Increase in aqueous solubility, stability and in vitro corneal permeability of anandamide by hydroxypropyl-8-cyclodextrin
Increase in aqueous solubility, stability and in vitro corneal permeability of anandamide by hydroxypropyl-8-cyclodextrin
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DOI：
10.1016/0378-5173(96)04522-x
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发表时间：
1996-06-28
影响因子：
5.8
通讯作者：
Jarvinen, T
中科院分区：
文献类型：
--
作者：
Jarho, P;Urtti, A;Jarvinen, T
花生四烯乙醇酰胺（AEA）是大麻素受体的内源性配体，具有低的水溶性和不稳定性，这阻碍了其在水性制剂中的使用。本文研究了环糊精（CD）对AEA水溶性、稳定性和体外角膜渗透性的影响。通过使用离体兔角膜研究HP-β-CD制剂中的AEA的角膜渗透性。HP-β-CD的相溶解度图属于A β型，计算出1：1和1：2包合物的稳定常数（K-1：1和K-1：2）分别为39 419 M（-1）和12 M（-1）。AEA与DIME-β-CD和HP-γ-CD的相溶解度图均为A（L）型，表明AEA与DIME-β-CD和HP-γ-CD形成1：1的复合物。1：1复合物的稳定常数分别为744 877 M（-1）和15 469 M（-1）。AEA与HP-β-CD的复合作用显著提高了AEA的稳定性。AEA在10.0% HP-β-CD溶液中在50 ℃下的有效期（t（90%））确定为166天。与化合物的悬浮液相比，AEA与HP-β-CD的复合增加了AEA的角膜渗透。在完全溶解AEA的最低HP-β-CD浓度下实现最大渗透性。AEA的渗透率与溶液中游离AEA的浓度有很好的相关性。
Arachidonylethanolamide (AEA), an endogenous ligand for the cannabinoid receptor, has a low aqueous solubility and an instability which hinder its use in aqueous formulations. In the present study, the effect of cyclodextrins (CDs) on the aqueous solubility, stability and in vitro corneal permeability of AEA was studied. The corneal penetration of AEA in HP-beta-CD formulations was investigated in vitro by using isolated corneas of rabbits. The phase solubility diagram with HP-beta-CD was classified as Ap-type and stability constants (K-1:1, and K-1:2) for 1:1 and 1:2 inclusion complexes were calculated to be 39 419 M(-1) and 12 M(-1), respectively. The phase solubility diagram of AEA with DIME-beta-CD and HP-gamma-CD were of the A(L)-type, indicating the formation of 1:1-complexes. The stability constants for 1:1-complexes were 744 877 M(-1) and 15 469 M(-1), respectively. The complexation of AEA with HP-beta-CD markedly increased the stability of AEA. The shelf-life (t(90%)) of AEA in 10.0% HP-beta-CD solution at 50 degrees C was determined to be 166 days. The complexation of AEA with HP-beta-CD increased corneal penetration of AEA compared to a suspension of the compound. Maximum permeability was achieved with the lowest HP-beta-CD concentration that dissolved AEA completely. The permeability of AEA correlated well with the concentration of free AEA in solution.