Study of the extent of ocular absorption of acetazolamide from a developed niosomal formulation, by microdialysis sampling of aqueous humor

Abstract

Acetazolamide, a carbonic anhydrase inhibitor is used orally (no topical formulation being available in the market) for the reduction of intraocular pressure (IOP) in patients suffering from glaucoma. Two major reasons responsible for the failure to develop a topically effective formulation of acetazolamide are its low solubility (0.7 mg/ml) and its low permeability coefficient. It is generally recognized that topical acetazolamide formulation possessing efficacy similar to that achieved upon oral administration would be a significant advancement in the treatment of glaucoma. In order to enhance the bioavailability of acetazolamide by topical route and to improve the corneal permeability of the drug, the niosomes of acetazolamide were prepared (by reverse phase evaporation method) and coated with Carbopol for the latter's bioadhesive effect. The pharmacodynamic studies showed 33% fall in IOP with the developed formulation, and the effect was sustained for 6 h after instillation. The effect compared well with a four times higher concentration of dorzolamide (Dorzox ®), a topical CAI available in the market. In the present study, the aqueous humor disposition of the drug from the developed bioadhesive coated niosomal formulation (ACZREVbio) is compared with the aqueous suspension of the drug (containing 1% (w/v) Tween 80 as a dispersing agent) at similar concentrations. The concentration of acetazolamide absorbed in the aqueous humor at various times from the control suspension and from ACZREVbio was determined by microdialysis in male albino rabbits. Microdialysis provides a complete concentration versus time profile and hence is an important advance to the regional sampling of tissues. The peak concentration of drug absorbed in the aqueous humor from the ACZREVbio formulation (14.94 μg/ml) was almost two times of that obtained with the equivalent amount of acetazolamide control suspension (6.93 μg). The results show a significant broadening of peak from 80 to 120 min with the concentration of more than 13 μg being maintained at these times, for the bioadhesive coated niosomal formulation (ACZREVbio). An important observation was the fact that a high drug concentration of 12.02 μg reached immediately, i.e., 20 min after instillation of ACZREVbio indicating a high penetration being achieved, while a meagre concentration of only 3.53 μg is obtained at 60 min after instillation of the control suspension. The aqueous humor disposition indicates peaks and troughs in drug concentration which may be related to the decrease in aqueous humor formation, such that the drug concentration/volume increased at these points.