Preparation and characterization of a multiple-unit system for pulsatile and time-dependent colon delivery

Swellable/erodible devices for pulsatile or time-based colon delivery are designed in the form of a drug-containing core and a hydrophilic polymeric coating that undergoes glassy-rubbery transition upon contact with aqueous fluids, thereby delaying the onset of drug liberation. When a multiple-unit configuration of these systems is pursued, the issue of relatively high amounts of functional coating polymer has to be faced to obtain lag times of few hours. The resulting coat thickness would in fact be inconsistent with the size requirements of such dosage forms, thus preventing their well-known benefits from being achieved. In this respect, insoluble films provided with flexibility and increasing permeability have recently been proposed for application to a swellable/erodible device (ChronotopicTM) in order to slow down water penetration through its functional hydroxypropyl methylcellulose (HPMC) coating and improve the relevant efficiency in delaying drug release. Particularly, films of poly(ethyl acrylate, methyl methacrylate) (Eudragit® NE), selected for its good mechanical properties and mild operating conditions, and the superdisintegrant sodium starch glycolate (Explotab® V17), added as a permeability modulator (15-20% on polymer), showed in principle adequate functional properties. In the present work, such film-forming formulations were thus applied to a swellable/erodible device based on HPMC-coated mini-tablet cores. Moreover, the impact of the applied films on the release performance was evaluated. For this purpose, a paracetamol (80%)-containing powder mixture was compacted in a rotary machine (AM-8S, Officine Ronchi, I) equipped with concave punches (2.5 mm diameter, 2 mm curvature radius). Mini-tablets were subsequently coated in fluid bed (GPCG 1.1, Glatt GmbH, D) equipped with rotor insert using an HPMC (Methocel® E50) aqueous solution up to ~250 μm thickness. HPMC-coated cores were in turn coated in bottom-spray fluid bed with Eudragit® NE 30D aqueous dispersions containing 15 or 20% w/w on polymer of Explotab® V17 up to 10, 20 and 30 μm thickness. Curing was then carried out at 40°C for 24 h. In vitro release was tested (n=3) by disintegration apparatus (800 ml of deionized water, 37±1°C, 31 cycles/min, UV analysis, λ=248 nm). Visual inspection of the systems after immersion in aqueous medium (oscillating bath, deionized water, 37±1°C, 100 rpm) and diameter measurements on digital photographs were also performed at predetermined time intervals (n=3). When tested for in vitro release, both formulations were proven able to extend the duration of the lag phase imparted by HPMC, their effect being dependent on the coating level. Although longer lag times were observed in the case of systems provided with films containing 15% of Explotab® V17, the relevant data were impaired by a marked variability. Because of a lower hydrophilicity, such films would probably exert a higher impact on the release mechanism based on swelling/erosion of HPMC. This hypothesis was confirmed by the morphological changes of systems exposed to aqueous fluids. Indeed, the HPMC layer kept swelling even after disruption of the Eudragit® NE film containing 15% Explotab® V17, which was thus hypothesized to hamper a full polymer hydration. On the other hand, the film with 20% of superdisintegrant was shown to affect the kinetics of HPMC hydration but not its extent. Therefore, the latter formulation was proven effective in enhancing the efficiency of the HPMC coating in a multiple-unit swellable/erodible device without altering the inherent release controlling mechanism.