Investigational New Drugs

, Volume 19, Issue 2, pp 143–153 | Cite as

Progress in the Development of Alternative Pharmaceutical Formulations of Taxanes

  • Bastiaan Nuijen
  • Marjan Bouma
  • Jan H.M. Schellens
  • Jos H. Beijnen


The currently available taxanes paclitaxel(Taxol®) and docetaxel(Taxotere®) are clinically effectiveagainst advanced breast, ovarian andnon-small cell lung cancer. Due to theirlow aqueous solubility, both taxanes poseddifficulties to the pharmaceuticalscientists with respect to the developmentof an intravenous dosage form. At present,paclitaxel is formulated in a mixture of50:50% (v/v) Cremophor EL and dehydratedethanol. However, this formulation vehicleis associated with a number ofpharmacological, pharmacokinetic andpharmaceutical concerns amongst whichserious hypersensitivity reactions. Thisreview deals with the attempts made intothe development of alternative dosage formsof paclitaxel devoid of the CremophorEL/ethanol excipients and potential futuretaxane formulations.

taxanes paclitaxel docetaxel alternative formulation co-solvents surfactants emulsions micro-encapsulation systems liposomes cyclodextrines prodrugs 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Huizing MT, Sewberath Misser VH, Pieters RC, ten Bokkel Huinink WW, Veenhof CHN, Vermorken JB, Beijnen JH: Taxanes: a new class of antitumor agents. Cancer Inv 13: 381–404, 1995Google Scholar
  2. 2.
    Straubinger RM: Biopharmaceutics of paclitaxel (Taxol): formulation, activity, and pharmacokinetics. In: Suffness M (ed) Taxolr: Science and Applications. CRC press, 1996, pp 237–258Google Scholar
  3. 3.
    Adams JD, Flora KP, Goldspiel BR, Wilson JW, Arbuck SG, Finley R: Taxol: a history of pharmaceutical development and current pharmaceutical concerns. J Natl Cancer Inst 15: 141–147, 1993Google Scholar
  4. 4.
    Meerum Terwogt JM, Nuijen B, Ten Bokkel Huinink WW, Beijnen JH: Alternative formulations of paclitaxel. Canc Treat Rev 23: 87–95, 1997Google Scholar
  5. 5.
    Nannan Panday VR, Huizing MT, ten Bokkel Huinink WW, Vermorken JB, Beijnen JH: Hypersensitivity reactions to the taxanes paclitaxel and docetaxel. Clin Drug Invest 14: 418–427, 1997Google Scholar
  6. 6.
    Lorenz W, Reimann HJ, Schmal A, Dormann P, Schwarz B, Neugebauer E, Doenicke A: Histamine release in dogs by Cremophor ELr and its derivatives: oxethylated oleic acid is the most effective constituent. Agents Actions 7: 63–67, 1977PubMedGoogle Scholar
  7. 7.
    Wilson DB, Beck TM, Gundlach CA: Paclitaxel formulation as a cause of ethanol intoxication. Ann Pharmacother 31: 873–875, 1997PubMedGoogle Scholar
  8. 8.
    Sparreboom A, van Tellingen O, Nooijen WJ, Beijnen JHM: Nonlinear pharmacokinetics of paclitaxel in mice results from the pharmaceutical vehicle Cremophor EL. Canc Res 56: 2112–2115, 1996Google Scholar
  9. 9.
    van Tellingen O, Huizing MT, Panday VR, Schellens JH, Nooijen WJ, Beijnen JH: Cremophor EL causes (pseudo-) non-linear pharmacokinetics of paclitaxel in patients. Br J Cancer 81: 330–335, 1999PubMedGoogle Scholar
  10. 10.
    Liebmann J, Cook J, Lipschultz C: The influence of Cremophor EL on the cell cycle effects of paclitaxel (Taxol) in human tumor cell lines. Cancer Chemother Pharmacol 33: 331–339, 1994PubMedGoogle Scholar
  11. 11.
    Trissel LA: Pharmaceutical properties of paclitaxel and their effects on preparation and administration. Pharmacotherapy 17: 133S–139S, 1997PubMedGoogle Scholar
  12. 12.
    Jonkman-de Vries JD, Flora KP, Bult A, Beijnen JH: Pharmaceutical development of (investigational) anticancer agents for parenteral use – a review. Drug Develop Indust Pharm 22: 475–494, 1996Google Scholar
  13. 13.
    Sweetana S, Akers MJ: Solubility principles and practices for parenteral drug dosage form development. PDA J Pharm Sci Technol 50: 330–342, 1996PubMedGoogle Scholar
  14. 14.
    Product information Taxol (Bristol-Myers Squibb, Princeton, US)Google Scholar
  15. 15.
    Ramaswamy M, Zhang X, Burt HM, Wasan KM: Human plasma distribution of free paclitaxel and paclitaxel associated with diblock copolymers. J Pharm Sci 86: 460–464, 1997PubMedGoogle Scholar
  16. 16.
    Zhang X, Burt HM, Von Hoff D, Dexter D, Mangold G, Degen D, Oktaba AM, Hunter WL: An investigation of the antitumour activity and biodistribution of polymeric micellar paclitaxel. Cancer Chemother Pharmacol 40: 81–86, 1997PubMedGoogle Scholar
  17. 17.
    Zhang X, Burt HM, Mangold G, Dexter D, Von Hoff D, Mayer L, Hunter WL: Anti-tumor efficacy and biodistribution of intravenous polymeric micellar paclitaxel. Anticancer Drugs 8: 696–701, 1997PubMedGoogle Scholar
  18. 18.
    Product information Taxotere (Rhône-Poulenc Rorer)Google Scholar
  19. 19.
    Tarr BD, Sambandan TG, Yalkowsky SH: A new parenteral emulsion for the administration of Taxol. Pharm Res 4: 162–165, 1987PubMedGoogle Scholar
  20. 20.
    Simamora P, Dannenfelser RM, Tabibi SE, Yalkowski SH: Emulsion formulations for intavenous administration of paclitaxel. PDA J Pharm Sci Technol 52: 170–172, 1998PubMedGoogle Scholar
  21. 21.
    Lundberg BB: A submicron lipid emulsion coated with amphipathic polyethylene glycol for parenteral administration of paclitaxel (Taxol). J Pharm Pharmacol 49: 16–21, 1997PubMedGoogle Scholar
  22. 22.
    Kan P, Chen ZB, Lee CJ, Chu IM: Development of nonionic surfactant/phospholipid o/w emulsion as a paclitaxel delivery system. J Controlled Release 58: 271–278, 1999Google Scholar
  23. 23.
    Bartoli MH, Boitard M, Fessi H, Beriel H, Devissaguet JP, Picot F, Puisieux F: In vitro and in vivo antitumoral activity of free, and encapsulated taxol. J Microencapsulation 7: 191–197, 1990PubMedGoogle Scholar
  24. 24.
    Sharma D, Chelvi TP, Chakravorty K, De TK, Maitra A, Ralhan R: Novel Taxol formulation: polyvinylpyrrolidone nanoparticle-encapsulated Taxol for drug delivery in cancer therapy. Oncol Res 8: 281–286, 1996PubMedGoogle Scholar
  25. 25.
    Dordunoo SK, Jackson JK, Arsenault LA: Taxol encapsulation in poly(—-caprolactone) microspheres. Cancer Chemother Pharmacol 36: 279–282, 1995PubMedGoogle Scholar
  26. 26.
    Burt HM, Jackson JK, Bains SK, Liggins RT, Oktaba AM, Arsenault AL, Hunter WL. Controlled delivery of taxol from microspheres composed of a blend of ethylene-vinyl acetate copolymer and poly (d,l-lactic acid). Cancer Lett 88: 73–79, 1995PubMedGoogle Scholar
  27. 27.
    Harper E, Dang W, Lapidus RG, Garver RI: Enhanced efficacy of a novel controlled release paclitaxel formulation (PACLIMER Delivery System) for local-regional therapy of lung cancer tumor nodules in mice. Clin Canc Res 5: 4242–4248, 1999Google Scholar
  28. 28.
    Alkan-Onyuksel H, Ramakrishnan S, Chai HB, Pezzuto JM: A mixed micellar formulation suitable for the parenteral administration of Taxol. Pharm Res 11: 206–212Google Scholar
  29. 29.
    Straubinger RM, Sharma A, Murray M, Mayhew E: Novel Taxol formulations: Taxol containing liposomes. J Natl Cancer Inst Mon 15: 69–78, 1993Google Scholar
  30. 30.
    Sharma A, Straubinger RM: Novel Taxol formulations: preparation and characterization of Taxol-containing liposomes. Pharm Res 11: 889–896, 1994PubMedGoogle Scholar
  31. 31.
    Sharma A, Mayhew E, Bolcsak L, Cavanaugh C, Harmon P, Janoff A, Bernacki RJ: Activity of paclitaxel liposome formulations against human ovarian tumor xenografts. Int J Canc 71: 103–107, 1997Google Scholar
  32. 32.
    Bekers O, Uijtendaal EV, Beijnen JH, Bult A, Underberg WJM: Cyclodextrins in the pharmaceutical field. Drug Dev Ind Pharm 17: 1503–1549, 1991Google Scholar
  33. 33.
    Loftsson T, Brewster ME: Pharmaceutical applications of cyclodextrins. 1. Drug solubilization and stabilization. Pharm Sci 85: 1017–1025, 1996Google Scholar
  34. 34.
    Sharma US, Balasubramanian SV, Straubinger RM: Pharmaceutical and physical properties of paclitaxel (Taxol) complexes with cyclodextrines. J Pharm Sci 84: 1223–1230, 1995PubMedGoogle Scholar
  35. 35.
    Mellado W, Magri NF, Kingston DGI, Garcia-Arenas R, Orr GA, Horwitz SB: Preparation and biological activity of taxol acetates. Biochem Biophys Res Com 124: 329–336, 1984PubMedGoogle Scholar
  36. 36.
    Vyas DM, Wong H, Crosswell AR, Casazza AM, Knipe JO, Mamber SW, Doyle TW: Synthesis and antitumor evaluation of water soluble taxol phosphates. Bioorganic Med Chem Lett 3: 1357–1360, 1993Google Scholar
  37. 37.
    Vyas DM: Paclitaxel (Taxolr) formulation and prodrugs. In: Farina V (ed) The Chemistry and Pharmacology of Taxol and its Derivatives, 103–130, 1995Google Scholar
  38. 38.
    Ueda Y, Mikkilineni AB, Knipe JO, Rose WC, Casazza AM, Vyas DM: Novel water soluble phosphate prodrugs of Taxolr possessing in vivo antitumor activity. Bioorganic Med Chem Lett 3: 1761–1766, 1993Google Scholar
  39. 39.
    Ueda Y, Wong H, Matiskella JD, Mikkelineni AB, Farina V, Fairchild C, Rose WC, Mamber SW, Long BH, Kerns EH, Casazza AM, Vyas DM: Synthesis and antitumor evaluation of 20-oxycarbonylpaclitaxels (paclitaxel-20-carbonates). Bioorganic Med Chem Lett 4: 1861–1864, 1994Google Scholar
  40. 40.
    Mathew AE, Mejillano MR, Nath JP, Himes RH, Stella VJ: Synthesis and evaluation of some water-soluble prodrugs and derivatives of Taxol with antitumor activity. J Med Chem 35: 145–151, 1992PubMedGoogle Scholar
  41. 41.
    Paradis R, Pagé M: New active paclitaxel amino acids derivatives with improved water solubility. Anticancer Res 18: 2711–2716, 1998PubMedGoogle Scholar
  42. 42.
    Nicolaou KC, Riemer C, Kerr MA, Rideout D, Wrasidlo W: Design, synthesis and biological activity of protaxols. Nature 364: 464–466, 1993PubMedGoogle Scholar
  43. 43.
    Greenwald RB, Pendri A, Bolikal D, Gilbert CW: Highly water-soluble taxol derivatives: 20-polyethyleneglycol esters as potential prodrugs. Biorganic Med Chem Lett 4: 2465–2470, 1994Google Scholar
  44. 44.
    Greenwald RB, Gilbert CW, Pendri A, Conover CD, Xia J, Martinez A: Drug delivery systems: water soluble Taxol 20-poly(ethylene glycol) ester prodrugs-design and in vivo effectiveness. J Med Chem 39: 424–431, 1996PubMedGoogle Scholar
  45. 45.
    Li C, Yu D, Inoue T, Yang DJ, Milas L, Hunter NR, Kim EE, Wallace S: Synthesis and evaluation of water-soluble polyethylene glycol-paclitaxel conjugate as a paclitaxel prodrug. Anticancer Drugs 7: 642–648, 1996PubMedGoogle Scholar
  46. 46.
    Pendri A, Conover CD, Greenwald RB: Antitumor activity of paclitaxel-20-glycinate conjugated to poly(ethylene glycol): a water soluble prodrug. Anticancer Drug Des 13: 387–395, 1998PubMedGoogle Scholar
  47. 47.
    Dosio F, Brusa P, Crosasso, P, Arpicco S, Cattel L: Preparation and characterization and properties in vitro and in vivo of a paclitaxel-albumin conjugate. J Control Rel 47: 293–304, 1997Google Scholar
  48. 48.
    Presenti E, Franzetti C, Biasoli G: Synthesis and biological activity of water soluble polymer-bound taxol derivatives. Proc Am Ass Cancer Res 36: 307, 1995Google Scholar
  49. 49.
    Ojima I, Park YH, Sun CM, Fenoglio I, Appendino G, Pera P, Bernacki RJ: Structure-activity relationships of new taxoids derived from 14—-hydroxy-10-deacetylbaccatin III. J Med Chem 37: 1408–1410, 1994PubMedGoogle Scholar
  50. 50.
    Ali SM, Hoemann MZ, Aubé J, Mitscher LA, Georg GI: Novel cytotoxic 30-(tert-butyl) 30-diphenyl analogs of paclitaxel and docetaxel. J Med Chem 38: 3821–3828, 1995PubMedGoogle Scholar
  51. 51.
    Alder JD, Jarvis KP, Marsh KC, Klein LL, Clement JJ: Preclinical in vivo efficacy of two 9-dihydrotaxane analogues against human and murine tumors. Br J Cancer 73: 560–564, 1996PubMedGoogle Scholar
  52. 52.
    Merisko-Liversidge E, Sarpotdar P, Bruno J, Hajj S, Wei L, Peltier N, Rake J, Shaw JM, Pugh S, Polin L, Jones J, Corbett T, Cooper E, Liversidge GG: Formulation and antitumor activity evaluation of nanocrystalline suspensions of poorly soluble drugs. Pharm Res 13: 272–278, 1996PubMedGoogle Scholar
  53. 53.
    Winternitz CI, Jackson JK, Oktaba AM, Burt HM: Development of a polymeric surgical paste formulation for taxol. Pharm Res 13: 368–375, 1996PubMedGoogle Scholar
  54. 54.
    Smith J, Stock E, Orenberg EK, Yu NY, Kanekal S, Brown DM: Intratumoral chemotherapy with sustained-release drug delivery system inhibits growth of human pancreatic cancer xenografts. Anticancer Drugs 6: 717–726, 1995PubMedGoogle Scholar
  55. 55.
    Meerum Terwogt JM, Beijnen JH, ten Bokkel Huinink WW, Rosing H, Schellens JHM: Co-administration of cyclosporin enables oral therapy with paclitaxel. Lancet 352: 285, 1998Google Scholar

Copyright information

© Kluwer Academic Publishers 2001

Authors and Affiliations

  • Bastiaan Nuijen
    • 1
  • Marjan Bouma
    • 1
  • Jan H.M. Schellens
    • 1
  • Jos H. Beijnen
    • 1
  1. 1.Department of Pharmacy and PharmacologySlotervaart Hospital/The Netherlands Cancer InstituteAmsterdamThe Netherlands

Personalised recommendations