Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, New York, 11439, USA.
Center of Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, 20903, USA.
Pharm Res. 2018 Apr 25;35(7):127. doi: 10.1007/s11095-018-2407-4.
The purpose of this study was to explore the feasibility of developing amorphous solid dispersion (ASD) by inducing acid-base interaction at an elevated temperature using hot melt extrusion.
Itraconazole and glutaric acid, which do not form salt with each other, were selected as, respectively, model basic drug and weak organic acid. A 1:4:1w/w mixture of itraconazole, glutaric acid and a polymer, Kollidon®VA64, was melt extruded at 95°C. The ground extrudate was characterized by DSC and PXRD and then tested for dissolution at pH 1.2, followed by a change in pH to 5.5.
Despite the high melting point of 168°C, itraconazole dissolved in glutaric acid at around the melting temperature of acid (~98°C), and physically stable ASD was produced when the formulation was extruded at 95°C. Capsules containing 100-mg equivalent of itraconazole dissolved rapidly at pH 1.2 producing highly supersaturated solution. When the pH was changed from 1.2 to 5.5, very fine suspensions, facilitated by the presence of Kollidon®VA64, was formed.
Physically stable ASD of itraconazole with high drug load was prepared by interaction with glutaric acid in a hot melt extruder. This may be used as a platform technology for the development ASD of most poorly water-soluble basic drugs.
本研究旨在探索通过在高温下利用热熔挤出诱导酸碱相互作用来开发无定形固体分散体（ASD）的可行性。
选择伊曲康唑和戊二酸作为模型碱性药物和弱有机酸，它们彼此不形成盐。将伊曲康唑、戊二酸和聚合物 Kollidon®VA64 以 1:4:1w/w 的比例在 95°C 下热熔挤出。将挤出物粉碎后，通过 DSC 和 PXRD 进行表征，然后在 pH 1.2 下进行溶解测试，随后将 pH 改变至 5.5。
尽管伊曲康唑的熔点为 168°C，但它在酸的熔融温度（~98°C）左右溶解在戊二酸中，当制剂在 95°C 下挤出时，会产生物理稳定的 ASD。含有 100 毫克当量伊曲康唑的胶囊在 pH 1.2 下迅速溶解，产生高度过饱和溶液。当 pH 从 1.2 改变到 5.5 时，由于存在 Kollidon®VA64，形成了非常细的悬浮液。
通过在热熔挤出机中与戊二酸相互作用，制备了具有高药物负载的伊曲康唑物理稳定的 ASD。这可能成为开发大多数水溶性差的碱性药物 ASD 的平台技术。
