Synthesis, physicochemical properties and ocular pharmacokinetics of thermosensitive <i>in situ</i> hydrogels for ganciclovir in cytomegalovirus retinitis treatment

<p>Ganciclovir (GCV) is one of the most widely used antiviral drugs for the treatment of cytomegalovirus (CMV) retinitis. In this context, the aim of this study was to design <i>in situ</i> thermosensitive hydrogels for GCV ocular delivery by intravitreal injection to achieve sustained drug release behavior and improved ocular bioavailability in the treatment of CMV retinitis. A thermosensitive poly-(β-butyrolactone-co-lactic acid)-polyethylene glycol-poly (β-butyrolactone-co-lactic acid) (PBLA-PEG-PBLA) triblock copolymer was synthesized by ring-opening polymerization and characterization. The GCV-loaded PBLA-PEG-PBLA <i>in situ</i> hydrogels (15%, <i>w/w</i>) were then prepared with drug concentration at 2 mg·mL<sup>−1</sup> and the gelation temperatures, rheological properties, <i>in vitro</i> degradation and syringeability of <i>in situ</i> hydrogels for intravitreal injection were also investigated. Membraneless dissolution model was used to explore drug release behavior of PBLA-PEG-PBLA <i>in situ</i> hydrogel. The results indicated that more than 45 and 85% of GCV can be released within 24 and 96 h, respectively, which was verified by a non-Fickian diffusion mechanism. <i>In vivo</i> ocular pharmacokinetics study showed that area under drug-time curve (AUC) and half-life of PBLA-PEG-PBLA <i>in situ</i> hydrogel was higher (AUC was 61.80 μg·mL<sup>−1</sup>·h (<i>p</i> < .01) and <i>t</i><sub>1/2</sub> was 10.29 h in aqueous humor; AUC was 1008.66 μg·mL<sup>−1</sup>·h (<i>p</i> < .01) and <i>t</i><sub>1/2</sub> was 13.26 h (<i>p</i> < .01) in vitreous) than GCV injection with extended therapeutic activity. Based on obtained results, it was concluded that the thermosenstive PBLA-PEG-PBLA <i>in situ</i> hydrogel is a promising carrier of GCV for intravitreal injection.</p>