An efficient ternary complex of acetazolamide with HP-ß-CD and TEA for topical ocular administration

In order to enhance the ocular bioavailability of acetazolamide (ACZ), a multicomponent complex with hydroxypropyl-ß-cyclodextrin (HP-ß-CD) and triethanolamine (TEA) was prepared to be applied topically. In vitro corneal permeation across isolated rabbit cornea of proposed ACZ formulations and the marketed AZOPT® formulation (1% w/v brinzolamide) was studied. Formulations were also tested for their effect on the intraocular pressure (IOP) in rabbits. 1H- and 13C-NMR experiments were undertaken to verify the real inclusion of ACZ in the ACZ–HP-ß-CD–TEA multicomponent complex. The binding of ACZ to HP-ß-CD in the presence of TEA is described. The increase of TEA concentration decreases the apparent equilibrium constant for the ACZ–HP-ß-CD complex. The ternary system ACZ–HP-ß-CD–TEA seemed to be able to reduce IOP in about 30%. This effect was sustained for 4 h after instillation. In vitro corneal permeation studies demonstrated that the ACZ permeation was increased. RMN experiments indicated that TEA can weaken the association between ACZ and HP-ß-CD increasing the drug ocular hypotensive effect by increasing the free drug available for absorption. Our formulations were considered practically non-irritant. These results indicate that the ternary system ACZ–HP-ß-CD–TEA might be a useful tool for formulating aqueous ACZ eye drop solutions.

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