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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

[ Vol. 14 , Issue. 8 ]

Author(s):

Xiaoxi Li, Meiyan Yang, Yueqing Li, Wei Gong, Yuli Wang, Li Shan, Shuai Shao, Chunsheng Gao* and Wu zhong*   Pages 1130 - 1143 ( 14 )

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.

Conclusion: Generally, the optimized ternary cyclodextrin complexation might be a potential formulation strategy for enhancing the solubility and bioavailability of poorly water-soluble ST-246.

Keywords:

Poorly water-soluble drug, solubilization, inclusion complex, 2-hydroxypropyl-β-cyclodextrin, meglumine, scanning electron microscope (SEM).

Affiliation:

State key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, State key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, School of Pharmaceutical Science and Technology, Dalian University of Technology, Dalian 116024, State key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, State key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, State key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, State key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, State key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, State key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850

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