An objective in the development of ophthalmic formulations is the use of in vitro or animal models that closely resemble the clinical situation. For this reason, experiments with conventional pilocarpine nitrate eyedrops and a depot formulation of pilocarpine nitrate sorbed to poly (butylcyanoacrylate) nanoparticles were carried out. In vitro, the diffusion of pilocarpine through bovine cornea was measured using Edelhauser cells. In vivo, the rabbit aqueous humor concentration of pilocarpine and miosis were determined after application of the above formulations. In addition, intraocular pressure was measured. Since pilocarpine has little influence on intraocular pressure in healthy rabbits, the pressure had to be increased artificially. Three models were employed that are described in the literature, namely, the betamethasone model, the alpha-chymotrypsin model, and the water-loading model. Pilocarpine could be loaded onto nanoparticles by 15% but was rapidly released from the nanoparticles based on the bovine corneal experiment. Nanoparticles only enhanced the aqueous humor concentration at 30 min; this increase, however, led to a considerably extended period of miosis as well as a reduction in intraocular pressure. The duration of the action and the intensity of the response were different among the three models tested. According to the present results, the betamethasone model seems to represent the best correlation to the clinical situation.

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The effect of chlorhexidine acetate on the corneal penetration of sorbitol was evaluated in vitro using the enucleated pigmented rabbit cornea mounted in a modified Ussing chamber. Sorbitol penetrated the cornea poorly when compared with arnolol, a beta blocker. Sorbitol penetration was improved 85% by 0.01% chlorhexidine acetate, 2.9 times by 0.1% EDTA, and 9.6 times by stripping the corneal epithelium prior to the start of the experiment. By comparison, 0.01% chlorhexidine acetate and stripping the corneal epithelium improved the corneal penetration of arnolol only 30% and 74%, respectively, whereas stripping the corneal epithelium did not affect the corneal penetration of chlorhexidine acetate.Collectively, the above findings indicate that changes in corneal integrity may dramatically affect the corneal penetration of some inert excipients in ophthalmic formulations. Such a possibility must be considered carefully in the selection of excipients.