(M0930-03-21) Hot-Melt Extruded Implants Loaded with Brinzolamide for Intravitreal Drug Delivery

Purpose: Intravitreal (IVT) injections are the main administration route for the treatment of retinal diseases. However, the duration of action is limited due to short half-lives of the drug compounds. This is especially the case with small molecules, for which the half-life can be only hours [1,2]. This results in monthly hospital visits, which are expensive, and poor patient compliance. Our aim was to develop injectable IVT implants using hot-melt extrusion (HME). Brinzolamide (Bz) is an intra-ocular pressure lowering drug that reduces the production of aqueous humor by inhibiting carbonic anhydrase. It is administered as eye drops and has not been formulated as an IVT implant before. The crystalline and the amorphous form of brinzolamide were incorporated into five polymers, then the size of the implants, their burst release and impurities were studied. The challenge was to ensure adequate drug loading in implants small enough to fit through a 25G needle.

Methods: Brinzolamide (PharmaBlock, China) was chosen as the model API. Haake™ MiniCTW micro-conical twin screw compounder (ThermoFisher Scientific, USA) and M22 transport conveyor were used to produce the implant rods. Five grams of polymer and API blend were fed to the extruder at 20 rpm, circulated for 2 minutes at 50 rpm, and extruded through a 0.5- or 1.0-mm extrusion port. The size of the implant could be adjusted based on the speed of rotating screws and the conveyor belt. Torque-controlled speed was used for the extruder to maintain the width of the implant throughout the extrusion. Five different polymers with 50wt% and 75 wt% API were screened: Viatel™ DLG 5005E, Purasorb® PDL 05, Purasorb® PDLG 7507, Purasorb® PDLG 8503, and Resomer® RG752H. The crystalline systems were manufactured at 95°C and the amorphous ones at 140°C.

Results: All studied polymers were suitable to produce implants with a diameter < 0.21 mm at 50 wt% API content. The extrusion methodology was developed to limit the exposure to elevated temperatures and ensure the desired extrusion diameter of the rod. Drug loading of 50 wt% was feasible for all polymers, and 75wt% could be achieved with DLG5005E. Amorphous systems presented only single glass transition between 30.86 to 35.59°C (Tg’) as a combination of Tg’ of both the API (17.64 °C) and polymer (42.36 to 48.34 °C). This combination Tg’ confirmed that the system maintained the amorphous state. On the contrary, the crystalline systems presented only Tg’ of the polymer, and the API was fully crystalline. All implants demonstrated burst release less than 10 % of the total drug amount in one day. The daily release ranged between 4.70 to 22.44 µg/day during the 8-day screening period. No impurities were found in the implants.

Conclusion: Small injectable intravitreal implants were manufactured using hot melt extrusion. The API was incorporated into the polymer as crystalline or amorphous dispersion. This difference and multiple polymers enable us to fine-tune the daily drug release and the release timeframe. For IVT implant, the release timeline should be months to reduce the number of injections required. HME is a promising approach to formulate small molecules into controlled-release implants also in the field of ocular drug delivery. Developing implants that fit through small needles allow for easier experimentation in smaller animals such as rats and rabbits and might reduce the risk of adverse effects associated with IVT injections.

References: 1. del Amo EM, Vellonen K-S, Kidron H, Urtti A. Intravitreal clearance and volume of distribution of compounds in rabbits: In silico prediction and pharmacokinetic simulations for drug development. Eur J Pharm Biopharm. 2015;95:215–26.
2. Sadeghi A, Puranen J, Ruponen M, Valtari A, Subrizi A, Ranta V-P, et al. Pharmacokinetics of intravitreal macromolecules: Scaling between rats and rabbits. Eur J Pharm Sci. 2021;159:105720.

Acknowledgements: This study was financially supported by Johnson & Johnson Innovative Medicine and Government of Flander by VLAIO (Vlaams Agentschap Innoveren & Ondernemen, HBC.2021.1130)


Brinzolamide release from the implants