Increase in aqueous solubility, stability and in vitro corneal permeability of anandamide by hydroxypropyl-8-cyclodextrin

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.