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Multi-kinetics and site-specific release of gabapentin and flurbiprofen from oral fixed-dose combination: in vitro release and in vivo food effect

Sonvico, Fabio, Conti, Chiara, Colombo, Gaia, Buttini, Francesca, Colombo, Paolo, Bettini, Ruggero, Barchielli, Marco, Leoni, Barbara, Loprete, Luca, Rossi, Alessandra
Journal of Controlled Release 2017 v.262 pp. 296-304
absorption, bioavailability, coatings, drug formulations, drugs, gastric juice, hydrophilic polymers, hydrophilicity, pH
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.