Macroporous acrylamide phantoms improve prediction of in vivo performance of in situ forming implants

Abstract

In situ forming implants (ISFIs) have shown promise as a sustained, local drug delivery system for therapeutics in a variety of applications. However, development of ISFIs has been hindered by poor correlation between in vitro study results and in vivo performance. In contrast to oral dosage forms, there is currently no clear consensus on a standard for in vitro drug dissolution studies for parenteral formulations. Recent studies have suggested that the disparity between in vivo and in vitro behavior of phase-inverting ISFIs may be, in part, due to differences in injection site stiffness. Accordingly, this study aimed to create acrylamide-based hydrogel phantoms of various porosities and stiffness, which we hypothesized would better predict in vivo performance. Implant microstructure and shape were found to be dependent on the stiffness of the phantoms, while drug release was found to be dependent on both phantom porosity and stiffness. Specifically, SEM analysis revealed that implant porosity and interconnectivity decreased with increasing phantom stiffness and better mimicked the microstructure seen in vivo. Burst release of drug increased from 31% to 43% when in standard acrylamide phantoms vs macroporous phantoms (10 kPa), improving the correlation to the burst release seen in vivo. Implants in 30 kPa macroporous phantoms had the best correlation with in vivo burst release, significantly improving (p < 0.05) the burst release relative to in vivo from 64%, using a standard PBS dissolution method, to 92%. These findings confirm that implant behavior is affected by injection site stiffness. Importantly, with appropriate optimization and validation, hydrogel phantoms such as the one investigated here could be used to improve the in vitro-in vivo correlation of in situ forming implant formulations and potentially augment their advancement to clinical use.

Increasing Distribution of Drugs Released from In Situ Forming PLGA Implants Using Therapeutic Ultrasound

“…Implants injected into the phantoms had a mass of 47.8 ± 11.1 and 51.0 ± 6.2 mg for control and ultrasound-treated groups, respectively. Using the same criteria release kinetics 8, 28, 35 , the ultrasound-treated group showed an increase in release during the diffusion phase (> 72 h) compared with the control, Figure 5B. This is consistent with the increase in drug distribution on days 3, 5, 7 and 10.…”

“…The hydrogel phantom provides a physical structure with high water content and tunable biologically-relevant mechanical properties. 8,27 …”

“…8 The phantoms (17 mL) were polymerized within a 6-well plate and kept in PBS solution for 5 days before implantation. The mixture solution of an implant was described in the previous work.…”

“…The mixture solution of an implant was described in the previous work. 8, 34 Briefly, PLGA was dissolved in NMP solvent and incubated at 37°C for 1 hour until PLGA was completely dissolved. Fluorescein was then added into the mixture solution and left in the incubator with circulation mixture at 37 °C for another 1 day.…”

Improving Treatment Efficacy of In Situ Forming Implants via Concurrent Delivery of Chemotherapeutic and Chemosensitizer

“…A limitation to the current work is that the treatment only consisted of a single injection of ISFI at the beginning of the study. As shown with the release curves, approximately 50% of the Dox is released within 10 days and another 10% in the following 10 days 22,31,[57][58][59] . Allowing the study to progress further than 20 days and using multiple injections of the ISFI will likely elicit stronger therapeutic effects.…”