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Eur J Pharm Sci. 2019 Aug 1;136:104958. doi: 10.1016/j.ejps.2019.104958. Epub 2019 Jun 15.

Exploration of long-acting implant formulations of hepatitis B drug entecavir.

Author information

1
Pharmaceutical Sciences, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA.
2
Pharmaceutical Sciences, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA. Electronic address: stephanie_barrett@merck.com.
3
Safety Assessment and Laboratory Animal Resources (SALAR), Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA.

Abstract

Alternative formulations of entecavir, a once daily oral hepatitis B antiretroviral, may improve treatment adherence by patients. We explored the use of biocompatible polymers to control entecavir dissolution in two formats suitable for subcutaneous implantation. Hot melt extrudates were prepared by extruding entecavir-polymer blends at specified weight ratios. Dip-coated tablets were prepared by compressing entecavir in a multi-tip tooling. Tablets were dip-coated in solutions of polymer and dried. In rodents, entecavir-poly(caprolactone) extrudates demonstrated >180 days of continuous drug release, although below the estimated efficacious target input rate. Drug pharmacokinetic profiles were tunable by varying the polymer employed and implant format. The rank order trends of drug input rates observed in vitro were observed in vivo in the detected plasma concentrations of entecavir. In all dose groups entecavir was not tolerated locally at the site of administration where adverse event severity correlated with drug input rate. These polymer-based implantable formats have applicability to long-acting formulations of high solubility compounds beyond entecavir.

KEYWORDS:

Entecavir; Hepatitis B; Hot melt extrudate; Long-acting parenteral; Subcutaneous implant

PMID:
31212018
DOI:
10.1016/j.ejps.2019.104958

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