An Injectable Formulation of a Beta-Adrenergic Antagonist Prodrug for Sustained Reduction of Intraocular Pressure (IOP)

Abstract

Purpose : Effective treatments to lower and maintain IOP by sustained drug release remains a substantial unmet medical need. A prodrug (GB-6249-192) of a beta-adrenergic antagonist compound was designed and synthesized by conjugating a hydrophobic oligomer to the parent compound via a biodegradable linker. The novel prodrug was expected to have different physiochemical properties allowing encapsulation in polymeric microparticles (MP) to enable prolonged drug delivery. This study elucidates the in vitro characteristics of the prodrug and its encapsulated formation, and ocular safety and IOP-lowering effect of this MP system in an ocular hypertensive (OHT) rat model.

Methods : Physiochemical properties of GB-6249-192 were characterized in vitro, including solubility and degradation kinetics. Particle size, drug loading and drug release were assessed for the drug-loaded MP. Experimental ocular hypertension was induced by injecting hypertonic saline via the episcleral veins in the left eye of brown Norway rats twice over a period of two weeks. The drug-loaded MP formulations were administrated by a single subconjunctival (SC) injection in the left eye at three different doses. IOP was measured in both eyes prior to the MP injection and on Days 2, 7, 14, 21 and 28 using a Tonopen. Ten consecutive readings were taken in each eye at each session and the average of these ten readings was presented as the IOP measurement. Both eyes in all animals were examined and scored using a combined Draize and McDonald-Shadduck scoring system at the same time as IOP measurements.

Results : In comparison to the parent compound, GB-6249-192 was substantially more hydrophobic, which made it feasible for encapsulation in hydrophobic polymer MP and enabled sustained drug release. The linker of GB-6249-192 was degraded by hydrolysis allowing full conversion of the prodrug to the parent compound. Significant IOP reduction in OHT rats was observed with all three dosages starting from the first week of SC injection of the MP and was sustained for over one month showing a maximal IOP reduction of ~20% (~7 mmHg). The formulation at the three dosages was well tolerated without any signs of ocular or systemic toxicity.

Conclusions : The injectable MP formulation of a beta-adrenergic antagonist prodrug may provide sustained reduction of IOP and lead to a new long-term and effective treatment for ocular hypertension.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.