Development of a gastroretentive delivery system for acyclovir by 3D printing technology and its in vivo pharmacokinetic evaluation in Beagle dogs

PLoS One. 2019 May 15;14(5):e0216875. doi: 10.1371/journal.pone.0216875. eCollection 2019.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyclovir* / chemistry
  • Acyclovir* / pharmacokinetics
  • Acyclovir* / pharmacology
  • Administration, Oral
  • Animals
  • Delayed-Action Preparations / chemistry
  • Delayed-Action Preparations / pharmacokinetics
  • Delayed-Action Preparations / pharmacology
  • Dogs
  • Drug Evaluation, Preclinical
  • Female
  • Male
  • Printing, Three-Dimensional*
  • Tablets

Substances

  • Delayed-Action Preparations
  • Tablets
  • Acyclovir

Grants and funding

Funding Statement: “This work was supported by the National Research Foundation of Korea (NRF) grant 2017R1D1A1A02018615 (SS) and 2018R1A2B6004928 (BSS). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. KNOTUS. Co., Ltd. provided support in the form of salaries for DHK but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of this author are articulated in the ‘author contributions’ section.”