pH值对马来酸噻吗洛尔角膜透过性的影响

目的　研究pH值对马来酸噻吗洛尔(TM)角膜透过性的影响,为其处方设计提供理论依据。方法　测定TM的表观油水分配系数(DC_app)。用体外扩散实验考察各种pH值条件下离体兔眼角膜对TM的透过性。结果　由DC_app求得TM的分配系数和pKa分别为63.63和9.17。在生理介质中,TM的表观透过系数为1.43×10^-5cm·s^-1。随着pH值由6.65升高至9.20 ,TM透过角膜的滞后时间缩短到1/20 ,累积透过量增加1.3倍。计算得到游离型噻吗洛尔的角膜透过系数为解离型的3.3倍。结论　噻吗洛尔主要以分子状态经细胞内途径透过角膜,且角膜上皮是其扩散的主要屏障。

EFFECT OF pH ON THE PERMEABILITY OF TIMOLOL MALEATE ACROSS ISOLATED RABBIT CORNEA

AIM: To study the effect of pH on the transcorneal permeability of timolol maleate (TM). METHODS: The apparent distribution coefficients of TM were determined. The permeability of TM across isolated rabbit cornea was measured using in vitro method at various pH. RESULTS: The partition coefficient and pKa of TM were 63.63 and 9.17 respectively. At neutral pH, the apparent permeation coefficient of TM was 1.43 x 10(-5) cm.s-1. When the pH varied from 6.65 to 9.20, the cumulative amount for timolol transcorneal penetration increased 1.3 times and the lag time decreased more than 19-folds. The calculated permeability coefficients of ionized and un-ionized timolol were 1.29 x 10(-5) cm.s-1 and 4.22 x 10(-5) cm.s-1, respectively. CONCLUSION: Timolol penetrated corneal membrane mainly as free base by intracellular pathway, and corneal epithelium was the rate-limiting barrier.