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David Voegeli
PhD BSc RN Lecturer,
Faculty of Health
Sciences, University
of Southampton
The use of urea as a healing agent goes back
thousands of years. Urea was the first organic
compound to be synthesised in a laboratory
from inorganic materials, and urea prepara-
tions were used in the late 19th and early 20th
century for the topical treatment of infections.1
Interest in urea as a topical agent to treat dry
skin disorders developed over 50 years ago, fol-
lowing the discovery that urea played an im-
portant role in moisture regulation, and was a
key constituent of natural moisturising factor
(NMF).2It was also observed that skin urea lev-
els appeared to be depleted in some dry skin
conditions and the logical way forward was to
develop urea-containing preparations to re-
plenish epidermal levels and skin hydration.
Dry skin is seen in several skin disorders, such
as atopic eczema, ichthyosis, and contact der-
matitis. The reduction in the water content of
the epidermis changes the properties of the
skin barrier, favouring the penetration of irri-
tants, as well as reducing the itching threshold
and predisposing the skin to infections. This
paper outlines the chemical properties of urea
and its clinically proven effectiveness in the
management of dry skin disorders, when incor-
porated into emollient formulations.
Chemistry
Urea is an important molecule involved in nitro-
gen metabolism and transport in humans. It is an
end product of protein catabolism, formed in the
body by the oxidation of amino acids in the liver,
and regulated by the enzyme N-acetylglutamate.
Pure urea forms as small white crystals, giving it a
powdery appearance. It is highly water-soluble,
only slightly soluble in alcohol, and virtually in-
soluble in other organic solvents, such as chloro-
form and ether. Due to the relatively low cost of
production, urea has become an important raw
material in several manufacturing processes, rang-
ing from agricultural fertilisers, plastics and paper,
through to pharmaceuticals and cosmetics. Urea
crystals are hygroscopic; they attract and hold
water molecules from the surrounding environ-
ment, making it an ideal ingredient for a skin
moisturiser. Hygroscopic substances are fre-
quently used in pharmaceuticals, cosmetics and
processed foods to attract water and retain mois-
ture. When used in this context, the term humec-
tant is generally used to describe a substance that
absorbs water or helps another substance retain
moisture. Substances, that have similar properties
to urea and also act as humectants to increase the
water content of the stratum corneum (CSC), in-
clude glycerin, sorbitol, alpha hydroxy acids, and
some complex sugars.
As urea is a fairly simple molecule and highly
water-soluble, it is easily incorporated into derma-
tological preparations. However, urea and urea so-
lutions are relatively unstable and on standing,
heating, or exposure to acids or alkalis, urea is hy-
drolysed to ammonia and carbon dioxide. This in-
stability in water-based formulations led to
problems in the development of the original urea
creams, producing an unpleasant smell of ammo-
nia, necessitating refrigeration and shortening
shelf-lives.3Decomposition is solved by adding
stabilisers, such as sodium lactate, lactic acid, lac-
tones or the use of a water/propylene glycol mix
as a solvent. Numerous patents have been filed
specifically related to the stabilisation of urea in
dermatological and cosmetic products. However,
it has been shown that the addition of excipients
can influence the moisturising efficacy of urea
when Couteau et al compared different formula-
tions of an emollient with the same concentration
of urea (5%).4Similarly, the keratolytic effects of
urea that occur with concentrations greater than
10% are enhanced in the presence of highly occlu-
sive agents, such as petrolatum.
Action of urea on the skin
In normal health, the SC contains approximately
10–20% water and, should the water content fall
below 10%, then the clinical signs of xerosis be-
come obvious. This water is divided between the
relatively constant amount associated with the hy-
drophilic parts of the intercellular lipids and keratin
fibres in the corneocytes, and that bound to hygro-
scopic substances found within the skin, which
varies according to the relative humidity of the en-
vironment.5The hygroscopic substances found
within the corneocytes are collectively termed
13
DERMATOLOGY IN PRACTICE 2012; Vol 18 No 3 Therapeutics
www.dermatologyinpractice.co.uk
Urea creams in skin
conditions: composition
and outcomes
NMF, and the increase in intracellular water they
promote helps the corneocytes to retain their
turgidity and shape, thus maintaining a coherent
barrier. The presence of NMF tends to increase the
water content of the SC whenever the ambient rel-
ative humidity exceeds 40–50%.6NMF is princi-
pally derived from the breakdown of the protein
filaggrin, and consists of a complex mixture of free
amino acids, amino acid derivatives and salts, with
urea being a major factor – constituting about 7%
(see Table 1).5Thus, urea is able to attract water
from two sources; it enhances water absorption
from the dermis into the epidermis and, in humid
conditions, it can also help to absorb water from
the external environment.
Urea is traditionally used in dermatology as part
of the management of xerotic conditions such as
atopic eczema, ichthyosis, contact dermatitis, pso-
riasis and as an antipruritic. The main sources of
urea in the epidermis are from sweat and the de-
composition of arginine by arginase during the
keratinisation process.7The unique properties of
urea in the skin are mainly due to its ability to
break the hydrogen bonds in protein chains and
alter their configuration, particularly keratin. At
high concentrations (over 10%), it exerts a pro-
nounced keratolytic effect, and has been shown
to enhance cutaneous permeability to some sub-
stances (such as, steroids), thereby showing a syn-
ergistic effect with other topical agents. At
concentrations ≤10%, it favours the bonding of
water to the protein chains in the SC, increasing
hydration.3The increase in SC hydration and
restoration of the skin barrier reduces the itching
sensation (correct?) – making low concentration
(5%) urea creams a useful agent in pruritus.
Dermatological preparations
A number of topical urea preparations are avail-
able in the UK. Most are available over the counter
(see Table 2).8 For general emollient uses, the urea
content ranges from 5 to 10%, although prepara-
tions with a urea concentration ranging from 5 to
22% are marketed elsewhere, and are potentially
available via the internet. A lower concentration
is generally used on the face and body, whereas a
higher concentration may be applied to thickened
skin areas or where a quicker response is desired.
An improvement in skin hydration, as measured
by corneometry, has been reported in as little as
four hours following application of one dose of a
10% urea-containing emollient, and can last for
over six hours. Similar results were obtained with
a 5% cream, although the hydrating effects started
to decrease after four hours.9 In podiatry, 25% urea
creams are used to treat and remove dry skin, par-
ticularly on the heels and feet, and urea-contain-
ing products have proved useful in the treatment
of anhidrosis in the diabetic foot.10 Urea solutions
of 40% can be used to avulse toenails, or enhance
the penetration of antifungal agents into the nail.
Numerous clinical evaluations of urea-contain-
ing products across a range of dermatological dis-
eases have been performed over the years and,
although now rather dated, most have demon-
strated a significant improvement in skin condi-
tion following the application of urea across a
range of concentrations.3They have also been
shown to accelerate barrier repair following surfac-
tant-induced irritation and protect against further
irritation with repeated exposure.11 A more recent
application of urea-based creams has been in the
prevention and management of the skin reaction
14
Therapeutics DERMATOLGY IN PRACTICE 2012; Vol 18 No 3
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Table 1. Chemical composition of NMF
found in the epidermis (Adapted from
Verdier-Sévrain
et al
,2007).5
Substance Composition (%)
Free amino acids 12
Pyrrolidone carboxylic acid (PCA) 12
Lactate 12
Sugars 8.5
Urea 7
Chloride 6
Sodium 5
Potassium 4
Ammonia, uric acid, glucosamine, creatine 1.5
Calcium 1.5
Magnesium 1.5
Phosphate 0.5
Citrate, formate 0.5
Table 2. Urea-containing emollients listed in the
British
National Formulary
(September 2012)8
Product Manufacturer Form Urea content (%) Net price
(£)/100g
Aquadrate® Alliance Cream 10 4.37
Balneum® Almirall Cream 5 4.60
Calmurid® Galderma Cream 10 5.70
Dermatonics Dermatonics Cream 25 4.75
Heel Balm®
E45® Itch Relief Cream Reckitt Benckiser Cream 5 3.47
Eucerin® Intensive Beiersdorf Cream 10 7.59
Hydromol® Intensive Alliance Cream 10 4.37
Nutraplus® Galderma Cream 10 4.37
Alphaderm® Alliance Cream 10 plus 1 hydrocortisone 7.03
Calmurid HC® Galderma Cream 10 plus 1 hydrocortisone 8.76
Hydromol® Alliance Cream 10 plus 1 hydrocortisone 7.03
HC Intensive
seen in oncology patients being treated with mul-
tikinase inhibitors (sorafenib and sunitinib). In
this indication, urea cream prophylactic use
proved effective in trials in preventing or delaying
the onset of skin problems.12 Urea creams have
been extensively studied in the management of
atopic eczema, and it is here that they have really
found their niche. Although the moisturising and
skin barrier restoring effects of urea are well docu-
mented the correlation between efficacy and con-
centration has not been extensively studied. More
recent attempts to explore this have compared low
urea concentrations (3% and 5%) with a higher
concentration (10%). Sant'Anna Addor et al9con-
firmed a significant increase in moisturisation with
both a 5% and 10% urea formulation, although
the 10% concentration achieved a faster response
and lasted longer. Unfortunately, the 10% formu-
lation was associated with increased reports of ir-
ritation. A similar study by Bissonnette et al13 in
atopic eczema, showed a significant improvement
in skin condition following application of both
concentrations of urea, as measured using the
Scoring Atopic Dermatitis tool.14 However, they
also reported that some volunteers experienced ir-
ritation with the 10% urea concentration, and
that, overall, volunteers expressed a preference for
the 5% formulation.
Generally, urea-containing emollients are well
suited to the care of large areas of skin, even over
long periods. It is recommended that such emol-
lients are used once or twice a day as an add-on
therapy to the regular emollient regimen, which
should form part of ‘complete emollient therapy’
– that is, using a combination of cream, ointment,
bath oil and emollient soap substitute.15
Adverse effects of urea creams
Urea creams are generally regarded as having few
adverse effects, and there are no reports of sensiti-
sation to urea, despite its widespread use. Indeed,
a recent toxicology report by the US Environmen-
tal Protection Agency confirms it as having a good
safety profile.16 Some patients have reported skin
irritation from urea preparations, such as redness,
stinging, and a burning sensation, as already men-
tioned. In most cases, these sensations are transient
and relate to urea concentration, and were more of
a problem with the early formulations of urea-con-
taining emollients.17 Newer formulations appear
to be well tolerated and suitable, even for sensitive
skin, with the standard concentration being 5%
urea. The application of any topical agent can
cause stinging, but this is not necessarily sensitisa-
tion. However, the risk of sensitisation to excipi-
ents still exists, as with any emollient. Although
this may occur, in practice it is not a significant
problem. Fewer than 20% of patients report ad-
verse reactions to their emollient, compared with
more than 55% of those using aqueous cream.18
Summary
Urea has a long history in the treatment of dry skin
conditions, and has proved to be a safe, reliable
agent. Urea-containing creams provide a useful
adjuvant emollient in the treatment of atopic
eczema, ichthyosis, psoriasis and the diabetic foot.
At low concentrations, urea is able to change the
structure of proteins, particularly keratin, in the
SC, increasing water-binding capacity and hydra-
tion, while at high concentrations it exhibits a
proteolytic action, dissolving keratin. Overall,
urea creams are also able to affect epidermal lipid
synthesis and promote skin barrier repair ■
Declaration of interest
The author declares that there is no conflict of interest in the writing of this paper.
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DERMATOLOGY IN PRACTICE 2012; Vol 18 No 3 Therapeutics
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■Urea-containing formulations are a useful adjuvant emollient
in dry skin conditions and pruritis.
■Urea creams have been shown to have a significant positive
effect on skin hydration and barrier function.
■A range of concentrations of urea creams is available, although
a low-concentration 5% preparation is recommended for
general use.
■Although suitable for sensitive skin, application of urea
creams can cause transient stinging or burning.
Key points
