Solid-state screening and dry powder inhaler development of ziyuglycoside II sodium salt for enhanced bioavailability

The pharmacological effects of ziyuglycoside II (ZYG II), a saponin derived from Sanguisorba officinalis L., were partially limited by low oral bioavailability (< 5 %) attributable to its poor water solubility, low membrane permeability and extensive first-pass metabolism. To enhance solubility, salt form was selected as ZYG II sodium salt (ZYG-II-Na) in this study, with systematic screening and characterization of its solid forms. To improve the bioavailability, the dry powder inhaler (DPI) of ZYG-II-Na was designed using the optimized solid form. Three crystalline forms (I, II, and III) and two amorphous forms (I and II) of ZYG-II-Na were identified and thoroughly characterized by structural analysis, stability assessment, powder evaluation, in vitro solubility studies, and in vivo pharmacokinetic assessments. Among these, amorphs I and II maintained supersaturation for longer period of time in purified water and Gamble's solution, respectively, indicating enhanced solubility stability. Crystal III exhibited remarkable humidity stability, whereas other solid forms required controlled humidity conditions for storage. The aerodynamic properties of ZYG-II-Na support its suitability for pulmonary delivery. In rats, the oral bioavailability of crystal I was only 3.53 %, whereas the bioavailability of its DPI administration increased to 8.54 %. Remarkably, amorph II further enhanced absorption, reaching an absolute bioavailability of 16.8 %, representing a 4.8-fold enhancement over oral administration. In conclusion, the cooperation of solid form optimization and inhalation delivery successfully overcomes the key barriers associated with poor bioavailability of saponin ZYG II.