A novel reverse micelle based cationic double nanoemulsion as a potential nanoplatform for enhancing the anitglucomal activity of betaxolol hydrochloride; formulation, in vitro characterization, ex vivo permeation and in vivo pharmacodynamic evaluation in glaucomatous rabbits’ eyes

Abstract

Glaucoma is one of the most common causes of irreversible vision loss worldwide. The hydrophilic nature of the anti-glaucoma drug Betaxolol hydrochloride (BH) limits its ocular permeation necessitating repeated dosing. This can reduce patient compliance and increase the risk of experiencing adverse side effects. Our research is the first to encapsulate BH into reverse micelle-based cationic double W1/O/W2 nanoemulsions (RM-CDNEs) as a new platform capable of enhancing both the corneal permeability and IOP lowering efficacy of this drug. BH-loaded RM-CDNEs were prepared by a modified two-step emulsification method using sonication technique and applying 24 full factorial design to assess the impact of formulation variables and select the optimal delivery system. The in vitro drug-release, ex vivo permeation and in vivo performance of this novel nanocarrier were also assessed. The optimal delivery system (RM-CDNE 10) has mean DS, PDI, ZP and entrapment efficiency of 46.53 ± 1.30 nm, 0.217 ± 0.02, +40.9 ± 5.04 mV and 95.1 ± 2.44 %, respectively. A 90.77 % of drug was released over 7h. RM-CDNE 10 showed 2.5-fold increase in ex vivo corneal BH permeation with a prolonged IOP reduction of 58.77 % ± 1.18 % and AUC0-48 of 2537.82 ± 12.8%h. While, the marketed product (Epitaxol®) had only 33.63 ± 1.54 % IOP reduction with AUC0–48 h of 823.14 ± 3.67%h when tested in rabbits (P ≤ 0.05). Histopathological and Draize irritation studies confirmed that RM-CDNEs were non-irritant. These findings proved that the novel BH-loaded RM-CDNEs system improved the outcomes for patients suffering from glaucoma and thus decreasing the liability for disease progression into blindness.