Development of a bladder instillation of the indoloquinone anticancer agent EO-9 using tert-butyl alcohol as lyophilization vehicle

被引:0
|
作者
Sabien C. van der Schoot
Bastiaan Nuijen
Frits M. Flesch
Ashok Gore
Dorla Mirejovsky
Luigi Lenaz
Jos H. Beijnen
机构
[1] Slotervaart Hospital/The Netherlands Cancer Institute,Department of Pharmacy and Pharmacology
[2] Utrecht University,Faculty of Pharmaceutical Sciences
[3] Spectrum Pharmaceuticals,undefined
[4] Inc,undefined
关键词
Mitomycin analogue; EO-9; formulation development; freeze drying; tert-butyl alcohol;
D O I
10.1208/pt0803061
中图分类号
学科分类号
摘要
The purpose of this research was to develop a stable bladder instillation of EO-9 for the treatment of superficial bladder cancer. First, stability and dissolution studies were performed. Subsequently, the freeze-drying process was optimized by determination of the freeze-drying characteristics of the selected cosolvent/water system and differential scanning calorimetry analysis of the formulation solution. Furthermore, the influence of the freeze-drying process on crystallinity and morphology of the freeze-dried product was determined with x-ray diffraction analysis and scanning electron microscopy, respectively. Subsequently, a reconstitution solution was developed. This study revealed that tert-butyl alcohol (TBA) can be used to both dramatically improve the solubility and stability of EO-9 and to shorten the freeze-drying cycle by increasing the sublimation rate. During freeze drying, 3 TBA crystals were found: TBA hydrate-ice crystals, crystals of TBA hydrate, and a third crystal, probably composed of TBA hydrate crystals containing ≈90% to 95% TBA. Furthermore, it was shown that crystallization of TBA hydrate was inhibited in the presence of both sodium bicarbonate (NaHCO3) and mannitol. Addition of an annealing step resulted in a minor increase in the crystallinity of the freeze-dried product and formation of the δ-polymorph of mannitol. A stable bladder instillation was obtained after reconstitution of the freeze-dried product (containing 8 mg of EO-9, 20 mg of NaHCO3, and 50 mg of mannitol per vial) to 20 mL with a reconstitution solution composed of propylene glycol/water for injection (WfI)/NaHCO3/sodium edetate 60%/40%/2%/0.02% vol/vol/wt/wt, followed by dilution with Wfl to a final volume of 40 mL.
引用
收藏
相关论文
共 4 条
  • [1] Development of a bladder instillation of the indoloquinone anticancer agent EO-9 using tert-butyl alcohol as lyophilization vehicle
    van der Schoot, Sabien C.
    Nuijen, Bastiaan
    Flesch, Frits M.
    Gore, Ashok
    Mirejovsky, Dorla
    Lenaz, Luigi
    Beijnen, Jos H.
    AAPS PHARMSCITECH, 2007, 8 (03):
  • [2] Purity profile of the indoloquinone anticancer agent EO-9 and chemical stability of EO-9 freeze dried with 2-hydroxypropyl-β-cyclodextrin
    Van der Schoot, S. C.
    Vainchtein, L. D.
    Nuijen, B.
    Gore, A.
    Mirejovsky, D.
    Lenaz, L.
    Beijnen, J. H.
    PHARMAZIE, 2008, 63 (11): : 796 - 805
  • [3] Using tert-butyl alcohol as an adductive agent for separation of an m-cresol and 2,6-xylenol mixture
    Lee, LS
    Lin, CW
    Kao, CH
    INDUSTRIAL & ENGINEERING CHEMISTRY RESEARCH, 2000, 39 (06) : 2068 - 2075
  • [4] Design, Synthesis and Biological Evaluation of of Novel anticancer agent tert-butyl 1-phenyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate
    Shi, Biao
    Wang, Yiqian
    Yang, Yao
    Yu, Peng
    Lu, Kui
    ADVANCES IN CHEMICAL ENGINEERING III, PTS 1-4, 2013, 781-784 : 2211 - 2214