title: Formulation and Characterization of a Ternary Inclusion Complex Containing Hydroxypropyl-β-cyclodextrin and Meglumine for Solubility Enhancement of Poorly Water-Soluble ST-246, an Anti-Smallpox Drug.
abstract: BACKGROUND
  The solubilization of poorly water-soluble drugs remains challenging. The purpose of this study was to design a liquid formulation that can improve the solubility of poorly water-soluble and weakly acidic ST-246, an anti-smallpox drug.
  
  
  METHODS
  Soluble ternary cyclodextrin complexations (t-CDs) containing ST-246, 2-hydroxypropyl-β- cyclodextrin (HP-β-CD) and meglumine (MEG) were prepared and optimized. The optimized t-CDs were further characterized using a scanning electron microscope (SEM), Powder X-ray Diffractometry (PXRD), Differential Scanning Calorimetry (DSC), Fourier Transform Infrared Spectroscopy (FTIR) and Nuclear Magnetic Resonance Spectroscopy (NMR).
  
  
  RESULTS
  The solubility of ST-246 improved dramatically from 3 µg/ml (in water, 37°C) to 50 mg/ml in the optimized t-CDs (ST-246/MEG/HP-β-CD, 1:2:6 weight ratio). The results suggested that the drug was associated with MEG through hydrogen bonds and then included into the hydrophobic cavity of HP-β-CD, which might be a major factor for solubility improvement. To determine the exact inclusion mechanism, a Phase Soluble Study (PSS) was also conducted, and it indicated that a 1:1 soluble complex was formed between ST-246 and HP-β-CD and that the action mechanism of MEG was complicated and relied on more than pH modulation.
  
  
  CONCLUSIONS
  Generally, the optimized ternary cyclodextrin complexation might be a potential formulation strategy for enhancing the solubility and bioavailability of poorly water-soluble ST-246.
authors.affiliation: State key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850. China.
authors.forename: Xiaoxi
authors.initials: X
authors.lastname: Li
authors.affiliation: State key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850. China.
authors.forename: Meiyan
authors.initials: M
authors.lastname: Yang
authors.affiliation: School of Pharmaceutical Science and Technology, Dalian University of Technology, Dalian 116024. China.
authors.forename: Yueqing
authors.initials: Y
authors.lastname: Li
authors.affiliation: State key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Gong
authors.affiliation: State key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850. China.
authors.forename: Yuli
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850. China.
authors.forename: Li
authors.initials: L
authors.lastname: Shan
authors.affiliation: State key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850. China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Shao
authors.affiliation: State key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850. China.
authors.forename: Chunsheng
authors.initials: C
authors.lastname: Gao
authors.affiliation: State key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850. China.
authors.forename: Wu
authors.initials: W
authors.lastname: Zhong
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin / Q000737:chemistry*; D000998:Antiviral Agents / Q000737:chemistry* / Q000627:therapeutic use; D001549:Benzamides / Q000737:chemistry*; D004339:Drug Compounding; D006863:Hydrogen-Ion Concentration; D054833:Isoindoles / Q000737:chemistry*; D008536:Meglumine / Q000737:chemistry*; D012899:Smallpox / Q000188:drug therapy / Q000821:virology*; D012995:Solubility; D014867:Water / Q000737:chemistry; D010797:Phthalimides
chemical_list: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000998:Antiviral Agents; D001549:Benzamides; D054833:Isoindoles; D008536:Meglumine; D014867:Water; C505045:tecovirimat; D010797:Phthalimides
keywords: 2-hydroxypropyl-β-cyclodextrin; Poorly water-soluble drug; inclusion complex; meglumine; scanning
  electron microscope (SEM); solubilization