Effect of pH and buffer on the precorneal disposition and ocular penetration of pilocarpine in rabbits

Abstract

An in vivo technique was utilized to study the effect of pH and buffer capacity on the precorneal disposition and ocular penetration of pilocarpine in the rabbit eye. Tear film pH, tear drug concentration and aqueous humor levels were measured at various times following the instillation of 25 μl of a 1 × 10−2 M isotonic pilocarpine solution. Test solutions were prepared in 0.0667 M phosphate buffer at various pHs (4.5, 6.0, 7.2) and at various phosphate buffer concentrations (0 M, 0.00667 M, 0.0667 M, 0.1 M) at pH 4.5. It appears that following the instillation of pilocarpine nitrate solutions buffered below the physiological pH of the lacrimal fluid, the extent of depression of the tear film pH and the tear pH re-equilibration time depends not only on the pH of the solution, but also on the precorneal fluid dynamics, and the buffer capacities of the instilled solution and that of the tears. As the buffer capacity of the instilled solution is increased, the ability of incoming tears to raise the pH in the precorneal area to its physiological value is reduced. The increase in the drainage rate due to reflex tear production is an effective mechanism by which the tear film pH re-equilibrates and is also responsible for the large reduction in the drug concentration in the precorneal area. This study examines this mechanism in detail.The depression in the tear film pH can also reduce the ocular penetration of pilocarpine by reducing its corneal permeability. Buffering of the pilocarpine nitrate solution with 0.0667 M phosphate buffer at pH 4.5 causes a two-fold reduction in the aqueous humor level as compared to an unbuffered solution at the same pH. Such a decrease is also predicted based on tear pH-time and tear concentration-time measurements of pilocarpine. This study shows the practical utility of such information in estimating the ocular penetration of drugs. Based on such information it is expected that at least a two-fold reduction in pilocarpine absorption may be caused by reflex tear production. In order to ensure optimum ocular penetration of pilocarpine, the system should not depress the tear film pH appreciably, and should allow rapid tear pH re-equilibration.