(W1230-03-21) Fabrication of Bio-Adhesive Gastric Floating Pellets Using Hot-Melt Extrusion

Purpose: The gastric floating drug delivery system is a dosage form that retains buoyant in the stomach for a period of time by virtue of lower density than the normal gastric content. It enhances the drug bioavailability since the prolonged retention time in the stomach can increase drug absorption. The bio-adhesive polymers would link the dosage from to the biological membranes and avoid them from being removed by the gastric fluid. In this study, novel bio-adhesive gastric floating systems were developed. The formulation was successfully floating in the dissolution media, and 100% release was achieved at 6h. This drug delivery system extended drug release by prolonging the gastric retentive time combining floating and bio-adhesive mechanisms.

Methods: Theophylline (Sigma-Aldrich, Inc. USA) was used as the model drug. Hydroxypropyl cellulose (HPC HF, Ashland, USA) and chitosan (Spectrum Chemical Mfg. Corp. USA) were selected as swellable matrices. Due to the high viscosity of these polymers, they were expected to achieve bio-adhesive properties. Sodium bicarbonate (Fisher Scientific, USA) was utilized as the gas-generating agent. Three formulations including 10% NaHCO3 with different ratio of HPC and chitosan were prepared. Initially, the API and excipients of each formulation were weighed and physically mixed by a V-blender. The extrudates were produced by a co-rotating twin-screw extruder which equipped with a 1.5 mm circular die at 200 °C at a screw speed of 50 rpm. Finally, the extrudates were manually cut into pellets for further studies. The diameter of the pellet is 1.5mm, and the length is around 0.2 cm. A differential scanning calorimetry (DSC) system (TA Instruments, USA) was used to investigate the crystallinity of the drug. The dissolution studies of 200 mg pellets were operated in 0.1 N HCL (PH=1.2) using a United States Pharmacopeia (USP)-II dissolution apparatus at 37 °C with a basket speed at 50 rpm. Samples were collected at predetermined time intervals and analyzed using a UV-Vis spectrophotometer at the wavelength of 270 nm. The floating behavior of formulations was also recorded during the release process.

Results: The formulations were successfully prepared and remained floating during the whole dissolution period (Fig 1a, 1b). As shown in the picture (Fig 1c), after contact with the dissolution media for a while, bubbles appear on the surface of the pellets, which could potentially support the formulation floating behavior by decreasing the pellet density. The DSC thermograms for pure excipients and each extrudate were shown in Fig.2. The pure theophylline exhibits a sharp endothermic melt peak around 276 °C, and sodium bicarbonate showed sharp melting peaks at 175°C. However, the peaks completely disappeared in hot melt extruded formulations, indicating that the drug was successfully transformed from the crystalline to the amorphous state. The in-vitro release study was shown in Fig.3. For each pellet’s formulation, 100% release was achieved in 6h. Compared to pure theophylline, the developed gastric floating pellets exhibit extended-release properties.

Conclusion: The designed bio-adhesive gastric floating pellets can be successfully fabricated using HME. Theophylline was dispersed in the polymer excipients forming an amorphous solid dispersion during the HME process. The addition of sodium bicarbonate as a gas-generating agent helps to form bubbles on the pellet’s surface, which could potentially support the formulation floating behavior by decreasing the pellet density. The formulations showed extended-release properties, and further bio-adhesive studies are warranted.

Figure 1. The pictures of each formulation. (a.) The pellets after hot-melt extrusion and manually cut. (b.) The floating behavior of the pellets. (c.) The surface morphology of the pellets after contact with the dissolution media for a while.

Figure 2. The DSC thermograms of the pure excipients and the extruded filaments.

Figure 3. The dissolution profile of the formulations.