Relative effectiveness of prodrug and viscous solution approaches in maximizing the ratio of ocular to systemic absorption of topically applied timolol.

The effectiveness of the prodrug approach in maximizing the ratio of ocular to systemic absorption of topically applied timolol was compared with that based on viscous solutions. The pigmented rabbit was the experimental animal. o-Butyryl timolol, a lipophilic ester prodrug of timolol, was found to be twice as effective as hyaluronic acid and poly(vinyl alcohol) solutions in enhancing the ocular absorption of timolol. In addition, it was slightly more effective than retaining the instilled dose in the conjunctival sac for 240 min via nasolacrimal blockade. On the other hand, due to its inability to minimize contact of the instilled dose with the nasal mucosa, o-butyryl timolol was less capable than the viscous solutions in reducing systemic drug absorption. But this could be corrected by reducing the instilled solution volume from 25- to 5 microliter, resulting in a nine-fold reduction in plasma timolol levels while still providing the same amount of drug in the aqueous humor as a five times higher dose of timolol. The net result was a 15-fold improvement in the ratio of ocular to systemic drug absorption, which was also achieved upon retaining the instilled dose in the conjunctival sac for 240 min. It thus appears that the approach based on improved corneal absorption would be as effective as that based on improved retention in the conjunctival sac in maximizing the ratio of ocular to systemic drug absorption, so long as a smaller instilled dose volume of the prodrug is used.