Development of novel monolithic matrices for drug delivery using conventional and non-conventional polymer processing technologies.

Abstract

The aim of this study was to produce a range of polymer based monolithic matrices for controlled oral drug delivery using conventional polymer processing equipment. Poly (ethylene oxide) (PEO) was chosen as the primary matrix forming polymer for the work described herein. The molecular weight of the matrix forming polymer was found to play a substantial role not only in the processing of the polymer but also in modulating the release rate of an active agent from the dosage form. PEO was found to be thermally and chemically stable when exposed to both multiple processing operations in conventional extrusion equipment and extended storage. PEO was melt blended with poly(e-caprolactone) (PCL) to investigate the effect of the addition of a second biodegradable polymer to the monolithic matrix. Dissolution studies indicated that the drug release from PEO / PCL blends could be modulated by altering the ratio of PEO to PCL present in the blend. PCL was found to improve the processability of the matrix. The processing parameters used during manufacture of the monolithic matrices were seen to have little effect on the end properties of the drug delivery devices. Blends of PEO and Eudragit were melt processed using a supercritical fluid (SCF) assisted process. The use of SCF in the extrusion of monolithic matrices was found to have several benefits when compared to conventional extrusion. Dissolution analysis showed that the use of supercritical CO2 during the extrusion process resulted in a faster dissolution of drug when compared with unassisted extrusion. μTA also showed that the use of SCF in the processing operation had an effect on the morphology of the resultant polymer matrix. The supercritical CO2 incorporation also resulted in reduced viscosity during processing, therefore allowing for quicker throughput and productivity. The effect of novel filler materials on monolithic matrices produced from hot melt extrusion was also investigated. Agar and microcrystalline cellulose were used as the filler materials in varying ratios, to examine the effect of filler content as well as filler type on the properties of hot melt extruded matrices. Rheological analysis concluded that the fillers used resulted in an increase in the matrix viscosity. Thermal analysis showed negligible effects on the melting behaviour of the matrix as a result of the filler inclusion. Dissolution analysis showed that the presence of the fillers resulted in a slower release rate of an active pharmaceutical ingredient (API) than for the matrix alone. Initial cytotoxic and genotoxic testing carried out indicated that the agar filler systems were suitable for biological contact. In addition to agar and microcrystalline cellulose, an organically modified layered silicate was also investigated as a filler material at various levels of inclusion. Mechanical analysis indicated that the nanoclay filler incorporation resulted in an increase in all of the mechanical properties of the matrix. Dissolution analysis showed that the presence of the filler particles resulted in a slower release rate of API than for the matrix alone. Finally, matrices were manufactured using micro-moulding equipment and compared to matrices produced by ram injection moulding and by extrusion alone. Processing of the matrices selected showed that not all of the materials were capable of being processed in conventional screw-type injection moulding equipment. However, all of the materials could be processed using ram-type injection moulding equipment. Different drug release profiles were successfully achieved using the various materials, including pH sensitive and pH insensitive drug release. These matrices could easily be combined within a single capsule to deliver a range of release profiles for a single API or to deliver more than one API to targeted regions along the GI tract.