Abstract
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.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
REFERENCES
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.
A. Sharma and U.S. Sharma. Liposomes in drug delivery: prog-ress and limitations. Int. J. Pharm. 4:123–140 (1997).
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.
W. Mehnert and K. Mäder. Solid lipid nanoparticles. Production, characterization and applications. Adv. Drug. Deliver. Rev. 7: 165–196 (2001).
Y. A. Carpentier and I. E. Dupont. Advances in intravenous lipid emulsions. World J. Surg. 4:1493–1497 (2000).
C. Washington and K. Evans. Release rate measurements of model hydrophobic solutes from submicron triglyceride emul-sions. J. Control. Rel. 3:383–390 (1995).
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).
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).
K. Westesen and B. Siekmann. Investigation of the gel formation of phospholipid-stabilized solid lipid nanoparticles. Int. J. Pharm. 1:35–45 (1997).
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).
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).
G. S. Ginsburg, D. Atkinson, and D. M. Small. Physical proper-ties of cholesteryl esters. Prog. Lipid Res. 3:135–167 (1984).
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).
R. A. Firestone. Low-density lipoprotein as vehicle for targeting antitumor compounds to cancer cells. Bioconj. Chem. 5:105–113 (1994).
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).
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).
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).
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).
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.
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).
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).
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).
D. Chapman. The polymorphism of glycerides. Chem. Rev. 2: 433–456 (1962).
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).
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).
J. H. Wendorff and F. P. Price. The structure of mesophases of cholesteryl esters. Mol. Cryst. Liquid Cryst. 4:129–144 (1973).
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.
R. Finsy. Particle sizing by quasi-elastic light scattering. Adv. Coll. Interface Sci. 2:79–143 (1994).
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).
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.
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).
R. Van Antwerpen and J. C. Gilkey. Cryo-electron microscopy reveals human low density lipoprotein substructure. J. Lipid Res. 5:2223–2231 (1994).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Kuntsche, J., Westesen, K., Drechsler, M. et al. Supercooled Smectic Nanoparticles: A Potential Novel Carrier System for Poorly Water Soluble Drugs. Pharm Res 21, 1834–1843 (2004). https://doi.org/10.1023/B:PHAM.0000045237.46019.6e
Issue Date:
DOI: https://doi.org/10.1023/B:PHAM.0000045237.46019.6e