Abstract
Curcumin-loaded chitosan nanoparticles were synthesised and evaluated in vitro for enhanced transdermal delivery. Zetasizer® characterisation of three different formulations of curcumin nanoparticles (Cu-NPs) showed the size ranged from 167.3 ± 3.8 nm to 251.5 ± 5.8 nm, the polydispersity index (PDI) values were between 0.26 and 0.46 and the zeta potential values were positive (+ 18.1 to + 20.2 mV). Scanning electron microscopy (SEM) images supported this size data and confirmed the spherical shape of the nanoparticles. All the formulations showed excellent entrapment efficiency above 80%. FTIR results demonstrate the interaction between chitosan and sodium tripolyphosphate (TPP) and confirm the presence of curcumin in the nanoparticle. Differential scanning calorimetry (DSC) studies of Cu-NPs indicate the presence of curcumin in a disordered crystalline or amorphous state, suggesting the interaction between the drug and the polymer. Drug release studies showed an improved drug release at pH 5.0 than in pH 7.4 and followed a zero order kinetics. The in vitro permeation studies through Strat-M® membrane demonstrated an enhanced permeation of Cu-NPs compared to aqueous curcumin solution (p ˂ 0.05) having a flux of 0.54 ± 0.03 μg cm−2 h−1 and 0.44 ± 0.03 μg cm−2 h−1 corresponding to formulations 5:1 and 3:1, respectively. The cytotoxicity assay on human keratinocyte (HaCat) cells showed enhanced percentage cell viability of Cu-NPs compared to curcumin solution. Cu-NPs developed in this study exhibit superior drug release and enhanced transdermal permeation of curcumin and superior percentage cell viability. Further ex vivo and in vivo evaluations will be conducted to support these findings.
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References
Ren C, Fang L, Ling L, Wang Q, Liu S, Zhao L, et al. Design and in vivo evaluation of an indapamide transdermal patch. Int J Pharm. 2009;370:129–35.
Zhao Y, Brown MB, Jones SA. Pharmaceutical foams: are they the answer to the dilemma of topical nanoparticles? Nanomedicine. 2010;6:227–36. https://doi.org/10.1016/j.nano.2009.08.002.
Palmer BC, DeLouise LA. Nanoparticle-enabled transdermal drug delivery systems for enhanced dose control and tissue targeting. Molecules. 2016;21:1719.
Williams AC, Barry BW. Penetration enhancers. Adv Drug Deliv Rev. 2004;56:603–18. https://doi.org/10.1016/j.addr.2003.10.025.
Pegoraro C, MacNeil S, Battaglia G. Transdermal drug delivery: from micro to nano. Nanoscale. 2012;4:1881–94.
Naksuriya O, Okonogi S, Schiffelers RM, Hennink WE. Curcumin nanoformulations: a review of pharmaceutical properties and preclinical studies and clinical data related to cancer treatment. Biomaterials. 2014;35:3365–83.
Sun M, Su X, Ding B, He X, Liu X, Yu A, et al. Advances in nanotechnology-based delivery systems for curcumin. Nanomedicine. 2012;7:1085–100.
Wang Y-J, Pan M-H, Cheng A-L, Lin L-I, Ho Y-S, Hsieh C-Y, et al. Stability of curcumin in buffer solutions and characterization of its degradation products. J Pharm Biomed Anal. 1997;15:1867–76. https://doi.org/10.1016/S0731-7085(96)02024-9.
Sharma RA, Gescher AJ, Steward WP. Curcumin: the story so far. Eur J Cancer. 2005;41:1955–68. https://doi.org/10.1016/j.ejca.2005.05.009.
Chaudhary H, Kohli K, Kumar V. Nano-transfersomes as a novel carrier for transdermal delivery. Int J Pharm. 2013;454:367–80.
Jose A, Labala S, Ninave KM, Gade SK, Venuganti VVK. Effective skin cancer treatment by topical co-delivery of curcumin and STAT3 siRNA using cationic liposomes. AAPS PharmSciTech. 2018;19(1):166–75. https://doi.org/10.1208/s12249-017-0833-y.
Alves TF, Chaud MV, Grotto D, Jozala AF, Pandit R, Rai M, et al. Association of silver nanoparticles and curcumin solid dispersion: antimicrobial and antioxidant properties. AAPS PharmSciTech. 2018;19:225–31. https://doi.org/10.1208/s12249-017-0832-z.
Raju YP, N H, Chowdary VH, Nair RS, Basha DJ, N T. In vitro assessment of non-irritant microemulsified voriconazole hydrogel system. Artif Cells Nanomed Biotechnol. 2017;45:1539–47. https://doi.org/10.1080/21691401.2016.1260579.
Rachmawati H, Yulia LY, Rahma A, Nobuyuki M. Curcumin-loaded PLA nanoparticles: formulation and physical evaluation. Sci Pharm. 2016;84(1):191–202.
Mangalathillam S, Rejinold NS, Nair A, Lakshmanan V-K, Nair SV, Jayakumar R. Curcumin loaded chitin nanogels for skin cancer treatment via the transdermal route. Nanoscale. 2012;4:239–50.
Sintov AC. Transdermal delivery of curcumin via microemulsion. Int J Pharm. 2015;481(1–2):97–103. https://doi.org/10.1016/j.ijpharm.2015.02.005.
Liu CH, Chang FY, Hung DK. Terpene microemulsions for transdermal curcumin delivery: effects of terpenes and cosurfactants. Colloids Surf B. 2011;82:63–70. https://doi.org/10.1016/j.colsurfb.2010.08.018.
Ariamoghaddam AR, Ebrahimi-Hosseinzadeh B, Hatamian-Zarmi A, Sahraeian R. In vivo anti-obesity efficacy of curcumin loaded nanofibers transdermal patches in high-fat diet induced obese rats. Mater Sci Eng C. 2018;92:161–71. https://doi.org/10.1016/j.msec.2018.06.030.
Ravikumar R, Ganesh M, Senthil V, Ramesh YV, Jakki SL, Choi EY. Tetrahydro curcumin loaded PCL-PEG electrospun transdermal nanofiber patch: preparation, characterization, and in vitro diffusion evaluations. J Drug Deliv Sci Technol. 2018;44:342–8. https://doi.org/10.1016/j.jddst.2018.01.016.
Ravikumar R, Ganesh M, Ubaidulla U, Young Choi E, Tae Jang H. Preparation, characterization, and in vitro diffusion study of nonwoven electrospun nanofiber of curcumin-loaded cellulose acetate phthalate polymer. Saudi Pharm J. 2017;25:921–6. https://doi.org/10.1016/j.jsps.2017.02.004.
Li M, Gao M, Fu Y, Chen C, Meng X, Fan A, et al. Acetal-linked polymeric prodrug micelles for enhanced curcumin delivery. Colloids Surf B. 2016;140:11–8. https://doi.org/10.1016/j.colsurfb.2015.12.025.
Li H, Li M, Chen C, Fan A, Kong D, Wang Z, et al. On-demand combinational delivery of curcumin and doxorubicin via a pH-labile micellar nanocarrier. Int J Pharm. 2015;495(1):572–8. https://doi.org/10.1016/j.ijpharm.2015.09.022.
Cao Y, Gao M, Chen C, Fan A, Zhang J, Kong D, et al. Triggered-release polymeric conjugate micelles for on-demand intracellular drug delivery. Nanotechnology. 2015;26:115101. https://doi.org/10.1088/0957-4484/26/11/115101.
Wang Z, Chen C, Zhang Q, Gao M, Zhang J, Kong D, et al. Tuning the architecture of polymeric conjugate to mediate intracellular delivery of pleiotropic curcumin. Eur J Pharm Biopharm. 2015;90:53–62. https://doi.org/10.1016/j.ejpb.2014.11.002.
Pathan IB, Jaware BP, Shelke S, Ambekar W. Curcumin loaded ethosomes for transdermal application: formulation, optimization, in-vitro and in-vivo study. J Drug Deliv Sci Technol. 2018;44:49–57. https://doi.org/10.1016/j.jddst.2017.11.005.
Gupta NK, Dixit VK. Development and evaluation of vesicular system for curcumin delivery. Arch Dermatol Res. 2011;303:89–101. https://doi.org/10.1007/s00403-010-1096-6.
Naik A, Kalia YN, Guy RH, Fessi H. Enhancement of topical delivery from biodegradable nanoparticles. Pharm Res. 2004;21:1818–25.
Abdel-Hafez SM, Hathout RM, Sammour OA. Tracking the transdermal penetration pathways of optimized curcumin-loaded chitosan nanoparticles via confocal laser scanning microscopy. Int J Biol Macromol. 2018;108:753–64. https://doi.org/10.1016/j.ijbiomac.2017.10.170.
Merisko-Liversidge EM, Liversidge GG. Drug nanoparticles: formulating poorly water-soluble compounds. Toxicol Pathol. 2008;36:43–8. https://doi.org/10.1177/0192623307310946.
Kean T, Thanou M. Biodegradation, biodistribution and toxicity of chitosan. Adv Drug Deliv Rev. 2010;62:3–11. https://doi.org/10.1016/j.addr.2009.09.004.
Wedmore I, McManus JG, Pusateri AE, Holcomb JB. A special report on the chitosan-based hemostatic dressing: experience in current combat operations. J Trauma. 2006;60:655–8. https://doi.org/10.1097/01.ta.0000199392.91772.44.
Gan Q, Wang T, Cochrane C, McCarron P. Modulation of surface charge, particle size and morphological properties of chitosan–TPP nanoparticles intended for gene delivery. Colloids Surf B. 2005;44:65–73.
Koukaras EN, Papadimitriou SA, Bikiaris DN, Froudakis GE. Insight on the formation of chitosan nanoparticles through ionotropic gelation with tripolyphosphate. Mol Pharm. 2012;9:2856–62.
Taveira SF, Nomizo A, Lopez RFV. Effect of the iontophoresis of a chitosan gel on doxorubicin skin penetration and cytotoxicity. J Control Release. 2009;134:35–40. https://doi.org/10.1016/j.jconrel.2008.11.002.
Calvo P, Remunan-Lopez C, Vila-Jato J, Alonso M. Novel hydrophilic chitosan-polyethylene oxide nanoparticles as protein carriers. J Appl Polym Sci. 1997;63:125–32.
Chuah LH, Billa N, Roberts CJ, Burley JC, Manickam S. Curcumin-containing chitosan nanoparticles as a potential mucoadhesive delivery system to the colon. Pharm Dev Technol. 2013;18:591–9. https://doi.org/10.3109/10837450.2011.640688.
Luo Y, Zhang B, Cheng W-H, Wang Q. Preparation, characterization and evaluation of selenite-loaded chitosan/TPP nanoparticles with or without zein coating. Carbohydr Polym. 2010;82:942–51.
Amekyeh H, Billa N, Yuen K-H, Chin SLS. A gastrointestinal transit study on amphotericin b-loaded solid lipid nanoparticles in rats. AAPS PharmSciTech. 2015;16:871–7.
Pawar HA, Mane SS, Attarde VB. Novel vesicular drug delivery system for topical delivery of indomethacin. Drug Deliv Lett. 2015;5:40–51.
Ajun W, Yan S, Li G, Huili L. Preparation of aspirin and probucol in combination loaded chitosan nanoparticles and in vitro release study. Carbohydr Polym. 2009;75:566–74. https://doi.org/10.1016/j.carbpol.2008.08.019.
Nair RS, Nair S. Permeation studies of captopril transdermal films through human cadaver skin. Curr Drug Deliv. 2015;12:517–23.
Chen H, Chang X, Du D, Li J, Xu H, Yang X. Microemulsion-based hydrogel formulation of ibuprofen for topical delivery. Int J Pharm. 2006;315:52–8.
Rajesh S, Sujith S. Permeation of flurbiprofen polymeric films through human cadaver skin. Int J Pharm Tech Res. 2013;5:177–82.
Ohya Y, Shiratani M, Kobayashi H, Ouchi T. Release behavior of 5-fluorouracil from chitosan-gel nanospheres immobilizing 5-fluorouracil coated with polysaccharides and their cell specific cytotoxicity. J Macromol Sci A. 1994;31:629–42.
Fan W, Yan W, Xu Z, Ni H. Formation mechanism of monodisperse, low molecular weight chitosan nanoparticles by ionic gelation technique. Colloids Surf B. 2012;90:21–7.
Shu X, Zhu K. The influence of multivalent phosphate structure on the properties of ionically cross-linked chitosan films for controlled drug release. Eur J Pharm Biopharm. 2002;54:235–43.
Wang QZ, Chen XG, Liu N, Wang SX, Liu CS, Meng XH, et al. Protonation constants of chitosan with different molecular weight and degree of deacetylation. Carbohydr Polym. 2006;65:194–201. https://doi.org/10.1016/j.carbpol.2006.01.001.
Kotze AF, Thanou MM, Luessen HL, de Boer BG, Verhoef JC, Junginger HE. Effect of the degree of quaternization of N-trimethyl chitosan chloride on the permeability of intestinal epithelial cells (Caco-2). Eur J Pharm Biopharm. 1999;47:269–74.
Hamman JH, Stander M, Kotzé AF. Effect of the degree of quaternisation of N-trimethyl chitosan chloride on absorption enhancement: in vivo evaluation in rat nasal epithelia. Int J Pharm. 2002;232:235–42. https://doi.org/10.1016/S0378-5173(01)00914-0.
He W, Guo X, Xiao L, Feng M. Study on the mechanisms of chitosan and its derivatives used as transdermal penetration enhancers. Int J Pharm. 2009;382:234–43. https://doi.org/10.1016/j.ijpharm.2009.07.038.
Gallo RL, Hooper LV. Epithelial antimicrobial defence of the skin and intestine. Nat Rev Immunol. 2012;12:503–16. https://doi.org/10.1038/nri322853.
de Pinho Neves AL, Milioli CC, Müller L, Riella HG, Kuhnen NC, Stulzer HK. Factorial design as tool in chitosan nanoparticles development by ionic gelation technique. Colloid Surf A. 2014;445:34–9.
Grenha A, Seijo B, Serra C, Remuñán-López C. Chitosan nanoparticle-loaded mannitol microspheres: structure and surface characterization. Biomacromolecules. 2007;8:2072–9. https://doi.org/10.1021/bm061131g.
Wan S, Sun Y, Qi X, Tan F. Improved bioavailability of poorly water-soluble drug curcumin in cellulose acetate solid dispersion. AAPS PharmSciTech. 2012;13:159–66. https://doi.org/10.1208/s12249-011-9732-9.
Chereddy KK, Coco R, Memvanga PB, Ucakar B, des Rieux A, Vandermeulen G, et al. Combined effect of PLGA and curcumin on wound healing activity. J Control Release. 2013;171:208–15. https://doi.org/10.1016/j.jconrel.2013.07.015.
Naghibzadeh M, Amani A, Amini M, Esmaeilzadeh E, Mottaghi-Dastjerdi N, Faramarzi MA. An insight into the interactions between α-tocopherol and chitosan in ultrasound-prepared nanoparticles. J Nanomater. 2010;2010:44.
Singh AV, Nath LK. Synthesis and evaluation of physicochemical properties of cross-linked sago starch. Int J Biol Macromol. 2012;50:14–8.
Paradkar A, Ambike AA, Jadhav BK, Mahadik KR. Characterization of curcumin–PVP solid dispersion obtained by spray drying. Int J Pharm. 2004;271:281–6. https://doi.org/10.1016/j.ijpharm.2003.11.014.
Sarmento B, Ferreira D, Veiga F, Ribeiro A. Characterization of insulin-loaded alginate nanoparticles produced by ionotropic pre-gelation through DSC and FTIR studies. Carbohydr Polym. 2006;66:1–7. https://doi.org/10.1016/j.carbpol.2006.02.008.61.
Borges O, Borchard G, Verhoef JC, de Sousa A, Junginger HE. Preparation of coated nanoparticles for a new mucosal vaccine delivery system. Int J Pharm. 2005;299:155–66. https://doi.org/10.1016/j.ijpharm.2005.04.037.
Parize AL, Stulzer HK, Laranjeira MCM, da Costa Brighente IM, de Souza TCR. Evaluation of chitosan microparticles containing curcumin and crosslinked with sodium tripolyphosphate produced by spray drying. Quim Nova. 2012;35:1127–32.
Dudhani AR, Kosaraju SL. Bioadhesive chitosan nanoparticles: preparation and characterization. Carbohydr Polym. 2010;81:243–51.
Tsai M-L, Chen R-H, Bai S-W, Chen W-Y. The storage stability of chitosan/tripolyphosphate nanoparticles in a phosphate buffer. Carbohydr Polym. 2011;84:756–61. https://doi.org/10.1016/j.carbpol.2010.04.040.
Hariharan S, Bhardwaj V, Bala I, Sitterberg J, Bakowsky U, Ravi Kumar MNV. Design of estradiol loaded PLGA Nanoparticulate formulations: a potential oral delivery system for hormone therapy. Pharm Res. 2006;23:184–95. https://doi.org/10.1007/s11095-005-8418-y.
Ko J, Park HJ, Hwang S, Park J, Lee J. Preparation and characterization of chitosan microparticles intended for controlled drug delivery. Int J Pharm. 2002;249:165–74.67.
Katas H, Hussain Z, Ling TC. Chitosan nanoparticles as a percutaneous drug delivery system for hydrocortisone. J Nanomater. 2012;2012:45.
Uchida T, Kadhum WR, Kanai S, Todo H, Oshizaka T, Sugibayashi K. Prediction of skin permeation by chemical compounds using the artificial membrane, Strat-M™. Eur J Pharm Sci. 2015;67:113–8. https://doi.org/10.1016/j.ejps.2014.11.002.
Tiyaboonchai W, Tungpradit W, Plianbangchang P. Formulation and characterization of curcuminoids loaded solid lipid nanoparticles. Int J Pharm. 2007;337:299–306. https://doi.org/10.1016/j.ijpharm.2006.12.043.
Sartorelli P, Andersen HR, Angerer J, Corish J, Drexler H, Göen T, et al. Percutaneous penetration studies for risk assessment. Environ Toxicol Pharmacol. 2000;8:133–52. https://doi.org/10.1016/S1382-6689(00)00035-1.71.
Ruela ALM, Perissinato AG, Lino MES, Mudrik PS, Pereira GR. Evaluation of skin absorption of drugs from topical and transdermal formulations. Braz J Pharm Sci. 2016;52:527–44.
Ratanajiajaroen P, Watthanaphanit A, Tamura H, Tokura S, Rujiravanit R. Release characteristic and stability of curcumin incorporated in β-chitin non-woven fibrous sheet using Tween 20 as an emulsifier. Eur Polym J. 2012;48:512–23. https://doi.org/10.1016/j.eurpolymj.2011.11.020.
Doaa Nabih M, Sanjay RM, Lijia W, Abd-Elgawad Helmy A-E, Osama Abd-Elazeem S, Marwa Salah E-D, et al. Water-soluble complex of curcumin with cyclodextrins: enhanced physical properties for ocular drug delivery. Curr Drug Deliv. 2017;14:875–86. https://doi.org/10.2174/1567201813666160808111209.74.
Hasanovic A, Zehl M, Reznicek G, Valenta C. Chitosan-tripolyphosphate nanoparticles as a possible skin drug delivery system for aciclovir with enhanced stability. J Pharm Pharmacol. 2009;61(12):1609–16.
Sun J, Han J, Zhao Y, Zhu Q, Hu J. Curcumin induces apoptosis in tumor necrosis factor-alpha-treated HaCaT cells. Int J Immunopharmacol. 2012;13:170–4. https://doi.org/10.1016/j.intimp.2012.03.025.
Scharstuhl A, Mutsaers H, Pennings S, Szarek W, Russel F, Wagener F. Curcumin-induced fibroblast apoptosis and in vitro wound contraction are regulated by antioxidants and heme oxygenase: implications for scar formation. J Cell Mol Med. 2009;13:712–25.
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The authors would like to acknowledge the Faculty of Science at the University of Nottingham Malaysia (UNM) for the financial support of this project.
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Nair, R.S., Morris, A., Billa, N. et al. An Evaluation of Curcumin-Encapsulated Chitosan Nanoparticles for Transdermal Delivery. AAPS PharmSciTech 20, 69 (2019). https://doi.org/10.1208/s12249-018-1279-6
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DOI: https://doi.org/10.1208/s12249-018-1279-6