The study was aimed to develop a gastro-retentive mucoadhesive sustained release matrix formulation for milnacipran HCl (MCN) by using the design of experiment (DoE). The gastro-retentive swellable mucoadhesive matrix tablets were prepared by modified solvent-based wet granulation through mixing milnacipran (MCN), chitosan low molecular weight (CH-LM), chitosan medium molecular weight (CH-MM), and polycaprolactone (PCL). Optimization of the formulation was carried out via DoE. Formulations were characterized by DSC, FTIR, and in vitro drug release testing. In vitro mucoadhesive studies were performed on rabbit's intestinal mucosa. In vivo drug release studies were performed on dogs. Optimized matrix formulations showed no significant interaction among the polymers and MCN, confirmed by DSC and FTIR, and were characterized as swellable controlled release matrix systems. The optimized formulations MOPT3 and MOPT4 showed significantly improved adhesion time of 12 h on the gastric mucosa. Based on the in vivo analysis, the elimination half-life of MCN was increased that proved the matrix formulation to be sustained release DDS. The Tmax was extended from 2 to 12 ± 1.63 h for MOPT4. Cmax of matrix was reduced to 121.60 ± 9.496 ng/ml as compared to 149.22 ± 9.942 ng/ml of solution. The bioavailability of the matrix formulation was significantly improved as compared to the MCN solution by 272.20 ± 48.11%. The controlled drug release and strong mucoadhesive properties of the gastro-retentive matrix formulations suggested the potential application of the formulations for the extended oral delivery of MCN.
Keywords: anomalous release; bioavailability; canine-based controlled delivery; milnacipran; mucoadhesion.