Received: 10 May 2018 Revised: 9 July 2018 Accepted: 19 July 2018

DOI: 10.1111/dth.12690

REVIEW ARTICLE

Topical urea in skincare: A review

Leonardo Celleno

Catholic University of Sacred Heart, Rome,

Italy Abstract
Correspondence Alterations in barrier function are associated with a number of skin diseases, including xerosis,
Leonardo Celleno, MD, atopic dermatitis, and psoriasis. Urea, a component of the natural moisturizing factor of the skin,
Catholic University of Sacred Heart,
plays an important role in the preservation of skin hydration and integrity. Several studies have
Largo Francesco Vito 1,
00168, Rome, Italy. investigated the effects of urea in the clinical setting. Here, we summarize the available clinical
Email: lcelleno@gmail.com evidence regarding the effects of urea in the maintenance of healthy skin and management of
skin disorders. At lower doses (≤10%), urea-containing topical formulations act as a skin moistur-
izer, while at higher concentrations (>10% urea), urea-based preparations exert a keratolytic
action. Urea is also useful in combination therapies with anti-inflammatory and anti-fungal
drugs, due to its activity as a penetration enhancer.

KEYWORDS

atopic dermatitis, ichthyosis vulgaris, keratolytic agent, moisturizer, onychomycosis, psoriasis,

topical urea, xerosis

1 | I N T RO D UC T I O N environment, particularly trans-epithelial water loss (TEWL). The

The role of the skin is to protect the body from environmental damage
while maintaining adequate mechanical properties, including elasticity.
Healthy skin is characterized by efficient control of water loss that
allows the maintenance of a good level of hydration, and consequently,
a strong physical and chemical barrier (Verdier-Sévrain & Bonté, 2007).
Urea is a polar, hygroscopic molecule produced endogenously by
the human body and naturally found in the skin. Urea is originated
from the metabolism of proteins and other organic nitrogen com-
pounds and excreted in the urine and sweat (Kapuscinska & Nowak,
2014; Mosher, 1933). As one of the components of the Natural Mois-
turizing Factor (NMF), urea contributes to the preservation of healthy
skin hydration levels. Despite the continuous discovery of new ingre-
dients and novel formulations for skincare, urea is still one of the most
structural organization of the SC and the presence of hygroscopic
molecules, collectively named NMF, allow the SC to retain water,
thus keeping the epidermis moisturized and elastic. The SC is com-
posed of terminally differentiated keratinocytes, named corneo-
cytes, which are arranged into tight multilayers and brought
together by corneodesmosomes. Corneocytes are embedded in a
hydrophobic lipid extracellular matrix, the cornified cell envelope
(Pouillot, Dayan, Polla, Polla, & Polla, 2008). Although the barrier
provided by the SC structurally resembles a brick wall, the SC pos-
sesses a dynamic and more complex nature (Elias, 1983). Indeed,
the cornified cell envelope that surrounds the non-dividing
keratin-filled corneocytes is an active medium composed of
enzymes that are involved in epidermal differentiation and NMF
formation (Pouillot et al., 2008).

useful molecules available to dermatologists due to its molecular and An appropriate level of hydration is necessary to maintain the

functional characteristics. Here, we present an overview of the clinical mechanical properties of the skin, such as strength, flexibility, and

evidence supporting the use of urea in the maintenance of skin integ- elasticity (Mojumdar, Pham, Topgaard, & Sparr, 2017). In vivo, nor-

rity and treatment of diseases involving skin barrier dysfunction.
2 | UREA AND THE SKIN
The stratum corneum (SC), the outermost layer of the skin, protects
the body from external agents and controls exchanges with the
mal hydration levels are within the range of 30–50% of the SC dry
weight (Caspers, Lucassen, Carter, Bruining, & Puppels, 2001). The
water found in the SC is mostly absorbed by corneocytes, which
can swell up to 50% of their weight (Richter, Müller, Schwarz,
Wepf, & Wiesendanger, 2001; Mojumdar et al., 2017). In condi-
tions of low relative humidity (RH), the SC is fragile and breakable,
becoming more elastic as RH increases (Mojumdar et al., 2017).

Dermatologic Therapy. 2018;31:e12690. wileyonlinelibrary.com/journal/dth © 2018 Wiley Periodicals, Inc. 1 of 5

https://doi.org/10.1111/dth.12690
2 of 5 CELLENO

Changes in RH also alter the mobility of the keratin filaments pre-
sent in corneocytes, arguing for a role of water in the plasticisa-
tion of keratin (Mojumdar et al., 2017).
The NMF is crucial for the maintenance of a healthy SC since it
plays a critical role in skin hydration (Robinson, Visscher, Laruffa, &
Wickett, 2010). A decrease in NMF levels induces loss of water in the
SC and reduces epidermal elasticity (Verdier-Sévrain & Bonté, 2007).
The NMF is composed of molecules that are derived from the break-
down of proteins or secreted by sebaceous and sweat glands. A detailed
composition of the NMF is depicted in Figure 1. The degradation of
filaggrin, a keratin-aggregating protein of the cornified cell envelope
that is formed during keratinocyte differentiation (Simon et al., 1996;
1996, 1997; Borelli et al., 2011), improve hydration (Borelli et al.,
2011), and water retention (Treffel & Gabard, 1995). In addition,
urea can increase the amount of free water in conditions of high
humidity (Bettinger et al., 1995) and act as a potent skin humidifier
and descaling agent (Serup, 1992).
Interestingly, all these clinical studies used topical formulations,
either as cream, emulsion, or foam, with urea concentrations of 10%
or less. No adverse events were reported, confirming the safety of
use of topical urea formulations.
Urea increases water content in the SC by acting as a humectant
but also by retaining SC fluidity (Albèr et al., 2014; Mojumdar et al.,
2017). Using corneometry measurements, Albèr et al. demonstrated

Kezic, Kammeyer, Calkoen, Fluhr, & Bos, 2009), yields hygroscopic that urea promotes skin hydration even when applied in a formulation

amino acids and other by-products, including urea (Björklund et al., with reduced water activity (Albèr et al., 2014). A subsequent study

2014). In healthy SC, urea corresponds to 7% of the NMF, a percentage investigated the molecular characteristics of keratin and the macro-

that decreases with age (Verdier-Sévrain & Bonté, 2007). scopic properties of the SC after adding urea to dehydrated SC and
corneocytes and observed that changes were similar to those occur-
ring with increasing relative humidity in the absence of urea
3 | UREA AND THE FUNCTIONAL (Mojumdar et al., 2017). These data support the hypothesis that urea
I N T E G R I T Y OF TH E S T R A T U M C O R N E U M functions as a natural endogenous humectant by replacing water in
low humidity conditions and maintaining a fluidic SC (Mojumdar
Over the years, the moisturizing action of urea has been investigated et al., 2017).
in vivo (Serup, 1992; Bettinger, Gloor, Gehring, & Wolf, 1995; Treffel & At higher concentrations (>10%), urea exerts an emollient/keratolytic
Gabard, 1995; Loden, 1996, 1997; Kuzmina, Hagströmer, & Emtestam, action. The first evidence came from studies by Swanbeck in the 60s.
2002; Grether-Beck, Mühlberg, Brenden, & Krutmann, 2008; Borelli, These studies showed that formulations with a high concentration of
Bielfeldt, Borelli, Schaller, & Korting, 2011). Pan and colleagues have urea could be used to treat ichthyosis and other hyperkeratotic condi-
reviewed these clinical data in 2013 (Pan, Heinecke, Bernardo, tions (Swanbeck, 1968a, 1968b; Swanbeck & Rajka, 1970). Swanbeck
Tsui, & Levitt, 2013). Urea has been shown to reduce TEWL (Loden, postulated that at high concentrations, urea was able to dissolve kera-
tin, by promoting the breakdown of hydrogen bonds. Further studies
NMF components (%) have shown that urea can induce keratin conformational changes
causing denaturation of the protein structure (Pan et al., 2013).
Ammonia,
Uric acid, Phosphate In addition to acting as a humectant, retaining SC fluidity and
Glucosamine, 0,5% promoting keratin denaturation, urea may also be involved in the
Creatine Citrate
1,5% and formate regulation of gene expression (Friedman, von Grote, & Meckfessel,
Calcium
1,5% 0,5% 2016). A study by Grether-Beck et al. reported that urea induces the
Potassium expression of epidermal genes (Grether-Beck et al., 2012). Although
4%
additional studies are needed to gain a better understanding of the
involvement of urea in the regulation of gene expression in the SC,
an active role of urea as an inducer of epidermal gene expression
Sodium
5% may explain the positive effects of urea in the preservation of skin
barrier function.
Chloride
Magnesium
6%
1,5%

Urea Free 4 | U R E A A N D TH E T R E A T M E N T OF
7% amino acids
40% D E R M A T O L O G I C A L C O N DI T I O N S

Sugars Keratinizing disorders are characterized by qualitative or quantitative

8,5% changes to the structure of the SC. Urea, either alone or in combina-
tion therapies, improves the management of such pathological condi-
Lactate
Pyrrolidone tions, including xerosis, atopic dermatitis, ichthyosis vulgaris, psoriasis,
12%
carboxylic acid
and onychomycosis (Pan et al., 2013).
12%
Xerosis, or dry skin, can result from dehydration or changes in
lipid production. Dehydrated skin, typical of elderly subjects, whose
FIGURE 1 Chemical composition of the NMF. Data from (Verdier- tissues lack water, is thin, weak, and breakable. Low quantities of
Sévrain & Bonté, 2007) sebum and abnormal levels of epidermal lipids (as seen in atopic
CELLENO
Urea-containing
topical formulations
≤ 10% Urea > 10% Urea
• Moisturising Action • Keratolytic Action
• Beneficial effects • Beneficial effects
in Xerosis, AD, IV, in Psoriasis,
Psoriasis Onychomycosis
Useful as
Monotherapy Combination Therapy
• Urea is a Penetration
Enhancer forcorticosteroids,
salicylic acid,
and antifungal drugs
FIGURE 2 Summary of the known effects of urea-containing topical
formulations in the clinical setting. AD, topic dermatitis; IV, ichthyosis
vulgaris
dermatitis) make the skin delicate, opaque, red, and hypersensitive to
external agents. In both cases, urea-containing topical formulations
are instrumental in disease management. When used at a low dose
(mostly <10%, one study used 40% urea), urea regulates TEWL and
restores the ability of the SC to attract and maintain hydration (Pan
et al., 2013; Danby et al., 2016). Urea-containing moisturizers
improve fissure healing in patients with diabetes (Federici, Federici, &
Milani, 2015; Gin et al., 2017). Open heel fissures allow the entrance
of bacteria and may lead to infections and further complications. In
addition, a skincare routine involving a moisturisation step halts the
progression of dry skin diseases involving epidermal hyperprolifera-
tion and inflammation (Friedman, von Grote, & Meckfessel, 2016).
Skin barrier dysfunction has been associated with increased risk
of developing atopic dermatitis (AD) (Egawa & Kabashima, 2018). A
weakened skin barrier facilitates the entry of allergens and other
external agents and predisposes the body for inflammation. If skin
inflammation is persistent, barrier function is further impaired
(Egawa & Kabashima, 2018). AD is the most common inflammatory
skin disease and affects up to 30% of children worldwide (Bieber,
2008). AD is the skin manifestation of a genetic predisposition for
allergy and is characterized by very itchy chronic-relapsing skin lesions
on dry skin (Egawa & Kabashima, 2018). Appropriate SC hydration
seems crucial to prevent AD since the application of moisturizers in
newborns reduces the prevalence of the disease (Horimukai et al.,
2014; Simpson et al., 2014).
Several clinical trials have investigated the clinical effects of topi-
cal urea formulations in AD (Pan et al., 2013). At a concentration of
10%, urea was shown to improve skin hydration and to decrease
TEWL in AD patients (Sasaki, Tadaki, & Tagami, 1989). However, two
3 of 5
recent studies claim that urea enhances skin hydration in AD without
reducing TEWL (Hoppe et al., 2015; Ahmad Nasrollahi et al., 2018).
These contradictory results might be explained by the low concentra-
tion of urea used in the formulation used (only 5%).
The clinical benefit of urea in AD was observed alone and in combi-
nation therapy with hydrocortisone or betamethasone-17-valerate
(Bohnsack, Tausch, Gassmuller, & Rippke, 1997; Wilhelm, Scholermann, &
Bohnsack, 1998; Loden et al., 2002; Wirén et al., 2009; Pan et al., 2013).
Of note, combination therapy with urea was found to be more effective
than treatment with hydrocortisone or betamethasone-17-valerate
alone (Pan et al., 2013). A recent Cochrane review confirmed that, in
AD, treatment with moisturizers and topical corticosteroids is more
effective than treatment with topical corticosteroids alone (Van
Zuuren, Fedorowicz, & Arents, 2017). A systematic review con-
firmed the positive effect of moisturizers in AD but alerted to the
need for better-designed studies that allow direct comparisons
between moisturizing agents (Lindh & Bradley, 2015). The available
data, however, support the use of urea-containing moisturizers as
first-line therapy in AD (Lindh & Bradley, 2015).
Ichthyosis vulgaris (IV) is a genetic disease with a prevalence
of 1:300, caused by loss-of-function mutations in the filaggrin
(FLG) gene (Brown & McLean, 2012). IV is characterized by flaky,
dry skin with symmetric white or gray scales. Scaling occurs due to
the absence of the filaggrin protein in the SC, which originates low
cellular turn-over in the SC and chronic keratin accumulation. A
recent systematic review concluded that urea-containing formula-
tions should be used as first-line treatment in IV (Lindh & Bradley,
2015). Maintenance treatment with 10% urea is as good as treat-
ments containing 1% hydrocortisone, 2% salicylic acid or paraffinic
moisturizers (Pan et al., 2013).
Psoriasis is a chronic inflammatory skin disease with a worldwide
prevalence of 2% (Parisi, Symmons, Griffiths, & Ashcroft, 2013). Psori-
asis is characterized by the development of erythematous, desqua-
mating plaques that result from enhanced keratinocyte proliferation
and altered epidermal differentiation (Zhang et al., 2009). Clinical trials
have been performed to investigate the effect of urea on the psoriatic
skin (Pan et al., 2013). One study observed that when used at a con-
centration of 10% urea decreases TEWL and enhances SC hydration
(Sasaki, Tadaki, & Tagami, 1989). Subsequently, Hagemann and
Proksch also found that urea induces epidermal differentiation
(Hagemann & Proksch, 1996). When used at concentrations ranging
from 10 to 40%, alone or in combination therapy with bifonazole or
dithranol, most studies reported improved scaling and clinical condi-
tion in patients with psoriasis (Pan et al., 2013).
At a concentration of 40%, urea shows clinical benefit in the
treatment of fungal nail infections, such as onychomycosis (Pan et al.,
2013). Topical treatment with fluconazole 1% and urea 40% is more
effective than fluconazole alone in the treatment of onychomycosis
(Bassiri-Jahromi, Ehsani, Mirshams-Shahshahani, & Jamshidi, 2012).
Urea enhances the penetration of the anti-fungal agent and, thus,
increases the treatment effect (Pan et al., 2013).
Urea can be classified as a penetration enhancer due to the ability
to facilitate the transport of numerous molecules across the nail and
skin (Trommer & Neubert, 2006). These molecules include the above
mentioned anti-fungal drugs, but also other compounds used in the
4 of 5
treatment of skin diseases, such as corticosteroids (Trommer &
Neubert, 2006). An earlier study by Ayres and Hooper has investi-
gated the enhancing effects of urea on the penetration of cortisol
across the skin (Ayres & Hooper, 1978). The authors observed that
a topical preparation of 1.0% cortisol and 10% urea delivered eight
times more cortisol to the skin than the topical cream used as con-
trol (1.0% cortisol in a water miscible cream). Subsequent studies
have shown that urea enhances the penetration of hydrocortisone, pro-
gesterone, and leuprolide across the SC (Trommer & Neubert, 2006). Of
note, in an in vitro study that investigated the percutaneous diffusion of
progesterone, urea enhanced the penetration of progesterone by 2.5
times (Valenta & Wedenig, 1997).
The mechanism by which urea increases the permeability of the
SC is not completely understood but is thought to derive from the
capacity to increase the amount of water absorbed by corneocytes,
a direct consequence of a high water-binding capacity (Mueller
et al., 2016). At higher doses, urea’s keratolytic action might also
play a role in drug penetration enhancement (Trommer & Neubert,
2006). Due to a recognized action as a chemical penetration
enhancer, urea should be used together with topical corticosteroids,
salicylic acid, or anti-fungal drugs to improve drug delivery and
treatment outcomes.
5 | CO NC LUSIO N
Urea is a well-known moisturizer and keratolytic agent. Urea has
been safely used for over a century in the maintenance of healthy
skin and the treatment of several skin conditions. Clinical studies
have confirmed the positive effects of urea in skin barrier dysfunc-
tion diseases. When used at different concentrations, urea exerts
different actions (Figure 2). A reduced concentration of urea (≤10%)
is associated with a moisturizing effect while a higher concentration
(>10%) exerts an emollient/keratolytic action. As a penetration
enhancer of the skin, urea facilitates the crossing of the skin barrier
by other molecules and thus, improves the effects of drugs used in
combination therapies. Urea-containing topical formulations are
available at different concentrations and provide clinicians with a
wide array of alternatives to improve the management of skin condi-
tions and the patient’s well-being.
ACKNOWLEDGMENTS
Medical writing and editorial support were provided by Raquel
Carvalhosa, Ph.D., and ERA MS SRL. Financial support for medical
writing and editorial services was provided by RELIFE SRL.
CONF LICT OF IN TE RE ST
The authors declare no conflicts of interest.
ORCID
Leonardo Celleno https://orcid.org/0000-0002-7129-198X
CELLENO
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How to cite this article: Celleno L. Topical urea in skincare: A
review. Dermatologic Therapy. 2018;31:e12690. https://doi.
org/10.1111/dth.12690