OPERATING AND COMPOSITIONAL VARIABLES FOR PREPARATION OF BETULINIC ACID NANOEMULSIONS
Betulinic acid is a triterpene with remarkable biological activities, including anticancer and highlights the anti -HIV activity. In recent years, nanoemulsions have been used as delivery systems to improve the bioavailability of lipophilic bioactive compounds. In this work response surface methodology (RSM) by a central composite design was employed to evaluate the effects of emulsification power, ultrasonication time, emulsifier concentration in the characteristics of betulinic acid nanoemulsions. Optimal conditions for nanoemulsions formation were obtained and different emulsifiers and oils as the dispersed phase were studied. The effect of pH on globule size and zeta potential of betulinic acid nanoemulsions was studied. The statistical model used for globule size effectively fitted the experimental data with a R2 of 0.94. Operating conditions (power and emulsification time) and the quadratic terms, had significant effects on globule size. The optimal conditions to prepare nanoemulsions with an mean diameter of 64 nm were using 15% emulsifier (tween 60), and an ultrasonication power of 20 W during 220 s. Nanoemulsions prepared with medium chain oil as the dispersed phase had the lowest mean globule size; however, after storage time, nanoemulsions with the mixture medium chain oil:olive oil, the globule size remained unaltered. The pH variation changed the globule surface charge, values from -30 mV were obtained, and after storage time there was no significant change in the zeta potential.
Aiken, C. and Chen, C.H. (2005). Betulinic acid derivatives as HIV-1 antivirals. Trends in Molecular Medicine 11, 31-36.
Akowuah, G.A. and Zhari, I. (2008). Determination of betulinic acid from Orthosiphon stamineus leaf extract in rat plasma. Pharmazie 63, 788- 790.
Alakurtti, S., Makela T., Koskimies, S. and Kauhaluoma, Y.J. (2006). Pharmacological properties of the ubiquitous natural product betulin. European Journal of Pharmaceutical Sciences 29, 1-13.
Araujo, S.C., Mattos, A.C.A., Teixeira, H.F., Coelho, P.M.Z., Nelson, D.L. and Oliveira, M.C. (2007). Improvement of in vitro efficacy of novel schistomicidal drug by incorporation into nanoemulsions. International Journal of Pharmaceutics 337, 307-315.
Chaparro-Mercado, M.C., García-Ochoa, F., Hernández-Sánchez, H., Alamilla-Beltrán, L., Quintanilla-Carvajal, M.X., Cornejo-Mazón, M., Pedroza-Islas, R. and Gutiérrez-López, G.F. (2012). Design of an interstitial structure for a grape seed oil emulsion by design of experiments and surface response. Revista Mexicana de Ingeniería Química 11, 11-21.
Chau, C.F., Wu S.H. y Yen, G.C. (2007). The development of regulations for food nanotechnology. Trends in Food Science & Technology 18, 269-280
Chen, H., Weiss, J. and Shahidi, F. (2006). Nanotechnology in nutraceuticals and functional foods. Food Technology 60, 30-6.
Chintharlapalli, S. Papineni, S. Lei, P., Pathi S. and Safe, S. (2011). Betulinic acid inhibits colon cancer cell and tumor growth and induces proteasome-dependent and -independent downregulation of specificity proteins (Sp) transcription factors. BioMed Central Cancer 11, 371.
Ciurlea, S.A., Dehelean, C.A., Ionescu, D., Berko, S., Csanyi, E., Hadaruga, D.I., Ganta, S., and Amiji, M.M. (2010). A comparative study regarding melanoma activity of Betulinic acid on topical ointment vs. systemic nanoemulsion delivery systems. Journal of Agroalimentary Processes and Technologies 16, 420-426.
Clark, R.M., Yao, L., She, L. and Furr, H.C. (2000). A Comparison of Lycopene and Astaxanthin Absorption from Corn Oil and Olive Oil Emulsions. Lipids 35, 803-806.
Constantinides, P.P., Tustian, A. and Kessler, D.R. (2004). Tocol emulsions for drug solubilization and parenteral delivery. Advanced Drug Delivery Reviews 56, 1243- 1255.
Dehelean, C.A., Feflea, S., Ganta, S. and Amiji, M. (2011). Anti-angiogenic effects of betulinic acid administered in nanoemulsion formulation using chorioallantoic membrane assay. Journal of Biomedical Nanotechnology 7, 317-24.
De Melo, C.L., Queiroz, M.G.R., Arruda, A.C., Rodriguez, A.M., De Sousa, D.F., Almeida, J.G., Pessoa, O.D., Silveira, E.R., Menezes, D.B., Melo, T.S., Santos, F.A. and Rao, V.S. (2009). Betulinic Acid, a Natural Pentacyclic Triterpenoid, Prevents Abdominal Fat Accumulation in Mice Fed a High-Fat Diet. Journal of Agricultural and Food Chemistry 57, 8776-8781.
Donsí, F., Sessa, M., and Ferrari, G. (2012). Effect of Emulsifier Type and Disruption Chamber Geometry on the Fabrication of Food Nanoemulsions by High Pressure Homogenization. Industrial & Engineering Chemistry Research 51, 7606-7618.
Dowling, A.P. (2004). Development of nanotechnologies. Materials Today 7, 30-35
El Kinawy, O. S., Petersen, S. and Ulrich, J. (2012). Technological Aspects of Nanoemulsion Formation of Low-Fat Foods Enriched with Vitamin E by High-Pressure Homogenization. Chemical Engineering & Technology 35, 937- 940
Fulda, S. y Debatin, K.M. (2005). Sensitization for Anticancer Drug-Induced Apoptosis by Betulinic Acid. Neoplasia 7, 162-170.
Fulda, S. (2008). Betulinic acid for cancer treatment and prevention. International Journal of Molecular Sciences 9, 1096-1107.
Ganta, S. and Amiji, M. (2009). Coadministration of Paclitaxel and Curcumin in Nanoemulsion Formulations To Overcome Multidrug Resistance in Tumor Cells. Molecular Pharmaceutics 6, 928-939.
Gutiérrez, J.M., González, C., Maestro, A., Solé, I., Pey, C.M., and Nolla, J. (2008). Nanoemulsions: New applications and optimization of their preparation. Current Opinion in Colloid and Interface Science 13, 245-251.
Hsu, J.P. and Nacu, A. (2003). Behavior of soybean oil-in-water emulsion stabilized by nonionic surfactant. Journal of Colloid and Interface Science 259, 374-381.
Jafari, S.M., He, Y., & Bhandari, B. (2006). Nano-emulsion production by sonication and microfluidization - A comparison. International Journal of Food Properties 9, 475-485.
Jafari, S.M., He, Y. and Bhandari, B. (2007). Production of sub-micron emulsions by ultrasound and microfluidization techniques. Journal of Food Engineering 82, 478-488.
Jäger, S., Laszczyk, M.N. and Scheffler, A. (2008). A Preliminary Pharmacokinetic Study of Betulin, the Main Pentacyclic Triterpene from Extract of Outer Bark of Birch (Betulae alba cortex). Molecules 13, 3224-3235.
Kabanov A.V., Batrakova E.V. and Alakhov V.Y. (2002) Pluronic block copolymers as novel polymer therapeutics for drug and gene delivery. Journal of Controlled Release 82, 189-212.
Kelmann, R.G., Kuminek, G., Teixeira, H.F. and Koester, L.S. (2007). Carbamazepine parenteral nanoemulsions prepared by spontaneous emulsification process. International Journal of Pharmaceutics 342, 231-239.
Kentish, S., Wooster, T.J., Ashokkumar, M., Balachandran, S., Mawson, R., and Simons, L., (2008). The use of ultrasonics for nanoemulsion preparation. Innovative Food Science & Emerging Technologies 9, 170-175.
Klang, V. y Valenta, C. 2011. Lecithin-based nanoemulsions. Journal of Drug Delivery Science and Technology 21, 55-76.
Lee, S.J., Choi, S.J., Li, Y., Decker, E.A. and McClements, D.J. (2011). Protein-Stabilized Nanoemulsions and Emulsions: Comparison of Physicochemical Stability, Lipid Oxidation, and Lipase Digestibility. Journal of Agricultural and Food Chemistry 59, 415-427.
Li, P.H. y Chiang, B.H. (2012). Process optimization and stability of D-limonene-inwater nanoemulsions prepared by ultrasonic emulsification using response surface methodology. Ultrasonics Sonochemistry 19, 192-197.
Maali, A. and Hamed-Mosavian, M.T. (2013). Preparation and Application of Nanoemulsions in the Last Decade (2000-2010). Journal of Dispersion Science and Technology 34, 92-105.
Pisha, E., Chai, H., Lee, I.S., Chagwedera, T.E., Farnsworth, N.R., Cordell, G.A., Beecher, C.W.W., Fong, H.H.S., Kinghorn, A.D., Brown, D.M., Wani, M.C., Wall, M.E., Hieken, T.J., Gupta, T.K. and Pezzuto, J.M. (1995). Discovery of betulinic acid as a selective inhibitor of human melanoma that functions by induction of apoptosis. Nature Medicine 1, 1046 - 1051.
Qian, C., Decker, E.A., Xiao, H. and McClements, D.J. (2012). Physical and chemical stability of β-carotene-enriched nanoemulsions: Influence of pH, ionic strength, temperature, and emulsifier type. Food Chemistry 132, 1221- 1229.
Sadurní, N., Solans, C., Azemar, N. and García-Celma, M.J. (2005). Studies on the formation of O/W nano-emulsions, by lowenergy emulsification methods, suitable for pharmaceutical applications. European Journal of Pharmaceutical Sciences 26, 438-445.
Santos-Magalhaes, N.S. and Mosqueira, V.C. (2010). Nanotechnology applied to the treatment of malaria. Advanced Drug Delivery Reviews 62, 560-575.
Sawada, N., Kataoka, K., Kondo, K., Arimochi, H., Fujino, H., Takahashi, Y., Miyoshi, T., Kuwahara, T., Monden, Y. and Ohnishi, Y. (2004). Betulinic acid augments the inhibitory effects of vincristine on growth and lung metastasis of B16F10 melanoma cells in mice. British Journal of Cancer 90, 1672-1678.
Shafik, A., El Sibai, O., Shafik, A.A., and Shafik, I.A. (2007). Mechanism of gastric emptying through the pyloric sphincter: A human study. Medical Science Monitor 13, CR24-CR29.
Shah, L.K. and Amiji, M.M. (2006). Intracellular delivery of Saquinavir in biodegradable polymeric nanoparticles for HIV/AIDS. Pharmaceutical Research 23, 2638-2645.
Sharma, N., Bansal, M., Sharad, V., Sharma, P.K. and Kulkarni, G.T. (2010). Nanoemulsion: A new concept of delivery system. Chronicles of Young Scientists 1, 2-6.
Silva, H.D., Cerqueira M.A., and Vicente, A.A. (2012). Nanoemulsions for Food Applications: Development and Characterization. Food and Bioprocess Technology 5, 854-867.
Singh K. and Vingkar S. (2008). Formulation, antimalarial activity and biodistribution of oral lipid nanoemulsion of primaquine. International Journal of Pharmaceutics 347, 136-143.
Solans, C., Izquierdo, P., Nolla, J., Azemar, N. and Garcia, C.M.J. (2005). Nano-emulsions. Current Opinion in Colloid and Interface Science 10, 102-110.
Solans, C. and Solé, I. (2012). Nano-emulsions: Formation by low-energy methods. Current Opinion in Colloid and Interface Science 17, 246-254.
Sozer, N. and Kokini, J.L. (2009). Nanotechnology and its applications in the food sector. Trends in Biotechnology 27, 82-89.
Stalidis, G., Avranas, A., and Jannakoudakis, D. (1990). Interfacial properties and stability of oil-in-water emulsions stabilized with binary mixtures of surfactants. Journal of Colloid and Interface Science 35, 313-324.
Subramanian, B., Kuo, F., Ada, E., Kotyla, T., Wilson, T., Yoganathan, S. and Nicolosi, R. (2008). Enhancement of antiinflammatory property of aspirin in mice by a nano-emulsion preparation. International Immunopharmacology 8, 1533.
Tadros, T., Izquierdo, P. Esquena, J. and Solans, C. (2004). Formation and stability of nanoemulsions. Advances in Colloid and Interface Science 108-109, 303-318.
Tagne J.B., Kakumanu S. and Nicolosi R.J. (2008). Nanoemulsion preparations of the anticancer drug dacarbazine significantly increase its efficacy in a xenograft mouse melanoma model. Molecular Pharmaceutics 5, 1055-63.
Tang, S.Y., Shridharan, P. and Sivakumar, M. (2013). Impact of process parameters in the generation of novel aspirin nanoemulsions -Comparative studies between ultrasound cavitation and microfluidizer. Ultrasonics Sonochemistry 20, 485-497.
Tiwari, S.B. and Amiji, M.M. (2006). Improved oral delivery of paclitaxel following administration in nanoemulsion formulations. Journal of Nanoscience and Nanotechnology 6, 3215- 3221.
Vyas, T.K., Shahiwala, A. and Amiji, M.M. (2008). Improved oral bioavailability and brain transport of Saquinavir upon administration in novel nanoemulsion formulations. The International Journal of Pharmaceutics 347, 93-101.
Wang, L., Dong. J., Chen, J., Eastoe, J. and Li, X. (2009). Design and optimization of a new selfnanoemulsifying drug delivery system. Journal of Colloid and Interface Science 330, 443-448.
Yogeeswari, P. and Sriram, D. (2005). Betulinic acid and its derivatives: a review on their biological properties. Current Medicinal Chemistry 12, 657-666.
Yuan, Y., Gao, Y., Mao, L., Zhao, J. (2008). Optimization of conditions for the preparation of β-carotene nanoemulsions using response surface methodology. Food Chemistry 107, 1300-1306
Zhao, Y., Wang, C.G., Chowb, A.H.L., Ren, K., Gong, T., Zhang, Z.R. (2010). Selfnanoemulsifying drug delivery system (SNEDDS) for oral delivery of zedoary essential oil: Formulation and bioavailability studies. Int. J. Pharm. 383, 170-177.
Zuco, V., Supino, R., Righetti, S.C., Cleris, L., Marchesi, E., Gambacorti, P., and Formelli, F. (2002). Selective cytotoxicity of betulinic acid on tumor cell lines, but not on normal cells. Cancer Letters 175, 17-25.
By publishing your paper in our journal you are also granting it the copyright of the information that it contains.