Abstract
Gastroretentive (GR) systems are designed to prolong gastric residence time to allow sustained absorption and improve the oral bioavailability of drugs with a narrow absorption window in the upper part of the gastrointestinal tract. The present study aimed to develop a GR system for acyclovir using 3D printing technology and evaluate its in vivo pharmacokinetics after oral administration in Beagle dogs. The system consisted of a gastro-floating device, which can float in the gastric fluid, prepared by a fused deposition modeling 3D printer and conventional acyclovir sustained-release (SR) tablet. The acyclovir SR tablet was inserted to the floating device to allow sustained release of the drug in the stomach. The buoyancy and sustained-release property of the developed GR system were determined using an in vitro dissolution test, in vivo pharmacokinetic study, and abdominal X-ray imaging in Beagle dogs. The in vivo dissolution profiles of the GR system were also predicted based on the in vivo pharmacokinetic data using a population pharmacokinetic (POP-PK) model. In the dissolution test, the sustained-release characteristic of the GR system was identified with a time corresponding to 80% dissolution (T80) of 2.52 h. Following oral administration of the GR system, the time to reach the maximum concentration (Tmax) of acyclovir was significantly prolonged, whereas the maximum concentration (Cmax) decreased and the area under the curve increased compared with those obtained after the administration of immediate-release and SR tablets, indicating prolonged absorption. By X-ray imaging, we showed that the developed GR system stayed in the stomach for more than 12 h. The POP-PK model successfully described the observed plasma concentration-time data and predicted the in vivo biphasic dissolution profiles of the GR system, which was significantly different from the in vitro dissolution. The developed GR system could be applied to various drugs and had great prospects in the design and development of novel controlled-release formulations.
Highlights
Gastroretentive (GR) systems are designed to retain drug formulations in the stomach for an extended period and increase the oral bioavailability of drugs that have limited absorption window in the upper small intestine
By comparing GR systems with different structures of drug-releasing windows, we showed that the shape and size of the drug-releasing windows did not affect the in vitro floating ability of the GR system
We have successfully showed the potential of a gastro-floating device combined with a conventional SR tablet of acyclovir to reduce the dosing frequency and improve the oral bioavailability of acyclovir. 3D printing technology allowed simple and efficient production of various prototypes of the device, as well as optimization of its structure, to achieve prolonged gastric residence
Summary
Gastroretentive (GR) systems are designed to retain drug formulations in the stomach for an extended period and increase the oral bioavailability of drugs that have limited absorption window in the upper small intestine. Since GR system was introduced almost three decades ago, various approaches have been applied to extend the gastric residence time of GR systems [1] including low-density (floating), high-density (sinking), expandable (swelling), and mucoadhesive systems. Innovative approaches, such as magnetic field-assisted gastro-retentive systems, plug-type swelling systems, floating systems with or without effervescence, have been applied to prolong gastric retention time [3]. The main challenge is to maintain the drug delivery system in the stomach for a sufficient time until all the drugs are released at a predetermined rate in a dynamic physiological condition
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