Continuous manufacture of polymeric cellular dosage forms

Abstract

The most prevalent pharmaceutical dosage forms at present are granular solids in the form of oral tablets and capsules. While effective in releasing drug rapidly upon contact with gastrointestinal fluid, their manufacture, which relies on particulate processing, is fraught numerous difficulties. Such difficulties, however, could be overcome by transitioning to a liquid-based process. Therefore, we have recently introduced melt-processed polymeric cellular (i.e., highly porous) dosage forms. The drug release behavior was tailored by altering the microstructure, but preparation of the dosage forms relied on the nucleation and growth of gas bubbles in the melt. This is inferior for the manufacture of pharmaceuticals because it requires high temperature and pressure, and is further difficult to control at the cell-scale. Here we present a continuous microfluidic melt extrusion and molding process where the gas bubbles are directly injected into the melt stream. A model is first developed to demonstrate that the cell size and volume fraction of voids in the so produced dosage forms are determined by the width and frequency of gas injection pulses, and the mass flow rates of gas and drug-laden polymeric melt. The experimental results confirm that the microstructural parameters are indeed predictable, and the disintegration rate of the dosage forms increases as the volume fraction of voids is increased. Furthermore, because the cellular dosage forms presented here are lighter than the dissolution medium, they are expected to float over the gastric content in the stomach, which opens possibilities for achieving longer and more predictable gastric residence times. It is thus demonstrated that polymeric cellular dosage forms with tailored drug release properties and density can be manufactured by a continuous process.

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