Skip to main content

Advertisement

SpringerLink
Log in

Novel Lipid and Preservative-free Propofol Formulation: Properties and Pharmacodynamics

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

Propofol is a water-insoluble intravenous anesthetic agent that is actually formulated as a water-in-oil emulsion with known drawbacks such as pain on injection, microorganism growth support and stability. We report on the properties of formulations of propofol in poly (N-vinyl-2-pyrrolidone)-block-poly(d,l-lactide), PVP–PLA, polymeric micelles (Propofol-PM).

Methods

Microbial growth in these formulations was evaluated with Pseudomonas aeruginosa (ATCC 9027), Staphylococcus aureus (ATCC 6538), Escherichia coli (ATCC 25922) and Candida albicans (ATCC 10231). Sleep-recovery studies in female Sprague–Dawley rats, at a dose of 10mg/kg were performed to compare pharmacodynamic profiles of the new Propofol-PM formulations with those of Diprivan®, a commercially available lipid based propofol formulation.

Results

Growth of microorganisms was not supported in the Propofol-PM formulations tested. No significant differences in times to unconsciousness, awakening, recovery of righting reflex and full recovery were observed between Propofol-PM formulations and Diprivan®.

Conclusions

Propofol loaded in PVP–PLA micelles (Propofol-PM) is not significantly different in terms of pharmacodynamic but demonstrates no microorganism growth support and improved stability that opens up the door to pain on injection reduction strategy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. J. B. Glen, and S. C. Hunter. Pharmacology of an emulsion formulation of ICI 35 868. Br. J. Anaesth. 56:617–626 (1984).

    Article  PubMed  CAS  Google Scholar 

  2. P. E. Marik. Propofol: therapeutic indications and side-effects. Curr. Pharm. Des. 10:3639–3649 (2004).

    Article  PubMed  CAS  Google Scholar 

  3. J. R. Sneyd. Recent advances in intravenous anaesthesia. Br. J. Anaesth. 93:725–736 (2004).

    Article  PubMed  CAS  Google Scholar 

  4. D. S. Ward, J. R. Norton, P. H. Guivarc’h, R. S. Litman, and P. L. Bailey. Pharmacodynamics and pharmacokinetics of propofol in a medium-chain triglyceride emulsion. Anesthesiology 97:1401–1408 (2002).

    Article  PubMed  CAS  Google Scholar 

  5. D. Song, M. A. Hamza, P. F. White, S. I. Byerly, S. B. Jones, and A. D. Macaluso. Comparison of a lower-lipid propofol emulsion with the standard emulsion for sedation during monitored anesthesia care. Anesthesiology 100:1072–1075 (2004).

    Article  PubMed  CAS  Google Scholar 

  6. D. Song, D. Hamza, P. F. White, K. Klein, A. Recart, and O. Khodaparast. The pharmacodynamic effects of a lower-lipid emulsion of propofol: a comparison with the standard propofol emulsion. Anesth. Analg. 98:687–691 (2004).

    Article  PubMed  CAS  Google Scholar 

  7. E. Kam, M. S. Abdul-Latif, and A. McCluskey. Comparison of Propofol-lipuro with propofol mixed with lidocaine 10mg on propofol injection pain. Anaesthesia. 59:1167–1169 (2004).

    Article  PubMed  CAS  Google Scholar 

  8. T. E. Morey, J. H. Modell, D. Shekhawat, T. Grand, D. O. Shah, N. Gravenstein, S. P. McGorray, and D. M. Dennis. Preparation and anesthetic properties of propofol microemulsions in rats. Anesthesiology 104:1184–1190 (2006).

    Article  PubMed  CAS  Google Scholar 

  9. H. Chen, Z. Zhang, O. Almarsson, J. F. Marier, D. Berkovitz, and C. R. Gardner. A novel lipid-free nanodispersion formulation of propofol and its characterization. Pharm. Res. 22:356–361 (2005).

    Article  PubMed  CAS  Google Scholar 

  10. T. D. Egan, S. E. Kern, K. B. Johnson, and N. L. Pace. The pharmacokinetics and pharmacodynamics of propofol in a modified cyclodextrin formulation (Captisol) versus propofol in a lipid formulation (Diprivan): an electroencephalographic and hemodynamic study in a porcine model. Anesth. Analg. 97:72–79 (2003).

    Article  PubMed  CAS  Google Scholar 

  11. A. Trapani, V. Laquintana, A. Lopedota, M. Franco, A. Latrofa, G. Talani, E. Sanna, G. Trapani, and G. Liso. Evaluation of new propofol aqueous solutions for intravenous anesthesia. Int. J. Pharm. 278:91–98 (2004).

    Article  PubMed  CAS  Google Scholar 

  12. P. K. Dubey, and A. Kumar. Pain on injection of lipid-free propofol and propofol emulsion containing medium-chain triglyceride: a comparative study. Anesth. Analg. 101:1060–1062 (2005).

    Article  PubMed  CAS  Google Scholar 

  13. M. T. Baker, and M. Naguib. Propofol: the challenges of formulation. Anesthesiology 103:860–876 (2005).

    Article  PubMed  CAS  Google Scholar 

  14. J. Fechner, H. Ihmsen, D. Hatterscheid, C. Jeleazcov, C. Schiessl, J. J. Vornov, H. Schwilden, and J. Schuttler. Comparative pharmacokinetics and pharmacodynamics of the new propofol prodrug GPI 15715 and propofol emulsion. Anesthesiology 101:626–639 (2004).

    Article  PubMed  CAS  Google Scholar 

  15. J. Fechner, H. Ihmsen, D. Hatterscheid, C. Schiessl, J. J. Vornov, E. Burak, H. Schwilden, and J. Schuttler. Pharmacokinetics and clinical pharmacodynamics of the new propofol prodrug GPI 15715 in volunteers. Anesthesiology 99:303–13 (2003).

    Article  PubMed  CAS  Google Scholar 

  16. M. G. Banaszczyk, A. T. Carlo, V. Millan, A. Lindsey, R. Moss, D. J. Carlo, and S. S. Hendler. Propofol phosphate, a water-soluble propofol prodrug: in vivo evaluation. Anesth. Analg. 95:1285–1292 (2002).

    Article  PubMed  CAS  Google Scholar 

  17. A. Benahmed, M. Ranger, and J. C. Leroux. Novel polymeric micelles based on the amphiphilic diblock copolymer poly(N-vinyl-2-pyrrolidone)-block-poly(d,l-lactide). Pharm. Res. 18:323–328 (2001).

    Article  PubMed  CAS  Google Scholar 

  18. D. Le Garrec, S. Gori, L. Luo, D. Lessard, D. C. Smith, M. A. Yessine, M. Ranger, and J. C. Leroux. Poly(N-vinylpyrrolidone)-block-poly(d,l-lactide) as a new polymeric solubilizer for hydrophobic anticancer drugs: in vitro and in vivo evaluation. J. Control. Rel. 99:83–101 (2004).

    Article  CAS  Google Scholar 

  19. L. Luo, M. Ranger, D. G. Lessard, D. Le Garrec, S. Gori, J. C. Leroux, S. Rimmer, and D. Smith. Novel amphiphilic diblock copolymer of low molecular weight poly(N-vinylpyrrolidone)-block-poly(d,l-lactide): synthesis, characterization, and micellization. Macromol. 37:4008–4013 (2004).

    Article  CAS  Google Scholar 

  20. S. W. Provencher. A constrained regularization method for inverting data represented by linear algebraic or integral equations. Comput. Phys. Commun. 27:213–227 (1982).

    Article  Google Scholar 

  21. J. W. Park, E. S. Park, S. C. Chi, H. Y. Kil, and K. H. Lee. The effect of lidocaine on the globule size distribution of propofol emulsions. Anesth. Analg. 97:769–771 (2003).

    Article  PubMed  CAS  Google Scholar 

  22. M. Yamakage, S. Iwasaki, J. I. Satoh, and A. Namiki. Changes in concentrations of free propofol by modification of the solution. Anesth. Analg. 101:385–388 (2005).

    Article  PubMed  CAS  Google Scholar 

  23. A. W. Doenicke, M. F. Roizen, J. Rau, W. Kellerman, and J. Balb. Reducing pain during propofol injection: the role of the solvent. Anesth. Analg. 82:472–474 (1996).

    Article  PubMed  CAS  Google Scholar 

  24. P. Picard, and M. R. Tramer. Prevention of pain on injection with propofol: a quantitative systematic review. Anesth. Analg. 90:936–969 (2000).

    Google Scholar 

  25. C. B. Berry, T. Gillespie, J. Hood, and N. B. Scott. Growth of microorganisms in solutions of intravenous anaesthetic agents. Anaesthesia. 48:30–32 (1993).

    Article  PubMed  CAS  Google Scholar 

  26. S. N. Bennett, M. M. McNeil, L. A. Bland, and M. J. Arduino et al. Postoperative infections traced to contamination of an intravenous anesthetic propofol. N. Engl. J. Med. 333:147–154 (1995).

    Article  PubMed  CAS  Google Scholar 

  27. Information for Healthcare Professions Propofol (marketed as Diprivan and as generic products), United States Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) website: http://www.fda.gov/cder/drug/InfoSheets/HCP/propofolHCP.pdf

  28. T. Fukada, M., and Ozaki. Microbial growth in propofol formulations with disodium edentate and the influence of venous access system dead space. Anesthesia 62:575–580 (2007).

    Article  CAS  Google Scholar 

  29. Package insert. Diprivan®, 2006.

  30. M. Tessler, A. Dascal, S. Gioseffini, M. Miller, and J. Mendelson. Growth curves of Staphylococcus aureus, Candida albicans, and Moraxella osloensis in propofol and other media. Can. J. Anaesth. 39:509–511 (1992).

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Dr. Serge Messier for his expertise in reviewing and performing the microbial study protocol.

Author information

Authors and Affiliations

  1. Labopharm Inc., 480 Blvd. Armand-Frappier, Laval, Québec, Canada, H7V 4B4

    François Ravenelle, Sandra Gori, Dorothée Le Garrec, David Lessard, Laibin Luo, Dana Palusova & Damon Smith

  2. Peninsula Medical School, University of Plymouth, Plymouth, UK

    J. Robert Sneyd

Authors
  1. François Ravenelle
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sandra Gori
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dorothée Le Garrec
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. David Lessard
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Laibin Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dana Palusova
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J. Robert Sneyd
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Damon Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to François Ravenelle.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ravenelle, F., Gori, S., Le Garrec, D. et al. Novel Lipid and Preservative-free Propofol Formulation: Properties and Pharmacodynamics. Pharm Res 25, 313–319 (2008). https://doi.org/10.1007/s11095-007-9471-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-007-9471-5

Key words

Search

Navigation