Miyajima M, Koshika A, Okada J, Kusai A, Ikeda M
Product Development Laboratories, Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
J Control Release. 1998 Dec 4;56(1-3):85-94. doi: 10.1016/s0168-3659(98)00076-5.
Effects of drug content and medium pH on the release of papaverine (PAP) from biodegradable poly(l-lactic acid) [P(L)LA] matrix were investigated to reveal the predominant factors affecting the two-stage diffusion-controlled release mechanism. A drug-dissolved cylindrical matrix (rod; 10 mmx1 mm diameter) was prepared by heat compression method. In the case of a PAP content below 10%, pH was found to have a strong effect on the release rate, and drug content was found to have no effect on the release profile. The release profile consisted of two sequential diffusion stages due to P(L)LA transformation from amorphous to the semicrystalline state prior to release. In the first release stage PAP diffused through the swollen matrix. The release accelerated with increasing medium pH due to an increase in water content in the acidic P(L)LA rod. In the second release stage PAP diffused through the water-filled micropores developed as a result of the polymer crystallization. On the assumption that the drug partition between the polymer and the medium in the micropores affects the diffusion and the partition is controlled by pH, we derived a modified diffusion kinetic equation. The observation that the release decelerated with increasing medium pH can be explained by the derived equation as resulting from the increase in the drug partition to the polymer. In the case where the rods contained more than 15% of PAP, the drug precipitated out as crystals during release. Accordingly, these rods showed a slower release.
研究了药物含量和介质pH值对生物可降解聚（L-乳酸）[P（L）LA]基质中罂粟碱（PAP）释放的影响，以揭示影响两阶段扩散控制释放机制的主要因素。通过热压法制备了药物溶解的圆柱形基质（棒；直径10mm×1mm）。当PAP含量低于10%时，发现pH值对释放速率有强烈影响，而药物含量对释放曲线没有影响。由于在释放前P（L）LA从无定形转变为半结晶状态，释放曲线由两个连续的扩散阶段组成。在第一个释放阶段，PAP通过膨胀的基质扩散。由于酸性P（L）LA棒中含水量增加，释放速率随介质pH值的增加而加快。在第二个释放阶段，PAP通过聚合物结晶形成的充满水的微孔扩散。假设微孔中聚合物与介质之间的药物分配影响扩散，且分配受pH值控制，我们推导了一个修正的扩散动力学方程。释放速率随介质pH值增加而减慢的观察结果可以用推导方程解释为药物向聚合物分配增加的结果。当棒中PAP含量超过15%时，药物在释放过程中以晶体形式析出。因此，这些棒显示出较慢的释放速率。
