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. 2020 Jun 21;13(6):126.
doi: 10.3390/ph13060126.

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

Elissavet Taka  1 , Christina Karavasili  1 , Nikolaos Bouropoulos  2   3 , Thomas Moschakis  4 , Dimitrios D D Andreadis  5 , Constantinos K K Zacharis  6 , Dimitrios G G Fatouros  1
Affiliations

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

Elissavet Taka et al. Pharmaceuticals (Basel). .

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.

Keywords: ex vivo ocular permeability; glaucoma; self-assembling peptide hydrogel; timolol maleate/brimonidine tartrate combination.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
(A), (C). Oscillatory time sweep (0.5% strain, 1 Hz, 37 °C) and (B), (D). frequency sweep experiments (0.5% strain, 0.1–100 Hz, 37 °C) of the ac-(RADA)4-CONH2 peptide hydrogel and the single (BR, TM) and dual (TM + BR) drug loaded peptide hydrogel.
Figure 2
Figure 2
(A,B) 2D and (C,D) 3D AFM images of the ac-(RADA)4-CONH2 peptide hydrogel (A–C) prior and (B–D) post drug loading. Scale bar: 200 nm.
Figure 3
Figure 3
In vitro release profiles of brimonidine tartrate and timolol maleate from the ac-(RADA)4-CONH2 peptide hydrogel in STF pH 7.4 at 37 °C (n = 4).
Figure 4
Figure 4
Ex vivo permeability profiles of (A). timolol maleate in ac-(RADA)4-CONH2 peptide hydrogel and in PBS solution and of (B). brimonidine tartrate in ac-(RADA)4-CONH2 peptide hydrogel and in PBS solution across porcine cornea (n ≥ 4).
Figure 5
Figure 5
(A) FTIR spectra of pure brimonidine tartrate, pure timolol maleate and of the control cornea and the corneas treated with the peptide hydrogel, the drug solution and the drug loaded peptide hydrogel. (B) Thermograms of the control cornea and the corneas treated with the peptide hydrogel, the drug solution and the drug loaded peptide hydrogel.
Figure 6
Figure 6
Histological sections of the (A). control (untreated) cornea, (B). cornea treated with the peptide hydrogel, (C). cornea treated with TM + BR solution and (D). cornea treated with TM + BR peptide hydrogel after the completion of the ex vivo permeability studies (ep: epithelium; Bw: Bowman’s layer; st: stroma). Scale bar: 200 μm.
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