ACTIVITY OF UREA

Being a by-product of proteins and other nitrogen compounds metabolism, urea naturally occurs in
human organisms. It is mainly produced in the liver and excreted with urine and sweat. Urea plays
an important role in a water soluble fraction of the epidermal horny layer, where it is present in
intercellular spaces and surrounds keratin fibers in keratinocytes.

A large part of epidermal urea derives from sweat. Some amounts are liberated during keratinization
process (in the course of protein restructuring), while trace amounts penetrate the epidermis
together with lymph . Epidermal concentration of urea fluctuates in different parts of the body and it
depends on the gender, age, climatic conditions, ambient temperature and yearly seasons. Its content
increases with physical strain and due to a protein-rich diet . Urea is an important component of the
Natural Moisturizing Factor (NMF) that is responsible for appropriate moisturization of the stratum
corneum. It is assumed that urea amounts to 1% of the epidermis mass (7% w/w of the NMF) and it
is the main constituent responsible for binding water in the stratum corneum. Clinical symptoms of
skin dryness are usually accompanied by a reduced urea content in the epidermis
Urea has been used for a long time in cosmetology and pharmacy due to its well proven activity
related to moisturizing, keratolytic, proteolytic, antiproliferative, antipruritic and disinfecting
properties. It also helps maintain therapeutic activity of other pharmaceutical preparations . Physical
and chemical properties of urea From the chemical point of view, urea (carbamide) is a diamide of
carbonic acid. It is a white, colourless and odourless compound with molecular weight of 60,6 and
the melting point of 132.7°C. At room temperature, it is in the form of crystalline powder, soluble in
water and ethanol, but insoluble in lipids . When dissolved in water, its 10% solution has the pH of
7.2. Urea undergoes hydrolysis in aqueous solutions as well as in emulsions to form ammonia and
carbon dioxide as the end-products. Elevated temperatures accelerate this reaction. Hydrolysis
causes some changes in the pH of urea solutions and destabilizes emulsions. e cosmetics industry

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brings down the pH value by adding lactic acid, salicylic acid or 2-aminoethanesulphonic acid
(frequently referred to as taurine) to consumer products. ere are also known more stable urea

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derivatives. One of them is hydroxyethyl urea (INCI: Hydroxyethyl Urea) . It is quite easy to
introduce urea into cosmetic powders and emulsions as well as to creams and ointments that contain
water, paraffin and fatty acids. erefore, there is a variety of cosmetic and pharmaceutical

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formulations having this compound in the composition

NMF - the natural moisturizing factor e NMF is an intracellular component of the stratum

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corneum that secures adequate moisturization of the epidermis. It is a complex mixture containing
hydrophilic constituents of low molecular weight such as amino acids, pyrrolidone carboxylic acid
(PCA), urea, lactates, creatinine, glucosamine, and ammonia as well as sodium, potassium, calcium,
magnesium, chloride and other ions. Similarly to the majority of NMF constituents, urea is
produced from filaggrin, a basic protein formed in the epidermal stratum granulosum. Filaggrin has
the molecular weight of about 37 kD and it is rich in histidine. Its key function consists in binding
keratin fibres. Profilaggrin, the main component of keratohyalin granules, is the filaggrin precursor.
It is a protein of molecular weight above 400 kD, composed of 10 – 12 filaggrin monomers. When
cells migrate to the horny layer, profilaggrin undergoes decomposition, initially to filaggrin
oligomers undergoing further disintegration to filaggrin monomers e problem of skin dryness

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Properly functioning skin acts as a physiologic barrier that separats a living organism from
surrounding environment and exerts its influence on maintaining homeostasis of internal organs.

ese functions require adequate skin hydration and depend on the actual state of the outer hydro-

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lipid mantle [5]. Water plays an important role in the skin, since both intracellular and intercellular
biochemical processes take place in aqueous environment [18]. Moreover, it is indispensable to
fibrous proteins structure and functioning, enzyme activity, keratinocyte differentiation as well as
epidermis exfoliation and regeneration. About 50 – 70% of water is stored in the dermis and
approximately 10 – 30% is found in the epidermis. e epidermal stratum corneum retains 10% of

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water. Such a gradient exerts the influence on important functions of corneocytes (e.g. filaggrin
proteolysis) and secretion of lipids present in stratum corneum. On the other hand, it constrains
migration of water to the skin surface by means of a natural process, known as Transepidermal
Water Loss (TEWL). TEWL is a principal parameter that is used to evaluate the epidermal barrier in
a non-invasive way and with relatively high precision. e term “skin dryness” refers to skin

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pathology manifested by excessive exfoliation of the epidermis, sensation of skin roughness as well
as cracking, redness, burning/stinging and itching. e dry skin is particularly suscep- tible to

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influence of physical stimuli (e.g. wind, frost, UV radiation), chemical substances (water,
detergents, preservatives, colorants, fragrances) and biological agents (microorganisms). Skin
dryness is o en accompanied by intolerance of commonly occurring factors. Such a state is known

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as skin hypersensitivity. e dry skin gives frequently rise to mechanical injuries (as a result of

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scratching) leading to secondary bacterial infections. Properly functioning skin acts as a physiologic
barrier that separates a living organism from surrounding environment and exerts its influence on
maintaining homeostasis of internal organs. ese functions require adequate skin hydration and

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depend on the actual state of the outer hydro-lipid mantle [5]. Water plays an important role in the
skin, since both intracellular and intercellular biochemical processes take place in aqueous
environment [18]. Moreover, it is indispensable to fibrous proteins structure and functioning,
enzyme activity, keratinocyte differentiation as well as epidermis exfoliation and regeneration [5,
6]. On one hand, skin dryness could be predominantly related to restricted degradation of
corneodesmosomes, leading to their retention in the outer layer of the stratum corneum. On the
other hand however, excessive loss of water usually results from impairment of one or both
components responsible for epidermal barrier parameters, i.e. NMF and lipid coating. In fact, there
is a number of factors contributing to skin dryness. e y have been classified as intraneous and

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extraneous causes giving rise to above mentioned skin disorders. Intraneous ones encompasses the
following: a) genetic defects leading to disordered keratinization and abnormally functioning
epidermis (atopic dermatitis, psoriasis, ichthyosis), b) disturbed secretion of sweat and sebum (dry
dandruff), c) some diseases (diabetes, hypothyreosis, some tumors), d) body dehydration (chronic
diarrhea, vomiting, taking diuretic pharmaceuticals), e) endogenous skin ageing. A group of
exogenous causes includes the following factors: a) climatic factors (extremely low or high ambient
temperature, wind, UV radiation), b) environmental and occupational factors (air conditioning,
exposure to toxic or allergenic substances), c) skin care treatments (taking a hot bath, the use of
highly degreasing cleansing products, application of steroids, tars and retinoids), d) vitamin
deficiency (the vitamin A in particular). e most efficient way to treat skin dryness is the use of

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traditional moisturizing preparations (containing occlusive agents or humectants). Modern methods
are based on supplementation of barrier lipids in the form of direct application or increased
intraneous lipogenesis Dry skin pathogenesis in selected dermatoses ATOPIC DERMATITIS (AD)

is disease is manifested by different intensity of skin dryness and sensitivity. It is believed that

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contributing factors include the deficiency of free fatty acids (predominantly gamma-linolenic acid),
abnormal expression of sphingomyelinase and some disturbances in epidermal lipid metabolism.

ese consequently lower the content of ceramides in the horny layer (mainly the ceramide 1 and

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ceramide 3) and give rise to epidermal barrier disorders – the barrier becomes more sensitive to
environmental factors.

PSORIASIS It is a chronic skin disease, manifesting itself by scaly eruption in the form of red-
brown or pinkish, flat patches covered with silvery or silver-grey scales. Characteristic patches of
different size have well-marked borders. Numerous studies on psoriasis have confirmed

considerably reduced content of free fatty acids in the scales, inhibited ceramide 1 production and
extensive loss of water through the epidermis. e skin dryness is additionally intensified by

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keratolytic, antimitotic and reductive pharmaceuticals as well as by phototherapy. ICHTHYOSIS It
is a genodermatosis (related to a genetic defect) giving rise to excessive and abnormal keratinization
of the epidermis. Patches of dry skin could be developed on the whole surface of the body.
Eventually, they only appear on lower or upper extremities. Several different types of ichthyosis
have common features – abnormal keratinization, callous cells in the epidermal stratum corneum,
and disordered biosynthesis of various epidermal lipids. Patients suffering from ichthyosis should
take a bath in salted water (with table salt added)

and apply exfoliating ointments that contain salicylic acid and urea. SKIN INFLAMMATION
Several conditions of skin inflammation are related to the presence of abnormal cells in the
epidermis, excessive production of inflammatory mediators and development of inflammation
within the skin. Due to hydrolipid coat impairment, accelerated water loss, and penetration of the
epidermis by irritating agents, the skin becomes dry and is prone to excessive keratinization.
FOLLICULAR KERATOSIS Heightened keratinization of hair follicle openings results in dry and
rough skin with callous papules having white, yellowish or reddish colour. It has been postulated
that vitamin A deficiency, lack of sunshine or hereditary predisposition are the main causes of
enhanced keratinization . Moisturizing activity of urea Applied topically, urea easily penetrates into
the epidermal stratum corneum increasing water content in the intercellular cement and keratinous
structures of corneocytes. Urea exerts its impact on filaggrin metabolism by breaking down
hydrogen bonds between protein filaments. It also decreases the ability of phospholipids and
cholesterol sulphate to form strong ionic bonds. erefore, urea enlarges hydrophobic spaces in the

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epidermal stratum corneum and makes intercellular connections to become loose Such effects lead
to improvement of lipid organization, tightening the epidermal barrier and a decrease in the
transepidermal water loss . Some studies have shown that biological activity of urea depends on
both its concentration and the type of a formulation vehicle. Researchers conducted several
experiments, making use of colorimetric methods and radioisotope testing (tritium-labeled water) as
well as by evaluating electric potential of the epidermis, and studying the ultrastructure of the
epidermal surface . If urea is present in O/W emulsions (with water as the external phase), it acts
quicker, but for a shorter time (up to tens of minutes). On the contrary, longer lasting activity (up to
several hours) has been observed in W/O emulsions . Nevertheless, the best penetrating results have
been obtained when urea was present in the water phase of multiple emulsions W/O/W.