Latanoprost Acid-Brimonidine, a New Amide Prodrug for Glaucoma Management Based on the Concept of Sustained Release

Glaucoma is an ocular disease caused by the improper management of elevated intraocular pressure (IOP). IOP-lowering via topical administration is the first choice to prevent further progression. However, patients may forget to administer their medication, compromising IOP control. To address this problem, a prolonged active pharmaceutical ingredient (API) release system is proposed. A new prodrug (latanoprost acid-brimonidine conjugate, LBJ) was designed and expected to achieve potential long-lasting release of APIs. LBJ was synthesized by two methods. First, Steglich esterification without protecting the hydroxyl group led to a yield of 34.24%. However, the integral ratio between LPA and BM obtained from NMR was 1.25:1, indicating a potential side product resulting from further coupling through the unprotected hydroxyl group in LBJ. As an alternative route, Steglich esterification with a protecting agent, tert-butyldimethylchlorosilane (TBDMSCl), resulted in a yield of 39.35%, and the integral ratio between LPA and BM obtained from NMR was 1:1. The hydrolysis time of LBJ was investigated and compared with that of latanoprost (LP). In the presence of esterase (0.4 U/mL), the hydrolysis times of LP and LBJ were 4 h and 28 days, respectively. The prolonged hydrolysis time results in sustained APIs release, which is beneficial for the development of a sustained drug release system.