P. Saarinensavolainen et al., BETA-CYCLODEXTRIN DERIVATIVES (2-HP-BETA-CD, SBE4-BETA-CD) DECREASE THE AMPHIPHILICITY AND MEMBRANE PERTURBING EFFECTS OF PILOCARPINE PRODRUGS, European journal of pharmaceutical sciences, 5(2), 1997, pp. 89-96
The ocular bioavailability of pilocarpine has been improved by bispilo
carpic acid diesters but the ocular irritation associated with these p
rodrugs is the main limitation of their clinical usefulness. Pilocarpi
ne prodrugs show amphiphilic lipid bilayer disrupting properties which
partly contribute to the eye irritation. In the present study, the in
fluence of complexation with hydrophilic beta-cyclodextrin derivatives
, 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and sulfobutyl ether
beta-cyclodextrin with an average degree of substitution of four (SBE4
-beta-CD), on pilocarpine prodrug-induced bilayer perturbation was inv
estigated using rabbit erythrocyte hemolysis and calcein release from
liposomes as test models. Bispilocarpic acid diesters form 1:1 and 1:2
complexes with HP-beta-CD and 1:1 complexes with SBE4-beta-CD at pH 7
.4. Both beta-CD derivatives decreased the surface activity of the pro
drug solutions. The hemolytic activity and liposome disruption of prod
rug-CD solutions were 3-10 times and 4-15 times lower than that of par
ent prodrug, respectively. The protecting effect of CDs was dependent
on the apparent complexation constant of prodrug/CD complex which dete
rmines the active free prodrug concentration in CD solution. The prese
nt study shows that amphiphilic properties and lipid bilayer perturbin
g effects of pilocarpine prodrugs are reduced by complexing them with
hydrophilic beta-CD derivatives.