Evaluation Of The Effect Of Controlling Myopia By Pirenzepine Penetration Enhancer-iontophoresis

Objective: Pirenzepine, an antagonist selective for the M1 muscarinic receptor subtype ,has been shown to be effective in preventing myopia, without the side-effects of cycloplegia and mydriasis seen with atropine. In order to enhance the corneal penetration of pirenzepine, the purpose of this study was to investigate the possibility of using iontophoresis as a kind of corneal penetration enhancer. Methods: (1) HPLC method was established for determining pirenzepine in aqueous humor. (2) The concentrations of pirenzepine were determined at different time intervals after instilling into the cul-de-sac. Four formulations(pH=3, 5 and 7, hydolgel concentration=2%) were administered to the rabbits. (3) 36 rabbits were randomly divided into 9 groups: pirenzepine was applied to the eye by positive electrode iontophoresis in 8 groups, including different intensity of electricity, different material of electrode and different formulations of solution; 1 group only received pirenzepine instillation as controll. The level of pirenzepine in the aqueous humor were measured by HPLC after 20 minutes. (4) Three-week-old guinea pigs were monocularly deprived (MD) by lid-suture for a period of 30 days. In four of the MD groups, guinea pigs received daily iontophoresis of either pirenzepine (including three groups) or vehicle control. Control groups were used to assess the effects of MD, iontophoresis regimen, and drug effects. Retinoscopy, anterior posterior dimension, eye weight and histological examination were taken.Results: (1) When the pH of solution was 3, 5, 7 and the concentration of HPMC was 2%(pH=7), the AUC of pirenzepine in the aqueous humor was 5418.72,1510.605,671.685 and 726.85 ng·h·ml-1, respectively; The elimination half-life(t1/2) from the aqueous humor was 13.67,6.85,5.77 and 5.67 hours, respectively. (2) The concentrations of pirenzepine in the aqueous humor were higher in the groups by iontophoresis than that by instillation. When the pH of solution was the lowest, theconcentration was the highest(5.11μg/ml). The other factors were of no effect on the penetration. (3) In normal-MD and vehicle-MD guinea pigs, 30 days of MD produced -4.64 and -4.33 D of axial myopia, respectively. In PIR iontophoresis MD guinea pigs, 30 days of MD induced an axial myopia of only -2.15, -0.17 and -1.30 D, respectively. Increased anterior posterior dimension and eye weight were prevented in pirenzepine iontophoresis MD guinea pigs. Histological examination revealed no evidence of gross toxic effects.Conclusions: (1) it is hard for pirenzepine to penetrate the corneal and pirenzepine was found to be more potent when administered topically to the eye in acidic solution. (2) Iontophoresis can enhance the corneal penetration of pirenzepine. The pH of solution was the only factor which could affect the effect of iontophoresis. (3) Chronic administration of pirenzepine by iontophoresis prevents experimentally induced myopia more effectively than topical instillation.