Skip to main content
SpringerLink
Log in

Formulation and evaluation of an alternative triglyceride-free propofol microemulsion

  • Research Articles
  • Drug Actions
  • Published:
Archives of Pharmacal Research Aims and scope Submit manuscript

Abstract

A new triglyceride-free propofol microemulsion for intravenous injection was formulated using nonionic surfactants, poloxamers and polyethylene glycol 660 hydroxystearate. The aim of this investigation was to evaluate the formulation for storage stability, antimicrobial activity, toxicity and preclinical efficacy. The results were compared to the characteristics obtained for the most commonly used formulation of propofol (Diprivan®). The mean particle diameter of the microemulsion was less than 100 nm so that it could be readily sterilized using a 0.22 μm membrane at room temperature. The microemulsion formulation demonstrated enhanced stability compared to the marketed macroemulsion formulation. In a stress storage condition, it was physicochemically stable for at least 40 months. This new formulation showed higher antimicrobial activity, lower risk of hyperlipidemia and better tolerability than Diprivan®. In preclinical studies, the efficacy and pharmacokinetic profile of the microemulsion were similar to those of Diprivan®. Nevertheless, the administration of the microemulsion caused considerably low histamine release compared to the macroemulsion. Based on these results, the newly developed microemulsion of propofol appeared to have several advantages and, thus, could be an alternative to the fat macroemulsions of propofol.

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

Similar content being viewed by others

References

  • Adam, H. K., Glen, J. B., and Hoyle, P. A., Pharmacokinetics in laboratory animals of ICI 35 868, a new I.V. anesthetic agent. Br. J. Anaesth., 52, 743–746 (1980).

    Article  CAS  PubMed  Google Scholar 

  • Alexandridis, P. and Holzwarth, J. F., Differential scanning calorimetry investigation of the effect of salts on aqueous solution properties of an amphiphilic block copolymer (Poloxamer). Langmuir, 13, 6074–6082 (1997).

    Article  CAS  Google Scholar 

  • Altomare, C., Trapani, G., Latrofa, A., Serra, M., Sanna, E., Biggio, G., and Liso, G., Highly water-soluble derivatives of the anesthetic agent propofol: In vitro and in vivo evaluation of cyclic amino acid ester. Eur. J. Pharm. Sci., 20, 17–26 (2003).

    Article  CAS  PubMed  Google Scholar 

  • Aydin, O. N., Aydin, N., Gultekin, B., Ozgun, S., and Gurel, A., Bacterial contamination of propofol: the effects of temperature and lidocaine. Eur. J. Anaesth., 19, 455–458 (2002).

    CAS  Google Scholar 

  • Babu, M. K. and Godiwala, T. N., Toward the development of an injectable dosage form of propofol: preparation and evaluation of propofol-sulfobutyl ether 7-b-cyclodextrin complex. Pharm. Dev. Technol., 9, 265–275 (2004).

    Article  CAS  PubMed  Google Scholar 

  • Baker, M. T., Gregerson, M. S., Martin, S. M., and Buettner, G. R., Free radical and drug oxidation products in an intensive care unit sedative: Propofol with sulfite. Crit. Care Med., 31, 787–792 (2003).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Banaszczy, M. G., Carlo, A. T., Millan, V., Lindsey, V. A., Moss, R., Carlo, D. J., and Hendler, S. S., Propofol phosphate, a water-soluble propofol prodrug: In Vivo Evaluation. Anesth. Analg., 95, 1285–1292 (2002).

    Article  Google Scholar 

  • Barker, A. N., Laboratory handbook, LabPlus, Auckland District Health Board, Auckland, New Zealand, (2008).

    Google Scholar 

  • Bennett, S. N., McNeil, M. M., Bland, L. A., Arduino, M. J., Villarino, M. E., and Perrotta, D. M., Postoperative infections traced to contamination of an intravenous anesthetic propofol. New Engl. J. Med., 333, 147–154 (1995).

    Article  CAS  PubMed  Google Scholar 

  • Boodhwani, M., Feng, J., Mieno, S., Ramlawi, B., Sodha, N., Clements, R., and Sellke, F. W., Effect of purified poloxamer 407 gel on vascular occlusion and the coronary endothelium. Eur. J. Cardiothorac. Surg., 29, 736–741 (2006).

    Article  PubMed  Google Scholar 

  • Cho, J., Cho, J. C., and Oh, E., Preparation and characterization of a propofol-loaded polymeric micellar system: nanoparticular stability. J. Kor. Pharm. Sci., 38, 393–398 (2008).

    CAS  Google Scholar 

  • Collins-Gold, L., Feichtinger, N., and Wärnheim, T., Are lipid emulsions the drug delivery solution? Mod. Drug Discov., 3, 44–48 (2000).

    CAS  Google Scholar 

  • Cooke, A., Anderson, A., Buchanan, K., Byford, A., Gemmell, D., Hamilton, N., McPhail, P., Miller, S., Sundaram, H., and Vjin, P., Water-soluble propofol analogues with intravenous anesthetic activity. Bioorg. Med. Chem. Lett., 11, 927–930 (2001).

    Article  CAS  PubMed  Google Scholar 

  • Date, A. A. and Nagarsenker, M. S., Design and evaluation of microemulsions for improved parenteral delivery of propofol. AAPS PharmSciTech, 9, 138–145 (2008a).

    Article  CAS  PubMed  Google Scholar 

  • Date, A. A. and Nagarsenker, M. S., Parenteral microemulsions: an overview. Int. J. Pharm., 335, 19–30 (2008b).

    Article  Google Scholar 

  • Domb, A. J., Kost, J., and Wiseman, D. M., Handbook of biodegradable polymers — Chapter 12. The poloxamers; their chemistry and medical applications, Harwood academic publishers, Netherlands, (1997).

    Google Scholar 

  • Donicke, A., Lorenz, W., Stanworth, D., Duka, T., and Glen, J. B., Effect of propofol (’Diprivan’) on histamine release, immunoglobin levels and activation of complement in healthy volunteers. Postgrad. Med. J., 61, 15–20 (1985).

    Article  Google Scholar 

  • Driscoll, D. F., Bhargava, H. N., Li, L., Zaim, R. H., Babayan, V. K., and Bistrian, B. R., Physicochemical stability of total nutrient admixtures. Am. J. Health Syst. Pharm., 52, 623–634 (1995).

    CAS  PubMed  Google Scholar 

  • Dumortier, G., Grossiord, J. L., Agnely, F., and Chaumeil, J. C., A review of poloxamer 407 pharmaceutical and pharmacological characteristics. Pharm. Res., 23, 2709–2728 (2006).

    Article  CAS  PubMed  Google Scholar 

  • Dutta, S., Matsumoto, Y., Muramatsu, A., Matsumoto, M., Fukuoka, M., and Ebling, W. F., Steady-state propofol brain: Plasma and brain: blood partion coefficient and the effectsite equilibration paradox. Br. J. Anaesth., 81, 422–424 (1988).

    Google Scholar 

  • Egan, T. D., Kern, S. E., Johnson, K. B., and Pace, N. L., The pharmacokinetic and pharamacodynamic of propofol in a modified cyclodextrin formulation (Captisol®) versue propofol in a lipid formulation (Diprivan®): An elelctroencephalographic and hemodynamic study in a porcine model. Anesth. Analg., 97, 72–79 (2003).

    Article  CAS  PubMed  Google Scholar 

  • Garrett, E. R. and Carper, R. F., Prediction of stability in pharmaceutical preparations I. Color stability in a liquid multisulfa preparation. J. Am. Pharm. Assoc. Am. Pharm. Assoc (Baltim)., 44, 515–518 (1955).

    CAS  Google Scholar 

  • Glen, J. B., Animal studies of the anesthetic activity of ICI 35 868. Br. J. Anaesth., 52, 731–742 (1980).

    Article  CAS  PubMed  Google Scholar 

  • Han, J., Davis, S. S., and Washington, C., Physical properties and stability of two emulsion formulations of propofol. Int. J. Pharm., 215, 207–220 (2001).

    Article  CAS  PubMed  Google Scholar 

  • Han, J. and Washington, C., Partition of antimicrobial additives in an intravenous emulsion and their effect on emulsion physical stability. Int. J. Pharm., 288, 263–271 (2005).

    Article  CAS  PubMed  Google Scholar 

  • Harrey, B. R. and Ganzberg, S., Growth of microorganisms in propofol and methohexital mixtures. J. Oral Maxillofac. Surg., 61, 132–134 (2003).

    Article  Google Scholar 

  • Hart, B., “Diprivan”: A change of formulation. Eur. J. Anaesthesiol., 17, 71–73 (2000).

    CAS  PubMed  Google Scholar 

  • Herman, C. J. and Groves, M. J., The influence of free fatty acid formation on the pH of phospholipid-stabilized triglyceride emulsions. Pharm. Res., 10, 774–776 (1993).

    Article  CAS  PubMed  Google Scholar 

  • Hunter, R. L., Papadea, C., Gallaqher, C. J., Finlayson, D. C., and Check, I. J., Increased whole blood viscosity during coronary artery bypass surgery: Studies to evaluate the effects of soluble fibrin and poloxamer 188. Thromb. Haemostasis, 63, 6–12 (1990).

    CAS  Google Scholar 

  • Jiwaid, Q., Presti, M. E., Neuschwander-Tetri, B. A., and Burton, F. R., Acute pancreatitis after single-dose exposure to propofol. Dig. Dis. Sci., 47, 614–618 (2002).

    Article  Google Scholar 

  • Jones, C. B. and Platt, J. H., Pharmaceutical compositions of propofol and edetate. U.S. Patent, 005731356A, 24 Mar (1998).

  • Jones, C. B., Fundamentals of emulsions. Am. J. Anesth., 27, 12–15 (2000).

    Google Scholar 

  • Kay, B. and Stephenson, D. K., ICI 35868 (Diprivan): A new intravenous anaesthetic. A comparison with althesin. Anaesthesia, 35, 1182–1187 (1980).

    Article  CAS  PubMed  Google Scholar 

  • Kim, H. M. and Kim, J. H., Anti-allergic agent containing the extract of microplant of Siberian ginseng as an effective ingredient. Kor. Patent, 0041937, 27 Feb (2002).

    Google Scholar 

  • Kim, K.-M., Choi, B.-M., Park, S.-W., Lee, S.-H., Christensen, L. V., Zhou, J., Yoo, B.-H., Bae, K.-S., Kern, S. E., Kang, S.-H., and Noh, G.-J., Pharmacokinetics and pharmacodynamics of propofol microemulsion and lipid emulsion after intravenous bolus and variable rate infusion. Anesthesiology, 106, 924–934 (2007).

    Article  CAS  PubMed  Google Scholar 

  • Knibbe, C. A. J., Naber, H., Aarts, L. P. H., Kuks, P. F., and Danhof, M., Long-term sedation with propofol 60 mg mL−1 vs. 10 mg mL−1 in critically ill, mechanically ventilated patients. Acta Anaesthesiol. Scand., 48, 302–307 (2004).

    Article  CAS  PubMed  Google Scholar 

  • Koster, V. S., Kuks, P. F. M., Lange, R., and Talsma, H., Particle size in parenteral fat emulsions, what are the true limitations? Int. J. Pharm., 134, 235–238 (1996).

    Article  CAS  Google Scholar 

  • Langley, M. S. and Heel, R. C., Propofol: A review of its pharmacodynamic and pharmacokinetic properties and use as an intravenous anaesthetic. Drugs, 33, 334–372 (1988).

    Article  Google Scholar 

  • Lee, H., Jin, J., and Cho, H., Anesthetic composition for intravenous injection comprising propofol. WO Patent, 2000 078301, 28 Dec (2000).

    Google Scholar 

  • List, G. R., Neff, W. E., Holliday, R. L., and Holser, R., Hydrogenation of soybean oil triglycerides: Effect of pressure on selectivity. J. Am. Oil Chem. Soc., 77, 311–314 (2000).

    Article  CAS  Google Scholar 

  • Mirenda, J., Prolonged propofol sedation in the critical care unit. Crit. Care Med., 23, 1304–1305 (1995).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Morey, T. E., Modell, J. H., Shekhawat, D., Klatt, B., Thomas, G. P., Kero, F. A., Booth, M. W., and Dennis, D. M., Anesthetic properties of propofol microemulsions in dogs. Anesth. Analg., 103, 882–887 (2006b).

    Article  CAS  PubMed  Google Scholar 

  • Palmer, W. K., Emeson, E. E., and Johnston, T. P., Poloxamer 407-induced atherogenesis in the C57BL/6 mouse. Atherosclerosis, 136, 115–123 (1998).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Rabinovich-Guilatt, L., Dubernet, C., Gaudin, K., Lambert, G., Couvreur, P., and Chaminade, P., Phospholipid hydrolysis in a pharmaceutical emulsion assessed by physicochemical parameters and anew analytical method. Eur. J. Pharm. Biopharm., 61, 69–76 (2005).

    Article  CAS  PubMed  Google Scholar 

  • Rowe, R. C., Sheskey, P. J., and Owen, S. C., Handbook of Pharmaceutical Excipients, 5th Ed., Pharmaceutical Press, London, (2006).

    Google Scholar 

  • Ryoo, H.-K., Park, C.-W., Chi, S.-C., and Park, E.-S., Development of propofol-loaded microemulsion systems for parenteral delivery. Arch. Pharm. Res., 28, 1400–1404 (2005).

    Article  CAS  PubMed  Google Scholar 

  • Sabry, S. M., Abdel-Hady, M., Elsayed, M., Fahmy, O. T., and Maher, M., Study of stability of methoterxate in acidic solution spectrofluorimetric determination of methotrexate in pharmaceutical preparations through acid-catalyzed degradation reaction. J. Pharm. Biomed. Anal., 32, 409–423 (2003).

    Article  CAS  PubMed  Google Scholar 

  • Sakragi, T., Yanagisawa, K., Shirai, Y., and Dan, K., Growth of Escherichia coli in propofol, lidocaine, and mixture of propofol and lidocaine. Acta Anaesthesiol. Scand., 43, 476–479 (2002).

    Article  Google Scholar 

  • Schaer, G. L., Spaccavento, L. J., Browne, K. F., Krueger, K. A., Krichbaum, D., Phelan, J. M., Fletcher, W. O., Grines, C. L., Edwards, S., Jolly, M., and Gibbons, R. J., Beneficial effects of rheothrx injection in patients receiving thrombolytic therapy for acute myocardial infarction: Results of a randomized, double-blind, placebo-controlled trial. Circulation, 94, 298–307 (1996).

    CAS  PubMed  Google Scholar 

  • Shafer, A., Doze, V. A., Shafter, S. L., and White, P. F., Pharmacokinetics and pharmacodynamics of propofol Infusions during general anesthesia. Anesthesiology, 69, 348–356 (1988).

    Article  CAS  PubMed  Google Scholar 

  • Smint, I., White, P. F., Nathanson, M., and Gouldson, R., Propofol. An update on its clinical use. Anesthesiology, 81, 1005–1043 (1994).

    Article  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Steegers, P. A. and Foster, P. A., The use of propofol in a group of older patients undergoing oesophagoscopy. S. Afr. Med. J., 73, 279–281 (1988).

    CAS  PubMed  Google Scholar 

  • Sznitowska, M., Janicki, S., Dabrowska, E. A., and Gajewska, M., Physicochemical screening of antimicrobial agents as potential preservatives for submicron emulsions, Er. J. Pharm. Sci., 15, 489–495 (2002).

    Article  CAS  Google Scholar 

  • Tanaka, K., Amano, T., Muramtsu, N., Tatsuki, M., Asakura, T., Ito, I., Ishikawa, E., and Sato, K., Histamine release inhibitor. Eur. Patent, 1550448A1, 07 June (2005).

  • Thompson, K. A. and Goodale, D. B., The recent development of propofol (DIPRIVAN®). Intensive Care Med., 26, S400–S404 (2000).

    Article  PubMed  Google Scholar 

  • Trappni, G., Latrofa, A., Fanco, M., Lopedota, A., Sanna, E., and Liso, G., Propofol in anesthesia. Mechanism of action, structure-activity relationships, and drug delivery. Curr. Med. Chem., 7, 249–271 (2000).

    Google Scholar 

  • Veyries, M. L., Gouarraze, G., Geiger, S., Agnely, F., Massias, L., Kunzli, B., Faurisson, F., and Rouveix, B., Controlled release of vanocomycin formulation from poloxamer 407 gels. Int. J. Pharm., 192, 183–193 (1999).

    Article  CAS  PubMed  Google Scholar 

  • Wachowski, I., Jolly, D. T., Hrazdil, J., Galbraith., J. C., Greacen, M., and Clanachan, A. S., The growth of microorganisms in propofol and mixtures of propofol and lidocanie. Anesth. Analg., 88, 209–212 (1988).

    Article  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Wissing, S. A., Kayser, O., and Müller, R. H., Solid lipid nanoparticles for parenteral drug delivery. Adv. Drug Deliv. Rev., 56, 1257–1272 (2004).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. R&D Center, Kuhnil Pharm Co., Ltd., Seoul, 153-787, Korea

    Jaepyoung Cho, Jin Cheol Cho, Pungsok Lee & Mase Lee

  2. College of Pharmacy, Catholic University of Korea, Bucheon, 420-743, Korea

    Euichaul Oh

Authors
  1. Jaepyoung Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jin Cheol Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pungsok Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mase Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Euichaul Oh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Euichaul Oh.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cho, J., Cho, J.C., Lee, P. et al. Formulation and evaluation of an alternative triglyceride-free propofol microemulsion. Arch. Pharm. Res. 33, 1375–1387 (2010). https://doi.org/10.1007/s12272-010-0911-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12272-010-0911-0

Key words

Search

Navigation