Chronotherapeutic Drug Delivery of Ketoprofen and Ibuprofen for Improved Treatment of Early Morning Stiffness in Arthritis Using Hot-Melt Extrusion Technology.

Abstract

This work developed a chronotherapeutic drug delivery system (CTDDS) utilizing a potential continuous hot-melt extrusion (HME) technique. Ketoprofen (KTP) and ibuprofen (IBU) were used as two separate model drugs. Eudragit S100 (ES100) was the matrix-forming agent, and ethyl cellulose (EC) (2.5 and 5%) was the release-retarding agent. A 16-mm extruder was used to develop the CTDDS to pilot scale. The obtained extrudate strands were transparent, indicating that the drugs were homogeneously dispersed in the matrix in an amorphous form, confirmed by both differential scanning calorimetry and powder X-ray diffraction. The strands were pelletized into 1, 2, and 3mm size pellets. A 100% drug release from 1, 2, and 3mm pellets with 2.5% EC was observed at 12, 14, and 16h, whereas the drug release was sustained for 14, 16, and 22h from 5% EC pellets, respectively, for KTP. The release characteristics of IBU were similar to those of KTP with modest variations in release at lag time. The in vitro drug release study conducted in three-stage dissolution media showed a desired lag time of 6h. The percent drug release from 1, 2, and 3mm pellets with 40% drug load showed < 20% release from all formulations at 6h. The amount of ethyl cellulose and pellet size significantly affected drug release. Formulations of both KTP and IBU were stable for 4months at accelerated stability conditions of 40°C/75% RH. In summary, HME is a novel technique for developing CTDDS.