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Current Medicinal Chemistry


ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Review Article

Topical Application of Ascorbic Acid and its Derivatives: A Review Considering Clinical Trials

Author(s): Louise Idalgo Vasques, Cristina Wöhlke Vendruscolo and Gislaine Ricci Leonardi*

Volume 30, Issue 29, 2023

Published on: 23 November, 2022

Page: [3272 - 3286] Pages: 15

DOI: 10.2174/0929867329666221003102238

Price: $65


Background: The topical use of vitamin C has been explored for many decades due to its antioxidant potential, whitening action, and the essential role it plays in the synthesis and maintenance of collagen. As Ascorbic Acid (AA) is unstable, derivative molecules and stabilization strategies have been explored to facilitate its incorporation into dermatological products. Even though these molecules are already for sale, there is still a shortage of scientific data regarding efficacy studies of these assets, especially in vivo.

Objective: The purpose of this review was to investigate and discuss issues regarding the topical application of vitamin C and its most common derivatives, including the difficulties, biases, and prospects for future clinical studies to better elucidate its effects.

Methods: A literature review was carried out to select studies that evaluated the topical use of ascorbic acid and/or its derivatives. The studies which are “fully available”, “in vivo” and “in vitro”, were used as inclusion criteria.

Results: Due to the instability of Ascorbic Acid, it is essential to study derivative molecules that maintain or even improve their effectiveness in dermatological products. Despite this, the studies of these derivatives presented in the scientific literature are mostly in vitro. In recent years, it has been possible to observe an increase in in vivo efficacy tests, and this trend is expected to continue in the future. However, they present very different approaches and issues.

Conclusion: Studies of stability, safety, adverse reactions, and especially in vivo efficacy studies with a relevant number of subjects and standardized parameters are essential for better elucidating the effects of the topical application of vitamin C derivatives in comparison to ascorbic acid formulations for the skin.

Keywords: Vitamin C, ascorbic acid, ascorbic acid derivatives, antioxidant molecules, clinical trial, vitamin C derivatives.

Traikovich, S.S. Use of topical ascorbic acid and its effects on photodamaged skin topography. Arch. Otolaryngol. Head Neck Surg., 1999, 125(10), 1091-1098.
[] [PMID: 10522500]
Manela-Azulay, M.; Bagatin, E. Cosmeceuticals vitamins. Clin. Dermatol., 2009, 27(5), 469-474.
[] [PMID: 19695478]
Zetterström, R. Nobel Prize 1937 to Albert von Szent- Györgyi: Identification of vitamin C as the anti-scorbutic factor. Acta Paediatr., 2009, 98(5), 915-919.
[] [PMID: 19239412]
Telang, P. Vitamin C in dermatology. Indian Dermatol. Online J., 2013, 4(2), 143-146.
[] [PMID: 23741676]
Li, Y.; Schellhorn, H.E. New developments and novel therapeutic perspectives for vitamin C. J. Nutr., 2007, 137(10), 2171-2184.
[] [PMID: 17884994]
Bei, R.; Bei, R.; Mistretta, A.; Marventano, S.; Calabrese, G.; Masuelli, L.; Giganti, M.G.; Modesti, A.; Galvano, F.; Gazzolo, D. Effects of vitamin C on health: A review of evidence. Front. Biosci., 2013, 18(3), 1017-1029.
[] [PMID: 23747864]
Ivanov, V.; Ivanova, S.; Kalinovsky, T.; Niedzwiecki, A.; Rath, M. Inhibition of collagen synthesis by select calcium and sodium channel blockers can be mitigated by ascorbic acid and ascorbyl palmitate. Am. J. Cardiovasc. Dis., 2016, 6(2), 26-35.
[PMID: 27335688]
Farris, P.K. Topical vitamin C: A useful agent for treating photoaging and other dermatologic conditions. Dermatol. Surg., 2005, 31(7 Pt 2), 814-818.
[] [PMID: 16029672]
Pullar, J.; Carr, A.; Vissers, M. The roles of vitamin C in skin health. Nutrients, 2017, 9(8), 866.
[] [PMID: 28805671]
Rhie, G.; Shin, M.H.; Seo, J.Y.; Choi, W.W.; Cho, K.H.; Kim, K.H.; Park, K.C.; Eun, H.C.; Chung, J.H. Aging- and photoaging-dependent changes of enzymic and nonenzymic antioxidants in the epidermis and dermis of human skin in vivo. J. Invest. Dermatol., 2001, 117(5), 1212-1217.
[] [PMID: 11710935]
Matsuda, S.; Shibayama, H.; Hisama, M.; Ohtsuki, M.; Iwaki, M. Inhibitory effects of a novel ascorbic derivative, disodium isostearyl 2-O-L-ascorbyl phosphate on melanogenesis. Chem. Pharm. Bull. (Tokyo), 2008, 56(3), 292-297.
[] [PMID: 18310938]
Pinnell, S.R.; Yang, H.; Omar, M.; Monteiro-Riviere, N.; DeBuys, H.V.; Walker, L.C.; Wang, Y.; Levine, M. Topical L-ascorbic acid: Percutaneous absorption studies. Dermatol. Surg., 2001, 27(2), 137-142.
[PMID: 11207686]
Pinnell, S.R. Cutaneous photodamage, oxidative stress, and topical antioxidant protection. J. Am. Acad. Dermatol., 2003, 48(1), 1-22.
[] [PMID: 12522365]
Fisher, G.J.; Kang, S.; Varani, J.; Bata-Csorgo, Z.; Wan, Y.; Datta, S.; Voorhees, J.J. Mechanisms of photoaging and chronological skin aging. Arch. Dermatol., 2002, 138(11), 1462-1470.
[] [PMID: 12437452]
Ortolan, M.C.A.B.; Biondo-Simões, M.D.L.P.; Baroni, E.D.R.V.; Auersvald, A.; Auersvald, L.A.; Montemor Netto, M.R.; Biondo-Simões, R. Influence of aging on the skin quality of white-skinned women: The role of collagen, elastic material density, and vascularization. Rev. Bras. Cir. Plást., 2013, 28, 41-48.
Duarte, T.; Cooke, M.; Jones, G. Gene expression profiling reveals new protective roles for vitamin C in human skin cells. Free Radic. Biol. Med., 2009, 46(1), 78-87.
[] [PMID: 18973801]
Stamford, N.P.J. Stability, transdermal penetration, and cutaneous effects of ascorbic acid and its derivatives. J. Cosmet. Dermatol., 2012, 11(4), 310-317.
[] [PMID: 23174055]
Burke, K.E. Interaction of vitamins C and E as better cosmeceuticals. Dermatol. Ther., 2007, 20(5), 314-321.
[] [PMID: 18045356]
Draelos, Z.D. Skin lightening preparations and the hydroquinone controversy. Dermatol. Ther., 2007, 20(5), 308-313.
[] [PMID: 18045355]
Choi, Y.K.; Rho, Y.K.; Yoo, K.H.; Lim, Y.Y.; Li, K.; Kim, B.J.; Seo, S.J.; Kim, M.N.; Hong, C.K.; Kim, D.S. Effects of vitamin C vs. multivitamin on melanogenesis: Comparative study in vitro and in vivo. Int. J. Dermatol., 2010, 49(2), 218-226.
[] [PMID: 20465650]
Zaid, A.N.; Al Ramahi, R. Depigmentation and anti-aging treatment by natural molecules. Curr. Pharm. Des., 2019, 25(20), 2292-2312.
[] [PMID: 31269882]
Gallarate, M.; Carlotti, M.E.; Trotta, M.; Bovo, S. On the stability of ascorbic acid in emulsified systems for topical and cosmetic use. Int. J. Pharm., 1999, 188(2), 233-241.
[] [PMID: 10518678]
Lee, J.S.; Kim, J.W.; Han, S.H.; Chang, I.S.; Kang, H.H.; Lee, O.S.; Oh, S.G.; Suh, K.D. The stabilization of L-ascorbic acid in aqueous solution and water-in-oil-in-water double emulsion by controlling pH and electrolyte concentration. Int. J. Cosmet. Sci., 2004, 26(4), 217.
[] [PMID: 15037917]
Taylor, R.M.; Wilson, D.J. Ascorbic acid composition and transdermal administration method. U.S. Patent 5,308,621, 1994.
Sheraz, M.A. Formulation and stability of ascorbic acid in liquid and semisolid preparations. Sys. Rev. Pharm., 2011, 2(2), 86-90.
Wille, J.J. Thixogel™: Novel Topical Delivery Systems for Hydrophobic Plant Actives. In: Delivery System Handbook for Personal Care and Cosmetic Products; Rosen, M.R., Ed.; William Andrew Publishing: New York, 2005; 1, pp. 761-794.
Inui, S.; Itami, S. Perifollicular pigmentation is the first target for topical vitamin C derivative ascorbyl 2-phosphate 6-palmitate (APPS): Randomized, single-blinded, placebo- controlled study. J. Dermatol., 2007, 34(3), 221-223.
[] [PMID: 17291309]
Rattanawiwatpong, P.; Wanitphakdeedecha, R.; Bumrungpert, A.; Maiprasert, M. Anti-aging and brightening effects of a topical treatment containing vitamin C, vitamin E, and raspberry leaf cell culture extract: A split-face, randomized controlled trial. J. Cosmet. Dermatol., 2020, 19(3), 671-676.
[] [PMID: 31975502]
Lin, F.H.; Lin, J.Y.; Gupta, R.D.; Tournas, J.A.; Burch, J.A.; Angelica Selim, M.; Monteiro-Riviere, N.A.; Grichnik, J.M.; Zielinski, J.; Pinnell, S.R. Ferulic acid stabilizes a solution of vitamins C and E and doubles its photoprotection of skin. J. Invest. Dermatol., 2005, 125(4), 826-832.
[] [PMID: 16185284]
Maia, A.M.; Baby, A.R.; Pinto, C.A.S.O.; Yasaka, W.J.; Suenaga, E.; Kaneko, T.M.; Velasco, M.V.R. Influence of sodium metabisulfite and glutathione on the stability of vitamin C in O/W emulsion and extemporaneous aqueous gel. Int. J. Pharm., 2006, 322(1-2), 130-135.
[] [PMID: 16806754]
Tournas, J.A.; Lin, F.H.; Burch, J.A.; Angelica Selim, M.; Monteiro-Riviere, N.A.; Zielinski, J.E.; Pinnell, S.R. Ubiquinone, idebenone, and kinetin provide ineffective photoprotection to skin when compared to a topical antioxidant combination of vitamins C and E with ferulic acid. J. Invest. Dermatol., 2006, 126(5), 1185-1187.
[] [PMID: 16528359]
Sheraz, M.A.; Ahmad, I.; Vaid, F.M.; Ahmed, S.; Shaikh, R.H.; Iqbal, K. Formulation and stability of ascorbic acid in topical preparations. Syst. Rev. Pharm., 2011, 2(2), 86-90.
Ahmad, I.; Sheraz, M.A.; Ahmed, S.; Shaikh, R.H.; Vaid, F.H.M.; ur Rehman Khattak, S.; Ansari, S.A. Photostability and interaction of ascorbic acid in cream formulations. AAPS PharmSciTech, 2011, 12(3), 917-923.
[] [PMID: 21735345]
Alster, T.S.; West, T.B. Effect of topical vitamin C on postoperative carbon dioxide laser resurfacing erythema. Dermatol. Surg., 1998, 24(3), 331-334.
[] [PMID: 9537007]
Humbert, P.G.; Haftek, M.; Creidi, P.; Lapière, C.; Nusgens, B.; Richard, A.; Schmitt, D.; Rougier, A.; Zahouani, H. Topical ascorbic acid on photoaged skin. Clinical, topographical and ultrastructural evaluation: Double-blind study vs. placebo. Exp. Dermatol., 2003, 12(3), 237-244.
[] [PMID: 12823436]
Maione-Silva, L.; de Castro, E.G.; Nascimento, T.L.; Cintra, E.R.; Moreira, L.C.; Cintra, B.A.S.; Valadares, M.C.; Lima, E.M. Ascorbic acid encapsulated into negatively charged liposomes exhibits increased skin permeation, retention and enhances collagen synthesis by fibroblasts. Sci. Rep., 2019, 9(1), 522.
[] [PMID: 30679479]
Klock, J.; Ikeno, H.; Ohmori, K.; Nishikawa, T.; Vollhardt, J.; Schehlmann, V. Sodium ascorbyl phosphate shows in vitro and in vivo efficacy in the prevention and treatment of acne vulgaris. Int. J. Cosmet. Sci., 2005, 27(3), 171-176.
[] [PMID: 18492184]
Lee, W.J.; Kim, S.L.; Lee, K.C.; Sohn, M.Y.; Jang, Y.H.; Lee, S.J.; Kim, D.W. Effects of magnesium ascorbyl phosphate on the expression of inflammatory biomarkers after treatment of cultured sebocytes with Propionibacterium acnes or ultraviolet B radiation. Ann. Dermatol., 2016, 28(1), 129-132.
[] [PMID: 26848238]
Miyai, E.; Yanagida, M.; Akiyama, J.; Yamamoto, I. Ascorbic acid 2-O-α-glucoside-induced redox modulation in human keratinocyte cell line, SCC: Mechanisms of photoprotective effect against ultraviolet light B. Biol. Pharm. Bull., 1997, 20(6), 632-636.
[] [PMID: 9212980]
Kim, H.M.; An, H.S.; Bae, J.S.; Kim, J.Y.; Choi, C.H.; Kim, J.Y.; Lim, J.H.; Choi, J.; Song, H.; Moon, S.H.; Park, Y.J.; Chang, S.J.; Choi, S.Y. Effects of palmitoyl-KVK-L-ascorbic acid on skin wrinkles and pigmentation. Arch. Dermatol. Res., 2017, 309(5), 397-402.
[] [PMID: 28303328]
Kumano, Y.; Sakamoto, T.; Egawa, M.; Tanaka, M.; Yamamoto, I. Enhancing effect of 2-O-α-D-glucopyranosyl-L-ascorbic acid, a stable ascorbic acid derivative, on collagen synthesis. Biol. Pharm. Bull., 1998, 21(7), 662-666.
[] [PMID: 9703245]
Meves, A.; Stock, S.N.; Beyerle, A.; Pittelkow, M.R.; Peus, D. Vitamin C derivative ascorbyl palmitate promotes ultraviolet-B-induced lipid peroxidation and cytotoxicity in keratinocytes. J. Invest. Dermatol., 2002, 119(5), 1103-1108.
[] [PMID: 12445199]
Ochiai, Y.; Kaburagi, S.; Obayashi, K.; Ujiie, N.; Hashimoto, S.; Okano, Y.; Masaki, H.; Ichihashi, M.; Sakurai, H. A new lipophilic pro-vitamin C, tetra-isopalmitoyl ascorbic acid (VC-IP), prevents UV-induced skin pigmentation through its anti-oxidative properties. J. Dermatol. Sci., 2006, 44(1), 37-44.
[] [PMID: 16935471]
Fossa Shirata, M.M.; Maia Campos, P.M.B.G. Sunscreens and cosmetic formulations containing ascorbyl tetraisopalmitate and rice peptides for the improvement of skin photoaging: A double-blind, randomized placebo-controlled clinical study. Photochem. Photobiol., 2021, 97(4), 805-815.
[] [PMID: 33529350]
Goldberg, D.J.; Robinson, D.M.; Granger, C. Clinical evidence of the efficacy and safety of a new 3-in-1 anti-aging topical night serum-in-oil containing melatonin, bakuchiol, and ascorbyl tetraisopalmitate: 103 females treated from 28 to 84 days. J. Cosmet. Dermatol., 2019, 18(3), 806-814.
[] [PMID: 30924254]
Yokota, M.; Yahagi, S. Evaluation of the anti-wrinkle effect of a lipophilic pro-vitamin C derivative, tetra-isopalmitoyl ascorbic acid. J. Cosmet. Dermatol., 2021, 2021, 14604.
Chorilli, M.; Tamascia, P.; Rossim, C.; Salgado, H.R.N. Biological assays for evaluating the saftey of cosmatic products. Rev. Cienc. Farm. Basica. Apl., 2009, 30, 19-30.
Chamberlain, M.; Parish, W.E. Hazard and risk based on in vitro test data. Toxicol. In Vitro, 1990, 4(4-5), 694-697.
[] [PMID: 20702259]
Indans, I. The use and interpretation of in vitro data in regulatory toxicology: Cosmetics, toiletries and household products. Toxicol. Lett., 2002, 127(1-3), 177-182.
[] [PMID: 12052656]
Hoffmann, S.; Cole, T.; Hartung, T. Skin irritation: Prevalence, variability, and regulatory classification of existing in vivo data from industrial chemicals. Regul. Toxicol. Pharmacol., 2005, 41(3), 159-166.
[] [PMID: 15748793]
Declaration of Helsinki. General Assembly, Helsinki, Finland, June 1964. 2022. Available from: (Accessed on: March 29, 2022).
Anvisa. Guide for safety assessment of cosmetic products. 2022; pp 1-72 Available from: (Accessed on: March 29, 2022).
Pandey, A.; Jatana, G.K.; Sonthalia, S. Cosmeceuticals. Adv. Integr. Dermatol., 2022.
Caritá, A.C.; Fonseca-Santos, B.; Shultz, J.D.; Michniak-Kohn, B.; Chorilli, M.; Leonardi, G.R.; Vitamin, C. Vitamin C: One compound, several uses. Advances for delivery, efficiency and stability. Nanomedicine, 2020, 24, 102117.
[] [PMID: 31676375]
Kobayashi, S.; Takehana, M.; Itoh, S.; Ogata, E. Protective effect of magnesium-L-ascorbyl-2 phosphate against skin damage induced by UVB irradiation. Photochem. Photobiol., 1996, 64(1), 224-228.
[] [PMID: 8787018]
Lin, C.C.; Lin, Y.C.; Gao, M.Y.; Fang, Y.P. In vitro evaluation of permeation ability and in vivo whitening of ascorbic acid 2-glucoside in microemulsion. Int. J. Pharm. Sci. Res., 2016, 3, 118.
Maia Campos, P.M.B.G.; Gianeti, M.D.; Camargo, F.B., Jr; Gaspar, L.R. Application of tetra-isopalmitoyl ascorbic acid in cosmetic formulations: Stability studies and in vivo efficacy. Eur. J. Pharm. Biopharm., 2012, 82(3), 580-586.
[] [PMID: 22974986]
Kameyama, K.; Sakai, C.; Kondoh, S.; Yonemoto, K.; Nishiyama, S.; Tagawa, M.; Murata, T.; Ohnuma, T.; Quigley, J.; Dorsky, A.; Bucks, D.; Blanock, K. Inhibitory effect of magnesium l-ascorbyl-2-phosphate (VC-PMG) on melanogenesis in vitro and in vivo. J. Am. Acad. Dermatol., 1996, 34(1), 29-33.
[] [PMID: 8543691]
Segall, A.I.; Moyano, M.A. Stability of vitamin C derivatives in topical formulations containing lipoic acid, vitamins A and E. Int. J. Cosmet. Sci., 2008, 30(6), 453-458.
[] [PMID: 19099546]
Lin, J.Y.; Selim, M.A.; Shea, C.R.; Grichnik, J.M.; Omar, M.M.; Monteiro-Riviere, N.A.; Pinnell, S.R. UV photoprotection by combination topical antioxidants vitamin C and vitamin E. J. Am. Acad. Dermatol., 2003, 48(6), 866-874.
[] [PMID: 12789176]
Lee, S.; Lee, J.; Choi, Y.W. Skin permeation enhancement of ascorbyl palmitate by liposomal hydrogel (lipogel) formulation and electrical assistance. Biol. Pharm. Bull., 2007, 30(2), 393-396.
[] [PMID: 17268089]
Rozman, B.; Zvonar, A.; Falson, F.; Gasperlin, M. Temperature-sensitive microemulsion gel: An effective topical delivery system for simultaneous delivery of vitamins C and E. AAPS PharmSciTech, 2009, 10(1), 54-61.
[] [PMID: 19148763]
Yang, J.H.; Lee, S.Y.; Han, Y.S.; Park, K.C.; Choy, J.H. Efficient transdermal penetration and improved stability of L-ascorbic acid encapsulated in an inorganic nanocapsule. Bull. Korean Chem. Soc., 2003, 24(4), 499-503.
Duarah, S.; Durai, R.D.; Narayanan, V.B. Nanoparticle-in-gel system for delivery of vitamin C for topical application. Drug Deliv. Transl. Res., 2017, 7(5), 750-760.
[] [PMID: 28597122]
Zhang, L.; Lerner, S.; Rustrum, W.V.; Hofmann, G.A. Electroporation-mediated topical delivery of vitamin C for cosmetic applications. Bioelectrochem. Bioenerg., 1999, 48(2), 453-461.
[] [PMID: 10379568]
Ebihara, M.; Akiyama, M.; Ohnishi, Y.; Tajima, S.; Komata, K.; Mitsui, Y. Iontophoresis promotes percutaneous absorption of l-ascorbic acid in rat skin. J. Dermatol. Sci., 2003, 32(3), 217-222.
[] [PMID: 14507447]
Lee, W.R.; Shen, S.C.; Wang, K-H.; Hu, C.H.; Fang, J.Y. Lasers and microdermabrasion enhance and control topical delivery of vitamin C. J. Invest. Dermatol., 2003, 121(5), 1118-1125.
[] [PMID: 14708614]

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