Nakano K, Ike O, Wada H, Hitomi S, Amano Y, Ogita I, Nakai N, Takada K
Department of Pharmaceutics and Pharmacokinetics, Kyoto Pharmaceutical University, Japan.
J Pharm Pharmacol. 1997 May;49(5):485-90. doi: 10.1111/j.2042-7158.1997.tb06828.x.
A new oral sustained-release solid-dispersion preparation of cisplatin (cis-diamminedichloroplatinum(II): cisplatin) has been developed for administration to small experimental animals such as mice. This preparation was obtained by formulating cisplatin with the water-insoluble polymer ethylcellulose and with stearic acid in different ratios. In-vitro dissolution studies showed that cisplatin release characteristics were zero-order for the formulation cisplatin-ethylcellulose-stearic acid (1:10:5) and levels equilibrated 7 h after the start of the experiment. The availability of cisplatin from this preparation was evaluated both in rats and mice. The cisplatin preparation (20 mg kg-1) was administered orally to rats and the resulting curve of serum cisplatin levels against time was compared with that obtained after intravenous infusion (20 mg kg-1) to rats. By comparing the areas under serum concentration-time curves (AUCs), the bioavailability of cisplatin was estimated to be 31%. The mean residence time (MRT) of cisplatin solid dispersion was 6.13 +/- 0.43 h, whereas the MRT of cisplatin administered by intravenous infusion was 3.89 +/- 0.05 h. Serum cisplatin levels were maintained above 0.3 mg mL-1 (believed from our clinical studies to be the minimum effective concentration) for 24 h. The curve of serum cisplatin level against time suggested that cisplatin was released from the solid dispersion preparation in a sustained-release fashion. Similar levels were also maintained in mice for 24 h. The MRT of the cisplatin preparation was 10-16 h in mice, which is longer than that obtained after oral administration of the physical mixture. The serum free-cisplatin concentration was determined to be 0.10 mg mL-1 in mice serum in which the total cisplatin concentration was 0.30 mg mL-1. The free fraction of cisplatin in mice serum was the same as that in human patient serum. Pathological examination showed that this new sustained-release oral cisplatin preparation did not have any side effects on the gastrointestinal tract. These results suggest usefulness of this new solid-dispersion preparation for oral cisplatin therapy in lung cancer patients.
已研发出一种新型的顺铂口服缓释固体分散体制剂（顺 - 二氯二氨合铂（II）：顺铂），用于给小鼠等小型实验动物给药。该制剂是通过将顺铂与水不溶性聚合物乙基纤维素以及硬脂酸按不同比例配制而成。体外溶出度研究表明，对于顺铂 - 乙基纤维素 - 硬脂酸（1:10:5）制剂，顺铂的释放特性呈零级，且在实验开始7小时后水平达到平衡。在大鼠和小鼠中评估了该制剂中顺铂的生物利用度。将顺铂制剂（20毫克/千克）口服给予大鼠，并将所得血清顺铂水平随时间变化的曲线与静脉输注（20毫克/千克）后大鼠的曲线进行比较。通过比较血清浓度 - 时间曲线下面积（AUCs），估计顺铂的生物利用度为31%。顺铂固体分散体的平均驻留时间（MRT）为6.13±0.43小时，而静脉输注顺铂的MRT为3.89±0.05小时。血清顺铂水平在24小时内维持在0.3毫克/毫升以上（根据我们的临床研究认为这是最低有效浓度）。血清顺铂水平随时间变化的曲线表明顺铂以缓释方式从固体分散体制剂中释放。在小鼠中也维持了24小时的相似水平。顺铂制剂在小鼠中的MRT为10 - 16小时，长于口服物理混合物后的MRT。在总顺铂浓度为0.30毫克/毫升的小鼠血清中，测定血清游离顺铂浓度为0.10毫克/毫升。小鼠血清中顺铂的游离分数与人类患者血清中的相同。病理检查表明，这种新型口服顺铂缓释制剂对胃肠道没有任何副作用。这些结果表明这种新型固体分散体制剂在肺癌患者口服顺铂治疗中具有实用性。
