Exploring the masking of berberine bitterness by natural polysaccharides based on a “net-hook” dual-effect mechanism

Bitterness masking is a crucial technical hurdle in the development and application of oral liquid medicines. Small-molecule excipients, such as cyclodextrin, often provide insufficient bitterness masking, thus prompting the exploration of large-molecule excipients, especially polysaccharides. In this study, the bitterness-masking effects of 10 polysaccharides were assessed using berberine as a model. Only iota-carrageenan significantly reduced the bitterness of berberine, decreasing it from strong to slight. A comparative study of the bitterness-masking mechanisms of three polysaccharides revealed that carrageenan polymer chains formed an interwoven network, decreasing the release of berberine by 40 %. Moreover, -OSO₃⁻ groups on the polymer chains exhibited strong electrostatic interactions with the N⁺ in berberine, significantly reducing the electron cloud density of N⁺. This combined effect traps berberine within the “net-hook” structure of the iota-carrageenan, markedly weakening the activation of bitter receptors by the berberine. Ultrasonic treatment-induced disruption of the iota-carrageenan network structure yielded a 29 % reduction in bitterness-masking efficacy, while carrageenan with a lower -OSO₃⁻ content achieved a 40 % reduction in efficacy. In conclusion, the “net-hook” structure of natural polysaccharides is a necessary condition for them to exert a bitterness-masking effect. This finding provides a scientific basis for expanding the applications of natural polysaccharides in taste-masking.