An Investigator-Blinded, Randomized Trial of a Broad-Spectrum Sunscreen Containing Sclareolide and Niacinamide for the Prevention of Post-inflammatory Hyperpigmentation in Skin of Color

Abstract

Introduction

Post-inflammatory hyperpigmentation (PIH) is common and distressing in skin of color. Ultraviolet (UV) radiation and visible light (VL) exacerbate PIH, yet most sunscreens do not target the oxidative and inflammatory pathways that drive it.

This study evaluated a broad-spectrum sunscreen with sclareolide and niacinamide for mitigating PIH induced by combined UV/VL exposure and inflammatory stimuli.

Methods

In an investigator-masked, randomized, intra-individual study, 20 participants with Fitzpatrick skin types IV–V underwent controlled UV/VL exposure with or without tape stripping. The test product was applied daily for 20 days. The primary endpoint was change in ΔITA° at Day 22; clinical pigmentation/erythema and colorimetry (ΔL*, Δa*, Δb*, ΔE) were secondary endpoints.

Results

The sunscreen significantly prevented pigmentation at all protected sites. In stripped, exposed zones, protected skin improved by + 5.96 ΔITA° versus − 9.88 ΔITA° in unprotected skin (net protection ~ 16 ITA°, p < 0.001). In non-stripped, exposed areas, the difference was + 11.76 ΔITA° (p < 0.001). Secondary endpoints improved by 48–87%. No adverse events were reported.

Conclusions

A broad-spectrum sunscreen with sclareolide and niacinamide mitigates PIH induced by inflammation and VL in darker phototypes. These findings support preventive use in PIH-prone populations. Comparative studies with and without these ingredients are warranted.

Clinical Trial Registration

This study was registered with ISRCTN under the identifier ISRCTN11448711.

Plain Language Summary

Post-inflammatory hyperpigmentation (PIH) is the darkening that can appear after acne, irritation, or procedures, and it often lasts longer and looks more noticeable in people with darker skin tones. Both ultraviolet (UV) and visible light (VL) can make PIH worse. Sunscreen helps, but most formulas are not designed to address the underlying triggers, such as inflammation and oxidative stress. In this study, we tested a broad-spectrum sunscreen that, in addition to UV/VL protection, contains two supportive ingredients: sclareolide (a plant-derived anti-inflammatory that may help reduce darkening) and niacinamide (a vitamin with well-known brightening and calming activities). Twenty adults with medium-to-dark skin (Fitzpatrick types IV–V) took part. Small test areas on the upper back were exposed to light, with or without mild skin barrier disruption, to mimic conditions that lead to PIH; the sunscreen was then applied daily. Compared with unprotected skin, areas treated with the sunscreen showed significantly less darkening and redness, with no side effects reported. These results suggest that a sunscreen containing sclareolide and niacinamide may help prevent dark spots that develop after inflammation and light exposure in people prone to PIH.

Key Summary Points

Post-inflammatory hyperpigmentation (PIH) is a common and distressing condition in individuals with skin of color, often worsened by ultraviolet (UV) and visible light (VL) exposure

Most existing sunscreens do not address the inflammatory and oxidative stress pathways that contribute to PIH development and persistence

This study evaluated whether a broad-spectrum sunscreen containing sclareolide and niacinamide could prevent pigmentation and inflammation associated with UV/VL exposure and skin barrier damage

The sunscreen significantly reduced pigmentation and redness, showing improvements of up to 16 ΔITA° units and up to 87% reductions in erythema and colorimetric indices compared to unprotected skin

These findings support the use of multifunctional sunscreens with anti-inflammatory and pigment-regulating ingredients as a targeted strategy for PIH prevention in skin of color

Introduction

Post-inflammatory hyperpigmentation (PIH) is a common sequela of cutaneous inflammation, particularly prevalent among individuals with Fitzpatrick skin types IV to VI [1, 2]. The resulting hypermelanosis can cause significant psychological and emotional distress and negatively impact on the quality of life [3].

The pathogenesis of PIH is still partially understood. It involves inflammation-mediated stimulation of melanogenesis, which is further exacerbated by exposure to ultraviolet (UV) and visible light (VL) [4]. Inflammatory mediators, such as interleukin (IL)-1α, endothelin-1, and stem cell factor (SCF), can directly activate melanocytes [5]. Additionally, reactive oxygen species (ROS) and reactive nitrogen species, such as superoxide and nitric oxide (NO), generated in damaged skin following UV or VL exposure or released by inflammatory cells, stimulate melanocyte activity. Epidermal damage may also lead to the release of endocrine pigmentation inducers, including α-melanocyte-stimulating hormone (α-MSH). Moreover, the oxidation of arachidonic acid by peroxidases, cyclooxygenases, and 5-lipoxygenases leads to the production of prostaglandins (i.e., PGE2) and leukotrienes, which further enhance melanin synthesis and pigment transfer to keratinocytes [6].

Emerging evidence suggests a synergistic interaction between long-wave UVA (UVA1; 340–400 nm) and VL (400–700 nm) in promoting cutaneous pigmentation, particularly in individuals with darker phototypes (Fitzpatrick skin types IV–VI) [7, 8]. UVA1 stimulates melanogenesis via oxidative stress and ROS-mediated pathways [9, 10], while VL, especially high-energy visible light (400–500 nm), activates Opsin-3 receptors on melanocytes, promoting sustained tyrosinase activity and melanin production [11, 12]. Sunscreen use has been shown to mitigate UV- and VL-induced melanogenesis and reduce the exacerbation of pigmentation [8, 13, 14]. However, only tinted sunscreens containing iron oxide or other pigments capable of reflecting VL have demonstrated efficacy to prevent VL-induced hyperpigmentation [15].

Photoprotection is therefore a cornerstone in the prevention and management of PIH. However, few sunscreens are formulated to address the dual mechanisms of oxidative stress and inflammation underlying this condition. Evidence suggests that incorporating anti-inflammatory agents into sunscreens can enhance their protective efficacy. For instance, a randomized, double-blind, split-face study reported a greater, albeit not statistically significant, reduction in PIH following picosecond laser procedures with a sunscreen containing anti-inflammatory agents compared to a standard sunscreen [16]. Similarly, another study found that use of an anti-inflammatory sunscreen immediately after ablative fractional resurfacing reduced PIH incidence at 1 week post-procedure [17].

In addition to photoprotection, topical depigmenting agents that inhibit melanogenesis or accelerate pigment removal through skin turnover are key in PIH treatment [18]. Agents such as hydroquinone, azelaic acid, kojic acid, licorice extract, and retinoids have shown efficacy when used alone or in combination [19, 20].

We hypothesized that integrating anti-inflammatory ingredients with depigmenting activity into a broad-spectrum sunscreen could improve PIH outcomes. Sclareolide, a sesquiterpene lactone derived from Salvia sclarea L., has demonstrated inhibition of PGE2 and IL-1α biosynthesis, NO release, and modulation of PIH-associated gene expression in vitro, as well as melanin inhibition and skin-lightening effects in melanocytes and human skin ex vivo [21, 22].

Niacinamide (vitamin B3) is a water-soluble precursor to NAD⁺ and NADP⁺, essential coenzymes involved in cellular metabolism, DNA repair, and oxidative stress regulation. Hakozaki et al. [23] showed that 5% niacinamide significantly reduced melanosome transfer to keratinocytes, resulting in visible skin lightening. Niacinamide also improves skin barrier function and exerts anti-inflammatory effects, making it a versatile and well-tolerated ingredient for pigmentary disorders such as PIH.

This study evaluates the clinical efficacy of a broad-spectrum sunscreen containing sclareolide and niacinamide in preventing experimentally induced PIH using a validated human model.

Methods

Study Design

This was a monocentric, investigator-masked, randomized, controlled study with intra-individual comparisons. The study was performed at one investigational center (Centre de Pharmacologie Clinique Appliquée à la Dermatologie; CPCAD in Nice, France) between August and December 2024.

Twenty subjects were deemed sufficient to detect a difference in Delta (Δ) ITA° of 2 units between two areas (paired data) with a probability of 95% and an alpha risk of 0.05 and a common standard deviation (SD) of ± 2.3 units. A difference of 2 units in ΔITA° corresponds to a clinically observable difference in skin pigmentation intensity.

The study was investigator blinded. The randomization list was prepared by the Biometrics Department of CPCAD using R software version 4.0.2 or higher (Foundation for Statistical Computing, Vienna, Austria 2012) by personnel not involved in the clinical conduct of the study. The investigational product was dispensed according to the randomization list by a responsible designated person not involved in clinical assessments. The randomization lists were masked to the investigator throughout the whole study.

Inclusion/Exclusion Criteria

Eligible participants were healthy male and female subjects aged 20–50 years with Fitzpatrick skin types IV–V and a documented history of PIH. Subjects could not have been exposed to UV radiation, including tanning beds, phototherapy, or natural sunlight on any part of the body, for at least 2 months prior to the screening visit and were required to maintain this avoidance throughout the study duration.

Participants were also instructed to refrain from bathing (including baths or swimming) and from applying any cosmetic, medical, or aesthetic treatments to the back that were not part of the study protocol for the entire study period.

The following additional exclusion criteria were applied:

1. Female subjects who were pregnant, parturient, or breast feeding.

2. Subjects with a medical history/condition or who were taking medication that could put him or her at undue risk or may have interfered with the study results.

3. Subjects who had known or suspected allergies or sensitivities to any of the components of the study product.

4. Subjects who had a recent history of (within the last 3 months) or with an active pityriasis versicolor.

5. Subjects with an excessive number of naevi, freckles, lentigines in test area site (middle back).

6. Subjects who had taken a systemic treatment, were able to induce an abnormal response to UV for > 5 days during the month preceding inclusion (steroids, non-steroidal anti-inflammatories, insulin, anti-hypertensives, antibiotics such as quinolones, tetracyclines, thiazides, and fluoroquinolones, and all other photosensitizing treatments), had undergone any treatment capable of inducing an abnormal response to UV or VL (e.g., vitamin A derivatives, psoralen, aminolevulinic acid derivatives), or planned to take these treatments during the study.

Ethical Approval

The study protocol (ID: 2023-A02785-40) was reviewed and approved by Comité de Protection des Personnes (CPP) Ouest III on 13 May 2024 and was conducted in accordance with the ethical principles initially outlined in the Declaration of Helsinki and its subsequent amendments and Good Clinical Practice (GCP). All subjects who participated in this clinical study were fully informed about the clinical study and, prior to inclusion, the subject and the investigator signed and dated the consent form(s).

Investigational Product

The investigation product, ISDIN FOTOULTRA 100 SPOT PREVENT, was a broad-spectrum SPF 50+ non-tinted sunscreen, combining organic and inorganic filters and supplemented with sclareolide and niacinamide (Table 1). The formulation has an in vitro UVA Protection Factor (UVA-PF) of 39.5. It has previously demonstrated the ability to protect against UVA, UVB, and VL (data on file).

Table 1.

INCI composition of the investigational sunscreen

INCI composition

Dibutyl adipate, aqua (water), silica, propylene glycol dicaprylate/dicaprate, diethylamino hydroxybenzoyl hexyl benzoate, isododecane, bis-ethylhexyloxyphenol methoxyphenyl triazine, diisopropyl sebacate, ethylhexyl salicylate, ethylhexyl triazone, caprylic/capric triglyceride, glycerin, niacinamide, titanium dioxide [nano], dimethicone, titanium dioxide, polyglyceryl-6 polyhydroxystearate, polyglyceryl-6 polyricinoleate, 1,2-hexanediol, sodium chloride, stearalkonium hectorite, hydroxyacetophenone, polyglyceryl-2 dipolyhydroxystearate, tocopheryl acetate, trimethylpentanediol/adipic acid/glycerin crosspolymer, polyglyceryl-3 diisostearate, polyglyceryl-3 polyricinoleate, sclareolide, diethylhexyl syringylidenemalonate, ethylhexylglycerin, glyceryl stearate, tetrasodium glutamate diacetate

UV filters are indicated in bold

Experimental Induction of PIH and Product Treatment

A schematic overview of the experimental protocol is presented in Fig. 1.

Fig. 1.

Schematic overview of the experimental protocol. On Day 1 (D1), the minimal erythema dose (MED) was determined using solar-simulated UV light (ssUV). On Day 2 (D2), six test areas (Z1–Z6) were delineated on the back and subjected to tape stripping as per group assignment. Sunscreen was applied to three areas (two stripped and one non-stripped) at 2 mg/cm², followed by UV (1.5 × MED) and visible light (14 J/cm²) exposures on four of the six areas. Daily product application continued (except Sundays) through D20. Clinical assessments, standardized photography, erythema and pigmentation scoring, colorimetric measurements, and tolerability evaluations were conducted at scheduled visits through Day 36 (D36)

Randomization

At baseline (Day 1), each subject who met all inclusion and exclusion criteria was assigned a randomization number. This number was dispensed in chronological order based on the subject’s inclusion in the trial, with no numbers omitted or skipped.

The randomization list was generated using R software version 4.3.0 (Foundation for Statistical Computing, Vienna, Austria, 2012). This list was prepared by a staff member who was not involved in the performance phase of the study.

The list assigned each test area (Z1 to Z6) a specific treatment condition per subject. Throughout the study, the randomization list remained concealed from the investigator/evaluator and was managed exclusively by the study research assistant responsible for product dispensation.

MED Determination

On D1 of the study, the MED of each participant was determined. Briefly, six areas of 1.5 cm × 1.5 cm were delineated on the scapular area of the back. Each area was then exposed to solar simulated UV light (ssUV) with a dose difference between two areas followed a geometric progression of 25%. The MED was defined as the lowest dose of ssUV (mJ/cm²), which produces just perceptible erythema (with clearly demarcated borders).

Tape Stripping

The following day (D2), in a prone position, six test areas of 19 mm × 60 mm (i.e., three areas on one side of the spine and three areas on the other side in the middle part of the back) were delineated. These six test areas (Z1 to Z6) comprised:

Z1: stripped, protected, and exposed.

Z2: stripped, protected, and unexposed.

Z3: stripped, unprotected, and exposed.

Z4: stripped, unprotected, and unexposed.

Z5: non-stripped, protected, and exposed.

Z6: non-stripped, not protected, and exposed.

A 19 mm × 60 mm strip of tape was placed on the four randomized areas to be stripped, ensuring they were completely covered. To ensure uniform adhesion, the tape was adhered by smoothing with a finger and constant pressure, passing forward four times and backward four times while covering the entire area at each pass. The tape was removed, with a sharp movement, using tweezers. Successive strippings were performed until the skin became shiny and the stratum corneum was completely removed. The number of strippings was limited to a maximum of 20.

Product Application and UV/VL Exposure

The sunscreen was applied to three randomly assigned areas (2 stripped and 1 non-stripped area) at a rate of 2 mg/cm² by a trained clinical study assistant. A Wood’s lamp was used to check that the product was evenly distributed over the test areas.

Fifteen minutes after product application, four areas (i.e., stripped, protected; stripped, unprotected; non-stripped, protected; non-stripped, not protected) were exposed to ssUV (1.5 × MED) and VL exposure (14 J/cm²). The two unexposed areas were protected with a physical opaque screen. The exposures were carried out using two solar simulators.

For the UV exposures, a solar simulator was used for irradiation (LOT ORIEL, model 92 292, equipped with a 1600-Watt high-pressure Xenon-vapor lamp). The solar ultraviolet spectrum (UVA + UVB) was simulated by in-line use of combined UG11/1-mm and Schott WG320/1.6-mm filters. Prior to performing the exposure, the intensity of the lamp was checked on each of the three test areas using a radiometer (PMA, Solar Light, Philadelphia, PA, USA).

For VL exposures, another ORIEL 1600-Watt simulator (model 92292-1000) was used. Infrared radiation was removed with a Schott KG3/3-mm filter. Residual UV (especially UVA) was removed by a Schott GG400/3-mm filter. Prior to performing the exposure, the intensity of the lamp was checked on each of the four test areas using a spectroradiometer (SpectraPen LM 500, Photon Systems Instruments, Drasov, Czech Republic).

Following UV/VL exposure, the sunscreen (2 mg/cm²) was applied on the same three treated test areas for the following 20 consecutive days (except Sundays) on D2 to D6, D8 to D13, and D15 to D20. After every application, a Wood’s lamp was used to check that the product was evenly distributed over the test areas.

Study Assessments

Study Endpoints

The primary endpoint was the change from baseline in the ΔITA° at D22.

Secondary endpoints were: (1) clinical scores of skin pigmentation and erythema and (2) change from baseline in the colorimetry parameters (ΔL*, Δa*, Δb*, ΔE, and ΔITA°) at each evaluation visit.

Local tolerability (irritancy global score) and general adverse events were recorded at each visit.

Colorimetry Measurements

Colorimetry measurements were performed on D1, D3 to D5, D8, D15, D22, and D36. Double colorimetry measurements were performed on each test area and on the surrounding untreated and unexposed skin. The mean of the double measures was used for the analyses.

Skin color was measured with a computer-controlled hand-held Chromameter^® CR 400 (Konica-Minolta, Osaka, Japan) using the L*a*b* color space where L* represents lightness (L* = 0 corresponds to black and L* = 100 indicates diffuse white), a* the position between green and red (negative values indicate green while positive values indicate red), and b* the position between blue and yellow (negative values indicate blue and positive values indicate yellow). The ITA°, which is well correlated with skin pigmentation, was calculated from the mean L* and b* values.

Standardized Photographs

To illustrate the effects of the treatment, standardized photographs of the six test areas were taken on D1, D3, D8, D15, and D22 using a digital CANON EOS 350D camera equipped with a 60-mm lens f1/2.8. The settings of the camera, the lighting (LED tubes, T 4000°K), and the distance were standardized to provide a reliable comparison of images between two different visits. Shooting and recording of images were managed using dedicated software (Zoombrowser, Canon).

Erythema Assessment

Erythema was assessed on each test area on D1, D3, D5, D8, D15, D22, and D36 using a 5-point grading scale (Table 2). Intermediate scores (i.e., 1.5 or 2.5) were allowed. This grading scale was also used to determine the MED.

Table 2.

Erythema visual assessment score system

Score	Erythema
0	Absent
0.5	Doubtful
1	Weak but well-defined erythema (= MED)
2	Moderate
3	Severe

Skin Pigmentation Assessment

Skin pigmentation was assessed on each test area on D1, D3 to D5, D8, D15, D22, and D36 using a standardized scale (Table 3).

Table 3.

Clinical score for pigmentation assessment

Score	Intensity
0	No pigmentation
1	Doubtful
2	Very pale brown −
3	Very pale brown
4	Very pale brown +
5	Pale brown −
6	Pale brown
7	Pale brown +
8	Brown −
9	Brown
10	Brown +

Local Tolerability Assessment

Local tolerability was assessed at each post-baseline evaluation visit before any procedure using a 5-point clinical scale (Table 4) [24]. At each visit, participants were asked about adverse events, and all adverse events were monitored and recorded.

Table 4.

Local tolerability scoring system

Clinical signs description	Score
No signs of irritation (erythema nor desquamation)	0
Doubtful signs of irritation (doubtful erythema and/or desquamation)	0.5
Slight signs of irritation (slight erythema and/or desquamation)	1
Moderate signs of irritation (moderate erythema and/or desquamation)	2
Severe signs of irritation (erythema and/or desquamation and/or bullous reaction)	3

Efficacy Analyses and Statistical Analyses

For each of the primary and secondary endpoints, the following comparisons were performed:

1. Protected, stripped and exposed area versus unprotected, stripped, and exposed area

2. Protected, not stripped and exposed area versus unprotected, not stripped, and exposed area

3. Unprotected, stripped and exposed area versus unprotected, stripped, and unexposed area

4. Protected, stripped and exposed area versus protected, stripped, and unexposed area

For the primary endpoint, a mixed model for repeated measures (MMRM) was used, with treatment (protected/unprotected), condition (stripped and exposed/not stripped and exposed/stripped and unexposed), and their interaction as fixed effects and subject as a random effect. When a significant overall effect was observed, pairwise comparisons were conducted using contrasts.

For each colorimetry parameter, paired t-tests were used to assess changes from baseline by comparing protected vs. unprotected zones within each area (stripped/exposed, not stripped/exposed, stripped/unexposed) and exposed vs. unexposed zones within the stripped/unprotected and stripped/protected areas.

The significance level was set at p = 0.05, and no correction for multiple comparisons was applied.

All statistical analyses were performed using SAS 9.4 (SAS Institute Inc., Cary, NC, USA), and graphics were generated with R version 4.3.0 (R Foundation for Statistical Computing, Vienna, Austria, 2012).

Results

Study Population

Twenty-three subjects were screened. Of these, two did not meet the inclusion/exclusion criteria, and one subject withdrew from the study before D1. The remaining 20 subjects were randomized and completed the study as planned in the protocol (Fig. 2). One minor protocol deviation was reported for one subject (5%) during the study (missed visit on D13) [25].

Fig. 2.

Study flow diagram [26]

There were 4 (20%) men and 16 (80%) women aged 24–49 (mean, 37.9) years. Subjects were divided between Fitzpatrick skin type IV (65%) and Fitzpatrick skin type V (35%) (Table 5).

Table 5.

Demographic characteristics of the study population

	Screened n (%)	Intention to treat N (%)	Per protocol N (%)
Gender
N	23	20	20
Male	4 (17.4%)	4 (20.0%)	4 (20.0%)
Female	19 (82.6%)	16 (80.0%)	16 (80.0%)
Age (years)
Mean ± SD	37.7 ± 7.6	37.9 ± 7.2	37.9 ± 7.2
(Min, max)	(24, 50)	(24, 49)	(24, 49)
Fitzpatrick skin type
Type IV	15 (65.2%)	13 (65.0%)	13 (65.0%)
Type V	8 (34.8%)	7 (35.0%)	7 (35.0%)

Primary Efficacy Endpoint

At D22, all tested conditions demonstrated statistically significant changes from baseline. In stripped, exposed skin, the mean difference in ΔITA° between protected and unprotected areas was + 5.96 ± 1.42 (p < 0.001), indicating a protection against PIH provoked by UV/VL (Fig. 3A, C).

Fig. 3.

Photoprotective effects assessed by ΔITA° and standardized photography. A Change in ITA° (ΔITA°) from baseline to Day 22 in exposed areas. Boxplots show the median and interquartile range (IQR) of ΔITA°. Red: protected area; blue: unprotected area. B Change in ITA° (ΔITA°) from baseline to Day 22 in stripped areas. Boxplots show the median and interquartile range (IQR) of ΔITA°. Red: exposed area; blue: unexposed area. C Standardized photographs of protected and unprotected skin in stripped and exposed zones (left) and in not stripped and exposed zones (right) on Day 22. FPT Fitzpatrick skin type

In non-stripped, exposed skin, this difference was more pronounced, with a ΔITA° of + 11.76 ± 1.42 (p < 0.001), suggesting the sunscreen provided highly significant protection against hyperpigmentation induced by UV/VL alone (Fig. 3A, C).

Comparisons of stripped, exposed skin versus stripped, unexposed skin further underscored the impact of photoprotection (Fig. 3B). In unprotected areas, ΔITA° was significantly reduced (–9.88 ± 1.42, p < 0.001), indicating increased pigmentation due to exposure. In contrast, in protected areas, the reduction was significantly less (− 3.88 ± 1.42, p = 0.008).

Secondary Efficacy Endpoints

Pigmentation

Across all conditions, pigmentation scores began to rise from D3, peaked around D8, and gradually declined through D36 (Fig. 4A). In all cases, pigmentation was higher in exposed vs. unexposed areas, and higher in unprotected vs. protected skin, confirming the protective effect of the sunscreen (Fig. 4A, Table 6).

Fig. 4.

Effect of protection on A pigmentation and B erythema in exposed zones from D1 to D36 (mean ± SD). Red line: protected; blue line: unprotected

Table 6.

Maximum values obtained in the study

Parameter	Stripping	Peak change (unprotected) (Mean ± SD)	Peak change (protected) (Mean ± SD)	% reduction (protected vs. unprotected)
Pigmentation	Stripped	8.10 ± 1.10	6.00 ± 1.10	25.93
	Non-stripped	7.90 ± 1.00	4.10 ± 0.90	48.10
Erythema	Stripped	2.10 ± 0.40	1.20 ± 0.50	42.86
	Non-stripped	1.60 ± 0.50	0.10 ± 0.20	93.75
ΔITA°	Stripped	− 36.13 ± 12.50	− 18.44 ± 9.74	48.96
	Unstripped	− 20.90 ± 8.24	− 4.69 ± 3.15	77.56
ΔL*	Stripped	− 11.10 ± 3.97	− 5.72 ± 2.80	48.47
	Unstripped	− 6.94 ± 2.22	− 1.71 ± 1.10	75.36
Δa*	Stripped	5.98 ± 2.48	3.09 ± 1.23	48.33
	Unstripped	3.94 ± 1.72	0.51 ± 0.49	87.06
Δb*	Stripped	− 6.54 ± 3.01	− 3.75 ± 2.36	42.66
	Unstripped	− 2.82 ± 2.23	− 0.93 ± 1.29	67.02
ΔE	Stripped	13.29 ± 4.39	7.27 ± 3.09	45.30
	Unstripped	7.79 ± 2.66	2.13 ± 1.16	72.66

On stripped, exposed skin, pigmentation on D8 was significantly lower in protected areas (5.60 ± 1.20) than in unprotected areas (8.00 ± 1.1), indicating a ~ 30% reduction due to photoprotection. This difference persisted until D36.

In non-stripped, exposed skin, the protective effect was even more marked. On D8, pigmentation was 3.60 ± 1.00 in protected areas and 7.70 ± 0.90 in unprotected areas, corresponding to a ~ 53% reduction. Pigmentation scores in protected, non-stripped areas remained stable or declined over time, reaching 2.70 ± 1.10 by D36.

Maximum pigmentation values observed across the study followed similar trends (Table 6).

Erythema

Across all test conditions, erythema peaked on D3, with subsequent resolution observed over time (Fig. 4B). Photoprotection significantly mitigated erythema intensity, particularly in exposed areas, and accelerated its resolution (Fig. 4B, Table 6).

On stripped, exposed skin, D3 erythema scores were markedly lower in protected areas (1.20 ± 0.50) than in unprotected areas (2.10 ± 0.40), reflecting a ~ 43% reduction. Erythema in unexposed stripped areas was also lower (1.00 ± 0.30), indicating that stripping alone induced mild inflammation, which was not notably amplified by subsequent light exposure when photoprotection was applied.

On non-stripped, exposed skin, erythema was minimal in protected areas (0.10 ± 0.20) and substantially lower than in unprotected areas (1.60 ± 0.50).

Erythema resolved by D8 in all protected areas, regardless of stripping. In contrast, erythema in unprotected areas persisted longer, resolving between D8 and D15. Peak scores (maximum values across the study) further emphasize the benefit of protection: the maximum erythema score in stripped/unprotected/exposed areas was 2.20 ± 0.40 compared to 1.30 ± 0.50 in stripped/protected/exposed areas (Table 6).

Colorimetry Parameters (ΔITA°, ΔL*, Δa*, Δb*, and ΔE)

Colorimetric analysis demonstrated that the sunscreen provided significant protection against changes in all parameters (Fig. 5; Table 6).

Fig. 5.

Effect of protection on A skin pigmentation (ΔITA°), B skin lightness (ΔL*), C erythema (Δa*), (D) brownness (Δb*), and E overall color (ΔE) in exposed zones from D1 to D36 (mean ± SD). Red line: protected; blue line: unprotected

ΔITA°, which inversely correlates with pigmentation, decreased significantly in all conditions, with values on unprotected exposed skin nearly double those in protected areas (Fig. 5A).

Similarly, a reduction in ΔL*, reflecting increased pigmentation, was observed across all test conditions, peaking around D8 and remaining significantly decreased through D36 (Fig. 5B). Protection reduced this darkening by approximately 50% on stripped skin and up to 75% on non-stripped skin.

Changes in Δb* (brownness) followed the same trend, with reductions two- to fourfold greater in unprotected vs. protected skin (Fig. 5C).

For Δa* (redness), values were up to three times greater than in protected sites (Fig. 5D). On non-stripped skin, erythema was sixfold higher in unprotected areas.

Delta E values, indicating overall color change, confirmed these findings, with unprotected exposed skin exhibiting significantly higher changes than protected skin (Fig. 5E).

Together, these parameters provide strong evidence that the sunscreen effectively mitigates both pigmentation and erythema, particularly in intact skin, and reduces the risk of PIH.

Local Tolerability and Adverse Events

Tolerability was excellent across all applications. There were no local safety concerns, and no product-related adverse events occurred during the study.

Discussion

PIH remains a challenging and distressing condition, particularly among individuals with darker skin phototypes who are more prone to prolonged and intense pigmentary responses following inflammation and light exposure [1, 2]. While the roles of UV and VL in exacerbating PIH are well established, few interventions effectively address the dual mechanisms of oxidative stress and inflammation that participate to its pathogenesis [13].

In this investigator-masked, randomized, intra-individual human model that combines standardized barrier disruption with controlled UV/VL exposure, we evaluated a multifunctional broad-spectrum sunscreen containing sclareolide and niacinamide, two active ingredients with established anti-inflammatory and depigmenting properties. To our knowledge, this is among the first sunscreen trials to test such a multifunctional formulation in a standardized, reproducible human PIH model integrating barrier disruption with UV/VL exposure, with objective colorimetric endpoints.

The sunscreen significantly reduced both clinical pigmentation and erythema, as well as objective colorimetric parameters (ΔITA°, ΔL*, Δa*, Δb*, ΔE). Notably, ΔITA°, a validated inverse correlate of skin pigmentation, improved by nearly 78% in protected, non-stripped areas and by 49% in inflamed, stripped areas, demonstrating efficacy in both inflammatory and non-inflammatory contexts.

Compared to previous studies of anti-inflammatory or antioxidant-enriched sunscreens, this formulation yielded quantitatively greater and statistically significant protection. Puaratanaarunkon et al. [16] reported a modest, non-significant reduction in PIH following picosecond laser treatment using a sunscreen with anti-inflammatory agents [16], while Wanitphakdeedecha et al. [17] showed reduced PIH incidence 1 week after ablative fractional resurfacing with early sunscreen use, although without long-term pigment quantification [17]. In contrast, our study demonstrated visible and sustained improvements in pigmentation, with ΔITA° changes exceeding 11 units in intact skin—values corresponding to clinically appreciable lightening. A study by Lyons et al. [25] further highlights the relevance of using topical anti-inflammatory agents in PIH models. In that study, bakuchiol, a botanical with anti-inflammatory, antioxidant, and antimicrobial properties, demonstrated statistically significant pigment improvement in a trichloroacetic acid-induced PIH model, although less consistently in acne-induced lesions. The authors emphasized the benefit of standardized PIH models for evaluating treatment efficacy. Although the mechanism of action and study design differ from ours, these data collectively reinforce the importance of targeting inflammation and oxidative stress in the prevention and treatment of PIH. The larger magnitude of pigmentation improvement observed with our formulation, achieved in a realistic UV/VL-induced pigmentation model, underscores its potential for broader application in skin of color.

The inclusion of niacinamide, which inhibits melanosome transfer and strengthens the epidermal barrier [23], and sclareolide, which downregulates inflammatory mediators such as IL-1α, PGE2, and NO [21, 22], likely contributed synergistically to these effects. Protection was evident even in stripped, unexposed skin, suggesting that the formulation offers benefits beyond filtering light through modulation of the inflammatory response. Further studies are warranted to explore the utility of this combination in other pigmentary disorders, such as melasma.

These findings underscore the importance of early and proactive photoprotection in preventing PIH. Pigmentation scores in protected areas plateaued or declined after peaking at Day 8, while unprotected areas continued to darken, suggesting that the sunscreen may not only prevent but also accelerate pigment resolution.

Limitations

First, we did not include a sunscreen comparator without sclareolide and niacinamide, which precludes isolating the specific contribution of these active ingredients to PIH prevention. This was primarily due to practical constraints on the number of test areas per participant; moreover, the primary objective was to evaluate the efficacy of the final, marketed formulation. A future comparative study using otherwise identical formulations with the same UV-filter system, differing only by the presence or absence of sclareolide and niacinamide, would be especially valuable to isolate ingredient-specific effects.

Second, the sample size was modest and limited to healthy volunteers with Fitzpatrick skin types IV–V. In accordance with French regulations, ethnicity data were not collected; thus, we could not analyze ethnicity-related differences. Additional studies are needed to confirm generalizability across a broader range of skin types and hyperpigmentary conditions (e.g., acne-induced PIH, melasma, post-procedural pigmentation). Third, while the study duration captured early and peak pigmentation responses, longer follow-up is required to assess the durability of the protective effects and pigment clearance. Finally, although colorimetry provided objective and quantitative data, complementary histological or molecular analyses would strengthen mechanistic interpretation.

Conclusion

This randomized, investigator-masked, intra-individual study using a validated human PIH model that integrates barrier disruption with UV/VL exposure shows that a broad-spectrum sunscreen enriched with sclareolide and niacinamide provides clinically meaningful protection against PIH. By combining high-level photoprotection with anti-inflammatory and depigmenting activity, the formulation addresses both extrinsic and intrinsic drivers of pigmentation. While additional comparative and longer-term studies are warranted, the present findings support the efficacy of this multifunctional sunscreen in PIH-prone populations.

Author Contributions

Thierry Passeron, Anthony Brown, Carles Trullas, and Jaime Piquero-Casals conceptualized and designed the study. Marta Furmanczyk coordinated study activities. Thierry Passeron oversaw study conduct and data analysis. Anthony Brown drafted the initial manuscript. All authors critically reviewed and revised the manuscript and approved the final version for submission.

Funding

This study and all associated publication costs were funded by ISDIN.

Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Conflict of Interest

Thierry Passeron and Jaime Piquero-Casals serve as consultants for ISDIN. Anthony Brown, Carles Trullas, Marta Furmanczyk, and Monica Foyaca are employees of ISDIN.

Ethical Approval

The study protocol (2023-A02785-40) was reviewed and approved by an appropriate IEC (Comité de Protection des Personnes (CPP) Ouest III) on 13 May 2024 and was conducted in accordance with the ethical principles initially outlined in the Declaration of Helsinki and its subsequent amendments and Good Clinical Practice (GCP). All subjects who participated in this clinical study were fully informed about the clinical study, and prior to inclusion, the subject and the investigator signed and dated the consent form(s).