Modified beta-cyclodextrin (SBE7-beta-CyD) with viscous vehicle improves the ocular delivery and tolerability of pilocarpine prodrug in rabbits.
The complexation of pilocarpine prodrug, O,O'-dipropionyl-(1,4-xylylene) bispilocarpate, with various beta-cyclodextrin (beta-CyD) derivatives was studied by the phase solubility method. The effects of coadministered sulphobutyl ether beta-CyD (SBE7-beta-CyD) with and without poly(vinyl alcohol) (PVA) on the miotic response and eye irritation of the prodrug were investigated in pigmented rabbits. The pilocarpine prodrug formed 1:1 inclusion complexes with variably substituted sulphobutyl ether derivatives of beta-CyD (SBE4-beta-CyD and SBE7-beta-CyD), and 1:1 and 1:2 complexes with hydroxypropyl-beta-CyD (HP-beta-CyD) at pH 7-4. Coadministered SBE7-beta-CyD eliminated the eye irritation due to the pilocarpine prodrug, but also decreased the miotic response. Ocular absorption of the prodrug was improved by increasing the viscosity of prodrug/SBE7-beta-CyD solution with PVA without inducing any eye irritation. Eye irritation due to viscous prodrug/SBE7-beta-CyD solutions was comparable with isotonic NaCl solution. We conclude that administration of pilocarpine prodrug in viscous SBE7-beta-CyD solution decreases substantially eye irritation while ocular absorption is not affected.
Jarho
P
P
Department of Pharmaceutical Chemistry, University of Kuopio, Finland.
Järvinen
K
K
Urtti
A
A
Stella
V J
VJ
Järvinen
T
T
D000818:Animals; D003505:Cyclodextrins / Q000737:chemistry*; D004361:Drug Tolerance; D005123:Eye / Q000187:drug effects*; D015877:Miosis / Q000139:chemically induced*; D014677:Pharmaceutical Vehicles; D010862:Pilocarpine / Q000008:administration & dosage* / Q000737:chemistry*; D011355:Prodrugs / Q000008:administration & dosage* / Q000737:chemistry*; D011817:Rabbits; D047392:beta-Cyclodextrins
D003505:Cyclodextrins; D014677:Pharmaceutical Vehicles; D011355:Prodrugs; D047392:beta-Cyclodextrins; D010862:Pilocarpine; C031215:betadex