Formulation and Characterization of a Kinetically Stable Topical Nanoemulsion Containing the Whitening Agent Kojic Acid

Gan Yi Yun(1), Nur Azzanizawaty Yahya(2), Roswanira Abdul Wahab(3*), Mariani Abdul Hamid(4)

(1) Department of Chemistry, Faculty of Science, Universiti Teknologi Malaysia, 81310 UTM Skudai, Johor, Malaysia
(2) Department of Chemistry, Faculty of Science, Universiti Teknologi Malaysia, 81310 UTM Skudai, Johor, Malaysia
(3) Department of Chemistry, Faculty of Science, Universiti Teknologi Malaysia, 81310 UTM Skudai, Johor, Malaysia
(4) School of Chemical and Energy Engineering, Faculty of Engineering, Universiti Teknologi Malaysia, 81310 Skudai, Johor, Malaysia
(*) Corresponding Author


The research was carried out to synthesize a stable kojic acid (KA) encapsulated nanoemulsion as a whitening agent for topical skin usage. In this study, the oil-in-water (O/W) KA nanoemulsion was formulated using integrated low and high energy methods that combined ultrasonic and hot temperature inversion methods. Several different combinations of parameters were screened, viz. xanthan gum amount (1.0 to 2.0 g), kojic acid (KA) amount (0.5 to 1.5 g), and surfactant-to-water ratio (1:10.75 to 1:4.875), to prepare a stable KA nanoemulsion. The identified best parameters to design the O/W KA nanoemulsion were then subjected to different stability tests: storage and pH stability (freeze-thaw and centrifugal tests). Results revealed that the Trial 6 formulation, with the highest ratio of Tween 80 to water (1:4.875 v/v), yielded the best polydispersity index at 0.255 ± 0.006 with an average particle size of 90.57 ± 1.401 nm. The formulation retained the recommended pH range (pH 4.95–5.18) for topical skin applications within six-week storage under room condition. The nanoemulsions were also kinetically stable as proven by the absence of phase separation after the centrifugation, freeze-thaw cycle, and storage temperature (2 and 25 °C) tests, except at the 37 °C three-week extended storage. The results collectively showed that the formulated O/W KA nanoemulsion is suitable for topical application on human skin.


oil-in-water nanoemulsion; kojic acid; topical skin application; skin whitening; ultrasonic; hot temperature inversion methods

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[1] Ha, J.H., Jeong, Y.J., Kim, A.Y., Hong, I.K., Lee, N.H., and Park, S.N., 2018, Preparation and Physicochemical properties of a cysteine derivative‐Loaded deformable liposomes in hydrogel for enhancing whitening effects, Eur. J. Lipid Sci. Technol., 120 (9), 1800125.

[2] Zhou, J., Ren, T., Li, Y., Cheng, A., Xie, W., Xu, L., Peng, L., Lin, J., Lian, L., Diao, Y., Jin, X., and Yang, L., 2017, Oleoylethanolamide inhibits α-melanocyte stimulating hormone-stimulated melanogenesis via ERK, Akt and CREB signaling pathways in B16 melanoma cells, Oncotarget, 8 (34), 56868–56879.

[3] Seino, H., Arai, Y., Nagao, N., Ozawa, N., and Hamada, K., 2016, Efficient percutaneous delivery of the antimelanogenic agent glabridin using cationic amphiphilic chitosan micelles, PloS One, 11 (10), e0164061.

[4] Hseu, Y.C., Cheng, K.C., Lin, Y.C., Chen, C.Y., Chou, H.Y., Ma, D.L., Leung, C.H., Wen, Z.H., and Wang, H.M.D., 2015, Synergistic effects of linderanolide B combined with arbutin, PTU or kojic acid on tyrosinase inhibition, Curr. Pharm. Biotechnol., 16 (12), 1120–1126.

[5] Wang, X.R., Cheng, H.M., Gao, X.W., Zhou, W., Li, S.J., Cao, X.L., and Yan, D., 2019, Intercalation assembly of kojic acid into Zn-Ti layered double hydroxide with antibacterial and whitening performances, Chin. Chem. Lett., 30 (4), 919–923.

[6] Saeedi, M., Eslamifar, M., and Khezri, K., 2019, Kojic acid applications in cosmetic and pharmaceutical preparations, Biomed. Pharmacother., 110, 582–593.

[7] Parvez, S., Kang, M., Chung, H.S., Cho, C., Hong, M.C., Shin, M.K., Bae, H., 2006, Survey and mechanism of skin depigmenting and lightening agents, Phytother. Res., 20 (11), 921–934.

[8] Ephrem, E., Elaissari, H., and Greige-Gerges, H., 2017, Improvement of skin whitening agents efficiency through encapsulation: Current state of knowledge, Int. J. Pharm., 526 (1-2), 50–68.

[9] Zhu, L.F., Zheng, Y., Fan, J., Yao, Y., Ahmad, Z., and Chang, M.W., 2019, A novel core-shell nanofiber drug delivery system intended for the synergistic treatment of melanoma, Eur. J. Pharm. Sci., 137, 105002.

[10] Calixto, G.M.F., de Annunzio, S.R., Victorelli, F.D., Frade, M.L., Ferreira, P.S., Chorilli, M., and Fontana, C.R., 2019, Chitosan-based drug delivery systems for optimization of photodynamic therapy: A review, AAPS PharmSciTech, 20 (7), 253.

[11] Mondal, S., Hoang, G., Manivasagan, P., Kim, H., and Oh, J., 2019, Nanostructured hollow hydroxyapatite fabrication by carbon templating for enhanced drug delivery and biomedical applications, Ceram. Int., 45 (14), 17081–17093.

[12] Anirudhan, T., and Nair, S.S., 2019, Development of voltage gated transdermal drug delivery platform to impose synergistic enhancement in skin permeation using electroporation and gold nanoparticle, Mater. Sci. Eng., C, 102, 437–446.

[13] Bangun, H., Tandiono, S., and Arianto, A., 2018, Preparation and evaluation of chitosan-tripolyphosphate nanoparticles suspension as an antibacterial agent, J. Appl. Pharm. Sci., 8 (12), 147–156.

[14] Ribeiro, R.C.A., Barreto, S.M.A., Ostrosky, E.A., da Rocha-Filho, P.A., Verissimo, L.M., and Ferrari, M., 2015, Production and characterization of cosmetic nanoemulsions containing Opuntia ficus-indica (L.) mill extract as moisturizing agent, Molecules, 20 (2), 2492–2509.

[15] Sung, H.J., Khan, M.F., and Kim, Y.H., 2019, Recombinant lignin peroxidase-catalyzed decolorization of melanin using in-situ generated H2O2 for application in whitening cosmetics, Int. J. Biol. Macromol., 136, 20–26.

[16] Roselan, M.A., Ashari, S.E., Faujan, N.H., Mohd Faudzi, S.M., and Mohamad, R., 2020, An Improved nanoemulsion formulation containing kojic monooleate: Optimization, characterization and in vitro studies, Molecules, 25 (11), 2616.

[17] Gonçalez, M.L., Marcussi, D.G., Calixto, G.M.F., Corrêa, M.A., and Chorilli, M., 2015, Structural characterization and in vitro antioxidant activity of kojic dipalmitate loaded W/O/W multiple emulsions intended for skin disorders, Biomed Res. Int., 2015, 304591.

[18] Che Marzuki, N.H., Wahab, R.A., and Abdul Hamid, M., 2019, An overview of nanoemulsion: concepts of development and cosmeceutical applications, Biotechnol. Biotechnol. Equip., 33 (1), 779–797.

[19] Mohd Narawi, M., Chiu, H.I., Yong, Y.K., Mohamad Zain, N.N., Ramachandran, M.R., Tham, C.L., Samsurrijal, S.F., and Lim, V., 2020, Biocompatible nutmeg oil-loaded nanoemulsion as phyto-repellent, Front. Pharmacol., 11, 214.

[20] Aboofazeli, R., 2010, Nanometric-scaled emulsions (nanoemulsions), Iran. J. Pharm. Res., 9 (4), 325–326.

[21] Ali, M.S., Alam, M.S., Alam, N., and Siddiqui, M.R., 2014, Preparation, characterization and stability study of dutasteride loaded nanoemulsion for treatment of benign prostatic hypertrophy, Iran. J. Pharm. Res., 13 (4), 1125–1140.

[22] Sumaiyah, and Leisyah, B.M., 2019, The effect of antioxidant of grapeseed oil as skin anti-aging in nanoemulsion and emulsion preparations, Rasayan J. Chem., 12 (13), 1185–1194.

[23] Ali, S.M., and Yosipovitch, G., 2013, Skin pH: From basic science to basic skin care, Acta Derm. Venereol., 93 (3), 261–267.

[24] Panther, D.J., and Jacob, S.E., 2015, The importance of acidification in atopic eczema: an underexplored avenue for treatment, J. Clin. Med., 4 (5), 970–978.

[25] Lambers, H., Piessens, S., Bloem, A., Pronk, H., and Finkel, P., 2006, Natural skin surface pH is on average below 5, which is beneficial for its resident flora, Int. J. Cosmet. Sci., 28 (5), 359–370.

[26] Garavaglia, J., Markoski, M.M., Oliveira, A., and Marcadenti, A., 2016, Grape seed oil compounds: Biological and chemical actions for health, Nutr. Metab. Insights, 9, 59–64.

[27] McClements, D.J., and Rao, J., 2011, Food-grade nanoemulsions: Formulation, fabrication, properties, performance, biological fate, and potential toxicity, Crit. Rev. Food Sci. Nutr., 51 (4), 285–330.

[28] Pulce, C., and Descotes, J., 1996, “Household products” in Human Toxicology, 1st Ed., Eds. Descotes, J., Elsevier Science B.V., Amsterdam, 683–702.

[29] Sharma, N., Mohanakrishnan, D., Sharma, U.K., Kumar, R., Richa, Sinha, A.K., and Sahal, D., 2014, Design, economical synthesis and antiplasmodial evaluation of vanillin derived allylated chalcones and their marked synergism with artemisinin against chloroquine resistant strains of Plasmodium falciparum, Eur. J. Med. Chem., 79, 350–368.

[30] Manning, M.C., Liu, J., Li, T., and Holcomb, R.E., 2018, Rational design of liquid formulations of proteins, Adv. Protein Chem. Struct. Biol., 112, 1–59.

[31] Rao, J., and McClements, D.J., 2010, Stabilization of phase inversion temperature nanoemulsions by surfactant displacement, J. Agric. Food Chem., 58 (11), 7059–7066.

[32] Anuar, N., Mohd Adnan, A.F., Saat, N., Aziz, N., and Mat Taha, R., 2013, Optimization of extraction parameters by using response surface methodology, purification, and identification of anthocyanin pigments in Melastoma malabathricum fruit, Sci. World J., 2013, 810547.

[33] Kumar, A., Rao, K.M., and Han, S.S., 2018, Application of xanthan gum as polysaccharide in tissue engineering: A review, Carbohydr. Polym., 180, 128–144.

[34] Sriprablom, J., Luangpituksa, P., Wongkongkatep, J., Pongtharangkul, T., and Suphantharika, M., 2019, Influence of pH and ionic strength on the physical and rheological properties and stability of whey protein stabilized O/W emulsions containing xanthan gum, J. Food Eng., 242, 141–152.

[35] Saberi, A.H., Fang, Y., and McClements, D.J., 2013, Fabrication of vitamin E-enriched nanoemulsions: Factors affecting particle size using spontaneous emulsification, J. Colloid Interface Sci., 391, 95–102.

[36] Nejadmansouri, M., Hosseini, S.M.H., Niakosari, M., Yousefi, G.H., and Golmakani, M.T., 2017, Changes in the surface tension and viscosity of fish oil nanoemulsions developed by sonication during storage, Iran. Food Sci. Technol. Res. J., 13 (6) 105-116.

[37] Wang, L., Dong, J. Chen, J. Eastoe, J., and Li, X., 2009, Design and optimization of a new self-nanoemulsifying drug delivery system, J. Colloid. Interface. Sci., 330 (2), 443–448.

[38] Mat Hadzir, N., Basri, M., Abdul Rahman, M.B., Salleh, A.B., Raja Abdul Rahman, R.N., and Basri, H., 2013, Phase behaviour and formation of fatty acid esters nanoemulsions containing piroxicam, AAPS PharmSciTech, 14 (1), 456–463.

[39] El-Din, M.R.N., El-Hamouly, S.H., Mohamed, H.M., Mishrif, M.R., and Ragab, A.M., 2014, Investigating factors affecting water-in-diesel fuel nanoemulsions, J. Surfactants Deterg., 17 (4), 819–831.

[40] Chang, Y., McLandsborough, L., and McClements, D.J., 2015, Fabrication, stability and efficacy of dual-component antimicrobial nanoemulsions: Essential oil (thyme oil) and cationic surfactant (lauric arginate), Food Chem., 172, 298–304.

[41] Samson, S., Basri, M., Fard Masoumi, H.R., Abedi Karjiban, R., and Abdul Malek, E., 2016, Design and development of a nanoemulsion system containing copper peptide by D-optimal mixture design and evaluation of its physicochemical properties, RSC Adv., 6 (22), 17845–17856.

[42] Suminar, M.M., and Jufri, M., 2017, Physical stability and antioxidant activity assay of a nanoemulsion gel formulation containing tocotrienol, Int. J. Appl. Pharm., 9, 140–143.


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