Physicochemical characterization of bisphosphonic carboxyfluorescein for osteotropic drug delivery.
Disodium (fluorescein-6-carbonyloxy)acetoaminomethylene bisphosphonate (CF-BP), a prodrug of 6-carboxy-fluorescein, is efficiently absorbed by the skeleton where it hydrolyses to carboxyfluorescein. An osteotropic drug-delivery system based on this bisphosphonic prodrug has been developed as a novel method for site-specific and controlled delivery of drugs to the bone. In this study the physicochemical properties of the prodrug have been characterized by investigating the affinity of CF-BP for hydroxyapatite and the hydrolysis of the compound to carboxyfluorescein. In the binding study, CF-BP bound very rapidly to hydroxyapatite without degradation and carboxyfluorescein was subsequently gradually released by hydrolysis of bound CF-BP. Hydrolysis of CF-BP in buffer solutions followed pseudo-first-order kinetics, and quantitative regeneration of carboxyfluorescein was observed. In addition, regeneration of carboxyfluorescein from CF-BP was accelerated in the presence of fresh rat plasma. These results suggest that CF-BP has the physicochemical properties required for site-specific and controlled delivery of carboxyfluorescein to bones.
Fujisaki
J
J
Pharmaceutical and Pharmacokinetic Research Laboratories, Fujisawa Pharmaceutical Company Ltd, Osaka, Japan.
Tokunaga
Y
Y
Takahashi
T
T
Murata
S
S
Shimojo
F
F
Hata
T
T
D000818:Animals; D004164:Diphosphonates; D005452:Fluoresceins / Q000737:chemistry*; D005456:Fluorescent Dyes / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D063065:Organophosphonates / Q000737:chemistry*; D011355:Prodrugs / Q000737:chemistry*; D051381:Rats
C104510:(fluorescein-6-carbonyloxy)acetoaminomethylene bisphosphonic acid; D004164:Diphosphonates; D005452:Fluoresceins; D005456:Fluorescent Dyes; D063065:Organophosphonates; D011355:Prodrugs; C024098:6-carboxyfluorescein