ELSEVIER
`
`European Journal of Pharmaceutical Sciences, 5 (199’7) ! |9- 127
`
`PflARM CEUTIC 4L
`
`Nail penetration of the antifungal agent oxiconazole after repeated topical
`application in healthy volunteers, and the effect of acetytcystelne
`"~
`,~,’ ’
`
`E.J. van Hoogda!em*, W.E. van den Hoven, I.J. Terpstra, J. van Zijtveld, ].S.C. Verschoor,
`J.N. Visser
`t’amano~.¢chi Europe B.’~i, P.O. Box ]08. 2350 AC L~iderdorp. A;gt;~eHands
`
`Received 21 December 1995: accepted !9 November 199o
`
`Abstract
`
`Poor response of fungal nail i~fections to toplca! treatment with antimycotics is probably related to poor drug penetration into the
`infected nail. The aim of the present study was to evaluate the in :’ivo nail penetration of ~he antimycotJc oxiconazole from a 1% w/v
`lotion, and to evaluate the potential penetration enhancing properties of co-delivered acetylcysteme. Six healthy volunteers ~e~
`with 1% w/v oxiconazole lotions with or without acetylcysteine (15% w/v), according to a left-right study design. Treatment was
`performed twice daily for 6 weeks. Nail clippings were collected every 2 weeks over an 8-~eek period, until 2 weeks aft~:r the treatmev.t
`.qopped. Oxiconazole levels at various depths in sectioned nail clippings were measured by gas chromatographic analysis of cthanolic nail
`extracts. Topical treatment with oxiconazole nitrate without acetylcysteine resulted in maximum drug levels in the upper 0--50-!am layers
`varying between !20 and 1420 ng mg-~’, levels decreased downwards. Total uptake into the nail was tess tha~. 0.2% of the topical dose,
`indicating a substantial barrier function of the nail. Co-delivery with acetyleysteine stazistica!ty significantiy pro!onged ~he mean residence
`time of oxico.nazole in the upper 51-!00-~xm ring finger nail layers from 37-4.9 week~ to 4. I-6.4 weeks, implyi.ng increased retention or
`the drug in the nail. Mean (-S.D,) peak drag levels increased from 790+420 t,g ms-~ to 1570+-820 ng m[-~ in the upper 0-50-~xm
`layer, which suggested a variably enhancing effect of acetylcysteine on the extent of oxiconazole nail penetratior~ in the upper ~ai! layers.
`The effect of acety[cysteine was speculated to be related to increased bincting of oxiconazole to nail constituents.
`
`Keywords: Oxiconazole; Nai! penetration; Acetylcysteine; Volunteers
`
`1. Introduction
`
`Onychomycosis, infection of the nail by fungi,
`represents a significant therapeutic problem in derma-
`tology because of failure in establishing and main-
`taining effective drug levels at the infection site
`(Zaias, 1990). Recent advances in this therapeutic
`area were made by the development of the an-
`timycotic agents terbinafine and itraeonazole, both
`diffusing into the nail up to efficacious levels on
`repeated ora! dosing (Roseeuw and De Doncker,
`
`*Co:responding ’-mthor, Tel: +3t 71 4555[5; Fax: +31 71 455560.
`
`0928.0987/97/$32.00 © 1997 EJsevicr Science BJv’. All rights reser,,ed
`PI1 S()C) 28-0987 (97)0027 0-4
`
`1993a; Sch~ifer-Kortmg, 1993). With respect to topi-
`cal drug application, amorolfine nail lacquer has
`become available, showing rapid intraungual diffu-
`sion in vitro and reaching effective drug levels at the
`target site (Reine! and Ciarke, 1992; Pc!ok, 1993).
`The present study addresses the nail uptake of the
`imidazole antifungal agent oxiconazole after its topi-
`cal application, and it explores the feasibility of nail
`penetration enhancement.
`Oxiconazole is applied topically es nitrate in
`cream, solution or powder in the treatment of fungal
`infections of the skin. It is actix, e against various
`dermatomycetic and non-defmatomycetic fungi and
`yeasts, comparable to econazole and miconazole
`(Jegasothy and Pakes, !991). A once-.daily applica-
`
`ARGENTUM EX1019
`
`Page 1
`
`

`

`lion frequency maintained for 2-7 weeks is generally
`adequate in the treatmem of cutaneous infections with
`oxiconazole.
`Concerning penetration into nails aad skin, it has
`been shown that oxiconazole penetration behaviour is
`dependent on the formulation; tinctures gave better in
`vitro nail penetration than ointments, but in abdomen
`skin the reverse was observed (StiJt~gen and Bauer,
`1982). In vitro data demonstrate an outspoken barrier
`function of Lhe nail for oxiconazole from a 1%
`tincture; amounts penetrating into the ventral nail
`plar.e proved to be a 30-fold lower than those into the
`dorsal side (Sttittgen and Bauer, 1932). Sttittgen
`suggested that co-delivery of !0% of urea increased
`uptake of oxiconazole into the nail, possibly by
`influencing keratin structure in the nail (StiJt’,gen,
`1989) Following this suggestion, the mucolytic agent
`N-ace~ylcysteine (acetylcy~teine) was speculated to
`exer~ a penetration promoting action by disrupting
`keratin disulfide bonds.
`The aim of the pre~ent study was to evaluate the
`penetration of oxiconazole into the human nail after
`repeated administration and to assess ~he potential
`influence of acetylcysteine on this process.
`
`2. Experimental procedures
`
`2.1. Chemicafs
`
`Oxiconazole nitrate (!ot ’no. 71t017) was obtained
`from Hoffman-La Roche (Basle, Switzerland).
`Econazole nitrate was purchased from Sigma (St.
`Louis, USA). E~hanol (99.8%; p.a.) was supplied by
`Merck (Darmstadt, Germany). Helium (pure; E-70-
`H) and nitrogen gas (very pure; S-71-H) were
`purchased from Hook Loos (Amsterdam, Nether-
`lands). Aqueous solutions were prepared u~ing deion-
`ized water supplied by a Milli-Q water purification
`system (Millipore-Waters, Et~en-Leur, Netherlands).
`Otl~er reagents were of analytical grade, and these
`were used as received.
`
`2.2. Clinical experimenz
`
`The clinical study protocol was reviewed by an
`independent Medical Erfflical Committee and the
`study was started after obtaining their approva!. The
`study was conducted in accordance with the Princi-
`
`pies of the Declaration of HelsinkJ on biomedical
`researcta involving human subject~, updated in Hong
`Kong in 1989.
`Healthy volunteers, 2 males and 4 females, were
`randomly selected from a volumeer panel. During a
`treatment period of 6 weeks, volumeers applied the
`oxiconazole lotion without penetration enhance~ on
`nails of one hand, and the lotion with acetylcysteine
`on nails of the other hand. Application was done
`twice daily, after getting up and before going to bed,
`on the nails of middle finger and ring firtgen A 10-l.tl
`volume of solution was agplied per finger hall, using
`a fixed vo!ume pipette (Socorex Micropipene; Om-
`nilabo Nederland, Breda, Netherlands). Volunteers
`were instructed to wasl: the nails with tap water prior
`to each application, and to avoid ali exposure to
`water within a l-h period of applicathm. In addition
`they were instructed to avoid circumstances giving
`strong nail hydration, such as swvnming, sauna visits
`and dish washing with ungloved hands, duzing the
`entire 8-weeks study period. To avoid in vivo ox-
`iconazole degradation, subjects were requested not to
`expose themselves to excessive UV-light.
`Volunteers returned to the laboratory on weekly
`intervals, fur nail inspection, photograplny of the
`naiis, collection of nail clippings and to check
`protocol adherence. Prior to application, during and
`after the 6-week treatment period, viz. after 2, 4 and
`6 weeks’ treatment and after week 8, nail cuttings
`were collected. Cutting was done prior to the sub-
`sequent application, after’ thoroughly br~.tshing the
`nails under tap water,
`Nail clippings were collected indi~idually in poly-
`ethylene vials (Packard Instrument, Groningen,
`Netherlands), and they wete stored at room tempera-
`ture until analysis.
`
`2.3. Sample analysis
`
`Clippings were fixed, ~.entral side downwards, on a
`specimen holder using cyanoacrylate giue (Permacol
`302 FS contact cement; Permacol-Ede, Ede, Nether-
`lands), thus enabling nail sectioning over its entire
`surface. Subsequently, the nail clippings were cut
`parallel to the sarface in sections of 20-1xrn thicknes~
`(Microtome 5030; Bright Instrument. Huntingdon,
`UK). Of the middle finger nails, three series of five
`subsequent sections were collected in separate vials,
`representing nai! Iayers at depths c.f 0-100, 101-200
`and 201-300 r~m, respectively. On interim analysis
`
`Page 2
`
`

`

`E.J. van Hoogdalem et aL / European ,fou.nal of PJzarmaceutical S¢iea¢¢s 5 t’U.~97) 119-.27
`
`of these results it was decided to collect the first
`100-~m layer of ring finger cuttings in two separate
`fractions. Consequently, three series of subsequent
`25-gin sections of ring finger nails were collected,
`representing the 0-50, 5!-100 and 101-200-~m
`Iayers. A!I sectioning was done at room temperature.
`Assuming an uniform density throughout the nai!,
`weights of the sections thus collected as one sample
`were calculated as:
`weight sectioned layer in sample
`--- (number of sections,’ sample)
`× (section thickness)
`× (total weight clipping) 1
`(total thickness clipping)
`
`One hundred txl of internal standard solution
`(econazole nitrate; 860 ngml-~) and 900 ~1 of
`ethanol were added to each sample of sections,
`Subsequently, the samples were incubated for 72 h at
`50°C in a water bath (GFL, Hannover-Vinnhorst,
`Germany). One ~xl of the resulting extracts was
`injected on a gas chromatograph with electron cap-
`ture detection (HP 5880A, Hewlett-Packard, Avon-
`dale, USA), using a HP 7673A automatic sampler.
`The temperature of injection port, column and detec-
`tor were maintained at 240°C, 250°C and 3000C,
`respectively. Helium (25 ml rain-L) and nitrogen (4(?
`ml min-~) were used as carrier gas and make-up gas,
`respectively. In order to accommodate for interfer-
`ence by glue components, the lower nail sections
`were chromatographed at flows of 18 ml rain-~ and
`150 mlmin-:, respectively. Split flow and septum
`flow were kept at 220 mlmin-L and 5 ml rain-1,
`respectively.
`Data processing was performed on a HP 5880A
`GC termina!. Oxiconazole contents in nail samples
`were calcu!ated by relating their detector responses to
`a calibration curve, using unweighted linear regres.-
`sion, The calibration curve spanned the range of
`5-650 ng!samp!e. Subsequently, nail concentrations,
`expressed as oxiconazoie nitrate levels (rig g- ~), were
`calculated as:
`nail concentration
`= (amount oxieonazole nitrate/sample)/
`(weight sectioned layer in sample)
`
`2.4. Data analysis
`
`Pharmacokinetic data analysis was performed
`using Siphar 4.0 b (SIMED, Cr~teil, France). For
`
`each nail layer, the maximum concentration reached
`during the 8-week study period .IC ...... ), the time at
`which the maximum level was reacl, ed (t ..... ), and the
`residual nail concentlation after 8 weeks tC,,.~ .0
`were determined. The areas under the nail concen-
`tration versus time curves from 0-8 weeks (AUCr,_s)
`were caIculated using the linear-logarflhmk trapezoi-
`dal rule (Chiou, !978). The mean residei~ce time
`(MRT) was calculated as AUMCc~_~!AUC~;_s.
`AUMC referring to the area under the moment versus
`time curve (Rowland and Tozer, 1989). The MRT
`reflects the mean time period during which a com-
`pound is present in the sampled compartment.
`The effects of the presence of acetylcysteine were
`analysed statistically by comparing within-subject
`results with and without enhancer, usfi~g the Wilcox-
`on rank sign test and maintaining a cmnparison-wise
`error of oL = 0.05.
`
`3. Results
`
`3.1. Bioana!yrical method
`
`In an attempt to spike blank nail material with
`oxiconazole, nail sectmns were pre-incubated in 50
`and 100 .t~g ml-~ solutions of ,)xiconazole nitrate in
`ethanol. Extraction of these spiked sections with
`ethanol during 1-72 h was found to reach a plateau
`after a 48 h incubation period (data not shown). After
`72 h extraction at 50°C, the recovery (±SD.) from
`sections pre-ineubated in 50 and 1CO ~,g ml-~ of
`oxiconazole amounted to 91±!5% ’n,=:!0) and
`114+_31% (n---.10), respectively. Recoveries were
`expressed relative to the amount of dl,.tg which
`penetrated into the naiI during incuba,ion, ::nd they
`were assessed in parallel experiments with radio-
`labelled oxiconazole, These results indicate comp!ete
`extraction of oxiconazole from nail sections in the
`currently used method.
`Under these circumstances retention times .’,f
`econazole and oxiconazole amounted to 3.2 and 5.5
`min, respectively (Fig. 1). The detection limit, de-
`fined as (2× noise level)/(slope calibration curve).
`amounted to 1.9 ng!sample. In the analysis, of tl~e
`lower layers, the modified flows of heliurn and
`nitrogen increased the detection limit to 2.4 ng/
`sample.
`Calibration curves proved to be linear in the
`concentration range used. Correlation coefficients
`
`Page 3
`
`

`

`Since the major trends in acetylcysteine effec~
`appeared to be observed in the upper 100-1xm layer at
`middle finger nails, it was decided to make furt/aer
`discrimination between the 0-50-~xm and 51-100-
`~xm layer using ring finger nails.
`In ring finger nails, the upper 50-p.,n layer showed
`a tendency of increased oxiconazole contents on
`delivery with acetytcysteine (Fig. 2a). In the lower
`layers, effects with and without acetylcysteine were
`comparable, apart from a statistical!v signiticant
`increase in MRT and C ..... s ~ (Table 1).
`Generally, the effect of acetyicysteine on C ..... and
`AUCo_8 of oxiconazole nitrate was not reproducible
`in all subjects. In terms of individual AUC0_s-values’
`
`the effect of acetylcysteine on upper layer drug
`contents vm’ied between a 7-fold decrease and a
`16-fold increase as compared with application with-
`out acetylcysteine. For the upper layers of ring finger
`nails, this implied a two-fold increase in mean uptake
`(]’able 1), as also observed for the upper 100-p~rn
`layer of middle finger nails (data not shown). Effects
`on the parameters C,~.~ and AUC0_~ however, did
`not reach statistical significance (Table !).
`The maximum extent of oxiconazole nail uptake
`was estimated from the data set shewing highest Cm,~,’
`
`and AUC0_8 values, viz. the rigl~t ring finger of one
`subject, treated with lotion containing acety]cysteine.
`From the last nail clipping, collected after week 8,
`1159 ng of oxiconazole nitrate was recovered. As-
`suming that this clipping represented I/7 of the total
`nai! plate, and assuming homogenous distribution of
`drug over the nail, the total amount of oxiconazole
`nitrate present in the nail after week 8 amounted to 8
`txg. From previously collecteca clippings, 3221 ng
`were collected, adding up to 1 i.3 Ixg of drug which
`penetrated into the nail over d:e entire treatment
`period. In this period, comprising t,vice daily applica-
`tion of 10 p,I of 1% wiv oxiconazo’,e for 6 weeks, a
`total dose of 9.7 mg of oxiconazole ,~itrate had been
`applied. Consequently, the extent ~! oxiconazole
`uptake into the nail may be estimated at 0.12% at the
`highest.
`
`Z
`
`Fig. 1. Chronlatograms of untreated nail (left panel), anct of a sample of 5
`pt~oIed sections (0-I00 lain) of a nail treated for 2 weeks with an
`c, xaconazol¢ 1% w/v lotion, the sample containing 261 ngmg-~ ox-
`iconazole nitrate (fight panel); peaks at 3.2 and 5.5 rain represent
`eeonazole and oxiconazole, respectively.
`
`amounted to 0.9991 or higher. Reproducibility of
`injection, expressed as coefficient of variation (n = 9),
`amounted to i.9-5,1% in the concentration range of
`5-700 rig/sample. Performance of the method was
`not affected by presence of acety!cysteine (data not
`shown).
`
`3.2. Penetration kinetics
`
`3.3. Adverse events
`
`Repeated application of oxiconazole nitrate on
`middle finger nails resulted in maximum drug levels
`in the upper 100-p.m layer varying between 70 and
`1200 ng mg- t and lower profiles were present in the
`t0t-200-p,m layer underneath (data not shown).
`
`Topical application of the lotions was wel! toler-
`ated. At post-study physical examination, n~ abnor-
`malities were reported. Concerning the influence ~f
`topical treatment with acetylcysteine on nail grow~E
`no outspoken effects of any additive on nail thickness
`
`Page 4
`
`

`

`E.J. t,att Hoogdalem et aL ! E~*ropean Jour,zal of Phcrmaceuttcal Sciences 5 I’i99"7) 1 I9-127
`
`123
`
`(a)
`
`350O
`
`d
`o
`
`M
`
`8
`©
`
`&
`
`o
`o
`
`Q
`N
`t"
`8
`"~
`0
`
`3000
`
`2500
`
`2000
`
`1500
`
`lOOO
`
`500
`
`o
`
`3500
`
`3000
`
`2500
`
`2000
`
`i
`
`1500
`
`~000
`
`500
`
`0
`
`4
`Time (week)
`
`"S
`
`/
`//
`
`/// /,/~ X
`
`; J ,
`2
`4
`0
`
`Time (week)
`
`,’" ................ g
`
`6
`
`8
`
`Fig. 2 individual oxiconazole ring. finger nail levels du:mg ant af’.er 6 weeks’ wealment wifla 1% wiv ehico~mzo~e lotion without (opper panels) and ’vith
`(’lower panels) acetylcysteine 15% w/v in 6 healthy subjects; profiles as observed at three subsequent nail layers are snowr,, viz. (a) the upper 5O-Vm, (b~
`51 IO0-~m and (c) 101-200-~m.
`
`or nai! clipping weight were observed (data not
`shown).
`
`4, Discussion
`
`Repeated application of oxi¢onazole lotions ~o the
`nail resulted in measurable drug leveis in the upper
`
`nail layer; the concentrations decreased downwards
`(Fig, 2; Table t), These profiles, and the iow extent
`of uptake in the nait, viz. less than 0,2%, indicate an
`important barrier furtetion of’ the upper nail iayer.
`This low permeating potential is in line with tl~,e
`previously reported poor systemic absorption of
`topicat oxiconazole, only 0.3% of the topical dose
`being recovered from urine and fae, ces (5egasothy and
`
`Page 5
`
`

`

`E.J, ym7 H~ogdaiem et at. I Et~ropemt Journal of Pharmaceu.:ical Scieaces 5 (1997) ! Jg-J27
`
`( b ) asoo -
`
`3~00
`
`2500
`
`2000
`
`1500
`
`10oo
`
`5oo
`
`o
`
`3500 --
`
`3O00
`
`2500
`
`20OO
`
`1500
`
`!000
`
`t--
`O
`o
`
`r"
`
`o
`
`0
`
`2
`
`4
`Time (week}
`
`6
`
`8
`
`500 .......
`
`o
`
`2
`
`4
`Time (week)
`
`Fig, 2. (co~z~inued)
`
`6
`
`6
`
`Pakes, t991). The nail level pattern during topical
`treatment indicates slow uptake into the :nail,. and a
`steady state was not convincingly reached during the
`6 weeks of treatment (Fig. 2), This profile of ongoing
`drug accumulation at the target site during treatment
`shows resemblance to the profiles reported for oral
`itraconazole (MattMeu et ai., 199!; Roseeuw and De
`
`Doncker, 1993b) and oral terbinafine (Finlay, 1992).
`In the latter case a steady state was reached at 8-12
`weeks, during a 16-week treatment period,
`On topical application of oxiconazde with
`acetylcysteine, a prolonged residence of oxiconazole
`was observed in the upper 100-1xm layer of ring
`finger nmls (Table 1 Fig. 2), as well as in middle
`
`Page 6
`
`

`

`E.,L van Hoogda!*m et at.
`
`European Joun a! of Pharmaceutical Scietzces 5 (!997) 119- !27
`
`(C) 3500 --
`
`3000 --
`
`~- 2500 --
`
`§ 2000 --
`
`1500 --
`
`lO00 -
`
`500 --
`
`2
`
`4
`
`Time (week)
`
`3500
`
`3000
`
`E
`’~ 2500
`,E.=
`
`o o 2000
`
`i
`
`8
`¯ ~
`©
`
`1500
`
`1000
`
`5OO
`
`~--------II--~r-----_____ -,,
`
`, ~--
`
`_. --
`
`0
`
`2
`
`4
`Time (week)
`
`Fig, 2. (continued)
`
`5
`
`finger nails. This phenomenon may reflect an in-
`creased oxiconazole binding to e,g. keratin in the .nail
`by action of acetylcysteine, increasing uptake in the
`upper layer and/or slowing of its elimination rate
`from that layer. In the lower lO1-200-F~m layer this
`effect was not observed, suggesting that
`acetylcysteine did not penetrate this layer, or that a
`
`difference in lower matrix structure precluded an
`action of that compound.
`An unambiguous actmr~ of acety!cysteine on total
`oxiconazole uptake was not demopstrated; a tendency
`of increasing oxiconazole levels was observed in the
`upper nai! layers of middle and ring finger, the effect
`not being consistent in all subjects. This observation
`
`Page 7
`
`

`

`E.J. van Hoogdatem el ai. / European Journal of Phar.u~ceutical Sciences 5 (!9971 119-/27
`
`TuNe !
`Pharma¢okinetic parameters (mean ±S.D.) of oxicon’,,,.zole in sectioned layers of ring finger nail clii~pings from 6 subjects treated for 6 weeks with !.% w/v
`oxicot~azot¢ lotion with and without 15% w/v acety!cysteine according to a left-right design
`
`Layer
`
`0-50
`
`51-I00
`
`101-200
`
`Parameter
`
`Without N-acetylcysteine
`
`With N-acetytcysteine
`
`t,,,~, (week)
`-t
`C,,.~ (rig mg )
`AUC (n8 week rag-’)
`
`MRT (week)
`C,~.o~ ~, (rig mg-~)
`
`t,.~. (week)
`Cm.~ (ng mg-~)
`AUC (ng ~veek mg-~)
`MRT (week)
`C~,,¢,k s~ (ng rng-’)
`
`t~,.. (week)
`C,~.. (ng ms-’)
`AUC (ng week mg-L)
`
`MRT (week)
`C~,~k ~ (rig rag- ~ )
`
`5 "t I
`790=420
`3110__.216(5
`4.4--_0.3
`7"2-6
`
`5= l
`3502360
`1160" 124C,
`4.2 ZO,4
`2+3
`
`5+2
`L04_’1-77
`380*--260
`4,5 ~0.6
`0=~- 1
`
`(4-6)
`( | 18- 1423)
`(586-6934)
`(4.1-4.9)
`(0-16)
`
`(,~-6)
`(65-938)
`(2!9-32571
`(3,7-4.9~
`(0-8)
`
`12-6)
`(12-2221
`(54-679)
`(3.8-5.3)
`(0~-21
`
`5 --- 1
`1570- t~20
`6160__.438(i
`5.6=0.7
`870:890
`
`6--.2
`330_*. 180
`990_+..580
`5,5 ---0,9’
`1202:150"
`
`a__.2
`55 .*-33
`200-* 130
`48 -’-0.5
`11 ~: 18
`
`(4-61
`1818-30361
`(1782-14 363)
`(4. 1-6)
`(cid:128) l 2-2530)
`
`(4-8)
`( i i4-5661
`(28(cid:128)-1888
`(4.1-6.4)
`(1-4101
`
`(2-61
`(28-1091
`(94-4571
`(3.9-5.4)
`(0-47)
`
`Ranges of individual values are specified between brackets.
`* S[gnificant!y different from value observed without enhancer (P<0.05; Wilcoxon rank sign test).
`
`suggested that a potential effect of acetylcysteine on
`upper nai! structure was insufficient to bring forth a
`reproducibly enhancing action on total drug uptake,
`in contrast with the effect on drug residence in tiae
`nail discussed above.
`Oxiconazole concentrations in the lower i01-200-
`~ln layers ranged between 2-350 ng oxiconazole
`nitrate per mg on delivery without additive. The
`fungistatic oxiconazole concentration has been re-
`ported to be in the range 0.03-10 ng tzl-~ (Jegasothy
`and Pakes, 1991). However, since the latter values
`were assessed in aqueous media, a comparison be-
`tween these values cannot be made with confidence.
`Consequently, the clinical value of the currently
`tested formulations remains to be assessed.
`The currently described in vivo nail penetration
`profile of oxiconazole is moderate, compared with
`previously described in vitro study data, Stiittgen and
`Bauer measured levels of 1000-1500 ng/Ixi in the
`upper 200-1xm nail layer 17 h after in vitro applica-
`tion of 1% oxiconazole ointment or tincture (Stiittgen
`and Bauer, 1982). In the present study, it took 5-+1
`(S.D.) week to reach a comparable level in the upper
`50-1.~m layer of ring finger nails in the presence of
`acetylcysteine, while levels in lower layers were
`substantially lower (Table 1 Fig. 2). The more
`pronounced penetration observed in -vitro is possibly
`brought about by continuous exposure of the nail to
`an excess of formulation. In addition, the nail bed
`
`may play a role in maiz~taining nail plate barrier
`function in vivo.
`
`5. Conclusion
`
`Results of the present nail penetration study in
`healthy volunteers demonstrated a promoting action
`of acetytcysteine on oxiconazole retention in upper
`nail layers, In addition, acetylcysteine tended ~o
`enhance o×iconazole uptake in the upper nail layer,
`
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