Skin Lightening: Topical Approaches To Treatment
Overview
The recent removal of hydroquinone from over-the-counter skin lightening products has created a demand for modern formulations that effectively address skin pigmentation issues. A successful skin lightening formulation should be non-irritating to prevent post-inflammatory hyperpigmentation, penetrate effectively to reach the epidermal/dermal junction, incorporate anti-inflammatory ingredients, and target multiple mechanisms of pigment production.
The objective of this research was to demonstrate the efficacy of a topical multimodal pigment lightening preparation containing tranexamic acid, niacinamide, and licorice. The study involved fifty female participants aged 18 and above, representing all Fitzpatrick skin types, with mild to moderate facial dyspigmentation.
Subjects were provided with the study product for twice-daily application on their entire faces, along with SPF50 sunscreen. Evaluations occurred at Week 4, Week 8, Week 12, and Week 16. Dermaspectrophotometer (DSP) measurements were conducted on a pigmented target site identified by the investigator using a face map. A dermatologist assessed baseline facial efficacy and tolerability, while subjects provided feedback on tolerability.
Results showed that 48 out of 50 subjects completed the study without any tolerability issues. DSP readings revealed a statistically significant reduction in target spot pigmentation by Week 16. The investigator observed a 37% decrease in pigment intensity, a 31% decrease in pigment extent, a 30% improvement in pigment homogeneity, a 45% enhancement in brightness, a 42% improvement in clarity, and a 32% overall improvement in facial skin dyspigmentation at Week 16.
This research demonstrated the effectiveness of a topical skin lightening preparation containing tranexamic acid, niacinamide, and licorice. The formulation proved to be well-tolerated and achieved significant improvements in various aspects of facial dyspigmentation, making it a promising solution for individuals seeking to address pigmentation issues.
Introduction
Facial dyspigmentation is a common challenge in dermatology and cosmetics. Hydroquinone, which inhibits melanin synthesis by targeting tyrosinase, has been a gold standard ingredient for skin pigmentation. However, concerns about hydroquinone’s safety have led to its withdrawal from the over-the-counter market due to the melanotoxic effects of its byproduct, benzoquinone.
Skin pigmentation disorders, including birthmarks, encompass various conditions that can manifest from birth or emerge shortly thereafter. Although most birthmarks are benign, some pose potential health risks. Pigmented birthmarks, such as Nevus of Ota, display bluish or grayish discoloration on the face and eyes due to increased melanin and melanocyte activity, elevating the risk of melanoma and glaucoma. Mongolian spots, appearing bruised or bluish on a baby’s back or buttocks, usually fade by age 4 without requiring treatment. Café-au-lait spots, light to dark brown flat spots, are common but may indicate neurofibromatosis when six or more spots exceed 0.5 cm in diameter. Nevi, or moles, should be monitored for changes that could signal melanoma. Vascular birthmarks, including macular stains and hemangiomas, are often harmless, with some hemangiomas requiring treatment if causing complications. Port wine stains, flat pink, red, or purple marks lasting a lifetime, are typically treated with lasers, while they may also signify underlying medical conditions such as Sturge-Weber Syndrome or Klippel-Trenaunay Syndrome, albeit rarely. Consultation with a physician or dermatologist for diagnosis and evaluation is crucial for individuals with suspected pigmentation abnormalities.
This regulatory change has prompted cosmetic chemists to seek alternative ingredients to inhibit melanin formation, with tranexamic acid being one such option.
Tranexamic acid, also known as trans-4-aminomethylcyclohexane carboxylic acid, is a synthetic lysine derivative that inhibits plasminogen activator, reducing arachidonic acid and prostaglandin levels. This, in turn, leads to reduced melanocyte tyrosinase activity and skin pigmentation. Additionally, tranexamic acid decreases tyrosinase-related proteins (TRP1 and TRP2). While it has been administered orally, intravenously, and intradermally for pigmentation disorders, topical tranexamic acid is also available for improving skin pigmentation.
Niacinamide complements tranexamic acid by employing a different mechanism to lighten pigmentation. It is the biologically active form of niacin (vitamin B3) and serves as a precursor to NADH and NADPH, co-factors present in all living cells. Niacinamide inhibits melanosome transfer from melanocytes to keratinocytes and may reduce collagen oxidation products, improving skin tone.
Another approach to facial pigmentation lightening involves inhibiting melanogenesis by enhancing the degradation of microphthalmia-associated transcription factor (MITF) through ERK activation. This suppresses the expression of tyrosinase and related proteins (TRP1 and TRP-2) genes. Glycyrrhiza glabra (licorice) root acts in this manner, with flavonoids and triterpene saponins as its bioactive components.
The research in question aimed to evaluate the efficacy of a multimodal formulation containing tranexamic acid, niacinamide, and licorice root, enhanced with hexylresorcinol for penetration. The study focused on mild to moderate facial dyspigmentation, including conditions such as melasma, UV-induced solar lentigines, and post-inflammatory hyperpigmentation. The evaluation was conducted over 16 weeks of twice-daily use of the product.
Methods
The study enrolled fifty healthy female participants aged 18 or older, representing all Fitzpatrick skin types. They had mild to moderate facial dyspigmentation, which included conditions like melasma, UV-induced solar lentigines, and post-inflammatory hyperpigmentation. These participants provided informed consent, and the research followed Good Clinical Practices 21CFR Part 50 guidelines. Exclusion criteria included pregnant or lactating individuals, those without adequate contraception, subjects with excessive sun exposure, indoor tanning booth use, recent OTC retinoid or prescription retinoid use, and those who underwent facial procedures within the past 6 months. Participants were instructed to continue using their existing cleanser, facial moisturizer, and makeup products that they had been using for at least 30 days before the study. They were provided with SPF50 sunscreen (Neutrogena Clear Face Break-Out Free Liquid Lotion Sunscreen Broad Spectrum SPF, Johnson & Johnson) for sun protection throughout the 16-week study period.
Each subject received a compliance diary and the study product, “PCA Skin Pigment Gel Pro” (manufactured by Colgate-Palmolive Co. and PCA Skin), for twice-daily application to the entire face over the 16 weeks. The key components of the study product, in descending order of concentration, included water, denatured alcohol, witch hazel water, lactic acid, niacinamide, sodium hydroxide, tranexamic acid, and several other ingredients known for their skin-enhancing properties.
Data collection involved various assessments and measurements. A dermatologist investigator utilized a face map to identify target areas on the face, including pigmented, sun-exposed, and sun-protected regions. Dermaspectrophotometer (DSP) measurements on the melanin scale were recorded from each area, objectively documenting improvements in skin pigmentation. The dermatologist investigator conducted a baseline facial efficacy assessment, rating parameters like pigment intensity, target spot size, pigment extent across the entire face, pigment homogeneity, sallowness, brightness, clarity, post-inflammatory hyperpigmentation, and overall skin dyspigmentation on a 5-point ordinal scale (ranging from 0 = none to 4 = severe). This assessment was performed at baseline, Week 4, Week 8, Week 12, and Week 16. The investigator also assessed tolerability, considering factors like erythema, edema, and irritation, while subjects self-assessed tolerability with regard to itching, stinging/burning, redness, and swelling using the same 5-point ordinal scale at the same intervals. Moreover, fifteen subjects chosen by the investigator underwent photography of their facial front, right, and left sides using Visia-CR 4.3 (Canfield Scientific) with standard lighting.
The collected data underwent statistical analysis, with numerical dermaspectrophotometer data being assessed using a Student’s t-test, and ordinal nonparametric data being analyzed using the Wilcoxon signed-rank test to determine changes from baseline. Significant change was defined as a p-value of less than or equal to 0.05.
Results
Out of the fifty subjects initially enrolled in the study, 48 successfully completed it. Two participants withdrew consent for personal reasons. The study involved a diverse group of participants, ranging in age from 35 to 86 years, with various ethnic backgrounds, including one American Indian, two Asians, one Hispanic, nine African Americans, and 37 Caucasians. The Fitzpatrick skin type distribution among the participants was as follows: 22 Fitzpatrick skin type I, 15 Fitzpatrick skin type II, three Fitzpatrick skin type III, two Fitzpatrick skin type IV, four Fitzpatrick skin type V, and four Fitzpatrick skin type VI. In terms of complexion types, 19 participants had dry skin, 18 had combination skin, 11 had normal skin, and two had oily skin. Importantly, the study was conducted during the COVID-19 pandemic, and four subjects contracted COVID-19 during the study, resulting in some missed visits. However, these individuals fully recovered. Three subjects experienced a sensation of burning when applying the study product to open wounds, acne lesions, or sensitive areas around the eyes. The discomfort resolved, and these participants completed the study without further issues. No other tolerability problems or product-related adverse events were reported by the subjects or the investigator throughout the study.
Dermaspectrophotometer readings were taken on the melanin scale from a hyperpigmented target site to assess the study formulation’s ability to lighten hyperpigmented skin. Additionally, measurements were taken on the jawline to evaluate the product’s effect on background facial pigmentation, while the area under the chin served as a control site where the product was not applied. The results showed statistically significant (p < 0.001) improvement in the target spot at Weeks 4, 8, 12, and 16, with the maximum pigmentation decrease observed at Week 16, amounting to a 7% improvement. Similarly, there was a statistically significant (p < 0.001) 3% pigmentation improvement on the left jawline at Week 16 compared to baseline. As expected, no significant improvement was observed beneath the chin where the product was not applied. These findings confirm the study product’s ability to enhance overall skin pigmentation and address hyperpigmented spots effectively.
The investigator’s assessment revealed statistically significant improvements at Week 4 in target spot pigment intensity (p < 0.001), size (p = 0.031), facial sallowness (p = 0.031), lack of brightness (p < 0.001), and lack of clarity (p = 0.001). These improvements continued into Week 8, with statistically significant enhancements observed in all parameters except post-inflammatory hyperpigmentation (PIH). PIH was the only parameter that did not achieve statistical significance during the 16-week study. This may be attributed to the nature of PIH, which involves dermal pigmentation that topical products may not reach effectively. From Week 12 onwards, and through Week 16, all other parameters assessed by the investigator, including pigment intensity of the target spot, size of the target spot, pigment extent over the entire face, pigment homogeneity of the entire face, sallowness, lack of brightness, lack of clarity, and overall skin dyspigmentation, exhibited highly significant improvements (p < 0.001).
The percentage of improvement in these investigator-assessed parameters increased progressively from Week 4 to Week 16. By Week 16, there was a substantial 37% reduction in pigment intensity of the target spot, a 31% decrease in target spot size, a 31% reduction in pigment extent across the entire face, a 30% improvement in pigment homogeneity across the entire face, a 35% decrease in facial sallowness, a remarkable 45% enhancement in facial brightness, a substantial 42% improvement in facial clarity, and a notable 32% amelioration in overall facial skin dyspigmentation.
Conclusion
The removal of 2% hydroquinone from the over-the-counter market in the United States has necessitated the development of alternative skin lightening formulations. These formulations must effectively reduce unwanted melanin in the skin and inhibit melanin production through a multifaceted approach while ensuring penetration to the dermal/epidermal junction. This study focused on a formulation enhanced for penetration using denatured alcohol, butylene glycol, and witch hazel (Hamamelis Virginiana) to gently disrupt the stratum corneum barrier. Further penetration was achieved with lactic acid and gluconolactone. To minimize potential irritation, the chamomile derivative bisabolol was included. Hydrolyzed hyaluronic acid served as a humectant to hydrate the skin beneath the sodium polyacryloyldimethyl taurate film, facilitating efficient delivery of skin pigmentation agents, including tranexamic acid, niacinamide, hexylresorcinol, and licorice root.
This research assessed pigmentation improvement through both instrumental and dermatologist-investigator evaluations. Dermaspectrophotometer (DSP) analysis provided objective data, while clinical assessments were crucial for a comprehensive evaluation of the product’s efficacy. The DSP measurements indicated a notable 7% decrease in pigment intensity of the selected target spot, representing the darkest area on the face. The investigator-assessed parameters demonstrated a significant 37% reduction in target spot pigmentation intensity and a 31% decrease in target spot size after 16 weeks of product use. Early improvements were observed as early as Week 4, suggesting the potential for continued enhancement beyond the 16-week study period. Rapid visible results within four weeks and sustained improvement with prolonged use are essential for consumer satisfaction, which was a challenge with hydroquinone due to its limited long-term use recommendation. Importantly, the study found no evidence of cutaneous toxicity associated with the use of tranexamic acid, niacinamide, hexylresorcinol, or licorice, making them suitable for continuous, uninterrupted long-term use. Both subjects and investigators reported an excellent tolerability profile, even with the necessary penetration enhancement for efficacy.
Comparatively, other skin pigmentation ingredients, such as kojic acid and arbutin, have raised concerns related to their potential toxicity. Kojic acid is effective but has toxicity worries, leading to its ban in European and Asian markets. Arbutin, while derived from natural sources, is a hydroquinone derivative, raising similar concerns. Several other ingredients claim to act as pigment-reducing agents but are often tested on non-human models, making their safety and efficacy for human skin uncertain. In contrast, the multimodal combination of tranexamic acid, niacinamide, hexylresorcinol, and licorice used in this study does not exhibit these safety concerns.
The study examined various types of facial pigmentation across all Fitzpatrick skin types, including melasma, UV-induced solar lentigenes, and post-inflammatory hyperpigmentation (PIH). Assessments considered target spot size and intensity for PIH and solar lentigenes, while pigment homogeneity and extent across the entire face were evaluated for all forms of facial pigmentation, including melasma. However, the study’s sample size of 50 subjects limited subset analysis for different types of pigmentation. Nonetheless, this consumer-purchased product formulation aimed to address all forms of increased facial pigmentation.
Furthermore, the formulation was tested across all Fitzpatrick skin types and demonstrated efficacy without causing irritation, ensuring that paradoxical skin darkening from irritation did not occur. The study noted excellent skin tolerability assessed by both dermatologists and subjects for all Fitzpatrick phototypes and skin types. Nevertheless, the formulation was unable to achieve statistically significant improvement in PIH, especially in individuals with higher Fitzpatrick skin types. This limitation is common among topical skin pigmentation preparations due to the challenges posed by pigmentary incontinence.
Oncology Related Tools
Other
Latest Research
