Pharmaceutical Research

, Volume 31, Issue 8, pp 2022–2034 | Cite as

Computed Tomography-Guided Screening of Surfactant Effect on Blood Circulation Time of Emulsions: Application to the Design of an Emulsion Formulation for Paclitaxel

  • Eun-Hye Lee
  • Soon-Seok Hong
  • So Hee Kim
  • Mi-Kyung Lee
  • Joon Seok Lim
  • Soo-Jeong Lim
Research Paper



In an effort to apply the imaging techniques currently used in disease diagnosis for monitoring the pharmacokinetics and biodisposition of particulate drug carriers, we sought to use computed tomography (CT) scanning methodology to investigate the impact of surfactant on the blood residence time of emulsions.


We prepared the iodinated oil Lipiodol emulsions with different compositions of surfactants and investigated the impact of surfactant on the blood residence time of emulsions by CT scanning.


The blood circulation time of emulsions was prolonged by including Tween 80 or DSPE-PEG (polyethylene glycol 2000) in emulsions. Tween 80 was less effective than DSPE-PEG in terms of prolongation effect, but the blood circulating time of emulsions was prolonged in a Tween 80 content-dependent manner. As a proof-of-concept demonstration of the usefulness of CT-guided screening in the process of formulating drugs that need to be loaded in emulsions, paclitaxel was loaded in emulsions prepared with 87 or 65% Tween 80–containing surfactant mixtures. A pharmacokinetics study showed that paclitaxel loaded in 87% Tween 80 emulsions circulated longer in the bloodstream compared to those in 65% Tween 80 emulsions, as predicted by CT imaging.


CT-visible, Lipiodol emulsions enabled the simple evaluation of surfactant composition effects on the biodisposition of emulsions.


lipiodol emulsion pharmacokinetics computed tomography paclitaxel 



This study was supported by grants from the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (Nos. 2010-0008838, 2012R1A2A2A01046171).


  1. 1.
    Mirtallo JM, Dasta JF, Kleinschmidt KC, Varon J. State of the art review: intravenous fat emulsions: current applications, safety profile, and clinical implications. Ann Pharmacother. 2010;44:688–700.PubMedGoogle Scholar
  2. 2.
    Hippalgaonkar K, Majumdar S, Kansara V. Injectable lipid emulsions-advancements, opportunities and challenges. AAPS PharmSciTech. 2010;11:1526–40.PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Prankerd RJ, Stella VJ. The use of oil-in-water emulsions as a vehicle for parenteral drug administration. J Parenter Sci Technol. 1990;44:139–49.PubMedGoogle Scholar
  4. 4.
    Zhao H, Lu H, Gong T, Zhang Z. Nanoemulsion loaded with lycobetaine-oleic acid ionic complex: physicochemical characteristics, in vitro, in vivo evaluation, and antitumor activity. Int J Nanomedicine. 2013;8:1959–73.PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Ragelle H, Crauste-Manciet S, Seguin J, Brossard D, Scherman D, Arnaud P, et al. Nanoemulsion formulation of fisetin improves bioavailability and antitumour activity in mice. Int J Pharm. 2012;427:452–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Bhandari R, Kaur IP. Pharmacokinetics, tissue distribution and relative bioavailability of isoniazid-solid lipid nanoparticles. Int J Pharm. 2013;441:202–12.PubMedCrossRefGoogle Scholar
  7. 7.
    Rajpoot P, Bali V, Pathak K. Anticancer efficacy, tissue distribution and blood pharmacokinetics of surface modified nanocarrier containing melphalan. Int J Pharm. 2012;426:219–30.PubMedCrossRefGoogle Scholar
  8. 8.
    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.PubMedCrossRefGoogle Scholar
  9. 9.
    Talegaonkar S, Vyas SP. Inverse targeting of diclofenac sodium to reticuloendothelial system-rich organs by sphere-in-oil-in-water (s/o/w) multiple emulsion containing poloxamer 403. J Drug Target. 2005;13:173–8.PubMedCrossRefGoogle Scholar
  10. 10.
    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
  11. 11.
    Jia L, Shen J, Zhang D, Duan C, Liu G, Zheng D, et al. In vitro and in vivo evaluation of oridonin-loaded long circulating nanostructured lipid carriers. Int J Biol Macromol. 2012;50:523–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Vonarbourg A, Passirani C, Saulnier P, Benoit JP. Parameters influencing the stealthiness of colloidal drug delivery systems. Biomaterials. 2006;27:4356–73.PubMedCrossRefGoogle Scholar
  13. 13.
    Liu F, Liu D. Long-circulating emulsions (oil-in-water) as carriers for lipophilic drugs. Pharm Res. 1995;12:1060–4.PubMedCrossRefGoogle Scholar
  14. 14.
    Rossi J, Giasson S, Khalid MN, Delmas P, Allen C, Leroux JC. Long-circulating poly(ethylene glycol)-coated emulsions to target solid tumors. Eur J Pharm Biopharm. 2007;67:329–38.PubMedCrossRefGoogle Scholar
  15. 15.
    Yoshizawa Y, Kono Y, Ogawara K, Kimura T, Higaki K. PEG liposomalization of paclitaxel improved its in vivo disposition and anti-tumor efficacy. Int J Pharm. 2011;412:132–41.PubMedCrossRefGoogle Scholar
  16. 16.
    He H, David A, Chertok B, Cole A, Lee K, Zhang J, et al. Magnetic nanoparticles for tumor imaging and therapy: a So-called theranostic system. Pharm Res. 2013;30:2445–58.PubMedCrossRefGoogle Scholar
  17. 17.
    Guthi JS, Yang SG, Huang G, Li S, Khemtong C, Kessinger CW, et al. MRI-visible micellar nanomedicine for targeted drug delivery to lung cancer cells. Mol Pharm. 2010;7:32–40.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Jarzyna PA, Skajaa T, Gianella A, Cormode DP, Samber DD, Dickson SD, et al. Iron oxide core oil-in-water emulsions as a multifunctional nanoparticle platform for tumor targeting and imaging. Biomaterials. 2009;30:6947–54.PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Soundararajan A, Bao A, Phillips WT, Perez R, Goins BA. [Re-186]Liposomal doxorubicin (Doxil): in vitro stability, pharmacokinetics, imaging and biodistribution in a head and neck squamous cell carcinoma xenograft model. Nucl Med Biol. 2009;36:515–24.PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Hallouard F, Briancon S, Anton N, Li X, Vandamme T, Fessi H. Iodinated nano-emulsions as contrast agents for preclinical X-ray imaging: impact of the free surfactants on the pharmacokinetics. Eur J Pharm Biopharm. 2013;83:54–62.PubMedCrossRefGoogle Scholar
  21. 21.
    Kircher MF, Willmann JK. Molecular body imaging: MR imaging, CT, and US. part I. principles. Radiology. 2012;263:633–43.PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Kweon S, Lee HJ, Hyung WJ, Suh J, Lim JS, Lim SJ. Liposomes coloaded with iopamidol/lipiodol as a RES-targeted contrast agent for computed tomography imaging. Pharm Res. 2010;27:1408–15.PubMedCrossRefGoogle Scholar
  23. 23.
    Chung YE, Hyung WJ, Kweon S, Lim SJ, Choi J, Lee MH, et al. Feasibility of interstitial CT lymphography using optimized iodized oil emulsion in rats. Invest Radiol. 2010;45:142–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Kong WH, Lee WJ, Cui ZY, Bae KH, Park TG, Kim JH, et al. Nanoparticulate carrier containing water-insoluble iodinated oil as a multifunctional contrast agent for computed tomography imaging. Biomaterials. 2007;28:5555–61.PubMedCrossRefGoogle Scholar
  25. 25.
    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
  26. 26.
    Yang SH, Choi HG, Lim SJ, Lee MG, Kim SH. Effects of morin on the pharmacokinetics of etoposide in 7,12-dimethylbenz[a]anthracene-induced mammary tumors in female Sprague–Dawley rats. Oncol Rep. 2013;29:1215–23.PubMedGoogle Scholar
  27. 27.
    Yang SH, Lee JH, Lee DY, Lee MG, Lyuk KC, Kim SH. Effects of morin on the pharmacokinetics of docetaxel in rats with 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors. Arch Pharm Res. 2011;34:1729–34.PubMedCrossRefGoogle Scholar
  28. 28.
    Kim SH, Choi YM, Lee MG. Pharmacokinetics and pharmacodynamics of furosemide in protein-calorie malnutrition. J Pharmacokinet Biopharm. 1993;21:1–17.PubMedCrossRefGoogle Scholar
  29. 29.
    Wang LZ, Ho PC, Lee HS, Vaddi HK, Chan YW, Yung CS. Quantitation of paclitaxel in micro-sample rat plasma by a sensitive reversed-phase HPLC assay. J Pharm Biomed Anal. 2003;31:283–9.PubMedCrossRefGoogle Scholar
  30. 30.
    Chiou WL. Critical evaluation of the potential error in pharmacokinetic studies of using the linear trapezoidal rule method for the calculation of the area under the plasma level–time curve. J Pharmacokinet Biopharm. 1978;6:539–46.PubMedCrossRefGoogle Scholar
  31. 31.
    Gref R, Domb A, Quellec P, Blunk T, Muller RH, Verbavatz JM, et al. The controlled intravenous delivery of drugs using PEG-coated sterically stabilized nanospheres. Adv Drug Deliver Rev. 2012;64:316–26.CrossRefGoogle Scholar
  32. 32.
    Kan P, Chen ZB, Lee CJ, Chu IM. Development of nonionic surfactant/phospholipid o/w emulsion as a paclitaxel delivery system. J Control Release. 1999;58:271–8.PubMedCrossRefGoogle Scholar
  33. 33.
    Lim SJ, Kim CK. Formulation parameters determining the physicochemical characteristics of solid lipid nanoparticles loaded with all-trans retinoic acid. Int J Pharm. 2002;243:135–46.PubMedCrossRefGoogle Scholar
  34. 34.
    Hinrichs WL, Mancenido FA, Sanders NN, Braeckmans K, De Smedt SC, Demeester J, et al. The choice of a suitable oligosaccharide to prevent aggregation of PEGylated nanoparticles during freeze thawing and freeze drying. Int J Pharm. 2006;311:237–44.PubMedCrossRefGoogle Scholar
  35. 35.
    Jansen T, Hofmans MP, Theelen MJ, Schijns VE. Structure-activity relations of water-in-oil vaccine formulations and induced antigen-specific antibody responses. Vaccine. 2005;23:1053–60.PubMedCrossRefGoogle Scholar
  36. 36.
    Lee IH, Park YT, Roh K, Chung H, Kwon IC, Jeong SY. Stable paclitaxel formulations in oily contrast medium. J Control Release. 2005;102:415–25.PubMedCrossRefGoogle Scholar
  37. 37.
    Park JH, Yan YD, Chi SC, Hwang DH, Shanmugam S, Lyoo WS, et al. Preparation and evaluation of Cremophor-free paclitaxel solid dispersion by a supercritical antisolvent process. J Pharm Pharmacol. 2011;63:491–9.PubMedCrossRefGoogle Scholar
  38. 38.
    Gelderblom H, Verweij J, van Zomeren DM, Buijs D, Ouwens L, Nooter K, et al. Influence of Cremophor EL on the bioavailability of intraperitoneal paclitaxel. Clin Cancer Res. 2002;8:1237–41.PubMedGoogle Scholar
  39. 39.
    Wang Y, Wu KC, Zhao BX, Zhao X, Wang X, Chen S, et al. A novel paclitaxel microemulsion containing a reduced amount of Cremophor EL: pharmacokinetics, biodistribution, and in vivo antitumor efficacy and safety. J Biomed Biotechnol. 2011;2011:854–72.Google Scholar
  40. 40.
    Malhi S, Dixit K, Sohi H, Shegokar R. Expedition of liposome to intracellular targets in solid tumors after intravenous administration. J Pharm Invest. 2013;43:75–87.CrossRefGoogle Scholar
  41. 41.
    Gabizon A, Papahadjopoulos D. The role of surface charge and hydrophilic groups on liposome clearance in vivo. Biochim Biophys Acta. 1992;1103:94–100.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of Bioscience and BioengineeringSejong UniversitySeoulRepublic of Korea
  2. 2.College of Pharmacy Research Institute of Pharmaceutical Science and TechnologyAjou UniversitySuwonRepublic of Korea
  3. 3.College of PharmacyWoosuk UniversityWanju-gunRepublic of Korea
  4. 4.Department of RadiologyYonsei University Health SystemSeoulRepublic of Korea

Personalised recommendations