Suhonen P, Järvinen T, Koivisto S, Urtti A
Department of Pharmaceutics, University of Kuopio, P.O. Box 1627, FIN-70211, Kuopio, Finland.
Eur J Pharm Sci. 1998 Jul;6(3):169-76. doi: 10.1016/s0928-0987(97)10002-1.
Ocular absorption of pilocarpine and many other ophthalmic drugs can be improved by prodrug derivatization. For stability and solubility reasons basic prodrugs must be formulated at acidic pH, which may affect the corneal drug permeability. We studied the effects of pH on in vitro permeation of pilocarpine, pilocarpic acid benzyl diester prodrugs [O-propionyl (I) and O-valeryl (II)] and O,O'-(1, 4-xylylene) bispilocarpic acid diester prodrugs [O,O'-diacetyl (III), O,O'-dipropionyl (IV) and O,O'-divaleryl (V)] through albino rabbit cornea. Reversed-phase high-performance liquid chromatography was used to assay pilocarpine and its prodrugs. The permeability coefficient for pilocarpine decreased more than three times, from 2. 8x10-6 cm/s to 0.9x10-6 cm/s, when the pH was decreased from 7.65 to 5.5. At pH 7.65 permeability of pilocarpine improved several fold with delivery as prodrugs. Acidic pH (5.5, 6.0) affected to a different extent the corneal permeability of pilocarpine given as prodrugs. Consequently, the rank order of the corneal permeabilities among the compounds was different at various pH values. The effect of pH was greatest (an order of magnitude) for prodrugs with intermediate lipophilicity (I, III, IV), while pH had only minor or no effect on permeability of the most lipophilic prodrugs (II, V). In conclusion, the effect of pH on pilocarpine delivery as prodrug is dependent on prodrug structure and the advantage gained with prodrugs relative to pilocarpine is dependent on formulation pH.
通过前药衍生化可改善毛果芸香碱及许多其他眼科药物的眼部吸收。出于稳定性和溶解性的原因，碱性前药必须在酸性pH值下配制，这可能会影响角膜药物渗透性。我们研究了pH值对毛果芸香碱、毛果芸香酸苄基二酯前药[O - 丙酰基（I）和O - 戊酰基（II）]以及O,O' -（1,4 - 亚二甲苯基）双毛果芸香酸二酯前药[O,O' - 二乙酰基（III）、O,O' - 二丙酰基（IV）和O,O' - 二戊酰基（V）]经白化兔角膜体外渗透的影响。采用反相高效液相色谱法测定毛果芸香碱及其前药。当pH值从7.65降至5.5时，毛果芸香碱的渗透系数下降了三倍多，从2.8×10⁻⁶ cm/s降至0.9×10⁻⁶ cm/s。在pH 7.65时，以前药形式给药时毛果芸香碱的渗透性提高了几倍。酸性pH值（5.5、6.0）对以前药形式给药的毛果芸香碱的角膜渗透性有不同程度的影响。因此，在不同pH值下，化合物之间角膜渗透性的排序不同。对于亲脂性中等的前药（I、III、IV），pH值的影响最大（一个数量级），而pH值对亲脂性最强的前药（II、V）的渗透性影响很小或没有影响。总之，pH值对作为前药的毛果芸香碱给药的影响取决于前药结构，并且相对于毛果芸香碱，前药获得的优势取决于制剂的pH值。
