Supercooled Smectic Nanoparticles: A Potential Novel Carrier System for Poorly Water Soluble Drugs
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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.
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- 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.A. Sharma and U.S. Sharma. Liposomes in drug delivery: prog-ress and limitations. Int. J. Pharm. 4:123–140 (1997).Google Scholar
- 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.W. Mehnert and K. Mäder. Solid lipid nanoparticles. Production, characterization and applications. Adv. Drug. Deliver. Rev. 7: 165–196 (2001).Google Scholar
- 5.Y. A. Carpentier and I. E. Dupont. Advances in intravenous lipid emulsions. World J. Surg. 4:1493–1497 (2000).Google Scholar
- 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.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.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.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.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.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.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.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.R. A. Firestone. Low-density lipoprotein as vehicle for targeting antitumor compounds to cancer cells. Bioconj. Chem. 5:105–113 (1994).Google Scholar
- 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.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.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.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.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.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.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.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.D. Chapman. The polymorphism of glycerides. Chem. Rev. 2: 433–456 (1962).Google Scholar
- 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.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.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.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.R. Finsy. Particle sizing by quasi-elastic light scattering. Adv. Coll. Interface Sci. 2:79–143 (1994).Google Scholar
- 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.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.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.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