Abstract
Nanoemulsions are a class of two-phase liquid systems with an internal phase droplet size of less than 200 nm. Although two-phase emulsion systems have been known for decades, the concept of nanoemulsions is fairly recent. Nanoemulsion stability is far more reliable than traditional two-phase “macro”-emulsion systems, which has led to nanoemulsions becoming an attractive option for the delivery of diverse categories of lipophilic small molecule drugs and bioactive agents. This chapter presents an overview of the theories underlying the formulation of emulsions for maximum stability and potential for scale-up. Both low and high energy dispersive techniques have been discussed with suggestions of suitable equipment. Various techniques for formulation have been discussed with specific attention to the nature of the drug and suitability of the excipients. Correlations have been established between stability of nanoemulsions and the nature and concentration of the surfactant, cosurfactant, oil phase, and temperature. A brief section has been devoted to the in vitro characterization of nanoemulsions with reference to instrumentation and techniques used in the pharmaceutical industry. The last part of the chapter is devoted to the application of nanoemulsions in anticancer drug delivery, with examples on how these novel delivery systems can enhance the efficacy of anticancer drugs while significantly reducing the toxic effects of the chemotherapeutic agents.
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References
Alakhov V, Klinski E, Li S, Pietrzynski G, Venne A, Batrakova E, Bronitch T, Kabanov A. Block copolymer-based formulation of doxorubicin. From cell screen to clinical trials. Colloids Surf B: Biointerfaces. 1999;16(1–4):113–34.
Bagwe RP, Palla JKB, Patanjali PK. Improved drug delivery using. Crit Rev Ther Drug Carrier Syst. 2001;18(1):77–140.
Barker N, Hadgraft J. Facilitated percutaneous absorption: a model system. Int J Pharm. 1981;8(3):193–202.
Batrakova EV, Li S, Alakhov VY, Elmquist WF, Miller DW, Kabanov AV. Sensitization of cells overexpressing multidrug-resistant proteins by pluronic P85. Pharm Res. 2003;20(10):1581–90.
Becher P, editor. Encyclopedia of emulsion technology – Volume 1. Basic theory. New York: Marcel Dekker, Inc.; 1983. p. 725.
Benita S. Biofate of fat emulsions. In: Benita S, editor. Submicron emulsions in drug targeting and delivery. 1st ed. Singapore: Harwood Academic Publisher; 1998a. p. 99–118.
Benita S. Introduction and overview. In: Benita S, editor. Submicron emulsions in drug targeting and delivery. 1st ed. Singapore: Harwood Academic Publisher; 1998b. p. 1–3.
Bolzinger-Thevenin MA, Grossiord JL, Poelman MC. Characterization of a sucrose ester microemulsion by freeze fracture electron micrograph and small angle neutron scattering experiments. Langmuir. 1999;15(7):2307–15.
Buyukozturk F, Benneyan JC, Carrier RL. Impact of emulsion-based drug delivery systems on intestinal permeability and drug release kinetics. J Control Release. 2010;142(1):22–30.
Chansri N, Kawakami S, Yamashita F, Hashida M. Inhibition of liver metastasis by all-trans retinoic acid incorporated into O/W emulsions in mice. Int J Pharm. 2006;321(1–2):42–9.
Chidambaran N, Burgess D. Emulsions: design and manufacture. In: Burgess DJ, editor. Injectable dispersed systems. Boca Raton: Taylor & Francis; 2005. p. 213–41.
Clark SB, Derksen A. Phosphatidylcholine composition of emulsions influences triacylglycerol lipolysis and clearance from plasma. Biochim Biophys Acta. 1987;920(1):37–46.
D’Souza S. A review of in vitro drug release test methods for nano-sized dosage forms. Adv Pharm. 2014;2014:304757.
Dias ML, Carvalho JP, Rodrigues DG, Graziani SR, Maranhao RC. Pharmacokinetics and tumor uptake of a derivatized form of paclitaxel associated to a cholesterol-rich nanoemulsion (LDE) in patients with gynecologic cancers. Cancer Chemother Pharmacol. 2007;59(1):105–11.
Evers R, Kool M, Smith AJ, Van Deemter L, De Haas M, Borst P. Inhibitory effect of the reversal agents V-104, GF120918 and Pluronic L61 on MDR1 Pgp-, MRP1-and MRP2-mediated transport. Br J Cancer. 2000;83(3):366–74.
Fang J, Sawa T, Maeda H. Factors and mechanism of “EPR” effect and the enhanced antitumor effects of macromolecular drugs including SMANCS. In: Polymer drugs in the clinical stage. Boston: Springer; 2004. p. 29–49.
Gao ZG, Choi HG, Shin HJ, Park KM, Lim SJ, Hwang KJ, Kim CK. Physicochemical characterization and evaluation of a microemulsion system for oral delivery of cyclosporin A. Int J Pharm. 1998;161(1):75–86.
Gao P, Rush BD, Pfund WP, Huang T, Bauer JM, Morozowich W, Kuo MS, Hageman MJ. Development of a supersaturable SEDDS (S-SEDDS) formulation of paclitaxel with improved oral bioavailability. J Pharm Sci. 2003;92(12):2386–98.
Garti A, and Aserin A. Pharmaceutical emulsions, double emulsions, and microemulsions. In: Benita S, ed. Microencapsulation. New York: Marcel Dekker, Inc.; 1996. p. 411–534.
Gershanik T, Benita S. Self-dispersing lipid formulations for improving oral absorption of lipophilic drugs. Eur J Pharm Biopharm. 2000;50(1):179–88.
Ghosh PK, Murthy RSR. Microemulsions: a potential drug delivery system. Curr Drug Deliv. 2006;3(2):167–80.
Goldstein D, Gofrit O, Nyska A, Benita S. Anti-HER2 cationic immunoemulsion as a potential targeted drug delivery system for the treatment of prostate cancer. Cancer Res. 2007;67(1):269–75.
Griffin WC. Calculation of HLB values of non-ionic surfactants. J Soc Cosmet Chem. 1954;5:249–56.
Gursoy RN, Benita S. Self-emulsifying drug delivery systems (SEDDS) for improved oral delivery of lipophilic drugs. Biomed Pharmacother. 2004;58(3):173–82.
Haskell RJ, Shifflett JR, Elzinga PA. Particle-sizing technologies for submicron emulsions. In: Submicron emulsions in drug targeting and delivery, vol. 9. Amsterdam: Harwood Academic Publishers; 1998. p. 21–98.
Hauss DJ, Fogal SE, Ficorilli JV, Price CA, Roy T, Jayaraj AA, Keirns JJ. Lipid-based delivery systems for improving the bioavailability and lymphatic transport of a poorly water-soluble LTB4 inhibitor. J Pharm Sci. 1998;87(2):164–9.
Karasulu HY, Karabulut B, Göker E, Güneri T, Gabor F. Controlled release of methotrexate from w/o microemulsion and its in vitro antitumor activity. Drug Deliv. 2007;14(4):225–33.
Kovarik JM, Mueller EA, Kutz K, Van Bree JB, Tetzloff W. Reduced inter-and intraindividual variability in cyclosporine pharmacokinetics from a microemulsion formulation. J Pharm Sci. 1994;83(3):444–6.
Kuo F, Kotyla T, Wilson T, Kifle L, Panagiotou T, Gruverman I, Tagne JB, Shea T, Nicolosi R. A nanoemulsion of an anti-oxidant synergy formulation reduces tumor growth rate in neuroblastoma-bearing nude mice. J Exp Ther Oncol. 2007;6(2):129–35.
Li P, Ghosh A, Wagner RF, Krill S, Joshi YM, Serajuddin AT. Effect of combined use of nonionic surfactant on formation of oil-in-water microemulsions. Int J Pharm. 2005;288(1):27–34.
Maali A, Mosavian MH. Preparation and application of nanoemulsions in the last decade (2000–2010). J Dispers Sci Technol. 2013;34(1):92–105.
Maeda H. SMANCS and polymer-conjugated macromolecular drugs: advantages in cancer chemotherapy. Adv Drug Deliv Rev. 1991;6(2):181–202.
Maeda HAYM, Matsumura Y. Tumoritropic and lymphotropic principles of macromolecular drugs. Crit Rev Ther Drug Carrier Syst. 1989;6(3):193–210.
Maeda H, Wu J, Sawa T, Matsumura Y, Hori K. Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J Control Release. 2000;65(1–2):271–84.
Magdassi S, Frenkel M, Garti N. On the factors affecting the yield of preparation and stability of multiple emulsions. J Dispers Sci Andtechnol. 1984;5(1):49–59.
Maranhao RC, Graziani SR, Yamaguchi N, Melo RF, Latrilha MC, Rodrigues DG, Couto RD, Schreier S, Buzaid AC. Association of carmustine with a lipid emulsion: in vitro, in vivo and preliminary studies in cancer patients. Cancer Chemother Pharmacol. 2002;49(6):487–98.
Mehta SK, Bala K. Phase behavior, structural effects, and volumetric and transport properties in nonaqueous microemulsions. Phys Rev E. 1999;59(4):4317.
Nakajima H, Tomomasa S, Okabe M. Proceedings of first world emulsion conference, vol. 1. Paris: EDS; 1993. p. 1–11.
Nishikawa M, Takakura Y, Hashida M. Biofate of fat emulsions. In: Submicron emulsions in drug targeting and delivery, vol. 9. Amsterdam: Harwood Academic Publisher; 1998. p. 99–118.
Pinnamaneni S, Das NG, Das SK. Comparison of oil-in-water emulsions manufactured by microfluidization and homogenization. Die Pharmazie. 2003;58(8):554–8.
Prete ACL, Maria DA, Rodrigues DBG, Valduga CJ, Ibañez OC, Maranhão RC. Evaluation in melanoma-bearing mice of an etoposide derivative associated to a cholesterol-rich nanoemulsion. J Pharm Pharmacol. 2006;58(6):801–8.
Rani S, Rana R, Saraogi GK, Kumar V, Gupta U. Self-emulsifying oral lipid drug delivery systems: advances and challenges. AAPS PharmSciTech. 2019;20(3):129.
Redgrave TG, Rakic V, Mortimer BC, Mamo JC. Effects of sphingomyelin and phosphatidylcholine acyl chains on the clearance of triacylglycerol-rich lipoproteins from plasma. Studies with lipid emulsions in rats. Biochim Biophys Acta. 1992;1126(1):65–72.
Rieger MM. Emulsions. In: Lachman L, Lieberman H, Kanig J, editors. The theory and practice of industrial pharmacy. 3rd ed. Philadelphia: Lea & Febiger; 1986. p. 502–32.
Rodrigues DG, Covolan CC, Coradi ST, Barboza R, Maranhão RC. Use of a cholesterol-rich emulsion that binds to low-density lipoprotein receptors as a vehicle for paclitaxel. J Pharm Pharmacol. 2002;54(6):765–72.
Rosoff M. Specialized pharmaceutical emulsions. In: Lieberman HA, Rieger MM, Banker GS, editors. Pharmaceutical dosage forms: disperse systems. 2nd ed. New York: Marcel Dekker, Inc.; 1996. p. 1–35.
Russel WB, Russel WB, Saville DA, Schowalter WR. Colloidal dispersions. New York: Cambridge University Press; 1991.
Salager JL. Formulation concepts for the emulsion maker. In: Nielloud F, Mart-Mestres G, editors. Pharmaceutical emulsions and suspensions. New York: Marcel Dekker, Inc.; 2000. p. 19–68.
Shinoda K, Araki M, Sadaghiani A, Khan A, Lindman B. Lecithin-based microemulsions: phase behavior and microstructure. J Phys Chem. 1991;95(2):989–93.
Singh Y, Meher JG, Raval K, Khan FA, Chaurasia M, Jain NK, Chourasia MK. Nanoemulsion: concepts, development and applications in drug delivery. J Control Release. 2017;252:28–49.
Solans C, Solé I. Nano-emulsions: formation by low-energy methods. Curr Opin Colloid Interface Sci. 2012;17(5):246–54.
Terek MC, Karabulut B, Selvi N, Akman L, Karasulu Y, Ozguney I, Sanli AU, Uslu R, Ozsaran A. Arsenic trioxide–loaded, microemulsion-enhanced cytotoxicity on MDAH 2774 ovarian carcinoma cell line. Int J Gynecol Cancer. 2006;16(2):532–7.
Venne A, Li S, Mandeville R, Kabanov A, Alakhov V. Hypersensitizing effect of pluronic L61 on cytotoxic activity, transport, and subcellular distribution of doxorubicin in multiple drug-resistant cells. Cancer Res. 1996;56(16):3626–9.
Yeşim Karasulu H, Karabulut B, Kantarci G, Özgüney I, Sezgin C, Sanli UA, Göker E. Preparation of arsenic trioxide-loaded microemulsion and its enhanced cytotoxicity on MCF-7 breast carcinoma cell line. Drug Deliv. 2004;11(6):345–50.
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Rafique, S., Das, N.G., Das, S.K. (2021). Nanoemulsions: An Emerging Technology in Drug Delivery. In: Patel, J.K., Pathak, Y.V. (eds) Emerging Technologies for Nanoparticle Manufacturing. Springer, Cham. https://doi.org/10.1007/978-3-030-50703-9_17
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