(M1230-06-36) In Situ Forming Implants: The Effect of Drug-Polymer-Solvent Interplay on Depot Behavior

Purpose: There have been few literature reports on the significance of drug-polymer-solvent interplay on in situ forming implant (ISFI) formation and behavior. Investigating this interplay remains a challenge due to the complex formation and release mechanisms demonstrated by these depots. Furthermore, characterizing this interplay is not straightforward. The current research aims to highlight the potential role of this interplay on depot behavior. active pharmaceutical ingredients (APIs) (i.e. risperidone and paliperidone) are highlighted in the present work. The chemical structure of paliperidone is identical to that of risperidone except for the presence of an additional hydroxyl group. This makes for a unique comparison as risperidone has no hydrogen bond donors whereas paliperidone has one due to the presence of the hydroxyl group. Elucidating drug-polymer-solvent interplay and methods will aid in bridging the knowledge gaps surrounding these complex depot systems. This is essential to expand the current generic and innovator commercial landscape of ISFI drug products.

Methods: Poly(lactide-co-glycolide) (PLGA) solutions and API powders were weighed into separate plastic syringes, coupled, and then mixed for a specified number of mixing cycles until a homogeneous suspension was achieved. After mixing, the suspensions were transferred into single syringes for injection. Formulations were prepared at a 1.24/1 ratio of N-methyl pyrrolidone (NMP) and PLGA (80/20 L/G ratio, acid end group, 24.2 kDa) with 15% w/w API. These specifications were employed to mimic that of the commercial product, PERSERIS®. Formulation depots were prepared for analysis by employing a direct injection technique. Formulations were injected in a drop-by-drop manner into a 50 mL centrifuge tube containing preheated media (0.01 M phosphate buffered saline (PBS), pH 7.4 and 0.15% (w/v) sodium azide). The depots were incubated at 37°C in a water shaker bath at 100 rpm. The depots were collected at predetermined timepoints, rinsed, flash frozen and lyophilized for 72 hours. Subsequently, the dried depots were analyzed to evaluate degradation and erosion patterns over time. Dried depots underwent gel permeation chromatography (GPC) analysis and imaging via laser confocal scanning microscopy (LCSM). The particle size of risperidone and paliperidone powders was determined using laser diffraction. Imaging was conducted on API powders using scanning electron microscopy (SEM).

Results: The implants prepared with paliperidone showed comparable PLGA degradation with time to that of the blank implants. This contrasts with the formulations prepared with risperidone, which showed more extensive degradation with time (Fig.1). This finding is particularly interesting given that the chemical structures of risperidone and paliperidone are nearly identical, except for the additional hydroxyl group in the paliperidone structure. It should be noted that although the particle size (D₅₀) of risperidone was different to that of paliperidone (Fig.1), it is suspected that particle size is not the driving force for the observed differences in PLGA degradation with time. This could be rationalized by evaluating the degradation behavior of depots prepared with risperidone possessing drastically different D_50s (~5 µm and ~150 µm) which showed very similar PLGA degradation behavior over time (Fig.1). Depot microstructural surface features were compared to gain further insight. Interestingly the depots prepared with paliperidone demonstrated notable differences in the depot surface where the drug appears to be integrated into the polymer surface as indicted by the red arrows in Fig.2B. This interesting finding was not observed for the blank or risperidone loaded formulations. This observation could be a result of drug-polymer-solvent interactions due to chemical interactions dictated by the drug, polymer and solvent interplay. Furthermore, these interactions could also be a result of enhanced physical interactions caused by particle morphology. It was observed that the paliperidone particles had a rougher surface with greater porosity as compared to the risperidone particles, thus possessing greater surface area for interactions (Fig.3). The images of the risperidone loaded depot surfaces show more obvious erosion as compared to the blank and paliperidone loaded depots which is consistent with the more extensive degradation that was observed for these depots.

Conclusion: This work provides insight into of the role of the drug-polymer-solvent interplay on depot behavior, more specifically, the degradation and erosion patterns of the depots over time. In this specific example, the drug-polymer-solvent interactions observed for paliperidone hindered PLGA degradation and erosion of the depot. These observations support our previously published findings where a slower release rate was observed for ISFIs prepared with APIs possessing a greater number of hydrogen bond donor and acceptor groups. This work also highlights an imaging strategy which can be helpful for observing depot erosion where more areas possessing greater depth are shown by the dark blue regions and areas that are more superficial in nature possess a more red-orange color. This imaging approach also proved useful for visualizing drug-polymer-solvent interactions.

References: Wang, X., Bao, Q., Wang, R., Wan, B., Wang, Y., Qin, B., Burgess, D.J., 2023. Reverse engineering of Perseris and development of compositionally equivalent formulations. International Journal of Pharmaceutics 639, 122948. https://doi.org/10.1016/j.ijpharm.2023.122948
Wang, X., Burgess, D.J., 2021. Drug release from in situ forming implants and advances in release testing. Advanced Drug Delivery Reviews 178, 113912. https://doi.org/10.1016/j.addr.2021.113912
Wang, X., Roy, M., Wang, R., Kwok, O., Wang, Yinhang, Wang, Yan, Qin, B., Burgess, D.J., 2024. Towards in vitro – In vivo correlation models for in situ forming drug implants. Journal of Controlled Release 372, 648–660. https://doi.org/10.1016/j.jconrel.2024.06.058
Wang, X., Wang, R., Roy, M., Kwok, O., Burgess, D.J., 2025. Long-acting injectable in situ forming implants: Impact of polymer attributes and API. International Journal of Pharmaceutics 670, 125080. https://doi.org/10.1016/j.ijpharm.2024.125080

Acknowledgements: Funding for this project was made possible by U.S Food and Drug administration BAA Contract 75F40123C00142 and the Pfizer Distinguished Chair of Pharmaceutical technology, Department of Pharmaceutical Sciences, University of Connecticut. This abstract reflects the views of the authors and should not be construed to represent FDA’s views or policies.


Figure 1: (Mean ±SD) Average PLGA molecular weight over 30 days (n=3): Blank (non-drug loaded), risperidone (D50 ~5 µm), risperidone (D50 ~150 µm), and paliperidone (D50 ~13 µm).


Figure 2: LSCM white light and 3D laser-based surface images of depots after 20 days of incubation: A) Blank (non-drug loaded), B) paliperidone (D50 ~13 µm), C) risperidone (D50 ~5 µm), and D) risperidone (D50 ~150 µm).


Figure 3: SEM images highlighting API particle morphology differences: A) risperidone (D50 ~5 µm), B) risperidone (D50 ~150 µm), and C) paliperidone (D50 ~13 µm).