Miyajima M, Koshika A, Okada J, Ikeda M
Product Development Laboratories, Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo, Japan.
J Control Release. 1999 Sep 20;61(3):295-304. doi: 10.1016/s0168-3659(99)00149-2.
We investigated the effect of drug physico-chemical properties on the release of basic drugs from poly(L-lactic acid) (P(L)LA) cylindrical matrices (rods; 10 mmx1 mm diameter). All the rods were revealed to exhibit two-stage diffusion-controlled release profiles resulting from the transformation of P(L)LA from an amorphous to a semicrystalline state in aqueous medium. On the assumption that interactions between polymer carboxyl residues and basic drugs control the drug release rate, we evaluated the strength of these interactions by the drug partition between the polymer and the aqueous medium. In the first release stage, the drugs diffused through the swollen polymer matrix. The polymer-drug interactions shielded the polymer terminal carboxyl residues, thereby resulting in a less hydrated matrix and consequent diminishment of drug diffusion. In the second release stage, the drugs diffused through the water-filled micropores which had developed as a result of polymer crystallization. The stronger polymer-basic drug interactions reduced the drug diffusion rate by decreasing not only the porosity of the matrix, but also the drug partition to the water-filled micropores. It was also found that the fractional drug release rate in the second stage increased with drug content of the rod at the pH where both the polymer carboxyl residues and the drugs were ionized. Since the polymer-drug interactions must be close to saturation with increasing drug content, we believe this result to be due to an increase in the ratio of the drug partition to the water-filled micropores.
我们研究了药物物理化学性质对碱性药物从聚（L-乳酸）（P（L）LA）圆柱形基质（棒；10mm×1mm直径）中释放的影响。所有棒均显示出两阶段扩散控制释放曲线，这是由于P（L）LA在水性介质中从无定形状态转变为半结晶状态所致。假设聚合物羧基残基与碱性药物之间的相互作用控制药物释放速率，我们通过聚合物与水性介质之间的药物分配来评估这些相互作用的强度。在第一个释放阶段，药物通过溶胀的聚合物基质扩散。聚合物-药物相互作用屏蔽了聚合物末端羧基残基，从而导致水合程度较低的基质，进而减少了药物扩散。在第二个释放阶段，药物通过由于聚合物结晶而形成的充满水的微孔扩散。较强的聚合物-碱性药物相互作用不仅通过降低基质的孔隙率，而且通过降低药物向充满水的微孔中的分配来降低药物扩散速率。还发现，在聚合物羧基残基和药物均电离的pH值下，第二阶段的药物释放分数速率随棒中药物含量的增加而增加。由于随着药物含量的增加，聚合物-药物相互作用必须接近饱和，我们认为这一结果是由于药物向充满水的微孔中的分配比例增加所致。
