering or questionnaire survey to 11 generic drug manufacturers headquartered in Japan. The transverse comparison suggested that “practical” amount of mannitol may not have significant impact on oral absorption of investigated molecules. This implication can be utilized to determine a no-effect threshold of sugar alcohol in the context of BCS-based biowaiver guideline as well as other guidelines such as formulation change and pharmaceutical line extension.