Download Biological functions and therapeutic properties of urea

J Appl Cosmetol 15, 115-123 (October-December 1997)
BIOLOGICAL FUNCTIONS ANO THERAPEUTIC
PROPERTIES OF UREA
W, Raab*
·Allergy Clinic 'lnnere Stadt' in Vienna, Austria
Received: October 25, 7995
Key words: Urea, Dry skin, Atopy, Glucocorticoid, Moisturizer,
Synopsis
Although urea is know for about 50 years, its use as a topica! drug or as an adjunct is obtaining
more and more attention in topica! dermatotherapy, Urea is absolutely non-toxic, undesirable actions occur only, if skin state and concentration of urea are on a disbalance. Urea proved to be a
most valuable substance for restoring hydration in dry skin and in eczemas due to skin dryness. Therefore, urea ranks among the standards in atopy, for the treatment of eczema as well as for the interval care.
Riassunto
Sebbene si conosca l'urea già da circa 50 anni, il suo uso come farmaco o cosmetico topico sta ottenendo sempre più attenzione nella dermoterapia topica.
L'urea è assolutamente atossica e si possono verificare effetti indesiderati solo nel caso in cui le
condizioni della pelle e la concentrazione di urea siano sbilanciate.
L'urea ha provato di essere una sostanza di grande valore per il ripristino dell'idratazione nella cute
secca e negli eczemi causati dalla cute secca. L'urea si colloca quindi tra le scelte standard nei casi
di atopia, per il trattamento degli eczema e per le terapie di intervallo.
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810/og1cal funct1ons and therapeutic propert1es of urea
INTRODUCTION
Urea (carbamide), the diamide of carbonic acid.
is a naturally occ uring degradation product of
various prote ins in man. Up to 30 g were produced dail y. Urca is found in ali organs and body
liquids. On thc skin s urface, urea is an important component of the natural moisturi zing factor containcd in the hydrolipid e mu lsion.
About 50 years back, urea was reccommended
for the top ica! treatm e nt of hand eczema but
onl y 30 years back. the first experimental data
were collected on its biochemical and pharmacolog ical acti vi ti es. The moi sturiz ing capacity
of urea in the s tratum corneum, especia lly in xerotic states, was discovered. In 1988, a symposium was he ld in Salzburg, Austria, the proceedings of which contain all the information available on the various acti ons of urea in dermatology and cosmetol ogy ( 1). The more recent pubblications are compi led in a rev iew article published 1993 (2).
Today, urea belongs to the standard s ubstances
used in dermatolog ica! therapy and skin care.
TOXICITY
Urea lacks any systemic tox ic ity. Urea formerly
was used as a diurctic drug; doses up to I .O g/kg
bodyweight were given intravenously, without
any undesirable action.
Therefore, fo ll owing absorption from exte rnal
pre paration s, no tox ic effects o f urea can be
found.
T he tolerance of urea de pends on the state of the
skin and on the concen tration of urea. The vehi cle applied may influence the tolerance, too. On
health y s kin , urea may be used in concentra tion s up to 20% . Most products, however, contain 5- 10% of urea, onl y, as iffitating effects on
slightl y da maged s kin s hould be avoided. S uch
e ffec ts might develop as a co nsequence of
osmotic act ivity.
116
BIOCHEMICAL FUNCTIONS
OF UREA ON THE SKIN
Urea is an important component of the natural
mo is turi z ing factor of the stratum corne um.
Water is bound by a n inc lusion in the c rysta l
s tru ct ure o f urea and o nly s lowly liberate d.
Urea s tems from the sweat a nd from the process o f keratinization. The natural moi s turi z ing fac to r co ns is ts of va ri ous ions (24%),
py rrolidone carbo xy lic acid ( 12%). va riou s
o the r ca rb oxy l ic ac id s (50%), am ines and
am ides ( 17%) and urea (7%). One s hou ld not
undcrsti mate the amount of natural mo is turi z in g fac to rs in the s tratum corneu m w ic h
make up abou t 25% of the d ry weig ht of the
total horny layer.
S tratum co rn e um of health y sk in co ntain s
about 40 M urea per lo M amino acids w hich
co rrespo nd s to about 28 µ g/2.5 c m2 (2). In
dry sk in , urea conte nt is signi ficant ly lowe r
(50% in some ins tances, only). C lin ically normai s kin of a topic individuals cont a ins o nl y
30% urea compared to normai va lues. In c li ni c all y d iseased s kin (a topi c eczema), urca
co nte ni is lowered to 20% of no rm a i va lu es
(Fig. 1, 2).
From these data the co nc lu sion may be reached tha t urea is one of the m ost im portant
components of the natural moi sturizing factor
of human sk in.
MOISTURIZING ACTIVITY OF
UREA
Urea exerts a wide ra nges of pharmacological
acti vities when applied on the skin:
- moisturi z ing acti vity,
- desquamating actio n (lysis of cementing subs tance),
- an timicrobial action (uptake of wate r in terferes with the growth requirements of microorganisms),
WRaab
U RF. \ IN HUMA'I SKI:\
µg/ 2.5 cm.!
30
29.8
lo~d pm cm 2
27.9
25A
20
16.1
13.7
12.3
10
Tot:.tl
Fcmalc'
10-'
Normai SkinO
Fig. I
UREA IN ll U\l AN SKIN, R EI.ATEO TO AGF. A'> D DRYNESS
25
µg/2.5 cm'
20
15
IO
101
IOOOmin
··-----··
16 - 20 a
lleallhJ Sk in
0
.11 - 40 a
21 - 30"
Skin of Alopic l'cr~ons
A•-----.t.a
0
Atopic Ectcma
O
Fig. 2
60
••t------i••
1orr urca in \\ ater-i n-oil emulsion
"•1ter-in -oil emulsion <ilone
trilialcd "ater alone
Fig. 4: The influence of ureo on the water binding copocity of humon strotum corneum (Wohlrob from 3).
%"/n \\:ll cr u ptnkc
50
40
30
20
IO
Il
20
34
Normai
o
23 38
P,orimic
nd: noi done
Pl:iin \\'::Her
O
4Mll glJcerol
O
o
nd 58
lchthyo1ic
5.1\111 urca
13
Fig. 3: Water uptoke of normai, psoriotic, ond ichfhyotic
strotum corneum following immersion in vorious solutions
(Swonbeck, from 3).
- "antiinfl amma to ry" acti o n (antipro li fe rat ive,
anti edcmatous, antipruritic).
- enzyme inh ibiting actio n (mostl y against proteases) and
- keratolyt ic act io n (true ke ratinolys is occurs
under the influence of urea in a concentration
o f 40%).
T he mos t impo rtant (and therapeuticall y most
w ide ly used) ac t ion of urea is its moist uri z in g capac it y. By imm e rs ing s t ra tu m co rne um fro m dry skin (psoriati c, ic hthyotic) in
S M ure a/ I, the uptake of water could be sig nifi cantly inc reased. In these experimen ts,
urea sho we d definite ly high e r a c tivity t han
g lyce ro l, a hum ectant whi c h is w ide ly used
in cosme ti c produc ts. In another se ries of e xpe rime nts, tritia ted wa te r was applie d o n the
s kin s ur face in th e fo rm of a wa te r-in -oi l
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81olog1col tunct1ons and theropeut1c propert1es of ureo
emulsion with 10% urea . The water retention , judged b y ho w long tritiated wa ter
could be detected and in which amount, was
s ig nificantly higher than in the controls with
the vehicle alone. (Fig.4).
The application of urea containing emuls ions
decreases skin roughness due to the mo isturizing action of urea; maybe, the desquamating
action of urea contributes to this effect. In
atopic skin, this decrease in roughness, judged by the repli ca method , was expec ia ll y
pronunced. (Fig. 5, 6).
A vast number of experiments has been conducted to ascertain the moisturizing property
of urea (figures 3, 4, 5, 6). Various methods
have been used to probe this effect: corneometry, measurement of conductivity, evaporimetry and profilometry. By electron microscopy,
a loosening of the Jayers within the stratum
corneum could be demonstrated, indicating a
moisturizing effect (2) . Cf. Fig. 7 , 8, 9.
In diseased skin , too, experimental investigations have been performed to demonstrate the
moisturizing (and antieczematous) action o f
urea. In the European Study (Barcelona, Hamburg, Vienna) a statistically significant increase in mo isture and a statisticall y significant
decrease in TEWL occu rred following a fo ur
week treatment of atopic eczema with a preparation containing I 0 % urea (4 ). Cf. Fig. I O.
% decrease of roughness parameters
30
20
IO
Placebo
Stan
Urca cream
Fig. 5: Decreose of skin roughness porometers RZ ond RA
60 min. otter the oppticotion of o silicone-contoining woter-in-oil emutsion with 5% ureo os compored to the vehicle without ureo. Meon volues of ten normai individuo/s
were given (Puschmonn from 3).
% dccrease or roughness parameters
30
20
KERATOLYTIC ANO
DESQUAMATING PROPERTIES
OF UREA
In concentrations up to 20%, urea exerts a concentration-depending desquamating action on
the stratum comeum. By this effect, skin penetration is facilitated. Cf. Fig. IO, 11.
In a 40% concentration, urea has been shown to
exert true keratinolytic properties. Nail plates in
fungal diseases may thus be dissolved.
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10
Stan
I day
5 day
8 day
Fig. 6: Decreose of skin roughness porometers RZ ond RA
following the use of o silicone-contoining woter-in-oil
emulsion with 5% ureo. Meon volues of 9 o topic individuols were given (Puschmonn, from 3).
W Roob
140
,.--~~~--t•t-~~~-·~~~---i·---------.
130
''
120
..:':
''
''
:,,'
'
'' '
110
'
''
'
'
''
"
'
.......... .. .. ...... ..
-·------ --------·------------..... -------------·------------··:&
60
90
75
105
120
time/min
••1----~•• Oil-in-water emulsion with 5% urea
•a-----..,••
Oil-in·water emu lsion without 5% urea
••1----~•• Untreated control site
Fig. 7: Skin moisture ofter opp/icotion of o silicone-contoining oil-in-woter emulsion with ond without 5% ureo. meosurement by determinotion of the dielectric constont. Meon volues of 35 heolthy individuols were given. (Puschmonn,
from 3).
140
130
120
110
100
90
IO
Pre-treatment phase
.Àr.ol~----•• Placebo
15
Treatment phase
••1-----••
25
Post-treatment phase
days
5 % Urea
Fig. 8: Skin moisture following the opp/icotion of o silicone-contoining oil-in-woter emulsion with ond without 5% ureo
tor two weeks. Meon volues of 6 heolthy individuo/s were given (Puschmonn, from 3).
119
Biologica! functions and therapeutic properties of urea
Fig. 9: Hyperkerototic skin in chronic eczema before ond offer the opplicotion of ureo 10% + solicylic acid 5% tor 10 days.
REM materio/ from biopsies, mognificotion 2.5(),J x.
From 2, with the permission of the outors Plugshoupt ond FrCih.
European Study
10% Urea in Chronic Eczema
Hydration
TEWL
+80%
69U(!)
+30%(!)
Start
4 wceks
Start
C oncomitant cli11ical ammelioration
Fig. 10
120
D
4 wceks
WRaab
ANTllNFLAMMATORY
ACTIONS OF UREA
USES OF UREA
IN DERMATOLOGY
An antiproliferative effect of urea has been demonstrated in states of accelerated cellular turnover (e.g. psoriasis vulgari s) but no atroph ogenic effect in norma i skin could be observed.
The antiedematous ac tion of urea is c onnected
with its diuretic acti vity. In states of lymphostasis, a dramatic response can be evoked by topic a! applications of I 0% urea.
The antipruritic acti vity of urea mainl y is due to
its moisturi zing capacity. On the other hand , a
directed influe nce of urea on those enzymatic
activ ities whi ch provoke itch could be de monstrated.
Urea alone
ANTIMICROBIAL ACTIVITY
OF UREA
By its strong wate r binding capac ity, urea inhibits the growth of mic roorganisms. Therefore,
urea may be regarded as a preservative-saving
substance.
Dry skin , old skin , photodamaged skin.
Atopic skin , (therapy and interval skin care).
Psoriasis vulgaris and other scaly derm atoses.
Ichth yosis and ichthyos iform skin c onditions,
hype rkeratoses, keratose s.
Onycholysis (40%!)
Urea in combinations
With glucocorticoids (hydrocortisone, halc inonid): atopic eczema, chroni c dry eczema, Psoriasis vulgaris, ali old, hype rkeratoti c, scaly, resistant inflammatory skin lesions. (5-1 0% urea,
O, 1- 1% steroid).
With anthralin ( 17% urea + 0,5-2% a nthral in):
Psoriasis v ulgaris, prolonged app licati ons or
short contact therapy.
M"ale score
Trnnsmissio n ( 1apc mcthod )
UREA COMBINED WITH
OTHER DRUGS
Via three mechanisms, urea increases the pharmacological acti vities of othe r simul taneously
applied drugs:
- v ia its moi sturizing ca pac ity (inc re ased absorption),
- via its desquamating properties (increased absorption) and
- vi a the formation of hydrophilic adducts (incre ased re lease from the pre paration and in creased uptake by the skin).
Lastly, synergistic effects much be mentioned
between urea and some topically applied drugs
with antiinflammatory or ke ratolyti c acti on. An
e xample is shown in Fig.9.
80
2.5
60
~o
1.5
20
0.5
O
C
\'
J'k U IOL
C: Control
V: Vehicle
Fig. 11 - Desquamating action o f urea
12 1
81olog1col funct1ons ond theropeut1c propert1es of ureo
With polydocanol (5% urea + 3% polydocanol): atopic eczema, treatment and interval skin
care.
With tretinoin (10% urea + 0,03% tretinoin):
non-inflammatory, non-erythrodermic ichthyosis.
With salicylic acid (10% urea + 5% salicylic
acid): stubborn hyperkeratosis, corns, eventually warts.
With bifonazole (40% urea+ 1% bifonazole):
onychomycosis.
Among the combinations of urea with other
drugs, the preparations containing urea and a
glucocorticoid have found widest application.
Urea increases the biovailability of the steroid
("hydrocortisone develops into triamcinolone")
but does not alter the incidence and severeness
of undesirable effects.
122
W Raab
REFERENCES
1. Raab, W. (Editor) (1989), Harnstoff in der Dermatologie, Hautarzt 40, Suppi. IX.
2. Raab, W. (1993), Harnstoff in der Dermatologie, TW Dermatologie 23: 257-269.
3. Raab, W. (1990), Use of urea in cosmetology, Cosmet. Toiletr. 1054: 97-102.
4. Vilaplana, J. et al. (1994), Jnternationale, multizentrische Prilfung der Wirksamkeit und Vertraglichkeit der externen Therapie chronischer Ekzeme mit ei nem 10% igen Harnstoffpraparat,
Akt. Dermat. 20: 227-231.
Author Address:
Univ. Prof Dr. W. Raab
Walfischgasse 3
A - 1010 Vienna, Austria
123