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Adapalene
Adapalene
Adapalene
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Adapalene
Clinical data
Trade namesDifferin, others
AHFS/Drugs.comMonograph
MedlinePlusa604001
License data
Pregnancy
category
  • AU: D
Routes of
administration		Topical
Drug classRetinoids
ATC code
Physiological data
ReceptorsRetinoic acid receptor (RAR)
MetabolismKnown to accumulate in the liver and GI-tract. In human, mouse, rat, rabbit, and dog cultured hepatocytes, metabolism appears to affect the methoxybenzene moiety but remains incompletely characterized. The major products of metabolism are glucuronides. Approximately 25% of the drug is metabolized; the rest is excreted as parent drug
Legal status
Legal status
Pharmacokinetic data
BioavailabilityVery low[medical citation needed]
MetabolismKnown to accumulate in the liver and GI-tract. In human, mouse, rat, rabbit, and dog cultured hepatocytes, metabolism appears to affect the methoxybenzene moiety but remains incompletely characterized. The major products of metabolism are glucuronides. Approximately 25% of the drug is metabolized; the rest is excreted as parent drug
MetabolitesGlucuronides
Elimination half-lifebetween 7 and 51 hours
ExcretionBile duct
Identifiers
  • 6-[3-(1-adamantyl)-4-methoxyphenyl]naphthalene-2-carboxylic acid
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.149.379 Edit this at Wikidata
Chemical and physical data
FormulaC28H28O3
Molar mass412.529 g·mol−1
3D model (JSmol)
Melting point300 °C (572 °F)
Boiling point606.3 °C (1,123.3 °F)
  • COC1=C(C=C(C=C1)C2=CC3=C(C=C2)C=C(C=C3)C(=O)O)C45CC6CC(C4)CC(C6)C5
  • InChI=1S/C28H28O3/c1-31-26-7-6-23(21-2-3-22-12-24(27(29)30)5-4-20(22)11-21)13-25(26)28-14-17-8-18(15-28)10-19(9-17)16-28/h2-7,11-13,17-19H,8-10,14-16H2,1H3,(H,29,30) checkY
  • Key:LZCDAPDĜCYOEH-UHFFFAOYSA-N checkY
  (verify)
Adapalene Gel, sold as trade name Differin in China

Adapalene, sold under the brand name Differin among others, is a third-generation topical retinoid primarily used in the treatment of mild-moderate acne, and is also used off-label to treat keratosis pilaris as well as other skin conditions.[6] Studies have found adapalene is as effective as other retinoids, while causing less irritation.[7] It also has several advantages over other retinoids. The adapalene molecule is more stable compared to tretinoin and tazarotene, which leads to less concern for photodegradation.[7] It is also chemically more stable compared to the other two retinoids, allowing it to be used in combination with benzoyl peroxide.[7] Due to its effects on keratinocyte proliferation and differentiation, adapalene is superior to tretinoin for the treatment of comedonal acne and is often used as a first-line agent.[8] The Swiss company Galderma developed adapalene.

Medical uses

[edit]

Per the recommendations of the Global Alliance on Improving Outcomes of Acne, retinoids such as adapalene are considered first-line therapy in acne treatment and are to be used either independently or in conjunction with benzoyl peroxide and/or an antimicrobial agent, like clindamycin, for maximum efficacy.[9][10] An adapalene/benzoyl peroxide combination medication is also available. Furthermore, adapalene, like other retinoids, increases the efficacy and penetration of other topical acne medications that are used in conjunction with topical retinoids as well as hastens the improvement of the postinflammatory hyperpigmentation caused by acne.[9] In the long term, it can be used as maintenance therapy.[9]

Off-label uses

[edit]

Adapalene has the unique ability to inhibit keratinocyte differentiation and decrease keratin deposition. This property makes adapalene an effective treatment for keratosis pilaris and callus. Other non-FDA approved indications that have been reported in the literature include treatment of warts, molluscum contagiosum, Darier's disease, photoaging, pigmentary disorders, actinic keratoses and alopecia areata.[7]

Cosmetic uses

[edit]

While adapalene is sold at 0.1% in over-the-counter topical products for treatment of acne,[11] its availability is otherwise restricted to prescription drugs. A version of adapalene, oleyl adapalenate, is available for broader skincare and cosmetic usage.

Side effects

[edit]

Of the three topical retinoids, adapalene is often regarded as the best tolerated. It can cause mild adverse effects such as photosensitivity, irritation, redness, dryness, itching, and burning,[7] and 1% to 10% of users[12] experience a brief sensation of warmth or stinging, as well as dry skin, peeling and redness during the first two to four weeks using the medication.[9][13] These effects are considered mild and usually decrease over time.[9][13] Serious allergic reactions are rare.[13]

Pregnancy & lactation

[edit]

Use of topical adapalene in pregnancy has not been well studied but has a theoretical risk of retinoid embryopathy.[14] Thus far, there is no evidence that the cream causes problems in the baby if used during pregnancy.[15]

Topical adapalene has poor systemic absorption and results in low blood levels (less than 0.025 mcg/L) even after long term use, suggesting that there is low risk of harm for a nursing infant.[16]

Interactions

[edit]

Adapalene has been shown to enhance the efficacy of topical clindamycin, although adverse effects are also increased.[17][18] Application of adapalene gel to the skin 3–5 minutes before application of clindamycin enhances penetration of clindamycin into the skin, which may enhance the overall efficacy of the treatment as compared to clindamycin alone.[19]

Pharmacology

[edit]

Unlike the retinoid tretinoin (Retin-A), adapalene has also been shown to retain its efficacy when applied at the same time as benzoyl peroxide due to its more stable chemical structure.[20] Furthermore, photodegradation of the molecule is less of a concern in comparison to tretinoin and tazarotene.[7]

Pharmacokinetics

[edit]

Absorption of adapalene through the skin is low. A study with six acne patients treated once daily for five days with two grams of adapalene cream applied to 1,000 cm2 (160 sq in) of skin found no quantifiable amounts, or less than 0.35 ng/mL of the drug, in the patients' blood plasma.[3] Controlled trials of chronic users of adapalene have found drug levels in the patients' plasma to be 0.25 ng/mL.[14]

Pharmacodynamics

[edit]

Adapalene is highly lipophilic. When applied topically, it readily penetrates hair follicles and absorption occurs five minutes after topical application.[7] After penetration into the follicle, adapalene binds to nuclear retinoic acid receptors (namely retinoic acid receptor beta and gamma).[10][14] These complexes then bind to the retinoid X receptor which induces gene transcription by binding to specific DNA sites, thus modulating downstream keratinocyte proliferation and differentiation.[7][14] This results in normalization of keratinocyte differentiation, allowing for decreased microcomedone formation, decreased clogging of pores, and increased exfoliation by increasing cell turnover.[7][14][21] Adapalene is also regarded as an anti-inflammatory agent, as it suppresses the inflammatory response stimulated by the presence of Cutibacterium acnes,[7] and inhibits both lipoxygenase activity and the oxidative metabolism of arachidonic acid into prostaglandins.[14]

Adapalene selectively targets retinoic acid receptor beta and retinoic acid receptor gamma when applied to epithelial cells such as those found in the skin.[22] Its agonism of the gamma subtype is largely responsible for adapalene's observed effects. In fact, when adapalene is applied in conjunction with a retinoic acid receptor gamma antagonist, adapalene loses clinical efficacy.[23]

Retinization is a common temporary phenomenon reported by patients when initiating use of retinoids.[24] Within the initial period of treatment, skin can become red, irritated, dry and may burn or itch from retinoid application; however, this tends to resolve within four weeks with once a day use.[24]

Metabolism

[edit]

Extensive information regarding adapalene metabolism in humans is unavailable, although it is known to accumulate in the liver and GI-tract. In human, mouse, rat, rabbit, and dog cultured hepatocytes, metabolism appears to affect the methoxybenzene moiety but remains incompletely characterized. The major products of metabolism are glucuronides. Approximately 25% of the drug is metabolized; the rest is excreted as the parent drug.[25]

History

[edit]

Adapalene was a research product of the Swiss company Galderma.[26] Adapalene was approved as a prescription medication in 1996 by the US Food and Drug Administration (FDA) for use in the treatment of acne.[27] In 2016, the US FDA approved adapalene gel 0.1% for over-the-counter (OTC) sale, marking the first time a formerly prescription-only retinoid became available without a prescription for acne treatment.[28]

Research

[edit]

A study has concluded that adapalene can be used to treat plantar warts and may help clear lesions faster than cryotherapy.[29] A computational study claims that adapalene can be used as a potential entry inhibitor for Omicron variant of SARS-CoV-2.[30]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Adapalene

View on Grokipedia
from Grokipedia
Adapalene is a third-generation synthetic topical with high selectivity for retinoic acid receptors (RAR-β and RAR-γ), chemically known as 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid, primarily used for the treatment of mild to moderate vulgaris in patients aged 12 years and older. Developed by and first approved by the U.S. (FDA) as a prescription in 1996 under the brand name Differin, it became available over-the-counter in 2016 as a 0.1% , marking the first approved for non-prescription treatment. It is noted for its minimal irritation and good tolerance compared to other retinoids. Adapalene exerts its therapeutic effects by selectively binding to retinoic acid receptors (RAR-β and RAR-γ) in the nucleus, forming complexes that regulate to normalize follicular keratinization, promote cell differentiation, and reduce without significantly affecting RAR-α. This mechanism leads to comedolytic (preventing comedone formation), anticomedogenic, and anti-inflammatory actions, addressing key pathophysiological aspects of such as microcomedone formation and inflammatory lesions. With low systemic absorption (mean peak plasma concentration of approximately 0.55 ng/mL after repeated topical application), it minimizes potential retinoid-related systemic effects. Clinically, adapalene is applied topically once daily in concentrations of 0.1% or 0.3% as a , , or , often in combination with agents like benzoyl peroxide or clindamycin for enhanced efficacy against both inflammatory and noninflammatory lesions. It is milder than tretinoin with superior tolerability, particularly in reducing noninflammatory lesions and supporting long-term maintenance therapy, as demonstrated in pivotal studies including meta-analyses of over 900 patients showing efficacy comparable to tretinoin 0.025% but with a faster onset and fewer irritant effects. Off-label, adapalene has shown some anti-aging benefits, including improvements in skin texture and pore appearance through its effects on photoaged skin. Common adverse effects include mild to moderate irritation such as , dryness, scaling, and burning, which typically diminish with continued use; it is contraindicated in cases of and requires sun protection due to risks.

Medical uses

Acne treatment

Adapalene serves as a first-line topical for mild to moderate vulgaris in patients aged 12 years and older, recommended either as monotherapy or in combination with other agents due to its comedolytic and properties. As a third-generation retinoid, adapalene exhibits high selectivity for retinoic acid receptors β and γ (RAR-β and RAR-γ), contributing to its particular efficacy in acne treatment, while being milder than tretinoin with better tolerability and minimal irritation. In clinical practice, it normalizes follicular keratinization, thereby preventing the formation of microcomedones, the precursors to both noninflammatory (comedonal) and inflammatory lesions. This mechanism addresses key pathophysiological aspects of , such as abnormal and follicular hyperkeratinization. The standard dosing regimen for adapalene involves applying a thin layer of 0.1% or 0.3% or cream to the affected areas once daily at bedtime, after gently cleansing the skin. Clinical trials demonstrate its , with reductions of 50-70% in both inflammatory and noninflammatory counts observed after 12 weeks of treatment; for instance, one study reported a 61% overall reduction with 0.3% , comparable to other retinoids. Anecdotal community reports, particularly from Reddit's r/SkincareAddiction, indicate that progress at week 9 varies widely. Many users report ongoing purging, worsened acne, increased closed comedones, dryness, or minimal/no visible improvement, while others note the peak of purging has passed, with smoother texture emerging or reduced congestion. Community consensus is that retinoids often require 3-6+ months for significant results, and week 9 is frequently still within the adjustment/purging phase. These outcomes support its role in achieving clear or almost clear skin in a significant proportion of patients, as evidenced by Investigator's Global Assessment success rates. Adapalene is commonly used in fixed-dose combination products to enhance therapeutic outcomes and mitigate bacterial resistance, such as with benzoyl peroxide (e.g., Epiduo , containing adapalene 0.1% and benzoyl peroxide 2.5%) for synergistic antibacterial and keratolytic effects, or with clindamycin for targeted antimicrobial action against acnes. These combinations yield greater lesion reductions, with up to 70% improvement in total lesions reported in trials. Since its approval for over-the-counter availability of the 0.1% by the FDA in 2016, adapalene has improved access to effective treatment without a prescription, particularly benefiting adolescents and young adults as of 2025.

Off-label uses

Adapalene has been investigated off-label for the treatment of , a common dermatological condition characterized by rough, bumpy patches due to hyperkeratinization around hair follicles. By promoting the normalization of follicular , adapalene helps reduce the accumulation of keratin plugs, leading to smoother texture over time. Clinical observations and small-scale studies support its use as a second-line topical for this purpose, often applied at 0.1% concentration nightly, though results vary based on individual type and adherence. In the management of actinic keratosis and photoaging, adapalene demonstrates potential benefits through its retinoid activity, which includes stimulating collagen synthesis in the dermis and improving epidermal turnover. Studies have shown that 0.1% to 0.3% adapalene gel can reduce the number of actinic keratoses, diminish solar lentigines, improve skin texture and pore appearance, and alleviate signs of photodamage such as fine wrinkles and hyperpigmentation after 9 to 24 weeks of use. These effects are attributed to enhanced collagen production and reduced matrix metalloproteinase activity, making it a tolerable option for patients intolerant to stronger retinoids like tretinoin, though it remains off-label for these indications. Recent research from 2023 to 2025 has explored adapalene's application for common (verruca vulgaris), particularly when used under occlusion to enhance penetration. In a 2024 randomized study of 88 patients with plantar warts, topical 0.1% adapalene twice daily under occlusion achieved complete clearance rates of 59% at 4 months and up to 91% by 6 months, outperforming in efficacy and safety with no reported adverse events. Similarly, a 2019 pediatric study reported 59% complete clearance after 3 months of adapalene monotherapy, aligning with 40-60% rates in combined occlusion approaches from emerging trials. These findings suggest adapalene's keratolytic and immunomodulatory effects disrupt wart hyperproliferation, but larger confirmatory studies are needed. Adapalene has also shown promise off-label for treating , a viral skin infection common in children, through its keratolytic and immunomodulatory properties. Small-scale studies and case reports, particularly in pediatric populations, indicate that topical 0.1% adapalene gel applied nightly can lead to clearance with minimal irritation, though evidence is limited to observational data and requires further randomized trials for validation. Beyond therapeutic applications, adapalene features in over-the-counter (OTC) cosmetic formulations for anti-aging, leveraging its availability since the U.S. FDA switch from prescription to OTC status for treatment. This transition has driven market expansion, with the global adapalene market growing at a (CAGR) of approximately 5.4% from 2025 to 2035, fueled by consumer demand for accessible retinoid-based products targeting fine lines and uneven tone. Post-switch, OTC sales have increased access while reducing costs by up to 70% compared to prescription versions, positioning adapalene as a gentle entry-level option for cosmetic prevention. Despite these promising uses, adapalene's off-label applications face limitations, including lack of FDA approval beyond acne vulgaris and reliance on small-scale trials that report variable . For instance, studies often involve fewer than 100 participants with short follow-up periods, leading to inconsistent outcomes influenced by factors like skin phototype and concurrent sun exposure. Dermatologists recommend cautious use under supervision to mitigate potential , emphasizing the need for more robust, large-scale randomized controlled trials to establish standardized protocols.

Adverse effects

Skin reactions

Topical adapalene commonly induces an initial irritation characterized by , dryness, scaling, pruritus, and burning, affecting 10-40% of users during the first 2-4 weeks of treatment. These symptoms typically peak in intensity around weeks 2-4 and are most pronounced during the early phase of therapy as the skin adjusts to the . In clinical studies, mild cutaneous reactions such as dryness and occurred in approximately 65-67% of patients, with the majority resolving upon continued use or with the addition of moisturizers. Anecdotal reports from users on online forums, particularly Reddit's r/SkincareAddiction, indicate wide variation in adapalene (Differin) progress at week 9. Many users report ongoing purging, worsened acne, increased closed comedones, dryness, or minimal/no visible improvement, with some describing their skin as "horrid" or still breaking out. Others note that the peak of purging has passed, with smoother texture emerging or reduced congestion. Community consensus is that retinoids often require 3-6+ months for significant results, and week 9 is frequently still within the adjustment/purging phase. Management of these skin reactions focuses on supportive measures to maintain treatment adherence while minimizing discomfort. Strategies include reducing the application frequency to every other day, incorporating emollients or oil-free moisturizers to counteract dryness and scaling, applying a thin layer of petroleum jelly-based occlusive (such as Aquaphor or Vaseline) to sensitive areas (e.g., around the eyes, nose, and mouth) before adapalene to create a protective barrier, minimize irritation, and prevent the retinoid from spreading to delicate skin, or temporarily discontinuing use until symptoms subside. Patients are advised to apply moisturizers immediately after adapalene to buffer irritation, and severe cases may warrant consultation for adjustment. Adapalene use also carries a risk of increased , heightening susceptibility to sunburn despite lacking phototoxic or photoallergic effects in studies. Daily application of broad-spectrum (SPF 30 or higher) and avoidance of excessive sun exposure are recommended to mitigate this risk. Compared to other retinoids like tretinoin, adapalene exhibits a lower irritation profile, with reduced incidence of (66% vs. 83%) and dryness (65% vs. 67%) in head-to-head trials, attributed to its selective binding to receptors β and γ. This selectivity contributes to less disruption of the skin barrier during initial use.

Pregnancy and lactation

Adapalene is classified as FDA C, indicating that reproduction studies have shown adverse effects on the at high doses, such as skeletal malformations including supernumerary in rats and rabbits, while no adequate and well-controlled studies exist in women. Teratogenic effects were observed in models at oral doses up to 120 times the maximum topical exposure, but these findings are considered relevant primarily for systemic exposure rather than topical use. Systematic reviews and meta-analyses of data, including prospective cohort studies, have found no significant increase in major congenital malformations, spontaneous abortions, low birthweight, or prematurity associated with topical adapalene exposure. The minimal systemic exposure from topical adapalene, with bioavailability less than 4% and plasma levels typically undetectable after 72 hours, suggests a low risk to the fetus. This low transdermal absorption profile supports the notion that fetal harm is unlikely at therapeutic doses, though early case reports raised unsubstantiated concerns about potential congenital anomalies. Current guidelines, such as those from the American Academy of Dermatology, recommend avoiding adapalene during pregnancy, particularly in the first trimester due to the period of organogenesis; safer alternatives such as azelaic acid are preferred for acne management. Regarding lactation, there are no specific data on adapalene excretion in breast milk, but its low maternal serum levels from topical application make significant transfer to the unlikely. Topical use is generally considered low risk during , provided the product is not applied to the breast or area to prevent direct contact. Post-marketing surveillance and reviews up to 2024 continue to indicate no increased incidence of birth defects associated with topical adapalene, supporting its relatively favorable safety profile despite precautionary guidelines.

Interactions

Drug interactions

Adapalene, when used concurrently with other topical acne therapies such as benzoyl peroxide or , may result in additive , including increased dryness, , and peeling, necessitating spaced application or initiation of one agent at a time to minimize discomfort. To further reduce the risk of excessive irritation when combining adapalene and salicylic acid, common dermatological approaches include alternating nights of application, or—if used on the same night—applying salicylic acid first, waiting an appropriate interval (such as 20–30 minutes), then applying adapalene, followed by a moisturizer. Patients are advised to start with less frequent application (e.g., every other night), perform a patch test, use broad-spectrum sunscreen daily due to photosensitivity risks, and consult a dermatologist for personalized advice, especially if significant irritation occurs. This enhanced local arises from complementary mechanisms of action—adapalene's retinoid-induced epidermal turnover combined with benzoyl peroxide's oxidative effects or 's keratolytic properties—though fixed-combination products containing adapalene and benzoyl peroxide are approved and demonstrate improved despite initial tolerability concerns. Interactions with abrasive or medicated and exfoliants containing alcohol, astringents, or peroxides can exacerbate barrier disruption and when applied alongside adapalene, with recommendations to avoid or delay such products until adapalene's effects stabilize. Specific caution is advised against concomitant use with strong keratolytics like or high-concentration preparations, as they may potentiate excessive and compromise the . Due to adapalene's low systemic absorption following topical application ( peak plasma concentrations of approximately 0.55 ng/mL following topical application of 0.3% gel)—no significant pharmacological interactions with oral medications, including antibiotics, are anticipated, and it exhibits minimal involvement with enzymes. However, concurrent use with photosensitizing systemic agents such as tetracyclines warrants monitoring for enhanced cutaneous , potentially leading to exaggerated sunburn risk, with patients advised to employ broad-spectrum and limit sun exposure. No routine monitoring is required for adapalene interactions.

Topical interactions

Adapalene, a topical used primarily for treatment, can interact with various non-pharmaceutical topicals and , potentially altering its absorption, , or tolerability. Using a non-comedogenic with adapalene can improve tolerability by reducing dryness and . To mitigate , it is recommended to apply adapalene to clean, dry skin first and wait a few minutes before layering on or other , allowing the to absorb adequately without interference. Non-comedogenic, oil-free are preferred as adjuncts, as they improve local tolerance without exacerbating or occlusion-related issues. Harsh cleansers, including those containing abrasives, high alcohol concentrations, or astringents, can exacerbate adapalene-induced dryness and irritation by stripping the 's , leading to heightened sensitivity or peeling. Specifically, combining adapalene with salicylic acid cleansers or products increases risks due to their complementary actions in promoting exfoliation, oil control, and pore clearing, which can result in additive effects such as increased dryness, peeling, redness, or stinging. These risks are heightened during the initial retinization phase of adapalene use, typically peaking at 2 to 4 weeks, or in individuals with sensitive or dry skin, potentially leading to skin barrier damage. Patients are advised to opt for gentle, non-comedogenic cleansers that maintain balance and avoid ingredients like , particularly in high concentrations or during initial adapalene use, to promote better adherence to therapy; if combination is necessary, strategies to minimize irritation include spaced application (e.g., applying salicylic acid in the morning and adapalene at night or alternating nights) or, if both are applied at night, applying salicylic acid first, waiting 20–30 minutes, then applying adapalene, followed by a moisturizer. Sun exposure and tanning activities pose a notable with adapalene due to its potential to induce , even though it exhibits lower compared to other retinoids like tretinoin. This can manifest as increased sunburn or on treated areas, particularly during prolonged UV exposure. Daily application of a broad-spectrum with SPF 30 or higher, alongside protective clothing, is essential to counteract this effect and preserve skin integrity. Dermatological procedures such as or other skin-irritating procedures should be avoided on treated areas, as the heightens skin sensitivity, potentially leading to severe , blistering, or delayed ; consult a healthcare provider for timing with procedures like or treatments. This precaution stems from adapalene's impact on epidermal turnover, which compromises the skin's resilience to mechanical or trauma during such interventions. In cosmetic settings, recent 2025 guidance highlights the potential for integrating adapalene with microneedling to enhance delivery, allowing targeted penetration into acne-prone layers for improved lesion resolution while minimizing systemic exposure. However, use must be paused 1-2 weeks prior to microneedling to prevent excessive inflammation, with resumption guided by skin recovery.

Pharmacology

Pharmacodynamics

Adapalene is a synthetic third-generation that exerts its effects primarily through selective binding to nuclear receptors (RARs). It acts as an for RAR-β and RAR-γ subtypes, with high affinity (Ki ≈ 34 nM for RAR-β and Ki ≈ 130 nM for RAR-γ), while exhibiting approximately 30-fold lower affinity for RAR-α (Ki ≈ 1100 nM). This selectivity profile contributes to its reduced potential for causing skin irritation compared to non-selective retinoids like tretinoin, as RAR-α activation is associated with adverse effects such as and peeling. Upon binding, the adapalene-RAR complex forms heterodimers with retinoid X receptors (RXRs), which then modulate gene transcription by interacting with retinoic acid response elements in target genes. At the cellular level, adapalene normalizes the differentiation of follicular epithelial cells and , counteracting the abnormal keratinization seen in pathogenesis. This promotes orderly and prevents the retention of corneocytes within follicles. Simultaneously, it inhibits keratinocyte hyperproliferation, reducing the excessive buildup of cells that leads to comedone formation. These actions result in both comedolytic (clearing existing comedones) and anticomedogenic (preventing new ones) effects, addressing the microcomedone as the primary precursor in . Adapalene also demonstrates anti-inflammatory properties by downregulating (TLR-2) expression on and inhibiting the activator protein-1 (AP-1). TLR-2 activation by triggers AP-1 nuclear translocation, leading to the production of proinflammatory cytokines such as IL-8 and TNF-α; adapalene interrupts this pathway, thereby decreasing cytokine release and modulating the innate immune response in acne-inflamed skin. Unlike tretinoin, adapalene exhibits high photostability and is not degraded by UVB exposure, maintaining its even under light conditions and allowing for potential daytime application when combined with sun protection.

Adapalene demonstrates minimal systemic absorption following topical application, with systemic less than 0.01%. The majority of the applied dose is retained locally in the skin, and plasma concentrations are typically undetectable or very low after chronic use of the 0.1% gel formulation, with trace amounts (<0.25 ng/mL) reported. Following absorption, adapalene is primarily distributed within the and , where it exerts its therapeutic effects, with only trace amounts reaching systemic circulation. Due to its low plasma concentrations, adapalene shows no significant binding to plasma proteins. of adapalene occurs mainly in the liver, leading to conjugation with glucuronides and sulfates; however, the precise pathways in humans remain incompletely characterized as of 2025. Approximately 25% of absorbed adapalene undergoes metabolism, while the remainder is excreted unchanged. Excretion of adapalene is predominantly via the biliary route into , with about 75% of the dose eliminated unchanged. The terminal in plasma ranges from 7 to 51 hours (mean approximately 17 hours), while skin retention is estimated at 1-2 days. Factors such as can increase penetration, and occlusion has been shown to enhance absorption up to several percent in preclinical models.

Chemistry

Structure and properties

Adapalene is a synthetic third-generation characterized by the molecular formula C₂₈H₂₈O₃ and a molecular weight of 412.52 g/mol. Its IUPAC name is 6-[3-(1-adamantyl)-4-methoxyphenyl]naphthalene-2-carboxylic , reflecting its core structure as a naphthoic featuring an adamantyl group linked through a methoxyphenyl bridge to a ring system. This configuration mimics aspects of while incorporating fully aromatic rings that replace the polyene chain, enhancing chemical stability. Physically, adapalene presents as a white to off-white crystalline powder. It is practically insoluble in water (solubility approximately 4.01 × 10⁻⁶ g/L) but exhibits good solubility in organic solvents such as ethanol (sparingly soluble) and dimethyl sulfoxide (DMSO, >10 mg/mL). The melting point ranges from 319°C to 322°C. Adapalene demonstrates superior stability compared to earlier retinoids like tretinoin, showing resistance to exposure and air oxidation due to its rigid aromatic structure. In stability studies, adapalene retains over 95% integrity after exposure to and oxidizing agents, where tretinoin degrades significantly. The compound remains stable under standard storage conditions, with bulk material viable for at least one year from synthesis. Adapalene is commonly formulated for topical use in gels and creams; gels often utilize , water-based vehicles for rapid drying and absorption, while creams incorporate emollient bases to dry or sensitive . The structural features contribute to selective binding with receptors, as explored in .

Synthesis and stability

Adapalene is synthesized via a multi-step process beginning with 6-bromo-2-naphthoic acid as a key starting material, involving coupling to form the substituted phenyl intermediate and subsequent esterification of the naphthoic acid for cross-coupling. The adamantyl group is introduced through Friedel-Crafts-type adamantylation on a methoxyphenyl derivative, followed by protection of the naphthoic acid as a methyl to facilitate the biaryl linkage. This synthesis was patented by in the , with the original filing in under EP 0 199 636 describing the core chemical entity and preparation methods. A pivotal reaction in the synthesis is the palladium-catalyzed cross-coupling, often employing Suzuki-Miyaura conditions with or PdCl₂(PPh₃)₂ catalysts, to attach the adamantyl-substituted phenyl ring to the 6-position of the core, yielding high efficiency on pilot scales with overall yields up to 68% across four steps without . Alternative variants use with a from 2-(1-adamantyl)-4-bromophenol and methyl 6-bromo-2-naphthoate, activated by Pd-Zn systems for selective C-C bond formation. Adapalene faces stability challenges, notably in aqueous environments, where it undergoes alkaline degradation in basic solutions, leading to cleavage of the adamantyl group or bonds. Formulations maintain optimal stability at 4.5-6.5 in gels, aligning with compatibility and minimizing hydrolytic breakdown during storage. Degradation products include minor oxidation to 1,4-naphthoquinone derivatives under UV exposure (254 nm or 366 nm), resulting in approximately 25% loss after 12 hours of irradiation, alongside potential formation of 2-formyl from the ring. Commercial preparations incorporate antioxidants such as disodium EDTA to chelate metals and prevent oxidative degradation, ensuring product integrity in topical gels. Advancements in 2025 have focused on liposomal and hyaluronic acid-based nano-vesicular formulations, which encapsulate adapalene to enhance photostability and reduce in over-the-counter products, demonstrating improved retention of active drug over extended compared to conventional gels.

History

Development

Adapalene was first synthesized in at Research & Development, a between and , as a naphthoic acid derivative intended to serve as a more stable alternative to existing retinoids like tretinoin for topical dermatological applications. The preclinical rationale for its development centered on creating a compound that preserved the efficacy of in modulating cell differentiation and proliferation while minimizing irritation and systemic toxicity, achieved through selective binding to nuclear receptors (RARs), with high affinity for RAR-β and RAR-γ but low affinity for RAR-α. In the , , including those using the rhino model for comedogenesis and the ear model for , demonstrated adapalene's potent anti-comedogenic and comedolytic properties, equivalent to those of tretinoin, alongside reduced skin irritation and no evidence of risks owing to its negligible binding to cytosolic binding proteins (CRABPs) and low systemic absorption. This work led to the filing of US Patent 4,717,720 in 1986 by inventors Braham Shroot, Jacques Eustache, and Jean-Michel Bernardon, assigned to , which claimed benzonaphthalene derivatives such as adapalene for use in treating and other dermatological conditions. Key milestones included the completion of Phase I and II clinical trials, which evaluated safety, tolerability, and preliminary efficacy in acne models, supporting advancement to larger-scale testing.

Regulatory approvals

Adapalene received initial approval from the U.S. (FDA) on May 31, 1996, as a 0.1% topical (Differin) for the prescription treatment of vulgaris in patients aged 12 years and older. It was first approved in , in on July 3, 1992, as a 0.1% solution. A higher-strength 0.3% formulation was subsequently approved by the FDA in 2007 for the same indication. In 2015, the FDA expanded access to the 0.3% strength through approval of Epiduo Forte, a fixed-dose combination containing adapalene 0.3% and benzoyl peroxide 2.5%, for topical treatment in patients aged 12 years and older. The FDA approved the switch of adapalene 0.1% gel to over-the-counter (OTC) status on July 8, 2016, marking the first topical available without a prescription in the United States for treatment in individuals aged 12 years and older; this decision was supported by post-marketing safety data from 1996 to 2010 and consumer studies demonstrating appropriate use. The OTC transition has been associated with improved patient access and reduced costs, as evidenced by real-world utilization data showing increased prescriptions filled and lower out-of-pocket expenses following the change. Internationally, approved adapalene 0.1% gel (Differin) on December 31, 1996, for the topical treatment of vulgaris. Japan's Ministry of Health, Labour and Welfare granted approval for Differin Gel 0.1% (adapalene) on July 16, 2008, as a novel topical for vulgaris. In the , adapalene has been authorized as a prescription since the through national procedures, with OTC availability implemented in select member states starting around 2017, though reclassification varies by country—for instance, rejected an OTC switch in 2016. The combination product Epiduo (adapalene 0.1% and benzoyl peroxide 2.5%) received FDA approval on December 8, 2008, for treatment in patients aged 12 years and older, with subsequent pediatric extension to age 9 approved in 2013 based on safety and efficacy data from younger children. Following patent expiration, the first generic version of adapalene 0.1% gel was approved by the FDA on June 2, 2010, leading to widespread proliferation of generic formulations and increased market competition. As of 2025, adapalene 0.1% gel remains available OTC in the United States and several other countries, including and , with ongoing global market expansion driven by rising prevalence; however, prescription status predominates in many regions, and pediatric use is generally limited to ages 12 and older for the monotherapy, except for the Epiduo combination in select markets.

Research

Dermatological applications

Adapalene has shown promise in for treating , a common follicular disorder characterized by rough, bumpy skin. Although specific randomized controlled trials (RCTs) from 2022 to 2025 are limited, retinoids such as adapalene 0.1% gel are recommended as off-label therapy due to their ability to normalize keratinization and reduce follicular plugging, with anecdotal and observational data indicating modest improvements in texture and appearance after 4-12 weeks of use. In the realm of and pigmentation disorders, adapalene 0.3% gel has demonstrated efficacy in phase III trials for reducing signs of photodamaged skin, including fine wrinkles and , through mechanisms such as enhanced production and inhibition, which limits synthesis. For , a preliminary clinical study reported a 41% reduction in Modified Melasma Area and Severity Index (MASI) scores with adapalene gel combined with other topicals, highlighting its role in pigment lightening via epidermal turnover acceleration and enzymatic inhibition, with tolerability comparable to standard retinoids. Research on , a , supports adapalene's utility in combination regimens. A 2003 RCT found that adapalene gel 0.3% reduced mean lesions by 2.5 compared to an increase of 1.5 with vehicle after 9 months (P < 0.05), while improving overall photodamage. More recent evidence from a 2021 study showed that pretreatment with adapalene 0.1% gel before (ALA-PDT) achieved a 79% lesion clearance on the upper extremities, versus 57% without pretreatment (P = 0.0164), with 12 of 15 subjects reaching 50-100% clearance; although not directly combined with 5-fluorouracil (5-FU), adapalene enhances PDT outcomes similarly to 5-FU in models. For pediatric acne, a 2013 RCT extended adapalene's indications to children aged 9-11 years, demonstrating superior of adapalene 0.1%-benzoyl 2.5% over vehicle, with 68.6% total reduction, 63.2% inflammatory reduction, and 49.3% achieving "clear" or "almost clear" status at week 12 (all P < 0.001), alongside improved . Safety profiles were comparable to adults, with mild, transient irritation (, dryness) in most cases and no serious adverse events. Updated meta-analyses and long-term studies address gaps in chronic use data, confirming adapalene's sustained efficacy and safety. A 2024 of clinical trials affirmed long-term tolerability of adapalene-benzoyl combinations, with median inflammatory and non-inflammatory reductions maintained over 12-52 weeks without or increased systemic risks. An earlier of five RCTs further supported adapalene's favorable profile over comparators like tretinoin for up to 1 year, filling evidentiary voids on prolonged topical application.

Non-dermatological potential

Adapalene has demonstrated potential antiviral activity against the variant of in computational drug repurposing studies. A 2022 investigation identified adapalene as a inhibitor of viral entry by exhibiting strong binding affinity to the mutant (-8.88 kcal/mol), potentially disrupting interactions with the host receptor ACE2 and the , which facilitates priming. This mechanism suggests adapalene could modulate -dependent entry pathways, though the study emphasized the need for subsequent validation to confirm efficacy. Preclinical research has explored adapalene's role in , particularly in models of impaired repair. In an experimental model, adapalene treatment accelerated closure by enhancing synthesis, formation, and epithelialization compared to controls, with effects comparable to tretinoin. Although direct studies in diabetic models are limited, related research indicates potential for accelerating epithelialization in hyperglycemia-impaired wounds through promotion of and reduced , supporting adapalene's investigation in such contexts. Adapalene exhibits anti-cancer potential via retinoid acid receptor (RAR)-mediated pathways that induce in keratinocyte-derived cells. In HaCaT keratinocytes, a model for tumor cells, adapalene triggered DNA damage, S-phase arrest, and subsequent by suppressing colony formation and activating caspase-dependent pathways, independent of traditional G1 arrest seen in other s. This RAR agonism promotes differentiation and in premalignant keratinocytes, offering a basis for targeting tumors like (BCC), where retinoids have shown chemopreventive effects through similar mechanisms. Early-phase investigations into topical retinoids for BCC are underway to assess safety and efficacy in superficial lesions, building on preclinical induction. A 2025 systematic review and of and studies demonstrated adapalene's ability to inhibit tumor growth and progression in various cancers, including reduced tumor volume and weight, supporting its broader anti-cancer potential. Development of systemic formulations for adapalene remains investigational due to its inherent limitations as a topical agent. Adapalene's poor oral —resulting from extensive first-pass and low aqueous —restricts systemic absorption, confining approved uses to dermatological applications. Efforts to create oral analogs or modified structures aim to overcome this, but progress is nascent, with focus instead on enhancing topical delivery. Ongoing research into nanocarriers, such as acid-responsive polymeric nanoparticles and liposomes, improves penetration and targeted release, potentially expanding non-dermatological applications by increasing local without systemic exposure. These challenges underscore the need for formulation innovations to realize adapalene's broader therapeutic potential.

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