Ocular Co-Delivery of Timolol and Brimonidine from a Self-Assembling Peptide Hydrogel for the Treatment of Glaucoma: In Vitro and Ex Vivo Evaluation

Abstract

Effective pharmacotherapy during glaucoma treatment depends on interventions that reduce intraocular pressure (IOP) and retain the IOP lowering effect for sufficient time so as to reduce dosing frequency and enhance patient adherence. Combination anti-glaucoma therapy and dosage forms that increase precorneal residence time could therefore constitute a promising therapeutic intervention. The in-situ gel forming self-assembling peptide ac-(RADA)4-CONH2 was evaluated as carrier for the ocular co-delivery of timolol maleate (TM) and brimonidine tartrate (BR). The hydrogel’s microstructure and mechanical properties were assessed with atomic force microscopy and rheology, respectively. Drug diffusion from the hydrogel was evaluated in vitro in simulated tear fluid and ex vivo across porcine corneas and its effect on the treated corneas was assessed through physicochemical characterization and histological analysis. Results indicated that TM and BR co-delivery affected hydrogel’s microstructure resulting in shorter nanofibers and a less rigid hydrogel matrix. Rapid and complete release of both drugs was achieved within 8 h, while a 2.8-fold and 5.4-fold higher corneal permeability was achieved for TM and BR, respectively. No significant alterations were induced in the structural integrity of the corneas treated with the hydrogel formulation, suggesting that self-assembling peptide hydrogels might serve as promising systems for combination anti-glaucoma therapy.

β-Sheet to Random Coil Transition in Self-Assembling Peptide Scaffolds Promotes Proteolytic Degradation

“…Specifically, given its ability to be degraded by trypsin, RAD16-I would be an excellent delivery platform for drug release into the small intestine. Moreover, RAD16-I has been used and demonstrated to be suitable as a carrier for drug encapsulation and controlled release kinetics [34,43,45,46] from the hydrogel by adjusting the peptide concentration and chemistry [53]. Finally, our results indicate that the self-assembling peptide RAD16-I can be digested into shorter peptide sequences and, subsequently, degraded into amino acids, which are a group of naturally biodegradable molecules.…”

“…In this paper, some physicochemical features of the synthetic self-assembling peptide RAD16-I have been studied. This peptide is currently commercialized under the name of PuraMatrix TM and is being used as a scaffold in many biomedical applications and studies such as in the development of in vitro cancer models [27,39,40], in different tissue engineering scenarios [29,30,41,42] and it has also been tested as a platform for drug delivery [43][44][45][46]. Thus, in addition to performing all the necessary experiments to characterize the biological systems obtained for each different application, it is also essential to control and study all the properties regarding the biodegradability of the scaffold, which, to date, has not been assessed.…”

Glaucoma Treatment and Hydrogel: Current Insights and State of the Art

“…Other polymer-based hydrogels evaluated for ophthalmic administration are stimulus-responsive gel [ 100 , 101 , 102 , 103 , 104 ]. These delivery strategies have been investigated for several ophthalmic drugs commonly used in the treatment of glaucoma, such as TM, brimonidine tartrate (BT), pilocarpine, and latanoprost, or combinations with each other [ 105 , 106 , 107 , 108 ] ( Table 2 ).…”

“…The studies showed an extended-release of TM for up to 80 h [ 124 ]. An in situ gel forming self-assembling peptide, ac-(RADA) 4 -CONH 2 , was evaluated as a carrier for the ocular co-delivery of TM and BT by Taka et al [ 105 ]. A complete release of both drugs was obtained within eight hours.…”

“…A complete release of both drugs was obtained within eight hours. A 5.4-fold and 2.8-fold higher corneal permeability was achieved for BT and TM, respectively [ 105 ]. Patel et al synthesized a combined pH and ion-sensitive in situ hydrogel using Carbopol and gellan gum, which compared with TM’s marketed eye drop formulation [ 104 ].…”