Budapest University of Technology and Economics, Organic Chemistry and Technology Department, H-1111 Budapest, Hungary.
Budapest University of Technology and Economics, Organic Chemistry and Technology Department, H-1111 Budapest, Hungary.
Eur J Pharm Sci. 2019 Mar 15;130:91-99. doi: 10.1016/j.ejps.2019.01.026. Epub 2019 Jan 23.
An orally dissolving web (ODW) formulation of poorly soluble carvedilol (CAR) was developed and manufactured continuously using electrospinning (ES) as a key technology. Phase solubility tests revealed that hydroxypropyl-β-cyclodextrin (HPβCD) solubilizer alone cannot ensure sufficient solubility (6.25 mg CAR in 20 mL) in the oral cavity even if citric acid was present to ionize the basic drug. In turn, electrospun amorphous nanofibers of polyvinylpyrrolidone K30 (PVPK30) and CAR exhibited notable supersaturation of the drug in the presence of citric acid. Differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD) confirmed the amorphous state of CAR. The final ODW was prepared by layering the nanofibers onto pullulan, a well-soluble polysaccharide film carrying citric acid. The double-layered formulation showed ultrafast disintegration and dissolution modeling the oral cavity meeting regulatory requirements (<30 s). The continuous production was accomplished using our recently developed continuous model system by controlled deposition of the nanofibers onto the carrier film strained to a wheel collector and followed by cutting into final dosage units. Performance tests of the continuous system revealed satisfactory content uniformity over time (average acceptance value = 9.45), while residual solvent content measurements showed trace amounts of ethanol (EtOH) after production and acceptable dimethyl-formamide (DMF) content with secondary drying at room temperature. The presented work demonstrates how ES can be part of a continuous manufacturing system as an advanced drying tool during the formulation of challenging drugs.
一种难溶性卡维地洛（CAR）的口服即溶膜（ODW）制剂，采用静电纺丝（ES）作为关键技术连续生产。相溶解度试验表明，羟丙基-β-环糊精（HPβCD）增溶剂单独使用即使存在柠檬酸使碱性药物离子化，也不能确保在口腔中有足够的溶解度（20ml 中 6.25mg CAR）。相反，在柠檬酸存在下，聚维酮 K30（PVPK30）和 CAR 的无定形纳米纤维表现出明显的药物过饱和。差示扫描量热法（DSC）和 X 射线粉末衍射（XRPD）证实了 CAR 的无定形状态。最终的 ODW 通过将纳米纤维分层到具有柠檬酸的普鲁兰（一种可溶性良好的多糖膜）上制备而成。双层制剂表现出超快的崩解和溶解特性，模拟了符合监管要求的口腔（<30s）。连续生产是使用我们最近开发的连续模型系统完成的，该系统通过将纳米纤维受控沉积到载体薄膜上，并在轮式收集器上拉伸，然后切割成最终剂量单位来实现。对连续系统的性能测试表明，随着时间的推移，含量均匀性令人满意（平均验收值=9.45），而残留溶剂含量测量表明生产后乙醇（EtOH）含量痕量，在室温下二次干燥时二甲基甲酰胺（DMF）含量可接受。本工作表明，静电纺丝如何作为一种先进的干燥工具，作为连续制造系统的一部分，用于具有挑战性药物的制剂。
