Design And Solubilization Of Albendazole-bile Acid Derivatives

Objectives According to WHO guidelines for the treatment of echinococcosis,longterm use of benzimidazole: albendazole(ABZ)is recommended in patients with echinococcosis.However,ABZ has many problems,such as low solubility,strong crystallization tendency and poor oral bioavailability,which seriously limit its clinical application.Based on the above problems,this topic proposed the design and preparation of albendazole-bile acid derivatives(ABZ-B),use apical sodium dependent bile salt transporter(ASBT)specific to intestinal ABZ-B transported into the blood,and physical pharmacy under the guidance of the theory analysis contrast ABZ-B and ABZ physical-chemical properties and in vitro,in vivo solubilization effect,aimed at improving ABZ dissolution effect in vivo and in vitro and clinical curative effect.Methods An in situ model of hepatic vesicular hydatid disease(HAE Rat)was established by open vision liver puncture,and the success of the model was determined by ultrasound examination.The expression distribution,protein expression level and gene expression level of ASBT in HAE Rat ileum were verified by immunohistochemistry,immunofluorescence,Western Blot and real-time quantitative PCR.ABZ-B was designed and prepared,and its structure was identified by mass spectrometry and nuclear magnetic resonance(NMR).The physical and chemical properties of ABZ-B were evaluated by wide-angle X-ray diffraction(WXRD),differential scanning calorimetry(DSC),scanning electron microscopy(SEM)and polarized light microscopy(POLM),and its solubilization mechanism was explained from the molecular layer by comparing with ABZ.The drug dissolution behavior of ABZ-B and ABZ in vitro and in vivo were evaluated by high performance liquid chromatography(HPLC)and ultra-performance liquid chromatography-mass spectrometry(UPLC-MS).Results The expression of ASBT in the ileum of HAE Rats was up-regulated compared with that of normal SD Rats(P<0.05).Through liquid NMR and mass spectrometry analysis,ABZ-B was successfully prepared from 4-amino-1-butanol as linker.The apparent solubility of ABZ in ABZ-B was 4 times higher than that of the original ABZ drug.The content of ABZ in plasma of SD rats was quantitatively analyzed,and the solubility of ABZ-B was 4 times higher than that of ABZ prototype drug.Physical and chemical characterization showed that ABZ-B was amorphous,which had an essential change in substance morphology compared with the original crystallized ABZ,which could explain the main reason why the dissolution behavior of ABZ-B was better than that of ABZ in vitro and in vivo.Conclusions The expression of ASBT in the ileum of HAE Rats was upregulated compared with that of normal SD Rats,and ASBT could be used as a prodrug transporter of ABZ.ABZ-B successfully inhibited the crystallization of the prototype drug and changed from the original crystalline state to the amorphous state,effectively solving the problem of poor solubility.At the same time,in vivo and in vitro solubility results showed that the solubility of ABZ-B was obvious,which provided a strong material basis for the follow-up pharmacodynamics study of ABZ-B.