Cancer Chemotherapy and Pharmacology

, Volume 34, Issue 5, pp 416–422 | Cite as

Pharmaceutical development of a parenteral lyophilized formulation of the novel indoloquinone antitumor agent EO9

  • Jantine D. Jonkman-de Vries
  • Herre Talsma
  • Roland E. C. Henrar
  • Jantien J. Kettenes-van den Bosch
  • Auke Bult
  • Jos H. Beijnen
Original Articles EO9, Parenteral Formulation, Lyophilization

Abstract

The aim of this study was to design a stable parenteral dosing form of the investigational cytotoxic drug, encoded EO9. EO9 exhibits poor aqueous solubility and stability characteristics. Freeze-drying was selected as the manufacturing process. Differential scanning calorimetry studies were conducted to determine the freezedrying cycle parameters. A stable lyophilized formulation of EO9 was developed. The prototype, containing 8.0 mg EO9 and 200 mg lactose/vial, was found to be the optimal formulation in terms of solubility, length of the freezedrying cycle, stability, and dosing requirements for phase I clinical trials. Quality control of the freeze-dried formulation showed that the manufacturing process does not change the integrity of EO9. Shelf-life studies demonstrated that the formulation remains stable for at least 1 year when stored at +4°C in a dark environment.

Key words

EO9 Parenteral formulation Lyophilization 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Bailey SM, Friedlos F, Knox RJ, Workman P (1992) Bioreductive activation of indoloquinone EO9: involvement of DT-diaphorase and DNA crosslinking. Ann Oncol 3: 185Google Scholar
  2. 2.
    Bailey SM, Suggett N, Walton MI, Workman P (1992) Structure-activity relationships for DT-diaphorase reduction of hypoxic cell directed agents: indoloquinones and diaziridinyl benzoquinones. Int J Radiat Oncol Biol Phys 22: 649Google Scholar
  3. 3.
    Binger M, Workman P (1990) Gradient high-performance liquid chromatographic assay for the determination of the novel indoloquinone antitumour agent EO9 in biological specimens. J Chromatogr 532: 321Google Scholar
  4. 4.
    Cammack KA, Adams GDJ (1985) Formulation and storage. Anim Cell Biotechnol 3: 251Google Scholar
  5. 5.
    Davignon JP, Slack JA, Beijnen JH, Vezin WR, Schoemaker TJ (1988) EORTC/CRC/NCI guidelines for the formulation of investigational cytotoxic drugs. Eur J Cancer Clin Oncol 24: 1535Google Scholar
  6. 6.
    Hendriks H, Pizao PE, Berger DP, Kooistra KL, Bibby MC, Boven E, Dreef-van der Meulen HC, Henrar REC, Fiebig HH, Double JA, Hornstra HW, Pinedo HM, Workman P, Schwartsmann G (1993) EO9: a novel bioreductive alkylating indoloquinone with preferential solid tumour activity and lack of bone marrow toxicity in preclinical models. Eur J Cancer 6: 897Google Scholar
  7. 7.
    Lange R, Hoeven RTM van der (1990) Quantitative determination of endotoxins in sterile fluids and raw materials. Ziekenhuisfarmacie 6: 33Google Scholar
  8. 8.
    Robertson N, Stratford IJ, Houlbrook S, Carmichael J, Adams GE (1992) The sensitivity of human tumour cells to quinone bioreductive drugs: what role for DT-diaphorase? Biochem Pharmacol 44: 409Google Scholar
  9. 9.
    Schellens JHM, Loos W, Beijnen JH, Stoter G, Verweij J (1993) Sensitive isocratic high-performance liquid chromatographic determination of a novel indoloquinone cytotoxic drug (EO9) in human plasma and urine. J Chromatogr 615: 309Google Scholar
  10. 10.
    Schellens JHM, Loos W, Boer-Dennert M de, Planting AST, Burg MEL van den, Stoter G, Verweij J (1993) Phase I and pharmacologic study of the novel indoloquinone bioreductive alkylating cytotoxic drug EO9. Proc Am Assoc Cancer Res 34: 392Google Scholar
  11. 11.
    Speckamp WN, Oostveen EA (1992) Indoloquinone compounds. Patent 5,079,257. U.K. Patent Office, Worthing, West Sussex, p 43Google Scholar
  12. 12.
    Vries JD de, Winkelhorst J, Underberg WJM, Henrar REC, Beijnen JH (1993) A systematic study on the chemical stability of the novel indoloquinone antitumour agent EO9. Int J Pharm 100: 181Google Scholar
  13. 13.
    Walton MI, Bibby MC, Double JA, Plumb JA, Workman P (1992) DT-diaphorase activity correlates with sensitivity to the indoloquinone EO9 in mouse and human colon carcinomas. Eur J Cancer 28: 1597Google Scholar
  14. 14.
    Williams NA, Polli GP (1984) The lyophilization of pharmaceuticals: a literature review. J Parent Sci Technol 38: 48Google Scholar
  15. 15.
    Winograd B, Lobbezoo MW, Double JA, Fiebig HH, Lelieveld P, Workman P, Pinedo HM (1989) Preclinical antitumour profile of EO9, a novel bioreductive alkylating indoloquinone derivative. Proc Am Assoc Cancer Res 30: 582Google Scholar
  16. 16.
    Workman P, Binger M, Kooistra KL (1992) Pharmacokinetics, distribution, and metabolism of the novel bioreductive alkylating indoloquinone EO9 in rodents. Int J Radiat Oncol Biol Phys 22: 713Google Scholar

Copyright information

© Springer-Verlag 1994

Authors and Affiliations

  • Jantine D. Jonkman-de Vries
    • 1
  • Herre Talsma
    • 2
  • Roland E. C. Henrar
    • 3
  • Jantien J. Kettenes-van den Bosch
    • 4
  • Auke Bult
    • 4
  • Jos H. Beijnen
    • 1
  1. 1.Department of PharmacySlotervaart Hospital/Netherlands Cancer InstituteAmsterdamThe Netherlands
  2. 2.Department of Pharmaceutics, Faculty of PharmacyUtrecht UniversityUtrechtThe Netherlands
  3. 3.EORTC-NDDOFree University HospitalAmsterdamThe Netherlands
  4. 4.Department of Pharmaceutical Analysis, Faculty of PharmacyUtrecht UniversityUtrechtThe Netherlands

Personalised recommendations