Food and Drug Department, University of Parma, Parco Area delle Scienze 27/A, Parma, Italy.
Department of Life Sciences and Biotechnology, University of Ferrara, Via Fossato di Mortara 17/19, Ferrara, Italy.
J Control Release. 2017 Sep 28;262:296-304. doi: 10.1016/j.jconrel.2017.07.042. Epub 2017 Jul 31.
In this work, a fixed-dose combination of gabapentin and flurbiprofen formulated as multilayer tablets has been designed, developed and studied in vitro and in vivo. The aim was to construct a single dosage form of the two drugs, able to perform a therapeutic program involving three release kinetics and two delivery sites, i.e., immediate release of gabapentin, intra-gastric prolonged release of gabapentin and intestinal (delayed) release of flurbiprofen. An oblong three-layer tablet was manufactured having as top layer a floating hydrophilic polymeric matrix for gastric release of gabapentin, as middle layer a disintegrating formulation for immediate release of a gabapentin loading dose and as bottom layer, an uncoated hydrophilic polymeric matrix, swellable but insoluble in gastric fluids, for delayed and prolonged release of flurbiprofen in intestinal environment. The formulations were studied in vitro and in vivo in healthy volunteers. The in vitro release rate assessment confirmed the programmed delivery design. A significant higher bioavailability of gabapentin administered 30min after meal, compared to fasting conditions or to dose administration 10min before meal, argued in favor of the gastro-retention of gabapentin prolonged release layer. The two drugs were delivered at different anatomical sites, since the food presence prolonged the gastric absorption of gabapentin from the floating layer and delayed the flurbiprofen absorption. The attainment of a successful delayed release of flurbiprofen was realized by a matrix based on a polymers' combination. The combined use of three hydrophilic polymers with different pH sensitivity provided the dosage form layer containing flurbiprofen with gastro-resistant characteristics without the use of film coating.
在这项工作中，设计、开发并研究了一种将加巴喷丁和氟比洛芬固定剂量组合制成多层片剂的方法。目的是构建两种药物的单一剂型，能够执行涉及三种释放动力学和两个给药部位的治疗方案，即加巴喷丁的即刻释放、胃内加巴喷丁的延长释放和肠道（延迟）释放氟比洛芬。制造了一种长方形三层片剂，顶层是用于胃释放加巴喷丁的亲水性聚合物基质，中层是用于即刻释放加巴喷丁负荷剂量的崩解制剂，底层是未涂层的亲水性聚合物基质，在胃环境中可溶胀但不溶解，用于在肠道环境中延迟和延长释放氟比洛芬。对这些制剂在健康志愿者中的体内外进行了研究。体外释放速率评估证实了编程的递药设计。与空腹条件或饭前 10 分钟给药相比，餐后 30 分钟给予加巴喷丁后，其生物利用度显著提高，这表明加巴喷丁延长释放层的胃滞留。两种药物在不同的解剖部位给药，因为食物的存在延长了漂浮层中加巴喷丁的胃吸收，并延迟了氟比洛芬的吸收。通过基于聚合物组合的基质实现了氟比洛芬成功的延迟释放。三种具有不同 pH 敏感性的亲水性聚合物的联合使用为含有氟比洛芬的剂型层提供了胃耐受力特征，而无需使用薄膜包衣。
