The Tape-Stripping Technique As A Method For Drug Quantification in Skin

J Pharm Pharmaceut Sci (www. cspsCanada.
org) 11 (1): 104-130, 2008
The Tape-Stripping Technique as a Method for Drug Quantification in

Skin
J. J. Escobar-Chávez1,2, V. Merino-Sanjuán1, M. López-Cervantes2, Z. Urban-Morlan2, E. Piñón-
Segundo2, D. Quintanar-Guerrero2, A. Ganem-Quintanar2.
1
Departamento de Farmacia y Tecnología Farmacéutica, Universidad de Valencia, Av. Vicente Andrés Estellés s/n,
Burjassot, Valencia, España. 2División de Estudios de Posgrado (Tecnología Farmacéutica), Facultad de Estudios
Superiores Cuautitlán-Universidad Nacional Autónoma de México, Cuautitlán Izcalli, Estado de México, México.
Received, November 26, 2007; Revised, March 10, 2008; Accepted March 17, 2008, Published, March 24, 2008.
ABSTRACT - Quantification of drugs within the A number of excellent reviews that have
skin is essential for topical and transdermal been published contain detailed discussions
delivery research. Over the last two decades, concerning many aspects of the tape stripping
horizontal sectioning, consisting of tape stripping technique [14-16]. The present review shows an
throughout the stratum corneum, has become one updated overview of the use of the tape stripping
of the traditional investigative techniques. technique (TS) in the pharmaceutical field,
Tape stripping of human stratum corneum specifically in the area of topical and transdermal
is widely used as a method for studying the drugs. This focus is justified due to the magnitude
kinetics and penetration depth of drugs. This of the experimental data available with the use of
paper shows the applications of the tape stripping this technique. The use of the tape stripping
technique to quantify drug penetration through the technique in experimental medicine and
skin, underlining its versatile application in the pharmaceutical sciences has a long history.
area of topical and transdermal drugs.
The skin
INTRODUCTION
The skin is the largest organ of the body [17-19],
Tape stripping with adhesive tape is a widely accounting for more than 10% of body mass, and
accepted and used method to examine the the one that enables the body to interact more
localization and distribution of substances within intimately with its environment. Essentially, the
the stratum corneum (SC) [1-7]. This is a skin consists of four layers: The SC, that is the
minimally invasive technique to sequentially outer layer of the skin (non-viable epidermis), and
remove SC by the repeated application of forms the rate-controlling barrier for diffusion for
appropriate adhesive tapes [8]. This technique can almost all compounds. It is composed of dead
be used to investigate SC cohesion in vivo by flattened, keratin-rich cells, the corneocytes.
quantifying the amount of SC removed [9]. These dense cells are surrounded by a complex
Today, weighing with precision balances is the mixture of intercellular lipids, namely, ceramides,
most frequently used method to determine the free fatty acids, cholesterol, and cholesterol
amount of SC removed on a tape strip. The sulphate. Their most important feature is that they
method is also used to provide information about are structured as ordered bilayer arrays [20]. The
the kinetics of transdermal drug delivery, offering predominant diffusional path for a molecule
an apparently easy and quite non-invasive crossing the SC appears to be intercellular [21-
methodology for skin tissue sampling, and is the 23]. The other layers are: the remaining layers of
basis of the FDA’s so-called the epidermis (viable epidermis), the dermis, and
dermatopharmacokinetic (DPK) approach to the the subcutaneous tissues (Figure 1). There are
assessment of topical bioavailability and also several associated appendages: hair follicles,
bioequivalence [10]. However, validation and sweat ducts, apocrine glands and nails.
optimization of the procedure have not come
quickly and the proposed guidance document has ________________________________________
been withdrawn for re-evaluation. More recent
work has addressed at least some of the important Corresponding Author: Jose Juan Escobar-Chavez,
limitations of the DPK approach [11-13] and has Universidad Nacional Autonoma de Mexico, Departamento
de Tecnología Farmacéutica, Mexico. E-Mail:
proposed modifications in order to incorporate it josefur@yahoo.com
into an improved protocol.
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J Pharm Pharmaceut Sci (www. cspsCanada.org) 11 (1): 104-130, 2008
Figure 1. Layers of human skin.
In a general context, the skin’s functions may be Tape stripping technique overview
classified as protective, homeostasis maintaining
functions, or sensing [25]. The simplest method for reducing the barrier
Many agents are applied to the skin either imposed by the SC is to remove it. Theoretically,
deliberately or accidentally, with either beneficial an adhesive tape removes a layer of corneocytes.
or deleterious outcomes. The main interest in In vivo, removal of the SC by TS is performed by
dermal absorption assessment is related to: a) the repeated application of adhesive tapes to the
Local effects in dermatology (e.g., corticosteroids skin’s surface. In Figure 3 we can observe a
for dermatitis); b) transport through the skin detailed procedure of the tape stripping technique.
seeking a systemic effect (e.g., nicotine patches, It has been found that on the flexor surface of the
hormonal drug patches, etc.); c) surface effects forearm, about 30 tape strips are needed to strip
(e.g., sunscreens, cosmetics, and anti-infectives) off most of the horny layer [8]. Multiple strips
[26]; d) targeting of deeper tissues (e.g., remove a substantial skin barrier, as evidenced by
nonsteroidal anti-inflammatory agents) [7, 27-35]; 20 to 25-fold increases in transepidermal water
and e) unwanted absorption (e.g., solvents in the loss (TEWL) [38].Usually, the amount of SC
workplace, pesticides or allergens) [36,37]. Figure removed by TS is not linearly proportional to the
2 summarizes the process of percutaneous number of tapes removed [8]. TS appears to be
absorption. simple and easy to perform [39-40], however
The skin became popular as a potential there are different parameters that can influence
site for systemic drug delivery, on the one hand, the quantity of SC removed by a piece of tape,
because of the possibility of avoiding the and these include TS mode [38, 41], skin
problems of stomach emptying, pH effects, hydration, cohesion between cells (which
enzyme deactivation associated with increases with SC’s depth), the body site and
gastrointestinal passage, and hepatic first-pass inter-individual differences [9, 42]. The impact of
metabolism; and on the other hand, due to its these factors has been frequently investigated
capability to enable input control. [8,38-44].
After its description by Pinkus [8], TS has
become a standard method in dermatological
research [45].
105
This method can be used to obtain a more drug concentration within the SC, which is
susceptible skin, e.g., prior to the application of expected to be related to the drug concentration at
an irritant [46] or an allergen [47–49]. Similarly, the target site (i.e., usually viable epidermis or
TS is performed to induce a defined disruption of dermis) since the SC is the rate limiting barrier
the water barrier, e.g., to evaluate the effect of a for percutaneous absorption. Similarly to the
subsequently applied skin care product in barrier determination of the drug concentration in blood
restoration [50]. It may be also used to obtain and/or urine as surrogate for the concentration at
cells for mycological culture [51,52] or to the target tissue, the determination of the drug
investigate SC quality [53]. In concentration in the SC may serve as a surrogate
dermatopharmacology, the SC barrier function for the concentration in the viable (epi-)dermis
[50,54] and the bioavailability and bioequivalence [58]. A typical profile obtained from a skin
of topical drugs [39,55-57] can be evaluated with permeation study with sodium naproxen is shown
the use of this technique [58,59]. in figure 4 [7]. TS, which enables the removal of
Tape stripping appears to be simple and the SC layer by layer, is a useful DPK technique
easy to perform. However, there are parameters for the assessment of drug amounts in SC as a
which have to be defined, as they may change the function of time [59].
outcome. Because various brands of tape differ in
shape, surface area, composition and adhesive Applications of the Tape-stripping technique
properties, the influence of the tape brand on the
outcome seems apparent [38,41]. Other Removal by TS of the outermost skin layer, the
parameters which influence the procedure can be SC, has become a common practice in recent
subsumed in the intrinsic properties of the SC years [60,61]. The determination of the kinetics
[38]. Although these properties are often and penetration depth of different kind of
investigated, little is known about the anatomical permeants by tracing the concentration profiles in
sites (intrinsic factor) as well as the pressure with SC, has been facilitated by the use of the virtually
which the tape is applied on to the skin, the non-invasive method of SC stripping with
duration of pressure and the removal process adhesive tape [1,2,5,43,44]. For this reason, TS
(extrinsic factors) influencing SC removal. also offers the possibility of evaluating
In the case of bioequivalence studies, bioequivalence of topical dermatological dosage
topical bioavailability can be estimated from the forms [5].
Figure 2. Processes of percutaneous absorption and transdermal delivery.
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Figure 3. The tape stripping technique procedure
Figure 4. Penetration profiles across human SC of Sodium naproxen formulated in PF-127 gels with different
penetration enhancers [Azone®-Transcutol® mixture▲, Transcutol® ∆ applying an infinite dose, and a film with
Azone®-Transcutol® mixture, Transcutol® {] (Mean± SD; n = 6).
107
DPK characterization of active drugs in human that found following passive diffusion for each
volunteers has been suggested to be able to application time.
replace comparative clinical trials as a means of Escobar-Chávez et al. [7] determined the
documenting bioequivalence [59]. Moreover, in penetration of sodium naproxen, formulated in
vitro methods are encouraged by regulatory Pluronic F-127 gels containing Azone® and
agencies regarding the provision of percutaneous Transcutol as penetration enhancers, through
absorption data for drugs, pesticides and human skin in vivo by using the TS technique. It
cosmetics [62]. All these points are emphasized in was found that the combination of Azone® and
Table 1, which summarizes the research with the Transcutol in PF-127 gels enhanced sodium
TS technique to determine the kinetics and naproxen penetration, with up to two-fold
penetration depth of permeants (drugs and toxic enhancement ratios compared with the
chemicals) [7, 26, 35, 37, 44, 63-97], in order to formulation containing Transcutol only. These
evaluate the factors that influence the physiology results were confirmed by TEWL and ATR-FTIR
of the SC [42, 44, 105,106], to determine the spectroscopy, suggesting a synergistic action for
composition of the SC [108], superficial Azone® and Transcutol®.
infections in the skin [110, 111], and evaluate Esposito et al. [64] produced and
skin regeneration [112, 113], etc. characterized monoleine (MO) dispersions as
drug delivery systems for indomethacin. An in
1) Kinetics and penetration depth of drugs vitro diffusion study was conducted using Franz
cells associated to SC epidermal membrane on
1.1 Analgesic and anti-inflammatory drugs cubosome dispersions viscosized by carbomer. In
vivo studies based on skin reflectance
Arima et al. [63] investigated the effect of spectrophotometry and TS were performed to
hydroxypropyl-P-cyclodextrin (HP-P-CD) on the better investigate the performance of cubosome as
cutaneous penetration and activation of ethyl 4- an indomethacin delivery system.
biphenylyl acetate (EBA), a prodrug of the non- Indomethacin incorporated in viscosized
steroidal anti-inflammatory drug 4- MO dispersions exhibited a lower flux with
biphenylylacetic acid (BPAA), from hydrophilic respect to the analogous formulation containing
ointment, using hairless mouse skin in vitro. the free drug in the aqueous phase and to the
When the hydrophilic ointment containing a control formulation based on carbomer gel.
complex of EBA with HP-P-CD was applied to Reflectance spectroscopy demonstrated that
full-thickness skin, HP-P-CD facilitated the indomethacin incorporated into MO dispersions
penetration of EBA into the skin. When the can be released in a prolonged fashion. TS
ointment containing the EBA:HP-P-CD complex experiments corroborated this finding. MO
was applied to the skin, the BPAA flux through dispersions can be proposed as nanoparticulate
the tape-stripped skin was greater than that systems able to control the percutaneous
through full-thickness skin, while the activation absorption of indomethacin
of the prodrug in the skin was slowed by TS. Ganem-Quintanar et al. [65] used
Their results suggest that the enhancing effect of naproxen-loaded nanoparticles to prepare, in a
HP-P-CD on the cutaneous penetration of EBA one-step process, unilaminar films of Eudragit E-
would be largely attributed to an increase in the 100. Nanoparticle films and conventional films
effective concentration of EBA in the ointment. were characterized in vitro by drug release studies
Curdy et al. [35] administered piroxicam through a cellulose membrane using Franz-type
from a commercially available gel to human cells, and in vivo by penetration experiments with
volunteers, both passively and under the the TS technique. Concerning in vivo penetration
application of an iontophoretic current. After studies, no statistical differences were found for
treatment, the SC at the site of application was the amount of naproxen penetrated across the SC
progressively tape-stripped and piroxicam and the depth of penetration for the two films.
transport into the membrane was assessed by UV- Herkenne et al. [66] investigated pig ear
analysis of drug extracted from the tape-strips. skin as a surrogate for human skin in the
Current application enhanced drug uptake into the assessment of topical drug bioavailability by
SC, as indicated by both increased piroxicam sequential TS of the SC.
concentrations in the horny layer and detectable Ex vivo experiments on isolated pig ears
concentrations at greater depths in the membrane. were compared with in vivo studies in human
The total amount of drug recovered in the SC volunteers. Four formulations including ibuprofen
post-iontophoresis was significantly higher than in different propylene glycol (PG)-water mixtures
108
(25:75, 50:50, 75:25 and 100:0), were compared. Wagner Steffen et al. [69] studied the penetration
Derived DPK parameters characterizing the kinetics of sesquiterpene lactones (SLs) in Arnica
diffusion and partitioning of the drug in the SC ex montana preparations; a stripping method with
vivo were consistent with those in vivo following adhesive tape and pig skin as a model was used.
a 30-minute application period. Furthermore, non- For the determination of SLs in the stripped layers
steady-state ex vivo results could be used to of the SC, a gas chromatography/mass
predict the in vivo concentration profile of the spectrometry method was developed and
drug across the SC when a formulation was validated.
administered for 3 h (i.e., close to steady-state). The penetration behavior of one gel
Taken together, the results obtained suggest that preparation and two ointment preparations was
pig ear skin ex vivo is promising as a tool for investigated. The SLs of all preparations showed
topical formulation evaluation and optimization. a comparable penetration and permeation through
Hostýnek et al. [67] sheded light on the the SC, in the uppermost layer of the skin.
long-standing controversy on whether wearing Interestingly, the gel preparation showed a
copper bangles benefits patients suffering from decreased penetration rate over 4 h, whereas the
inflammatory conditions such as arthritis. penetration rate of ointments remained constant
Sequential TS was performed on healthy over time. Moreover, they could demonstrate that
volunteers to examine the diffusion of copper the total amount of SLs penetrated depends only
through human SC in vivo, following application on the kind of formulation and the SLs-content in
of the metal as powder on the volar forearm for the formulation, but not on SLs composition or
periods of up to 72 h. Exposure sites were the extraction agent used.
stripped 20 times, and the strips were analyzed for Wagner Heike et al. [70] carried out
metal content by inductively coupled plasma- penetration experiments to investigate several
mass spectroscopy. incubation times with three different skin flaps
The results indicate that, in contact with using the Saarbruecken penetration model and the
skin, copper will oxidize and may penetrate the lipophilic model drug flufenamic acid. Drug
SC after forming an ion pair with skin exudates. distribution within SC was obtained by the TS
The rate of reaction seems to depend on contact technique, while the drug present in deep skin
time and oxygen availability. A marked inter- layers was determined by cryosectioning. In
individual difference was observed in baseline addition, for the lipophilic drug flufenamic acid, a
values and amounts of copper absorbed. direct linear correlation was found between
Lodén et al. [68] compared the SC/water partition coefficients and the drug
bioavailability of ketoprofen in a photostabilised amounts penetrated into the SC for all the time
gel formulation without photoprotection using a intervals tested. The authors concluded that
new DPK tape stripping model and an established SC/water-partition coefficients offer the
ex vivo penetration method using human skin. possibility to predict drug amounts within the SC
Analyses of the SC showed that during the first of different donor skin flaps, without a time-
45 minutes, about 12 μg/cm2 of ketoprofen were consuming determination of the lipid composition
absorbed into the skin from the formulations. The of the SC.
area under the ketoprofen concentration–time
curve (AUC0–6 h) for the photo-stabilised 1.2 Corticosteroids
gel/transparent gel ratio was 73%. The rate of
penetration of ketoprofen through isolated skin The aim of Pellanda et al. [71] was to investigate
was approximately 0.2 μg/cm2h for both the effect of i) dose and ii) application frequency
formulations. The ratio’s AUC0–36 h was 84%. on the penetration of triamcinolone acetonide
Thus, the two methods did not disagree in terms (TACA) into human SC in vivo. The experiments
of the relative efficacy of the two gels. The were conducted on the forearms of 15 healthy
comparison of the amount of ketoprofen in the volunteers, with i), single TACA doses (300
skin after 45 min with the amount penetrated μg/cm2 and 100 μg/cm2), and ii) single (1 x 300
through the excised skin during 36 h, suggests a μg/cm2) and multiple (3 x 100 μg/cm2) TACA
change in the thermodynamic activity of doses. SC samples were collected by TS after 0.5,
ketoprofen during exposure. A supersaturated 4 and 24 h (i) and after 4, 8 and 24 h (ii). In
formulation may have been formed initially due Experiment 1, TACA amounts within SC after
to evaporation of ethanol. application of 1 x 300 μg/cm2 compared to 1 x
100 μg/cm2 were only significantly different
immediately after application, and were similar at
109
4 and 24 h. In ii), multiple applications of 3 x 100 diffusion cell in abdominal rat skin samples.
μg/cm2 yielded higher TACA amounts compared Accumulation of the drug in the surface and skin
to a single application of 1 x 300 μg/cm2 at 4 and layers was evaluated by both the TS technique
8 h. At 24 h, no difference was observed. In and a dissection technique. The results show that
conclusion, by using this simple vehicle, RA encapsulation not only prolongs drug release,
considerable TACA amounts were retained within but also promotes drug retention in viable skin. At
the SC, independently of dose and application the same time, interaction between RA and
frequency. hyaluronic acid has an obstructive effect on
diffusion, which contributes to the formation of a
1.3 Disinfectants reservoir.
Lboutounne et al. [72] investigated the sustained 1.5 Anesthetics

bactericidal activity of chlorhexidine base loaded
poly(Є-caprolactone) nanocapsules against Padula et al. [74] studied the behavior of a skin
Staphylococcus epidermidis inoculated onto bioadhesive film containing lidocaine, in vitro
porcine ear skin. The antimicrobial activity of and in vivo. Film characterization included in
these colloidal carriers was evaluated (i) in vitro vitro and in vivo drug transport studies with and
against eight strains of bacteria, and (ii) ex vivo without iontophoresis. The release rate was
against Staphylococcus epidermidis inoculated for compared with a lidocaine commercial gel. The
12 h onto porcine ear skin surface treated for 3 permeation kinetics across the skin was not linear,
min either with 0.6% chlorhexidine base loaded but the patch acted as a matrix controlling drug
or unloaded nanocapsules suspended in hydrogel, delivery. Additionally, permeation rate increased
or 1% chlorhexidine digluconate aqueous with drug loading. The in vivo experiments with
solution. Chlorhexidine absorption into the SC TS indicated that the presence of water during
was evaluated by the TS technique. The results film application is essential to achieve not only
showed that chlorhexidine nanocapsules in the proper adhesion, but also an effective
aqueous suspension with a 200–300 nm size and a accumulation. The application of an electric
positive charge exhibited similar minimum current to the patch can further increase the
inhibitory concentrations against several bacteria, amount of drug accumulated in the SC.
compared with chlorhexidine digluconate aqueous
solution. Ex vivo, there was a significant 1.6 Keratolytics
reduction in the number of colony forming units
from skin treated with chlorhexidine Bashir et al. [75] studied the keratolytic efficacy
nanocapsules suspension for 3 min compared to of topical preparations containing salicylic acid
chlorhexidine digluconate solution after an 8-h (SA) in humans by the TS technique, quantifying
artificial contamination. Interestingly, SC removal by protein analysis. In combination
nanocapsules were present in porcine hair with TS, squamometry was used to evaluate the
follicles. Topical application of chlorhexidine influence of SA on skin surface scaliness and
base-loaded positively charged nanocapsules in desquamation. Furthermore, skin barrier
an aqueous gel achieved a sustained release of perturbation and skin irritability were recorded
bactericide against Staphylococcus epidermidis and related to the dermatopharmacological effect
for at least 8 h. of the preparations. In contrast to squamometry,
TS combined with protein analysis was sensitive
1.4 Drugs for keratinization disorders in detecting the keratolytic effect of SA within
hours of application. Importantly, whereas the pH
Fresno-Contreras et al. [73] designed an all-trans of the preparations had only a minimal influence
retinoic acid (RA) topical release system that on efficacy, local dermatotoxicity was
modifies drug diffusion parameters in the vehicle significantly increased at an acidic pH.
and the skin in order to reduce systemic This indicates that the intent to increase
absorption and side-effects associated with the the amount of free, non-dissociated SA is, in fact,
topical application of the drug to the skin. RA, counterproductive, as more acidic preparations
either in free form or encapsulated in SC lipid resulted in skin irritation and barrier disruption.
liposomes, was included in hydrogels prepared
with Carbopol® UltrezTM 10 and hyaluronic
acid. In vitro permeability experiments with [3H]-
t-RA were carried out using a Franz-type
110
1.7 Retinoids and antioxidants 1.10 Anti-Varicella Zoster virus nucleoside
Abdulmajed et al. [76] used a novel synthetic Jarvis et al. [79] determined the in-vitro dermal
technique to synthesize the co-drug retinyl delivery of a new class of lipophilic, highly potent
ascorbate (RA-AsA) ester from all-trans-retinyl and uniquely selective anti-Varicella Zoster virus
chloride (RA) and l-ascorbic acid (AsA) nucleoside (VZV) analogue compared with
suspended in ethanol at low temperature. The flux aciclovir. Three test compounds (Cf1698, Cf1743,
and permeation coefficient were determined using and Cf1712) and acyclovir were formulated in
heat separated human skin membrane, and skin propylene glycol/aqueous cream, and finite doses
penetration was determined by TS using full- were applied to full-thickness pig ear skin for 48
thickness human skin. All experiments were hours in vertical Franz-type diffusion cells. Depth
performed in parallel with retinyl palmitate and profiles were constructed following TS and
ascorbyl palmitate. Overall, the data suggest the membrane separation. All three test compounds
potential value of RA-AsA co-drug for treating reached the target basal epidermis in
damage to skin resulting from UV-induced concentrations suggesting they would be highly
production of free radicals. efficacious in reducing viral load. Furthermore,
the data showed that each of the test compounds
1.8 Aquaporine-3 would have a far superior performance than
aciclovir. The dermatomal site of viral replication
Hara et al. [77] showed that glycerol replacement during secondary infection —the basal
corrects each of the defects in aquaporine-3 epidermis— was successfully targeted.
(AQP3)-null mice. SC water content, measured .
by skin conductance and 3H2O accumulation, was 1.11 Vaccines
3-fold lower in AQP3-null vs. wild-type mice, but
was similar after topical or systemic The skin-associated lymphoid tissue, formed by
administration of glycerol in amounts that powerful antigen-presenting cells (APCs), such as
normalized glycerol content in the SC. Orally Langerhans cells (LCs), dermal dendritic cells
administered glycerol fully corrected reduced skin (DCs), re-circulating T cells, and regional LNs,
elasticity in AQP3-null mice, as measured by the ensures the efficient presentation of antigen to
kinetics of skin displacement after suction, and immunocompetent cells and the induction of
the delayed barrier recovery, as measured by strong immune responses. LCs and dermal DCs
TEWL after TS. The analysis of [14C]glycerol commonly exist in the skin and are easy to target
kinetics indicated a reduced blood-to-SC transport [80]. The TS technique has been used to study the
of glycerol in AQP3-null mice, resulting in effect of oligodeoxynucleotides on the immune
slowed lipid biosynthesis. These data provide response [81] and expression of immune receptors
functional evidence for a physiological role of [82].
glycerol transport by aquaglyceroporin, and Inoue et al. [81] examined the effect of
indicate that glycerol is a major determinant of CpG-oligodeoxynucleotide (CpG-ODN) on the
SC water retention and of mechanical and immune response to an antigen applied to tape-
biosynthetic functions. Their findings establish a stripped mouse skin, by evaluating the production
scientific basis for the >200 year old empirical of cytokines and Ig isotypes. Confocal laser
practice of including glycerol in cosmetic and scanning microscopy revealed that the OVA
medicinal skin formulations. (model antigen) and CpG-ODN easily penetrated
the tape-stripped skin. Co-administration of CpG-
1.9 Antiviral drugs ODN and OVA to the disrupted skin elicited an
antigen-specific, Th1-predominant immune
Morgan et al. [78] measured the contribution of response, and enhanced the production of Th1-
SC barrier and microvascular perfusion in type cytokines, IL-12 and IFN-γ. On the other
determining dermal tissue levels of two hand, the production of a Th2-type cytokine, IL-4,
hydrophilic drugs (aciclovir and penciclovir) in was drastically suppressed. In terms of antigen-
vivo. Removal of the SC by TS resulted in a specific antibody production, the IgG2a level,
1300-fold increase in penciclovir absorption and a which is regulated by IFN-γ, was increased by
440-fold increase in aciclovir absorption, CpG-ODN, but IgE production regulated by IL-4
confirming that SC is the major barrier to was suppressed. Furthermore, the administration
hydrophilic drug absorption. of CpG-ODN through the skin drastically
attenuated the production of IgE in mice
111
experiencing IgE-type immune response. model, Psc,v, was 70% smaller. Calculations
Administration of CpG-ODN through the skin show that chemical concentrations in TSs can be
may shift the immune response from a Th2 to a affected by diffusion during TS, but with tTS < 0.2
Th1-like response. tlag and an exposure time > 0.3 tlag, TS
Continuing with their studies, Inoue et al. concentrations are not significantly affected by
[82] also demonstrated that TS induces the tTS.
expression of toll-like receptor (TLR)-9 in the Jakasa et al. [85] developed a sensitive
skin, and enhances the Th1-type immune method for the determination of polyethylene
response triggered by CpG-ODN administered glycols (PEGs) with different molecular weights
through the tape-stripped skin. TS induces the (MW) in the human SC obtained by TS. The
expression of TLR-9 and tumor necrosis factor analysis is based on derivatization with
(TNF)-α in the skin, and CpG-ODN treatment pentafluoropropionic anhydride and gas
through the tape-stripped skin enhances the chromatography–electron capture detection. The
migration of antigen-presenting cells to the method showed to be suitable for studying
draining lymph nodes. On the other hand, TLR-9 permeability in normal and impaired skin with
mRNA and TNF-α mRNA were not observed in respect to MW in the range of 150–600 Da.
the skin when CpG-ODN was injected In order to obtain more data to assess the
intradermally, or in Th1-type immune response. barrier function of uninvolved skin in atopic
The transdermal application of CpG-ODN with an dermatitis (AD) patients, Jakasa et al. [86]
antigen through the tape-stripped skin is an determined the percutaneous penetration of PEGs
effective way to induce a Th1-type immune of various molecular sizes in vivo in AD patients
response, and is also a simple, cost-effective and and control subjects using TS of the SC. The
needle-free vaccination system. apparent diffusion coefficient of PEGs through
atopic skin was twice as high as through normal
1.12 Other kind of permeants (Polyethylene skin, and decreased with increasing MW in both
glycols, 4-cyanophenol) groups. The partition coefficient in the skin of AD
patients was half of that for normal skin, but as
Ayala-Bravo et al. [83] investigated the effect of for normal skin, there was no MW dependence.
sucrose esters (sucrose oleate and sucrose laureate Although atopic skin exhibited an altered barrier
in water or Transcutol®, TC) on the SC barrier with respect to diffusion and partitioning, the
properties in vivo, and examined the impact of permeability coefficients were nearly the same for
these surfactant-like molecules on the in vivo atopic and normal skin. The results support the
percutaneous penetration of a model penetrant, 4- assumption of an altered skin barrier in AD
hydroxybenzonitrile (4-cyanophenol, 4CP). The patients, even if the skin is visibly unaffected by
effect of the enhancers on 4CP penetration was the disease.
monitored in vivo using ATR-FTIR spectroscopy Tsai et al. [87] further investigated the
in conjunction with TS of the treated site. A dependence of permeability on MW with different
combination of sucrose esters (oleate or laureate) forms of barrier disruption. A series of PEGs with
and TC is able to temporarily alter the SC barrier a MW ranging from nearly 300 to over 1000 Da
properties, thereby promoting 4CP penetration. were used to study the effects of TS and sodium
Results from TS experiments can be dodecyl sulphate (SDS) treatment on MW
affected significantly by chemical diffusion into permeability profiles of mouse skin in vitro. The
the SC during the time required to apply and total penetration of PEG oligomers across control
remove all of the TSs, tTS (period of time required skin and tape-stripped skin and SDS-treated to
to completely remove the SC by tape stripping). different degrees of barrier disruption
For this reason, Reddy et al. [84] studied dermal progressively decreased with increasing MW.
absorption of 4CP in humans using TS Penetration enhancement relative to control skin
experiments to assess the conditions under which was more prominent with larger molecules. The
diffusion alters TS results. Mathematical models MW cut-off for skin penetration increased with
were developed to assess the effects of diffusion the degree of barrier disruption, irrespectively of
on parameter estimation. In an experiment with the treatment applied, and was 986 Da (TS) and
tTS > tlag (i.e., the lag time for a chemical to cross 766 Da (SDS treatment) at TEWL levels in the
the SC), the permeability coefficient for 4CP, range of 10–20 g/m2 per h, compared with 414 Da
Psc,v, calculated including tTS, was consistent for control skin. The results strongly suggest that,
with the values from the literature. When regardless of the form of barrier disruption
diffusion during stripping was not included in the applied, not only higher amounts, but also more
112
varieties of chemicals (larger molecules), may sunscreen applied were compared with the
penetrate into the skin in the presence of a COLIPA (European Cosmetic Toiletry and
compromised barrier compared with normal skin. Perfumery Association) standard. Most volunteers
had applied 10% or less of the COLIPA standard
1.13 UV absorbers amount to all body sites assessed.
Mavon et al. [91] assessed the
Alvárez-Román et al. [88] determined whether penetration of titanium dioxide (TiO2) and
encapsulation of lipophilic compounds in methylene bis-benzotriazoyl
polymeric nanoparticles is able to improve topical tetramethylbutylphenol (MBBT), included in a
delivery to the skin. The penetration of octyl broad-spectrum sunscreen formulation, into
methoxycinnamate (OMC) encapsulated in human skin in vivo, using the TS technique, and
poly(Є-caprolactone) nanoparticles, into and in vitro, using a compartmental approach. More
across porcine ear skin in vitro, was investigated than 90% of both sunscreens were recovered in
using TS. the first 15 tape strippings. In addition, they have
Quantification of OMC in the skin using shown that the remaining 10% did not penetrate
TS demonstrated that nanoparticulate the viable tissue, but was localized in the furrows.
encapsulation produced a 3.4-fold increase in the Less than 0.1% of MBBT was detected in the
level of OMC within the SC. Nanoparticulate receptor medium, and no TiO2 was detected in the
encapsulation of OMC increased its “availability” follicles, the viable epidermis or the dermis. Thus,
within the SC. this in vivo and in vitro penetration study showed
Olvera-Martínez et al. [26] prepared an absence of TiO2 penetration into viable skin
polymeric nanocapsules (NCs) containing OMC, layers through either transcorneal or
and their in vivo distribution profile through the transfollicular pathways, and a negligible
SC was determined by the TS technique. The transcutaneous absorption of MBBT. However,
penetration degree of OMC formulated in NCs differences in distribution within the SC
was compared with that obtained for a reinforced the need for a complementary
nanoemulsion (NE) and a conventional oil-in- approach, using a minimally invasive in vivo
water (o/w) emulsion (EM). In vivo percutaneous methodology and an in vitro compartmental
penetration, evaluated by the TS technique, analysis. This combination represents a well-
demonstrated that NE increased the extent of adapted method for testing the safety of topically
OMC penetration relative to the penetration applied sunscreen formulations in real-life
achieved by NCs or EM. Likewise, OMC conditions.
accumulation in the skin was significantly greater
with NE than with EM or NCs. 1.14 Fragances
Sarveiya et al. [89] developed a reverse
HPLC assay to quantify four common sunscreen In-vitro human skin permeation and distribution
agents, namely, 2-hydroxy-4- of geranyl nitrile (GN) were determined by Brian
methoxybenzophenone, 2-ethylhexyl-p- et al. [92] using epidermal membranes, following
methoxycinnamate, octylsalicylate and salicylic application in 70% ethanol, under non-occlusive
acid 3,3,5-trimethcyclohexyl ester in a range of conditions, at maximum in-use concentration
biological matrices. This assay was further (1%). Levels of GN in the epidermis (plus any
applied to study skin penetration and systemic remaining in SC after TS), filter paper membrane
absorption of sunscreen filters after topical support, and receptor fluid were combined to
application to human volunteers. The assay produce a total absorbed dose value of
allows the analysis of sunscreen agents in 4.72±0.32%. The systemic exposure resulting
biological fluids, including bovine serum albumin from the use of GN as a fragrance ingredient,
solution, plasma and urine, and in human under unoccluded conditions, would be low based
epidermis by using the TS technique. The results on the currently reported use levels.
from the preliminary clinical study demonstrate a
significant penetration of all sunscreen agents into 1.15 Dyes
the skin.
Lademann et al. [90] determined the Teichmann et al. [93] developed a method to
amount of sunscreen present on the skin of people investigate the effectiveness of reservoir closure
at the beach. The amounts of sunscreen applied to by different formulations. Patent Blue V in water
different body sites were quantitatively was used as a model penetrant. Its penetration,
determined by TS. The actual amounts of with and without barrier cream treatment, was
113
analyzed by TS in combination with UV/VIS to further establishing the credibility of the tape
spectroscopic measurements. The investigations stripping technique, but also to demonstrate that
showed that the SC represents a reservoir for useful and relevant measurements can be made on
topically applied Patent Blue V in water. a surrogate, ex vivo skin model.
Furthermore, the barrier investigations showed
that vaseline and bees wax form a 100% barrier 2) Dermal absorption of toxic or irritant
on the skin surface. The third barrier cream, chemicals
containing waxes and surfactant, only partially
showed a protective effect against the penetration The rate and extent of dermal absorption are
of Patent Blue V in water. Strong inter-individual important in the analysis of risk from dermal
differences were observed for this barrier product. exposure to toxic chemicals, and for the
In conclusion, it was assumed that the application development of topically applied drugs, barriers,
of barrier creams cannot replace other protective insect repellents, and cosmetics, and the TS
measures, and should be used to inhibit low-grade technique has been widely used to determine the
irritants or in combination with other protectants, penetration of these kind of substances [36, 37,
or in body areas where other protective measures 95-97].
are not applicable. Mattorano et al. [36] developed and tested
Jacobi et al. [94] studied the penetration a simple, non-invasive dermal sampling technique
of highly hydrophilic (Patent blue V) and on 22 human volunteers to estimate acute dermal
lipophilic (curcumin) dyes into the skin using exposure to jet fuel (JP-8). Two sites on the
pure oil (o) or water (w), and comparing them ventral surface of each forearm were exposed to
with an o/w emulsion. The penetration and 25 μl of JP-8, and the SC was sequentially tape-
localization of both dyes were investigated in vivo stripped using an adhesive tape. The analysis of
using TS and microscopy techniques. Differences the first tape strips indicated that JP-8 was rapidly
in the distribution and the localization of both removed from the SC over the 20-min study
dyes within the SC were observed. These period. On average, after 5 min of exposure, the
differences depend on the physicochemical first two tape strips removed 69.8% of the applied
properties of both the vehicles and the dyes. The dose. The amount recovered with two tape strips
vehicle appears to affect, in particular, the decreased over time, to a recovery of 0.9% 20
penetration pathways. min after exposure. By fitting a mixed-effect
As we can observe, there is an ongoing linear regression model to the TS data, the authors
search for the identification of testing methods to were able to accurately estimate the amount of JP-
optimize topical dosage forms and to assess 8 initially applied. This study indicates that
topical drug bioavailability. While in vitro naphthalene has a short retention time in the
screening continues to play an important role (and human SC and that the TS technique, if used
is relatively inexpensive and easy to use), within 20 min of initial exposure, can be used to
regulatory approval of drug delivery systems to reliably measures the amount of naphthalene
the skin, with few exceptions, requires clinical initially present in the SC due to a single exposure
trials to be performed. For many drugs used to jet fuel.
topically, the problem remains unsolved, since an Chao et al. [37] presented a TS method
easily visualized pharmacodynamic response is for the removal and quantification of keratin from
not elicited. the SC for normalization of extracted
As a consequence, various alternative concentrations of naphthalene (as a marker for jet
techniques have been considered, of which SC fuel exposure) from 12 human volunteers before
tape-stripping is being given the greatest attention and after exposure to jet fuel (JP-8). Due to the
[7,26,35,63-94]. While the former is technically potential for removal of variable amounts of
more challenging, the potential reward is a drug squamous tissue from each tape strip sample,
concentration-time profile in a compartment keratin was extracted and quantified using a
presumed to be in close communication with the modified Bradford method. Naphthalene was
site of action of most dermatological drugs. The quantified in the sequential tape strips collected
latter, in contrast, offers an apparently easy and from the skin between 10 and 25 min after a
quite non-invasive methodology for skin tissue single dose of JP-8 was initially applied. The
sampling, and is the basis of the FDA’s so-called penetration of jet fuel into the SC was
DPK. Validation and optimization of the demonstrated by the fact that the average mass of
procedure have not come quickly. The goal of the naphthalene recovered by a tape strip decreased
research described here is not only to contribute with increasing exposure time and subsequent
114
tape strips. The actual concentration of Lundgren et al. [97] modified and tested a
naphthalene (as a marker for JP- 8 exposure) per vacuuming sampler for removing particles from
unit of keratin in a tape-strip sample can be the skin. The sampler was compared with two
determined by using this method, and may prove other skin and surface exposure sampling
necessary when measuring occupational techniques. These were based on surrogate skin (a
exposures under field conditions. patch sampler-adhesive tape on an optical cover
Van der Merwe et al. [95] described a glass) and a TS removal procedure. All three
physiologically based pharmacokinetic model samplers measure the mass of dust on the skin.
developed to simulate the absorption of Dust containing starch was deposited onto the
organophosphate pesticides, such as parathion, skin in a whole-body exposure chamber. Samples
fenthion, and methyl parathion through porcine were taken from forearms and shoulders and
skin with flow-through cells. Three parameters analysed using optical microscopy. With the
were optimized based on experimental dermal different sampling techniques, small differences
absorption data, including solvent evaporation in results were obtained. There was a good
rate, diffusivity, and a mass transfer factor. agreement between the vacuuming sampler and
Diffusion cell studies were conducted to validate the TS technique.
the model under a variety of conditions, including
different dose ranges (6.3–106.9 μg/cm2 for 3) Evaluation of factors that influence the
parathion; 0.8–23.6 μg/cm2 for fenthion; 1.6–39.3 physiology of the stratum corneum
μg/cm2 for methyl parathion), different solvents
(ethanol, 2-propanol and acetone), different Many factors are known to influence the
solvent volumes (5–120 μL for ethanol; 20–80 μL physiology of the SC. In this way, increasing age
for 2-propanol and acetone), occlusion versus is related to decreased skin thickness [98] and a
open to atmosphere dosing, and corneocyte variation in skin lipids [99] and flora [100]. The
removal by TS. The study demonstrated the utility anatomical region also influences lipid
of PBPK models for studying dermal absorption. distribution [101, 102], microflora [103] and
The similarity between the overall shapes of the physical parameters such as TEWL [104].
experimental and model-predicted flux/time However, there are already a few studies
curves and the successful simulation of altered reporting conflicting results for the effect of
system conditions for this series of small, gender [105] on skin physiology, as well as for
lipophilic compounds, indicated that the the effect of anatomical site, pressure, pressure
absorption processes described in the model duration and tape removal rate in skin physiology
successfully simulated important aspects of [42], or the effect of skin transport technology, as
dermal absorption in flow-through cells. These iontophoresis, on human skin [106].
data have a direct relevance in the assessment of Jacobi et al. [105] studied the effect of
topical organophosphate pesticides’ risk. gender on the physiology of the SC. The
Jongh et al. [96] studied whether sodium physiological parameters: TEWL, pH value,
lauryl sulphate (SLS) penetration rate into the SC hydration and sebum content were determined on
is related to an impairment of skin’s water barrier the flexor forearms of 6 female and 6 male
function and inflammation. The penetration of volunteers. In addition, SC samples, removed by
SLS into the SC was assessed using a non- TS, were studied for amount, spectroscopic
invasive TS procedure in 20 volunteers after a 4-h properties, protein content, and mass. The skin of
exposure to 1% SLS. Additionally, the effect of a women was characterized by a significantly
24-h exposure to 1% SLS on the skin water higher pH value (5.6±0.4) than that of men
barrier function was assessed by measuring (4.3±0.4). Protein absorption was the only other
TEWL. A multiple regression analysis showed parameter significantly dependent on gender.
that the baseline TEWL, SC thickness and SLS Both effects might be caused by differences in
penetration parameters K (SC ⁄water partition human biology, such as hormonal status.
coefficient) and D clearly influenced the increase Therefore, volunteers’ gender should be
in TEWL after the 24-h irritation test. They found considered in dermatologic studies.
that variation in barrier impairment and Löffler et al. [43] investigated the
inflammation of human skin depends on SLS’ influence of the procedures (anatomical site,
penetration rate, which was mainly determined by pressure, pressure duration, tape removal rate)
SC thickness. inherent to each stripping protocol on changes in
skin physiology. A significant influence of all
parameters on TEWL increase, as a function of
115
tape strip number was observed. The fastest SC lipid composition. For this purpose, SC
increase was demonstrated on the forehead, samples were collected by sequential stripping
followed by the back and, lastly, the forearm. with Leukoplex tape in five healthy volunteers.
Rapid removal produced a protracted increase Lipids were extracted with an ethyl acetate:
compared with slow removal. Pressure for 10s methanol mixture (20:80) and separated by means
induced a faster increase in TEWL than 2s of HPTLC. The results of this study revealed that
pressure. Likewise, pressure at 330 g cm-2 the free fatty acid level is higher, and cholesterol
induced an earlier increase than pressure at 165 g and ceramide levels are lower in the uppermost
cm-2. Skin hydration was not influenced by the SC layers. Levels remained unchanged in the
variables tested. underlying SC layers. In these layers, the
Van der Molen, et al. [44] investigated the ceramide level was about 60 wt % and free fatty
efficacy of TS in removing complete cell layers acid and cholesterol levels were about 20 wt %
from the superficial part of the human SC. A each. Ceramides could be separated into seven
histological section of skin that was tape-stripped different fractions, and the relative amounts of
20 times, clearly showed non-stripped skin in the individual ceramide fractions did not significantly
furrows, indicating persistent incomplete TS. change with the SC depth. The method developed
Replicates of tape-stripped skin surface allowed to study the differences in the SC lipid
demonstrated that even after removing 40 tape profile in healthy and diseased human skin
strips, furrows were still present. They emphasize relative to the SC lipid organization and the skin
that the results from studies using the TS method barrier function in vivo.
have to be viewed from the perspective that cells
on one tape strip of the SC may come from 5) Determination of stratum corneum thickness
different layers, depending on the position of the
tape strip in relation to furrow slope, and such Alberti et al. [108] evaluated, using attenuated
results should be interpreted with considerable total reflectance Fourier transform infrared
caution. spectroscopy, the SC bioavailability of terbinafine
Fatouros et al. [106] investigated the local (TBF) following topical treatment with four
changes in the ultrastructure of human skin after different formulations, based on a vehicle
iontophoresis in human skin in vitro and in vivo. consisting of 50% ethanol and 50% isopropyl
Human dermatomed skin was subjected to passive myristate. Three of these formulations included a
diffusion for 6 hours, followed by nine hours of percutaneous penetration enhancer: either 5%
iontophoresis at 0.5mA/cm2. In addition, oleic acid, 10% 2-pyrrolidone or 1% urea. The SC
iontophoresis patches were applied to healthy concentration profile of TBF was measured by
volunteers for 3.5h with 0.5h of passive delivery repeated infrared spectroscopic measurements
followed by 3h of iontophoresis at a current while sequentially stripping off the layers of this
density of 0.25mA/cm2. Subsequently, a series of barrier membrane with adhesive tape. TEWL
TSs were performed, and were visualized by measurements were also performed, to permit
freeze-fracture transmission electron microscopy. facile estimation of SC thickness. The SC
In vitro/in vivo studies suggest that iontophoresis concentration profiles of TBF were fitted to the
results in the formation of intercellular water appropriate solution of Fick's second law of
pools, and in a weakening of the desmosomal diffusion. This analysis enabled the efficacies of
structure only in the upper part of the SC. the different formulations tested to be compared
However, no changes in lipid organization were to the non-enhancer control. While it was found
observed in vitro and in vivo at the 0.5 and that the formulation containing 5% oleic acid
0.25mA/cm2 current densities, respectively. significantly enhanced the SC availability of TBF,
Therefore, even at relatively high current the other formulations did not improve the
densities, no drastic changes in the ultrastructure apparent drug delivery.
of the SC are observed. As far as structural Kalia et al. [109] determined whether a
changes in SC are concerned, iontophoresis is a structurally heterogeneous biomembrane, human
safe method under the experimental conditions SC, behaved as a homogeneous barrier to water
used. transport. Impedance spectra (IS) of the skin and
measurements of the rate of TEWL were recorded
4) Stratum corneum composition sequentially in vivo in human subjects as layers of
the SC were progressively removed by the serial
Weerheim et al. [107] established a suitable application of adhesive tape strips. The low-
analytical method for the determination of local frequency impedance of skin was much more
116
significantly affected by TS than the higher Forslund et al. [113] investigated 229
frequency values; removal of the outermost SC immunocompetent patients tested for human
layer had the largest effect. In contrast, TEWL papilloma virus (HPV) DNA in swab samples
changed little as the outer SC layers were stripped collected on top of skin tumors and in biopsies of
off, but increased dramatically when 6-8 microns the same tumors, obtained after stripping with
of the tissue had been removed. It follows that the tape to remove superficial layers. HPV DNA was
two noninvasive techniques probe SC barrier detected on top of 69% of the lesions, and in 12%
integrity in somewhat different ways. After SC of the stripped biopsies. A difference was seen for
removal, recovery of barrier function, as assessed the four types of tumors studied. Seborrheic
by increasing values of the low-frequency keratosis had 79% HPV positivity on top of
impedance, apparently proceeded faster than lesions versus 19% in biopsies; actinic keratosis
TEWL decreased to the pre-stripping control. The had 83% HPV positivity on top of lesions versus
variation of TEWL as a function of SC removal 11% in biopsies; basal cell carcinoma had 63% on
behaved in a manner entirely consistent with a top of lesions versus 8% in biopsies; and
homogeneous barrier, thereby permitting the squamous cell carcinoma had 58% on top of
apparent SC diffusivity of water to be found. Skin lesions versus 19% in biopsies. HPV DNA is
impedance (low frequency) was correlated with common in superficial layers of lesions, but is not
the relative concentration of water within the SC, necessarily present in tumors.
thus providing an in vivo probe for skin hydration.
Finally, the SC permeability coefficient to water, 7) Skin regeneration
as a function of SC thickness, was calculated and
correlated with the corresponding values of skin Malminen et al. [114] investigated the expression
admittance derived from IS. of tight junction components during
reepithelialization of suction blisters and
6) Determination of superficial infections and regeneration of the corneal layer after TS. Suction
viruses blisters were induced in eight healthy volunteers,
and skin biopsies were taken 4 or 6 days
Topical infections due to S. aureus and S. afterwards. The restoration of epidermal barrier
pyogenes are clinically relevant and cause a function was evaluated by measuring water
variety of serious symptoms, including toxic evaporation (WE) from the wound area. TS was
shock syndrome and skin lesions [110], that can performed on three volunteers to remove the
progress to sepsis and systemic shock if they are corneal layer. Prior to the biopsies, WE from the
left untreated [111]. These bacterial species are blister wounds was markedly elevated compared
also the most common causes of impetigo in with normal skin. In the epidermis surrounding
humans [111]. The TS technique has offered the the blister, occludin and ZO-1 (membrane-
possibility of studying superficial infections on associated guanylate kinase homologue protein
the skin [112], as well as viruses in skin tumors family) were expressed in the granular cell layer
[113]. only. In the hyperproliferative zone adjacent to
Kugelberg et al. [112] presented a new the border of the blister, the expression of ZO-1
animal model for the purpose of studying was redistributed into several spinous cell layers,
superficial infections. In this model, an infection while occludin expression was restricted to the
is established by disruption of the skin barrier by upper epidermis. In the leading edge of migrating
partial removal of the epidermal layer by TS and keratinocytes, both proteins were expressed solely
subsequent application of the pathogens in the most superficial layer of keratinocytes.
Staphylococcus aureus and Streptococcus Double labelling for ZO-1 and involucrin showed
pyogenes. The infection and the infection route expression of both proteins in the same layers of
were purely topical. Thus, the present model is hyperproliferative keratinocytes, while the
considered more biologically relevant for the expression patterns were clearly different in
study of superficial skin infections in mice and migrating keratinocytes. Tight junctions of
humans. Established topical antibiotic treatments regenerating epidermis may provide a functional
are shown to be effective. The procedures barrier prior to regeneration of the corneal layer.
involved in the model are simple, a feature that Sekkat et al. [115] developed an in vitro
increases throughput and reproducibility. This model for the developing skin of the premature
new model should be applicable to the evaluation neonate. Barriers of different levels of efficiency
of novel antimicrobial treatments for superficial were produced by differential tape-stripping of
infections caused by S. aureus and S. pyogenes. the SC from the skin of excised porcine ears, and
117
were characterized by measurements of TEWL. In outermost skin layer, the SC, is a fast and
this way, it was possible to express the recorded relatively non-invasive technique for measuring
TEWL as a function of percentage SC thickness the rate and extent of dermal absorption. Tape
(F), generating the following relationship: TEWL stripping data have been used to estimate
= 2.7+41.exp [-0.028.F]. These data were then permeability coefficients and partition
compared to previously published in vivo coefficients, SC mass, barrier function, drug
measurements of TEWL obtained from a reservoir from in vivo dermal exposures, and even
population of premature neonates at various post- to explain the SC physiology. TS has also been
conceptional ages (PCA). The former showed a proposed as a method for evaluating the
remarkably parallel relationship to that found in bioequivalence of topical dermatological dosage
vitro with the porcine skin model, namely TEWL forms. DPK characterization of the penetration of
= 3.3+41 exp [-0.026.(PCA-160)]. Therefore, it active drugs in human volunteers has been
can be suggested that the empirically adjusted suggested to be able to replace comparative
PCA (i.e., PCA-160) has a close correlation with clinical trials as means of documenting
the developing thickness of the neonate’s SC. bioequivalence. It is suggested that DPK
Consequently, porcine skin in vitro, tape-stripped assessment of drug concentrations in the SC is
to a particular level, can provide a barrier comparable to blood/urine measurements of
corresponding to a specific degree of neonate systemically administered drugs, where the
maturation, and thus, can serve as a useful tool to concentration of a drug in the SC is expected to
explore whether transdermal drug delivery in this relate to its concentrations in viable tissue. Short-
unique patient population may be beneficial. contact DPK experiments can be used to obtain
Zhai et al. [116] used an in vivo human diffusion and partitioning parameters that may
model to define the irritation potential of a topical subsequently be able to predict drug penetration
agent after partial removal of the SC by into the SC following longer application periods.
cellophane TS. The tape was applied to and Although tape stripping is widely used to
removed approximately 50 times (mean, 50.0 +/- determine dermal absorption through the SC,
16.7) from each test site on the volar aspect of the several factors can influence the actual technique.
forearm. TEWL was measured before and daily Recent reviews on this topic provide updated and
for 5 days. The TEWL values at baseline after additional insights (117, 118). The investigation
stripping represented the point of maximal of variations in skin condition (dry versus moist
stripping barrier disruption. The barrier disruption skin, skin defects, etc.) to determine their
and irritation potential were assessed with TEWL potential impact on the sampling method is
measurements. The results showed that the model warranted. For these reasons, the tape stripping
topical agent had no adverse effect on barrier technique requires further development.
repair, i.e. did not interfere with TEWL
normalization. This model provides a method for Acknowledgments
the prediction, with exaggerated sensitivity, of
chemical irritation and proclivity to enhance or José Juan Escobar-Chávez wishes to acknowledge
retard water barrier repair. They believe that the the PROFIP/UNAM grant. The authors also thank
model may predict the response of low irritation the financial support from PAPIIT/UNAM
materials and may be more sensitive than patch (Reference IN213205).
testing on normal skin, particularly for products to
be used on certain areas, e.g. the face, anus, etc.,
or even mucous membranes.
Conclusions
The quantification of drugs within the skin is

essential for topical and transdermal delivery
research. Over the last two decades, horizontal
sectioning, consisting of TS, has been the
traditional investigative technique.
Many in vivo methods for measuring
dermal absorption of chemicals are invasive (e.g.,
blood sampling) or slow (e.g., urine samples
collected for extended periods). TS of the
118
Table 1. Research on the tape stripping technique as a method to determine skin permeation of different kind of
permeants
1) Kinetics and penetration depth of drugs
Research Outcome Author (Ref.)-Year
Effect of Azone® and Transcutol® The combination of Azone® and Escobar-Chávez et al. (7),
on skin permeation of sodium Transcutol® in PF-127 gels enhanced 2005.
naproxen formulated in PF-127 sodium naproxen penetration, with up
gels. to two-fold enhancement ratios
compared with the formulation
containing Transcutol® only.
Administration of piroxicam from The total amount of drug recovered in Curdy et al. (35), 2001
a commercially available gel to the SC post-iontophoresis by TS was
human volunteers, both passively significantly higher than that found
and under the application of an following passive diffusion for each
iontophoretic current. application time.
Effect of hydroxypropyl-P- The enhancing effect of HP-P-CD on Arima et al. (63), 1998
cyclodextrin (HP-P-CD) on the the cutaneous penetration of EBA
cutaneous penetration and would be largely attributable to an
activation of ethyl 4-biphenylyl increase in the effective concentration
acetate (EBA), a prodrug of non- of EBA in the ointment.
steroidal anti-inflammatory drug 4-
biphenylylacetic acid (BPAA),
from hydrophilic ointment, using
hairless mouse skin in vitro.
Production and characterization of Reflectance spectroscopy demonstrated Esposito et al. (64),

monoleine (MO) dispersions as that indomethacin incorporated into 2005
drug delivery systems for MO dispersions can be released in a
indomethacin. prolonged fashion. TS experiments
corroborated this finding.
Unilaminar films of Eudragit E- In vivo penetration studies showed no Ganem-Quintanar et al.

100 prepared from naproxen- statistical differences for the penetrated (65), 2006
loaded nanoparticles vs. amount of naproxen across the SC and
conventional films. the depth of penetration for the two
films. The films formulated from
nanoparticle dispersions were shown to
be effective for the transdermal
administration of naproxen.
Investigation of pig ear skin as a Pig ear skin ex vivo is promising as a Herkenne et al. (66), 2006
surrogate for human skin in the tool for topical formulation evaluation
assessment of topical drug and optimization.
bioavailability by sequential TS of
the SC.
Examination of the diffusion of Copper will oxidize and may penetrate Hostýnek et al. (67), 2006
copper through human SC in vivo the stratum corneum after forming an
following application of the metal ion pair with skin exudates. The rate of
as powder on the volar forearm for reaction seems to depend on contact
periods of up to 72 h. time and oxygen availability. A marked
119
inter-individual difference was

observed in baseline values and the
amounts of copper absorbed.
Comparison of the bioavailability The comparison of the amount of Lodén et al. (68), 2004
of ketoprofen in a photostabilised ketoprofen in the skin after 45 min with
gel formulation without the amount penetrated through the
photoprotection using a new excised skin during 36 h, suggests a
dermatopharmacokinetic TS model change in the thermodynamic activity
and an established ex vivo of ketoprofen during exposure.
penetration method using human
skin.
Penetration kinetics of SLs Gel preparation showed a decrease in Wagner Steffen et al. (69),
(sesquiterpene lactones) in Arnica penetration rate, whereas the 2006
montana preparations, by using a penetration rate of ointments remained
stripping method with adhesive constant over time. The total amount of
tape and pig skin as a model. SLs penetrated depends only on the
kind of formulation and the SLs-
content, but not on SLs composition or
on the extraction agent used.
Penetration experiments A direct linear correlation was found Wagner Heike et al. (70),
investigating several incubation between the SC/water partition 2002
times with three different skin coefficients and the drug amounts
flaps, using the Saarbruecken penetrated into the SC for all time
penetration model and the intervals tested.
lipophilic model drug flufenamic
acid.
Effect of dose and application Considerable TACA amounts were Pallenda et al. (71), 2006
frequency on the penetration of retained within the SC, independently
triamcinolone acetonide (TACA) of dose and application frequency.
into human SC in vivo.
Sustained bactericidal activity of Topical application of chlorhexidine Lboutounne et al. (72),

chlorhexidine base loaded poly(Є- base-loaded positively charged 2002
caprolactone) nanocapsules against nanocapsules in an aqueous gel
Staphylococcus epidermidis achieved a sustained release of
inoculated onto porcine ear skin. bactericide against Staphylococcus
epidermidis for at least 8 h.
Design of an all-trans retinoic acid RA encapsulation not only prolongs Fresno-Contreras et al.
(RA) topical release system that drug release, but also promotes drug (73), 2005
modifies drug diffusion parameters retention in viable skin.
in the vehicle and the skin, in order
to reduce the systemic absorption
and side-effects associated with the
topical application of the drug to
the skin.
Behaviour of a skin bioadhesive In vivo experiments with TS indicated Padula et al. (74), 2003
film containing lidocaine in vitro that the presence of water during film
and in vivo. application is essential to achieve not
only the proper adhesion, but also an
effective accumulation.
120
Keratolytic efficacy of topical TS combined with protein analysis was Bashir et al. (75), 2005
preparations containing salicylic sensitive in detecting the keratolytic
acid in humans by TS, and effect of salicylic acid within hours of
quantification of SC removal by application.
protein analysis.
Novel synthetic technique to The data suggest the potential value of Abdulmajed et al. (76),
synthesize the co-drug retinyl RA-AsA co-drug for treating damage 2004
ascorbate (RA-AsA) ester from all- to skin resulting from UV-induced
trans-retinyl chloride (RA) and l- production of free radicals.
ascorbic acid (AsA) suspended in
ethanol at low temperature.
Glycerol replacement corrects each The findings establish a scientific basis Hara et al. (77), 2003
of the defects in aquaporine-3 for the >200-yr-old empirical practice
(AQP3)-null mice. of including glycerol in cosmetic and
medicinal skin formulations due to its
influence on water retention and the
mechanical and biosynthetic functions
of the SC.
Contribution of SC barrier and There was no relationship between Morgan et al. (78), 2003
microvascular perfusion in fibre depth and the amount of drug
determining dermal tissue levels of dialysed, which suggests free
hydrophilic drugs (aciclovir and movement of antiviral drug on reaching
penciclovir) in vivo. the aqueous environment of the dermis.
Determination of the in-vitro Topical delivery of these compounds is Jarvis et al. (79), 2004
dermal delivery of a new class of highly promising as a new first line
lipophilic, highly potent and treatment for VZV infections.
uniquely selective anti-VZV
nucleoside analogue compared
with aciclovir.
Effect of CpG Administration of CpG ODN through Inoue et al. (81,82), 2005,
oligodeoxynucleotide (CpG-ODN) skin is a simple strategy for patients 2006
on the immune response to an with diseases like atopic dermatitits,
antigen applied to tape-stripped which is characterized by Th2-
mouse skin by evaluating the dominated inflammation.
production of cytokines and Ig
isotypes.
Effect of sucrose esters (sucrose A combination of sucrose esters (oleate Ayala-Bravo et al. (83),
oleate and sucrose laureate in or laureate) and TC is able to 2003
water or Transcutol®, TC) on the temporarily alter the SC barrier
SC barrier properties in vivo. properties, thereby promoting 4-HB
Impact of these molecules on the in penetration.
vivo percutaneous penetration of 4-
hydroxybenzonitrile (4-HB).
Absorption of 4-cyanophenol Chemical concentrations in TSs can be Reddy et al. (84), 2002
(4CP) in humans using TS affected by diffusion during tape
experiments to assess the stripping, but with tTS < 0.2 tlag and an
conditions under which diffusion exposure time > 0.3 tlag, TS
alters tape stripping results. concentrations are not significantly
121
affected by tTS.
Development of a sensitive method The method showed to be suitable for Jakasa et al. (85, 86), 2004,
for the determination of studying permeability in normal and 2007
polyethylene glycols with different impaired skin with respect to MW in
molecular weights (MW) in the the range of 150–600 Da.
human SC obtained by TS.
Dependence of permeability on Irrespectively of the form of barrier Tsai et al. (87), 2003
molecular weight with different disruption, not only higher amounts,
forms of barrier disruption. but also more varieties of chemicals
(larger molecules) may penetrate into
the skin in the presence of a
compromised barrier, compared with
normal skin.
Penetration of octyl Nanoparticulate encapsulation of OMC Alvarez-Román et al.

methoxycinnamate (OMC) increased its “availability” within the (88), 2004
encapsulated in poly(Є- SC.
caprolactone) nanoparticles, into
and across porcine ear skin in
vitro.
In vivo distribution profile of OMC NE increased the extent of OMC Olvera-Martínez et al (26),
contained in nanocapsules (NCs) penetration relative to the penetration 2005
through the SC. Comparison with a achieved by NCs or EM.
nanoemulsion (NE) and a
conventional o/w emulsion (EM).
Quantification of four common A preliminary clinical study Sarveiya et al. (89), 2004
sunscreen agents, namely 2- demonstrates a significant penetration
hydroxy-4 methoxybenzophenone, of all sunscreen agents into the skin, as
2-ethylhexyl-p-methoxycinnamate, well as of oxybenzone and its
2-ethylhexylsalicylate metabolites across the skin.
(octylsalicylate) and salicylic acid
3,3,5-trimethcyclohexyl ester in a
range of biological matrices.
Amount of sunscreen present on The best protected areas were the upper Lademann et al (90), 2004
the skin of people at the beach. arm and décolleté, but even in these
areas, most volunteers had applied only
10% of the COLIPA standard amount.
Penetration of titanium dioxide In vivo and in vitro penetration studies Mavon et al. (91), 2007
(TiO2) and methylene bis- showed an absence of TiO2 penetration
benzotriazoyltetramethylbutyl- into viable skin layers through either
phenol (MBBT), included in a transcorneal or transfollicular
broad-spectrum sunscreen pathways, and a negligible
formulation, into human skin in transcutaneous absorption of MBBT.
vivo, using the TS method, and in
vitro, using a compartmental
approach.
In vitro human skin permeation Systemic exposure resulting from the Brian et al. (92), 2007
and distribution of geranyl nitrile use of GN as a fragrance ingredient,
(GN) under unoccluded conditions, would be
122
low based on the currently reported use

levels.
Development of a method to Application of barrier creams cannot Teichmann et al. (93),

investigate the effectiveness of replace other protective measures and 2006
reservoir closure by different should be maximally used to inhibit
formulations. Model penetrant: low-grade irritants or in combination
Patent Blue V. with other protectants, or in body areas
where other protective measures are
not applicable.
Penetration of highly hydrophilic Differences in the distribution and the Jacobi et al. (94), 2006
and lipophilic dyes into the skin localization of both dyes within the SC
using pure oil or water, comparing were observed. These differences
them with an o/w emulsion. depend on the physicochemical
properties of both the vehicles and the
dyes.
2) Dermal absorption of toxic or irritant chemicals
Development and testing of a Naphthalene has a short retention Mattorano et al. (36), 2004
simple, non-invasive dermal time in the human SC and the tape
sampling technique on human stripping method, if used within 20
volunteers under laboratory min of the initial exposure, can be
conditions to estimate acute dermal employed to measure the amount of
exposure to jet fuel (JP-8). naphthalene in the SC due to a single
exposure to jet fuel.
Normalization of extracted The amount of keratin removed with Chao et al. (37), 2004
concentrations of naphthalene (as a tape strips was not affected by an
marker for jet fuel exposure) from exposure of up to 25 min to JP-8, and
human volunteers, before and after there was a substantial decrease in the
exposure to jet fuel (JP-8). amount of keratin removed with
Removal and quantification of consecutive tape strippings from the
keratin by stratum corneum TS same site; thus, adjusting the amount
of naphthalene to the amount of
keratin measured in a tape-strip
sample should improve the
interpretation of the amount of this
analyte by using this sampling
approach.
Description of a physiologically The study demonstrated the utility of Van der Merwe et al. (95),
based pharmacokinetic (PBPK) PBPK models for studying dermal 2006
model developed to simulate the absorption, which can be useful as
absorption of organophosphate explanatory and predictive tools.
pesticides, such as parathion,
fenthion, and methyl parathion,
through porcine skin with flow-
through cells.
Study of whether the sodium lauryl Variation in barrier impairment and Jongh et al (96), 2006
sulphate (SLS) penetration rate inflammation of human skin depends
into the SC is related to an on SLS penetration rate, which was
123
impairment of skin’s water barrier mainly determined by SC thickness.

function and inflammation.
Modification and testing of a Agreement between the vacuuming Lundgren et al. (97), 2006
vacuuming sampler for removing sampler and the TS technique.
particles from the skin.
3) Evaluation of factors that influence the physiology of the stratum corneum.
Research Outcome Author (Ref.)
Effect of gender on the physiology The skin of women was characterized Jacobi et al. (105), 2005
of the SC. by a significantly higher pH value
(5.6±0.4) than that of men (4.3±0.4).
Protein absorption was the only other
parameter significantly dependent on
gender.
Influence of procedures inherent to Skin hydration was not influenced by Löffler et al. (43), 2004
each stripping protocol on changes the variables tested.
in skin physiology.
Efficacy of TS in removing Furrows in the skin can present Van der Molen et al. (44),
complete cell layers from the difficulties when performing depth 1997
superficial part of human SC. penetration studies. Although the
largest part of the skin surface will be
stripped properly, it has to be realized
that small areas, represented by
furrows, may still contain high
concentrations of the substance
applied.
Local changes in the ultrastructure No drastic changes in the Fatouros et al. (106), 2006
of human skin after iontophoresis ultrastructure of the SC were
in human skin in vitro and in vivo. observed.
4) Stratum corneum composition
Establishment of a suitable Study of the differences in the SC Weerheim et al. (107), 2001
analytical method for the lipid profile in healthy and diseased
determination of the local SC lipid human skin relative to the SC lipid
composition. organization and to the skin barrier
function in vivo.
5) Stratum corneum thickness
Evaluated, using attenuated total It was found that the formulation Alberti et al. (108),2001
reflectance Fourier transform containing 5% oleic acid significantly
infrared spectroscopy, the SC enhanced the SC availability of TBF.
bioavailability of terbinafine (TBF)
following topical treatment with
four different formulations, based
124
on a vehicle consisting of 50%

ethanol and 50% isopropyl
myristate.
Determined whether a structurally The variation of TEWL as a function Kalia et al. (109), 1996
heterogeneous biomembrane, of SC removal behaved in a manner
human SC, behaved as a entirely consistent with a
homogeneous barrier to water homogeneous barrier, thereby
transport. permitting the apparent SC diffusivity
of water to be found.
6) Determination of superficial infections and viruses
Research Outcome Author (Ref.)- Year
New animal model for the purpose Evaluation of novel antimicrobial Kugelberg et al. (110), 2005
of studying superficial infections. treatments for superficial infections
caused by S. aureus and S.
pyogenes.
Immunocompetent patients were HPV DNA is common in superficial Forslund et al. (111), 2004
tested for human papilloma virus layers of lesions, but is not
(HPV) DNA in swab samples necessarily present in tumors.
collected on top of skin tumors and
in biopsies of the same tumors,
obtained after stripping with tape
to remove superficial layers.
7) Skin regeneration
Expression of tight junction Tight junctions of regenerating Malminen et al. (112), 2003
components during the epidermis may provide a functional
reepithelialization of suction barrier prior to regeneration of the
blisters and the regeneration of the corneal layer.
corneal layer after TS.
In vitro model for the developing Porcine skin, in vitro, tape-stripped to Sekkat et al. (113), 2002
skin of the premature neonate. a particular level, can provide a
barrier corresponding to a specific
degree of neonate maturation, and
thus, can serve as a useful tool to
explore whether transdermal drug
delivery in this unique patient
population may be beneficial.
An in vivo human model was This model provides a method for the Zhai et al. (114), 1998
utilized to define the irritation prediction, with exaggerated
potential of a topical agent after sensitivity, of chemical irritation and
partial removal of the stratum proclivity to enhance or retard water
corneum by cellophane tape barrier repair.
stripping
125
REFERENCES
[1]. Bommannan D, Potts RO, Guy RH. and Drug Administration (FDA), Rockville,
Examination of stratum corneum barrier Maryland, November 29, (2001).
function in vivo by infrared spectroscopy. J [13]. Pershing LK. Bioequivalence assessment of
Invest Dermatol 95: 403–408, (1990). three 0.025% tretinoin gel products:
[2]. Higo N, Naik A, Bommannan DB, Potts RO, dermatopharmacokinetic vs clinical trial
Guy R. H. Validation of reflectance infrared methods, advisory committee for
spectroscopy as a quantitative method to pharmaceutical sciences meeting, Center for
measure percutaneous absorption in vivo. Drug Evaluation and Research (CDER), Food
Pharm Res.10:1500–1505, (1993). and Drug Administration (FDA), Rockville,
[3]. Lotte C, Wester RC, Rougier A, Maibach HI. Maryland, November 29, (2001).
Racial differences in the in vivo percutaneous [14]. Touitou E, Meidan VM, Horwitz E. Methods
absorption of some organic compounds: a for quantitative determination of drug localized
comparison between black, Caucasian and in the skin. J Control Rel. 56:7–21, (1998).
Asian subjects. Arch Dermatol Res. 284:456– [15]. Moser K, Kriwet K, Naik A, Kalia YN, Guy R.
459, (1993). H. Passive skin penetration enhancement and its
[4]. \Pershing LK, Silver BS, Krueger GG, Shah quantification in vitro. Eur J Pharm Biopharm.
VP, Skelley JP. Feasibility of measuring the 52:103-112, (2001).
bioavailability of topical betamethasone [16]. Pinkus H. Tape stripping in dermatological
dipropionate in commercial formulations using research. A review with emphasis on epidermal
drug content in skin and a skin blanching biology. G Ital Dermatol Minerva Dermatol.
bioassay. Pharm Res. 9:45–51, (1992). 107(5):1115-26, (1966).
[5]. Rougier A, Dupuis D, Lotte C, Roguet R, [17]. Forslind BA. Domain mosaic model of skin
Wester RC, Maibach HI. Regional variation in barrier. Acta Derm Venereol. 74:1-6, (1994).
percutaneous absorption in man: measurement [18]. Potts RO, Francoeur ML. The influence of
by the stripping method. Arch Dermatol Res. stratum corneum morphology on water
278:465–469, (1986). permeability. J Invest Dermatol. 96, 495-499,
[6]. Tojo K, Lee AC. A method for prediction of (1991).
steady-state of skin penetration in vivo. J [19]. Potts RO, Guy RH. Predicting skin
Invest. Dermatol., 92:105–108, (1989). permeability. Phar. Res, 9(5): 663-669, (1992).
[7]. Escobar-Chávez JJ, Quintanar-Guerrero D, and [20]. Ellias PM. Epidermal barrier function:
Ganem-Quintanar A. In vivo skin permeation of intercellular lamellar lipid structures, origin,
sodium naproxen formulated in PF-127 gels: composition and metabolism, J Control Rel. 15,
Effect of Azone® and Transcutol®, Drug 199-208, (1991).
Develop Ind Pharm. 31:447-454, (2005). [21]. Barry BW. Dermatological Formulations:
[8]. Pinkus H. Examination of the epidermis by the Percutaneous Absorption. In: Swarbick J, ed.
strip method of removing horny layers. I. Drugs and the Pharmaceutical Sciences. New
Observation on thickness of the horny layer, York and Basel: Marcel Dekker, Inc. p.202,
and on mitotic activity after stripping. J. Invest. (1983).
Dermatol., 16:383–386, (1951). [22]. Hadgraft J. Skin, the final frontier. Int J Pharm.
[9]. King CS, Barton SP, Nicholls S, Marks R. The 224 (1-2):1-18, (2001).
change in properties of the stratum corneum as [23]. Guy RH and Hadgraft J. Transdermal drug
a function of depth. Br J Dermatol., 100:165– delivery. New York: Marcel Dekker, Inc., p. 1-
172, (1979). Repetido 43 23, (2003).
[10]. Shah VP. Topical Dermatological Drug Product [24]. Walters KA and Roberts MS. Dermatological
NDAs and ANDAs-In Vivo Bioavailability, and transdermal formulations. New York:
Bioequivalence, In Vitro Release and Marcel Dekker, Inc., p. 1-39, (2002).
Associated Studies, US Department of Health [25]. Nevill AM. The need to scale for differences in
and Human Services, Rockville, (1998). body size and mass: and explanation of
[11]. Conner DP: Differences in DPK Methods. Klieber´s 0.75 mass exponent. Am Physiol Soc.
http://www.fda.gov/ 2870-2873, (1994).
ohrms/dockets/ac/01/slides/3804s2_05_conner/i [26]. Olvera-Martínez BI, Cazares-Delgadillo J,
ndex.htm, Advisory Committee for Calderilla-Fajardo SB, Villalobos-García R,
Pharmaceutical Sciences Meeting, Center for Ganem-Quintanar A, Quintanar-Guerrero D.
Drug Evaluation and Research (CDER), Food Preparation of polymeric nanocapsules
and Drug Administration (FDA), Rockville, containing octyl methoxycinnamate by the
Maryland, November 29, (2001). emulsification–diffusion technique: Penetration
[12]. Franz TJ. Study #1, Avita Gel 0.025% vs Retin- across the stratum corneum. J Pharm Sci.
A Gel 0.025%, Advisory committee for 94:1552–1559, (2005).
pharmaceutical sciences meeting, Center for [27]. Escobar-Chávez JJ, López-Cervantes M, Naïk
Drug Evaluation and Research (CDER), Food A, Kalia YN, Quintanar-Guerrero D, Ganem-
126
Quintanar A. Applications of the corneum and upper epidermis. Acta Derm

thermoreversible Pluronic F-127 gels in Venereol (Stockh). 74: 375–379, (1994).
pharmaceutical formulations, J Pharm [41]. Bashir, S. J., Chew, A. L., Anigbogu, A.
Pharmaceut Sci. 9(3):339-358, (2006). Physical and physiological effects of stratum
[28]. Miyazaki S, Yokouchi Ch, Nakamura T, corneum tape stripping. Skin Res Technol.
Hashiguchi N, Hou W-M, and Takada M. 7:40–48, (2001).
Pluronic F-127 gels as a novel vehicle for rectal [42]. Marttin E, Neelissen-Subnel MTA, De Haan
administration of indomethacin, Chem Pharm FHN, Boddé HE. A critical comparison of
Bull.34, 1801-1808, (1986). methods to quantify stratum corneum removed
[29]. Chi SCh, Do K, Tan HK, and Chun HW. Anti- by tape-stripping. Skin Pharmacol. 9:69–77,
inflammatory and analgesic transdermal gel, (1996).
United States Patents., Patent number [43]. Löffler H, Dreher F, Maibach HI. Stratum
5,527,832, (1996). corneum adhesive tape stripping: influence of
[30]. Fang JY, Leu YL, Wang YY, and Tsai YH. In anatomical site, application pressure, duration
vitro topical application and in vivob and removal. Br J Dermatol. 151: 746–752,
phramacodynamic evaluation of nonivamide (2004).
hydrogels using Wistar rat as an animal model, [44]. Van der Molen RG, Spies F, Van ‘t Noordende
Eur. J Pharm Sci. 15(5):417-423, (2002). JM, Boelsma E, Mommaas AM, Koerten HK.
[31]. Shin SC, Cho CW, and Oh IJ. Effects of non Tape stripping of human stratum corneum
ionic surfactants as permeation enhancers yields cell layers that originate from various
towards piroxicam from the poloxamer gel depths because of furrows in the skin. Arch
through rat skins, Int J Pharm. 222(2), 199-203, Dermatol Res. 289:514–518, (1997).
(2001). [45]. Surber C, Schwarb FP, Fmith EW. Tape
[32]. Liaw J, and Lin Y-Ch. Evaluation of stripping technique. In: Percutaneous
poly(ethylene oxide)-poly(propylene oxide)- Absorption – Drug – Cosmetics – Mechanisms
poly(ethylene oxide) (PEO-PPO-PEO) gels as – Methodology (Bronough H, Maibach HI,
a release vehicle for percutaneous fentanyl, J eds), 3rd ed. New York: Marcel Dekker, 395–
Control. Rel. 68:273-282, (2000). 409, (1999).
[33]. Wang YY, Hong CT, Chiu WT, and Fang JY. [46]. Nangia A, Camel E, Berner B. Influence of skin
In vitro and in vivo evaluations of topically irritants on percutaneous absorption. Pharm
applied capsaicin and nonivamide from Res.10:1756–1759, (1993).
hydrogels, Int J Pharm. 224,1-2, (2001). [47]. Van Voorst Vader PC, Lier JG, Woest TE.
[34]. Kattan El, A. F., Asbill, C. S., Kim, N., and Patch tests with house dust mite antigens in
Michniak, B. B. Effect of formulation variables atopic dermatitis patients: methodological
on the percutaneous permeation of ketoprofen problems. Acta Derm. Venereol
from gel formulations, Drug Deliv. 7,3, (2000). (Stockh).,71:301–305, (1991).
[35]. Curdy C, Kalia YN, Naïk A, Guy RH. [48]. Surakka J, Johnsson S, Rosen G. A method for
Piroxicam delivery into human stratum measuring dermal exposure to multifunctional
corneum in vivo: iontophoresis versus passive acrylates. J Environ Monit.1:533–540, (1999).
diffusion. J Control Rel. 76, 73-79, (2001). [49]. Kondo H, Ichikawa Y, Imokawa G.
[36]. Mattorano DA, Kupper LL, Nylander-French Percutaneous sensitization with allergens
LA. Estimating dermal exposure to jet fuel through barrier-disrupted skin elicits a Th2-
(naphthalene) using adhesive tape strip dominant cytokine response. Eur J Immunol.
samples. Ann Occup Hyg. 48(2): 139–146, 28: 769–779, (1998).
(2004). [50]. Fluhr JW, Gloor M, Lehmann L. Glycerol
[37]. Chao Y-Ch, Nylander-French LA. accelerates recovery of barrier function in vivo.
Determination of Keratin Protein in a Tape- Acta Derm Venereol (Stockh). 79:418–21,
stripped Skin Sample from Jet Fuel Exposed (1999).
Skin. Ann Occup Hyg. 48(1):65–73, (2004). [51]. Pechere M, Krischer J, Remondat C.
[38]. Tsai J-C, Weiner ND, Flynn GL, Ferry J. Malassezia spp. Carriage in patients with
Properties of adhesive tapes used for stratum seborrheic dermatitis. J Dermatol. 26:558–61,
corneum stripping, Int J Pharm. 72: 227-231, (1999).
(1991). [52]. Pechere M, Remondat C, Bertrand C. A simple
[39]. Sheth NV, McKeough MB, Spruance SL. quantitative culture of Malassezia spp. in HIV-
Measurement of the stratum corneum drug positive persons. Dermatology.191:348–349,
reservoir to predict the therapeutic efficacy of (1995).
topical iododeoxyuridine for herpes simplex [53]. Ghadially R, Brown BE, Sequeira-Martin SM.
virus infection. J Invest Dermatol. 89: 598–602, The aged epidermal permeability barrier.
(1987). Structural, functional, and lipid biochemical
[40]. Ohman H, Vahlquist A. In vivo studies abnormalities in humans and a senescent
concerning a pH gradient in human stratum murine model. J Clin Invest.95:2281–90,
(1995).
127
[54]. Van der Valk PG, Maibach HI. A functional nanoparticle dispersión. J Nanosci
study of the skin barrier to evaporative water Nanotechnol. 6(9-10):3235-3241, (2006).
loss by means of repeated cellophane-tape [66]. Herkenne C, Naik A, Kalia YN, Hadgraft J,
stripping. Clin Exp Dermatol.15:180–2, (1990). Guy RH. Pig ear skin ex vivo as a model for in
[55]. Hostynek JJ, Dreher F, Pelosi A. Human vivo dermatopharmacokinetic studies in man.
stratum corneum penetration by nickel. In vivo Pharm Res. 23(8), 1850-1856, (2006).
study of depth distribution after occlusive [67]. Hostýnek JJ, Dreher F, Maibach HI. 2006.
application of the metal as powder. Acta Derm Human stratum corneum penetration by copper:
Venereol (Stockh).212 (Suppl.):5–10, (2001). In vivo study after occlusive and semi-
[56]. Lademann J, Otberg N, Richter H. Investigation occlusive application of the metal as powder.
of follicular penetration of topically applied Food Chem Toxicol. 44:1539–1543, (2006).
substances. Skin Pharmacol Appl Skin Physiol. [68]. Lodén M, Akerstrom U, Lindahl K, Berne B.
14 (Suppl.1):17–22, (2001). 2004. Bioequivalence determination of topical
[57]. Wilhelm KP, Surber C, Maibach HI. Effect of ketoprofen using a dermatopharmacokinetic
sodium lauryl sulfate- induced skin irritation on approach and excised skin penetration. Int J
in vivo percutaneous penetration of four drugs. Pharm. 284:23–30, (2004).
J Invest Dermatol. 97:927–32, (1991). [69]. Wagner S and Merfort I. Skin penetration
[58]. Schafer U. Topical Absorption of behaviour of sesquiterpene lactones from
Dermatological Products. Robert L. Bronaugh different Arnica preparations using a validated
and Howard I. Maibach (Editors), Marcel GC-MSD method. J Pharm Biomed Anal. In
Dekker, New York, Basel, 544 p, (2001). press, (2006).
[59]. Shah VP, Flynn GL, Yacobi A, Maibach HI, [70]. Wagner H, Kostka K-H, Lehr C-M, Schaefer
Bon C, Fleischer NM, Franz TJ, Kaplan SAJK, UF. Correlation between stratum
Lesko LJ, Marty JP, Pershing LK, Schaefer H, corneum/water-partition coefficient and
Sequeira JA, Shrivastava SP, Wilkin J, amounts of flufenamic acid penetrated into the
Williams RL. Bioequivalence of topical stratum corneum. J Pharm Sci. 91(8):1915-
dermatological dosage forms-methods of 1921, (2002).
evaluation of bioequivalence. Pharm Res. 15, [71]. Pellanda C, Ottiker E, Strub C, Figueiredo V,
167–171, (1998). Rufli T, Imanidis G, Surber C. Topical
[60]. Surakka J, Lindh T, Rosen G. Workers’ dermal bioavailability of triamcinolone acetonide:
exposure to UV-curable acrylates in the Effect of dose and application frequency. Arch
furniture and parquet industry. Ann Occup Hyg. Dermatol Res. 298:221–230, (2006).
44:635–44, (2000). [72]. Lboutounne H, Chaulet JF, Ploton C, Falson F,
[61]. Nylander-French LA. A tape-stripping method Pirot F. Sustained ex vivo skin antiseptic
for measuring dermal exposure to activity of chlorhexidine in poly(e-
multifunctional acrylates. Ann Occup Hyg. caprolactone) nanocapsule encapsulated form
44:645–51, (2000). and as a digluconate. J Control Rel.82:319–334,
[62]. Howes D, Guy R, Hadgraft J, Heylings J, (2002).
Hoeck U, Kemper F, Maibach H, Marty JP, [73]. Fresno-Contreras MJ, Jiménez-Soriano MM,
Merk H, Parra J, Rekkas D, Rondelli I, Ramírez-Diéguez A. In vitro percutaneous
Schaefer H, Täuber U, Verbiese N. Methods for absorption of all-trans retinoic acid applied in
assessing percutaneous absorption. The report free form or encapsulated in stratum corneum
and recommendations of ECVAM workshop lipid liposomes. Int J Pharm. 297:134–145,
13. ATLA 24, 81–106, (1996). (2005).
[63]. Arima H, Miyajib T, Irie T, Hirayama F, [74]. Padula C, Colombo G, Nicoli S, Catellani PL,
Uekamaa K. 1998. Enhancing effect of Massimo G, Santi P. Bioadhesive film for the
hydroxypropyl-P-cyclodextrin on cutaneous transdermal delivery of lidocaine: in vitro and
penetration and activation of ethyl 4-biphenylyl in vivo behaviour. J Control Rel. 88: 277–285,
acetate in hairless mouse skin. Eur J Pharm Sci. (2003).
6:53-59, (1998). [75]. Bashir SJ, Dreher F, Chew AL, Zhai H, Levina
[64]. Esposito E, Cortesi R, Drechsler M, C, Stern R, Maibach HI. 2005. Cutaneous
Paccamiccio L, Mariani P, Contado C, Stellin bioassay of salicylic acid as a keratolytic. Int J
E, Menegatti E, Bonina F, Puglia C. Cubosome Pharm. 292:187–194, (2005).
dispersions as delivery systems for [76]. Abdulmajed K and Heard ChM. Topical
percutaneous administration of indomethacin. delivery of retinyl ascorbate co-drug 1.
Pharm Res., 22(12):2163-2173, (2005). Synthesis, penetration into and permeation
[65]. Ganem-Quintanar A, Silva-Alvarez M, across human skin. Int J Pharm. 280:113–124,
Alvarez-Roman R, Casas-Alancaster N, (2004).
Cazares-Delgadillo J, Quintanar-Guerrero D. [77]. Hara M, Verkman AS. Glycerol replacement
Design and evaluation of a self –adhesive corrects defective skin hydration, elasticity, and
naproxen-loaded film prepared from a barrier function in aquaporin-3-deficient mice.
PNAS. 100(12):7360–7365, (2003).
128
[78]. Morgan CJ, Renwick AG, Friedmann PS. The [90]. Lademann J, Schanzer S, Richter H, Pelchrzim
role of stratum corneum and dermal RV, Zastroe L, Golz K, Sterry W. Sunscreen
microvascular perfusion in penetration and application at the beach. J Cosmet
tissue levels of water-soluble drugs investigated Dermatol.3(2):62-68, (2004).
by microdialysis. Br J Dermatol. 148:434–443, [91]. Mavon A, Miguel C, Lejeune O, Payre B,
(2003). Moretto P. In vitro percutaneous absorption and
[79]. Jarvis CA, McGuigan C, Heard CM. In vitro in vivo stratum corneum distribution of an
delivery of novel, highly potent anti-Varicella organic and mineral sunscreen. Skin Pharmacol
Zoster virus nucleoside analogues to their target Physiol. 20(1):10-20, (2007).
site in the skin. Pharm Res. 21(6):914-919, [92]. Brian KR, Green DM, Lalko J, Api AM. In-
(2004). vitro human skin penetration of the fragrance
[80]. Strid J, Hourihane J, Kimber I, Callard R, material geranyl nitrile. Toxicology in Vitro
Strobel S. Disruption of the stratum corneum 21:133–138, (2007).
allows potent epicutaneous immunization with [93]. Teichmann A, Jacobi U, Waibler E, Sterry W,
protein antigens resulting in a dominant Lademann J. An in vivo model to evaluate the
systemic Th2 response. Eur J efficacy of barrier creams on the level of skin
Immunol.34:2100–9, (2004). penetration of chemicals. Contact Dermatitis.
[81]. Inoue J, Yotsumoto S, Sakamoto T, Tsuchiya S, 54:5–13, (2006).
Aramaki Y. Changes in immune responses to [94]. Jacobi U, Tassopoulos T, Surber C, Lademann
antigen applied to tape-stripped skin with CpG J. Cutaneous distribution and localization of
oligodeoxynucleotide in mice. J Control Rel. dyes affected by vehicles all with different
108:294– 305, (2005). lipophilicity. Arch Dermatol Res. 297:303–310,
[82]. Inoue, J. and Aramaki, Y. 2006. Toll-like (2006).
receptor-9 expression induced by tape-stripping [95]. Van der Merwe D, Brooks JD, Gehring R,
triggers on effective immune response with Baynes RE, Monteiro-Riviere NA, Riviere JE.
CpG-oligodeoxynucleotides. Vaccine. In press, A physiologically based pharmacokinetic
(2006). model of organophosphate dermal absorption.
[83]. Ayala-bravo HA, Quintanar-Guerrero D, Naik Toxicol Sci. 89(1):188–204, (2006).
A, Kalia YN, Cornejo-Bravo JM, Ganem- [96]. De Jongh CM, Jakasa I, Verberk MM, Kezic S.
Quintanar A. 2003. Effects of sucrose oleate Variation in barrier impairment and
and sucrose laureate on in vivo human stratum inflammation of human skin as determined by
corneum permeability. Pharm Res.20 (8):1267- sodium lauryl sulphate penetration rate. Br J
1273, (2003). Dermatol. 154:651–657, (2006).
[84]. Reddy MB, Stinchcomb AL, Guy RH, Bunge [97]. Lundgren L, Skare L, Lidén C. Measuring dust
AL. Determining dermal absorption parameters on skin with a small vacuuming sampler—A
in vivo from tape strip data. Pharm. Res., comparison with other sampling techniques.
19(3):292-298, (2002). Ann Occup Hyg.50(1):95–103, (2006).
[85]. Jakasa I, Calkoen F, Kezic S. Determination of [98]. Leveque JL, Corcuff P, de Rigal J, Agache, P.
polyethylene glycols of different molecular In vivo studies of the evolution of physical
weight in the stratum corneum. J Chromatogr properties of the human skin with age. Int J
B. 811:177–182, (2004). Dermatol. 23:322–329, (1984).
[86]. Jakasa I, Verbek MM, Esposito M, Bos JD, [99]. Denda M, Koyama J, Hori J, Horii I, Takahashi
Kezic S. Altered penetration of polyethylene M, Hara M, Tagami H. Age- and sex-dependent
glycols into uninvolved skin of atopic change in stratum corneum sphingolipids. Arch
dermatitis patients. J Investigative Dermatol. Dermatol Res. 285:415–417, (1993).
127:129–134, (2007). [100]. Somerville DA. The normal flora of the skin in
[87]. Tsai J-C, Shen L-C, Sheu HM, Lu C-C. Tape different age groups. Br J Dermatol. 81:248–
stripping and sodium dodecyl sulfate treatment 258, (1980).
increase the molecular weight cut-off of [101]. Schurer NY, Plewig G, Elias PM. Stratum
polyethylene glycol penetration across murine corneum lipid function. Dermatologica.
skin. Arch Dermatol Res. 295:169–174, (2003). 183:77–94, (1991).
[88]. Alvarez-Román R, Naik A, Kalia YN, Guy RH, [102]. Cua AB, Wilhelm KP, Maibach HI. Skin
Fessi H. Enhancement of topical delivery from surface lipid and skin friction: Relation to age,
biodegradable nanoparticles. Pharm Res. sex and anatomical region. Skin Pharmacol.
21(10):1818-1825, (2004). 8:246–251, (1995).
[89]. Sarveiya V, Risk S, Benson HAE. Liquid [103]. Marples RR. Sex, constancy, and skin bacteria.
chromatographic assay for common sunscreen Arch Dermatol Res. 272: 317–320, (1982).
agents: application to in vivo assessment of skin [104]. Fluhr JW, Dickel H, Kuss O, Weyher I,
penetration and systemic absorption in human Diepgen TL, Berardesca E. Impact of
volunteers. J Chromatogr B. 803:225–231, anatomical location on barrier recovery, surface
(2004). pH and stratum corneum hydration after acute
129
barrier disruption. Br J Dermatol. 146: 770– superficial skin infection model in mice by
776, (2002). using Staphylococcus aureus and Streptococcus
[105]. Jacobi U, Gautier J, Sterry W, Lademann J. pyogenes. Antimicrob Agents
Gender-Related Differences in the Physiology Chem.49(8):3435–3441, (2005).
of the Stratum Corneum. Dermatology. [113]. Forslund O, Lindelöf B, Hradil E, Nordin-
211:312–317, (2005). Stenquist B, Kirnbauer R, Slupetzky K, Dillner
[106]. Fatouros DG, Groeninka HWM, De Graaff J. High prevalence of cutaneous human
AM, Van Aelst AC, Koertenc HK, Bouwstra papillomavirus DNA on the top of skin tumors
JA. Visualization studies of human skin in but not in ‘‘Stripped’’ biopsies from the same
vitro/in vivo under the influence of an electrical tumors. J Invest Dermatol.123:388-394, (2004).
field. Eur J Pharm Sci.29:160–170, (2006). [114]. Malmminen M, Koivukangas V, Peltonen J,
[107]. Weerheim A. Ponec M. Determination of Karvonen S-L, Oikarinen A, Peltonen S.
stratum corneum lipid profile by tape stripping Immunohistological distribution of the tight
in combination with high-performance thin- junction components ZO-1 and occludin in
layer chromatography. Arch Dermatol regenerating human epidermis. Br J Dermatol.
Res.293:191–199, (2001). 149:255–260, (2003).
[108]. Alberti, I., Kalia, Y. N., Naik, A., Bonny, J. D., [115]. Sekkat N, Kalia YN, Guy RH. Biophysical
& Guy, R. H. In vivo assessment of enhanced study of porcine ear skin in vitro and its
topical delivery of terbinafine to human stratum comparison to human skin in vivo. J Pharm Sci.
corneum. J Control Rel. 71(3), 319–327, 91(11):2376-2381, (2002).
(2001). [116]. Zhai H, Poblete N, and Maibach HI. Stripped
[109]. Kalia, Y. N., Pirot, F., & Guy, R. H. skin model to predict irritation potential of
Homogeneous transport in a heterogeneous topical agents in vivo in humans. Int J
membrane: water diffusion across human Dermatol, 37(5), 386-389, (1998).
stratum corneum in vivo. Biophys J. 71(5), [117]. Choi MJ, Zhai H, Kim J-H, Maibach HI. Tape
2692–2700, (1996). stripping method versus stratum corneum. In:
[110]. Alouf JE, Muller-Alouf H. Staphylococcal and Zhai H, Wilhelm KP, & Maibach HI (eds.):
streptococcal superantigens: molecular, Dermatotoxicology, 7th edition.CRC Press,
biological and clinical aspects. Int J Med Boca Raton, 327-337, (2008).
Microbiol.292:429–440, (2003). [118]. Löffler H, Weimer C, Dreher F, Maibach HI.
[111]. George A, Rubin G. A systematic review and Parameters influencing stratum corneum
meta-analysis of treatments for impetigo. Br J removal by tape stripping. In: Zhai H, Wilhelm
Gen Pract. 53:480-487, (2003). KP, & Maibach HI (eds.): Dermatotoxicology,
[112]. Kugelberg E, Norström T, Petersen TK, Duvold 7th edition. CRC Press, Boca Raton, 339-342,
T, Andersson DI, Hughes D. Establishment of a (2008).
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The Tape-Stripping Technique As A Method For Drug Quantification in Skin

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J Pharm Pharmaceut Sci (www. cspsCanada.

org) 11 (1): 104-130, 2008

The Tape-Stripping Technique as a Method for Drug Quantification in

Figure 1. Layers of human skin.

Figure 2. Processes of percutaneous absorption and transdermal delivery.

Figure 3. The tape stripping technique procedure

Lboutounne et al. [72] investigated the sustained 1.5 Anesthetics

1.7 Retinoids and antioxidants 1.10 Anti-Varicella Zoster virus nucleoside

The quantification of drugs within the skin is

1) Kinetics and penetration depth of drugs

Research Outcome Author (Ref.)-Year

Production and characterization of Reflectance spectroscopy demonstrated Esposito et al. (64),

Unilaminar films of Eudragit E- In vivo penetration studies showed no Ganem-Quintanar et al.

inter-individual difference was

Sustained bactericidal activity of Topical application of chlorhexidine Lboutounne et al. (72),

Penetration of octyl Nanoparticulate encapsulation of OMC Alvarez-Román et al.

low based on the currently reported use

Development of a method to Application of barrier creams cannot Teichmann et al. (93),

2) Dermal absorption of toxic or irritant chemicals

Research Outcome Author (Ref.)-Year

impairment of skin’s water barrier mainly determined by SC thickness.

3) Evaluation of factors that influence the physiology of the stratum corneum.

Research Outcome Author (Ref.)

4) Stratum corneum composition

Research Outcome Author (Ref.)-Year

5) Stratum corneum thickness

Research Outcome Author (Ref.)-Year

on a vehicle consisting of 50%

6) Determination of superficial infections and viruses

Research Outcome Author (Ref.)- Year

Research Outcome Author (Ref.)-Year

Quintanar A. Applications of the corneum and upper epidermis. Acta Derm

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