(W1330-01-04) Prolonged Ocular Delivery of Sunitinib from Poly (diol-tricarballylate) Injectable Biodegradable Elastomeric Tiny Implant for Diabetic Retinopathy Treatment

Purpose: Diabetic Retinopathy (DR), which is damage to the retina caused by inflammatory changes to the blood vessels, is the most frequent and severe ocular complication of diabetes mellitus (DM). Sunitinib (SB), one of the tyrosine kinase inhibitors (TKI) with antiangiogenic and antitumor effects, has been reported to treat DR efficiently [1]. The current study aims to fabricate a prolonged-released injectable tiny implant to deliver SB loaded into poly (diol-tricarballylate) (PDT) biodegradable elastomer. The physicochemical properties of SB and its in vitro release from PDT are investigated. The new platform will solve the recurrent need to administer SB via the intravitreal route, saving and lowering expenses and retaining long-term bioactivity

Methods: The following represents the general preparation method for poly (octanediol-tricarballylate) (POT) SB-loaded implants. A total of 1.61 grams of tricarballylic acid (TCA) 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. A drop of catalyst was added to the solution, and mixing continued for 10 more minutes. The scintillation vial was then transferred to a vacuum oven set at 80°C and 10 cmHg pressure for 2 hours. Sunitinib powder of various loading percentages was then incorporated into the pre-crosslinked polymer by direct mixing or using the acetone solvent casting. 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 subjected to thermal, spectroscopic, and X-ray analysis using Differential Scanning Calorimetry (DSC), Fourier-transform infrared (FT-IR), and X-ray diffractometry (XRD). The SB-loaded micro-cylindrical implants (1.5 mm diameter X 10 mm length) were subjected to release studies in PBS of pH 7.4 using a shaking water bath. SB was analyzed using UV spectroscopic analysis.

Results: The presence of characteristic bands of SB in the FTIR spectra of the physical mixture (Drug: Polymer) indicated the absence of chemical interaction between SB and PDT polymers employed in the study. It also showed that thermal crosslinking did not impact the SB's chemical structure integrity or stability. The DSC analysis showed that pure SB is crystalline with a melting point of 245^oC. This crystallinity was either significantly decreased or diminished (i.e., the drug was in the amorphous state) once loaded into the thermally crosslinked PDT elastomers. The degree of crystallinity depended on the amount of SB loaded and the mixing method. The solvent casting loading method made SB amorphous regardless of the percentage loaded in the polymer. The release studies demonstrated the ability of the elastomeric implant to prolong the release of SB over a month release period with minimal burst effect or changes in the release medium pH. The mixing method had no statistical significance on the release rate and extent. On the other hand, implant volume, polymer elasticity, and drug % loading showed a statistically significant effect on drug release rate.

Conclusion: The developed and characterized injectable microcylindrical implant of SB in PDT biodegradable elastomer showed an excellent ability to prolong the release of the bioactive and stable drug over an extended time exceeding one month. This demonstrates the promising ability of the undergoing developed versions of these implants to solve the recurrent need to administer SB via the intravitreal route, saving and lowering expenses and retaining long-term bioactivity. A photo-cross-linkable version of these elastomers is currently under development in our lab to load thermosensitive therapeutic proteins such as anti-VEGF like Bevacizumab for RP and other ocular diseases.

References: 1. Salah, S.; Alabbassi, M.; Shakoor, D. Effect of sunitinib in treatment of retinal angiogenesis induced by VEGF165 in rabbit's eyes. Journal of Pharmaceutical Sciences and Research 2019, 11, 480-486.

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