In vivo evaluation of an oral pulsatile delivery system prepared by Injection-Molding

Purpose. To perform an in vivo evaluation of a novel capsular device intended for oral pulsatile delivery. The device, consisting of a swellable/erodible hydrophilic polymer (hydroxypropylcellulose, HPC), is prepared by an injection-molding process and was already proven able to delay the in vitro release of drugs as a function of the capsule shell thickness. Methods. A mixture of HPC(Klucel® LF) and PEG 1500 (90/10 w/w) was prepared in Turbula, dried in a ventilated oven for 24 h at 40°C and injection-molded by means of a bench-top press that allowed both capsule items (body and cap) with various shell thicknesses (300, 600 and 900 μm) to be produced in a single process cycle. Each capsule body was manually filled with 80 mg of acetaminophen, selected as the model drug because it can be assayed in saliva, and then closed with a matching cap. The assembled devices were sealed by applying an HPC aqueous solution. A single capsule of every shell thickness was administered to each of 3 healthy volunteers (age 35-55 years, weight 55-85 kg) with 200 ml water. Saliva samples were collected at predetermined time points and immediately frozen. After defrosting, samples were processed and analyzed by HPLC according to the method reported by C.K. Shim et al, J Kor Pharm Sci 20, 29, 1990. Results. Saliva concentration curves obtained following oral administration of devices with differing shell thicknesses showed a delayed appearance of acetaminophen with respect to the time of intake. The lag phase calculated as the time to 10% of AUC clearly depended on the thickness of the capsule shell and, indeed, turned out to correlate linearly with previously obtained in vitro lag times for all the systems administered. A fast increase in the salivary drug concentration was observed after the delay phase, thus indicating that the rate of release would not be limited by the swollen HPC layer. Conclusions. The proposed oral capsular device was demonstrated to be potentially suitable for providing an oral pulsatile liberation of bioactive compounds. Due to its scalability, versatility and release characteristics, it may thus be exploited as a chronopharmaceutical and/or time-based colonic delivery platform.