AAPS PharmSciTech

, Volume 11, Issue 4, pp 1526–1540 | Cite as

Injectable Lipid Emulsions—Advancements, Opportunities and Challenges

  • Ketan Hippalgaonkar
  • Soumyajit Majumdar
  • Viral KansaraEmail author
Review Article Theme: Sterile Products: Advances and Challenges in Formulation, Manufacturing, Devices and Regulatory Aspects


Injectable lipid emulsions, for decades, have been clinically used as an energy source for hospitalized patients by providing essential fatty acids and vitamins. Recent interest in utilizing lipid emulsions for delivering lipid soluble therapeutic agents, intravenously, has been continuously growing due to the biocompatible nature of the lipid-based delivery systems. Advancements in the area of novel lipids (olive oil and fish oil) have opened a new area for future clinical application of lipid-based injectable delivery systems that may provide a better safety profile over traditionally used long- and medium-chain triglycerides to critically ill patients. Formulation components and process parameters play critical role in the success of lipid injectable emulsions as drug delivery vehicles and hence need to be well integrated in the formulation development strategies. Physico-chemical properties of active therapeutic agents significantly impact pharmacokinetics and tissue disposition following intravenous administration of drug-containing lipid emulsion and hence need special attention while selecting such delivery vehicles. In summary, this review provides a broad overview of recent advancements in the field of novel lipids, opportunities for intravenous drug delivery, and challenges associated with injectable lipid emulsions.

Key words

biodisposition lipid emulsions microfluidization parenteral formulations sterilization 


  1. 1.
    Vinnars E, Hammarqvist F. 25th Arvid Wretlind’s Lecture—Silver anniversary, 25 years with ESPEN, the history of nutrition. Clin Nutr. 2004;23:955–62.PubMedCrossRefGoogle Scholar
  2. 2.
    Wretlind A. Development of fat emulsions. JPEN J Parenter Enteral Nutr. 1981;5:230–5.PubMedCrossRefGoogle Scholar
  3. 3.
    Vinnars E, Wilmore D. Jonathan roads symposium papers. History of parenteral nutrition. JPEN J Parenter Enteral Nutr. 2003;27:225–31.PubMedCrossRefGoogle Scholar
  4. 4.
    de Meijer VE, Gura KM, Le HD, Meisel JA, Puder M. Fish oil-based lipid emulsions prevent and reverse parenteral nutrition-associated liver disease: the Boston experience. JPEN J Parenter Enteral Nutr. 2009;33:541–7.PubMedCrossRefGoogle Scholar
  5. 5.
    Raghunathji NB, Albert EC, Madurai G, Charles ES, inventors; Emulsion compositions for the parenteral and/or oral administration of sparingly water soluble ionizable hydrophobic drugs patent EP0215313. 1992.Google Scholar
  6. 6.
    Calder PC, Jensen GL, Koletzko BV, Singer P, Wanten GJ. Lipid emulsions in parenteral nutrition of intensive care patients: current thinking and future directions. Intensive Care Med. 2010;36:735–49.PubMedCrossRefGoogle Scholar
  7. 7.
    Waitzberg DL, Torrinhas RS, Jacintho TM. New parenteral lipid emulsions for clinical use. JPEN J Parenter Enteral Nutr. 2006;30:351–67.PubMedCrossRefGoogle Scholar
  8. 8.
    Carpentier YA, Dupont IE. Advances in intravenous lipid emulsions. World J Surg. 2000;24:1493–7.PubMedCrossRefGoogle Scholar
  9. 9.
    Furst P, Kuhn KS. Fish oil emulsions: what benefits can they bring? Clin Nutr. 2000;19:7–14.PubMedCrossRefGoogle Scholar
  10. 10.
    Calder PC. Hot topics in parenteral nutrition. Rationale for using new lipid emulsions in parenteral nutrition and a review of the trials performed in adults. Proc Nutr Soc. 2009;68:252–60.PubMedCrossRefGoogle Scholar
  11. 11.
    Battistella FD, Widergren JT, Anderson JT, Siepler JK, Weber JC, MacColl K. A prospective, randomized trial of intravenous fat emulsion administration in trauma victims requiring total parenteral nutrition. J Trauma. 1997;43:52–8. discussion 8–60.PubMedCrossRefGoogle Scholar
  12. 12.
    Lenssen P, Bruemmer BA, Bowden RA, Gooley T, Aker SN, Mattson D. Intravenous lipid dose and incidence of bacteremia and fungemia in patients undergoing bone marrow transplantation. Am J Clin Nutr. 1998;67:927–33.PubMedGoogle Scholar
  13. 13.
    Clayton PT, Bowron A, Mills KA, Massoud A, Casteels M, Milla PJ. Phytosterolemia in children with parenteral nutrition-associated cholestatic liver disease. Gastroenterology. 1993;105:1806–13.PubMedGoogle Scholar
  14. 14.
    Ulrich H, Pastores SM, Katz DP, Kvetan V. Parenteral use of medium-chain triglycerides: a reappraisal. Nutrition. 1996;12:231–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Manuel-y-Keenoy B, Nonneman L, De Bosscher H, Vertommen J, Schrans S, Klutsch K, et al. Effects of intravenous supplementation with alpha-tocopherol in patients receiving total parenteral nutrition containing medium- and long-chain triglycerides. Eur J Clin Nutr. 2002;56:121–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Radermacher P, Santak B, Strobach H, Schror K, Tarnow J. Fat emulsions containing medium chain triglycerides in patients with sepsis syndrome: effects on pulmonary hemodynamics and gas exchange. Intensive Care Med. 1992;18:231–4.PubMedCrossRefGoogle Scholar
  17. 17.
    Gogos CA, Kalfarentzos FE, Zoumbos NC. Effect of different types of total parenteral nutrition on T-lymphocyte subpopulations and NK cells. Am J Clin Nutr. 1990;51:119–22.PubMedGoogle Scholar
  18. 18.
    Gogos CA, Zoumbos N, Makri M, Kalfarentzos F. Medium- and long-chain triglycerides have different effects on the synthesis of tumor necrosis factor by human mononuclear cells in patients under total parenteral nutrition. J Am Coll Nutr. 1994;13:40–4.PubMedGoogle Scholar
  19. 19.
    Bach AC, Babayan VK. Medium-chain triglycerides: an update. Am J Clin Nutr. 1982;36:950–62.PubMedGoogle Scholar
  20. 20.
    Bach AC, Storck D, Meraihi Z. Medium-chain triglyceride-based fat emulsions: an alternative energy supply in stress and sepsis. JPEN J Parenter Enteral Nutr. 1988;12:82S–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Chambrier C, Lauverjat M, Bouletreau P. Structured triglyceride emulsions in parenteral nutrition. Nutr Clin Pract. 2006;21:342–50.PubMedCrossRefGoogle Scholar
  22. 22.
    Lindgren BF, Ruokonen E, Magnusson-Borg K, Takala J. Nitrogen sparing effect of structured triglycerides containing both medium-and long-chain fatty acids in critically ill patients; a double blind randomized controlled trial. Clin Nutr. 2001;20:43–8.PubMedCrossRefGoogle Scholar
  23. 23.
    Lin M-T, Yeh S-L, Tsou S-S, Wang M-Y, Chen W-J. Effects of parenteral structured lipid emulsion on modulating the inflammatory response in rats undergoing a total gastrectomy. Nutrition. 2009;25:115–21.PubMedCrossRefGoogle Scholar
  24. 24.
    Wanten GJ, Calder PC. Immune modulation by parenteral lipid emulsions. Am J Clin Nutr. 2007;85:1171–84.PubMedGoogle Scholar
  25. 25.
    Sala-Vila A, Barbosa VM, Calder PC. Olive oil in parenteral nutrition. Curr Opin Clin Nutr Metab Care. 2007;10:165–74.PubMedCrossRefGoogle Scholar
  26. 26.
    Garcia-de-Lorenzo A. Monounsaturated fatty acid-based lipid emulsions in critically ill patients are associated with fewer complications. Br J Nutr. 2006;95:1029.PubMedCrossRefGoogle Scholar
  27. 27.
    Waitzberg DL, Torrinhas RS. Fish oil lipid emulsions and immune response: what clinicians need to know. Nutr Clin Pract. 2009;24:487–99.PubMedCrossRefGoogle Scholar
  28. 28.
    Diprivan Injectable Emulsion. AstraZeneca. Available at: Accessed 23 March 2010.
  29. 29.
    Rossi J, Leroux J-C. Principles in the Development of Intravenous Lipid Emulsions. In: Wasan KM, editor. Role of Lipid Excipients in Modifying Oral and Parenteral Drug Delivery. New York: Wiley; 2006. p. 88–123.CrossRefGoogle Scholar
  30. 30.
    Floyd AG, Jain S. Injectable emulsions and suspensions. In: Lieberman HA, Rieger MM, Banker GS, editors. Pharmaceutical dosage forms: dispersed systems. New York: Marcel Dekker; 1996. p. 261–310.Google Scholar
  31. 31.
    Levy MY, Langerman L, Gottschalk-Sabag S, Benita S. Side-effect evaluation of a new diazepam formulation: venous sequela reduction following intravenous (i.v.) injection of a diazepam emulsion in rabbits. Pharm Res. 1989;6:510–6.PubMedCrossRefGoogle Scholar
  32. 32.
    von Dardel O, Mebius C, Mossberg T, Svensson B. Fat emulsion as a vehicle for diazepam. A study of 9492 patients. Br J Anaesth. 1983;55:41–7.CrossRefGoogle Scholar
  33. 33.
    Lovell MW, Johnson HW, Hui HW, Cannon JB, Gupta PK, Hsu CC. Less-painful emulsion formulations for intravenous administration of clarithromycin. Int J Pharm. 1994;109:45–57.CrossRefGoogle Scholar
  34. 34.
    Suttmann H, Doenicke A, Kugler J, Laub M. A new formulation of etomidate in lipid emulsion—bioavailability and venous provocation. Anaesthesist. 1989;38:421–3.PubMedGoogle Scholar
  35. 35.
    Selander D, Curelaru I, Stefansson T. Local discomfort and thrombophlebitis following intravenous injection of diazepam. A comparison between a glycoferol-water solution and a lipid emulsion. Acta Anaesthesiol Scand. 1981;25:516–8.PubMedCrossRefGoogle Scholar
  36. 36.
    Venkataram S, Awni WM, Jordan K, Rahman YE. Pharmacokinetics of two alternative dosage forms for cyclosporine: liposomes and intralipid. J Pharm Sci. 1990;79:216–9.PubMedCrossRefGoogle Scholar
  37. 37.
    Constantinides PP, Lambert KJ, Tustian AK, Schneider B, Lalji S, Ma W, et al. Formulation development and antitumor activity of a filter-sterilizable emulsion of paclitaxel. Pharm Res. 2000;17:175–82.PubMedCrossRefGoogle Scholar
  38. 38.
    Tibell A, Larsson M, Alvestrand A. Dissolving intravenous cyclosporin A in a fat emulsion carrier prevents acute renal side effects in the rat. Transpl Int. 1993;6:69–72.PubMedCrossRefGoogle Scholar
  39. 39.
    Lamb KA, Washington C, Davis SS, Denyer SP. Toxicity of amphotericin B emulsion to cultured canine kidney cell monolayers. J Pharm Pharmacol. 1991;43:522–4.PubMedGoogle Scholar
  40. 40.
    Forster D, Washington C, Davis SS. Toxicity of solubilized and colloidal amphotericin B formulations to human erythrocytes. J Pharm Pharmacol. 1988;40:325–8.PubMedGoogle Scholar
  41. 41.
    Eccleston GM. Emulsions and Microemulsions. In: Swarbrick J, editor. Encylopedia of Pharmaceutical Technology. New York: Informa Healthcare USA. Inc; 2007. p. 1548–65.Google Scholar
  42. 42.
    Cannon BJ, Shi Y, Gupta P. Emulsions, microemulsions, and lipid-based drug delivery systems for drug solubilization and delivery—Part I: parenteral applications. In: Rong L, editor. Water-Insoluble Drug Formulation. New York: Taylor & Francis; 2008. p. 195–226.CrossRefGoogle Scholar
  43. 43.
    Rensen PC, van Dijk MC, Havenaar EC, Bijsterbosch MK, Kruijt JK, van Berkel TJ. Selective liver targeting of antivirals by recombinant chylomicrons—a new therapeutic approach to hepatitis B. Nat Med. 1995;1:221–5.PubMedCrossRefGoogle Scholar
  44. 44.
    Ishida E, Managit C, Kawakami S, Nishikawa M, Yamashita F, Hashida M. Biodistribution characteristics of galactosylated emulsions and incorporated probucol for hepatocyte-selective targeting of lipophilic drugs in mice. Pharm Res. 2004;21:932–9.PubMedCrossRefGoogle Scholar
  45. 45.
    Yeeprae W, Kawakami S, Higuchi Y, Yamashita F, Hashida M. Biodistribution characteristics of mannosylated and fucosylated O/W emulsions in mice. J Drug Target. 2005;13:479–87.PubMedCrossRefGoogle Scholar
  46. 46.
    Floyd AG. Top ten considerations in the development of parenteral emulsions. Pharm Sci Technol Today. 1999;2:134–43.CrossRefGoogle Scholar
  47. 47.
    Kan P, Chen Z-B, Lee C-J, Chu IM. Development of nonionic surfactant/phospholipid o/w emulsion as a paclitaxel delivery system. J Control Release. 1999;58:271–8.PubMedCrossRefGoogle Scholar
  48. 48.
    Constantinides PP, Tustian A, Kessler DR. Tocol emulsions for drug solubilization and parenteral delivery. Adv Drug Deliv Rev. 2004;56:1243–55.PubMedCrossRefGoogle Scholar
  49. 49.
    Strickley RG, Anderson BD. Solubilization and stabilization of an anti-HIV thiocarbamate, NSC 629243, for parenteral delivery, using extemporaneous emulsions. Pharm Res. 1993;10:1076–82.PubMedCrossRefGoogle Scholar
  50. 50.
    Herman CJ, Groves MJ. Hydrolysis kinetics of phospholipids in thermally stressed intravenous lipid emulsion formulations. J Pharm Pharmacol. 1992;44:539–42.PubMedGoogle Scholar
  51. 51.
    Wheeler JJ, Wong KF, Ansell SM, Masin D, Bally MB. Polyethylene glycol modified phospholipids stabilize emulsions prepared from triacylglycerol. J Pharm Sci. 1994;83:1558–64.PubMedCrossRefGoogle Scholar
  52. 52.
    Papahadjopoulos D, Allen TM, Gabizon A, Mayhew E, Matthay K, Huang SK, et al. Sterically stabilized liposomes: improvements in pharmacokinetics and antitumor therapeutic efficacy. Proc Natl Acad Sci USA. 1991;88:11460–4.PubMedCrossRefGoogle Scholar
  53. 53.
    Liu F, Liu D. Long-circulating emulsions (oil-in-water) as carriers for lipophilic drugs. Pharm Res. 1995;12:1060–4.PubMedCrossRefGoogle Scholar
  54. 54.
    Benita S, Friedman D, Weinstock M. Physostigmine emulsion: a new injectable controlled release delivery system. Int J Pharm. 1986;30:47–55.CrossRefGoogle Scholar
  55. 55.
    Levy MY, Benita S. Design and characterization of a submicronized o/w emulsion of diazepam for parenteral use. Int J Pharm. 1989;54:103–12.CrossRefGoogle Scholar
  56. 56.
    Jumaa M, Müller BW. Physicochemical properties of chitosan-lipid emulsions and their stability during the autoclaving process. Int J Pharm. 1999;183:175–84.PubMedCrossRefGoogle Scholar
  57. 57.
    Buszello K, Muller BW. Emulsions as drug delivery systems. In: Nielloud F, Marti-Mestres G, editors. Pharmaceutical Emulsions and Suspensions. New York: Marcel Dekker; 2000. p. 191–229.Google Scholar
  58. 58.
    Hansrani PK, Davis SS, Groves MJ. The preparation and properties of sterile intravenous emulsions. J Parenter Sci Technol. 1983;37:145–50.PubMedGoogle Scholar
  59. 59.
    Washington C. Stability of lipid emulsions for drug delivery. Adv Drug Deliv Rev. 1996;20:131–45.CrossRefGoogle Scholar
  60. 60.
    Benita S, Levy MY. Submicron emulsions as colloidal drug carriers for intravenous administration: comprehensive physicochemical characterization. J Pharm Sci. 1993;82:1069–79.PubMedCrossRefGoogle Scholar
  61. 61.
    Han J, Washington C. Partition of antimicrobial additives in an intravenous emulsion and their effect on emulsion physical stability. Int J Pharm. 2005;288:263–71.PubMedCrossRefGoogle Scholar
  62. 62.
    Propofol Injectable Emulsion 1%. Hospira Inc. Available at: Accessed 11 July 2010.
  63. 63.
    Driscoll DF, Dunbar JG, Marmarou A. Fat-globule size in a propofol emulsion containing sodium metabisulfite. Am J Health Syst Pharm. 2004;61:1276–80.PubMedGoogle Scholar
  64. 64.
    Collins-Gold LC, Lyons RT, Bartholow LC. Parenteral emulsions for drug delivery. Adv Drug Deliv Rev. 1990;5:189–208.CrossRefGoogle Scholar
  65. 65.
    Washington C, Davis SS. The production of parenteral feeding emulsions by Microfluidizer. Int J Pharm. 1988;44:169–76.CrossRefGoogle Scholar
  66. 66.
    Innocente N, Biasutti M, Venir E, Spaziani M, Marchesini G. Effect of high-pressure homogenization on droplet size distribution and rheological properties of ice cream mixes. J Dairy Sci. 2009;92:1864–75.PubMedCrossRefGoogle Scholar
  67. 67.
    USP. <729>Globule size distribution in Lipid Injectable Emulsions. The United states Pharmacopeia 33/National Formulary 28; 2009. pp. 314–6.Google Scholar
  68. 68.
    USP. Lipid injectable emulsions. The United States Pharmacopeia 33/National Formulary 28; 2009. pp. 3641–3.Google Scholar
  69. 69.
    Akkar A, Müller RH. Intravenous itraconazole emulsions produced by SolEmuls technology. Eur J Pharm Biopharm. 2003;56:29–36.PubMedCrossRefGoogle Scholar
  70. 70.
    Singh M, Ravin LJ. Parenteral emulsions as drug carrier systems. J Parenter Sci Technol. 1986;40:34–41.PubMedGoogle Scholar
  71. 71.
    Akkar A, Müller RH. Formulation of intravenous Carbamazepine emulsions by SolEmuls® technology. Eur J Pharm Biopharm. 2003;55:305–12.PubMedCrossRefGoogle Scholar
  72. 72.
    Müller RH, Schmidt S, Buttle I, Akkar A, Schmitt J, Brömer S. SolEmuls®–novel technology for the formulation of i.v. emulsions with poorly soluble drugs. Int J Pharm. 2004;269:293–302.PubMedCrossRefGoogle Scholar
  73. 73.
    Junghanns JU, Buttle I, Muller RH, Araujo IB, Silva AK, Egito ES, et al. SolEmuls technology: a way to overcome the drawback of parenteral administration of insoluble drugs. Pharm Dev Technol. 2007;12:437–45.PubMedCrossRefGoogle Scholar
  74. 74.
    Sila-on W, Vardhanabhuti N, Ongpipattanakul B, Kulvanich P. Influence of incorporation methods on partitioning behavior of lipophilic drugs into various phases of a parenteral lipid emulsion. AAPS PharmSciTech. 2008;9:684–92.PubMedCrossRefGoogle Scholar
  75. 75.
    Ferezou J, Bach AC. Structure and metabolic fate of triacylglycerol- and phospholipid-rich particles of commercial parenteral fat emulsions. Nutrition. 1999;15:44–50.PubMedCrossRefGoogle Scholar
  76. 76.
    Federal Register 56 (198); 51354, October 11, 1991.Google Scholar
  77. 77.
    Haskell RJ, Shifflett JR, Elzinga PA. Particle-sizing technologies for submicron emulsions. In: Benita S, editor. Submicron emulsions in drug targeting and delivery. Amsterdam: Harwood Academic Publisher; 1998. p. 21–98.Google Scholar
  78. 78.
    Jiao J, Burgess BJ. Characterization and Analysis of Dispersed Systems. In: Burgess BJ, editor. Injectable Dispersed Systems: Formulation, Processing, and Performance. New York: Taylor & Francis; 2005. p. 77–116.Google Scholar
  79. 79.
    Roland I, Piel G, Delattre L, Evrard B. Systematic characterization of oil-in-water emulsions for formulation design. Int J Pharm. 2003;263:85–94.PubMedCrossRefGoogle Scholar
  80. 80.
    Sherman P. Rheological properties of emulsions. In: Becher P, editor. Encylopedia of Emulsion Technology. New York: Marcel Dekker; 1983. p. 405.Google Scholar
  81. 81.
    Herman CJ, Groves MJ. The influence of free fatty acid formation on the pH of phospholipid-stabilized triglyceride emulsions. Pharm Res. 1993;10:774–6.PubMedCrossRefGoogle Scholar
  82. 82.
    Driscoll DF. Lipid injectable emulsions: pharmacopeial and safety issues. Pharm Res. 2006;23:1959–69.PubMedCrossRefGoogle Scholar
  83. 83.
    Washington C. Drug release from microdisperse systems: a critical review. Int J Pharm. 1990;58:1–12.CrossRefGoogle Scholar
  84. 84.
    Washington C. Evaluation of non-sink dialysis methods for the measurement of drug release from colloids: effects of drug partition. Int J Pharm. 1989;56:71–4.CrossRefGoogle Scholar
  85. 85.
    Chidambaram N, Burgess DJ. A novel in vitro release method for submicron sized dispersed systems. AAPS PharmSci. 1999;1:E11.PubMedCrossRefGoogle Scholar
  86. 86.
    Chidambaram N, Burgess BJ. Emulsions: design and manufacturing. In: Burgess BJ, editor. Injectable dispersed systems: formulation, processing, and performance. New York: Taylor & Francis; 2005. p. 213–41.Google Scholar
  87. 87.
    Tadros T, Izquierdo P, Esquena J, Solans C. Formation and stability of nano-emulsions. Adv Colloid Interface Sci. 2004;108–109:303–18.PubMedCrossRefGoogle Scholar
  88. 88.
    Ishii F, Sasaki I, Ogata H. Effect of phospholipid emulsifiers on physicochemical properties of intravenous fat emulsions and/or drug carrier emulsions. J Pharm Pharmacol. 1990;42:513–5.PubMedGoogle Scholar
  89. 89.
    Benita S, Levy MY. Design and characterization of a submicronized o/w emulsion of Diazepam for parenteral use. Int J Pharm. 1989;54:103–12.CrossRefGoogle Scholar
  90. 90.
    Jumaa M, Müller BW. The effect of oil components and homogenization conditions on the physicochemical properties and stability of parenteral fat emulsions. Int J Pharm. 1998;163:81–9.CrossRefGoogle Scholar
  91. 91.
    Jumaa M, Muller BW. Lipid emulsions as a novel system to reduce the hemolytic activity of lytic agents: mechanism of the protective effect. Eur J Pharm Sci. 2000;9:285–90.PubMedCrossRefGoogle Scholar
  92. 92.
    Trotta M, Pattarino F, Ignoni T. Stability of drug-carrier emulsions containing phosphatidylcholine mixtures. Eur J Pharm Biopharm. 2002;53:203–8.PubMedCrossRefGoogle Scholar
  93. 93.
    Jafari SM, He Y, Bhandari B. Production of sub-micron emulsions by ultrasound and microfluidization techniques. J Food Eng. 2007;82:478–88.CrossRefGoogle Scholar
  94. 94.
    Zeringue HJ, Brown ML, Singleton WS. Chromatographically homogeneous egg lecithin as stabilizer of emulsions for intravenous nutrition. J Am Oil Chem Soc. 1964;41:688–91.CrossRefGoogle Scholar
  95. 95.
    Ishii F, Nii T. Properties of various phospholipid mixtures as emulsifiers or dispersing agents in nanoparticle drug carrier preparations. Colloids Surf B Biointerfaces. 2005;41:257–62.PubMedCrossRefGoogle Scholar
  96. 96.
    Rydhag L. The importance of the phase behaviour of phospholipids for emulsion stability. Fette Seifen Anstrichm. 1979;81:168–73.CrossRefGoogle Scholar
  97. 97.
    Rubino JT. The influence of charged lipids on the flocculation and coalescence of oil-in-water emulsions. II: electrophoretic properties and monolayer film studies. J Parenter Sci Technol. 1990;44:247–52.PubMedGoogle Scholar
  98. 98.
    Nii T, Ishii F. Properties of various phosphatidylcholines as emulsifiers or dispersing agents in microparticle preparations for drug carriers. Colloids Surf B. 2004;39:57–63.CrossRefGoogle Scholar
  99. 99.
    Kawaguchi E, Shimokawa K-i, Ishii F. Physicochemical properties of structured phosphatidylcholine in drug carrier lipid emulsions for drug delivery systems. Colloids Surf B Biointerfaces. 2008;62:130–5.PubMedCrossRefGoogle Scholar
  100. 100.
    Sznitowska M, Janicki S, Dabrowska E, Zurowska-Pryczkowska K. Submicron emulsions as drug carriers. Studies on destabilization potential of various drugs. Eur J Pharm Sci. 2001;12:175–9.PubMedCrossRefGoogle Scholar
  101. 101.
    Groves MJ, Herman CJ. The redistribution of bulk aqueous phase phospholipids during thermal stressing of phospholipid-stabilized emulsions. J Pharm Pharmacol. 1993;45:592–6.PubMedGoogle Scholar
  102. 102.
    Jumaa M, Müller BW. The stabilization of parenteral fat emulsion using non-ionic ABA copolymer surfactant. Int J Pharm. 1998;174:29–37.CrossRefGoogle Scholar
  103. 103.
    Jumaa M, Muller BW. Parenteral emulsions stabilized with a mixture of phospholipids and PEG-660-12-hydroxy-stearate: evaluation of accelerated and long-term stability. Eur J Pharm Biopharm. 2002;54:207–12.PubMedCrossRefGoogle Scholar
  104. 104.
    Chaturvedi PR, Patel NM, Lodhi SA. Effect of terminal heat sterilization on the stability of phospholipid-stabilized submicron emulsions. Acta Pharm Nord. 1992;4:51–5.PubMedGoogle Scholar
  105. 105.
    Carpentier YA. Intravascular metabolism of fat emulsions: the Arvid Wretlind Lecture, ESPEN 1988. Clin Nutr. 1989;8:115–25.PubMedCrossRefGoogle Scholar
  106. 106.
    Dupont IE, Carpentier YA. Clinical use of lipid emulsions. Curr Opin Clin Nutr Metab Care. 1999;2:139–45.PubMedCrossRefGoogle Scholar
  107. 107.
    Kurihara A, Shibayama Y, Mizota A, Yasuno A, Ikeda M, Hisaoka M. Pharmacokinetics of highly lipophilic antitumor agent palmitoyl rhizoxin incorporated in lipid emulsions in rats. Biol Pharm Bull. 1996;19:252–8.PubMedGoogle Scholar
  108. 108.
    Tibell A, Lindholm A, Sawe J, Chen G, Norrlind B. Cyclosporin A in fat emulsion carriers: experimental studies on pharmacokinetics and tissue distribution. Pharmacol Toxicol. 1995;76:115–21.PubMedCrossRefGoogle Scholar
  109. 109.
    Hosokawa T, Yamauchi M, Yamamoto Y, Iwata K, Mochizuki H, Kato Y. Role of the lipid emulsion on an injectable formulation of lipophilic KW-3902, a newly synthesized adenosine A1-receptor antagonist. Biol Pharm Bull. 2002;25:492–8.PubMedCrossRefGoogle Scholar
  110. 110.
    Ames MM, Kovach JS. Parenteral formulation of hexamethylmelamine potentially suitable for use in man. Cancer Treat Rep. 1982;66:1579–81.PubMedGoogle Scholar
  111. 111.
    Dundee JW, Clarke RS. Propofol. Eur J Anaesthesiol. 1989;6:5–22.PubMedGoogle Scholar
  112. 112.
    Lu Y, Zhang Y, Yang Z, Tang X. Formulation of an intravenous emulsion loaded with a clarithromycin-phospholipid complex and its pharmacokinetics in rats. Int J Pharm. 2009;366:160–9.PubMedCrossRefGoogle Scholar
  113. 113.
    Takino T, Konishi K, Takakura Y, Hashida M. Long circulating emulsion carrier systems for highly lipophilic drugs. Biol Pharm Bull. 1994;17:121–5.PubMedGoogle Scholar
  114. 114.
    Sakaeda T, Hirano K. O/W lipid emulsions for parenteral drug delivery. II. Effect of composition on pharmacokinetics of incorporated drug. J Drug Target. 1995;3:221–30.PubMedCrossRefGoogle Scholar
  115. 115.
    Sakaeda T, Hirano K. O/W lipid emulsions for parenteral drug delivery. III. Lipophilicity necessary for incorporation in oil particles even after intravenous injection. J Drug Target. 1998;6:119–27.PubMedCrossRefGoogle Scholar
  116. 116.
    Ganta S, Paxton JW, Baguley BC, Garg S. Pharmacokinetics and pharmacodynamics of chlorambucil delivered in parenteral emulsion. Int J Pharm. 2008;360:115–21.PubMedCrossRefGoogle Scholar
  117. 117.
    Shi S, Chen H, Lin X, Tang X. Pharmacokinetics, tissue distribution and safety of cinnarizine delivered in lipid emulsion. Int J Pharm. 2010;383:264–70.PubMedCrossRefGoogle Scholar
  118. 118.
    Gao K, Sun J, Liu K, Liu X, He Z. Preparation and characterization of a submicron lipid emulsion of docetaxel: submicron lipid emulsion of docetaxel. Drug Dev Ind Pharm. 2008;34:1227–37.PubMedCrossRefGoogle Scholar
  119. 119.
    Azevedo CH, Carvalho JP, Valduga CJ, Maranhao RC. Plasma kinetics and uptake by the tumor of a cholesterol-rich microemulsion (LDE) associated to etoposide oleate in patients with ovarian carcinoma. Gynecol Oncol. 2005;97:178–82.PubMedCrossRefGoogle Scholar
  120. 120.
    Matsuo H. Preliminary evaluation of AS-013 (prodrug of prostaglandin E1) administration for chronic peripheral arterial occlusive disease. Int J Angiology. 1998;7:22–4.Google Scholar
  121. 121.
    Rodrigues DG, Maria DA, Fernandes DC, Valduga CJ, Couto RD, Ibanez OC, et al. Improvement of paclitaxel therapeutic index by derivatization and association to a cholesterol-rich microemulsion: in vitro and in vivo studies. Cancer Chemother Pharmacol. 2005;55:565–76.PubMedCrossRefGoogle Scholar
  122. 122.
    Jang JH, Kim CK, Choi HG, Sung JH. Preparation and evaluation of 2-(allylthio)pyrazine-loaded lipid emulsion with enhanced stability and liver targeting. Drug Dev Ind Pharm. 2009;35:363–8.PubMedCrossRefGoogle Scholar
  123. 123.
    Nishikawa M, Takakura Y, Hashida M. Biofate of fat emulsions. In: Benita S, editor. Submicron emulsions in drug targeting and delivery. Amsterdam: Harwood Academic Publisher; 1998. p. 99–118.Google Scholar
  124. 124.
    Deckelbaum RJ, Calder PC, Carpentier YA. Using different intravenous lipids: underutilized therapeutic approaches? Curr Opin Clin Nutr Metab Care. 2004;7:113–5.PubMedCrossRefGoogle Scholar
  125. 125.
    Kruimel JW, Naber TH, van der Vliet JA, Carneheim C, Katan MB, Jansen JB. Parenteral structured triglyceride emulsion improves nitrogen balance and is cleared faster from the blood in moderately catabolic patients. JPEN J Parenter Enteral Nutr. 2001;25:237–44.PubMedCrossRefGoogle Scholar
  126. 126.
    Oliveira FL, Rumsey SC, Schlotzer E, Hansen I, Carpentier YA, Deckelbaum RJ. Triglyceride hydrolysis of soy oil vs fish oil emulsions. JPEN J Parenter Enteral Nutr. 1997;21:224–9.PubMedCrossRefGoogle Scholar
  127. 127.
    Qi K, Seo T, Jiang Z, Carpentier YA, Deckelbaum RJ. Triglycerides in fish oil affect the blood clearance of lipid emulsions containing long- and medium-chain triglycerides in mice. J Nutr. 2006;136:2766–72.PubMedGoogle Scholar
  128. 128.
    Qi K, Seo T, Al-Haideri M, Worgall TS, Vogel T, Carpentier YA, et al. Omega-3 triglycerides modify blood clearance and tissue targeting pathways of lipid emulsions. Biochemistry. 2002;41:3119–27.PubMedCrossRefGoogle Scholar
  129. 129.
    Maranhao RC, Tercyak AM, Redgrave TG. Effects of cholesterol content on the metabolism of protein-free emulsion models of lipoproteins. Biochim Biophys Acta. 1986;875:247–55.PubMedGoogle Scholar
  130. 130.
    Handa T, Eguchi Y, Miyajima K. Effects of cholesterol and cholesteryl oleate on lipolysis and liver uptake of triglyceride/phosphatidylcholine emulsions in rats. Pharm Res. 1994;11:1283–7.PubMedCrossRefGoogle Scholar
  131. 131.
    Clark SB, Derksen A, Small DM. Plasma clearance of emulsified triolein in conscious rats: effects of phosphatidylcholine species, cholesterol content and emulsion surface physical state. Exp Physiol. 1991;76:39–52.PubMedGoogle Scholar
  132. 132.
    Lenzo NP, Martins I, Mortimer BC, Redgrave TG. Effects of phospholipid composition on the metabolism of triacylglycerol, cholesteryl ester and phosphatidylcholine from lipid emulsions injected intravenously in rats. Biochim Biophys Acta. 1988;960:111–8.PubMedGoogle Scholar
  133. 133.
    Clark SB, Derksen A. Phosphatidylcholine composition of emulsions influences triacylglycerol lipolysis and clearance from plasma. Biochim Biophys Acta. 1987;920:37–46.PubMedGoogle Scholar
  134. 134.
    Illum L, Washington C, Davis SS. The effect of stabilising agents on the organ distribution of lipid emulsions. Int J Pharm. 1989;54:41–9.CrossRefGoogle Scholar
  135. 135.
    Lee M-J, Lee M-H, Shim C-K. Inverse targeting of drugs to reticuloendothelial system-rich organs by lipid microemulsion emulsified with poloxamer 338. Int J Pharm. 1995;113:175–87.CrossRefGoogle Scholar
  136. 136.
    Ueda K, Yamazaki Y, Noto H, Teshima Y, Yamashita C, Sakaeda T, et al. Effect of oxyethylene moieties in hydrogenated castor oil on the pharmacokinetics of menatetrenone incorporated in O/W lipid emulsions prepared with hydrogenated castor oil and soybean oil in rats. J Drug Target. 2003;11:37–43.PubMedCrossRefGoogle Scholar
  137. 137.
    Arimoto I, Matsumoto C, Tanaka M, Okuhira K, Saito H, Handa T. Surface composition regulates clearance from plasma and triolein lipolysis of lipid emulsions. Lipids. 1998;33:773–9.PubMedCrossRefGoogle Scholar
  138. 138.
    Morita SY, Okuhira K, Tsuchimoto N, Vertut-Doi A, Saito H, Nakano M, et al. Effects of sphingomyelin on apolipoprotein E- and lipoprotein lipase-mediated cell uptake of lipid particles. Biochim Biophys Acta. 2003;1631:169–76.PubMedGoogle Scholar
  139. 139.
    Redgrave TG, Rakic V, Mortimer BC, Mamo JC. Effects of sphingomyelin and phosphatidylcholine acyl chains on the clearance of triacylglycerol-rich lipoproteins from plasma. Studies with lipid emulsions in rats. Biochim Biophys Acta. 1992;1126:65–72.PubMedGoogle Scholar
  140. 140.
    Reddy PR, Venkateswarlu V. Pharmacokinetics and tissue distribution of etoposide delivered in long circulating parenteral emulsion. J Drug Target. 2005;13:543–53.PubMedCrossRefGoogle Scholar
  141. 141.
    Chung H, Kim TW, Kwon M, Kwon IC, Jeong SY. Oil components modulate physical characteristics and function of the natural oil emulsions as drug or gene delivery system. J Control Release. 2001;71:339–50.PubMedCrossRefGoogle Scholar
  142. 142.
    Nii T, Ishii F. Dialkylphosphatidylcholine and egg yolk lecithin for emulsification of various triglycerides. Colloids Surf B Biointerfaces. 2005;41:305–11.PubMedCrossRefGoogle Scholar
  143. 143.
    Kurihara A, Shibayama Y, Mizota A, Yasuno A, Ikeda M, Sasagawa K, et al. Lipid emulsions of palmitoylrhizoxin: effects of composition on lipolysis and biodistribution. Biopharm Drug Dispos. 1996;17:331–42.PubMedCrossRefGoogle Scholar
  144. 144.
    Lutz O, Meraihi Z, Mura JL, Frey A, Riess GH, Bach AC. Fat emulsion particle size: influence on the clearance rate and the tissue lipolytic activity. Am J Clin Nutr. 1989;50:1370–81.PubMedGoogle Scholar
  145. 145.
    Takino T, Nagahama E, Sakaeda T, Yamashita F, Takakura Y, Hashida M. Pharmacokinetic disposition analysis of lipophilic drugs injected with various lipid carriers in the single-pass rat liver perfusion system. Int J Pharm. 1995;114:43–54.CrossRefGoogle Scholar
  146. 146.
    Kurihara A, Shibayama Y, Mizota A, Yasuno A, Ikeda M, Sasagawa K, et al. Enhanced tumor delivery and antitumor activity of palmitoyl rhizoxin using stable lipid emulsions in mice. Pharm Res. 1996;13:305–10.PubMedCrossRefGoogle Scholar
  147. 147.
    Cleviprex Injectable Emulsion. Orange book. Available at: Accessed 11 July 2010.
  148. 148.
    Erickson AL, DeGrado JR, Fanikos JR. Clevidipine: a short-acting intravenous dihydropyridine calcium channel blocker for the management of hypertension. Pharmacotherapy. 2010;30:515–28.PubMedCrossRefGoogle Scholar
  149. 149.
    Klang S, Benita S. Design and evaluation of submicron emulsions as colloidal drug carriers for intravenous adminsitration. In: Benita S, editor. Submicron emulsions in drug targeting and delivery. Amsterdam: Harwood Academic Publishers; 1998. p. 119–52.Google Scholar
  150. 150.
    Klang S, Parnas M, Benita S. Emulsions as drug carriers—possibilities, limitations and future prespectives. In: Muller RH, Benita S, Bohm B, editors. Emulsions and nanosuspensions for the formulation of poorly soluble drugs. Stuttgart: Medpharm Scientific Publishers; 1998. p. 31–60.Google Scholar
  151. 151.
    Wabel C (1998). Influence of lecithin on structure and stability of parenteral fat emulsions. Ph.D. thesis, University Erlangen-Nuremberg.Google Scholar
  152. 152.
    Wang J, Maitani Y, Takayama K. Antitumor effects and pharmacokinetics of aclacinomycin A carried by injectable emulsions composed of vitamin E, cholesterol, and PEG-lipid. J Pharm Sci. 2002;91:1128–34.PubMedCrossRefGoogle Scholar
  153. 153.
    Chansri N, Kawakami S, Yamashita F, Hashida M. Inhibition of liver metastasis by all-trans retinoic acid incorporated into O/W emulsions in mice. Int J Pharm. 2006;321:42–9.PubMedCrossRefGoogle Scholar
  154. 154.
    Suzuki S, Kawakami S, Chansri N, Yamashita F, Hashida M. Inhibition of pulmonary metastasis in mice by all-trans retinoic acid incorporated in cationic liposomes. J Control Release. 2006;116:58–63.PubMedCrossRefGoogle Scholar
  155. 155.
    Kleberg K, Jacobsen F, Fatouros DG, Müllertz A. Biorelevant media simulating fed state intestinal fluids: colloid phase characterization and impact on solubilization capacity. J Pharm Sci. 2010;99:3522–32.PubMedCrossRefGoogle Scholar
  156. 156.
    Fernandes PB, Hardy DJ, McDaniel D, Hanson CW, Swanson RN. In vitro and in vivo activities of clarithromycin against Mycobacterium avium. Antimicrob Agents Chemother. 1989;33:1531–4.PubMedGoogle Scholar
  157. 157.
    Bravo Gonzalez RC, Huwyler J, Walter I, Mountfield R, Bittner B. Improved oral bioavailability of cyclosporin A in male Wistar rats. Comparison of a Solutol HS 15 containing self-dispersing formulation and a microsuspension. Int J Pharm. 2002;245:143–51.PubMedCrossRefGoogle Scholar
  158. 158.
    Qiu Y, Gao Y, Hu K, Li F. Enhancement of skin permeation of docetaxel: a novel approach combining microneedle and elastic liposomes. J Control Release. 2008;129:144–50.PubMedCrossRefGoogle Scholar
  159. 159.
    Sakaeda T, Kakushi H, Shike T, Takano K, Harauchi T, Hirata M, et al. O/W lipid emulsions for parenteral drug delivery. IV. Changes in the pharmacokinetics and pharmacodynamics of a highly lipophilic drug, menatetrenone. J Drug Target. 1998;6:183–9.PubMedCrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2010

Authors and Affiliations

  • Ketan Hippalgaonkar
    • 1
  • Soumyajit Majumdar
    • 1
    • 2
  • Viral Kansara
    • 3
    Email author
  1. 1.Department of PharmaceuticsUniversity of MississippiOxfordUSA
  2. 2.Research Institute of Pharmaceutical SciencesUniversity of MississippiOxfordUSA
  3. 3.RNAi Delivery and Process Development, Biologics and VaccinesMerck Sharp & Dohme CorpWest PointUSA

Personalised recommendations