Dermal substance collection method

A dermal substance collection device (DSCD) is described which provides ms for the non-invasive, instantaneous and continuous monitoring of chemical substances which are present in a detectable amount in either or both interstitial fluid or sweat or which are on or in the skin. The transdermal substance collection device of this invention is comprised of three essential components: (1) a substance binding reservoir, wettable by (2) a liquid transfer medium which allows for liquid bridge transfer of a soluble substance from the skin surface to the binding reservoir by virtue of its wettability by the liquid, and (3) an occlusive cover.

FIELD OF THE INVENTION 
This invention relates to a convenient integral or self-contained 
non-invasive dermal substance collection device easily reversibly 
attachable to a dermal surface for use in detection, routine monitoring 
and research in the areas of compliance With therapeutic regimens and 
exposure to substances of abuse or environmental toxic chemicals or 
xenobiotics, and investigation of endogenous substances. 
BACKGROUND OF THE INVENTION 
A variety of imperfect techniques are available to assess human exposure to 
chemicals. Detection of environmental levels of chemicals by means of, for 
example, air sampling devices fails to yield information on actual extent 
of body exposure e.g., actual entry into the body. Most known techniques 
for assessing the actual extent of body exposure to chemicals suffer from 
their invasiveness (e.g. tissue biopsies, blood sampling) or their 
impracticality (e.g. collection of urine or saliva). With the exception of 
continuous urine collections, most known systems do not provide 
information on cumulative exposure over a period of time. 
A system which addresses the need to provide detection of a drug material 
with correlation with time in order to obtain useful information 
concerning drug absorption, excretion, metabolism rates and metabolites is 
described in U.S. Pat. No. 3,649,199 to D. P. Littlejohn; however, 
attachment of the patient to the analytical instrumental is required. This 
patent describes a method for detecting trace quantities of an organic 
drug material in a living animal which involves passing a sample of 
gaseous material effusing from the animal by breath, through the skin or 
from the blood stream through a multi-stage membrane gas separator to 
enrich the concentration of the organic drug material in the gaseous 
sample. The enriched sample gas output of the membrane separator is fed to 
a gas analyzer such as a mass spectrometer for detection of the organic 
drug material. This patent describes the obtention of a sample of gaseous 
material from a region immediately adjacent the skin of the animal by 
means of a gas impervious sleeve clamped to the forearm of a person for 
the containment of a carrier gas such as nitrogen or helium. 
U.S. Pat. No. 3,552,929 to R. P. Fields et al. describes a device for 
detecting halide ion concentration in a fluid such as human perspiration 
for the diagnosis of cystic fibrosis. The device is used in conjunction 
with an absorptive sweat collection patch which is described as a piece of 
filter paper under a polyethylene overlayer to prevent evaporation. 
U.S. Pat. No. 4,329,999 to M. Phillips is directed to a clinical test 
device more specifically described as a sweat collection patch for 
monitoring a human patient for the presence of sweat-excreted drugs such 
as alcohol. Other drugs such as digoxin, lithium, anti-convulsants, or 
morphine excreted in sweat are also disclosed as detectable by the patch 
but no specific details or experiments are provided. The patch device 
according to this patent is disclosed as inexpensive, easy to use, 
non-intrusive and capable of yielding accurate and precise measurements in 
that the patch is capable of collecting sweat in a continuous manner and 
at a steady rate. The circular shaped patch is described as including a 
backing member, a stripping member, a base, a collecting pad and a cover 
member having an adhesive surface contiguous to the collecting pad. This 
patent further discloses that the collecting pad includes a plurality of 
layers of polyester-type absorbent material formed by a certain method 
including thoroughly wetting the polyester with a saturated aqueous 
solution of sodium chloride and subsequently causing the precipitation of 
sodium chloride in the polyester material The discs formed from the dried 
polyester are then wetted with a solution, preferably containing Nystatin, 
sodium fluoride and reduced methylene blue. This patent discloses that the 
Nystatin is used to inhibit fungal proliferation since fungi could cause 
metabolic breakdown of ethanol and/or metabolic breakdown of glucose in 
sweat to ethanol and methanol. The sodium fluoride is described as 
inhibiting anaerobic glycolysis in bacteria and fungi and hence the 
production of ethanol. The reduced methylene blue is used as a visual 
indicator when the patch is removed since in a wet patch it turns bright 
blue in the presence of oxygen. This patent further discloses that 
magnesium sulfate, fructose or urea may be used in lieu of sodium chloride 
in that this patch element must be an osmotically active highly soluble 
crystalloid. 
The patch according to this patent is said to yield for drug assay 
virtually all of the collected sweat when, presumably, the pad of the 
patch is spun in a specially constructed centrifuge tube. The reverse flow 
of sweat from the absorbent pad in the cover member chamber through the 
base member is described as controlled by the relative size and 
orientation of the base member hole and the chamber containing the pad 
which is said to permit sweat to easily enter the absorbent pad but 
inhibit the reverse flow of sweat out of the chamber. 
An earlier sweat collecting device is described in M. Phillips, R. E. 
Vandervoort and C. E. Becker, "Long-term Sweat Collection Using Salt 
impregnated Pads"; J. Invest. Dermatol., 68:221-224 (1977). The pad 
described therein was a square cut from a commercially available 
disposable diaper material consisting of a layer of absorbent cotton 
sandwiched between a sheet of waterproof polyurethane on one side and two 
layers of porous, woven rayon on the other. Both sodium chloride 
impregnated as well as control pads were prepared. The device 
incorporating this pad was constructed by applying to the patient an 
adhesive template, then placing the pad over the template, covering the 
pad with a square of this plastic sheet and thereafter sealing the 
assembled device in place on the patient with a square of waterproof 
adhesive tape. 
The foregoing work, inter alia, is referred to in C. C. Peck, M. Phillips, 
C. E. Becker and K. L. Melmon "Drug Measurement in Sweat: A New Approach 
in Clinical Pharmacology", Abstracts, Fifth Pharmacology-Toxicology 
Program Symposium, National Institute of General Medical Sciences, p. 29; 
(1977). 
The authors, noting problems created by intermittent or erratic alcohol 
ingestion, disclosed the undertaking of a theoretical analysis to 
determine technical requirements for an optimal sweat collection device 
which involved mathematical simulation of the dynamics of a drug in sweat 
assuming drug disposition with one compartment, zero or first-order 
excretion kinetics and first-order transfer of drug between the body and 
the sweat collection device. The authors disclose the conclusion that (1) 
sweat flow into the device must be continuous and constant, (2) drug 
losses from the device, both external and back-transfer into the body, 
must be minimized, (3) drug bound in the device must be extractable for 
qualitative analysis, and (4) the sweat collection device should be small 
(&lt;2 cm.sup.2), safe, and acceptable to the subject being studied. It is 
stated that development of a suitable sweat collection device may 
contribute particularly to the study of bioavailability, to the clinical 
assessment of compliance with therapeutic regimens, and to the diagnosis 
of addictive states such as alcoholism. 
A later article by M. Phillips, "An Improved Adhesive Patch For Long-Term 
Collection of Sweat", Biomat., Med. Dev., Art. Org., 8(1), 13-21 (1980), 
refers to the practical limitations of the adhesive skin patch of the 
above-referred to M. Phillips et al. 1977 article and describes the 
structure and structure and evaluation of an improved adhesive patch 
similar in some respects to that described in U.S. Pat. No. 4,329,999 to 
M. Phillips. The use of soluble crystalloid material such as sodium 
chloride, magnesium sulfate, urea, fructose and sucrose is disclosed. The 
adhesive patch device of the M. Phillips et al. 1977 article was also 
referred to in C. C. Peck et al., "Continuous Transepidermal Drug 
Collection:Basic for Use in Assessing Drug Intake and Pharmacokinetics", 
J. Pharmacokinetics and Biopharmaceutics 9(1):41-58 (1981) which report 
explores a theoretical basis for the use of transepidermal drug collection 
in assessing various aspects of drug pharmacokinetics, with emphasis on 
its use in the quantitation of cumulative amount of drug exposure. The 
influence and implications of single and polyexponential drug disposition 
kinetics; zero-, first-order, and Michaelis-Menten excretion functions; 
and back transfer of drug from the collection device were explored. 
The M. Phillips et al. 1977 article and the M. Phillips 1980 article Were 
also referred to in C. C. Peck et al. "Mechanism of Noninvasive Collection 
of Substances Dissolved in Interstitial Fluid", Clinical Research, Vol. 
30, No. 2 (256A) April 1982. This excerpt reports test of the hypothesis 
that the transepidermal fluid collection method according to M. Phillips 
can be used to collect substances dissolved in interstitial fluid by 
application to rabbits, a species without sweat glands. Collection devices 
according to the Phillips 1980 paper were tested on the rabbits for 
detection of .sup.22 Na with observations leading to postulation of a 
mechanistic theory of transepidermal fluid collection of non-volatile 
substances dissolved in interstitial fluid: (1) pre-wetting the Phillips 
pads leads to hydration of stratum corneum, thus increasing its 
permeability to substances in the interstitial fluid; (2) hydrated stratum 
corneum acts as a semi-permeable membrane separating two aqueous regions; 
(3) movement of substances from interstitial fluid across stratum corneum 
into the Phillips collection device follows thermodynamic principles. Peck 
et al. conclude that this theory is consistent with that postulated 
previously by Peck et al. (1981) and should be tested in man. 
The device of the Phillips (1980) article as well as the theoretical 
analysis of Peck et al. (1981) was also treated in C. C. Peck et al., "A 
Noninvasive Transepidermal Toxicological Monitoring Device", Pittsburgh 
Conference and Exposition on Analytical Chemistry and Applied 
Spectroscopy, p. 366 Abstract, 1982. Therein is disclosed the modification 
of a Phillips experimental prototype transepidermal fluid collection 
device by the insertion of an activated charcoal cloth or a Teflon disk, 
on which is impregnated activated charcoal, between the pads of the 
collection device. The abstract discloses that incorporation of activated 
charcoal into the device retards back-transfer of theophylline by an 
average of 50% but results were variable. The abstract concludes with the 
statement that improvements in the adhesiveness, water-tightness and other 
structural features of the device are required in order to reduce the 
variable uptake and binding of theophylline and that reliable xenobiotic 
uptake and prevention of back-transfer may lead to extension of the 
utility of transepidermal fluid collection from qualitative to 
quantitative surveillance of human exposure to xenobiotics. 
Other dermal patch devices are known which differ in components and which 
serve different purposes than the device of this invention. One is a drug 
delivery device comprising a drug-containing polymeric diffusion matrix 
which can be applied as a transdermal patch with means for fastening the 
matrix to the skin of a person as disclosed in U.S. Pat. No. 4,321,252. 
Another is what appears to be an adhesively attachable electrode for 
monitoring vital signs. The metal electrode projects through a molded 
plastic shell which contains a rather porous sponge-like packing with a 
liquid substance, presumably containing an electrolyte. The shell is 
encircled by an attached ring of a form substance having an adhesive 
surface for dermal attachment. 
Similarly, in the context of ease of application, the discovery of the 
dermal substance collection device according to this invention makes 
available means for the convenient, non-invasive, immediate and continuous 
collection of a chemical substance from a body's dermal surface by simple 
application of the device thereto. 
SUMMARY OF THE INVENTION 
A dermal substance collection device (DSCD) is described, which provides 
means for the non-invasive, immediate and continuous monitoring of 
chemical substances which have either entered the body or are synthesized 
in the body and which are present in a detectable amount in either or both 
interstitial fluid or sweat or which are on or in the skin. The dermal 
substance collection device of this invention is comprised of three 
essential components: (1) a substance binding reservoir, (2) a liquid 
transfer medium which allows for liquid bridge transfer of a soluble 
substance from the skin surface to the binding reservoir by virtue of its 
wettability by the liquid, and (3) an occlusive cover. 
An embodiment of this invention concerns a flexible and adhesive cover 
having a cavity completely occupied by the liquid transfer medium and 
substance binding reservoir and which occlusively maintains the liquid 
transfer medium in contact with a dermal surface to which the device is 
applied. Another embodiment relates to a dermal substance collection 
device comprising an immobilized collection composition composed of an 
immobilized liquid transfer medium and a substance binding reservoir, 
maintained in contact with a dermal surface by an occlusive cover. The 
collection composition can be gelled and the occlusive cover can then be 
limited to a metallic foil having an adhesive surface or it can 
additionally comprise an overlaying layer of flexible waterproof adhesive 
tape. A further embodiment of this invention found to be particularly 
suitable for monitoring a water soluble chemical utilizes an aqueous salt 
solution immobilized by agarose as a gel matrix liquid transfer medium, 
activated charcoal powder as the substance binding reservoir dispersed and 
immobilized in the gel matrix wherein the gel matrix transfer medium is 
contained in a cavity defined by a surrounding occlusive flexible covering 
comprised of closed cell foam, metallic foil, and an overlayer of 
waterproof plastic adhesive tape so that an exposed protruding portion of 
the gel matrix composition, relative to the device-dermal surface 
interface, is capable of maintaining positive pressure contact with the 
dermal surface to which the device is adhesively applied. The device 
according to this invention provides immediate and continuous 
juxtaposition of the transfer medium with the surface of the skin enabling 
movement of the target chemical by a liquid bridge from the body into 
contact with the binding reservoir in order to provide for early 
accumulation and minimize back transfer of the chemical. A method for the 
non-invasive, immediate and continuous monitoring of a human or lower 
animal chemical substance, either endogenous or by virtue of exposure to 
these substances, comprising use of the subject device and analysis for 
the chemical substance collected is also described. More precisely, this 
invention relates to a composition of matter and the use thereof in a 
method for the non-invasive, immediate and continuous collection of a 
chemical substance from a dermal surface. The method comprises applying to 
the dermal surface a dermal substance collection device which is comprised 
of (a) a binding reservoir material for binding with said dermal substance 
to prevent back transfer loss of said dermal substance from said 
collection device to the dermal surface; (b) a liquid bridge transfer 
medium which allows the instantaneous and continuous transfer of said 
dermal substance from the dermal surface to said binding reservoir 
material, said binding reservoir material being maintained in a wet-state 
by said liquid transfer medium; and (c) a cover means for occlusively 
containing said binding reservoir material and said liquid bridge transfer 
medium and for occlusively maintaining said liquid bridge transfer medium 
in continuous contact with the dermal surface upon application of said 
collection device to the dermal surface. The dermal collection device is 
preferably circular in shape. Moreover, it has a flat profile relative to 
the dermal surface upon adhesive, an immobilized liquid transfer medium, 
approximately 1 millimeter to 7 centimeters in diameter and 1 millimeter 
to 0.5 centimeters in thickness and a strippable backing. The liquid 
transfer medium is immobilized and contains binding reservoir material 
dispersed therein. This binding reservoir material is selected from the 
group consisting of activated charcoal, ion exchange resin, immobilized 
antibody, silica, zeolite and molecular sieve and the immobilized liquid 
bridge transfer medium is an aqueous gel. The gel may contain osmotically 
active substance such as, a penetration enhancing agent, which includes 
n,n-di-ethyl-m-toluamide, 1-dodecylazacyclo-heptan-2-one, and 
dimethylsulfoxide or a gelling agent. The gelling agent is preferably 
agarose or polyvinyl alcohol polymer, or a combination thereof. The 
osmotically active aqueous solution may contain sodium chloride in an 
amount up to the saturation level of the aqueous gel. In such a solution, 
the amount of agarose can be 0.5 to 30 percent by weight of the aqueous 
sodium chloride solution preferably about 3 percent, and the amount of 
activated charcoal can be 0.5 to 30% by weight of the aqueous gel, 
preferably, about 5 percent. The occlusive cover means is comprised of an 
outer adhesive layer and an inner metallic foil layer contiguous to the 
immobilized liquid bridge transfer medium. Additionally, the occlusive 
cover means may comprise a transfer medium-surrounding closed-cell foam 
layer contiguous to the foil layer. The immobilized liquid bridge transfer 
medium comprises a protruding surface relative to the occlusive cover 
means and the dermal surface-interface to maintain positive pressure 
contact between the transfer medium and the dermal surface.

DETAILED DESCRIPTION OF THE INVENTION 
A dermal substance collection device 1 (DSCD) according to this invention 
broadly can be described as comprised of three essential components: (1) a 
substance binding reservoir wettable by (2) a liquid transfer medium, and 
(3) an occlusive cover. The DSCD of FIG. 2 describes internally, a 
composition 3 containing a substance binding reservoir and a liquid 
transfer medium, the composition 3 contained in a cavity defined by 
occlusive cover 2 which can be a smooth, transparent or opaque plastic 
such as a polyolefin. The device can have a strippable layer 9 for storage 
and the occlusive cover can comprise a waterproof flexible overlayer 7 
with adhesive layer 8 or can alternatively be fixed to the dermal surface 
with other fastening means such as a VELCRO or elastic band. 
A DSCD device having a preferred feature is described in FIG. 3 wherein is 
shown a substance collection composition 3 having an immobilized shape, 
for example, a gel surrounded by an occlusive adhesive cover of components 
2 and 7. In this instance, the substance collection composition is 
self-supporting and component 2 may not be necessary, an occlusive layer 7 
of adhesive foil and/or flexible waterproof adhesive tape being 
satisfactory to maintain contiguity between the device's collection 
composition and the dermal surface to which it is applicable. Upon 
application to a dermal surface after stripping of protection layer 9, the 
gelled composition's protruding shape facilitates maintenance of a 
positive pressure contact with the dermal surface. This protruding portion 
of the composition can be facilitated by provision of the composition as 
variously a gel, thixotropic mixture, paste or semi-solid depending upon 
the components and their physical or chemical state as related to the 
desired target chemical. The immobilizing agents are, of course, 
compatible for contact with the skin. Immobilization of the liquid 
transfer medium by formation of a gel from addition of a polymeric gelling 
agent has been found particularly suitable for the experimental procedures 
utilized in development of this invention and described below in detail. 
FIG. 4 describes a preferred device in storage form, where the device 
contains an immobilized collection composition having a gel matrix. FIG. 5 
shows this device as applied to a dermal surface 10 as shown in FIG. 1. 
This device as constructed according to the procedure later described 
contains an immobilized composition 3 containing a substance binding 
reservoir and a liquid transfer medium so that the bottom stem portion 4 
insures contact with a dermal surface. Laminate components 11 are 
advantageously an occlusive closed cell polyurethane foam, layer 12 is a 
wax-paper protective and advantageous separative layer which originally is 
formed as a component of a commercial tape of the polyurethane foam. 
Laminate component 13 is advantageously an occlusive metallic foil such as 
an impermeable aluminum foil. The preferred DSCD is constructed so that 
upon application, the immobilized liquid transfer medium is juxtaposed 
directly to skin, enabling the continuous migration of a substance from 
the body across the skin into the liquid medium and binding reservoir. 
After wearing the DSCD for a period of time (hours to days), the DSCD is 
removed from analysis. Analysis consists of chemically separating the 
bound substance of interest from the binding reservoir for qualitative and 
quantitative measurement by conventional techniques. The measured amount 
of collected substance is related to cumulative body exposure of the 
substance using known data analytic techniques such as described in the C. 
C. Peck et al. (1981) paper (supra). 
The term immediate as used to describe the action of the collection device 
according to this invention, in contradistinction to the delayed onset of 
collection of the Phillips device referred to previously, refers to both 
time and space conditions necessary for passive transfer of a chemical 
substance from the skin, interstitial fluid or sweat into the device which 
are established without delay upon emplacement of the device on the dermal 
surface by virtue of the insured contact which the liquid bridge provides 
to the stratum corneum of the dermal surface which hydrates thereby 
creating the permeable membrane in contact with both fluid spaces. 
The device of this invention provides for reproducible results. In order to 
obtain this reproducibility, the surface area of adherence of the 
composition such as a gel medium to the skin should be fixed insofar as 
feasible and the composition in contact with the dermal surface rendered 
stationary. This is facilitated by use of a binding means such as a 
surrounding adhesive bordering the composition which maintains the 
location of the composition vis-a-vis the dermal surface and facilitates 
reproducibility of results. 
A Phillips device obtained from 3M Company as referred to previously has an 
important limitation in that the transparent plastic used to construct the 
right-angular raised cylindrical container and surrounding rim is very 
rigid compared to the encircling area of translucent flexible adhesive so 
that the device as a whole is relatively non-flexible in comparison to the 
flexible and relatively flat-profiled device of comparable diameter 
according to this invention. This limitation promotes deleterious leakage 
or unintended abrasive removal of the Phillips device from the skin of a 
person by virtue of its raised profile and bulk. 
An embodiment of this invention particularly suitable for monitoring water 
soluble substance utilizes an aqueous sodium chloride solution immobilized 
by agarose as a gel matrix transfer medium, activated charcoal powder 
dispersed and immobilized in the gel matrix as a binding reservoir, and an 
occlusive flexible adhesive cover comprising an overlayer of a water-proof 
plastic adhesive tape. For example 3 gm agarose+5 gm activated charcoal 
powder are mixed with 100 cc 30% saline (30 gm NaCl in 100 gm distilled 
water) at a temperature of about 100.degree. C. When the agarose is 
completely dissolved and the charcoal is uniformly dispersed in the 
solution, the mixture is poured into a 2 mm.times.1.5 ca diameter circular 
mold made in adhesive closed cell foam polyethylene tape. In order to 
insure that the DSCD will enable constant pressure contact of the transfer 
medium against skin, the mold is constructed so that a 0.5 mm diameter 
circular stub of agarose gel will protrude 2 mm beyond the level of the 
inner surface of the adhesive closed cell foam polyurethane tape. Cooling 
to room temperature (25.degree. C.) results in gelling of the mixture. The 
external side is covered with a circular layer of adhesive foil. Circular 
DSCD's conveniently measuring 4 cm in diameter are cut around the 
tape-encased activated charcoal gel. The DSCD is then placed in a suitable 
cleansed (defatted with soap or isopropyl alcohol) hairless part of the 
body (e.g., back or ankle) or is stored for later use. 
During use or after the DSCD is removed from the body, the chemical of 
interest which has migrated into the DSCD and accumulated on the binding 
reservoir must be detected or measured in order to interpret body content 
during the period of monitoring. This may be accomplished by incorporation 
of a direct-reading chemical, immunochemical or electro-chemical detection 
system directly in conjunction with the DSCD or the DSCD may be 
disassembled for further analytic processing of the reservoir-bound 
chemical. As an example of the latter, consider a water/agarose 
gel/activated charcoal DSCD devised to monitor exposure to parathion. 
After wearing the DSCD throughout a period of exposure (1 hour to 1 week), 
the gel/activated charcoal matrix is separated from the removed DSCD and 
placed in 0.5 ml of concentrated HCl which dissolves the gel. The liquid 
phase of the mixture which contains some parathion resulting from the 
action of the acid on the activated charcoal is then separated from the 
charcoal by centrifugation and is saved. The charcoal is subjected to 
extraction by tumbling it in 1 ml of toluene for 30 minutes; following 
centrifugation and saving the liquid phase, the sides of the test tube are 
washed downwards using 0.5 ml of methanol. This procedure is repeated once 
and all saved liquid phases are combined and brought to dryness by 
nitrogen evaporation. Greater than 90% of charcoal-bound parathion can be 
separated using this procedure. The dried residue is then reconstituted in 
0.5 ml of mobile phase for high pressure liquid chromatography analysis 
(HPLC). Using the following HPLC conditions, total parathion separated 
from the charcoal can be detected and quantitated: Column-Bondapak C18 by 
Waters Associates, 1.0 ml/min. flow rate, MeOH/H.sub.2 O/glacial acetic 
acid in proportion 70/29/1, U. V. determined at 280 nm. 
The following disclosure describes the fabrication of a preferred 
embodiment of the dermal substance collection device according to this 
invention as depicted in the drawing of FIG. 4. 
Initially a layer of 3M brand one-sided adhesive tape (white opaque 
strippable layer on transparent double sided adhesive layer) is applied to 
the strippable backing layer side of 3M brand closed-cell foam 
polyurethane adhesive tape and a hole of dimension about 0.9 cm is created 
in the compound laminate. 
The resulting compound laminate with orifice is applied to a layer of 
plastic, for example, a sheet of polyvinylidene plastic such as Sara Wrap 
brand to create a plastic-polyurethane foal interface. The white opaque 
topside layer of the first compound laminate is then stripped exposing an 
adhesive surface. A second closed-cell foam polyurethane layer having a 
larger hold (about 1.2 cm) than the first compound laminate is placed on 
the exposed adhesive layer of the first laminate with the axes of the hole 
cylinders aligned so as to create a well mold with a larger upper diameter 
relative to the smaller lower diameter having the polyvinylidene plastic 
bottom. 
A selected immobilized liquid gel component such as saline agarose with 
dispersed activated charcoal is poured hot into the created mold and 
allowed to cool and gel resulting in, from a side view according to FIG. 
4, the preferred "mushroom" shaped positive pressure contact gel of this 
invention upon stripping of the narrower diameter foam layer with the 
polyvinylidene backing. The bottom stem portion 4 can have a variable 0.5 
mm to about 7 cm diameter ranging conveniently, preferably from about 3 cm 
in order to insure sufficient surface area for dermal contact. Subsequent 
to formation of the selected gel, the uppermost strippable backing (on 
opposite side of the laminate remote from the polyvinylidene layer) is 
removed leaving exposed a surface of closed-cell polyurethane foam to 
which is applied an occlusive covering of foil such as flesh colored 
aluminum foil supplied by 3M, the bonding of which is facilitated by 
interlaid transparent double sided adhesive. 
In use, the "bottom" narrower diameter foam layer with plastic backing is 
stripped exposing a stub or raised cylinder of gel to promote positive 
pressure contact with the skin; the "upper" bulk of the gel is surrounded 
by the remaining foam layer with adhesive lower surface for retention on 
the dermal surface to which applied. The whole device when applied to a 
dermal surface may be further held in place and protected from 
unintentional removal by an additional adhesive overlying layer such at 
"The Pink Tape", a plastic zinc oxide-containing adhesive tape by Nu-Hope 
Laboratories described as washable, flexible and waterproof. 
The optimal device structure consists of a generally flat (1 mm to 0.5 cm 
thick, preferably 1-2 mm), circular (about 1 to 5 cm, preferably 1 to 3 cm 
diameter disk) gel matrix containing the binding reservoir which is 
occluded against skin by larger occlusive aluminum foil and adhesive 
circles having an adhesive surface sufficient for binding. A device found 
useful is about 1-2 mm thick, has a 1.5 cm diameter disk, a 2 cm diameter 
foil and 4 cm diameter adhesive cover. 
In addition to the inventive embodiment described in detail above, a number 
of additional component systems are considered useful within the broad 
scope of this invention. It will be apparent that in some instances the 
binding reservoir can also serve the dual function of an immobilizing 
agent generating, for example, a gel or a paste with the liquid medium 
dependent on its chemical and/or physical properties such as particle size 
in the colloid range. 
In addition to activated charcoal, molecular sieves, silica gels, modified 
with aromatic or aliphatic group-containing silanes, various activated 
alumina, ion exchange resins and chelating agents such as 
ethylenediaminetetraacetic acid are examples of binding reservoirs. 
Molecular sieves are alkaline metaloaluminosilicates quite similar to many 
natural clays and feldspars. When the water of hydration is driven off, 
the crystal does not collapse or rearrange as is the case for most other 
hydrated metals. Instead, the physical structure of the crystal remains 
unchanged which results in a network of empty pores and cavities that 
comprise about one-half of the total volume of the crystals. Molecular 
sieves generally have a total (internal and external) potential surface 
area of 650 to 800 square meters per gram, while the external surface area 
is only one to two square meters per gram. Due to their unique crystalline 
structure, molecular sieves have cavities and pores of uniform size. This 
uniformity permits a sieving or screening action in the molecular size 
range making separation easy and specific. The material is supplied in 
powder and pellet forms. These materials are considered valuable in 
trapping alcohol. 
Silica-gel is considered useful to trap highly polar liquids. In a given 
homologous series such as ethyl alcohol, propyl alcohol, and butyl 
alcohol, the extent of absorbability decreases in order of decreasing 
polarity. Compounds with hydroxyl groups such as alcohols and phenols are 
strongly absorbed as well as oxygen-containing compounds such as esters, 
aldehydes, ketones, and organic acids. The selectivity of the particular 
grade of silica gel to determine the preferential absorption of one 
compound over another depends upon the pore diameter and partially upon 
the mesh size and percolation rate. In the case of digoxin, incorporation 
into the subject collection device of the digoxin binding resin, 
cholestyramine, is considered useful. Digoxin, bound to the strongly basic 
cholestyramine resin, can be released by mixing in strong alkali. 
The liquid medium when aqueous should contain an osmotically active 
substance such as sodium chloride or albumin; amounts up to and including 
saturation amounts are acceptable. An aqueous saline solution optimally 
containing about 30% (30 g salt/100 g water) salt sodium chloride has been 
found preferable. 
For some chemical substance to be collected, it may be desirable to provide 
with the liquid medium a penetration enhancing amount, for example, 0.01% 
upward to 20% by weight of the liquid medium, of a penetration enhancing 
agent which can be glycerine or preferably one or a mixture of 
n,n-diethyl-m-toluamide, 1-dodecylazacyclopheptan-2-one, or 
dimethylsulfoxide which may augment the movement of substance into the 
collection device. In the instance where the liquid medium is immobilized 
as an aqueous gel, the penetration enhancing agent may be contained on the 
gel surface which is to be placed in contact with the dermal surface. It 
has also been found advantageous to apply alternatively a small amount of 
the penetration enhancing agent directly to the skin prior to placement of 
the collection substance of the device on the agent. The binding reservoir 
component can be present in an amount from about 0.5% to about 30% by 
weight of binding agent based on the weight of the liquid transfer medium 
in which incorporated. Activated charcoal present in saline at about 5% 
has been found acceptable. The gelling agent is present in a gelling 
amount. For example, about 0.5% to about 30% agarose has been found 
acceptable. Agarose in an amount of about 3-4% has been found to be 
suitable in, for example, a 5% saline system. 
In addition to aqueous gels containing the natural gelling agent agarose, 
gel matrices containing other natural or synthetic gelling agents such as 
polyvinyl alcohol in gelling amounts are also suitable for use in the 
device of this invention. Suitable gelling agents can be selected from the 
polymers or polymeric mixtures disclosed in U.S. Pat. No. 4,321,252, the 
disclosure of which, in this regard, is hereby specifically incorporated 
by reference. 
A prototype gel consists of 4% in 30% saline. Pulverized activated charcoal 
mixed into the gel @5% by weight serves as a suitable binding reservoir 
and provides quantitative binding for weak aqueous solutions of 
theophylline, delta-9-tetrahydrocannabinol, parathion, dimethylacetamide, 
cimetidine and nicotine. The following binding reservoir materials (with 
the chemical to be bound in parentheses) are useful in this invention: 
Whatman PSI ion exchange paper (na, Li, Pb); Na polystyrene sulfate 
Kayexalate brant (Na,Li); gel and paper bound antibodies (theophylline); 
activated charcoal cloth (theophylline); Amberlite IR 120+2 (Na); Dowet 
HGR--H HCR--S--H (Na). 
Examples of additional procedures for off-loading bound chemical from 
gel/charcoal disks which have been developed are as follows (with the 
solvent system in parentheses): theophylline (Acid/toluene/methanol), 
parathion (acid/tolune/methanol), delta-9-tetrahydrocannabinol 
(toluene/ethanol), and nicotine (acid/methanol/ethanol). Non-acid gel 
disruption techniques including the use of sonication, heat, DMSO, KI, and 
Na perchlorate, and an off-loading procedure for theophylline bound to 
antibody paper are also applicable to this invention. 
For study of the broad utility of this invention, selected model chemicals 
of the group theophylline, delta-9-tetrahydrocannabinol, parathion, 
dimethylacetamide, cimetidine, nicotine, inulin, T-2 mycotoxin were chosen 
in part because together they exhibit physicochemical properties which 
span broad ranges of molecular size, water/fat solubility and acid/base 
dissociation properties. 
Extensive In vivo testing of the dermal substance collection device (DSCD) 
has been undertaken in rabbits (R, Rhesus monkeys (M) and humans (H). 
Orally or intravenously administered substances for dermal collection have 
included aminophylline 80% theophylline, or 20% ethylenediamine (R,M), 
14C-nicotine (M), 22-Na (R), 14C-parathion (R,M), 
delta-9-tetrahydrocannabinol THC (M,H), 14C-inuline (M), cimetidine (M,H), 
and dimethylacetamide (M). Experimental conditions were varied in order to 
evaluate various binding reservoirs including activated charcoal dispersed 
in a saline/gel matrix, various DSCD embodiments which provide a liquid 
bridge including saline, immobilized by various gels such as agarose or 
polyvinyl alcohol as the gelling agent, various DSCD embodiments which 
provide persistent occlusive contact of the liquid bridge with the skin 
(single layer adhesive tape overlying the DSCD liquid bridge/binding 
reservoir complex vs multiple tape/foil layers enveloping a liquid 
bridge/binding reservoir complex vs multiple tape/foil layers enveloping a 
liquid bridge/binding reservoir complex which protrudes into the skin 
effecting positive pressure during emplacement), various preparatory 
procedures (shaving, clipping of hair, use of a chemical depilitant, 
cleansing of the skin with soap and isopropyl alcohol), and various skin 
penetration enhancing agents (Azone, DET, DMSO). 
In a typical animal experiment, a Rhesus monkey is anesthetized with 
ketamine 10 mg/kg and the hair on the chest and abdomen is clipped prior 
to washing the underlying skin (with a mild soap or isopropyl alcohol). Up 
to 30 DSCD's are emplaced on the skin after which a non-toxic dose of 
non-radioactive test-substance or 50 uCi of 14C-labeled test-substance is 
injected intravenously into a leg vein. Blood samples are taken at 
intervals ranging from 20 minutes to 96 hours; DSCD's are removed at 
intervals ranging from 3 hours to 96 hours. Blood plasma samples are 
analyzed for the test-substance and its known metabolites (1) in a 
non-radioactive experiment by an appropriate chemical assay (e.g. high 
pressure liquid chromatography [HPLC], gas chromatography [GC], 
radio-immunoassay [RIA], enzyme-immunoassay [EI], etc.); (2) in a 
radioactive experiment by scintillation counting techniques applied to the 
plasma directly or following chromatographic separation of derivatives of 
the test-substance. The binding reservoir elements of the DSCD's are 
subjected to chemical extraction of the charcoal-bound test-substance 
derivatives using organic solvent extractants in conjunction with 
disruption of the gel/binding reservoir or vigorous tumbling or 
sonication. The extracted test-substance derivatives may be further 
subjected to chromatographic separation followed by direct chemical 
detection (non-radiolabeled test-substances) or scintillation counting 
(radio-labeled test-substance). FIGS. 6 and 7 depict results of a typical 
animal experiment involving 14C-parathion as the test substance. 
FIG. 6 describes the chromatographic separation of extracted transepidermal 
liquid collected at 24 hours on a rhesus monkey (open bars). The percent 
activity of the eluant collected every 30 seconds (0.5 ml) following 
extraction and chromatographic separation of DSCD device liquid is plotted 
as a function of time. The hatched areas represent the chromatogram 
obtained for parathion, paroxon, and p-nitrophenol (pnp) standards. 
Chromatographic conditions are substantially the same as those described 
previously. 
FIG. 7 shows the time course of transdermal dosimetry of 14C-parathion 
injected intravenously in a rhesus monkey. The device contained agarose 
gel without ("pain") or with dispersed activated charcoal (A.C.), the 
underlying skin being untreated or pre-treated with Azone. A.C. gel DSCD 
devices using Azone showed particularly satisfactory transdermal 
collection. 
TABLE 1 
______________________________________ 
EXTENT OF SUBSTANCE COLLECTION IN 
ANIMAL STUDIES EMPLOYING AGAROSE 
GEL/ACTIVATED CHARCOAL DSCS'S 
EXTENT OF 
TRANSDERMAL 
MIGRATION* 
TEST-SUBSTANCE (% Dose .times. 10.sup.4) 
______________________________________ 
THEOPHYLLINE 25 
NICOTINE 2.5 
ATHION 0.7 
TETRAHYDROCANNABINOL 0.1 
INULIN 0.5 
CIMETIDINE 8.3 
DIMETHYLACETAMIDE 8.4 
______________________________________ 
*These values represent collection of all testsubstance relative 
derivatives (includes parent compound and metabolites) except in the case 
of THC and cimetidine which reflect the collection of parent compound 
only. The diameter of the liquid bridge contact with the skin was 9 mm. 
Table 1 summarizes the results of studies in Rhesus monkeys of the 
above-named test substances in terms of the maximum percentage of the 
administered dose collected in agarose/activated charcoal DSCD's. 
Preliminary studies using the DSCD's have been undertaken in humans 
ingesting either delta-9-tetrahydrocannabinol (THC) or cimetidine. 
Eighteen DSCD's (1 cm gel diameter) were emplaced for up to 48 hours on 
the lower legs of a cancer patient after receiving orally a single gelatin 
capsule containing 10 mg THC. Assaying the THC by RIA following extraction 
of the gel/activated charcoal complex with toluene/ethanol yielded 224 
+/-22 pg of THC from DSCD's containing agarose gel without activated 
charcoal and 601 +/-302 pg THC from DSCD's containing gel with activated 
charcoal. In one healthy human volunteer, twelve DSCD's each (25 mm liquid 
bridge diameter, all containing agarose gel and activated charcoal) 
emplaced for 24 hours on posterior-aricular, ventral forearm and medical 
lower leg areas after receiving orally or intravenously 5 mg/kg cimetidine 
solution or tablets yielded 62-461 ng cimetidine (assayed by HPCC). 
Variations of the embodiments of this invention as disclosed above will be 
apparent to the skilled artisan having the benefit of this disclosure. 
These modifications are to be considered within the scope of the claims to 
this invention which follow. 
The DSCD according to this invention may be viewed as having broad utility 
for monitoring cumulative exposure of mammals including man to chemicals.