Pharmaceutical Research

, Volume 21, Issue 10, pp 1834–1843 | Cite as

Supercooled Smectic Nanoparticles: A Potential Novel Carrier System for Poorly Water Soluble Drugs

  • J. Kuntsche
  • K. Westesen
  • M. Drechsler
  • M. H. J. Koch
  • H. Bunjes


Purpose. The possibility of preparing nanoparticles in the supercooled thermotropic liquid crystalline state from cholesterol esters with saturated acyl chains as well as the incorporation of model drugs into the dispersions was investigated using cholesteryl myristate (CM) as a model cholesterol ester.

Methods. Nanoparticles were prepared by high-pressure melt homogenization or solvent evaporation using phospholipids, phospholipid/bile salt, or polyvinyl alcohol as emulsifiers. The physicochemical state and phase behavior of the particles was characterized by particle size measurements (photon correlation spectroscopy, laser diffraction with polarization intensity differential scattering), differential scanning calorimetry, X-ray diffraction, and electron and polarizing light microscopy. The viscosity of the isotropic and liquid crystalline phases of CM in the bulk was investigated in dependence on temperature and shear rate by rotational viscometry.

Results. CM nanoparticles can be obtained in the smectic phase and retained in this state for at least 12 months when stored at 23°C in optimized systems. The recrystallization tendency of CM in the dispersions strongly depends on the stabilizer system and the particle size. Stable drug-loaded smectic nanoparticles were obtained after incorporation of 10% (related to CM) ibuprofen, miconazole, etomidate, and 1% progesterone.

Conclusions. Due to their liquid crystalline state, colloidal smectic nanoparticles offer interesting possibilities as carrier system for lipophilic drugs. CM nanoparticles are suitable model systems for studying the crystallization behavior and investigating the influence of various parameters for the development of smectic nanoparticles resistant against recrystallization upon storage.

cholesterol ester colloidal drug carrier colloidal emulsion lipid nanoparticles smectic phase 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    S. Klang and S. Benita. Design and evaluation of submicron emulsions as colloidal drug carriers for intravenous administra-tion. In S. Benita (ed.), Submicron Emulsions in Drug Targeting and Delivery, Harwood Academic Publishers, Amsterdam, 1998, pp. 119–152.Google Scholar
  2. 2.
    A. Sharma and U.S. Sharma. Liposomes in drug delivery: prog-ress and limitations. Int. J. Pharm. 4:123–140 (1997).Google Scholar
  3. 3.
    E. Fattal and C. Vauthier. Nanoparticles as drug delivery sys-tems. In J. Swarbrick and J. C. Boylan (eds.), Encyclopedia of Pharmaceutical Technology, Marcel Dekker, New York, 2002, pp. 1864–1882.Google Scholar
  4. 4.
    W. Mehnert and K. Mäder. Solid lipid nanoparticles. Production, characterization and applications. Adv. Drug. Deliver. Rev. 7: 165–196 (2001).Google Scholar
  5. 5.
    Y. A. Carpentier and I. E. Dupont. Advances in intravenous lipid emulsions. World J. Surg. 4:1493–1497 (2000).Google Scholar
  6. 6.
    C. Washington and K. Evans. Release rate measurements of model hydrophobic solutes from submicron triglyceride emul-sions. J. Control. Rel. 3:383–390 (1995).Google Scholar
  7. 7.
    K. Westesen, H. Bunjes, and M. H. J. Koch. Physicochemical characterization of lipid nanoparticles and evaluation of their drug loading capacity and sustained release potential. J. Control. Rel. 8:223–236 (1997).Google Scholar
  8. 8.
    H. Bunjes, K. Westesen, and M. H. J. Koch. Crystallization ten-dency and polymorphic transitions in triglyceride nanoparticles. Int. J. Pharm. 9:159–173 (1996).Google Scholar
  9. 9.
    K. Westesen and B. Siekmann. Investigation of the gel formation of phospholipid-stabilized solid lipid nanoparticles. Int. J. Pharm. 1:35–45 (1997).Google Scholar
  10. 10.
    H. Bunjes, M. H. J. Koch, and K. Westesen. Influence of emul-sifiers on the crystallization of solid lipid nanoparticles. J. Pharm. Sci. 2:1509–1520 (2003).Google Scholar
  11. 11.
    C. Freitas and R. H. Müller. Effect of light and temperature on zeta potential and physical stability in solid lipid nanoparticles (SLN) dispersions. Int. J. Pharm. 8:221–229 (1998).Google Scholar
  12. 12.
    G. S. Ginsburg, D. Atkinson, and D. M. Small. Physical proper-ties of cholesteryl esters. Prog. Lipid Res. 3:135–167 (1984).Google Scholar
  13. 13.
    T. Hevonoja, M. O. Pentikäinen, M. T. Hyvönen, P. T. Kovanen, and M. Ala-Korpela. Structure of low density lipoprotein (LDL) particles: Basis for understanding molecular changes in modified LDL. Biochim. Biophys. Acta 8:189–210 (2000).Google Scholar
  14. 14.
    R. A. Firestone. Low-density lipoprotein as vehicle for targeting antitumor compounds to cancer cells. Bioconj. Chem. 5:105–113 (1994).Google Scholar
  15. 15.
    R. C. Maranhāo, S. R. Graziani, N. Yamaguchi, R. F. Melo, M. C. Latrilha, D. G. Rodrigues, R. D. Couto, S. Schreier, and A. C. Buzaid. Association of carmustine with a lipid emulsion: In vitro, in vivo and preliminary studies in cancer patients. Cancer Che-moth. Pharmacol. 9:487–498 (2002).Google Scholar
  16. 16.
    K. Westesen, A. Gerke, and M. H. J. Koch. Characterization of native and drug-loaded human low density lipoproteins. J. Pharm. Sci. 4:139–147 (1995).Google Scholar
  17. 17.
    A. Gerke, K. Westesen, and M. H. J. Koch. Physicochemical characterization of protein-free low density lipoprotein models and influence of drug loading. Pharm. Res. 3:1–8 (1996).Google Scholar
  18. 18.
    B. Sjöström, B. Kronberg, and J. Carlfors. A method for the preparation of submicron particles of sparingly water soluble drugs by precipitation in o/w-emulsions. I. Influence of emulsification and surfactant concentration. J. Pharm. Sci. 2:579–583 (1993).Google Scholar
  19. 19.
    Renliang Xu. Improvements in particle size analysis using light scattering. In R. H. Müller and W. Mehnert (eds.), Particle and Surface Characterizing Methods.Scientific Publisher, Stuttgart, 1997, pp. 27–56.Google Scholar
  20. 20.
    M. H. J. Koch and J. Bordas. X-ray diffraction and scattering on disordered systems using synchrotron radiation. Nucl. Instrum. Methods 8:461–469 (1983).Google Scholar
  21. 21.
    G. Rapp, A. Gabriel, M. Dosie` re, and M. H. J. Koch. A dual detector single readout system for simultaneous small (SAXS) and wide angle X-ray (WAXS) scattering. Nucl Instrum Methods A7:178–182 (1995).Google Scholar
  22. 22.
    P. V. Konarev, V. V. Volkov, A. V. Sokolova, M. H. J. Koch, and D. I. Svergun. PRIMUS-a Windows-PC based system for small-angle scattering data analysis. J. Appl. Crystallogr. 6:1277–1282 (2003).Google Scholar
  23. 23.
    D. Chapman. The polymorphism of glycerides. Chem. Rev. 2: 433–456 (1962).Google Scholar
  24. 24.
    C. W. Hoerr and F. R. Paulicka. The role of X-ray diffraction in studies of the crystallography of monoacid saturated triglycer-ides. J. Am. Oil Chem. Soc. 5:793–797 (1968).Google Scholar
  25. 25.
    G. J. Davis, R. S. Porter, and E. M. Barrall. Evaluation of thermal transitions in some cholesteryl esters of saturated aliphatic acids. Mol. Cryst. Liquid Cryst. 0:1–19 (1970).Google Scholar
  26. 26.
    J. H. Wendorff and F. P. Price. The structure of mesophases of cholesteryl esters. Mol. Cryst. Liquid Cryst. 4:129–144 (1973).Google Scholar
  27. 27.
    K. Sakamoto, R.S. Porter, and J.F. Johnson. The viscosity of mesophases formed by cholesteryl myristate. In G. H. Brown (ed.), Liquid Crystals 2,Part II, Gordon and Breach Science Publishers, New York, 1969, pp. 237–249.Google Scholar
  28. 28.
    R. Finsy. Particle sizing by quasi-elastic light scattering. Adv. Coll. Interface Sci. 2:79–143 (1994).Google Scholar
  29. 29.
    J. Snow and M. C. Philipps. Phase behavior of cholesteryl ester dispersions which model the inclusions of foam cells. Biochemis-try 9:2464–2471 (1990).Google Scholar
  30. 30.
    H. Bunjes, B. Siekmann, and K. Westesen. Emulsions of super-cooled melts-a novel drug delivery system. In S. Benita (ed.), Submicron Emulsions in Drug Targeting and Delivery, Harwood academic publishers, Amsterdam, 1998, pp. 175–204.Google Scholar
  31. 31.
    M. J. Janiak, D. M. Small, and G. G. Shipley. Interactions of cholesterol esters with phospholipids: cholesteryl myristate and dimyristoyl lecithin. J. Lipid Res. 0:183–199 (1979).Google Scholar
  32. 32.
    R. Van Antwerpen and J. C. Gilkey. Cryo-electron microscopy reveals human low density lipoprotein substructure. J. Lipid Res. 5:2223–2231 (1994).Google Scholar

Copyright information

© Springer Science+Business Media, Inc. 2004

Authors and Affiliations

  • J. Kuntsche
    • 1
  • K. Westesen
    • 1
  • M. Drechsler
    • 1
    • 2
  • M. H. J. Koch
    • 3
  • H. Bunjes
    • 1
  1. 1.Friedrich-Schiller-University Jena, Institute of PharmacyDepartment of Pharmaceutical TechnologyJenaGermany
  2. 2.University of Bayreuth, Institute of ChemistryDepartment of Macromolecular ChemistryBayreuthGermany
  3. 3.European Molecular Biology LaboratoryHamburgGermany

Personalised recommendations