Melasma as a common chronic refractory disorder of skin pigmentation, contributed to average prevalence of 8.8% and 40% of populations. Management of melasma treatment is a challenging task due to high recurrence rates which have critical impacts on the quality of life . Although a large number of randomized controlled trials have been conducted to test the safety and efficacy of different therapeutic methods for melasma, there is no universal treatment for this disorder.
Figure 1 adapted from a recent review article , which represents the rational algorithm for treatment of melasma. According to the figure, topical treatment strategies offer easier options for treatment of moderate to severe conditions and at the same time resulted in less adverse side effects. Therefore, providing the most effective topical formulation could be beneficial in saving skins for these dark spots.
Mechanistic optimization of topical formulation requires a comprehensive understanding of the melanogenesis pathway which resulted in the best selection of topical agents as well as adjuvant treatments. Figure 2 represents the schematic description of the pathway as well as the specific effect of some of the available agents for melasma treatment .
Regarding the rich clinical literature of this disorder and available critical reviews in this field, triple combination therapy is recognized as the best topical treatment for melasma. Table 1 represents the results of a recent meta-analysis article for comparison of different therapies for melasma .
Table 1- Results of  for comparing different options for melasma treatment.
The efficacy of triple combination therapy contributed to the synergistic effect of individual components and time taken for its beneficial effect with a twice-daily application. According to the specific effect of different ingredients as well as the structure of the melanogenesis pathway, it is suggested to classify the active ingredients into three categories. As a result, the optimal triple combination formulation could be the result of selection of one agent from each category. Table 2 provides the classification with available active ingredients in each group.
Table 2 – Mechanistic Classification of active ingredients for preparation of optimal triple combination formulation for melasma treatment.
|Categories||API||Dosage (Rec.)||Safety Notes||Efficacy Notes|
|Tyrosinase Inhibitors||Hydroquinone||2% to 5%||Pruritus was the major adverse effect from hydroquinone||Complete or partial clearance of melasma in 95% patients versus 67% patients in the placebo group at 12 weeks|
|Silymarin||1.40%||No adverse effects from topical silymarin as compared to erythema, burning, and scaling in HQ group||Significant decrease in MASI scores in all groups|
|Kojic Acid||1–4%||Potentially an irritant and a contact sensitizer and known to cause paradoxical pigmented contact dermatitis||Efficacy almost equal to other therapies|
|Azelic Acid||15%–20%||Mild and transient itching and burning may occur while acneiform eruptions and telangiectasias, hypertrichosis, vitiligo, and asthma are extremely rare occurrences||Effective in melasma and post-inflammatory hyperpigmentation|
|Licorice||4%||Mild burning sensation is reported||Significant improvement|
|4-N-Butylresorcinol||Liposomal- 0.1 %||Mild erythema and itching||More than 60 % of participants considered treatment efficacious after 8 weeks|
|Arbutin||2%||Skin irritation||Effects equal to that of hydroquinone and deoxyarbutin in an in vitro study but is less effective than kojic acid|
|N-Acetyl Glucosamine||4%||Skin rash||Improves facial hyperpigmentation|
|Mequinol (4-hydroxyanisole)||2%||Side effects were minimal (Skin irritation, redness, peeling)||Complete clearance of melasma at 12 weeks in 80% of cases|
|Glutathione||2%||Well tolerated with no significant adverse events||Efficacy to treat melasma remain variable|
|Aleosin||NA||Suppressed pigmentation by 34% (pigmentation suppression in a dose-dependent manner)|
|Cysteamine||5%||erythema, dryness, pruritus, dyspigmentation (hypo or hyperpigmentation), burning and/or irritation; mostly reported as mild||Decrease in MASI score comparable to the MKF treated group at Week 8 and 16|
|Melanogenesis Interferers||Niacinamide||4-5%||Erythema, pruritus, and burning were less frequent and milder with nicotinamide compared to hydroquinone||Significantly decreased hyperpigmentation and increased skin lightness compared with vehicle alone|
|Undecylenoyl Phenylalanine||No significant adverse event||Significant improvement|
|Soy Extracts (Flavonoids)||NA||Significant reduction noted in mottled hyperpigmentation and blotchiness|
|Tranexamic Acid||2% or 5%||NA||Effective and safe medication for the treatment of melasma.|
|Methimazole||5%||Theoretical risk of systemic thyroid adverse effects||Significant improvement noted in 2 hydroquinone resistance cases|
|Retinoic Acid (Trentinoin)||0.05%–0.1%||88% patients experienced burning, itching, erythema, and scaling from continuous therapy||Treat melasma even as monotherapy but needs at least 24 weeks|
|ROS Scavengers||Ascorbic Acid||5%||Side effects such as allergic or irritant reactions are rare and occur because of poor permeability of ascorbic acid in natural form||More effective when used in combination|
|Melatonin||5%||NA||Decreased MASI, malondialdehyde decreased, GSH levels increased|
|Tocopherol (Vit. E) Acetate||Allergic or irritant reactions from topical use are infrequent||Significant improvement in melasma and pigmented contact dermatitis lesions|
The appropriate selection of target ingredients from each category may depend on available resources for the manufacturer, the compatibility with the formulation and final affordability of cost of the finished products.
Here in Sushiyant Derma Biotech, the knowledge platforms guide us towards the optimal formulation of our products. Additionally, consistent R&D, compiled clinical knowledge and experience and our scientific approach in development of our products help us to save your skin in the best way…
 Ogbechie-Godec, O.A. and Elbuluk, N. (2017). Melasma: an Up-to-Date Comprehensive Review. Dermatology and Therapy, [online] 7(3), pp.305–318. https://doi.org/10.1007/s13555-017-0194-1.
 Mahajan, V.K., Patil, A., Blicharz, L., Kassir, M., Konnikov, N., Gold, M.H., Goldman, Mitchel P., Galadari, H. and Goldust, M. (2022). Medical Therapies for Melasma. Journal of Cosmetic Dermatology, 21(9), pp.3707–3728. https://doi.org/10.1111/jocd.15242.
 González-Molina V, Martí-Pineda A, González N. Topical Treatments for Melasma and Their Mechanism of Action. J Clin Aesthet Dermatol. 2022 May;15(5):19-28. PMID: 35642229; PMCID: PMC9122278.
 Liu, Y., Wu, S., Wu, H., Liang, X., Guo, D. and Zhuo, F. (2021). Comparison of the Efficacy of Melasma Treatments: A Network Meta-Analysis of Randomized Controlled Trials. Frontiers in Medicine, 8. https://doi.org/10.3389/fmed.2021.713554.