Pharmaceutical Research

, Volume 11, Issue 6, pp 889–896 | Cite as

Novel Taxol Formulations: Preparation and Characterization of Taxol-Containing Liposomes

  • Amarnath Sharma
  • Robert M. Straubinger


Taxol is a promising anticancer agent under investigation for therapy of ovarian, breast, colon, and head and neck cancer. One problem associated with the administration of taxol is its low solubility in most pharmaceutically-acceptable solvents; the formulation used clinically contains Cremophor EL® (polyethoxylated castor oil) and ethanol as excipients, which cause serious adverse effects. To eliminate this vehicle and possibly improve the antitumor efficacy of taxol, we have formulated taxol in liposomes of various compositions. Liposome formulations containing taxol and phospholipid in the molar ratio 1:33 were prepared from phosphatidylglycerol (PG) and phosphatidylcholine (PC) (1:9 molar ratio), and were physically and chemically stable for more than 2 months at 4°C, or for 1 month at 20°C. A method of producing taxol-liposomes by lyophilization has been developed, by which large batches can be prepared reproducibly in a ‘pharmaceutically rational’ manner. Taxol-liposomes retained the growth-inhibitory activity of the free drug in vitro against a variety of tumor cell lines. In mice, taxol-liposomes were well-tolerated when given in bolus doses by both iv and ip routes. The Maximum Tolerated Dose (MTD) was >200 mg/kg; it exceeded that of free taxol, which had a MTD of 30 mg/kg by iv or 50 mg/kg by ip administration. Free taxol administered in the Cremophor vehicle was toxic at doses >30 mg/kg, as was the equivalent volume of vehicle without drug. Taxol-liposomes may prove to be useful not only for eliminating the toxic effects attributed to the Cremophor vehicle, but also for providing opportunities to widen the taxol therapeutic index through alterations in route and schedule of administration.

taxol liposomes lyophilization 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    M. C. Wani, H. L. Taylor, M. E. Wall, P. Coggon and A. T. McPhail. The isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia. J. Am. Chem. Soc. 93:2325–2327 (1971).Google Scholar
  2. 2.
    E. K. Rowinsky, L. A. Cazenave and R. C. Donehower. Taxol—a Novel Investigational Antimicrotubule Agent. J. Nat. Canc. Inst. 82:1247–1259 (1990).Google Scholar
  3. 3.
    E. K. Rowinsky, N. Onetto, R. M. Canetta and S. G. Arbuck. Taxol: The first of the taxanes, an important new class of antitumor agents. Seminars Oncol. 6:646–662 (1992).Google Scholar
  4. 4.
    P. B. Schiff, J. Fant and S. B. Horwitz. Promotion of microtubule assembly in vitro by taxol. Nature 277:665–7 (1979).PubMedGoogle Scholar
  5. 5.
    M. DeBrabander, G. Geuens, R. Nuydens, R. Willebrods and J. Demay. Taxol induces the assembly of free microtubules in living cells and blocks the organizing capacity of centrosomes and kinetochores. Proc. Natl. Acad. Sci. 78:5608–5612 (1981).Google Scholar
  6. 6.
    W. P. McGuire, E. K. Rowinsky, N. B. Rosenshein, F. C. Grumbine, D. S. Ettinger, D. K. Armstrong and R. C. Donehower. Taxol: a unique antineoplastic agent with significant activity in advanced ovarian epithelial neoplasms. Ann. Intern. Med. 111:273–279, 1989.Google Scholar
  7. 7.
    F. A. Holmes, R. S. Walters, R. L. Theriault, A. D. Forman, L. K. Newton, M. N. Raber, A. U. Buzdar, D. K. Frye and G. N. Hortobagyi. Phase II trial of taxol, an active drug in the treatment of metastatic breast cancer. J. Natl. Cancer Inst. 83:1797–1805, 1991.Google Scholar
  8. 8.
    W. Lorenz, H. J. Riemann and A. Schmal. Histamine release in dogs by Cremophor EL and its derivatives: oxyethylated oleic acid is the most effective constituent. Agents Actions 7:63–67 (1977).Google Scholar
  9. 9.
    R. B. Weiss, R. C. Donehower, P. H. Wiernik, T. Ohnuma, R. J. Gralla, D. L. Trump, J. R. Baker, D. A. VanEcho, D. D. VonHoff and B. Leyland-Jones. Hypersensitivity reactions from taxol. J. Clin. Oncol. 8:1263–1268 (1990).Google Scholar
  10. 10.
    W. N. Waugh, L. A. Trissel and V. J. Stella. Stability, compatibility, and plasticizer extraction of taxol (NSC-125973) injection diluted in infusion solutions and stored in various containers. Amer. J. Hosp. Practice 48:1520–1524 (1991).Google Scholar
  11. 11.
    E. K. Rowinsky, W. P. McGuire, T. Guarnieri, J. S. Fisherman, M. C. Christian and R. C. Donehower. Cardiac Disturbances during the administration of taxol. J. Clin. Oncol. 9:1704–1712 (1991).Google Scholar
  12. 12.
    C. D. Runowicz, P. H. Wiernik, A. I. Einzig, G. L. Goldberg and S. B. Horwitz. Taxol in ovarian cancer. Cancer 71:1591–1596 (1993).Google Scholar
  13. 13.
    E. Mayhew and D. Papahadjopoulos. Therapeutic applications of liposomes. In M. J. Ostro (ed.), Liposomes, New York, Marcel Dekker, Inc. 1983, pp. 289–341.Google Scholar
  14. 14.
    M. C. Popescu, C. E. Swenson and R. S. Ginsberg. Liposome-mediated treatment of viral, bacterial, and protozoal infections. In M. J. Ostro (ed.), Liposomes: From Biophysics to Therapeutics. New York, Marcel Dekker, Inc. 1987, pp. 219–251.Google Scholar
  15. 15.
    R. M. Fielding. Liposomal drug delivery: Advantages and limitations from a clinical pharmacokinetic and therapeutic perspective. Clin. Pharmacokinet. 21:155–164 (1991).Google Scholar
  16. 16.
    A. Coune, J. P. Sculies, J. Frahling, P. Stryckmans, C. Brassinne, G. Ghanem, C. Laduron, G. Atassi, J. M. Ruysschaert and J. Hildebrand. I.V. administration of a water insoluble antitumor compound in liposomes. Preliminary report on infusion of liage volumes of liposomes to man. Cancer Treat. Report 67:1031–1033 (1983).Google Scholar
  17. 17.
    J. P. Sculier, A. Coune, C. B. Rassinne, C. Laduran, G. Atassi, J. M. Ruysschaert and J. Fruhling. Intravenous infusion of high doses of liposomes containing NSC251635, a water-insoluble cytostatic agent. A pilot study with pharmacokinetics data. J. Clin. Oncol. 4:789–797 (1986).Google Scholar
  18. 18.
    B. Chapuis, C. Helg, M. Jeannet, G. Zulian, P. Huber and P. Gumovski. Anaphylactic reactions to intravenous cyclosporin. New Engl. J. Med. 312:1259 (1985).Google Scholar
  19. 19.
    S. A. Gruber, S. Venkataram, D. M. Canafax, R. J. Cipolle, L. Bowers, D. Elsberry, M. McGuiggan, P. E. Hynes, J. A. Ritz, F. H. Gould, A. Matas, W. J. M. Hrusheski and Y. E. Rahman. Liposomal formulation eliminates acute toxicity and pump incompatibility of parenteral Cyclosporine. Pharm. Res. 6:601–607 (1989).Google Scholar
  20. 20.
    R. Perez-Soler, G. Lopez-Berestein, J. Lautersztain, S. AlBaker, K. Francis, D. Macias-Kiger, M. N. Raber and A. R. Khokhar. Phase I clinical and pharmacological study of liposome-entrapped cis-Bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum(II). Cancer Res. 50:4254–4259 (1990).Google Scholar
  21. 21.
    A. Sharma, W. D. Conway and R. M. Straubinger. Reversedphase high-performance liquid chromatographic determination of taxol in mouse plasma. J. Chromatography (in press).Google Scholar
  22. 22.
    G. R. Bartlett. Phosphorus assay in column chromatography. J. Biol. Chem. 234:466–468 (1959).Google Scholar
  23. 23.
    F. Szoka and D. Papahadjopoulos. Comparative properties and methods of preparation of lipid vesicles (liposomes). Ann. Rev. Biophys. Bioeng. 9:467–508 (1980).Google Scholar
  24. 24.
    R. Fraley, R. M. Straubinger, G. Rule, L. Springer, and D. Papahadjopoulos. Liposome-mediated delivery of DNA to cells: enhanced efficiency of delivery by changes in lipid composition and incubation conditions. Biochemistry, 20:6978–6987 (1981).Google Scholar
  25. 25.
    T. D. Heath, N. G. Lopez and D. Papahadjopoulos. Effects of liposome size and charge on liposome-mediated delivery of methotrexate-γ-aspartate to cells in vitro. Biochim. Biophys. Acta, 820:74–86 (1985).Google Scholar
  26. 26.
    A. Sharma, N. L. Straubinger and R. M. Straubinger. Modulation of Human Ovarian Tumor Cell Sensitivity to N-(Phosphonacetyl)-L-Aspartate (PALA) by Liposome Drug Carriers. Pharm. Res., 10:1434–1441 (1993).Google Scholar
  27. 27.
    T. H. Corbett, D. P. Griswold, B. J. Roberts, J. Peckham and F. M. Schabel. A mouse colon-tumor model for experimental therapy. Cancer Chemother. Reports 5:169–186 (1975).Google Scholar
  28. 28.
    K. Crickard, M. J. Niedbala, U. Crickard, M. Yoonessi, A. A. Sandberg, K. Okuyama, R. J. Bernacki and S. K. Satchidanand. Characterization of human ovarian and endometrial carcinoma cell lines established on extracellular matrix. Gyne. Oncol. 32:163–173 (1989).Google Scholar
  29. 29.
    F. C. Szoka, D. Milholland and M. Barza. Effect of lipid composition and liposome size on toxicity and in vitro fungicidal activity of liposome-intercalated amphotericin B. Antimicrob. Agents Chemother. 31:421–429, (1987).Google Scholar
  30. 30.
    T. D. Heath and C. S. Brown. Liposome dependent delivery of N-(phosphonacetyl)-L-aspartic acid to cells in vitro. J. Liposome Res. 1:303–317, (1989–90).Google Scholar
  31. 31.
    R. Straubinger, A. Sharma, M. Murray and E. Mayhew. Novel taxol formulations: taxol-containing liposomes. J. Natl. Cancer Inst. monographs, 15:69–78 (1993).Google Scholar
  32. 32.
    W. C. Rose, Taxol: a review of its preclinical in vivo antitumor activity. Anti-Cancer Drugs 3:311–321 (1992).Google Scholar
  33. 33.
    H. M. Deutsch, J. A. Glinski, M. Hernandez, R. D. Haugwitz, V. L. Narayanan, M. Suffness and L. H. Zalkow. Synthesis of congeners and prodrugs. 3. water-soluble prodrugs of taxol with potent antitumor activity. J. Med. Chem. 32:788–792 (1989).Google Scholar
  34. 34.
    C. S. Swindell, N. E. Krauss, S. B. Horwitz and I. Ringel. Biologically active taxol analogues with deleted A-ring side chain substituents and variable C-2′ configurations. J. Med. Chem. 34:1176–1184 (1991).Google Scholar
  35. 35.
    M-C. Bissery, D. Guenard, F. Gueritte-Voegelein and F. Lavelle. Experimental antitumor activity of taxotere (RP 56976, NSC 628503), a taxol analogue. Cancer Res. 51:4845–4852 (1991).Google Scholar
  36. 36.
    B. D. Tarr, T. G. Sambandan and S. H. Yalkowsky. A new parenteral emulsion for the administration of taxol. Pharm. Res. 4:162–165 (1987).Google Scholar
  37. 37.
    A. Sharma, E. Mayhew and R. M. Straubinger. Antitumor effect of taxol-containing liposomes in a taxol-resistant murine tumor model. Cancer Res. 53:5877–5881 (1993).Google Scholar

Copyright information

© Plenum Publishing Corporation 1994

Authors and Affiliations

  • Amarnath Sharma
    • 1
  • Robert M. Straubinger
    • 1
  1. 1.The Department of PharmaceuticsUniversity at Buffalo, State University of New YorkAmherst

Personalised recommendations