Improving in vivo release prediction from in situ forming depots with a novel flow-through in vitro dissolution apparatus

Abstract

Having an in vitro dissolution method providing meaningful and translatable data is critical for early-stage research and development. For long-acting injectables, such as in situ forming depots (ISFD), the extended duration of the release test and the different release mechanisms involved do not allow the use of classical in vitro dissolution systems. To facilitate the transition from bench to animal studies, an alternative dissolution apparatus was developed.

Highlights

Predicting in vivo release of in situ forming depots is challenging.

A novel flow-through in vitro dissolution equipment was developed.

In vivo predictability was improved with the flow-through apparatus.

So far, in vitro release mechanisms are not biorelevant but release profiles are comparable to those in vivo.

This flow-through system was designed to be more biorelevant, with the addition of temperature-controlled reaction chambers filled with an agarose hydrogel. This allows for a continuous constraint of the depot during dissolution testing as well as a continuous buffer flow in an open circuit. The release properties of the phase-inverting ISFD technology BEPO® were investigated with a large range of conditions (i.e. temperatures ranging from 25 °C to 45 °C and buffer flow rates from 1 to 10 mL/h) and different active pharmaceutical ingredients. The in vitro release profiles could be tailored while using the new dissolution apparatus.

In particular, the temperature was the critical parameter, with higher temperatures leading to an increase of the release rate and generally more translatable in vitro release profiles to the respective in vivo data. Flow rate had a lower impact than temperature in modifying release kinetics. Overall, the most translatable release conditions were not the most biorelevant but led to comparable release profiles to those obtained in vivo. The in vitro setup developed can thus be considered an interesting and valuable surrogate to in vivo evaluation.

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Materials

Diblock (DB) and triblock (TB) copolymers based of polyethylene glycol (PEG) and polylactic acid (PLA) were produced by CM Biomaterials (Tucker, GA, USA). Two triblocks (i.e. TB1 and TB2 with TB1 of a higher molecular weight than TB2) and two diblocks (i.e. DB1 and DB2 with DB1 of a higher molecular weight than DB2) were used in this study. The organic solvent used in this study was Dimethyl Sulfoxide (DMSO) USP grade (Procipient®) from Gaylord Chemical (Los Angeles, CA, USA). Phosphate-buffered Saline (PBS) solution (pH 7.4) was prepared by dilution of a PBS 10X solution (BP399-20, Fisher Bioreagents, Waltham, MA, USA) in ultrapure water. Meloxicam was supplied by Swati Spentose (Mumbai, India), bupivacaine by Interchim (Montluçon, France), and 4′-Ethynyl-2-fluoro-2′-deoxyadenosine (EFdA) by BioDuro (Beijing, China).

Charlotte Peloso, Etienne Yvorra, Romain Delamare, Mélanie Campana, Sylvestre Grizot, Adolfo Lopez-Noriega, Improving in vivo release prediction from in situ forming depots with a novel flow-through in vitro dissolution apparatus, International Journal of Pharmaceutics, Volume 681, 2025, 125884, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2025.125884.