Dierickx L, Van Snick B, Monteyne T, De Beer T, Remon J P, Vervaet C
Laboratory of Pharmaceutical Technology, Ghent University, Belgium.
Laboratory of Pharmaceutical Process Analytical Technology, Ghent University, Belgium.
Eur J Pharm Biopharm. 2014 Oct;88(2):502-9. doi: 10.1016/j.ejpb.2014.06.010. Epub 2014 Jul 5.
The aim of this study was to develop by means of co-extrusion a multilayer fixed-dose combination solid dosage form for oral application characterized by immediate release for both layers, the layers containing different drugs with different water-solubility. In this study polymers were selected which can be combined in a co-extruded dosage form. Several polymers were screened on the basis of their processability via hot-melt extrusion, macroscopic properties, acetylsalicylic acid (ASA) decomposition and in vitro drug release. ASA and fenofibrate (FF) were incorporated as hydrophilic and hydrophobic model drugs, respectively. Based on the polymer screening experiments Kollidon® PF 12 and Kollidon® VA 64 were identified as useful ASA carriers (core), while Soluplus®, Kollidon® VA 64 and Kollidon® 30 were applicable as FF carriers (coat). The combination of Kollidon® 30 (coat) with Kollidon® PF 12 or Kollidon® VA 64 (core) failed in terms of processability via co-extrusion. All other combinations (containing 20% ASA in the core and 20% FF in the coat) were successfully co-extruded (diameter core: 2mm/thickness coat: 1mm). All formulations showed good adhesion between core and coat. ASA release from the core was complete within 15-30 min (Kollidon® PF 12) or 30-60 min (Kollidon® VA 64), while FF release was complete within 20-30 min (Kollidon® VA 64) or 60 min (Soluplus®). Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) revealed that both drugs were molecularly dispersed in the carriers. Raman mapping exposed very little intermigration of both drugs at the interface. Fixed-dose combinations with good in vitro performance were successfully developed by means of co-extrusion, both layers providing immediate release.
本研究的目的是通过共挤出技术开发一种用于口服的多层固定剂量复方固体剂型，其特点是两层均为速释，两层含有不同水溶性的不同药物。在本研究中，选择了可用于共挤出剂型的聚合物。基于热熔挤出的加工性能、宏观性质、乙酰水杨酸（ASA）分解情况和体外药物释放情况，对几种聚合物进行了筛选。分别将ASA和非诺贝特（FF）作为亲水性和疏水性模型药物加入。基于聚合物筛选实验，确定聚乙烯吡咯烷酮（Kollidon®）PF 12和聚乙烯吡咯烷酮（Kollidon®）VA 64作为有用的ASA载体（核心层），而固体分散体聚合物（Soluplus®）、聚乙烯吡咯烷酮（Kollidon®）VA 64和聚乙烯吡咯烷酮（Kollidon®）30可作为FF载体（包衣层）。聚乙烯吡咯烷酮（Kollidon®）30（包衣层）与聚乙烯吡咯烷酮（Kollidon®）PF 12或聚乙烯吡咯烷酮（Kollidon®）VA 64（核心层）的组合在共挤出加工性能方面存在问题。所有其他组合（核心层含20% ASA，包衣层含20% FF）均成功共挤出（核心层直径：2mm/包衣层厚度：1mm）。所有制剂的核心层和包衣层之间均表现出良好的黏附性。ASA从核心层的释放在15 - 30分钟内（聚乙烯吡咯烷酮（Kollidon®）PF 12）或30 - 60分钟内（聚乙烯吡咯烷酮（Kollidon®）VA 64）完成，而FF的释放在20 - 30分钟内（聚乙烯吡咯烷酮（Kollidon®）VA 64）或60分钟内（固体分散体聚合物（Soluplus®））完成。差示扫描量热法（DSC）和X射线衍射（XRD）表明，两种药物均分子分散在载体中。拉曼映射显示两种药物在界面处的相互迁移极少。通过共挤出技术成功开发出了具有良好体外性能的固定剂量复方制剂，两层均为速释。
