Abstract
The present study was aimed at synthesizing an imidazole-based ionic liquid 1-butyl-3-methylimidazolium bromide (BMIMBr) and subsequent development of a novel ionic liquid-in-oil (IL/o) microemulsion (ME) system for dermal delivery of a poorly permeating drug 5-fluorouracil (5-FU). A significant enhancement in the solubility of 5-FU was observed in BMIMBr. IL/o MEs of 5-FU were prepared using isopropyl myristate, Tween 80/Span 20, and BMIMBr. Results of ex vivo skin permeation studies through mice skin indicated that the selected IL/o ME exhibited 4-fold enhancement in percent drug permeation as compared to aqueous solution, 2.3-fold as compared to hydrophilic ointment, and 1.6-fold greater permeation than water in oil (w/o) ME. The results of in vivo studies against dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mice skin carcinogenesis demonstrated that the IL/o ME could effectively treat skin cancer in 4 weeks. In addition, the side effects such as erythema and irritation associated with the conventional formulations were not observed. Histopathological studies showed that the use of IL/o ME caused no anatomic and pathological changes in the skin structure of mice. These studies suggest that the use of IL-based ME system can efficiently enhance the solubility and permeability of 5-FU and hence its therapeutic efficacy.
Similar content being viewed by others
REFERENCES
Sun P, Daniel W, Armstrong W. Ionic liquids in analytical chemistry. Anal Chim Acta. 2010;661(1):1–16.
Zhou F, Liang Y, Liu W. Ionic liquid lubricants: designed chemistry for engineering applications. Chem Soc Rev. 2009;38:2590–9.
Berthod A, Ruiz-Angel MJ, Carda-Broch S. Ionic liquids in separation techniques. J Chromatogr A. 2008;1184:6–18.
Roy SR, Chakraborti AK. Supramolecular assemblies in ionic liquid catalysis for aza-Michael reaction. Org Lett. 2010;12:3866–9.
Stoimenovski J, MacFarlane DR, Bica K, Rogers RD. Crystalline vs. ionic liquid salt forms of active pharmaceutical ingredients: a position paper. Pharm Res. 2010;27:521–6.
Pernak J, Sobaszkiewicz K, Mirska I. Anti-microbial activities of ionic liquids. Green Chem. 2003;5:52–6.
Jaitely V, Karatas A, Florence AT. Water-immiscible room temperature ionic liquids (RTILs) as drug reservoirs for controlled release. Int J Pharm. 2008;354:168–73.
Mizuuchi H, Jaitely V, Murdan S, Florence A. Room temperature ionic liquids and their mixtures: potential pharmaceutical solvents. Eur J Pharm Sci. 2008;33:326–31.
Viau L, Tourné-Péteilh C, Devoisselle J-M, Vioux A. Ionogels as drug delivery system: one-step sol–gel synthesis using imidazolium ibuprofenate ionic liquid. Chem Commun. 2010;46:228–30.
Shah DO, Bagwe RP, Kanicky JR, Palla BJ, Patanjali PK. Improved drug delivery using microemulsions: rationale, recent progress, and new horizons. Crit Rev Ther Drug Carrier Syst. 2001;18:77–140.
Tenjarla S. Microemulsions: an overview and pharmaceutical applications. Crit Rev Ther Drug Carrier Syst. 1999;16:461–521.
Mandal S, Ghosh S, Banerjee C, Kuchlyan J, Banik D, Sarkar N. A novel ionic liquid-in-oil microemulsion composed of biologically acceptable components: an excitation wavelength dependent fluorescence resonance energy transfer study. J Phys Chem B. 2013;117(11):3221–31.
Eastoe J, Gold S, Rogers SE, Paul A, Welton T, Heenan RK, et al. Ionic liquid-in-oil microemulsions. J Am Chem Soc. 2005;127(20):7302–3.
Cao J, Qu H, Cheng Y. The use of novel ionic liquid-in-water microemulsion without the addition of organic solvents in a capillary electrophoretic system. Electrophoresis. 2010;31(20):3492–8.
Pavlidis IV, Tzafestas K, Stamatis H. Water-in-ionic liquid microemulsion-based organogels as novel matrices for enzyme immobilization. Biotechnol J. 2010;5(8):805–12.
Moniruzzaman M, Noriho K, Masahiro G. Ionic liquid based microemulsion with pharmaceutically accepted components: formulation and potential applications. J Colloid Interface Sci. 2010;352:136–42.
Moniruzzaman M, Tahara Y, Tamura M, Kamiya N, Goto M. Ionic liquid assisted transdermal delivery of sparingly soluble drugs. Chem Commun. 2010;47:1452–4.
Kumar N, Goindi S, Kumar S, Jana AK. The effect of N-alkyl substituents on the usability of imidazolium cation-based ionic liquids in microemulsion systems: a technical note. AAPS PharmSciTech. 2013. In press. DOI:10.1208/s12249-013-9939-z.
Heng CL, Yu LX, Lee HL, Yang CY, Lue CS, Chou CH. Biowaiver extension potential to BCS class III high solubility-low permeability drugs: bridging evidence for metformin immediate-release tablet. Eur J Pharm Sci. 2004;22(4):297–304.
Kurwa HA, Yong-Gee SA, Seed PT, Markey AC, Barlow RJ. A randomized paired comparison of photodynamic therapy and topical 5-fluorouracil in the treatment of actinic keratoses. J Am Acad Dermatol. 1999;41:414–8.
Epstein E. Does intermittent "pulse" topical 5-fluorouracil therapy allow destruction of actinic keratoses without significant inflammation? J Am Acad Dermatol. 1998;38:77–80.
Avdeef A. Solubility of sparingly-soluble ionizable drugs. Adv Drug Deliv Rev. 2007;59:568–90.23.
Shishu K, Maheshwari M. Development and evaluation of novel microemulsion based oral formulations of 5-fluorouracil using non-everted rat intestine sac model. Drug Dev Ind Pharm. 2012;38(3):294–300.
Tchakalova V, Testard F, Wong K, Parker A, Benczedi D, Zemb T. Solubilization and interfacial curvature in microemulsions: II. Surfactant efficiency and PIT. Colloids Surf A Physicochem Eng Asp. 2008;331:40–7.
Wankhade V, Pande S, Tapar K, Bobade N. Design and evaluation of self-nanoemulsifying drug delivery systems (SNEDDS) for Gliclazide. Der Pharmacia Lett. 2010;2(4):132–43.
Alani R, Tucker I, Davies N, Rades T. Characterizing colloidal structures of pseudoternary phase diagrams formed by oil/water/amphiphile systems. Drug Dev Ind Pharm. 2001;27:31–8.
Chen H, Chang X, Weng T, Zhao X, Gao Z, Yang Y, et al. A study of microemulsion systems for transdermal delivery of triptolide. J Controlled Release. 2004;98:427–36.
Oyewumi M, Yokel R, Jay M, Coakley T, Mumper R. Comparison of cell uptake, biodistribution and tumor retention of folate-coated and PEG-coated gadolinium nanoparticles in tumor-bearing mice. J Controlled Release. 2004;95:613–26.
Welin-Berger K, Neelissen B, Bergenstahl B. The effect of rheological behaviour of a topical anaesthetic formulation on the release and permeation rates of the active compound. Eur J Pharm Sci. 2001;13:309–18.
Shafiq S, Shakeel F, Talegaonkar S, Ahmad F, Khar R, Ali M. Development and bioavailability assessment of ramipril nanoemulsion formulation. Eur J Pharm Biopharm. 2007;66:227–43.
Bolzinger MA, Briancon S, Pelletier J, Fessi H, Chevalier Y. Percutaneous release of caffeine from microemulsion, emulsion and gel dosage forms. Eur J Pharm Biopharm. 2008;68:446–51.
Venter J, Muller D, du Plessis J, Goosen C. A comparative study of an in situ adapted diffusion cell and an in vitro Franz diffusion cell method for transdermal absorption of doxylamine. Eur J Pharm Sci. 2001;13:169–77.
Braun E, Wagner A, Furnschlief E, Katinger H, Vorauer-Uhl K. Experimental design for in vitro skin penetration study of liposomal superoxide dismutase. J Pharm Biomed Anal. 2006;40:1187–97.
Aggarwal N, Goindi S, Mehta SD. Preparation and evaluation of dermal delivery system of griseofulvin containing vitamin E-TPGS as penetration enhancer. AAPS PharmSciTech. 2012;13:67–74.
Basti′c M, Bastl′c L, Jovanovi′c JJ, Spiteller G. Hydrocarbons and other weakly polar unsaponifiables in some vegetable oils. J Am Oil Chem Soc. 2007;55(12):886–91.
Warisnoicharoen W, Lansley A, Lawrence M. Nonionic oil-in-water microemulsions: the effect of oil type on phase behaviour. Int J Pharm. 2000;198(1):7–27.
Shah D, Khandavilli S, Panchagnula R. Alteration of skin hydration and its barrier function by vehicle and permeation enhancers: a study using TGA, FTIR, TEWL and drug permeation as markers. Methods Find Exp Clin Pharmacol. 2008;30(7):499–512.
Moniruzzaman M, Tumara M, Tahara Y, Kamiya N, Goto M. Ionic liquid-in-oil microemulsion as apotential carrier of sparingly soluble drug: characterization and cytotoxicity evaluation. Int J Pharm. 2010;400(1–2):243–50.
Moniruzzaman M, Tahara Y, Tamura M, Kamiya N, Goto M. Ionic liquid assisted transdermal delivery of sparingly soluble drugs. Chem Commun. 2010;47(9):1452–4.
Baboota S, Alam M, Sharma S, Sahni JK, Kumar A, Ali J. Nanocarrier-based hydrogel of betamethasone dipropionate and salicylic acid for treatment of psoriasis. Int J Pharm Investig. 2011;1(13):139–47.
Lee CH, Moturi V, Lee Y. Thixotropic property in pharmaceutical formulations. J Controlled Release. 2009;136:88–98.
Dreher F, Walde P, Walther P, Wehrli E. Interaction of a lecithin microemulsion gel with human stratum corneum and its effect on transdermal transport. J Controlled Release. 1997;45:131–40.
Suh H, Jun HW. Effectiveness and mode of action of isopropyl myristate as a permeation enhancer for naproxen through shed snake skin. J Pharm Pharmacol. 1996;48:812–6.
Kreilgaard M. Influence of microemulsions on cutaneous drug delivery. Adv Drug Deliv Rev. 2002;54:77–98.
Peltola S, Saarinen-Savolainen P, Kiesvaara J, Suhonen TM, Urtti A. Microemulsions for topical delivery of estradiol. Int J Pharm. 2003;254:99–107.
Buyuktimkin N, Buyuktimkin S, Rytting JH. Chemical means of transdermal drug permeation enhancement. In: Ghosh T, Yum S, Pfister W, editors. Transdermal drug permeation enhancement. Buffalo Grove, IL, USA: Interpharm Press; 1997. p. 357–475.
Asbill CS, Michniak BB. Percutaneous penetration enhancers: local versus transdermal activity. Pharm Sci Technol Today. 2000;3(1):36–41.
Helman MD, Lukacsko AB, Thomas A, Zusi FC, inventors; Bristol-Myers Squibb Co., assignee. Method for enhancing transdermal penetration and compositions useful therein. USA patent US 5,164,406. 1992.
Sinha VR, Kaur MP. Permeation enhancers for transdermal drug delivery. Drug Dev Ind Pharm. 2000;26:1131–40.
Ahad A, Aqil M, Kohli K, Chaudhary H, Sultana Y, Mujeeb M, et al. Chemical penetration enhancers: a patent review. Expert Opin Ther Pat. 2009;19:969–88.
Acknowledgments
The authors acknowledge the kind help provided by Biochem Pharmaceutical Industries, Mumbai, in the form of free gift sample of 5-flurouracil.
Declaration of Interest
The authors report no declaration of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Goindi, S., Arora, P., Kumar, N. et al. Development of Novel Ionic Liquid-Based Microemulsion Formulation for Dermal Delivery of 5-Fluorouracil. AAPS PharmSciTech 15, 810–821 (2014). https://doi.org/10.1208/s12249-014-0103-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1208/s12249-014-0103-1