メカノケミカル固相重合による新規ハイブリッド型高分子プロドラッグの構築とその薬物放出特性

Abstract

Polymeric prodrugs having a basic side chain were synthesized by mechanochemical solid-state polymerization, and the nature of drug release of these polymeric prodrugs was investigated. Two kinds of methods, flow-through-cell and flask-shaking method, were used for hydrolysis of polymeric prodrugs. Drug release in flow-through-cell method can be considered to be a model experiment under in vivo condition, and the polymeric prodrugs synthesized in the present reactions eventually released the drugs quantitatively. It was also shown that the hydrolysis (drug release) profiles apparently follow a first-order kinetics. On the other hand, the drug release in flask-shaking method ceased before its completion due to lack of sink conditions. The flask-shaking method, however, was used in this study, since the 100% drug release time can be deduced by the rate constant of apparent first-order reaction calculated from the data of initial stage of drug release. The polymeric prodrugs having 5-fluorouracil (5-FU) and pyridyl group as a side chain were prepared by mechanochemical polymerization. The rate of drug release increased with an increase in the content of basic group in the copolymer. The plots of the rate constant as a function of the ratio of the basic monomer in copolymer exhibited exponential curves under the present experimental conditions. It was also shown that the rate of drug release is influenced by the nature of the basic group. The hybrid polymeric prodrugs were synthesized by mechanochemical polymerization of the methacryloyl derivatives of 5-FU and pyridoxamine which possesses a pyridyl group. Although pyridoxamine was not released from the hybrid polymeric prodrugs thus obtained, the rate of drug release of 5-FU can be controlled by the amount of the pyridoxamine in polymeric prodrug. These results provided the fundamental and significant information for the syntheses of novel hybrid polymeric prodrugs possessing a wide variety of drug as a side chain.