The effects of supramolecular nicotinamide combined with supramolecular salicylic acid on chloasma

To observe the efficacy and safety of supramolecular salicylic acid monotherapy and supramolecular nicotinamide in the treatment of chloasma.

in the treatment of pigmented diseases.A new supramolecular intelligent slow-release delivery system has been widely used in the clinic in recent years to overcome the limitations of insoluble drug instability and insolubility.This study focuses on the efficacy and safety of supramolecular salicylic acid single treatment and supramolecular nicotinamide combined treatment of melasma and whether there are differences between the two to provide a reference for the treatment of melasma.

| Clinical data
The subjects were selected from January 2021 to June 2022.
Twenty-eight patients with melasma who met the inclusion criteria were aged 32-47 years old, with an average age of 39.21 ± 4.00 years, and the course of disease ranged from 2 to 10 years, with an average of 5.07 ± 2.19 years.All of them had a history of being free from smoking and drinking and were premenopausal and nonpregnant.
The patients were completely randomly divided into an experimental group and a control group, with 14 patients in each group.
Diagnostic criteria refer to the diagnosis and treatment criteria for chloasma formulated by the Pigmentation Group, Dermatology and Venereal Diseases Professional Committee of the Chinese Association of Integrated Traditional and Western Medicine (2010 edition). 3Inclusion criteria were as follows: meeting the above clinical diagnostic criteria for melasma, female patients aged 25-55 years, volunteering to participate in this experiment, and signing an informed consent.Exclusion criteria were: ① salicylic acid allergy, or history of 30% supramolecular salicylic acid use; ② active herpes simplex, warts; ③ patients with recent history of surgery; ④ oral contraceptives for nearly half a year, pregnant and lactating women; ⑤ oral administration of whitening products such as peracetic acid, tranexamic acid, and/or topical antioxidant or whitening products in the past 3 months; ⑥ people who work outdoors for more than 2 h a day, get sunburned, or have insufficient light protection; ⑦ photosensitive skin diseases, SLE, dermatomyositis, scleroderma, rheumatoid arthritis, and other diseases; ⑧ patients with a history of thrombosis, angina pectoris, myocardial infarction, and cerebral ischemia before treatment; ⑨ mental abnormalities, such as emotional and skin sensitivities; and ⑩ poor compliance, high expectations for efficacy, and other conditions deemed unsuitable for enrollment by the investigator.Subjects fully understood the purpose and methods of the study and signed the informed consent form.

| Treatment methods
Salicylic acid stripping was treated with 30% supramolecular salicylic acid products (trade name: Borda; Manufacturer: Shanghai Ruizhi Medical Technology Co., Ltd).The patient first cleaned their face, smeared the corners of the eyes and around the mouth with petroleum jelly to cover for protection, evenly smeared salicylic acid on the face to avoid the protected area, sprayed distilled water to promote infiltration, gently massaged for 5-10 min to keep the face moist, flexibly adjusted the action time according to the skin tolerance, and were able to repeat the operation two to three times.
If the skin appeared erythematous, frosty, or other reactions occurred, the operation was stopped.The patient then washed their face with water and applied a cold medical compress (trade name: Bolda; Manufacturer: Shanghai Ruizhi Medical Technology Co., LTD).For external application, a cold atomization spray was applied for 20 min.Topical use of nicotinamide using 10% supramolecular nicotinamide (trade name: Bo Leda; Manufacturer: Shanghai Ruizhi Medical Technology Co., Ltd).Patients in both groups received exfoliation treatment once every 2 weeks for a total of eight treatments.The experimental group was treated with nicotinamide for the whole treatment period after morning and evening cleansing, and the control group was the blank control.A VISIA skin image analyzer (Guangzhou Meili Plus Beauty Equipment Co., Ltd) was used to detect the patient's face.After cleaning the face prior to each chemical abridging, facial images of the subject were collected with a VISIA skin image analyzer and analyzed without hair interference and regional reflection.All tests were performed by the same staff.

Key criteria
Using the modified chloasma lesion area and severity index (melasma area and severity index [MASI]) 4 rate, two clinicians with enough related clinical experience in the field of dermatology were selected as fixed judges to jointly evaluate and record the regression of melasma lesions.Area of lesions: the face was divided into four areas: forehead, right cheek, left cheek, and mandible, with corresponding areas of 30%, 30%, 30%, and 10%, respectively.Skin lesions were classified as follows: 0 was no skin lesions, 1 was less than 10% skin lesions, 2 was 10%-29% skin lesions, 3 was 30%-49% skin lesions, 4 was 50%-69% skin lesions, 5 was 70%-89% lesions, and 6 was 90%-100% lesions.The severity was scored as follows: 4 was severe deepening, 3 was obvious deepening, 2 was general deepening, 1 was slight deepening, and 0 was no deepening.The mMASI score was the sum of the score of the area of lesions in each area and the score of the severity of the corresponding area, with the total score ranging from 0 to 24 points.mMASI decline rate was calculated by (%) = (total score before treatment − total score after treatment)/ total score before treatment ×100%.

Secondary criteria
The secondary criteria were the subjects' self-score on the Griffiths10 for their own chloasma (0-10), the VISIA test results (including pigmentation spots, wrinkles, texture, pores, purple matter), and adverse reactions during treatment.

| Statistical methods
SPSS 23.0 software was used for data analysis.Due to the small sample size, Fisher's exact probability method was used to test the efficacy classification.A t test was used for the other data.

| General characteristics
A total of 28 eligible patients with chloasma in the outpatient department of our hospital from January 2021 to June 2022 were randomly divided into an experimental group and a control group.
All patients signed informed consent forms and completed treatment without loss to follow-up.There was no statistical significance in age, course of disease, lesion area, or severity between the two groups of patients (p > 0.05).

| MASI scores
There was no statistical difference between the two groups in mMASI scores before and after treatment (p > 0.05).After treatment, mMASI scores in both groups were decreased (p > 0.05), but the difference in reduction in the experimental group was higher than that in the control group (p < 0.05, see Table 1).

| Comparison of clinical efficacy of the two groups
The experimental group had two cases of basic recovery and seven cases of obvious recovery, with an effective rate of 64.29%.The control group had no basic recovery, with two cases of obvious recovery, and an effective rate of 14.29%.There was a significant difference in graded efficacy between the two groups.The effective rate of the experimental group was higher than that of the control group, and the difference was statistically significant (p< 0.05, see Figure 1).

| VISIA detection results
Before treatment, there was no significant difference in the detection results (pigment spots, wrinkles, texture, pores, and purple matter) between the two groups (p > 0.05).After treatment, there were statistically significant differences in all indices (p < 0.05).
The difference between the two groups was statistically significant (p < 0.05, see Table 2).The experimental group had a better curative effect.A comparison before and after VISIA detection is shown in Figure 2.

| The subjects' self-score of Griffiths10
There was no significant difference in self-scores between the two groups before treatment (p > 0.05).After treatment, the scores of both groups decreased (p < 0.05), and the experimental group decreased more significantly (p < 0.05, see Table 2).

| Adverse reactions
When 30% supramolecular salicylic acid treatment was administered for the first time, almost all patients experienced varying degrees of burning and itching, and the majority of patients experienced reduced discomfort and gradually tolerated it.After each treatment, a medical cold compress was applied externally, and the discomfort disappeared after 20 min of cold spray.In both groups, 1 patient developed erythema with the whitening cream within a short period of time during skin replacement treatment, and the pain was obvious.After a cold compress and enhanced moisturizing treatment, all patients were relieved within a week, and no other serious adverse reactions occurred.

TA B L E 1
Difference between the two groups in mMASI scores.

| DISCUSS ION
Melasma, as a skin pigment disorder, occurs frequently in women of childbearing age.There are many related pathogenic factors.6][7][8][9] It is generally believed that melasma is caused by complex interactions among epidermal melanocytes, dermal fibroblasts, keratinocytes and vascular endothelial cells, as well as by hormonal and genetic factors and UV exposure. 10The etiology of melasma is complex and prone to relapse, and the treatment is relatively difficult, affecting the quality of life. 11Clinical drugs are mainly used to reduce inflammation and free radical production, and inhibit the transfer of melanosomes to keratinocytes.
Some newer drugs may work by restoring the skin barrier or hormone levels, while others will target the dermal vascular system and mast cells. 12Current treatments include topical and systemic medications, as well as chemical peels and electro-optical therapy.
Improvement of existing lesions and prevention of recurrence are the clinical goals.Salicylic acid's functions are: dissolving keratin, antibacterial, and anti-inflammatory effects, reducing the accumulation of melanin bodies and epidermal pigmentation, and blocking UVA to play a photoprotective role in local skin. 13As a kind of chemical exfoliator with good safety and little irritation, salicylic acid is widely used in the clinical treatment of acne, rosette acne and epidermal hyperpigmentation diseases, including melasma. 14In recent years, supramolecular salicylic acid was produced under the background of new technology.It maintained the therapeutic effect of salicylic acid itself, and its properties were stable without adding a strong alkali neutralizer.The supramolecular system also had the characteristics of controlled and slow release.
Niacinamide, also known as vitamin B3, is the pyridine-3-carboxylate amide form of niacin, which increases collagen production and reduces the increase of dermo glucose aminoglycosides The two groups were compared according to the efficacy of MMASI reduction rate (%).p = 0.046 < 0.05, calculated by Fisher's exact probability method, and the efficacy difference was statistically significant.
TA B L E 2 VISIA test and scores of Griffiths10.

| CON CLUS IONS
In short, supramolecular salicylic acid and supramolecular nicotinamide are effective in the treatment of chloasma, with high safety and a low incidence of adverse reactions, but the combined treatment effect is more significant.The skin condition of all patients who received the treatment was improved, which can be used in clinical application.This study is temporarily limited to single-center data and a limited sample size, and more studies will be conducted in the future.

CO N FLI C T O F I NTE R E S T S TATE M E NT
All authors have contributed significantly to the manuscript and declare that the work is original and has not been submitted or published elsewhere.None of the authors have any financial disclosure or conflict of interest.
F I G U R E 2 A 38-year-old woman with melasma got a skin test before and after combined treatment.On the left is before treatment, and on the right is after treatment.The zygomatic spots obviously faded.

Timing of treatment n Pigmented spots Wrinkle Texture Pore Sclererythrin Griffiths 10
2 value is the result of intergroup comparison.