|Year : 2020 | Volume
| Issue : 2 | Page : 374-382
The effect of Vitamin C on melanin pigmentation – A systematic review
Rizwan M Sanadi1, Revati S Deshmukh2
1 Department of Periodontics, Dr GD Pol Foundation's YMT Dental College, Kharghar, Sector - 4, Navi Mumbai, Maharashtra, India; PhD Student
2 Department of Oral Pathology & Microbiology, Bharati Vidyapeeth Deemed to be University, Dental College & Hospital, Satara Road, Katraj, Dhankawadi, Pune, Maharashtra, India
|Date of Submission||14-May-2020|
|Date of Decision||30-Jun-2020|
|Date of Acceptance||04-Jul-2020|
|Date of Web Publication||09-Sep-2020|
Rizwan M Sanadi
Bharati Vidyapeeth Deemed to be University, Dental College and Hospital, Satara Road, Katraj, Dhankawadi, Pune - 411 043, Maharashtra; Department of Periodontics, Dr. G D Pol Foundation’s, YMT Dental College, Kharghar, Sector – 4, Navi Mumbai - 410 210, Maharashtra, India
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Vitamin C, also known as ascorbic acid, is used as a treatment modality in depigmentation of hyperpigmented spots on the skin and gingiva. This systematic review discusses the studies conducted to assess the effect of Vitamin C on melanin pigmentation. The primary objective was to evaluate the effect of Vitamin C on melanin pigmentation. The secondary objective was to analyze the effect of Vitamin C administration on melanin pigmentation. An electronic database search was conducted from the following databases: PubMed, EBSCOhost, ScienceOpen, EMBASE and Google Scholar. Randomized controlled trials, experimental studies, case–control studies and cohort studies published in peer-reviewed journals in English language were included. Case reports, case series, animal model studies, in vitro studies, studies where Vitamin C was used along with other agents and unpublished research were excluded. Out of 22,580 studies, only 7 studies satisfied the selection criteria. Data extraction sheet was prepared, and the studies were analyzed. Out of the 7 studies analyzed, 1 was a randomized controlled trial and 6 were experimental studies. Vitamin C has been used widely as a depigmenting agent in dermatology. However, there are limited studies conducted on the use of Vitamin C for gingival depigmentation.
Keywords: Ascorbic acid, depigmentation, gingival melanin hyperpigmentation, melanin pigmentation, melanogenesis, tyrosinase, Vitamin C
|How to cite this article:|
Sanadi RM, Deshmukh RS. The effect of Vitamin C on melanin pigmentation – A systematic review. J Oral Maxillofac Pathol 2020;24:374-82
|How to cite this URL:|
Sanadi RM, Deshmukh RS. The effect of Vitamin C on melanin pigmentation – A systematic review. J Oral Maxillofac Pathol [serial online] 2020 [cited 2020 Sep 21];24:374-82. Available from: http://www.jomfp.in/text.asp?2020/24/2/374/294614
| Introduction|| |
Vitamin C, also known as ascorbic acid (AA) and ascorbate, abounds in nature and is highly labile. It is a water-soluble vitamin that is lost in large amounts during food processing. AA is vital for the growth and maintenance of healthy bones, teeth, gums, ligaments and blood vessels and is involved in important metabolic functions. The minimal daily requirement for AA in healthy adults is 40–60 mg.
Vitamin C plays significant functions in the body. The biochemical functions of Vitamin C include stimulation of certain enzymes, collagen biosynthesis, hormonal activation, antioxidant, detoxification of histamine, phagocytic functions of leukocytes, formation of nitrosamine and proline hydroxylation.
AA is required for the hydroxylation of prolyl and lysyl residues during collagen biosynthesis, which is essential for wound healing. Vitamin C has been associated with reduction in incidence of cancer. Vitamin C is effective in protecting against oxidative damage in tissues and also suppresses the formation of carcinogens like nitrosamines. Vitamin C increases the levels of antibodies that fight against germs and viruses. Vitamin C regulates the urinary excretion of hydroxyproline.
This vitamin is needed for the proper metabolism of drugs in the body through adequate hepatic mixed-function oxidase system. There is an inverse relationship with blood pressure and Vitamin C. Vitamin C has a lowering effect on blood pressure, especially on systolic pressure more than diastolic pressure. Low levels of plasma Vitamin C are associated with stroke and with an increased risk of mortality.
Vitamin C (AA) is synthesized by all plants and most animals. It is an essential vitamin for humans because the gene for gulonolactone oxidase, the terminal enzyme in the AA synthesis pathway, has undergone mutations that make it nonfunctional in humans. Therefore, humans obtain this vitamin from diet and/or vitamin supplements. It is an essential nutrient for the biosynthesis of collagen, L-carnitine and the conversion of dopamine to norepinephrine.
Under physiological conditions, Vitamin C plays a role in photoprotection, skin strengthening, immunomodulation and cancer therapy and is used for the removal of hyperpigmented spots. It is also a potent antioxidant.
Vitamin C interacts with the copper (Cu) ions at the tyrosinase active site and inhibits action of the enzyme tyrosinase, thereby reducing melanin formation. It also acts on the perifollicular pigment. However, it is an unstable compound. Therefore, it is used in combination with soy and liquorice for depigmentation in dermatology.
Vitamin C is used as a treatment modality in depigmentation of hyperpigmented spots on the skin. It can be used topically, transdermally as well as intravenously. It is a water-soluble antioxidant and an essential nutrient for cells. Despite its tremendous significance, humans are unable to synthesize this vitamin due to mutation of the gene needed for its synthesis.
It also plays a significant role in collagen synthesis, provides photoprotection and reduces the melanin, scavenger (free radicals) and immunomodulation.
Vitamin C was found to be effective in depigmentation as a result of its direct effect on melanogenesis. Melanin is said to be a reservoir for reactive oxygen species (ROS), Cu and calcium (Ca) within the cells. Following its entry into the target tissue, it binds to melanin. This causes a deficiency of the ROS, Cu and Ca, resulting in reduction of melanin production.
| Rationale|| |
Studies have been conducted to determine the effect of Vitamin C on melanin pigmentation on skin and gingiva. Different formulations were used either in the form of oral administration or topical application or intravenous injection or intraepithelial injection. Although the use of Vitamin C as a depigmenting agent is common in dermatology, there is limited documentation on the use of Vitamin C as a depigmenting agent for gingival melanin hyperpigmentation. Therefore, this systematic review attempts to analyze the existing evidence on the effect of Vitamin C on melanin pigmentation on the skin and gingiva.
Is there a possible effect of Vitamin C on melanin pigmentation?
Another research question
Does administration of Vitamin C reduce melanin pigmentation?
To evaluate the effect of Vitamin C on melanin pigmentation.
To analyze the effect of Vitamin C administration on melanin pigmentation.
| Materials and Methods|| |
This is a systematic review of randomized controlled trials, experimental studies, case–control studies and cohort studies which aims to analyze the effect of Vitamin C on melanin pigmentation and administration of Vitamin C as a depigmenting agent.
- Randomized controlled trials, experimental studies, case–control studies and cohort studies
- Full-text articles published in peer-reviewed journals in English language
- Vitamin C levels, tyrosinase levels or melanin pigmentation index scores assessed.
- Case reports and case series
- Animal model studies andin vitro studies
- Studies where Vitamin C was used along with other agents or in conjunction with other treatment modality
- Unpublished research.
An electronic database search for randomized controlled trials, experimental studies, case–control studies and cohort studies published in peer-reviewed journals in English was conducted from the following databases: PubMed, EBSCOhost, ScienceOpen, EMBASE and Google Scholar.
The search terms used were:
Vitamin C OR Ascorbic acid OR
AND Melanin pigmentation OR Melanin synthesis OR
Melanin production OR melanocyte activity OR
Melanin hyperpigmentation AND Depigmentation
Study selection was carried out in two phases:
- Assessment of titles and abstracts
- Assessment of full text.
Data collection process
Data extraction sheet was prepared based on variables associated, and the articles were analyzed. Using data extraction sheet, the following data were collected: authors, year of publication, country, aim, tissue assessed, type of study, sample size, comparison group and control group, methodology and conclusion.
| Results|| |
A total of 22,580 articles were found after electronic search. 22,100 articles, which were of other languages and duplicates, were excluded leaving 480 articles. 450 articles were excluded as they did not fulfill the eligibility criteria leaving 30 articles. [Figure 1] shows the Flow chart of literature search results and study selection.
Studies included for the analysis
Seven studies were included for the qualitative synthesis. Out of the 7 studies, 1 was a randomized controlled trial and 6 were experimental studies. In all, 7 studies suggested that Vitamin C has a role in melanin pigmentation. An overview of the included studies for the analysis is presented in [Table 1].
|Table 1: Characteristics of the studies included in the Systematic Review|
Click here to view
Assessment of risk of bias in included studies
This assessment was conducted using the recommended approach for assessing the risk of bias in studies included in Cochrane Reviews (Higgins 2011)22 using the tool RevMan 5.0.
We used the two-part tool to address the six specific domains (namely random sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting and other bias). Each domain includes one or more specific entries in a risk of bias table. Within each entry, the first part of the tool involves describing what was reported to have happened in the study. The second part of the tool involves assigning a judgment relating to the risk of bias for that entry: either low risk, unclear risk or high risk.
The domains of random sequence generation, allocation concealment, blinding, incomplete outcome data and selective reporting are addressed in the tool by a single entry for each study. We completed a “risk of bias' table for each included study. The risk of bias of the included studies is presented in [Table 2] and [Graph 1], [Graph 2].
Studies excluded from the analysis
Twenty-three studies were excluded, in which 2 were animal studies, 8 werein vitro studies, 2 were case reports, 7 were studies where Vitamin C was used along with other agents, 2 were studies where Vitamin C was used for the purpose of scar reduction, 1 study where Vitamin C was used in conjunction with iontophoresis and 1 study where Vitamin C was used in conjunction with fluorescent pulsed light (FPL). An overview of the excluded studies is presented in [Table 3].
| Discussion|| |
Skin pigmentation is the result of melanin synthesis in the melanosomes of melanocytes (MCs), followed by the progressive transfer of this melanin to keratinocytes. Melanin is the pigment responsible for skin color and plays normal physiological roles within the skin. It is worthwhile to note that the antimelanogenic mechanism employed by most skin-lightening agents mediates the suppression of tyrosinase activity at various levels.
When choosing a depigmenting agent, it is important to differentiate between substances that are toxic to the MC and substances that interrupt the key steps of melanogenesis. Vitamin C falls into the latter category of depigmenting agents.
Vitamin C is essential for a number of processes in human skin, such as dermal collagen synthesis, antiaging and antioxidation. It is a weak acid and is only slightly stronger than vinegar. The acidification of MCs by Vitamin C could inhibit the catalytic activity of tyrosinase, the rate-limiting enzyme required for melanin biosynthesis.
Vitamin C and its derivatives inhibit tyrosinase activity and melanin content in a dose-dependent manner. It is highly unstable in aqueous solution. The instability of AA is due to its oxidation to dehydroascorbic acid, which is a reversible reaction, and subsequently to 2,3-diketo-L-gulonic acid. The latter reaction is irreversible, thereby resulting in loss of its physiological properties.
It has good photoprotective ability against ultraviolet A-mediated phototoxicity. Effective delivery of AA through topical preparations is a major factor, as it may be dependent on the nature or type of the formulation. The pH of the formulation should be on the acidic side (pH 3.5) for effective penetration of the vitamin in the skin.
Vitamin C is available in the market as a variety of creams, serum and transdermal patches. It is in an almost colorless form and unstable. On exposure to light, gets oxidized to dehydro-AA, which imparts a yellow color. Topical AA formulations have been used in the concentration range of 1%–20%.
From a clinical point of view, it is important to note that the efficacy of the Vitamin C serum is proportional to the concentration but only up to 20%. The half-life in the skin after achieving maximum concentration is 4 days. A persistent reservoir of Vitamin C is important for adequate photoprotection and can be achieved by regular 8-hourly applications. A combination of tyrosine, zinc and Vitamin C has been shown to increase the bioavailability of Vitamin C 20-times vis-a-vis using just Vitamin C.
The present systematic review summarizes the results of the studies that assessed the effect of Vitamin C on melanin pigmentation on the skin as well as the gingiva. There are limited studies available, which assessed the effect of Vitamin C alone on melanin pigmentation.In vitro studies, animal studies and case reports were excluded due to the low level of evidence of these studies.
Lee reported the management of a case of postlaser hyperpigmentation in a woman suffering from melasma. He concluded that intravenous administration of Vitamin C appears to be useful in treating postlaser hyperpigmentation. Sheel et al. evaluated the efficacy of Vitamin C as a depigmenting agent after surgical scalpel depigmentation on the gingiva. They reported satisfactory esthetic results with low subjective pain levels, and no recurrence was observed after 9 months of follow-up. However, as case reports have a level low of evidence, they were excluded.
In the present review, studies in which Vitamin C was used along with other agents were excluded. As Vitamin C is highly unstable, it is often used in combination with other agents such as Vitamin E, Vitamin B, lycopene and β-carotene. We excluded those studies, as we wanted to analyze the effect of Vitamin C alone on melanin pigmentation.
Vitamin C has been used in conjunction with other treatment modalities. Huh et al. used Vitamin C in conjunction with iontophoresis so as to enhance the penetration of Vitamin C into the skin tissue with a favorable outcome. Shaikh and Mashood used Vitamin C in conjunction with FPL for treating refractory melasma in Asian patients and reported a favorable outcome. However, isolated effect of Vitamin C was not assessed; hence, these studies were excluded.
Seven studies were included for the qualitative synthesis. Out of the 7 studies, 1 was a randomized controlled trial and 6 were experimental studies. Three of the studies analyzed assessed the effect of Vitamin C on the gingiva and 4 studies assessed the effect of Vitamin C on skin.
Shimada et al. investigated the inhibitory effect of AA gel on gingival melanin pigmentation in a double-masked placebo-controlled trial with a split-mouth design and reported that AA gel inhibited the gingival melanin pigmentation. As this study was a randomized controlled trial, when the risk of bias was assessed, the lowest risk of bias was observed.
Intraepithelial injections were used on gingiva (Yussif et al., 2016, and Yussif et al., 2019), which helps in direct delivery of Vitamin C at the site. This provides for assessment of effect of Vitamin C alone on melanin pigmentation. However, when the risk of bias was assessed, a higher risk of bias was observed in the study conducted by Yussif et al., 2019.
Vitamin C has been used in dermatology for skin depigmentation in the form of tablets (Ratnam et al., 1977), cream (Kameyama et al., 1996, and Kim et al., 2017) and Vitamin C concentrate (Jaros A et al., 2018). The authors have reported a favorable outcome, suggesting the possible effect of Vitamin C on melanin pigmentation. However, when the risk of bias was assessed, these studies showed a higher risk of bias.
Except for one study, the risk of bias existed in the studies as randomization of study participants and blinding was not performed. This could have influenced the outcome of the studies. However, based on the studies analyzed, it was observed that Vitamin C did have an effect on reducing melanin pigmentation and has been used as a depigmenting agent on the skin as well as gingiva. There remains a future scope for randomized controlled studies to be conducted
| Conclusion|| |
Vitamin C is a naturally occurring substance and an essential nutrient. It has various biological and pharmaceutical functions. It inhibits melanin synthesis through downregulation of tyrosinase enzyme activity. It is widely used in dermatology as a treatment modality in depigmentation of hyperpigmented spots on the skin. It has also been used for treatment of gingival melanin hyperpigmentation. However, there is limited documentation on the use of Vitamin C as a depigmenting agent for gingival melanin hyperpigmentation, although it has shown promising results.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Walingo KM. Role of Vitamin C (ascorbic acid) on human health – A review. Afr J Food Agric Nutr Dev 2005;5:1-12.
Sheraz MA, Ahmed S, Ahmad I, Shaikh RH, Vaid FH, Iqbal K. Formulation and stability of ascorbic acid in topical preparations. Syst Rev Pharm 2011;2:86-90. [Full text]
Smirnoff N, Conklin PL, Loewus FA. Biosynthesis of ascorbic acid in plants: A renaissance. Annu Rev Plant Physiol Plant Mol Biol 2001;52:437-67.
Linster CL, Van Schaftingen E. Vitamin C. Biosynthesis, recycling and degradation in mammals. FEBS J 2007;274:1-22.
Yussif NM, Zayed SO, Hasan SA, Sadek SS. Evaluation of injectable Vitamin C as a depigmenting agent in physiologic gingival melanin hyperpigmentation: A clinical trial. Rep Opinion 2016;8:113-20.
Padayatty SJ, Levine M. Vitamin C: The known and the unknown and Goldilocks. Oral Dis 2016;22:463-93.
Telang PS. Vitamin C in dermatology. Indian Dermatol Online J 2013;4:143-6.
] [Full text]
Velisek J, Cejpek K. Biosynthesis of food constituents: Vitamins, water-soluble vitamins, part 2 – A review. Czech J Food Sci 2007;25:49-64.
Nishikimi M, Fukuyaman R, Minoshiman I, Shimizux N, Yag K. Cloning and chromosomal mapping of the human non-functional gene for L-Gulonolactone oxidase, the enzyme for L-ascorbic acid biosynthesis missing in man. J Biol Chem 1994;269:13685-8.
Urban K, Höhling HJ, Lüttenberg B, Szuwart T, Plate U; Biomineralisation Research Unit. Anin vitro
study of osteoblast vitality influenced by the Vitamins C and E. Head Face Med 2012;8:25.
Panich U, Tangsupa-a-nan V, Onkoksoong T, Kongtaphan K, Kasetsinsombat K, Akarasereenont P, et al
. Inhibition of UVA-mediated melanogenesis by ascorbic acid through modulation of antioxidant defense and nitric oxide system. Arch Pharm Res 2011;34:811-20.
Choi HI, Park JI, Kim HJ, Kim DW, Kim SS. A novel L-ascorbic acid and peptide conjugate with increased stability and collagen biosynthesis. BMB Rep 2009;42:743-6.
Weidinger A, Kozlov AV. Biological activities of reactive oxygen and nitrogen species: Oxidative stress versus signal transduction. Biomolecules 2015;5:472-84.
Diaz V, Miramontes M, Hurtado P, Allen K, Avila M, de Oca E. Ascorbic acid, ultraviolet C rays and glucose but not hyperthermia are elicitors of human β-defensin 1 mRNA in normal keratinocytes. Bio Med Res Int. 2015; 3: 1-9.
Tsai TH, Huang CJ, Wu WH, Huang WC, Chyuan JH, Tsai PJ. Antioxidant, cell-protective, and anti-melanogenic activities of leaf extracts from wild bitter melon (Momordica charantia
Linn. var. abbreviata Ser.) cultivars. Bot Stud 2014;55:78.
Shimada Y, Tai H, Tanaka A, Ikezawa-Suzuki I, Takagi K, Yoshida Y, et al
. Effects of ascorbic acid on gingival melanin pigmentationin vitro
and in vivo
. J Periodontol 2009;80:317-23.
Yussif NM, Abdel Rahman AR, Elbarbary E. Minimally invasive non-surgical locally injected Vitamin C versus the conventional surgical depigmentation in treatment of gingival hyperpigmentation of the anterior esthetic zone: A prospective comparative study. Clin Nutr Exp 2019;24:54-65.
Ratnam AV, Sastry PB, Satyanarayana BV. Ascorbic acid and melanogenesis. Br J Dermatol 1977;97:201-4.
Kameyama K, Sakai C, Kondoh S, Yonemoto K, Nishiyama S, Tagawa M, et al
. Inhibitory effect of magnesium L-ascorbyl-2-phosphate (VC-PMG) on melanogenesisin vitro
and in vivo
. J Am Acad Dermatol 1996;34:29-33.
Kim HM, An HS, Bae JS, Kim JY, Choi CH, Kim JY, et al
. Effects of palmitoyl-KVK-L-ascorbic acid on skin wrinkles and pigmentation. Arch Dermatol Res 2017;309:397-402.
Jaros A, Zasada M, Budzisz E, Dębowska R, Gębczyńska-Rzepka M, Rotsztejn H. Evaluation of selected skin parameters following the application of 5% vitamin C concentrate. J Cosmet Dermatol 2019;18:236-41.
Higgins JP, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0 (Updated March 2011). The Cochrane Collaboration; 2011. Available from: http://www.handbook.cochrane.org
. [Last accessed on 20-4-2020]
Takenouchi K, Aso K. The relation between melanin formation and ascorbic acid. J Vitaminol (Kyoto) 1964;10:123-34.
Yussif NM, Korany NS, Abbass MM. Evidence of the effect of intraepidermic Vitamin C injection on melanocytes and keratinocytes in gingival tissues:In vivo
study. Dentistry 2017;7:417-23.
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;56:292-7.
Lee SA, Son YO, Kook SH, Choi KC, Lee JC. Ascorbic acid increases the activity and synthesis of tyrosinase in B16F10 cells through activation of p38 mitogen-activated protein kinase. Arch Dermatol Res 2011;303:669-78.
Taira N, Katsuyama Y, Yoshioka M, Okano Y, Masaki H. 3-O-Glyceryl-2-O-hexyl ascorbate suppresses melanogenesis by interfering with intracellular melanosome transport and suppressing tyrosinase protein synthesis. J Cosmet Dermatol 2018;17:1209-15.
Katsuyama Y, Taira N, Yoshioka M, Okano Y, Masaki H. 3-O-Glyceryl-2-O-hexyl Ascorbate suppresses melanogenesis through activation of the autophagy system. Biol Pharm Bull 2018;41:824-7.
Taira N, Katsuyama Y, Yoshioka M, Muraoka O, Morikawa T. Structural requirements of alkylglyceryl-l-ascorbic acid derivatives for melanogenesis inhibitory activity. Int J Mol Sci 2018;19:1-22.
Yim S, Lee J, Jo H, Scholten J, Willingham R, Nicoll J, et al
. Chrysanthemum morifolium extract and ascorbic acid-2-glucoside (AA2G) blend inhibits UVA-induced delayed cyclobutane pyrimidine dimer (CPD) production in melanocytes. Clin Cosmet Investig Dermatol 2019;12:823-32.
Miao F, Su MY, Jiang S, Luo LF, Shi Y, Lei TC. Intramelanocytic acidification plays a role in the antimelanogenic and antioxidative properties of Vitamin C and its derivatives. Oxid Med Cell Longev 2019;2019:2084805.
Lee GS. Intravenous Vitamin C in the treatment of post-laser hyperpigmentation for melasma: A short report. J Cosmet Laser Ther 2008;10:234-6.
Sheel V, Purwar P, Dixit J, Rai P. Ancillary role of vitamin C in pink aesthetics. BMJ Case Rep 2015;2015:27-31.
Postaire E, Jungmann H, Bejot M, Heinrich U, Tronnier H. Evidence for antioxidant nutrients-induced pigmentation in skin: Results of a clinical trial. Biochem Mol Biol Int 1997;42:1023-33.
Broekmans WM, Vink AA, Boelsma E, Klöpping-Ketelaars WA, Tijburg LB, van't Veer P, et al
. Determinants of skin sensitivity to solar irradiation. Eur J Clin Nutr 2003;57:1222-9.
Hwang SW, Oh DJ, Lee D, Kim JW, Park SW. Clinical efficacy of 25% L-ascorbic acid (C'ensil) in the treatment of melasma. J Cutaneous Med Surg 2009;13:74-81.
De Dormael R, Bastien P, Sextius P, Gueniche A, Ye D, Tran C, et al
. Vitamin C prevents ultraviolet-induced pigmentation in healthy volunteers: Bayesian meta-analysis results from 31 randomized controlled versus vehicle clinical studies. J Clin Aesthet Dermatol 2019;12:E53-9.
Ishikawa Y, Niwano T, Hirano S, Numano K, Takasima K, Imokawa G. Whitening effect of L-ascorbate-2-phosphate trisodium salt on solar lentigos. Arch Dermatol Res 2019;311:183-91.
Kim J, Kim J, Lee YI, Almurayshid A, Jung JY, Lee JH. Effect of a topical antioxidant serum containing Vitamin C, Vitamin E, and ferulic acid after Q-switched 1064-nm Nd: YAG laser for treatment of environment-induced skin pigmentation. J Cosmet Dermatol. 2020;2:1-13. doi: 10.1111/jocd.13323. [Epub ahead of print].
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;19:671-6.
Huh CH, Seo KI, Park JY, Lim JG, Eun HC, Park KC. A randomized, double-blind, placebo-controlled trial of vitamin C iontophoresis in melasma. Dermatology 2003;206:316-20.
Shaikh ZI, Mashood AA. Treatment of refractory melasma with combination of topical 5% magnesium ascorbyl phosphate and fluorescent pulsed light in Asian patients. Int J Dermatol 2014;53:93-9.
Yun IS, Yoo HS, Kim YO, Rah DK. Improved scar appearance with combined use of silicone gel and Vitamin C for Asian patients: A comparative case series. Aesthetic Plast Surg 2013;37:1176-81.
Amirlak B, Mahedia M, Shah N. A clinical evaluation of efficacy and safety of hyaluronan sponge with Vitamin C versus placebo for scar reduction. Plast Reconstr Surg Glob Open 2016;4:e792.
Yilmaz S, Sadikoglu M, Saglikoglu G, Yagmur S, Askin G. Determination of ascorbic acid in tablet dosage forms and some fruit juices by differential pulse voltammetry (DPV). Int J Electrochem Sci 2008;3:1534-42.
Farris PK. Cosmetical Vitamins: Vitamin C. In: Draelos ZD, Dover JS, Alam M, editors. Cosmeceuticals Procedures in Cosmetic Dermatology. 2nd
ed. New York: Saunders Elsevier; 2009. p. 51-6.
Traikovich SS. Use of topical ascorbic acid and its effects on Photo damaged skin topography. Arch Otorhinol Head Neck Surg 1999;125:1091-8.
[Table 1], [Table 2], [Table 3]