Joel S P, Clark P I, Slevin M L
Department of Medical Oncology, St. Bartholomew's Hospital, West Smithfield, London, UK.
Cancer Chemother Pharmacol. 1995;37(1-2):117-24. doi: 10.1007/BF00685638.
Etoposide is a widely used cytotoxic drug that requires complex formulation for both the i.v. and oral preparation to ensure drug stability. Data on the stability of the i.v. formulation when diluted in infusion fluids are contradictory, and there is little information on the stability of the oral preparation in gastric or intestinal fluids. The stability of both i.v. and oral etoposide was therefore evaluated in the present investigation. The stability of the i.v. preparation was investigated across a range of concentrations in infusion fluids, being determined by regular sampling for high-performance liquid chromatography (HPLC) analysis and by visual inspection. The stability of the oral preparation was studied in both artificial gastric and intestinal fluids, again with regular sampling for HPLC analysis, and the influence of pH, concentration and the addition of ethanol and bile salts on oral stability was determined. The i.v. preparation showed a marked decrease in stability with increasing drug concentration, but stability was additionally reduced in i.v. bags regularly sampled with a syringe and needle as compared with bags that were inspected visually only (minimal stability in sampled bags, 24 h at 0.5 mg/ml and 5 h at 1.0 mg/ml, as compared with 10 days and 18 h at the respective concentrations in unsampled bags). Stability was also greater at room temperature, 20-23 degrees C, as compared with 8-12 degrees C. Loss of stability was indicated by a decrease in etoposide concentration (measured by HPLC) and the appearance of a fine white precipitate, shown to be pure etoposide. Importantly, the appearance of precipitate was as sensitive as a specific HPLC assay in detecting loss of stability and was in many cases apparent when the etoposide concentration was within 5% of the starting concentration. The oral formulation also showed a marked concentration-dependent decrease in stability in artificial intestinal fluid at pH 7.5 (percentage of etoposide in solution after 2 h at 0.5, 1.0, 1.5 and 2.0 mg/ml, 94 +/- 2%, 80 +/- 5%, 68 +/- 13% and 41 +/- 9%, respectively). There was no concentration effect on stability in gastric fluid at pH 3.0, although stability was much greater at pH 3 and pH 5 as compared with pH 1 or in intestinal fluid at pH 7.5.(ABSTRACT TRUNCATED AT 250 WORDS)
依托泊苷是一种广泛使用的细胞毒性药物，其静脉注射和口服制剂都需要复杂的配方以确保药物稳定性。关于静脉注射制剂在输液中稀释后的稳定性数据相互矛盾，且关于口服制剂在胃液或肠液中的稳定性信息很少。因此，本研究评估了静脉注射和口服依托泊苷的稳定性。通过在一系列输液浓度下对静脉注射制剂进行研究，通过定期取样进行高效液相色谱（HPLC）分析和目视检查来确定其稳定性。在人工胃液和肠液中研究口服制剂的稳定性，同样通过定期取样进行HPLC分析，并确定pH值、浓度以及乙醇和胆盐的添加对口服稳定性的影响。静脉注射制剂的稳定性随药物浓度增加而显著降低，但与仅目视检查的袋子相比，用注射器和针头定期取样的静脉输液袋中的稳定性进一步降低（取样袋中稳定性最低，0.5mg/ml时为24小时，1.0mg/ml时为5小时，而未取样袋中相应浓度下分别为10天和18小时）。与8-12摄氏度相比，在20-23摄氏度的室温下稳定性也更高。依托泊苷浓度降低（通过HPLC测量）和出现细小白色沉淀表明稳定性丧失，该沉淀被证明是纯依托泊苷。重要的是，沉淀的出现与特定的HPLC测定法在检测稳定性丧失方面一样敏感，并且在许多情况下，当依托泊苷浓度在起始浓度的5%以内时沉淀就很明显。口服制剂在pH 7.5的人工肠液中也显示出稳定性随浓度显著降低（0.5、1.0、1.5和2.0mg/ml时2小时后溶液中依托泊苷的百分比分别为94±2%、
