Current drug delivery · 2017
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.
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Li Xiaoxi, Yang Meiyan, Li Yueqing, Gong Wei, Wang Yuli, Shan Li, Shao Shuai, Gao Chunsheng, Zhong Wu
Аннотация
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.
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.