HYDROXYPROPYL-BETA-CYCLODEXTRIN INCREASES THE AQUEOUS SOLUBILITY AND STABILITY OF PILOCARPINE PRODRUGS

Purpose. The effects of 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) on the aqueous solubility and stability of two lipophilic bispilocarpine prodrugs were investigated at pH 7.4. Methods. The solubility of prodrugs was studied by phase-solubility method (0-72.5 mM HP-beta-CD). The stability of one of the prodrugs was investigated as a function of temperature (40 degrees C-70 degrees C) and HP-beta-CD concentration (0-72.5 mM). The apparent rate constants (k(1), k(2)) for degradation of prodrug in I:1 and 1:2 inclusion complexes and apparent stability constants (K-1:1, K-1:2) were calculated by the curve-fitting method. Results. The phase-solubility diagrams were classified as A(p)-type and the apparent stability constants (K-1:1, K-1:2) for 1:1- and 1:2-inclusion complexes were calculated to be 143-815 M(-1) and 29-825 M(-1), respectively. The stability of prodrug increased as a function of HP-beta-CD concentration over the studied temperature range. The shelf-life (t(90%), calculated by the Arrhenius equation) of the prodrug in 72.5 mM HP-beta-CD solution increased 5.1-fold and 6.1-fold at 25 degrees C and 4 degrees C, respectively. Conclusions. The solubility of the prodrugs was shown to increase markedly in phase-solubility studies. The degradation rate of prodrug in stability studies was shown to be slower in the 1:2-complex than in the I:l-complex and the relative amounts of complex species were found to be dependent on CD concentration.