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Enhanced Stability of the Pharmacologically Active Lactone Form of 10-Hydroxycamptothecin by Self-Microemulsifying Drug Delivery Systems

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Abstract

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.

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Funding

The authors received financial support from the Science and Technology Foundation of Guangzhou (Project No. 201904010425) and the Research Project of Traditional Chinese Medicine of the Health Bureau of Shenzhen Guangming District (Project No. GM2019020026).

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Author notes

  1. Ruiming Li and Yong Wang contributed equally to this work.

Authors and Affiliations

  1. School of Pharmaceutical Sciences, Sun Yat-sen University, University Town, Guangzhou, 510006, People’s Republic of China

    Ruiming Li, Yong Wang, Qiang Yang, Baolong Lai, Xie Zhou & Min Feng

  2. Department of Pharmacy, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, 518107, People’s Republic of China

    Ruiming Li & Baolong Lai

Authors
  1. Ruiming Li
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  2. Yong Wang
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  5. Xie Zhou
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  6. Min Feng
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Correspondence to Xie Zhou or Min Feng.

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Li, R., Wang, Y., Yang, Q. et al. Enhanced Stability of the Pharmacologically Active Lactone Form of 10-Hydroxycamptothecin by Self-Microemulsifying Drug Delivery Systems. AAPS PharmSciTech 21, 324 (2020). https://doi.org/10.1208/s12249-020-01860-4

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  • DOI: https://doi.org/10.1208/s12249-020-01860-4

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