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Title
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Formulation development of poorly water-soluble compounds using solubility enhancement methods
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Author
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Abstract
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| Formulation development of two poorly water-soluble compounds, UAMC 00523 (developed by the Medicinal Chemistry Laboratory of the University of Antwerp) and mangiferin, has been performed using the following techniques: cyclodextrin complexation, PLGA nanoparticle formulations, amorphous solid dispersions and dry amorphization with mesoporous silica. UAMC 00523 is a non-nucleoside transcriptase derivate with potential activity against Human African Trypanosomiasis. Mangiferin is a natural compound with a broad range of potential health-improving activities including anti-inflammatory, anticancer and antidiabetic effects. UAMC 00523 was first formulated with different ?-cyclodextrin derivatives, with a maximum solubility enhancement factor of 80. This formulation was tested in vivo (performed by the Laboratory of Microbiology, Hygiene and Parasitology of the University of Antwerp) with no detectable effect. Subsequently, PLGA nanoparticle formulations were prepared with different PLGA’s and different preparation conditions. Formulations were tested in a 50 mg/kg concentration in vivo after oral administration with no detectable effect. Next, a metabolic stability study was performed, confirming the lack of in vivo activity due to the extensive metabolic clearance of the compound. Mangiferin was formulated by spray-drying of PLGA nanoparticles with an entrapment efficiency above 70% but with a low yield (less than 40%) due to the adhesion of particles on the drying chamber and the cyclone. Considering the low solubility of mangiferin in a common solvent with PLGA and the technical limitations, no further development was performed with this technique. Amorphous solid dispersions were also prepared using different HPMC grades as carrier. Partial amorphization of the compound was achieved with increased solubility. The poor solubility of mangiferin limited the further formulation development with solvent-based techniques, therefore a solvent-free method, the dry amorphization with mesoporous silica using a planetary mono mill was further applied. Binary and ternary systems have been prepared using HPMC and Soluplus® as third component in the formulations. By adjusting the milling settings, amorphous samples were prepared in a significantly shorter time than already reported with other carriers. The stability of the samples was evaluated at accelerated stability conditions in open and closed containers. Increased solubility and amorphous stability of 6 months were achieved for the high energy milled sample. The addition of polymer enhanced the amorphization rate of the samples and improved the stability in open and closed conditions. |
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Language
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English
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Publication
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Antwerp
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University of Antwerp, Faculty of Pharmaceutical, Biomedical, and Veterinary Sciences, Department of Pharmaceutical Sciences
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2019
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Note
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Kiekens, Filip [Supervisor]
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Augustyns, Koen [Supervisor]
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