(M1430-01-02) Revolutionizing Ocular Drug Delivery: Prolonged Sunitinib Release from Elastomeric Biodegradable Injectable Tiny Implants for Treatment of Diabetic Retinopathy

Purpose: Diabetic retinopathy (DR), one of the primary causes of diabetes-related blindness, is treated mainly using several intravitreal administration of therapeutic agents into the posterior segment of the eye, a method associated with potential ocular complications, challenges, and patient discomfort. This study presents a promising solution through developing biodegradable, biocompatible elastomeric injectable implants for prolonged-release of Sunitinib (SB), a tyrosine kinase inhibitor (TKI) with proven antiangiogenic and antitumor properties effective in treating DR.

Methods: The following represents a preparation method for poly (octanediol-tricarballylate) (POT) SB-loaded implants. A total of 1.61 grams of tricarballylic acid and 2 grams of 1-8 Octanediol were accurately weighed and combined in a scintillation vial. The mixture was placed on a temperature-controlled hotplate at 140°C for 10 minutes to ensure complete melting. Mixing continued for 10 more minutes after adding one catalyst drop to the solution. The scintillation vial was then transferred to a vacuum oven set at 80°C and 10 cmHg pressure for 2 hours. SB powder of various loading percentages was then incorporated into the pre-crosslinked polymer by direct mixing or using the acetone solvent casting method. The resulting mixture was poured into either glass or silicon cylindrical molds in a vacuum oven for thermal crosslinking at 120°C for 18 hours under a vacuum of 20 cm Hg. The prepared implants were characterized using differential scanning calorimetry (DSC), Fourier-transform infrared (FT-IR) spectroscopy, and X-ray diffractometry (XRD) to analyze thermal, spectroscopic, and crystallographic properties. The SB release and its kinetics were investigated in phosphate-buffered saline (PBS) at pH 7.4, using a shaking water bath quantified through UV spectroscopic analysis. In vitro, cell viability, cytotoxicity, and apoptosis were assessed using ARPE-19 retinal cells.

Results: FT-IR analysis revealed characteristic peaks of SB, indicating no chemical interaction between the drug and the PDT matrix, confirming that crosslinking did not affect the chemical integrity or stability of the SB. DSC analysis demonstrated that crystalline SB transitioned into an amorphous state upon loading into the crosslinked PDT elastomers. Release studies revealed that the elastomeric implants could sustain the release of SB over 7 months with minimal burst release and no significant changes in the pH of the release medium. Degradation studies indicated only a 1% polymer weight loss after one month, highlighting the system's ability to provide prolonged drug release. The mixing drug-polymer method did not significantly affect the release rate or extent. However, implant volume, polymer elasticity, and drug loading percentage significantly influenced the SB release rate. Cell viability studies over 7 days showed no toxic effects on ARPE-19 cells. However, slight toxicity was observed in elastomers prepared using the highly drug-loaded solvent casting method, potentially due to the higher SB dose and the residual solvent in the elastomer matrix.

Conclusion: The injectable microcylindrical implant of SB-loaded PDT biodegradable elastomer demonstrated excellent capability in sustaining the release of the bioactive and stable drug for over 7 months. This highlights the potential of these implants to address the recurring need for intravitreal administration, offering a cost-effective solution while maintaining long-term drug bioactivity in treating DR.

Acknowledgements: This project was made possible by NPRP13S-0126-200173 from the Qatar National Research Fund (a member of Qatar Foundation) through its National Priorities Research Program. The statements made herein are solely the authors' responsibility. The technical Support from the Central Laboratory Unit at Qatar University is also highly appreciated.