SULFOBUTYL ETHER BETA-CYCLODEXTRIN (SBE-BETA-CD) IN EYEDROPS IMPROVES THE TOLERABILITY OF A TOPICALLY APPLIED PILOCARPINE PRODRUG IN RABBITS

被引:47
作者
JARVINEN, T [1 ]
JARVINEN, K [1 ]
URTTI, A [1 ]
THOMPSON, D [1 ]
STELLA, VJ [1 ]
机构
[1] UNIV KANSAS,DEPT PHARMACEUT CHEM,LAWRENCE,KS 66045
关键词
D O I
10.1089/jop.1995.11.95
中图分类号
R77 [眼科学];
学科分类号
100212 ;
摘要
The effects of a novel, modified p-cyclodextrin (SBE4-beta-CD; a variably substituted sulfobutyl ether with an average degree of substitution of four) on eye irritation and miotic response of an ophthalmically applied pilocarpine prodrug, O,O'-dipropionyl-(1,4-xylylene) bispilocarpate, in albino rabbits were studied. Compared to the commercial pilocarpine eyedrop solution (163 mM, equivalent to 3.4% pilocarpine), 12 - 24 mM pilocarpine prodrug solutions (equivalent to 0.5 1.0% pilocarpine, respectively) decreased peak miotic intensity (I-max) and increased the time to reach peak (t(max)), but did not significantly affect values for the area under the miosis versus time curves (AUG), i.e. 12 - 24 mM pilocarpine prodrug appeared to be equivalent to 163 mM pilocarpine. Ocularly applied 12 - 24 mM pilocarpine prodrug solutions, however, were more irritating than a commercial pilocarpine eyedrop solution. Coadministered SBE4-beta-CD significantly decreased the eye irritation of the pilocarpine prodrug solutions. Coadministered SBE4-beta-CD did not affect the miotic response of prodrug solution when the molar ratio of SBE4-beta-CD to prodrug was low. However, increasing the molar ratio of SBE4-beta-CD to prodrug decreased the I-max and AUC values. The results show that eye irritation of the pilocarpine prodrug is prevented by levels of SBE4-beta-CD that do not affect the apparent ocular absorption of the prodrug.
引用
收藏
页码:95 / 106
页数:12
相关论文
共 40 条
[11]  
Loftsson T., Bjorndottir S., Palsdottir G., Bodor N., The effects of 2-hydroxypropyl-p-cyclodextrin on the solubility and stability of chlorambucil and melphalan in aqueous solution, Int. J. Pharm., 57, pp. 63-72, (1989)
[12]  
Pop E., Loftsson T., Bodor N., Solubilization and stabilization of a benzylpenicillin chemical delivery system by 2-hydroxypropyl-p-cyclodextrin, Pharm. Res., 8, pp. 1044-1049, (1991)
[13]  
Szejtli J., Cyclodextrins in drug formulations: Part I, Pharm. Techn. Int., 3, pp. 15-21, (1991)
[14]  
Uekama K., Fujinaga T., Hirayama F., Otagiri M., Yamasaki M., Seo H., Hashimoto T., Tsuruoka M., Improvement of the oral bioavailability of digitalis glycosides by cyclodextrin complexation, J. Pharm. Sci., 72, pp. 1338-1341, (1983)
[15]  
Bekers O., Uijtendaal E.V., Beijnen J.H., Bult A., Underberg W.J.M., Cyclodextrins in the pharmaceutical field, Drug Dev. Ind. Pharm., 17, pp. 1503-1549, (1991)
[16]  
Duchene D., Vaution C., Glomot F., Cyclodextrins, their value in pharmaceutical technology, Drug Dev. Ind. Pharm., 12, pp. 2193-2215, (1986)
[17]  
Hedges A.R., Minutes of the Sixth International Symposium on Cyclodextrins, (1992)
[18]  
Wheeler L.A., The use of inclusion complexes of prostaglandins with cyclodextrins in the treatment of ocular hypertension, Eur. Pat. O 435 682 A3, (1991)
[19]  
Usayapant A., Karara A.H., Narurkar M.M., Effect of 2-hydroxypropyl-|3-cyclodextrin on the ocular absorption of dexamethasone and dexamethasone acetate, Pharm. Res., 8, pp. 1495-1499, (1991)
[20]  
Freedman K.A., Klein J.W., Crosson C.E., Beta-cyclodextrins enhance bioavailability of pilocarpine, Curr. Eye Res., 12, pp. 641-647, (1993)