Hydroxysafflor yellow A (HSYA), the main active pharmaceutical ingredient of the safflower plant (Carthamus tinctorius L.), is a hydrophilic drug with low oral bioavailability (BA).The objective of the present study was to improve the oral BA of HSYA by formulation design.The main reason for the low oral BA of HSYA is its low liposolubility and high water-solubility, which can hinder its penetration across the epithelial monolayer.Some pharmaceutical excipients have been shown to enhance the permeability of BCS Ⅲ drugs, such as sodium caprate (SC), sodium deoxycholate, β-cyclodextrin (β-CD) and Poloxamer 188 (P188).Therefore, the above five excipients were selected to investigate their ability to enhance the oral BA of HSYA through animal models.