A cream of herbal mixture to improve melasma

Summary Background Melasma is an acquired, common hyperpigmented disorder on the face. While many therapeutic approaches are available, their efficacy is moderate. Objective To investigate the safety and efficacy of a cream containing herbal mixture for melasma. Methods A total of 90 volunteers with melasma were enrolled in this randomized, double‐blind, controlled clinical study, and they were randomly divided into three groups (A, B, and C). Patients in group A were treated with a cream containing herbal mixture, while groups B and C were treated with arbutin cream and placebo, respectively, twice daily for 12 weeks. Melasma area and severity index (MASI) score, melanin index (MI), erythema index (EI), changes in density of inflammatory cells, and adverse events were evaluated every 4 weeks. Results Although MASI scores declined significantly in both groups A and B (P < 0.05), a greater reduction was seen in group A (13.00−9.82 = 3.18 for group A; 12.65−10.84 = 1.81 for group B). Moreover, the cream containing herbal mixture, but not arbutin cream and placebo, significantly reduced EI and density of inflammatory cells after 12‐week treatment (P < 0.05). No adverse reactions were observed in either group A or group C. In group B, two subjects experienced mild erythema and itching, which disappeared after stop using the arbutin cream. Conclusion The cream containing herbal mixture is safe and effective for melasma.


| INTRODUC TI ON
Melasma is an acquired pigmentary condition, commonly occurring on the face of females, which can be classified into centrofacial pattern, malar pattern, mandibular pattern, and mixed. [1][2][3] The prevalence of melasma is 1% in general population and as high as 50% in high-risk populations. 4 Previous studies have shown that at least four pathogenesis are involved in the development of melasma, that is melanogenesis/melanin, 5 inflammation, [6][7][8][9] vascularization/vascular factor, 10,11 and defective skin barrier. [12][13][14][15] Although melasma is not life-threatening, it greatly impacts the quality of the life of patients.
Although many therapeutic regimens are available for melasma, the efficacy is moderate. 4 In some cases, they can cause severe adverse reactions. For example, repeated applications of hydroquinone, commonly used for the treatment of hyperpigmentation, can cause toxic reactions, depigmentation, vitiligo-like hypochromia, or leukoderma. 16,17 Therefore, development of effective and safe products for melasma is becoming emergent.
In the present study, we evaluated the efficacy and safety of a newly developed formulation in a randomized, double-blind, and controlled trial in 90 volunteers. Certain ingredients in this formulation specifically target respective aspect involved in the pathogenesis of melasma. For example, China camellia can antioxidant and inhibit tyrosinase activity, 18 leading to inhibition of melanogenesis. Sanchi can promote blood circulation by suppressing the aggregation of platelets. 19 Portulaca oleracea exhibits anti-inflammatory and anti-allergy properties, 20 resulting in improvement in inflammation. Prinsepia utilis can improve epidermal permeability barrier function, via stimulation of epidermal ceramide production. 21

| Treatments
Volunteers were randomly divided into three groups using a table of random numbers. Patients in group A were treated with a cream containing herbal mixture, while groups B and C were treated with arbutin cream and placebo, respectively, twice daily on the whole face for 12 weeks. Because ultraviolet light can aggravate pigmentation, all volunteers were instructed to apply the same sunscreen every 3 hours while being outdoor during the trial period.  7 To evaluate the density of inflammatory cells in melasma, each image (500 × 500 μm) was assessed and scored independently by two individual observers. In comparison to normal controls, the density was scored as 0 = no increase, 1 = slight increase, 2 = moderate increase, and 3 = marked increase. 23 The score is presented as mean ± standard deviation. The higher the score was, the higher density of inflammatory cells was.

| Evaluation method
Safety, efficacy, and tolerability were evaluated at the end of week 4, week 8, and week 12. The volunteers were asked to evaluate their satisfaction with the following criteria: 0 = not satisfied, 1 = partially satisfied, 2 = satisfied, or 3 = very satisfied. We recorded adverse events, including itching, scaling, erythema, burning, and erosion at each visit.

| Statistical analysis
The data were analyzed by SPSS version19.0 and were expressed as mean ± standard deviation. Repeated Measures ANOVA were used to compare data among three groups at different times. Statistical significance was assumed for a P < 0.05.

| Demographic characteristics of patients
The patients were 40.35 ± 6.02 years old and had skin type III or IV (Fitzpatrick skin types). The mean duration of melasma was 5.46 ± 3.72 years. The baseline MASI scores were 12.83 ± 6.49 (detailed in Table 1).

| The cream of herbal mixture improves MASI scores, MI, and EI
As shown in Table 2

| The cream of herbal mixture decreases inflammation
As seen in Figure Table 2). These results demonstrate that the cream of herbal mixture alleviates cutaneous inflammation in melasma.

| Subjective satisfaction score
The subjective satisfaction scores were markedly improved in both group A and group B (Figure 3). In particular, the number of patients with "very satisfied" (score 3) increased from 4 (13.3%) at week 4 to

| Adverse reactions
No itching, scaling, erosion, burning, or ulcer was reported at any visit in group A and group C. Two subjects treated with arbutin cream experienced slight erythema and pruritus, which disappeared after stop using the arbutin cream.

| D ISCUSS I ON
Current regimens for melasma include chemical peels, oral drugs, topical therapy, prevention of UV radiation and laser therapies, most of which are easy to relapse and incomplete clearance. 24 Because hyperpigmentation is the major clinical manifestation of melasma, much attention has been paid to decrease melanin by inhibition of the exacerbated activity of melanocytes and dispersion of melanin granules. 25 Indeed, the strategies decreasing melanin can improve skin pigment to some extent. But recurrence is inevitable in most cases, if not in all cases. However, here we developed a cream containing herbal mixture, in which each natural ingredient specifically targets respective pathogenic aspect of melasma (Figures 4 and 5).
Our results showed that topical applications of this cream containing herbal mixture markedly improved melasma. Defective epidermal permeability barrier has be proposed to contribute to the development of melasma. [12][13][14][15] Accordingly, improvement in epidermal permeability barrier could benefit melasma.
It has been demonstrated that Prinsepia utilis, an ingredient in the test cream, could improve epidermal permeability barrier via stimulation of epidermal lipid production, including ceramides, major component of lamellar lipids in the stratum corneum. 21,35 Thus, Prinsepia utilis induced improvement in epidermal permeability barrier could be additional mechanism by which the cream of herbal mixture improves melasma.
F I G U R E 5 Formula design of the new whitening cream aimed at four main pathogenesis of melasma Taken together, the present study demonstrated that the cream containing herbal mixture improves melasma by multiple mechanism, including anti-inflammation, antioxidant, improving microcirculation, inhibition of melanogenesis as well as improving in epidermal permeability barrier.

| CON CLUS ION
The cream containing herbal mixture is effective and safe to melasma.