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Percutaneous Absorption of Salicylic Acid in Man after Topical Administration

of Three Different Formulations

Article  in  Dermatology · February 1999

DOI: 10.1159/000018063 · Source: PubMed

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 Pharmacology and Treatment

Dermatology 1999;198:44–51 Received: March 12, 1998

Accepted: August 20, 1998

Percutaneous Absorption of Salicylic

Acid in Man after Topical Administration of
Three Different Formulations
F.P. Schwarb¤a, b B. Gabard¤c Th. Rufli¤a Ch. Surber¤a, b
a¤
Department of Dermatology and b¤Institute of Hospital Pharmacy, University Hospital, Basel, and
c¤
Biopharmacy Department, Spirig Ltd., Egerkingen, Switzerland

Key Words Conclusions: Significant differences in the doses ab-

Salicylic acid • Percutaneous absorption • sorbed were detected between the two formulations a
Tape stripping • Topical bioavailability • Poisoning and b (same concentration) with different vehicles (p
value¤¤<¤¤0.001) as well as between b and c (same vehicle)
with different concentrations (p value¤¤=¤¤0.018) using Stu-
Abstract dent’s paired t test. These results demonstrate that sali-
Objective: To determine the amount of drug which is cylic acid is well absorbed by healthy skin.
absorbed during 1 day following topical application of
three different preparations containing salicylic acid.
Methods: Ten grams of the formulations, either (a)
Kerasal™ 5% ointment, (b) salicylic acid 5% or (c) 10% Introduction
in petrolatum, were administered consecutively to a
600-cm2 area on alternating sides of the back of healthy In dermatology, salicylic acid has been used for a long
volunteers (n¤¤=¤¤9). Thirty minutes after application, a skin time for keratolytic treatment. In 1882, Unna [1] gave a
area of 2.54 cm2 was stripped with D-Squame™ adhesive first overview on the therapeutic properties of topical sali-
disks to determine the amount of salicylic acid in the cylic acid. Today salicylic acid is commonly used as a
stratum corneum. The entire application site was then remedy for the keratolytic treatment of psoriasis, eczema
covered by a thin gauze bandage and was not washed and ichthyosis.
for the next 24 h. Urine was collected for 26 h following In the last century, there was a heated debate on the per-
administration, hydrolyzed and assayed by HPLC analy- meability of intact skin. The major interests were focused on
sis. Results: The absolute amounts absorbed and ex- water and vapor absorption. However, auxiliary substances
creted were 52.6¤¤±¤¤29.4 mg (mean¤¤±¤¤SD), 127.1¤¤±¤¤43.9 mg such as salicylic acid were also incorporated into water to
and 208.0¤¤±¤¤81.7 mg, and the doses absorbed in relation investigate skin permeability. Inadequate experimental set-
to the doses applied (500 mg salicylic acid in case of tings and the researchers’ personal anticipation of the exis-
formulations a and b and 1,000 mg for formulation c) tence or nonexistence of skin permeability led to an unsci-
were 9.3¤¤±¤¤3.8, 25.1¤¤±¤¤8.5 and 20.2¤¤±¤¤7.7%, respectively. entific and controversial debate.
The amounts of salicylic acid in the skin 30 min after ap- Bourget [2] was one of the first who recognized that an
plication were 36.3¤¤±¤¤16.5, 18.2¤¤±¤¤11.9 and 31.3¤¤±¤¤15.4 µg/ appropriate study design, sampling techniques and an ac-
cm2 as determined by the tape stripping procedure. curate analytical assay are necessary to produce reliable

© 1999 S. KargerAG, Basel PD Dr. Christian Surber

1018–8665/99/1981–0044$17.50/0 Institut für Spital-Pharmazie, Kantonsspital
Fax¤+¤41 61 306 12 34 CH–4031 Basel (Switzerland)
E-Mail karger@karger.ch Accessible online at: Tel. +41 61 265 2905, Fax +41 61 265 3275
www.karger.com http://BioMedNet.com/karger E-Mail csurber@swissonline.ch
results. In his publication in 1893 [2] he stated that salicylic of the Department of Internal Medicine of the University Hospital,
acid was absorbed through skin rapidly and to a significant Basel, Switzerland. All subjects gave their written, informed consent
before participation in the trial. The subjects were 25–67 years of
extent. He stated that the absorption rate and the quantity age (34.7¤¤±¤¤13.5 years) and weighed in the range from 54 to 84 kg
absorbed were influenced by the vehicle, age and state of the (71.6¤¤±¤¤9.9 kg). All subjects were judged to be healthy based on med-
skin. ical history, physical evaluation and clinical laboratory testing (hema-
Since the beginning of this century, several attempts have tology, blood chemistry). The application areas of all subjects were
been made to quantify the extent of percutaneous absorption free from skin diseases, uneven skin tones, sunburn, tattoos and scars.
There were neither dropouts nor protocol violators among the study
of salicylic acid. In 1929, Moncorps [3] recovered 0.72% of population.
the dose applied from urine after having applied 5% sali-
cylic acid in petrolatum occlusively onto the legs of volun- Study Design and Medication
teers. The metabolism of salicylic acid was neglected. The study was designed as a monocentric, open, randomized, three-
Würbach [4] investigated in 1964 the urinary excretion way crossover comparison. Three formulations containing salicylic
acid were used in this trial: (a) Kerasal™ ointment which contained
of salicylic acid and metabolites (gained by acidic hydroly- salicylic acid 5% and urea 10% in a base consisting of polyethylene
sis) after topical, occlusive administration. For salicylic acid glycol, glycerol and petrolatum; Kerasal ointment was supplied by
5% and 10% in petrolatum, he determined an absorption Spirig Ltd., Egerkingen, Switzerland; (b) salicylic ointment 5% and
rate of 7.4 and 14.8% of the dose applied, respectively. In (c) salicylic ointment 10% were obtained from the Institute of Hospital
1975, Taylor and Halprin [5] published the data of a pilot Pharmacy, University Hospital, Basel, Switzerland; both contained
salicylic acid in a concentration of 5 and 10%, respectively, in a mix-
study in 4 psoriatic patients. Nine to twenty-three grams of ture of mineral oil and petrolatum.
an alcoholic preparation, containing salicylic acid 6%, were Each study period was separated by a washout period of at least
topically administered for 5 consecutive days on diseased 2 weeks.
skin areas under a 10-h occlusion. Urinary excretion within Application. The medications studied were administered in the
7 days was approximately 70% of the dose applied. In a morning between 8 and 9 a.m. The washing procedure of the skin
before the treatment was performed individually by the volunteers
very recent investigation, Davis et al. [6] determined the according to their daily routine. In each cycle a 600-cm2 area, alternat-
relative bioavailability of salicylic acid (2%) in a hydro- ing between both sides of the back (left/right/left and vice versa), was
alcoholic and a cream formulation after repeated application delimited with Sparablanc™ tape (IVF, Schaffhausen, Switzerland).
(14 days) in three different skin conditions (normal, aged Ten grams of ointment were spread manually over the application
and acnegenic skin). Bioavailabilities among normal skin area by gentle rubbing. This corresponded to salicylic acid doses of
0.83 mg/cm2 for Kerasal and salicylic ointment 5%, and 1.67 mg/cm2
types were 58 and 44% for the hydroalcoholic and cream for salicylic ointment 10%. The whole site was left uncovered for 1 h
formulation, respectively. No relevant differences were ob- from the time point of application. It was then covered by a thin gauze
served for aged and acnegenic skin. bandage.
Apart from the previous paper on percutaneous absorp- Stratum corneum Samples. Thirty minutes after application, a
tion of 2% salicylic acid from two over-the-counter formu- small area on the border of the application site was gently wiped with
four independent soft cloth tissues in order to remove the remaining
lations no systematic in-depth information on the influence ointment. A small piece of polypropylene foil with a hole (18 mm
of vehicle and drug concentration on the amount absorbed diameter) was then placed onto the cleansed skin and affixed by a piece
is currently available. Against this background we inves- of self-adhesive tape (Cover-Roll™ Stretch, Beiersdorf Inc., Norwalk,
tigated the percutaneous salicylic acid absorption of two Conn., USA) from which a hole of 25 mm diameter had been cut out.
magistral and one brand name formulation in 9 healthy vol- This template ensured that all tape stripping procedures took place
at the same site. The skin was stripped 21 times with adhesive disks
unteers using the standard tape stripping and urine recovery (D-Squame™; Difa Cooper S.p.A., Caronno, Italy). The first disk was
techniques [7], respectively. discarded. Five sequential tape strip disks were combined in 15-ml
Based on these data a risk assessment for topical salicylic Falcon™ polypropylene conical screw-capped tubes (Becton Dickin-
acid as a keratolytic agent is made and compared with clin- son Labware, Franklin Lakes, N.J., USA) for extraction and submitted
ical information on salicylic acid toxicity following topical to HPLC analysis for quantification of drug content.
Urine Samples. Salicylic acid is metabolized rapidly when the
administration. amount present in the body is low [8], and it is reported that approxi-
mately 80% of an oral sodium salicylate dose (≤¤1 g) can be recovered
from urine within 24 h [9]. For that reason it is possible to recover
Materials and Methods considerable fractions of the absorbed amount of salicylic acid within
26 h following topical application.
Subjects and Ethical Considerations Before each application, a urine sample was collected to prove
Nine healthy (7 male, 2 female) subjects entered the study. The absence of salicylates prior to administration of the study medication.
study was performed in accordance with the 1989 version (Hongkong) Urine was quantitatively collected in plastic containers during the
of the Declaration of Helsinki and approved by the ethical committee 26-hour period following topical administration. At the end of a

Percutaneous Absorption of Salicylic Acid Dermatology 1999;198:44–51 45

collection interval, the urine was mixed and aliquots of 10 ml were were stored in a deep freezer at –30°C. Aliquots of 20 µl were injected
transferred to 3 Falcon screw-capped tubes (see above) and immedi- onto the column for HPLC quantification. The mobile phase consisted
ately frozen. The tubes were stored at –20 to –30¤°C until analysis. of 75% phosphate buffer, pH 2.0, and 25% acetonitrile. The flow rate
Plasma Samples. In 1 subject serial plasma samples were drawn was 1.0 ml/min and the column was kept at 34¤°C. The absorption was
after each topical treatment and additionally subsequent to a compar- measured at 237 nm. Calibration was done by running standards in
ative intravenous administration of 20 ml of a parenteral sodium every sample set by linear regression of peak area versus concentration
salicylate solution (equivalent to 300 mg of salicylic acid). (standard concentrations: 0, 0.5, 1, 5, 10, 25 µg/ml salicylic acid in
Blood was collected in chilled 5.5-ml test tubes (Monovette™ LH; methanol). The mean retention time for salicylic acid was 13 min and
Sarstedt, Nümbrecht, Germany) containing 15 IU lithium-heparin/ml. the coefficients of correlation were r¤≥0.998.
Urine Samples. Urine samples were hydrolyzed to transform the
Analytical Procedures metabolites (salicyluric acid and glucuronides of salicylic and salicyl-
Methods for sample preparation and quantification were devel- uric acid) back to free salicylic acid. Gentisic acid, a metabolite which
oped by modification of different methods published in the literature is formed to a very small extent (approx. 1%) was ignored [14, 15]. Six
[10–13]. milliliters of thawed urine were transferred to a 20-ml glass vial and
mixed with 6 ml of hydrochloric acid. The vials were heated for 1 h at
Materials 120¤°C. After cooling, the vial was vortexed for 15 s. The hydrolyzed
Reagents. The reagents used include: salicylic acid (Siegfried Ltd., urine was then purified and concentrated by means of solid-phase
Zofingen, Switzerland; pharmacopeial grade); sodium salicylate (Hän- extraction. For this, the extraction column was first conditioned with
seler Ltd., Herisau, Switzerland; pharmacopeial grade); salicyluric 2 ml of acetonitrile, then twice with 2 ml of distilled water. Hydrolyzed
acid (Sigma-Chemical, St. Louis, Mo., USA; analytical grade); anhy- urine was put onto the column in five portions of 2,000 µl, each fraction
drous potassium dihydrogen phosphate, hydrochloric acid 37%, per- being pressed manually through the column. The column was then
chloric acid 20% and orthophosphoric acid 85% (Fluka Ltd., Buchs, washed with 2 ml of phosphate buffer. The column was eluted with
Switzerland; all analytical grade); acetonitrile, methanol and water for 2 ml of a mixture of 20% phosphate buffer and 80% acetonitrile, which
chromatography (E. Merck Ltd., Dietikon, Switzerland; LiChrosolv™ was slowly pressed through the column. The eluent was collected in a
grade). volumetric flask and mobile phase was added to give a volume of 5 ml.
Distilled water was obtained from the Institute of Hospital Phar- Hydrolysis of salicyluric acid was judged to be complete by the
macy. Phosphate buffer for chromatography was prepared by dis- quantitative recovery as salicylic acid (98.4¤¤±¤¤1.27%, n¤¤=¤¤5) from
solving 2.72 g of potassium dihydrogen phosphate in distilled water. salicyluric acid added to blank urine.
By addition of orthophosphoric acid 85% the pH was adjusted to Aliquots of 10 µl were injected onto the column for HPLC quantifi-
2.00. Distilled water was added to produce 1 liter and the solution cation. The mobile phase consisted of 75% phosphate buffer, pH 2.0,
was filtered (Nylon 66 membrane, 0.45 µm¤×¤47 mm; Supelco Inc., and 25% acetonitrile and the flow rate was 0.3 ml/min. The samples
Bellefonte, Pa., USA) and degassed before use by ultrasonication for were kept at 20¤°C and the column was heated to 34¤°C. After each sam-
15 min. ple run of 10 min, the column was washed for 5 min with acetoni-
Solid-Phase Extraction. Solid-phase extraction was performed trile/water (25:75) at 0.35 ml/min and reconditioned for 7 min with the
using Chromabond™ C18, 3-ml columns packed with 500 mg of mobile phase at 0.35 ml/min. Identity and purity of the salicylate peak
sorbent (Machery-Nagel Ltd., Oensingen, Switzerland). Pressure was was determined with photodiode array detector data and quantification
applied by a 10-ml syringe which was fixed with an adapter at the top was performed at the absorption wavelength of 305 nm, which was
of the column. chosen to avoid interference with endogenous compounds present in
Apparatus. Our chromatographic system for determination of urine [16]. Calibration was done within every sample set by linear
stratum corneum concentration of salicylic acid consisted of a Merck- regression of peak area versus standard concentration (standards:
Hitachi L-6200A solvent pump, an AS 4000A autosampler, a T6300 salicylic acid in mobile phase at concentrations of 0, 0.5, 1, 5, 10, 20,
column thermostat, a D 6000 interface, an L4250 UV-VIS detector and 50, 100 and 200 µg/ml). The mean retention time was approximately
an L3000 photodiode array detector (all Hitachi Ltd., Tokyo, Japan). 6.5 min and the correlation coefficients were r¤¤¤≥¤¤0.998. The limit of
The system was equipped with a LiChrospher™ 100 RP-18 column detection for salicylic acid was¤¤<¤¤0.2 µg/ml. The recovery of salicylic
(250 ¤×¤4 mm i.d., 5 µm average particle size) and a LiChrospher™ 100 acid added to blank urine (2–200 µg/ml) was 100.0¤¤±¤¤2.6% (n¤¤=¤¤7).
RP-18 guard column (4¤×¤4 mm i.d., 5 µm average particle size; both The interassay standard deviation of the hydrolyzation, extraction and
from E. Merck Ltd.). analytical procedure was 1.07% (n¤¤=¤¤5).
Plasma and urine samples were assayed by a Waters 2690 sep- Plasma Samples. Plasma was separated by centrifugation at 1,000 g
aration module Alliance™ equipped with a Waters 996 photodiode for 10 min at 4¤°C; 2,000 µl of plasma were transferred to a conical tube
array detector which were controlled by Millenium™ 2010 software, (Falcon 15 ml; see above) and 200 µl of perchloric acid 20% added.
version 2.21 (all Waters Corp., Milford Mass., USA). Separation and The mixture was then vortexed for 1 min and 2,000 µl of methanol
quantification of analytes was performed on a reversed-phase Sym- were added. The sample was vortexed for 2 min and centrifuged at
metry™ C18 column (150¤×¤2.1 mm i.d., 5 µm average particle size; 1,500 g for 10 min. The clear supernatant solution was transferred to
Waters Corp.). a 350-µl vial and placed in the autosampler. Aliquots of 10 µl were
injected onto the column for HPLC quantification. Chromatographic
Sample Preparation conditions (mobile phase, flow, column and sample temperature) were
Stratum corneum Samples. The tapes were extracted twice with as per the urine assay. The run time was 15 min, and detection and
methanol. This was performed by adding 2 ml methanol to the tube and quantification were done at 237 nm. Calibration was carried out by
vortex-mixing for 1 min. The two extracts were transferred to a volu- running standards for salicylic acid within every sample set by linear
metric flask and methanol was added to a total of 5 ml. The samples regression of peak area versus concentration. Standards were produced

46 Dermatology 1999;198:44–51 Schwarb/Gabard/Rufli/Surber

 ▲ ▲
▲
▲

Fig. 1. Relative amounts of salicylic acid absorbed. Fig. 2. Plasma concentration (mmol/l) of salicylic acid after intra-
venous administration (square) and topical administration of Kerasal
(rhombus), salicylate ointments 5% (circle) and 10% (triangle),
respectively.

from spiked blank plasma according to the procedure mentioned above in figure 1. In 1 volunteer, the gauze bandage and the shirt
for the plasma samples. Concentrations were 0.2, 0.5, 1, 5 and 25 µg/ml were extracted after each treatment period. The relative
referred to concentration before processing. The correlation coefficient
amounts recovered from bandage and shirt were approxi-
was r¤>0.999.
mately 50% and are comparable with previous data [17].
Statistical Analysis
The different formulations were compared by the percentage of Comparison of Formulations a and b
dose absorbed in relation to the dose applied. Kerasal ointment (a) was These two formulations contained salicylic acid 5% in
compared to salicylate ointment 5% (b), and salicylate ointment 5% (b)
pharmaceutically different vehicles. The doses absorbed and
was compared to salicylate ointment 10% (c), by paired Student t test.
The null hypotheses were formulated that a and b as well as b and c recovered from urine within 26 h were significantly differ-
were equivalent in terms of percent dose absorbed. The formulations ent. Percutaneous absorption from the magistral mineral
were considered to be significantly different and the null hypotheses oil/petrolatum formulation was more than 2.5-fold higher
had to be rejected if the p values of both tests were¤¤<¤¤0.025 (signifi- than from Kerasal, which contained polyethylene glycol,
cance value of 5% corrected by Bonferroni procedure).
glycerol and petrolatum (p¤<0.001).

Comparison of Formulations b and c

Results These two formulations contained salicylic acid in con-
centrations of 5% (b) and 10% (c) in the same magistral
The quantity of salicylic acid applied was approximately mineral oil/petrolatum formulation. The relative absorption
500 mg for Kerasal and the salicylate ointment 5% and was slightly higher for the preparation with the lower con-
1,000 mg for the salicylate ointment 10%, respectively. centration (p¤¤=¤¤0.018).
The absolute amounts of salicylic acid recovered (mean
±¤SD) from 26-hour urine and the doses recovered in rela-
tion to the doses applied are given in table 1 and visualized

Percutaneous Absorption of Salicylic Acid Dermatology 1999;198:44–51 47

Table 1. Doses absorbed
¤Preparation Absolute Relative to dose Range
absorptiona applied

KerasalTM 52.6¤¤±¤¤29.4 mg 9.3¤¤±¤¤3.8% 4.6–16.5%

p¤¤<¤¤0.001
Salicylate ointment 5% 127.1¤¤±¤¤43.9 mg 25.1¤¤±¤¤¤8.5% 13.8–40.4%
p¤¤=¤¤0.018
Salicylate ointment 10% 208.0¤¤±¤¤81.7 mg 20.2¤¤±¤¤7.7% 11.8–37.0%

a
Absolute amount recovered from urine.

Table 2. Dose absorbed and amount of

salicylic acid in stratum corneum Kerasal Salicylate Salicylate
determined by tape stripping, 30 min after ointment 5% ointment 10%
administration
Dose absorbed per area, µg/cm2 87.6¤¤±¤¤48.9 211.9¤¤±¤¤73.2 346.6¤¤±¤¤136.1
Amount extracted from 20 tape stripping, µg/cm2 36.3¤¤±¤¤16.5 18.2¤¤±¤¤11.9 31.3¤¤±¤¤15.4

Plasma Concentration time curve of salicylic acid after topical administration,

The log plasma salicylic acid concentration-time plot is obtained from 1 subject, was in accordance with previous
illustrated in figure 2. The tmax values were about 5, 7 and data [6, 18].
10 h, and the Cmax values were 0.021, 0.033 and 0.069 mmol/l Despite the considerable amount of information on per-
for Kerasal, salicylate ointments 5 and 10%, respective- cutaneous salicylic acid absorption, few data on the influence
ly. The calculated AUC0–24 h were 0.233, 0.408 and 0.997 of vehicle and drug concentration on the amount absorbed
mmol¤·¤h¤·¤l–1. There was a linear relation (r¤>0.999) between are currently available. The magistral product containing
the amount excreted in 26-hour urine and the area under the 5% salicylic acid in a petrolatum/mineral oil preparation
plasma concentration-time curve from 0 to 24 h. showed a percutaneous absorption which was 2.5 times
higher (p¤¤<¤¤0.001) than that of the brand name product
Tape Stripping Kerasal (5% salicylic acid in an ointment containing emul-
The amounts of salicylic acid extracted from 20 D- gators, glycerol and urea). A plausible explanation is that
Squame adhesive disks successively removed from the skin the self-occluding effect of petrolatum, the vehicle of the
are summarized in table 2. No correlation between the magistral formulations, may have led to an enhanced per-
amount of salicylic acid in the stratum corneum as deter- meation. These findings suggest that different salicylic acid
mined by the tape stripping technique and the doses ab- preparations at the same concentration level are not bio-
sorbed (table 2) was detected. equivalent. Doubling the drug concentration in the magistral
salicylic acid preparation (from 5 to 10%) resulted in an
increase in absolute drug absorption by a factor of 1.6, and
Discussion in a decrease in relative drug absorption by the factor of 0.8,
respectively (table 2).
In vivo percutaneous absorption of salicylic acid through Comparing drug penetration into skin and drug perme-
human skin and its systemic availability was in the range ation through skin it is obvious that Kerasal delivered more
of 20–25% for the two magistral mineral oil/petrolatum salicylic acid to the stratum corneum than the two magistral
preparations and a little less than 10% for the brand name formulations. From a therapeutic point of view it can be
preparation. Compared to earlier data [4] the extent of argued that the brand name product better fulfils the assign-
absorption in the present investigation was about twice ment to deliver the drug to the target organ – the stratum
higher. This difference may be explained by the different corneum – for keratolytic activity and has a lower potential
application sites (leg vs. back) or by different pharmaceuti- for excessive drug delivery to the body. Rougier et al. [7]
cal properties of the preparation. The plasma concentration- found a linear relationship between the stratum corneum

48 Dermatology 1999;198:44–51 Schwarb/Gabard/Rufli/Surber

Table 3. Clinical references of toxicity from topical salicylates: a selection of references published from 1964 to 1997 where plasma/serum
concentration data were provided

¤Published Ref. Gender Underlying Concentration of Plasma/serum Clinical features

No. and diseases ointment and concentration
age dosing regimens mmol/l

1997 19 f/5 years ichthyosis 10% plus urea, entire body, 2.1 tachycardia, lethargy, fever,
three times in 36 h hyperpnea
1996 20 m/7 years ichthyosis 1,000 g ointment (10%) 7.12 deep somnolence, tinnitus, vertigo,
per week for 4 weeks tachypnea, vomiting
1996 21 f/80 years erythroderma 2–10%, 4×/day for 6 days 3.36 confusion, hyperpnea, metabolic
acidosis
1994 22 f/79 years psoriasis, hypertension, 2%, from days 1 to 3 3.24 unresponsiveness, hypoglycemia
renal failure, diabetes 5%, from days 4 to 5,
(glyburide 2.5 mg b.i.d.) frequency?
1994 23 f/42 years psoriasis 10%, 50 g (estimated) 2.6 deafness, nausea, metabolic
per day for 10 days acidosis
1992 24 m/27 years psoriasis, alcoholism 40%, single application 6.04 nausea, vomiting, ague, sweating,
to 41% of body surface hyperthermia, confusion,
tachycardia
1991 25 m/72 years psoriasis, renal disease, 10%, 3×/day to 80% of 3.2 fever, confusion, hypoglycemia,
diabetes body surface for 3–4 weeks metabolic acidosis
1990 26 m/neonate skin coverd by 2%, every 3–4 h for 3 days 3.1 vomiting, metabolic acidosis
collodion like membrane
1990 26 m/12 years ichthyosis 2%, 2×/day for 2 days; 3.3 not specified in reference
5%, 2×/day for 2 days;
10%, 2×/day for 4 days
to the whole body
1989 27 f/neonate harlequin fetus 1%, every 3 h for 24 h only 4.24 tachypnea, fever
1986 28 m/45 years psoriasis, psoriatic 3% plus coal tar, 3×/day to 1.82 tinnitus due to increase in unbound
arthritis entire body for 5 days plasma salicylate fraction(?) by
(naproxen 375 mg b.i.d.) concomitant naproxen competing
for albumin binding
1975 29 f/62 years psoriasis 10%, 2×/day to almost 75% 16.15 discrete symptoms: tinnitus, dry
of body skin surface mouth, headache; high salicylic
for 1.5 years acid concentrations tolerated due to
chronic exposure
1964 30 f/39 years psoriasis 6% plus sulfur, 6×/day to 4.63 from 6th day on: tachypnea,
involved skin/scalp areas (11th day) lethargy, nausea, hearing impair-
for 11 days ment; diagnosis of intoxication on
11th day of treatment

reservoir content and the in vivo percutaneous absorption the rank order of percutaneous permeation. In addition, no
(total amount of drug permeated in 4 days) using the stan- intrasubject correlation between penetration into skin and
dard urinary excretion method. They showed for a variety permeation through skin was found. The vehicle and the
of simple pharmaceutical vehicles that the percutaneous drug’s inherent properties may directly influence the cohe-
absorption of benzoic acid is vehicle dependent and can sion of corneocytes as well as the adhesive properties of the
be predicted from the amount of drug within the stratum tapes. Both may influence the amount of stratum corneum
corneum 30 min after application. In the present study using being removed by the adhesive tapes and may therefore
the standard tape stripping methodology the amounts recov- complicate the interpretation of the data.
ered from 20 consecutive tape strippings were on average From 1 subject in the present study, serial plasma sam-
36.3, 18.2 and 31.3 µg/cm2 for Kerasal, salicylate ointments ples were analyzed for salicylic acid concentrations. Peak
5 and 10%, respectively. This rank order is different from plasma concentrations were 0.02, 0.033 and 0.069 mmol/l

Percutaneous Absorption of Salicylic Acid Dermatology 1999;198:44–51 49

for Kerasal, salicylate ointments 5 and 10%. Times to plasma ing systemic intoxication. Once moderate to high salicylic
peak concentrations after application of salicylic acid oint- acid plasma concentrations are reached continual dosing or
ments were in the range of 5–10 h as shown in the present drug absorption from the skin reservoir may result in a dis-
and an earlier [18] investigation. For a hydroalcoholic and a proportionate increase in plasma concentrations.
cream formulation, Davis et al. [6] determined the times to A survey of the literature yielded several clinical refer-
peak plasma salicylic acid levels to be approximately 2 and ences on systemic intoxication resulting from topical treat-
4 h, respectively (note that the determination was done after ment (table 3). Our data and the data from the literature
2 weeks of daily pretreatment). From these findings we can suggest that specific patient and age groups – e.g. the skin
conclude either that percutaneous absorption of salicylic surface area per body weight ratio is 2.4 times higher in
acid from hydroalcoholic and cream formulations is faster neonates (620 cm2/kg) than in adults (260 cm2/kg) [31] –,
than from ointment formulations or that repeated applica- the area treated (in our study 600 cm2), the vehicle and
tions lead to a faster absorption after some time resulting repeated application to diseased skin are risk factors for top-
from the keratolytic activity. ical intoxication. The sudden, disproportionate increase in
For optimal anti-inflammatory therapy of rheumatic dis- salicylate plasma concentrations into the toxic range from
eases plasma salicylate concentrations of 1.1–2.2 mmol/l constantly high (borderline) levels, due to its inherent phar-
are required. Tinnitus (above 1.4 mmol/l) may be a reliable macokinetic properties (see above), represents a major risk
index for therapeutic plasma concentration in rheumatic to develop a systemic intoxication.
patients with normal hearing. Hyperventilation generally Nevertheless, compared to other routes of administra-
occurs at concentrations above 2.5 mmol/l and other signs tion (e.g. oral) adverse systemic drug effects of topical drug
of intoxication at concentrations above 3.3 mmol/l [15]. formulations are observed infrequently; a brief overview is
Elimination of salicylic acid is dose dependent. Due to the given by Breathnach and Hintner [32].
limited ability of the liver to form salicyluric acid and the The current investigation has provided new information
phenolic glucuronide, the half-life increases from 2.4 h up on the percutaneous absorption of salicylic acid from two
to about 12–15 h at anti-inflammatory doses. These pharma- magistral formulations and one brand formulation used in
cokinetic properties and the fact that salicylic acid is very keratolytic treatments. The pharmacokinetic information
well absorbed and not entirely removed from the systemic allows for an improved estimate of the contribution of sys-
circulation within 24 h represent the potential for develop- temic salicylic acid from topically applied products.

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