School of Pharmaceutical Sciences, Sun Yat-sen University, University Town, Guangzhou, 510006, People's Republic of China.
Department of Pharmacy, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, 518107, People's Republic of China.
AAPS PharmSciTech. 2020 Nov 16;21(8):324. doi: 10.1208/s12249-020-01860-4.
10-Hydroxycamptothecin (HCPT) is a DNA inhibitor of topoisomerase I and exerts antitumor activities against various types of cancer. However, reversible conversion from a pharmacologically active lactone form to an inactive carboxylate form of HCPT and poor water solubility hamper its clinical applications. To overcome these shortcomings, we designed a fine self-microemulsifying drug delivery system (SMEDDS) for HCPT to effectively protect HCPT in its active lactone form as well as improving dissolution rates. A formulation of HCPT-SMEDDS that contained ethyl oleate, D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), and polyethylene glycol 400 (PEG400) was optimized by using the central composite design and response surface methodology. Following 1:100 aqueous dilution of the optimized HCPT-SMEDDS, the droplet size of resulting microemulsions was 25.6 ± 0.7 nm, and the zeta potential was - 15.2 ± 0.4 mV. The optimized HCPT-SMEDDS appeared to stabilize the lactone moiety of HCPT with 73.6% being present in the pharmacologically active lactone forms in simulated intestinal fluid, but only 45.7% for free HCPT. Furthermore, the physically stable formulation showed the active lactone form predominated in HCPT-SMEDDS (> 95%) for 6 months under the accelerated storage condition. Meanwhile, the optimized SMEDDS formulation also significantly improved dissolution rates and membrane permeability of the lactone form of HCPT. Therefore, HCPT-SMEDDS involved designing for the ease of manufacture, and provided a potent oral dosage form for preserving its active lactone form as well as enhancing the dissolution rate.
10-羟基喜树碱（HCPT）是拓扑异构酶 I 的 DNA 抑制剂，对多种类型的癌症具有抗肿瘤活性。然而，HCPT 可从具有药理活性的内酯形式可逆地转化为无活性的羧酸形式，且其水溶性差，这限制了它的临床应用。为了克服这些缺点，我们设计了一种精细的自微乳药物传递系统（SMEDDS）用于 HCPT，以有效地将 HCPT 保护在其活性内酯形式，并提高其溶解速率。通过使用中心复合设计和响应面法，优化了包含油酸乙酯、D-α-生育酚聚乙二醇 1000 琥珀酸酯（TPGS）和聚乙二醇 400（PEG400）的 HCPT-SMEDDS 配方。在将优化的 HCPT-SMEDDS 以 1:100 的比例稀释于水后，所得微乳液的粒径为 25.6±0.7nm，zeta 电位为-15.2±0.4mV。优化的 HCPT-SMEDDS 似乎可以稳定 HCPT 的内酯部分，在模拟肠液中 73.6%以具有药理活性的内酯形式存在，而游离 HCPT 仅有 45.7%。此外，在加速储存条件下，该物理稳定的制剂在 6 个月内仍显示出以活性内酯形式为主（>95%）。同时，优化的 SMEDDS 配方还显著提高了 HCPT 内酯形式的溶解速率和膜透过性。因此，HCPT-SMEDDS 的设计易于制造，并提供了一种有效的口服剂型，可保持其活性内酯形式并提高其溶解速率。
