Xanthan gum to tailor drug release of sustained-release ethylcellulose mini-matrices prepared via hot-melt extrusion: in vitro and in vivo evaluation

Abstract

Mini-matrices (multiple-unit dosage form) with release-sustaining properties were developed by means of hot-melt extrusion using ibuprofen as the model drug and ethylcellulose as sustained-release agent. Xanthan gum, a hydrophilic polymer, was added to the formulation to increase the drug release since ibuprofen release from the ibuprofen/ethylcellulose matrices (60/40, w/w) was too slow (20% in 24 h). Changing the xanthan gum concentration as well as its particle size modified the in vitro drug release. Increasing xanthan gum concentrations yielded a faster drug release due to a higher liquid uptake, swelling and erosion rate. Regarding the effect of the xanthan gum particle size, no difference was observed for formulations containing 10% and 20% xanthan gum. However, using 30% xanthan gum, drug release was influenced by the particle size of the hydrophilic polymer due to the susceptibility of the coarser xanthan gum particles to erosion. Drug release from the mini-matrices was mainly diffusion controlled, but swelling played an important role to obtain complete drug release within 24 h. Drug release was influenced by the ionic strength of the medium as the conformation of xanthan gum molecules is determined by the salt concentration. An oral dose of 300 mg ibuprofen was administered to dogs ( n = 6) in a cross-over study design either as an immediate-release preparation (Junifen ®), as a sustained-release formulation (Ibu-Slow ® 600 mg (1/2 tablet)) or as the experimental mini-matrices (varying in xanthan gum concentration). Administration of the experimental formulations sustained the ibuprofen release. Although a significant difference in dissolution rate of the 20% and 30% xanthan gum mini-matrices was detected in vitro, the difference in relative bioavailability was limited (70.6% and 73.8%, respectively).