Effect of Temperature on Drug Release from Copoly (_L-Lactic Acid/δ-Valerolactone) Microspheres

Abstract

Copoly (_L-lactic acid/δ-valerolactone) microspheres (PLV-MS) containing p-hydroxybenzoic acid ester (ethyl (PE), n-propyl (PP), n-butyl (PB)) or 3',5'-dibutyryl-2'-deoxy-5-fluorouridine (C4-FUdR) were prepared. The effect of temperature on the drug release rate constant (KH) and the release mechanism from PLV-MS were investigated in vitro. All KH values observed for PLV-MS increased with a rise in temperature. In the relationship between log KH and the reciprocal of absolute temperature, relatively hydrophilic PE and PP gave the liner profiles throughout the temperature range examined; lipophilic PB and C4-FUdR exhibited a break point at a temperature near glass transition temperature (Tg) of copolymer in the profiles. The relationship between the initial content of the drugs in the PLV-MS and KH suggested that PB was contained mainly in the suspended state in PLV-MS and that the release of PB from PLV-MS occurs by the dissolution and diffusion of PB in the copolymer phase, which formed PLV-MS. On the other hand, KH observed in PLV-MS containing PE or PP and the diffusion coefficient of PE or PP in the PLV-MS were independent on the initial content of drugs. Therefore we estimated that PE or PP was contained in the completely dissolved state in PLV-MS. These results suggest that temperature dependency of the release rate from PLV-MS is governed by the states of contained drug in PLV-MS.