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Claims  |
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What is claimed is:
1. An apparatus for the detection of a target substance which migrates to
the surface of the skin of a subject by diffusion, comprising
detector means including (a) at least one detector chemical contained in
solution and capable of chemically reacting with the target substance as
the target substance migrates to the surface of the skin of the subject to
produce a detectable signal and (b) a barrier means for substantially
preventing said detector chemical from migrating into the skin of the
subject; and
attachment means for maintaining the detector means adjacent the surface of
the skin of the subject.
2. An apparatus as defined by claim 1, wherein the detector means is
capable of chemically reacting with the target substance as the target
substance migrates to the surface of the skin of the subject to produce an
electrically detectable signal.
3. An apparatus as defined by claim 2, wherein the detector means is
capable of chemically reacting with the target substance as the target
substance migrates to the surface of the skin of the subject to produce an
electrically detectable change in an ion concentration in the detector
means.
4. An apparatus as defined by claim 1, wherein the detector means further
comprises a carrier substantially saturated with the detector chemical
contained in solution and capable of chemically reacting with the target
substance as the target substance migrates to the surface of the skin of
the subject.
5. An apparatus as defined by claim 4, wherein the carrier comprises a
porous support member.
6. An apparatus as defined by claim 5, wherein the carrier comprises a
microporous membrane containing covalent functional groups capable of
covalently binding with the detector chemical contained in solution.
7. An apparatus as defined by claim 1, wherein the barrier means comprises
a permeable or a semipermeable membrane.
8. An apparatus as defined by claim 1, wherein the barrier means comprises
a layer of gel.
9. An apparatus as defined by claim 1, wherein the barrier means comprises
a microporous membrane containing covalent functional groups capable of
covalently binding with the detector chemical contained in solution.
10. An apparatus as defined by claim 1, wherein the detector chemical is
selected from chemical reagents, antibodies, enzymes and biological
receptors and is contained in solution in a solvent.
11. An apparatus as defined by claim 1, wherein the detector means includes
a mixture of detector chemicals contained in solution and capable of
chemically reacting with the target substance as the target substance
migrates to the surface of the skin of the subject to produce a detectable
signal.
12. An apparatus as defined by claim 1, wherein the attachment means
includes an adhesive area for adhesively maintaining the detector means
adjacent the surface of the skin of the subject.
13. An apparatus as defined by claim 1, further comprising an impermeable
cover means covering the surfaces of the detector means which are not
positionable adjacent the surface of the skin of the subject.
14. An apparatus as defined by claim 1, further including a removable
impermeable cover means covering the surface of the detector means which
is positionable adjacent the surface of the skin of the subject, which
removable cover means is adapted to be removed from the apparatus prior to
use for the detection of a target substance migrating to the surface of
the skin of the subject.
15. An apparatus as defined by claim 1, further including a signalling
means capable of converting the detectable signal produced by the detector
means into a form which is observable by the human eye.
16. An apparatus as defined by claim 15, wherein the signalling means
includes microprocessing means.
17. An apparatus for the detection of a target substance which migrates to
the surface of the skin of a subject by diffusion, comprising
detector means including (a) at least one detector chemical contained in
solution and capable of chemically reacting with the target substance as
the target substance migrates to the surface of the skin of the subject to
produce an optically detectable signal and (b) a barrier means for
substantially preventing said detector chemical from migrating into the
skin of the subject; and
attachment means for maintaining the detector means adjacent the surface of
the skin of the subject.
18. An apparatus as defined by claim 17, wherein the detector means is
capable of chemically reacting with the target substance as the target
substance migrates to the surface of the skin of the subject to produce a
visually detectable color change in the detector means.
19. An apparatus for the detection of a target substance which migrates to
the surface of the skin of a subject by diffusion, comprising
detector means including (a) at least one detector chemical contained in
solution and capable of chemically reacting with the target substance as
the target substance migrates to the surface of the skin of the subject to
produce a detectable signal, said detector chemical being selected from
chemical reagents, antibodies, enzymes and biological receptors contained
in solution in a solvent and including an oxidase in solution in a
solvent, and (b) a barrier means for substantially preventing said
detector chemical from migrating into the skin of the subject; and
attachment means for maintaining the detector means adjacent the surface of
the skin of the subject.
20. An apparatus as defined by claim 19, wherein the oxidase is selected
from alcohol oxidases and glucose oxidases.
21. An apparatus for the detection of a target substance which migrates to
the surface of the skin of a subject by diffusion, comprising
detector means including (a) at least one detector chemical including a
mixture of an oxidase and a peroxidase contained in solution in an aqueous
solvent and capable of chemically reacting with the target substance as
the target substance migrates to the surface of the skin of the subject to
produce a detectable signal and (b) a barrier means for substantially
preventing said detector chemical from migrating into the skin of the
subject; and
attachment means for maintaining the detector means adjacent the surface of
the skin of the subject.
22. An apparatus as defined by claim 21, wherein the oxidase is selected
from alcohol oxidases and glucose oxidases.
23. An apparatus as defined by claim 21, wherein the peroxidase comprises
horseradish peroxidase.
24. An apparatus for the detection of ethanol which migrates to the surface
of the skin of a subject by diffusion, comprising
detector means including (a) detector chemicals comprising an alcohol
oxidase, horseradish peroxidase and tetramethylbenzidine contained in
solution and capable of chemically reacting with the ethanol as the
ethanol migrates to the surface of the skin of the subject to produce a
detectable color change and (b) a barrier means for substantially
preventing migration of said detector chemicals into the skin of the
subject; and
attachment means for maintaining the detector means adjacent the surface of
the skin of the subject.
25. An apparatus for the detection of glucose which migrates to the surface
of the skin of a subject by diffusion, comprising
detector means including (a) detector chemicals comprising glucose oxidase,
horseradish peroxidase and tetramethylbenzidine contained in solution and
capable of chemically reacting with the glucose as the glucose migrates to
the surface of the skin of the subject to produce a detectable color
change and (b) a barrier means for substantially preventing migration of
said detector chemicals into the skin of the subject; and
attachment means for maintaining the detector means adjacent the surface of
the skin of the subject.
26. A method for the detection of a target substance which migrates to the
surface of the skin of a subject by diffusion, comprising maintaining a
detector means adjacent the surface of the skin of the subject, the
detector means including (a) at least one detector chemical contained in
solution and capable of chemically reacting with the target substance as
the target substance migrates to the surface of the skin of the subject to
produce a detectable signal, and (b) a barrier means for substantially
preventing migration of said detector chemical into the skin of the
subject. |
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Claims |
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Description |
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FIELD OF THE INVENTION
The present invention relates to a transdermal detection system for the
detection of a target substance which migrates to the surface of the skin
of a subject by diffusion. More, particularly, the invention relates to a
transdermal detection system which produces a detectable signal as the
target substance migrates to the surface of the skin of the subject.
BACKGROUND OF THE INVENTION
Various transdermal devices and systems are known for collecting and
monitoring body fluids. For example, in Peck et al, "A Non-Invasive
Transepidermal Toxicological Monitoring Device", Pittsburgh Conference and
Exposition on Analytical Chemistry and Applied Spectroscopy, Mar. 9, 1982,
Meeting Abstracts Book, page 366, a transepidermal device is disclosed
including an adhesive plastic chamber containing sodium
chloride-impregnated absorbant pads and an activated charcoal impregnated
disc for capturing a xenobiotic to prevent back transfer from the
collection device into the body. The Peck copending application Ser. No.
660,778 filed Feb. 11, 1985 discloses a dermal substance collection device
including a liquid bridge transfer medium for transferring a dermal
substance to a binding reservoir material which binds the substance and
prevents back transfer loss of the substance from the collection device.
The Phillips U.S. Pat. No. 4,329,999 discloses a dermal patch for
collecting sweat from a patient which includes a collecting pad for
absorbing sweat. Similarly, the Phillips U.S. Pat. No. 4,595,011 discloses
a transdermal dosimeter device including a dermal contact bridge, a fluid
collecting component for collecting and storing fluids collected from the
skin and a process component for binding or chemically converting the
stored substances. The latter Phillips patent suggests that chemical
conversion of collected substances to produce an observable color change
in the device may be effected.
The Fogt et. al. U.S. Pat. No. 4,444,193 discloses an absorbent patch
device for absorbing sweat, which patch device includes a chemical
composition capable of reacting with chloride contained in the sweat.
The Pugliese U.S. Pat. No. 4,071,020 discloses an apparatus and methods for
performing in-vivo measurements of enzyme activity wherein one or more
reactants are placed directly on a predetermined area of the skin surface
and are free to migrate into the skin. While the apparatus and methods of
Pugliese are not dependent on collection of a substance such as sweat or
interstitial fluid, they may be dangerous to the subject if the reactants
have toxic effects upon migration into the skin of the subject.
Other devices are also known for measuring substances, particularly gases,
in or emanating from the skin. For example, the Clark, Jr. U.S. Pat. Nos.
4,401,122 and 4,458,686 disclose apparatus and methods for measuring
substances, particularly gases, which diffuse through the skin or are
present underneath the skin in the blood or tissue using polarographic
electrodes or enzyme electrodes. The Vesterager et al U.S. Pat. No.
4,274,418 discloses an apparatus for measuring gases, for example oxygen
and carbon dioxide, which diffuse from blood vessels and through skin
tissue wherein the gas is directed to a measuring chamber in which the
partial pressure is measured.
The present inventor has discovered that various substances migrate to the
skin surface of a subject by diffusion in the absence of a liquid
transport medium such as sweat and has discovered means for producing
detectable signals in a transdermal detection system at the skin surface
without direct placement of detector chemicals which are capable of
migrating into the skin on the skin surface. Known transdermal devices
rely on the collection of body fluids such as sweat or gaseous substances
emanating from the skin or the binding of substances transferred through a
liquid bridge transfer medium, without detection and signalling, or employ
direct epidermal application of potentially toxic detector chemicals, and
thus are disadvantageous for safely detecting and signaling substances
which migrate to the skin surface of a subject by diffusion.
SUMMARY OF THE INVENTION
It is therefore an object of the present invention to provide a transdermal
system for the detection of a substance which migrates to the skin surface
of a subject by diffusion. It is a more specific object of the invention
to provide a transdermal system for the detection of a substance which
migrates to the skin surface of a subject by diffusion in the absence of a
liquid medium such as sweat. It is a related object of the invention to
provide a transdermal system for the detection of a substance which
migrates to the surface of the skin of a subject by diffusion, which
transdermal system does not rely on collecting a fluid from the skin
surface and does not require direct placement of detector chemicals which
can migrate into the skin on the skin surface in order to detect the
target substance which has migrated to the skin surface of the subject.
These and additional objects are provided by the transdermal detection
system according to the present invention which comprises an apparatus for
detecting a target substance which has migrated to the surface of the skin
of a subject by diffusion. The apparatus includes detector means and
attachment means for maintaining the detector means adjacent to the
surface of the skin of the subject. The detector means includes at least
one detector chemical contained in solution and capable of chemically
reacting with the target substance as the target substance migrates to the
surface of the skin of the subject to produce a detectable signal, and
barrier means for substantially preventing the detector chemical from
migrating into the skin. The terminology "in solution" describes a
uniformly dispersed mixture at the molecular or ionic level of one or more
substances, the solute, in one or more other substances, the solvent, as
is set forth in The Condensed Chemical Dictionary, 10th edition, G. G.
Hawley, Van Nostrand Reinhold Co., 1981, pages 957-958. As is well-known
in the art, common types of solutions include liquid/liquid, solid/liquid
and solid/solid systems. In accordance with the apparatus of the present
invention, the detector means is maintained adjacent to the skin surface
of the subject by the attachment means, and the detector chemical
contained in solution in the detector means is capable of chemically
reacting with the target substance as the target substance migrates to the
surface of the skin of the subject in order to produce a detectable
signal. Thus, the apparatus of the invention is not dependent on the
collection of sweat or other liquid transport medium in order to detect a
target substance which migrates to the surface of the skin of a subject by
diffusion. Additionally, the apparatus of the invention substantially
prevents the detector chemical from migrating into the skin and avoids any
toxic effects in the subject which would result from the detector chemical
migrating the skin of the subject.
These and additional objects and advantages according to the present
invention will become more apparent in view of the following detailed
disclosure.
DESCRIPTION OF THE DRAWING
The following detailed description will be more fully understood in view of
the Figure which sets forth one embodiment of the transdermal detection
apparatus of the present invention.
DETAILED DESCRIPTION
As set forth above, the transdermal detection system of the present
invention comprises an apparatus for the detection of a target substance
which migrates to the surface of the skin of a subject by diffusion. The
apparatus is particularly suitable for detecting a target substance which
migrates to the surface of the skin of a subject by diffusion in the
absence of a liquid transport medium such as sweat or interstitial fluid.
The target substance may be any exogenous or endogenous chemical, or
microbiological or biological material which has migrated to the surface
of the skin by simple diffusion from within the body. The diffusion of the
target substance need not be dependent on sweating or on collection of
interstitial fluid.
The apparatus according to the invention comprises detector means including
at least one detector chemical contained in solution and capable of
chemically reacting with the target substance as the target substance
migrates to the skin surface of the subject to produce a detectable
signal. Depending on the target substance which is to be detected, the
detector means may include a mixture of two or more detector chemicals
contained in solution and capable of chemically reacting with the target
substance as the target substance migrates to the surface of the skin of
the subject to produce a detectable signal.
As set forth above, the term "in solution" refers to a uniformly dispersed
mixture at the molecular or ionic level of one or more substances, the
solute, in one or more other substances, the solvent. The detector
chemical may comprise a chemical reagent such as an acid or a base,
antibodies, enzymes, biological receptors, and/or mixtures thereof. The
detector chemical may be in a liquid or solid state as long as it is
contained in solution in a solvent as defined above. Preferred solvents
comprise liquid aqueous solvents, for example, water or a saline solution,
a gel or the like.
Suitable transdermal detection systems according to the present invention
have been provided wherein the detector chemical provided in the detector
means includes an oxidase enzyme contained in solution in an aqueous
solvent. As is set forth in detail in the examples, a transdermal ethanol
detection system may be provided wherein the detector chemical includes
alcohol oxidase and a transdermal glucose detection system may be provided
wherein the detector chemical includes glucose oxidase. Additionally, the
detector chemical may suitably comprise a mixture of an oxidase and a
peroxidase in solution in an aqueous solvent. Horseradish peroxidase, for
example, may be used in combination with an alcohol or glucose oxidase in
a specific embodiment of the detector means of the present invention.
The detector chemical contained in the detector means is capable of
chemically reacting with the target substance as the target substance
migrates to the surface of the skin of the subject to produce a detectable
signal. The detectable signal which results may be, for example, an
optically detectable signal such as a visible color change or an
electrically detectable signal such as a pH change, i.e. a change in the
hydrogen ion concentration, or other ion concentrations change. Other
optically and electrically detectable signals which may result from the
chemical reaction of the detector chemical with the target substance will
be apparent to one skilled in the art and are included within the scope of
the present invention.
The detector means of the present invention also includes a barrier means
for substantially preventing the detector chemical from migrating into the
skin of th subject. More particularly, the barrier means may comprise a
microporous membrane containing covalent linking functional groups which
covalently bind or link with the detector chemical to substantially
prevent the detector chemical from migrating into the skin of the subject.
Alternatively, the barrier means may comprise a permeable or
semi-permeable membrane which allows passage of the target substance
therethrough while substantially preventing passage of the detector
chemical to the skin surface of the subject and therefore substantially
prevents migration of the detector chemical into the skin. A suitable
permeable membrane may be formed of a permeable material such as tissue
paper while a suitable semipermeable membrane may comprise a semipermeable
material such as a dialysis membrane. A semipermeable membrane such as a
dialysis membrane provides a more complete prevention of migration of the
detector chemical into the skin than the permeable tissue membrane.
Alternatively, the barrier means may comprise a layer of gel, for example,
a silicone gel or other suitable gel, for substantially preventing the
detector chemical from migrating into the skin of the subject. The barrier
means is a particularly important component of the apparatus of the
invention since the migration of various detector chemicals into the skin
of a subject may cause a toxic reaction in the subject.
The apparatus according to the present invention also includes attachment
means for maintaining the detector means adjacent to the surface of the
skin of the subject. Because the detector means is adjacent the surface of
the skin of the subject, the detector chemical is available for chemically
reacting with the target substance as the target substance migrates to the
surface of the skin of the subject. The attachment means may comprise any
components capable of maintaining the detector means adjacent the surface
of the skin of the subject. In a preferred embodiment, the attachment
means includes an adhesive area for adhesively maintaining the detector
means adjacent to the surface of the skin of the subject. For example, one
or more adhesive strips or an adhesive perimeter portion may be provided
as the attachment means.
In one embodiment of the apparatus according to the present invention, the
detector means further comprises a carrier which is saturated with the
detector chemical contained in solution. Generally, the carrier acts as a
physical support for the detector chemical contained in solution and is
particularly suitable for use with solid/liquid solutions. The carrier may
comprise a porous support member such as filter paper or the like or a
microporous membrane similar to that described previously for use as the
barrier means. For example, the carrier may comprise a microporous
membrane containing covalent linking functional groups which covalently
link or bind with the detector chemical to hold the detector chemical on
the carrier. Thus, the carrier may also assist in preventing the detector
chemical from migrating into the skin of the subject. The detector means
comprising the carrier saturated with the detector chemical and the
previously described barrier means, for example, a semipermeable or
permeable membrane, are maintained adjacent the surface of the skin of the
patient so that the detector chemical may chemically react with the target
substance as the target substance migrates to the surface of the skin of
the subject to produce a detectable signal. Collection of sweat or
interstitial fluid containing the target substance is not necessary and,
when a substantially saturated carrier is included in the detector means,
sweat or interstitial fluid collection is not generally possible.
The apparatus according to the present invention may further include cover
means for preventing loss of the detector chemicals from the apparatus
and/or contamination of the apparatus from external environmental
substances. For example, an impermeable cover means may be provided for
covering the surfaces of the detector means which are not positionable
adjacent the surface of the skin of the subject. Suitable impermeable
cover means may comprise foil, an impermeable polymeric material or the
like. Additionally, a removable impermeable cover means may be provided
for covering the surface of the detector means which is positionable
adjacent the surface of the skin of the subject. The removable cover
serves to preserve the functionality of the detector chemicals and to
prevent contamination of the apparatus during storage and prior to use.
For example, a peelable foil or impermeable polymeric material may be
provided on the surface of the detector means which is positionable
adjacent the surface of the skin of the subject. The peelable material may
then be removed from the apparatus prior to its use for the detection of a
target substance migrating to the surface of the skin of the subject. In a
preferred embodiment, removal of the removable impermeable cover exposes
the detector means and the adhesive attachment means of the apparatus so
that the adhesive means may then be applied to the skin surface for use of
the apparatus in detecting a target substance.
The apparatus according to the invention may further include a signalling
means which is capable of converting the detectable signal produced by the
detector means into a form which is easily observable by the human eye.
For example, a chemical compound may be included which is capable of
reacting with the reaction product of the detector chemical and the target
substance to produce a color change in a visible portion of the
transdermal detection system. Furthermore, the signalling means may
comprise a reflectance spectrometer for indicating a color change in the
detector means or a pH or other electrode and meter for indicating a
change in the hydrogen or other ion concentration in the detector means.
Additionally, the signalling means may include a microprocessing unit for
converting the detectable signal into a numerical measured value.
Attention is directed to the FIGURE which discloses one embodiment of the
apparatus according to the present invention. The FIGURE discloses a
transdermal detection apparatus 10 including detector means 12 and
attachment means 14. The detector means 12 includes a porous carrier 16
formed of filter paper which is saturated with the detector chemical
contained in solution and a barrier means 18 comprising a membrane
material. The adhesive means 14 comprises an annular ring of a plastic
polymeric material having an adhesive coating on its lower surface 20
which is adapted for positioning adjacent the surface of the skin of a
subject. The apparatus further includes an impermeable cover 22 formed of
an impermeable polymeric material which covers the surfaces of the
detector means which are not positionable adjacent the surface of the skin
of the subject. A removable impermeable cover 24 comprising a peelable
material is also included in the apparatus and is adapted for removal from
the apparatus prior to use for the detection of the target substance
migrating to the surface of the skin of a subject. Once the cover 24 is
removed from the apparatus, the adhesive surfaces 20 of the attachment
means are positioned on the skin surface so that the detector means is
maintained adjacent the surface of the skin of the subject, with barrier
means 18 substantially preventing the detector chemical from migrating
into the skin surface.
The present invention will be more fully understood in view of the
following examples.
EXAMPLE 1
A transdermal ethanol detection system was prepared according to the
present invention. The detector means comprised a carrier saturated with a
mixture of detector chemicals contained in solution, and a barrier means
for substantially preventing migration of the detector chemicals into the
skin. Specifically, the carrier comprised a 5.times.7.5 mm. rectangular
piece of filter paper (Whatman No. 40) saturated with a mixture of 1.1
units of an alcohol oxidase, 1 unit of horseradish peroxidase and 80
micrograms tetramethylbenzidine contained in solution in 30 ul of 0.04
Molar potassium phosphate monobasicsodium phosphate dibasic buffer (pH
7.41) in 3% saline solution. The barrier means comprised a 1.1 cm.
circular permeable membrane of Kimwipe material (supplied by
Kimberly-Clark Corporation). An impermeable cover comprising Saran Wrap
(supplied by Dow Chemical Co.) was also included. The attachment means
comprised an annular disc member having adhesive on both sides
(Double-Stick Disc supplied by 3M Corporation), a 1.25 inch outer diameter
and an 11/32 inch inner aperture in which the detector means was
positioned.
The transdermal ethanol detection system as described above may be attached
to the skin surface of a subject in order to detect ethanol which migrates
to the surface of the skin of a subject by diffusion. When the apparatus
is placed on the skin surface, the detector means often turns from a light
bluish-green color to a pale cream color. It is believed that this color
change is caused by a change in the apparatus temperature from room
temperature (23.degree.-25.degree. C.) to the skin surface temperature
(30.degree.-32.degree. C.). The color will generally remain unchanged if
no ethanol migrates to the skin surface of the subject. However, as
ethanol migrates to the skin surface by diffusion, the detector means
changes to an increasingly dark green to purple-blue color. For example,
when attached to the skin of a person drinking alcohol at the rate of one
and a half beers per hour, the detector means changed to a dark green-blue
color within two to three hours after intake commencement. Additionally,
the detector means has turned a green-blue color within 30 minutes of
attaching the apparatus to the skin of a subject who h | | |
