Pharm. R&D Institute, Hanmi Pharm. Co., Ltd., Hwasung, Gyeonggi, Republic of Korea.
Int J Pharm. 2011 Jan 17;403(1-2):130-5. doi: 10.1016/j.ijpharm.2010.10.033. Epub 2010 Oct 23.
The efficacy of intravenous chemotherapy for breast cancer has been improving with newer agents. However, the fractional improvements in breast cancer progression-free survival were quite modest and these small gains are obtained at the cost of significant toxicity. To address this problem, paclitaxel solid dispersion (PSD), a Cremophor EL-free formulation prepared by supercritical antisolvent process using hydrophilic polymers as carrier, was developed to avoid Cremophor EL-associated toxicities in Taxol(®). In this study, we investigated the antitumor activity of PSD as a function of dose from 12 to 24mg/kg (dose-effect) and compared antitumor activity of 18mg/kg dose of PSD to that of Taxol(®) (relative efficacy) in female athymic mice bearing mammary tumor xenografts. In dose-effect study, PSD showed excellent activity and good tolerance at all doses tested with a significant increase in tumor growth inhibition, recurrence time, survival percent, and number of tumor free survivors compared to control (P<0.01). In all of the four doses tested in this study, the magnitude of the increase in effectiveness of PSD was quite substantial and statistically significant with similar degrees of weight loss. In relative efficacy study of PSD and Taxol(®), PSD demonstrated a greater degree of tumor growth inhibition with 10 complete tumor regressions (100%) and eight tumor-free survivors (80% cure). Besides, mice treated with PSD regained their initial body weight by day 27 following initial acute weight reductions, whereas mice treated with Taxol(®) required more than 40 days to regain their initial weight. In conclusion, PSD prepared by supercritical process was very effective and safe, without Cremophor EL-associated toxicities of Taxol(®), in human mammary tumor xenografts with possibilities of dose escalation.
静脉化疗治疗乳腺癌的疗效随着新型药物的出现而提高。然而，乳腺癌无进展生存期的改善幅度相当小，这些微小的获益是以显著的毒性为代价的。为了解决这个问题，我们开发了紫杉醇固体分散体（PSD），这是一种通过超临界抗溶剂工艺制备的、不含聚氧乙烯蓖麻油的制剂，使用亲水性聚合物作为载体，以避免 Taxol(®)中聚氧乙烯蓖麻油相关的毒性。在这项研究中，我们研究了 PSD 作为剂量函数的抗肿瘤活性，剂量范围从 12 到 24mg/kg（剂量效应），并将 18mg/kg 剂量的 PSD 的抗肿瘤活性与 Taxol(®)（相对疗效）进行了比较，在携带乳腺癌异种移植肿瘤的雌性无胸腺小鼠中。在剂量效应研究中，PSD 在所有测试剂量下均表现出优异的活性和良好的耐受性，与对照组相比，肿瘤生长抑制、复发时间、存活百分比和无肿瘤存活者数量均显著增加（P<0.01）。在本研究中测试的所有四个剂量中，PSD 的有效性增加幅度相当大，且具有统计学意义，体重减轻程度相似。在 PSD 和 Taxol(®)的相对疗效研究中，PSD 表现出更大程度的肿瘤生长抑制，10 只肿瘤完全消退（100%），8 只肿瘤无存活者（80%治愈）。此外，用 PSD 治疗的小鼠在最初急性体重减轻后第 27 天恢复初始体重，而用 Taxol(®)治疗的小鼠需要超过 40 天才能恢复初始体重。总之，通过超临界工艺制备的 PSD 非常有效且安全，没有 Taxol(®)相关的聚氧乙烯蓖麻油毒性，在人乳腺癌异种移植中具有剂量递增的可能性。
