Development and evaluation of p-chlorophenyl benzyl ether-loaded microemulsions for transdermal delivery

Authors

  • Kanokwan Singpanna Pharmaceutical Development of Green Innovations Group (PDGIG), Faculty of Pharmacy, Silpakorn University, Nakhon Pathom 73000, Thailand
  • Nopparat Nuntharatanapong Pharmaceutical Development of Green Innovations Group (PDGIG), Faculty of Pharmacy, Silpakorn University, Nakhon Pathom 73000, Thailand
  • Theerasak Rojanarata Pharmaceutical Development of Green Innovations Group (PDGIG), Faculty of Pharmacy, Silpakorn University, Nakhon Pathom 73000, Thailand
  • Panupan Limpachayaporn Department of Chemistry, Faculty of Science, Silpakorn University, Sanam Chandra Palace Campus, Nakhon Pathom 73000, Thailand
  • Prasopchai Patrojanasophon Pharmaceutical Development of Green Innovations Group (PDGIG), Faculty of Pharmacy, Silpakorn University, Nakhon Pathom 73000, Thailand
  • Praneet Opanasopit Pharmaceutical Development of Green Innovations Group (PDGIG), Faculty of Pharmacy, Silpakorn University, Nakhon Pathom 73000, Thailand

Keywords:

microemulsions, p-chlorophenyl benzyl ether, phase diagram, skin permeation, transdermal delivery

Abstract

p-Chlorophenyl benzyl ether (CBE) has been reported to be a new skin brightening agent.  Because of its strong inhibitory effect on tyrosinase and its high safety, CBE was selected as a model antityrosinase compound in this study.  Unfortunately, the poor aqueous solubility of CBE limits its use.  This study aimed to develop a CBE-loaded microemulsion (ME) with enhanced solubility and skin permeation capability for transdermal delivery.  The physicochemical properties, loading efficiency, and skin permeation of CBE-loaded ME were investigated, and results revealed that maximum CBE solubility could be achieved in lemon oil (211.81 ± 15.19 mg/mL).  Thus, lemon oil was selected as the oil phase for the ME formulation. Polysorbate 20 and ethanol at a ratio of 1:1 was employed as a surfactant and co-surfactant mixture (Smix).  A pseudo-ternary phase diagram was constructed to obtain the optimal concentration ranges of oil, Smix, and, water for ME formation.  Here, lemon oil, Smix, and water at a weight ratio of 20:70:10 was formulated with different amounts of CBE (3wt%, 5wt%, and 10wt%). The CBE-loaded ME had a particle size of 152–181 nm and negatively charged surfaces (–16.6 to –14.3 mV).  The percentage loading efficiency of CBE was approximately 70%–100%.  The ME preparation with 5wt% CBE was selected for skin permeation studies, and a 5wt% CBE aqueous suspension (free drug) was used as the control.  The 5wt% CBE-loaded ME exhibited a significantly higher skin permeation flux (32.74 ± 1.36 µg/cm2/h) compared with the 5% CBE suspension (2.35 ± 0.38 µg/cm2/h); specifically, the flux of the CBE-loaded ME was approximately 14-fold greater than that of the free drug.  Therefore, the prepared ME may potentially be used to improve the transdermal delivery of CBE.  However, skin irritation must be further investigated due to the concern on skin irritation of lemon oil and ethanol.

References

Agrawal, O. P., & Agrawal, S. (2012). An overview of new drug delivery system: microemulsion. Asian Journal of Pharmaceutical Science & Technology, 2(1), 5-12.

Baspinar, Y., & Borchert, H. H. (2012). Penetration and release studies of positively and negatively charged nanoemulsions--is there a benefit of the positive charge?. International Journal of Pharmaceutics, 430(1-2), 247-252. DOI: http://www.doi.org/10.1016/j.ijpharm.2012.03.040

Chandrashekar, N. S., & Hiremath, S. R. (2008). In vivo immunomodulatory, cumulative skin irritation, sensitization and effect of d-limonene on permeation of 6-mercaptopurine through transdermal drug delivery. Biological and Pharmaceutical Bulletin, 31(4), 656-661. DOI: http://www.doi.org/10.1248/bpb.31.656

Cichorek, M., Wachulska, M., & Stasiewicz, A. (2013). Heterogeneity of neural crest-derived melanocytes. Open Life Sciences, 8(4). DOI: http://www.doi.org/10.2478/s11535-013-0141-1

Gillet, A., Compere, P., Lecomte, F., Hubert, P., Ducat, E., Evrard, B., & Piel, G. (2011). Liposome surface charge influence on skin penetration behaviour. International Journal of Pharmaceutics, 411(1-2), 223-231. http://www.doi.org/10.1016/j.ijpharm.2011.03.049

Hashem, F. M., Shaker, D. S., Ghorab, M. K., Nasr, M., & Ismail, A. (2011). Formulation, characterization, and clinical evaluation of microemulsion containing clotrimazole for topical delivery. AAPS PharmSciTech, 12(3), 879-886. DOI: http://www.doi.org/10.1208/s12249-011-9653-7

Huang, Y. B., Lin, Y. H., Lu, T. M., Wang, R. J., Tsai, Y. H., & Wu, P. C. (2008). Transdermal delivery of capsaicin derivative-sodium nonivamide acetate using microemulsions as vehicles. International Journal of Pharmaceutics, 349(1-2), 206-211. DOI: http://www.doi.org/10.1016/j.ijpharm.2007.07.022

Jayne, L., & Gareth, R. (2000). Microemulsion-based media as novel drug delivery systems. Advanced Drug Delivery Reviews, 45, 89-121. DOI: http://www.doi.org/10.1016/s0169-409x(00)00103-4

Kobayashi, T., Urabe, K., Winder, A., Jimenez-Cervantes, C., Imokawa, G., Brewington, T., . . . Hearing, V. J. (1994). Tyrosinase related protein 1 (TRP1) functions as a DHICA oxidase in melanin biosynthesis. EMBO Journal, 13(24), 5818-5825.

Kogan, A., & Garti, N. (2006). Microemulsions as transdermal drug delivery vehicles. Advances in Colloid and Interface Science, 123-126, 369-385. DOI: http://www.doi.org/10.1016/j.cis.2006.05.014

Lachenmeier, D. W. (2008). Safety evaluation of topical applications of ethanol on the skin and inside the oral cavity. Journal of Occupational Medicine and Toxicology, 3, 26.

Li, E. P. H, Min, H. J., Belk, R. W., Kimura, J., & Bahl, S. (2008). Skin lightening and beauty in four Asian cultures. Advances in Consumer Research, 35, 444-449.

Liu, C. H., Chang, F. Y., & Hung, D. K. (2011). Terpene microemulsions for transdermal curcumin delivery: effects of terpenes and cosurfactants. Colloids and Surfaces B :Biointerfaces, 82(1), 63-70. DOI: http://www.doi.org/10.1016/j.colsurfb.2010.08.018

Masum, M., Yamauchi, K., & Mitsunaga, T. (2019). Tyrosinase Inhibitors from Natural and Synthetic Sources as Skin-lightening Agents. Reviews in Agricultural Science, 7, 41-58. DOI: https://doi.org/10.7831/ras.7.41

Mehta, S., & Kaur, G. (2011). Microemulsions: thermodynamic and dynamic properties. In M. Tadashi (Ed.), Thermodynamics (pp. 382-409): IntechOpen. DOI: http://www.doi.org/10.5772/12954

Ngawhirunpat, T., Worachun, N., Opanasopit, P., Rojanarata, T., & Panomsuk, S. (2013). Cremophor RH40-PEG 400 microemulsions as transdermal drug delivery carrier for ketoprofen. Pharmaceutical Development and Technology, 18(4), 798-803. DOI: http://www.doi.org/10.3109/10837450.2011.627871

Pandya, A. G., & Guevara, I. L. (2000). Disorders of hyperpigmentation. Dermatologic Clinics, 18(1), 91-98. DOI: http://www.doi.org/10.1016/s0733-8635(05)70150-9

Pawelek, J. M., & Korner, A. M. (1982). The biosynthesis of mammalian melanin. American Scientist, 70(2), 136-145.

Pillaiyar, T., Manickam, M., & Namasivayam, V. (2017). Skin whitening agents: medicinal chemistry perspective of tyrosinase inhibitors. Journal of Enzyme Inhibition and Medicinal Chemistry, 32(1), 403-425. DOI: http://www.doi.org/10.1080/14756366.2016.1256882

Rangsimawong, W., Wattanasri, P., Tonglairoum, P., Akkaramongkolporn, P., Rojanarata, T., Ngawhirunpat, T., & Opanasopit, P. (2018). Development of Microemulsions and Microemulgels for Enhancing Transdermal Delivery of Kaempferia parviflora Extract. AAPS PharmSciTech, 19(5), 2058-2067. DOI: http://www.doi.org/10.1208/s12249-018-1003-6

Rao, J., & McClements, D. J. (2012). Lemon oil solubilization in mixed surfactant solutions: Rationalizing microemulsion & nanoemulsion formation. Food Hydrocolloids, 26(1), 268-276. DOI: http://www.doi.org/10.1016/j.foodhyd.2011.06.002

Rao, S., Barot, T., Rajesh, K. S., & Jha, L. L. (2015). Formulation, optimization and evaluation of microemulsion based gel of Butenafine Hydrochloride for topical delivery by using simplex lattice mixture design. Journal of Pharmaceutical Investigation, 46(1), 1-12. DOI: http://www.doi.org/10.1007/s40005-015-0207-y

Riam-Amatakun, W., Limpachayaporn, P., Pizon, J. R. L., Opanasopit, P., & Nuntharatanapon, N. (2019). Anti-Melanogenic Activity of p-Chlorophenyl Benzyl Ether in α-MSH-Induced Mouse Melanoma B16F10 Cells. Key Engineering Materials, 819, 118-123. DOI: http://www.doi.org/10.4028/www.scientific.net/KEM.819.118

Solano, F., Briganti, S., Picardo, M., & Ghanem, G. (2006). Hypopigmenting agents: an updated review on biological, chemical and clinical aspects. Pigment Cell Research, 19(6), 550-571. DOI: http://www.doi.org/10.1111/j.1600-0749.2006.00334.x

Subongkot, T., & Ngawhirunpat, T. (2017). Development of a novel microemulsion for oral absorption enhancement of all-trans retinoic acid. International Journal of Nanomedicine, 12, 5585-5599. DOI: http://www.doi.org/10.2147/IJN.S142503

Suttisintong, K., Palakhachane, S., Athipornchai, A., Pimtong, W., & Limpachayaporn, P. (2018). Synthesis and evaluation of anti-tyrosinase activity of phenyl benzyl ether derivatives: Effects of functional groups and their positions. Science, Engineering and Health Studies, 12, 111-123. DOI: http://www.doi.org/10.14456/sehs.2018.10

Tsai, Y. H., Lee, K. F., Huang, Y. B., Huang, C. T., & Wu, P. C. (2010). In vitro permeation and in vivo whitening effect of topical hesperetin microemulsion delivery system. International Journal of Pharmaceutics, 388(1-2), 257-262. DOI: http://www.doi.org/10.1016/j.ijpharm.2009.12.051

Tsatmali, M., Ancans, J., & Thody, A. J. (2002). Melanocyte function and its control by melanocortin peptides. Journal of Histochemistry and Cytochemistry, 50(2), 125-133. DOI: http://www.doi.org/10.1177/002215540205000201

Valgimigli, L., Gabbanini, S., Berlini, E., Lucchi, E., Beltramini, C., & Bertarelli, Y. L. (2012). Lemon (Citrus limon, Burm.f.) essential oil enhances the trans-epidermal release of lipid-(A, E) and water-(B6, C) soluble vitamins from topical emulsions in reconstructed human epidermis. International Journal of Cosmetic Science, 34(4), 347-356. DOI: http://www.doi.org/10.1111/j.1468-2494.2012.00725.x

Valoppi, F., Frisina, R., & Calligaris, S. (2017). Fabrication of Transparent Lemon Oil Loaded Microemulsions by Phase Inversion Temperature (PIT) Method: Effect of Oil Phase Composition and Stability after Dilution. Food Biophysics, 12(2), 244-249. DOI: http://www.doi.org/10.1007/s11483-017-9480-9

Yotsawimonwat, S., Okonoki, S., Krauel, K., Sirithunyalug, J., Sirithunyalug, B., & Rades, T. (2006). Characterisation of microemulsions containing orange oil with water and propylene glycol as hydrophilic components. Pharmazie, 61(11), 920-926.

Downloads

Published

2021-01-30

How to Cite

Singpanna, K. ., Nuntharatanapong, N., Rojanarata, T. ., Limpachayaporn, P. ., Patrojanasophon, P. ., & Opanasopit, P. . (2021). Development and evaluation of p-chlorophenyl benzyl ether-loaded microemulsions for transdermal delivery. Journal of Current Science and Technology, 11(1), 90–99. Retrieved from https://ph04.tci-thaijo.org/index.php/JCST/article/view/360

Issue

Section

Research Article