Hydroxypropyl-beta-cyclodextrin increases the aqueous solubility and stability of pilocarpine prodrugs.
OBJECTIVE
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 (k1, k2) for degradation of prodrug in 1:1 and 1:2 inclusion complexes and apparent stability constants (K1:1, K1:2) were calculated by the curve-fitting method.


RESULTS
The phase-solubility diagrams were classified as Ap-type and the apparent stability constants (K1:1, K1:2) 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 (t90%, 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 1:1-complex and the relative amounts of complex species were found to be dependent on CD concentration.
Jarho
P
P
Department of Pharmaceutical Chemistry, University of Kuopio, Finland.
Urtti
A
A
Järvinen
T
T
D000073738:2-Hydroxypropyl-beta-cyclodextrin; D003505:Cyclodextrins; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008956:Models, Chemical; D015394:Molecular Structure; D010862:Pilocarpine / Q000031:analogs & derivatives / Q000737:chemistry*; D011355:Prodrugs / Q000737:chemistry*; D012995:Solubility; D014867:Water; D047392:beta-Cyclodextrins
D003505:Cyclodextrins; D011355:Prodrugs; D047392:beta-Cyclodextrins; D010862:Pilocarpine; D014867:Water; D000073738:2-Hydroxypropyl-beta-cyclodextrin