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J. Appl. Cosmetol. 9.

1-7 (Jonuory - Morch 1991)

USE ANO EFFICACY OF UREA


IN DERMATOLOGICAL PREPARATIONS
W. Wohlrab
Department of Dermatology, Martin-Luther-University, PSF 302-D-4010 Halle

Received: October 26, 7989; Presented at at 3rd lnternational Congress on Cosmetic Der-
matology "Progress in Cosmetic Dermatology" - 27 - 29th October 1989. Wien

Key words: Urea: Penetration: Water-binding capacity: Topica/ therapy.

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Synopsis
The bas is of the effects of urea on the human skin is its penetration kinetics into different skin layers.
A strong vehicle dependence can be estabilished. Therefore wide differences are found in the dura-
tion and intensity of increased water-binding capacity after application of different urea containing
emulsions. For therapy to increase the hydration and water-binding capacity in the homy layer of dis-
eased skin preparations with IO% urea are more suitable than those containing 2% or 5% urea. For
cosmetic preparations, the hi gher concentrations of urea are inappropriate, lower ones are sufficient.
By altering the fu nctional structure of the homy layer and increasing of drug liberation from oint-
ment bases, urea is one of the most effective penetration promoters. An increased penetration rate
of some corti costero ids, dithranol and other drugs in human skin. The resulting penetration has two
possible im plications for topica! therapy:
- an increased therapeutic effect for any given concentration of an active constituent
- the attainment of a g iven therapeutic effect with a reduced concentration of the active ingredient.

------------------Riassunto
G li effetti esplicati dall'urea sono connessi alla sua penetrazio ne attraverso i differenti strati
dell'epidermide e, quindi , direttamente dipendenti dal tipo di veicolo utilizzato. Per questi motivi
sono state riscontrate differenze nella durata e nella intensità della capacità del prodotto di legare
acqua in dipendenza del tipo di emulsione. Per incrementare l'idratazione cutanea e la capacità di
legare acqua della cute affetta da patolog ie si sono dimostrate più efficaci concentrazioni di urea del
10% rispetto a concentrazioni del 2 o del 5%. Per uso cosmetico sono più adatte e sufficienti
concentrazioni basse di urea.
L'urea può essere cons iderata una delle sostanze più atti ve nel promuovere la liberazione dei
farmaci dai veicoli e, quindi , il loro assorbimento. Facilita, perciò, l'attività dei corticosteroidi, del
ditranolo e di molti altri farmaci.
Queste sue caratteristiche ne consig liano l'uso terapeutico in due direzioni diverse:
-per incrementare l'effetto terapeutico di una data concentrazione di farmaci resi per questi motivi
ugualmente attivi a concentrazioni più basse.
Use and efficacy of urea in dermatologica/ preparations

The use of urea in topica! therapy and in cos- fondamenta! differences between w/o and o/w
metics has undergone a revival in recent years e mul s ions (7), and the s e y ie ld d ifferen t
(I , 3, 4, 11 and others). therapeutic effects.
Some reasons fo r this can be Jisted as follows: Urea penetrates the horny layer of huma n skin
more qu ickly from o/w e mul sions tha n fro m
1. By intensive basic research many properties w/o em ulsions (Fig. I). It should be noted that,
of urea have bee n d iscove red a nd precise ly at about 80%, the bulk of the urea whi ch has
defi ned. At the same time, the conditions for the penetrated is found in the upper horny layers.
the rape utic uti li zati on of these properties e.g.
problems of stabilization, have been delineated. dpm - cm·2
103 104 105
2. In topica! therapy inc reasing use is made of
5
pharmacok inetic information. The equa ! sig- 10
nificance of the properties of the active substan- 15
ces and of the veh icle, the condition of the ski n, (/) 20 30 min
-
Q.
a nd their mutua i interactions, are not o n ly ·;::
( /)
recognized but also increasingly util ized a bas ic
far overall therapeutic activity. Pha rmaceutical
o
(/)
5
10
I-
formu lations are selected and optimized in such Q) 15
.o 300 min
20 '
a way that a desirable concentration/time profile E '
::i
is achieved for the substance in the appropriate z 5
skin layer. 10
15
1000 min
20
3. The properties of urea itself make it ideai for
"-~~~~~~~~~~~~~~ ffGUREl
external use, as it is a natural moisturizer and is
Oistribution of urea in lhe horny /ayer of human skin affer
well to lerated. As a physiological substance it is external applicalion of 10% urea conlaining preparations.
the end product of protein metabolis m. In •- - -• w/o-emulsion (Ungi. Alcohol. Lanae aquosum.
human skin its concentration is I% and it is ex- Pharmacopoea GDR)
creted in sweat in considerable quantities. After o - o o/w-emulsion (Ungi. emulsiticans aquosum. Phar-
macopoea GDR)
ex ternal or sys temic adm inistration it is not
metabolized. No side effects, in particular non The s teep concentration gradient is la rgely
cases of sensitization or photosensitization, have maintained when o/w emu lsions a re used, even
so far been repo1ted unde r therape utic conditions. after as long as I000 min.
In contrast, the penetration of urea from w/o
em ulsions is noticeably smaller after short ex-
Principles of the action of posure. The concentration gradient within the
urea on skin horny layer decreases so that after 1000 min ap-
proximately equa! urea concentrations can be
measured throughout the stratum corneum.
The pe netration kine tics of urea, i.e. how much Thi's resul ts in different urea concentrations in
urea, in relation to exposure time, pene trates the epidermis and dermi s (Fig. 2), which are ap-
into individuai skin laye rs after external ap- prec iably higher for w/o emulsions. Overall ,
p lication, are of d ec isive importance to the however, the penetration of the lower epidermis
achievement of its effects. In relation to the and dermis are sma ll in comparison with that of
vehicle, the penetration kinetics of urea show the horny Jayer, regardless of the emulsion used.

2
W Wohlrab

C/) dpm - cm- 2 These diffe re nces in the course of penetration


a.
-
·;::

o
C/)
103 104 105 and he nce in the concentration/ time profile of
urea in the indi viduai skin layer provide for dif-
C/)
.....
5
10 . ferent degrees of efficacy. Different emulsions
can be used according to whether the urea is to

r·-:?_..;/_____
o:.);!·
. -----
Q)
_o
E
15
20
,. Horny layer
act on the functional skin structure (e.g. hydra-
=> tion and water-binding capacity, keratolysis, in-
z
-E 160
200
------: Epidermis hibition of proliferation, alleviation of itching,
etc.) orto aid penetration by other products.
-
:i
e
400 t• •
·''·
I
Dermis
~
(f)

o
600
·t·· I
• I'
/o
What is the necessary
·I: . ,..
o I •
..e 800 I•
Penetration concentration of urea
a_
Q)
o 1000 ·1. time: 300 min in the vehicle?
' - - - - - - - - - - - - - - - - FIGURE 2 From the findings so far di scussed, it is clear
Distribution of ureo in humon skin ofter externol opplico- that the decisive factor in therapeutic activity is
tion of 10% ureo contoining preporotions.
not th e conce ntra tion of urea in the appli ed
• - - -• w/o-emu/sion (Ungt. Alcohol. Lonoe oquosum, ve hicle but rathe r the quantity of urea whi c h
Phormocopoeo GDR)
o - o o/w-emulsion (Ungt. emulsificons oquosum. Phor- penetrates into the indi viduai skin layers, i.e. the
mocopoeo GDR) concentration/ time profile achieved. It has be

Table I
CONCENTRATION OF UREA PENETRATING TO THE STRATUM CORNEUM
(SC) OF HUMAN SKIN IN RELATION TO THE CONCENTRATION OF UREA
IN THE VEHICLE (9)
Veh icle: W/0-emulsion (Ungt. Alcohol. Lanae aquosum AB-DDR)

Pene tration Pe riod Urea Conce ntration Urea concentration


(min) (%) applied (mm) in the se

30 2 29,9
5 103, 1
10 2 12,6
-------------------------------------------------------------------------------
300 2 48,3
5 145,7
10 449,9
------------------------------------------------------------------------------
1000 2 95,8
5 23 1,6
10 602,9

3
Use and efficacv of urea in dermatologica/ preparations

noted that, at around 80%, the bulk of the urea


wh ic h penetrates is situated in the outer horny
layers (Tab. 1). When vehicles containing 2% or
5% a re used the urea concentration necessary
"' 104
E
(.) t.. •
• W/O - emulsion + 10% urea
W/O - emulsion without urea

fo r normai human stratum corneum cannot be


reached. To increase the water-binding capacity
E
o..
"O 103
:~I~-·T-r-iti-at-e-
d wa-t-er_ _ __
in the horn y layer of di seased skin products
containing 10% of urea are more suitable from
th e th erapeuti c point of v iew (9) . High urea
1~~--~--------~-
concentrations (over 2-3%) a re not, however 30 300 1000
suitable for cosmetic use without medicai super-
'----------------FIGURE 3
vision.
lnfluence of ureo on the woter-binding copocity of the
humon horny loyer (10).
Vehicle: w/o-emulsion (Ungt. Alcohol. Lonoe oquosum.
lnfluence of the vehicle on Phormocopoeo GDR) lobeled with tritioted water.

the water-binding capacity ing capacity of th e stratum corn eu m (5, 6).


due to urea. When the urea is used in o/w emulsions or lo-
tions, a hig h degree of hydration is q ui ck ly
Corresponding to the described differences in reac hed (i mm ediate effec t), but th is fairly
penetration, depending on the vehicle and the quickly declines (Fig. 3).
urea concentrations used , the re are also varia- In contrast, with w/o emulsions there is a more
tions in the effectiveness of the urea-containing marke t and longer-Iasting inc rease in water-
basic skin products to increase the water-bind- binding capacity.

Table Il
WATER-BINDING CAPACITY OF HUMAN HORNY LAYER AFTER APPLICATION
OF UREA CONTAINING PREPARATIONS (10).
Application: I Omg of urea containing preparati on labeled
with 5 µCi tritiated water at 4 cm2 skin surface.

preparation urea concentra tion Horny Iayer dpm/cm2 after


(%) 30 300 1000 min

Basodexan (R) Ointment 10 5422 ± 521 2478 ± 205 902±5 1


Basodexan (R) Cremé IO 8 104±514 1386 ± 169 472 ± 34
Basodexan (R) Soft 10 10606 ± 678 542 ± 98 185 ± 22
Carbamid-Cremé(R) 12 8666 ± 426 12 14 ± 100 475 ± 28
Elacutan-F(R) IO 3968 ± 275 994 ± 63 678 ±74
Elacutan-W(R) IO 7 185±376 426± 72 183 ± 19
Excipial(R)-U-Lotio 2 6804 ± 248 388 ± 26 126 ± 24
HTH(R) IO 12011±528 568 ± 59 223 ± 63

4
W Wohlrab

If o ne ex am in es these bas ic mec hani sm in above ali with glucocorticoids (e.g. Hydrodexan
re lati on to the various comme rciai urea-contain- (R), Hycozon (R ), A lphade rm (R), etc .) an d
ing bas ic skin products, la rge differences are dithranol (e.g. Psoradexan (R)), with impressive
found in the action o n th e w at e r-bindin g evide nce from nume rous clinica! studies.
capacity of the stratum corneum (Tab. 2). These With respect to hydrocorti sone, it has been shown
di ffe rences a re evide ntl y not primarily depen- that when low concentrati ons of urea are used
de nt on the urea concentration used but on the enhancement of pe netration is barely appare nt,
vehic le ( I 0) . whereas with a urea content of between 5% and
I 0% there is a partic ular increase (Fig. 5).

lnfluence of urea on the HC (µmol)

penetration of other products 90

Urea promotes the release of various drugs from 70


their base, a nd in additio n it is a very effecti ve
promote r of pene tration o f vari ous active sub-
sta nces ( I , 3, 4, 11 ). Essenti a ll y, the promoti on 50
of drug penetration by urea can be ex plo ited in
two ways (8) : 30
I . to improve therapeut ic efficacy at the same
conce nt rati on of acti ve substance and
2. to achie ve the same the rape utic efficacy with 10
a conside rabl y lower conce ntration (Fig. 4).
The optimization of the therapeuti c efficacy of o 2 5 7 10 1s Urea(%)
oth e r dru gs by urea has bee n de mons trated ' - - - - - - - - - - - - - - - - - FIGURE 5
Dependence of hydrocortisone penetrotion into epider-
mis of humon skin on ureo concentrotion ond used
vehicle.
Penetrotion time: 300 min.
Hydrocortisone concentro tion: 1%
• - - -• w/o-emulsion (Ungt. Alcohol. Lonoe oquosum,
Phormocopoeo GDR)
o o o/ w-emulsion (Ungt. emulsificons oquosum, Phor-
mocopoeio GDR)

Whe n the urea concentrations are rai sed further,


e no fu rther decisive c hanges are de tectable. In
~
Cl)
800 this connection o/w emulsions and w/o e mu l-
o
..e
1000 sions basically act in the same direction, but w/o
a. e mulsions have a conside rab ly greate r pene-
a.i tration-promoting effect.
o Penetration period: 300 min
- 1% HC On the bas is of these data hydrocortisone, the
~-~ 1% HC + 10% Urea de te rmination of the penetration kinetics of the
- 0,5%HC + 10% Urea
~---------------FIGURE 4
g lucocorticoid and of the urea in each vehicle is
indispensable for mak ing use of the penetration-
Distribution of hyd rocortisone (HC) in humo n skin ofter
externo l opplicotion (8). promoting acti on of urea in the development of

5
Use and efficocy ot ureo in dermatologica/ preporotions

glucocortic oids fo r external use (8). The urea beco m e s i d enti ca! in efficacy wi th a I %
and g lucocorticoid conce ntrations can then be hydrocortisone produc t in whi c h the re is no
optimi zed. urea.
Less attention has so far been paid to the pos- Viewing this subject as a whole, we still know
sibili ty of using the pene tra tion-promoting ac- too little about the pharn1 acological propertie s
tion of ure a to achie ve a particul ar therapeutic of urea fot ex te rna l use. Autom atic procedu res
efficacy with a considerably red uced quantity of in the a pplicatio n of urea in externa l therapy
g lucortic o id. One reason is very probab ly the and exam ination of th e prope rti es of urea in
w id e ly prac ti se d d il u t io n of pro pri e t a r y iso lation th erefo re promise little success a nd
glucocorticoid formulations. In 1984 Miiller (2) sho uld be avoided.
summari zed the reasons fo r this procedure and
its proble ms and risks in a ve ry inform at ive
review. T he examp le of hydrocortisone shows
ve ry c lea rly th a t a fte r red uc tio n to 0,5 % th e
qua ntity whi ch penetrates e.g. into the e pider-
mis ca n be reduced by 75-80 % (Tab. 3). In con-
trast, when vari ous qua ntities of urea are added,
a co nce ntr a t io n -de p e nd e nt p ro m o ti o n o f
pe netration is detectable, so that the form ulation

Table lii
INFLUENCE OF UREA ON THE PENETRATION OF REDUCED
HYDROCORTISONE CONCENTRATIONS INTO HUMAN SKIN (12).
Vehicle : W/0 -emulsion (Ungt. Alcohol. Lanae aquosum, Pharmacopea G DR)
HC = hydroco rti sone; u+ = Urea.

Preparati on pene trat ion time (min)


30 300

horn y layer (mmo l)


l ,0 % HC 13,9 16 , l
0,5% HC 2,9 3,9
0,5% HC + 5% u + 8,5 10,0
0 ,5% HC + 10% u+ 12 ,5 13,8
0 ,5% HC + 15% u+ 12,8 14,0
----------------------------------------------------------- --------------------
epidermis (µm ol)
l ,0% HC 12,8 23,2
0,5 % HC 2, 1 5,7
0,5%HC + 5% u+ 6,8 11 ,0
0,5% HC + 10% u+ 10,2 19 ,9
0,5% HC + 15% u+ l l ,9 20,7

6
W Wohlrob

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