title: Dramatic improvement of the solubility of pseudolaric acid B by cyclodextrin complexation: preparation, characterization and validation.
abstract: As one of the most important technologies to improve the solubility of poorly water-soluble drugs, the solubilization effects of cyclodextrins (CDs) complexation are, on occasions, not as large as expected, which tends to detract from the wider application of CDs. In this study, a dramatic improvement of the solubility of pseudolaric acid B (PAB) by CDs has been found with a 600 fold increase by HP-β-CD complexation. In addition, the solubility enhancement of PAB by various CDs, including α-CD, β-CD, γ-CD, HP-β-CD and SBE-β-CD was investigated by phase solubility studies. The inclusion complex of PAB/HP-β-CD was prepared by different methods and characterized by differential scanning calorimetry (DSC), powder X-ray diffractometry (XRD), nuclear magnetic resonance spectroscopy ((1)H NMR) together with molecular simulation. The results indicated that the solubility of PAB was increased to 15.78mgmL(-1) in the presence of 30% HP-β-CD, which is a 600 fold increase compared with that in pure water. And the chemical stability of PAB in PBS (pH 7.4) can be enhanced. The results of DSC and XRD showed the absence of crystallinity in the PAB/HP-β-CD inclusion complex prepared by the saturated water solution method. The results of (1)H NMR together with molecular simulation indicated the conjugated diene side-chain of PAB was included into the cavity of HP-β-CD, with the free energy of -20.34±4.69kJmol(-1). While the enzymatic degradation site of the carboxyl polar bond is located in the hydrophilic outer of HP-β-CD resulted in no significant difference for the enzymatic degradation rate between PAB and PAB/HP-β-CD complexes in rat plasma. In summary, the PAB/HP-β-CD inclusion complex prepared in this study can greatly improve the solubility and chemical stability of PAB, which will result in the in vivo administration of PAB as a liquid solution.
authors.affiliation: Center for Drug Delivery System, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Liandi
authors.initials: L
authors.lastname: Chi
authors.affiliation: Center for Drug Delivery System, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Ruihao
authors.initials: R
authors.lastname: Liu
authors.affiliation: Center for Drug Delivery System, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Guo
authors.affiliation: Center for Drug Delivery System, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Pharmaceutical Sciences, Anhui University of Chinese Medicine, Hefei 230038, China.
authors.forename: Manli
authors.initials: M
authors.lastname: Wang
authors.affiliation: Center for Drug Delivery System, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Zuhua
authors.initials: Z
authors.lastname: Liao
authors.affiliation: Center for Drug Delivery System, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Research Center for Drug Metabolism, College of Life Science, Jilin University, Changchun 130021, China.
authors.forename: Li
authors.initials: L
authors.lastname: Wu
authors.affiliation: Center for Drug Delivery System, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: hyli@mail.shcnc.ac.cn.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Li
authors.affiliation: School of Pharmaceutical Sciences, Anhui University of Chinese Medicine, Hefei 230038, China. Electronic address: dlwu7375@sina.com.
authors.forename: Deling
authors.initials: D
authors.lastname: Wu
authors.affiliation: Center for Drug Delivery System, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Pharmaceutical Sciences, Anhui University of Chinese Medicine, Hefei 230038, China. Electronic address: jwzhang@simm.ac.cn.
authors.forename: Jiwen
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002152:Calorimetry, Differential Scanning; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003460:Crystallization; D003505:Cyclodextrins / Q000737:chemistry*; D004224:Diterpenes / Q000008:administration & dosage* / Q000737:chemistry; D004339:Drug Compounding; D004355:Drug Stability; D005079:Excipients / Q000737:chemistry*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D009682:Magnetic Resonance Spectroscopy; D051381:Rats; D012995:Solubility; D014961:X-Ray Diffraction
chemical_list: D003505:Cyclodextrins; D004224:Diterpenes; D005079:Excipients; C058391:pseudolaric acid B
keywords: Cyclodextrins (CDs); Molecular simulation; Pseudolaric acid B (PAB); Solubilization; Validation