Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX 77030, USA.
Department of Neurosurgery, Houston Methodist Hospital, Neurological Institute, Houston, TX, 77030, USA.
Eur J Pharm Sci. 2018 Dec 1;125:1-10. doi: 10.1016/j.ejps.2018.09.004. Epub 2018 Sep 8.
Enterally administered riluzole is currently being investigated in a Phase II/III clinical trial for the treatment of acute spinal cord injury (SCI). Many SCI patients suffer from severe motor dysfunction and exhibit swallowing difficulties and cannot swallow riluzole tablets. The purpose of the present study was to develop a liquid solution formulation of riluzole, which can be administered more easily to this patient population with the capability to adjust the dose if needed. Riluzole was solubilized using water miscible organic solvents, namely, polyethylene glycol 400, propylene glycol and glycerin. A Central Composite Design (CCD) approach was used to develop an optimum co-solvent composition that can solubilize the entire 50 mg dose of riluzole in 5 ml. A three-factor five-level design was employed to investigate the effects of composition of co-solvents on riluzole solubility. The selected optimum formulation consists of 15% v/v PEG 400, 20% v/v propylene glycol and 10% v/v glycerin, with riluzole concentration of 10 mg/ml. The optimum composition was assessed for stability at different temperatures. Satisfactory stability was obtained at room temperature and 4 °C (t of 17 and 35 months, respectively). The optimum formulation of riluzole was suitable for both oral and intravenous administrations. Single dose pharmacokinetic studies of the optimum formulation by oral and IV routes were evaluated in rats, using commercially available Rilutek® tablets as a reference. The co-solvent formulation was well tolerated both orally and intravenously. In comparison to the commercial tablet, the co-solvent formulation had a faster rate of absorption and more sustained plasma levels with a significantly longer elimination half-life. Higher concentrations of riluzole in brain and spinal cord were achieved from co-solvent formulation as compared to tablet. The riluzole solution formulation is stable and offers advantages of ease of administration, consistent dosing, rapid onset and longer duration of action, better availability at site of action which can be extremely beneficial for the therapy in SCI patients.
目前，一种用于治疗急性脊髓损伤（SCI）的雷利度胺肠内给药正在进行 II/III 期临床试验。许多 SCI 患者患有严重的运动功能障碍，并表现出吞咽困难，无法吞咽雷利度胺片。本研究的目的是开发雷利度胺的液体溶液制剂，以便更容易地向这些患者群体给药，如果需要，还可以调整剂量。雷利度胺使用水溶性有机溶剂，即聚乙二醇 400、丙二醇和甘油进行溶解。采用中心组合设计（CCD）方法开发一种最佳共溶剂组成，可将 50mg 剂量的雷利度胺完全溶解在 5ml 中。采用三因素五水平设计研究共溶剂组成对雷利度胺溶解度的影响。选择的最佳制剂由 15%v/v 的 PEG 400、20%v/v 的丙二醇和 10%v/v 的甘油组成，雷利度胺浓度为 10mg/ml。评估了最佳配方在不同温度下的稳定性。在室温下和 4°C 下均获得了令人满意的稳定性（t 分别为 17 和 35 个月）。雷利度胺的最佳制剂适用于口服和静脉给药。通过口服和 IV 途径，以市售的 Rilutek®片剂作为参比，评估了最佳制剂的单剂量药代动力学研究。共溶剂制剂口服和静脉给药均耐受良好。与商业片剂相比，共溶剂制剂具有更快的吸收速度和更持久的血浆水平，消除半衰期明显延长。与片剂相比，共溶剂制剂在脑和脊髓中达到了更高的雷利度胺浓度。雷利度胺溶液制剂稳定，具有给药方便、剂量一致、起效迅速、作用持续时间长、作用部位可用性更好等优点，这对 SCI 患者的治疗极为有益。
