In vitro and in vivo evaluation of an erodible multiple-unit delivery system for oral pulsatile release

Purpose. To evaluate the in vitro and in vivo performance of an erodible multiple-unit delivery system for oral pulsatile release. This system consists of a mini-tablet core containing the drug, an inner hydroxypropyl methylcellulose (HPMC) layer that delays the onset of release and an outer film composed of EudragitNE and a superdisintegrant, ExplotabV17, as the pore-former. The latter film would be intended to slow down the penetration of water into the underlying HPMC coat thus improving its effectiveness in delaying drug release and allowing its thickness to be reduced. Methods. Acetaminophen (80%)-containing convex mini-tablets (2.5mm diameter, 10mg weight) for immediate release were coated up to 250μm thickness in rotary fluid bed with an 8% HPMC (Methocel®E50)–0.8% polyethylene glycol (PEG400) aqueous solution. HPMC-coated cores were then coated in bottom-spray fluid bed with poly(ethylacrylate, methylmethacrylate) water dispersion 30% (Eudragit®NE30D) containing 20% on polymer of sodium starch glycolate (Explotab®V17) up to 30μm thickness. Curing was performed at 40°C for 24h. In vitro release tests (n=3) were conducted at t0 and over two-year storage under ambient conditions by disintegration apparatus (800ml deionized water, 37±1°C, 31cycles/min). Acetaminophen was assayed in fluid samples withdrawn at successive time points by spectrophotometer (λ=248nm). For the in vivo study, specimens of the formulation (120mg acetaminophen) were administered with 200ml water to each of 3 fasted volunteers (35-45years, 55-85kg). Pre-treated saliva samples collected after defined time intervals were subjected to RP-HPLC analysis. Results: The delivery system under investigation was shown to delay the in vitro release onset more effectively than an HPMC-coated reference formulation. After the delay, a fast drug liberation occurred except for a minor initial phase of diffusive release. This behavior was consistent over two-year storage under ambient conditions. Following oral administration, the drug levels tended to increase rapidly although a slow absorption process was first observed in agreement with the in vitro results. Conclusion. The proposed two-layer erodible device pointed out extended in vitro lag phases as compared with a single-layer formulation and consistent performance over two years as well as reproducible in vivo lag times possibly suitable for pursuing chronotherapy and time-based colon delivery.