(W0930-09-52) Uncovering the Role of Risperidone Attributes on the In Vitro Release and Formation of In Situ Forming Implants

Purpose: This work aims to investigate the importance of risperidone attributes, namely, particle size and physical state, on the in vitro release behavior and formation of in situ forming implants. To date, commercially available poly (lactic-co-glycolic acid) (PLGA)-based in situ forming implant drug products lack generic equivalents, despite being off patent. This may be explained by the lack of compendial in vitro dissolution testing methods, as well as the limited knowledge surrounding their complex in vitro/in vivo behavior. Such knowledge gaps hinder the development of in vitro and in vivo correlations (IVIVCs).  Thus, elucidating the critical attributes governing their complex behavior is essential to further our current understanding of these products and to provide guidance to facilitate the translation of generic products.

Methods: Polymer solutions were prepared to be quantitively and qualitatively equivalent to the commercial product Perseris^®. These solutions were prepared at a 282/228 w/w ratio of N-methyl pyrrolidone (NMP) and PLGA, using PLGA with an L/G ratio of 80:20, acid end group, and a molecular weight of 24.2 kDa. Polymer solutions underwent continuous rotating overnight at room temperature to achieve complete PLGA dissolution. The active pharmaceutical ingredient (API) risperidone was utilized and was modified with respect to its physical state and particle size. The polymer solutions and risperidone were weighed into separate plastic syringes, coupled, mixed, and transferred into single syringes. Subsequently, a needle was attached prior to use. Suspension formulations with 15% w/w drug loading were prepared using risperidone with different D₅₀s (i.e., ~25 µm or ~150 µm). Formulations with 2.5% w/w drug loading were also prepared to achieve both solution and suspension formulations. Solution formulations were obtained via increasing the number of mixing cycles during formulation preparation. In vitro release testing was carried out using USP apparatus 2 (paddle) with an in-house adapter at 37°C and 50 rpm. Samples were collected at pre-determined time points and risperidone concentrations were quantified using reverse-phase high performance liquid chromatography (RP-HPLC). Furthermore, Laser confocal microscopy was used to examine microstructure differences in the implants. These samples were prepared via injecting the formulations in a drop-by-drop manner into 50 mL centrifuge tubes containing in vitro release media (PBS, pH 7.4 0.15% sodium azide). Subsequently, they were incubated at 37°C in a water shaker bath at 100 rpm. Samples were collected at specified time points, and freeze dried for 72 hours for imaging of the implant surfaces.

Results: Clear discrimination was observed between the solution and suspension formulations prepared with 2.5% w/w drug loading (see Fig.1). The slower release observed for the solution formulation is likely due to enhanced PLGA-risperidone interactions in the solution state. Discrimination was also observed in the release profiles for the suspension formulations prepared with 15% w/w drug loading prepared with different particles sizes. (see Fig.2). The observed discrimination was not dramatic, this may be in part due to aggregation of the smaller risperidone particles (D₅₀ ~25 µm). Clusters of small pores were observed via laser confocal microscopy which may suggest the formation of aggregates within the implants (see Fig.3). These aggregates would be larger in size than the original particles and thus would behave more like large particles.

Conclusion: These studies provide key insights which helped to expand the current understanding of these complex drug products. More specifically, these studies provided insights into the significance of risperidone attributes on the in vitro release behavior and formation of in situ forming implants. Such work will help to advance the clinical translation of generic in situ forming implant drug products.

References: Wang, X.; Burgess, D. J. Drug Release from in Situ Forming Implants and Advances in Release Testing. Advanced Drug Delivery Reviews 2021, 178, 113912. https://doi.org/10.1016/j.addr.2021.113912.
Wang, X.; Bao, Q.; Wang, R.; Kwok, O.; Maurus, K.; Wang, Y.; Qin, B.; Burgess, D. J. In Situ Forming Risperidone Implants: Effect of PLGA Attributes on Product Performance. Journal of Controlled Release 2023, 361, 777–791. https://doi.org/10.1016/j.jconrel.2023.08.029.

Acknowledgements: Funding for this project was made possible by U.S Food and Drug administration BAA Contracts 75F40120C00021 and 75F40123C00142. This abstract reflects the views of the authors and should not be construed to represent FDA’s views or policies.


Figure 1: Mean (±SD) cumulative in vitro release of risperidone solution and suspension formulations prepared with 2.5% w/w drug loading (n=3).


Figure 2: Mean (±SD) cumulative in vitro release of risperidone formulations prepared with 15% w/w drug loading and different D50s (n=3).

Figure 3: A laser confocal microscopy image of a freeze dried in situ forming implant formulation prepared with 15% w/w drug loading and a D50 of ~25 µm collected after 7 days of in vitro incubation.