A Novel Cream Formulation Containing Nicotinamide 4%, Arbutin 3%, Bisabolol 1%, and Retinaldehyde 0.05% for Treatment of Epidermal Melasma

The study population included women aged 18 to 50 years with Fitzpatrick skin types I through V who had clinically diagnosed epidermal melasma on the face. Eligibility requirements included confirmation of epidermal pigmentation on Wood lamp examination and RCM analysis and a MASI score of less than 10.5. A total of 35 participants were enrolled in the study (intention to treat [ITT] population). Thirty-three participants were included in the analysis of treatment effectiveness (ITTe population), as 2 were excluded due to lack of follow-up postbaseline. Four participants were prematurely withdrawn from the study—3 due to loss to follow-up and 1 due to treatment discontinuation following an adverse event (AE). The last observation carried forward method was used to input missing data from these 4 participants excluding repeated measure analysis that used the generalized estimated equation method.

At baseline, a 25-g tube of the study cream containing nicotinamide 4%, arbutin 3%, bisabolol 1%, and RAL 0.05% was distributed to all participants for once-daily application to the entire face for 30 days. Participants were instructed to apply the product in the evening after using a gentle cleanser, which also was to be used in the morning to remove the product residue. Additionally, participants were given a sunscreen with a sun protection factor of 30 to apply daily on the entire face in the morning, after lunch, and midafternoon. During the 30-day treatment period, treatment interruption of up to 5 consecutive days or 10 nonconsecutive days in total was permitted. At day 30, participants received another 30-day supply of the study product and sunscreen to be applied according to the same regimen for an additional 30-day treatment period.

Clinical Evaluation

At baseline, demographic data and medical history was recorded for all participants and dermatologic and physical examination was performed documenting weight, height, blood pressure, heart rate, and baseline MASI score. Following Wood lamp examination, participants’ faces were photographed and catalogued using medical imaging software that allowed for measurement of the total melasma surface area (Figure 1A). The photographs also were cross-polarized for further analysis of the pigmentation (Figure 1B).

Figure 1. Clinical (A) and cross-polarized (B) photographs of a patient before treatment with the novel compound containing nicotinamide 4%, arbutin 3%, bisabolol 1%, and retinaldehyde 0.05%.

A questionnaire evaluating treatment satisfaction was administered to participants (ITTe population [n=33]) at baseline and days 30 and 60. Questionnaire items pertained to skin blemishes, signs of facial aging, overall appearance, texture, oiliness, brightness, and hydration. Participants were instructed to rate their satisfaction for each item on a scale of 1 to 10 (1=bad, 10=excellent). For investigator analysis, scores of 1 to 4 were classified as “dissatisfied,” scores of 5 to 6 were classified as “satisfied,” and scores of 7 to 10 were classified as “completely satisfied.” A questionnaire evaluating product appreciation was administered at day 60 to participants who completed the study (n=29). Questionnaire items asked participants to rate the study cream’s ease of application, consistency, smell, absorption, and overall satisfaction using ratings of “bad,” “regular,” “good,” “very good,” or “excellent.”

Treatment efficacy in all participants was assessed by the investigators at days 30 and 60. Investigators evaluated reductions in pigmentation and total melasma surface area using ratings of “none,” “regular,” “good,” “very good,” or “excellent.” Local tolerance also was evaluated at both time points, and AEs were recorded and analyzed with respect to their duration, intensity, frequency, and severity.

Targeted hyperpigmented skin was selected for in vivo RCM analysis. At each time point, a sequence of block images was acquired at 4 levels of skin: (1) superficial dermis, (2) suprabasal layer/ dermoepidermal junction, (3) spinous layer, and (4) superficial granular layer. Blind evaluation of these images to assess the reduction in melanin quantity was conducted by a dermatopathologist at baseline and days 30 and 60. Melanin quantity present in each layer was graded according to 4 categories (0%–25%, 25.1%–50%, 50.1%–75%, 75.1%–100%). The mean value was used for statistical evaluation.

Results

Efficacy evaluation

The primary efficacy variable was the mean reduction in MASI score from baseline to the end of treatment (day 60), which was 2.25 ± 1.87 (P<.0001). The reduction in mean MASI score was significant from baseline to day 30 (P<.0001) and from day 30 to day 60 (P<.0001). The least root-mean-square error estimates of MASI score variation at days 30 and 60 were 1.40 and 2.25, respectively.

The mean total melasma surface area (as measured in analysis of clinical photographs using medical imaging software) was significantly reduced from 1398.5 mm² at baseline to 1116.9 mm² at day 30 (P<.0001) and 923.4 at day 60 (P<.0001). From baseline to end of treatment, the overall reduction in mean total melasma surface area was 475.1 mm² (P<.0001)(Figure 2). Clinical and cross-polarized photographs taken at day 60 demonstrated a visible reduction in melasma surface area (Figure 3), which was confirmed using medical imaging software.