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Assessment of clinical efficacy of different concentrations of topical ascorbic acid formulations in the treatment of melasma

Ali, Basma M.a; El-Ashmawy, Amal A.a; El-Maghraby, Gamal M.b; Khattab, Rania A.a,c

Journal of the Egyptian Women's Dermatologic Society: January 2014 - Volume 11 - Issue 1 - p 36–44
doi: 10.1097/01.EWX.0000437065.46995.3e
Original articles
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Background Several methods of treatment are available for patients with melasma but none are satisfactory. Ascorbic acid is used for the treatment of various skin problems. However, ascorbic acid has limited stability and permeability, and development of ascorbic acid derivatives with improved properties is needed.

Objective The aim of the study was to assess the clinical efficacy and safety of different concentrations of ascorbic acid cream in the treatment of melasma.

Patients and methods This study included 40 patients with different clinical varieties of melasma, such as centrofacial and malar. The patients were divided equally into four groups: groups I, II, III, and IV. The first three groups were treated with different concentrations of ascorbic acid cream (5, 10, and 25%), whereas the fourth group were treated with topical placebo and served as the control group. Melasma was evaluated with modified melasma area and severity index and patients were followed up for a period of 6 months.

Results Significant improvement in melasma (reduction in modified melasma area and severity index score) was observed with all ascorbic acid preparations in comparison with the control group, which showed no response. Group III treated with 25% ascorbic acid gave the best results, followed by the group treated with 10% ascorbic acid and the group treated with 5% ascorbic acid; however, there were nonstatistically significant differences between the three groups. The patients with epidermal melasma showed better response than those with mixed and dermal types.

Conclusion Ascorbic acid topical formulations can effectively treat melasma especially with 10 and 25% concentration with minimum and tolerable adverse effects.

aDepartment of Dermatology and Venereology, Faculty of Medicine

bDepartment of Pharmaceutical Technology, Faculty of Pharmacy, Tanta University, Tanta

cMinistry of Health, Tanta, Egypt

Correspondence to Amal A. El-Ashmawy, MD, Department of Dermatology and Venereology, Faculty of Medicine, Tanta University, Tanta, 31572 Egypt Tel: +20 127 105 7154; fax: +20 402 212 794; e-mail: elashmawy2013@yahoo.com

Received June 22, 2013

Accepted October 4, 2013

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Introduction

Melasma is an acquired hypermelanosis on sun-exposed areas of the face, particularly in female patients with III–V Fitzpatrick skin types. The etiology is unknown, but the most important predisposing factor is sun exposure. Other possible factors include pregnancy, use of contraceptives, race, genetic factors, and hormonal alterations. Melasma presents as brown to gray macules and patches, with serrated, irregular, and geographic borders. The pigmented patches are usually sharply demarcated and symmetrical. The three major distribution patterns are centrofacial (cheeks, forehead, upper lip, nose, and chin) in 65% of cases, malar (cheeks and nose) in 20% of cases, and mandibular (rami of the mandible) in 15% of cases 1.

Ascorbic acid is a water-soluble antioxidant and is the most plentiful antioxidant in the skin 2. Ascorbic acid has been widely used in formulations of skin care products because of its effects on collagen biosynthesis. It is considered an active moisturizing and antiaging ingredient 3. It is well known as a skin-whitening agent 4. Ascorbic acid is used topically in different concentrations and can be formulated with other depigmenting agents, such as hydroquinone. Topical ascorbic acid is generally well tolerated in colored skin and has a good safety profile 5. Ascorbic acid exhibits its whitening effects by several mechanisms: by antioxidation through inhibition of the peroxidase-catalyzed melanogenic reaction in melanocytes 6; by interaction with copper ions at the tyrosinase active site and reduction of oxidized dopaquinone (a substrate in the melanin synthetic pathway) to dihydroxyphenylalanine 7; and by prevention of free radical production and absorption of ultraviolet rays 8.

For optimal biological effectiveness, topical vitamin C preparations should contain a high concentration of L-ascorbic acid in a stable, aqueous, acidic pH formulation. Topical ascorbic acid is most commonly supplied as an equal mixture of D-ascorbic acid and L-ascorbic acid. These forms of ascorbic acid are stereoisomers, but only L-ascorbic acid is used by the body 9.

The aim of this work was to assess the clinical efficacy and safety of different concentrations of topical ascorbic acid formulations in the treatment of patients with melasma.

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Patients and methods

Patients

The current comparative single-blinded placebo-controlled study included 40 female patients with different clinical varieties of melasma (centrofacial and malar), diagnosed on the basis of typical clinical appearance of skin lesions. The patients were selected from the Outpatient Clinic of Dermatology and Venereology Department, Tanta University Hospitals, during the period from March 2011 to March 2012 after obtaining the approval of the research ethics committee of the hospital (code no. 520/04/11) and written informed consent from each participant. The studied patients were classified into four groups (10 patients in each group).

Group I: 10 patients with melasma were treated with topical 5% ascorbic acid cream. Group II: 10 patients with melasma were treated with topical 10% ascorbic acid cream. Group III: 10 patients with melasma were treated with topical 25% ascorbic acid cream. Group IV (control group): 10 patients with melasma were given topical placebo (drug-free formulation) in a cream form.

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Inclusion criteria

All newly diagnosed patients who had not received treatment for melasma within the 6 weeks preceding the study were included in the study.

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Exclusion criteria

Pregnant or nursing women, those who have undergone a miscarriage, women undergoing hormonal therapy or who have been using contraceptive pills for 12 months before the study, and melasma patients who have systemic or other dermatological diseases were excluded from the study. Special emphasis was on patient’s occupation with exclusion of those with inevitable sun exposure.

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Methods

All studied patients were subjected to a standard protocol that consisted of:

  • Complete history taking.
  • General examination.
  • Dermatological examination: the dermatological examination included the following:
    • Determination of the type of melasma by Wood’s light – where pigmentation appears more intense in epidermal melasma, is not intensified in dermal melasma, intensifies in some areas in mixed plasma and remains unchanged in other areas 10 – and dermoscopic examination (accentuation of the normal pseudorete of the facial skin, blue-gray, granular, annular structures around the follicles, and in some cases slate-gray dots or dark-brown streaks) 11.
    • Determination of modified melasma area and severity index (MASI) scores for clinical assessment of the patients’ condition before and after therapy, which is scored as follows:
      • Modified MASI score=0.3A (f)×D (f)+0.3A (lm)×D (lm)+0.3A (rm)×D (rm)+0.1A (c)×D (c), where A is the area of involvement and D is the darkness, with the forehead (f), left malar region (lm), right malar region (rm), and chin (c) corresponding to 30, 30, 30, and 10 of the total face, respectively. The area of involvement in each of these four regions is given a numeric value of 0–6 (0, no involvement; 1, <10%; 2, 10–29%; 3, 30–49%; 4, 50–69%; 5, 70–89%; and 6, 90–100%). Darkness is rated on a scale from 0 to 4 (0, absent; 1, slight; 2, mild; 3, marked; and 4, maximum). It is calculated by multiplying the value of the area of involvement by the severity rating for darkness for each of the four facial regions. The range of the total score is 0–24, with 0 indicating absence of melasma and 24 indicating severe melasma 12.
  • Therapeutic regimen: all melasma patients in the first three groups were instructed to apply a given concentration of ascorbic acid cream to melasma lesions only twice daily for 12 weeks or until clinical cure, whereas the fourth group (the control group) was instructed to apply a placebo cream for the same duration as that of the other three groups. All participants were instructed to avoid the use of any other melasma therapy (topical or systemic) during the whole duration of the study and during the follow-up period.
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Preparation of topical formulation

Semisolid emulsion-based formulations were prepared in the pharmaceutical technology laboratory in the Faculty of Pharmacy, Tanta University, according to the following formula: cetyl alcohol (6 g), stearic acid (3.5 g), white soft paraffin (14.5 g), propylene glycol (8 g), tween 80 (7 g), and distilled water (100 ml).

The emulsion was prepared by melting the fatty base according to the descending order of melting points. At the same time, tween 80 compounds were melted in water and heated to the same temperature of the oily phase. Then the aqueous phase was added to the melted oily phase while heating with stirring until a creamy color was formed. The emulsion was removed from the water bath and stirring was continued until it congealed. Different concentrations of ascorbic acid (5, 10, and 25%) were incorporated in the cream after cooling. The required amount of ascorbic acid was powdered and mixed with propylene glycol to form a smooth paste. This paste was mixed with the cream with trituration until homogeneity. The prepared cream formulations were packed in dark-covered glass containers and stored away from sun and fresh air at 4°C in a refrigerator. Any color change was considered an indication of the instability of the drug. Freshly prepared formulation was given to each patient every 2 weeks. For preparation of the placebo (drug-free formulation), the cream was used without adding ascorbic acid.

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Treatment procedure

Patients were instructed to clean the melasma area with thermal water before application of the drug. They then had to apply the topical medication as a thin layer over the entire affected site at mid-day and at night without rubbing using the tip of their finger.

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Post-treatment care

After each application, the patients were instructed to avoid sun exposure as much as possible and apply sun screen (zinc oxide) daily and avoid skin rubbing and friction. A bland emollient such as panthenol was applied if irritation occurred.

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Assessment of the clinical efficacy of the treatment

Global photographic assessment according to the modified melasma area and severity index score 12.

Digital image analysis of standard colored photographs was used to determine the percentage of improvement of melasma lesions. Baseline photographs of the lesions (front, right, and left views) were taken using a Nikon Coolpix P5100 digital camera (Shenzhen Jie Haixing Technology Co. Ltd, Shenzhen, China] to document images before treatment, every 2 weeks during treatment, at the end of therapy, and during the follow-up period to evaluate the clinical efficacy and side effects of the treatment. Evaluations were made by consensus between three dermatologists, blinded to the type of applications as follows: no response, no changes in modified MASI score at the end of therapy; fair response, less than 25% fall in modified MASI score; good response, 25–50% fall in modified MASI score; very good response, 50–75% fall in modified MASI score; and excellent response, more than 75% fall in modified MASI score.

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Side effects

Side effects were assessed in all patients at each visit every 2 weeks after enrollment in the study. All clinical medical events, whether observed by the investigator or reported by the patient and whether or not thought to be drug-related, are considered adverse events.

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Follow up

The patients were followed up (after the end of therapy) and evaluated clinically and using colored photographs monthly for 6 months to determine the degree of improvement, recurrence of melasma lesions, or complications.

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Statistical analysis

All data obtained were analyzed with SPSS version 15 (IBM Co., New York, New York, USA). Data were summarized using mean±SD. Comparison of quantitative data was made using Student’s t-test. Comparison between groups was made using the χ2-test and Fisher’s exact test for qualitative variables. Statistical significance was determined at a level of P less than or equal to 0.05, and P values less than or equal to 0.001 were considered highly significant.

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Results

Clinical results are given in Tables 1 and 2.

Table 1

Table 1

Table 2

Table 2

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Assessment of clinical efficacy of the therapy

With regard to response of the patients to ascorbic acid therapy, excellent results were seen in 30% of the patients, very good results in 33.3%, good results in 16.7%, and fair results in 16.7%. There was a highly statistically significant reduction in modified MASI score after therapy than before therapy in groups I, II, and III. In group IV (placebo) there was a nonsignificant difference in modified MASI score after therapy (Fig. 1). There was a statistically significant difference between group IV (control group) and groups I, II, and III. Group III showed the best results, followed by group II then group I, but there were nonsignificant differences between groups I, II, and III (Table 3 and Figs 2–4).

Figure 1

Figure 1

Table 3

Table 3

Figure 2

Figure 2

Figure 3

Figure 3

Figure 4

Figure 4

As regards the type of melasma, epidermal type showed excellent results, whereas dermal and mixed types showed good and fair response. Therefore, there was statistically significantly better response to therapy in epidermal type than in mixed and dermal types in groups I, II, and III (Table 4).

Table 4

Table 4

There was statistically significantly better response to therapy in patients aged 20–40 years than in those older than 40 years but up to 60 years in groups I, II, and III (Fig. 5). There was statistically significantly better response to ascorbic acid therapy in patients who have had melasma for less than 5 years than in those who have had melasma for more than 5 years in groups I, II, and III (Fig. 6).

Figure 5

Figure 5

Figure 6

Figure 6

There was statistically significantly better response to ascorbic acid therapy in patients with Fitzpatrick skin type III than in those with skin type IV (Fig. 7). There was statistically significantly better response to ascorbic acid therapy in patients with malar melasma pattern than in those with centrofacial melasma pattern (Fig. 8).

Figure 7

Figure 7

Figure 8

Figure 8

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Side effects

In group I, 20% of patients experienced mild burning sensation in the first 4 weeks of application of ascorbic acid, which resolved spontaneously. In group II, 30% of patients experienced mild burning sensation and 10% experienced dryness and scaliness at the site of application during the first 4 weeks of therapy, which resolved on using a bland emollient. In group III, 30% of patients experienced severe burning sensation and 30% experienced erythema (Fig. 9) lasting 7–14 days, which was resolved by application of cold compresses and a bland emollient; 10% experienced dryness and scaliness and 10% experienced pruritus at the site of application of ascorbic acid in the face, which resolved gradually within 7 days. In group IV, no side effects were reported in any patient.

Figure 9

Figure 9

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Follow up period assessment

Recurrence was seen in seven patients (23.3%) during the follow-up period. They were of skin type IV and of dermal or mixed melasma in groups I and II.

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Discussion

In the current study we used three concentrations of topical ascorbic acid (5, 10, and 25%) cream for the treatment of melasma. Although ascorbic acid is a very hydrophilic compound, its skin permeation has been confirmed 13,14. However, it has instability problems such as oxidation susceptibility when incorporated in a topical formulation. The pH of a topical formulation is crucial for optimal bioavailability; ascorbic acid in acidic formulation (pH<3.5) is crucial for its percutaneous absorption into the skin. The stability of ascorbic acid decreases by increasing the pH of aqueous solutions. Different parameters and formulation factors such as temperature of phases and duration and speed of mixing were evaluated 13. In the present study, several measures were used to decrease the instability of ascorbic acid in the formula. The preparation of oil in water emulsion with acidic pH and the adding of a cosurfactant, propylene glycol derivative, as a penetration enhancer to the formulation, and the packing of freshly prepared cream in dark-covered plastic containers, which were stored away from the sun and fresh air at 4°C, made the current formula more stable. The absence of any color change for 6 weeks indicates the stability of the drug.

In the current study, assessment of the clinical efficacy of treatment was made by objective assessment using the modified MASI score. In the current study, excellent results were seen in 30% of patients, very good results in 33.3%, good results in 16.7%, and fair results in 16.7%. On comparing the results of the studied groups, high concentration (25%) of ascorbic acid gave the best results, followed by the 10% concentration and the 5% concentration, but with insignificant difference. There was better response to therapy in the epidermal type than in the mixed and dermal types in groups I, II, and III. This is attributed to the inhibitory effect of ascorbic acid on melanogenesis in the epidermis 7,8. However, in dermal melasma, melanin is engulfed by melanophages deep in the dermis. Ascorbic acid cream is retained in the epidermis, which is an advantage over sunscreens that are easily removed. Therefore, it inhibits melanin production by diminishing the ability of ultraviolet radiation to stimulate the synthesis of melanin 15.

There was significant response to ascorbic acid therapy in patients aged 20–40 years compared with those older than 40 years but up to 60 years and in patients with melasma duration less than 5 years than in those with melasma duration more than 5 years in groups I, II, and III. This may be explained by the transformation of epidermal melasma to mixed or dermal type on long duration of the disease, which is usually resistant to therapy 16. There was significant response to ascorbic acid therapy in patients with skin type III than in those with skin type IV in groups I, II, and III. This may be because skin type IV tans more easily than skin type III.

The successful use of ascorbic acid in melasma was reported in previous studies 6,17–21. Hwang et al. 6 applied 25% ascorbic acid cream to the entire face twice daily for 16 weeks in melasma patients. They used N-methyl-2-pyrrolidone with hydrophilic character and dimethyl isocorbide with lipophilic character as a penetration enhancer. They found statistically significant reduction in MASI score at each study visit.

In another randomized, double-blind comparative trial 18, 20 melasma patients were treated with split face iontophoresis using either multivitamins or vitamin C. After 12 weeks, both multivitamins and vitamin C were seen to be effective for melasma treatment. A previous study 19 synthesized magnesium L-ascorbyl-2-phosphate 10% cream, which is a stable ester of ascorbic acid, and used 1–3% methylene glycol as a penetration enhancer, showed significant lightening effect on more than half of the patients with melasma. Furthermore, magnesium L-ascorbyl-2-phosphate has been shown to have a protective effect against skin damage induced by UVB irradiation and it inhibits melanogenesis in vitro and in vivo. Experiments demonstrated that magnesium L-ascorbyl-2-phosphate cream was absorbed into the epidermis and that 1.6% remained 48 h after application.

Ochiai et al. 20 reported that tetra-isopalmitoyl ascorbic acid suppresses UVB-induced skin pigmentation in treated areas 3 weeks after UVB irradiation. Coutanceau et al. 21 who applied a topical preparation containing L-ascorbyl-glucoside and niacinamide to the entire face and neck of melasma patients twice a day for 4 months reported a significant improvement in 88% of patients at 2 months and in 93% of patients at 4 months.

In contrast, Tadokoro et al. 22 showed that orchid-rich plant extracts as well as melasma and lentigo senilis possess efficacy similar to that of vitamin C derivative in whitening facial skin of Japanese women.

In the current study, the most common complaints during ascorbic acid treatment were burning sensation, erythema, dryness, scaliness, and pruritus. These were most common in group III (80%) than in group II (40%) or in group I (20%). This may be explained by the acidic nature of ascorbic acid and its keratolytic effect, especially at high concentrations, which was seen in previous studies 6,17,18,23,24. Hwang et al.6 found that 75% of their melasma patients experienced stinging, 57.5% experienced burning, 15% experienced pruritus, 20% experienced erythema, and 12.5% experienced scaling on using 25% ascorbic acid cream. Choi et al. 18 found that, on using vitamin C iontophoresis, burning sensation occurred in 25%, erythema in 10%, and itching in 10% of melasma patients. The irritation effect is lower in low concentrations as seen in the study by Espinal-Perez et al.17 who reported irritation in 6.25% of the patients using 5% ascorbic acid cream. Also, no patients were found to have any evidence of irritation or inflammation during the 12-week trial in photodamaged skin treatment by using 10% ascorbic acid and 7% tetrahexyldecyl ascorbate in an anhydrous polysilicone gel 20. It was reported that adverse effects were mild and resolved by application of moisturization within the first 2 months of topical ascorbic acid application in treating mild-to-moderate photodamaged and pigmented facial skin 23. Huh et al.24 mentioned that there were itching, erythema, burning sensation, and dryness of the face in a small number of their melasma patients who were treated with vitamin C solution iontophoresis.

The patients in this study were followed up for 6 months after the end of treatment and recurrence was recorded in 23.3% of the patients who were using 5 and 10% ascorbic acid cream. They were of skin type IV and had mixed or dermal melasma in which the pathology is still present deep in the dermis. Similarly, Coutanceau et al.21 found that recurrence occurred in 20% of their melasma patients during the 3-month follow-up period after using a topical preparation containing L-ascorbyl-glucoside and niacinamide.

According to the present results, topical ascorbic acid has shown effective depigmenting action on melasma with 5, 10, and 25% concentrations, especially with 10 and 25% concentration, and with minimal adverse effects. No cases of photodermatitis were recorded in this study as the patients avoided sun exposure during the cream application. It is well tolerated for all types of skin. Recurrence mostly occurred with skin type IV and in dermal and mixed melasma.

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Acknowledgements

Conflicts of interest

There are no conflicts of interest.

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Keywords:

ascorbic acid; melasma; modified melasma area and severity index score

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