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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. 115 810/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 117 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. 118 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