U.S. patent application number 09/852935 was filed with the patent office on 2002-01-24 for multiple mechanical microporation of skin or mucosa.
This patent application is currently assigned to SpectRx, Inc.. Invention is credited to Eppstein, Jonathan A..
Application Number | 20020010412 09/852935 |
Document ID | / |
Family ID | 21802981 |
Filed Date | 2002-01-24 |
United States Patent
Application |
20020010412 |
Kind Code |
A1 |
Eppstein, Jonathan A. |
January 24, 2002 |
Multiple mechanical microporation of skin or mucosa
Abstract
A device and methods of use for delivering a drug to the body,
or monitoring an analyte found in the body, are described. The
device includes a base, a plurality of puncturing members extending
from the base, a plurality of holes extending through the base for
the passage of the drug or the analyte, and a network of channels
for distributing the drug or collecting the analyte. Methods of
trans-dermal or trans-mucous delivery of a drug or monitoring of an
analyte are also described.
Inventors: |
Eppstein, Jonathan A.;
(Atlanta, GA) |
Correspondence
Address: |
D. Andrew Floam
NEEDLE & ROSENBERG, P.C.
The Candler Building, Suite 1200
127 Peachtree Street, N.E.
Atlanta
GA
30303-1811
US
|
Assignee: |
SpectRx, Inc.
|
Family ID: |
21802981 |
Appl. No.: |
09/852935 |
Filed: |
May 10, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09852935 |
May 10, 2001 |
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09614164 |
Jul 11, 2000 |
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09614164 |
Jul 11, 2000 |
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09202207 |
Jun 14, 1999 |
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6183434 |
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09202207 |
Jun 14, 1999 |
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PCT/US97/1670 |
Jul 3, 1997 |
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60021212 |
Jul 3, 1996 |
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Current U.S.
Class: |
604/10 |
Current CPC
Class: |
A61M 2037/0053 20130101;
A61M 2037/0038 20130101; A61M 37/0092 20130101; A61B 5/14514
20130101; A61M 2037/0007 20130101; A61M 37/0015 20130101; A61M
2037/0023 20130101 |
Class at
Publication: |
604/10 |
International
Class: |
A61M 005/00 |
Claims
I claim:
1. A device for reducing the barrier properties of skin or mucosa
to the delivery of a substance into the body or the withdrawal of
an analyte from the body comprising: (a) a base having a lower side
and an upper side; (b) a plurality of puncturing members extending
from the lower side of the base, said puncturing members configured
for puncturing said skin or mucosa to a depth sufficient to reduce
the barrier properties thereof without significantly damaging
underlying tissues; (c) a plurality of holes extending from the
lower side of the base to the upper side of the base, said holes
configured for permitting a liquid to move therethrough by
capillary action; and (d) a network of channels configured in the
upper side of said base to interconnect said holes.
2. The device of claim 1 wherein said device is fabricated by
microlithography.
3. The device of claim 1 wherein said device is fabricated of a
material selected from the group consisting of silicon, metal, and
plastic.
4. The device of claim 1 wherein said puncturing member is in the
shape of a pyramid or wedge.
5. The device of claim 4 wherein said pyramid or wedge comprises
sharp edges having corner radii of less than 1 .mu.m.
6. The device of claim 1 wherein said puncturing member is
configured for puncturing said skin or mucosa to a depth of about
30-50 .mu.m.
7. The device of claim 1 wherein said plurality of puncturing
members occupy up to about 50% of the surface area of the lower
surface of the base.
8. The device of claim 1 wherein said puncturing member has a
dimension at a base thereof of about 10-50 .mu.m.
9. The device of claim 1 wherein said each of said holes is
positioned adjacent to a puncturing member.
10. The device of claim 1 wherein said network of channels further
comprises a reservoir for holding liquid.
11. The device of claim 1 wherein said base is substantially
planar.
12. The device of claim 1 further comprising a mechanism for
producing vibrations, said vibrations for facilitating efficient
and non-traumatic penetration of the puncturing members into the
skin or mucosa.
13. The device of claim 12 wherein said mechanism for producing
vibrations comprises a piezo-electric transducer.
14. The device of claim 12 wherein said mechanism for producing
vibrations produces vibrations in the range of about 2000 Hz to
about 100 MHz.
15. The device of claim 1 further comprising an external reservoir
for holding a liquid drug composition to be delivered to the
body.
16. The device of claim 15 further comprising a mechanism for
limiting the rate of drug delivery, said mechanism positioned
between the external reservoir and the puncturing members.
17. The device of claim 1 wherein said device is disposable.
18. A method for reducing the barrier function of skin or mucosa to
the delivery of substances into a body or withdrawal of analytes
out of the body, comprising: (a) providing a device comprising: a
base having a lower side and an upper side; a plurality of
puncturing members extending from the lower side of the base, said
puncturing members configured for puncturing said skin or mucosa to
a depth sufficient to reduce the barrier properties thereof without
significantly damaging underlying tissues; a plurality of holes
extending from the lower side of the base to the upper side of the
base, said holes configured for permitting a liquid to move
therethrough by capillary action; and a network of channels
configured in the upper side of said base to interconnect said
holes; (b) contacting said device with the skin or mucosa such that
said plurality of puncturing members puncture the skin or mucosa to
a depth sufficient to reduce the barrier properties thereof.
19. The method of claim 18 wherein said device is fabricated by
microlithography.
20. The method of claim 18 wherein said device is fabricated of a
material selected from the group consisting of silicon, metal, and
plastic.
21. The method of claim 18 wherein said puncturing member is in the
shape of a pyramid or wedge.
22. The method of claim 21 wherein said pyramid or wedge comprises
sharp edges having corner radii of less than 1 .mu.m.
23. The method of claim 18 wherein said puncturing member is
configured for puncturing said skin or mucosa to a depth of about
30-50 .mu.m.
24. The method of claim 18 wherein said plurality of puncturing
members occupy up to about 50% of the surface area of the lower
surface of the base.
25. The method of claim 18 wherein said puncturing member has a
dimension at a base thereof of about 10-50 .mu.m.
26. The method of claim 18 wherein said each of said holes is
positioned adjacent to a puncturing member.
27. The method of claim 18 wherein said network of channels further
comprises a reservoir for holding liquid.
28. The method of claim 18 wherein said base is substantially
planar.
29. The method of claim 18 further comprising a mechanism for
producing vibrations, said vibrations for facilitating efficient
and non-traumatic penetration of the puncturing members into the
skin or mucosa.
30. The method of claim 29 wherein said mechanism for producing
vibrations comprises a piezo-electric transducer.
31. The method of claim 29 wherein said mechanism for producing
vibrations produces vibrations in the range of about 2000 Hz to
about 100 MHz.
32. The method of claim 18 further comprising an external reservoir
for holding a liquid drug composition to be delivered to the
body.
33. The method of claim 32 further comprising a mechanism for
limiting the rate of drug delivery, said mechanism positioned
between the external reservoir and the puncturing members.
34. The method of claim 18 wherein said device is disposable.
35. A method of transdermal or transmucosal monitoring of a
selected analyte in a body comprising: (a) providing a device
comprising: a base having a lower side and an upper side; a
plurality of puncturing members extending from the lower side of
the base, said puncturing members configured for puncturing said
skin or mucosa to a depth sufficient to reduce the barrier
properties thereof without significantly damaging underlying
tissues; a plurality of holes extending from the lower side of the
base to the upper side of the base, said holes configured for
permitting a liquid to move therethrough by capillary action; and a
network of channels configured in the upper side of said base to
interconnect said holes, said network of channels including a
reservoir; (b) contacting said device with the skin or mucosa such
that said plurality of puncturing members puncture the skin or
mucosa to a depth sufficient to reduce the barrier properties
thereof resulting in seepage of interstitial fluid to the surface
of said skin or mucosa such that interstitial fluid moves by
capillary action through the holes, through the channels, to the
reservoir; (c) collecting the interstitial fluid from the
reservoir; and (d) analyzing the interstitial fluid with respect to
the selected analyte.
36. The method of claim 35 further comprising applying suction to
increase the rate of collection of interstitial fluid.
37. The method of claim 35 further comprising applying ultrasonic
vibrations to the skin or mucosa to increase the rate of collection
of the selected analyte.
38. The method of claim 37 wherein said ultrasonic vibrations are
modulated in frequency, intensity, phase, or a combination
thereof.
39. The method of claim 38 wherein said ultrasonic vibrations are
in the range of about 2000 Hz to about 100 MHz.
40. The method of claim 35 wherein movement of interstitial fluid
by capillary action is enhanced by applying ultrasonic
vibrations.
41. The method of claim 35 wherein said selected analyte is
glucose.
42. The method of claim 35 further comprising applying an
anticoagulant to inhibit obstruction of the holes or channels.
43. A method of transdermally or transmucosally delivering a drug
in liquid form to a body comprising: (a) providing a device
comprising: a base having a lower side and an upper side; a
plurality of puncturing members extending from the lower side of
the base, said puncturing members configured for puncturing said
skin or mucosa to a depth sufficient to reduce the barrier
properties thereof without significantly damaging underlying
tissues; a plurality of holes extending from the lower side of the
base to the upper side of the base, said holes configured for
permitting a liquid to move therethrough by capillary action; and a
network of channels configured in the upper side of said base to
interconnect said holes, said network of channels including a
reservoir; (b) contacting said device with the skin or mucosa such
that said plurality of puncturing members puncture the skin or
mucosa to a depth sufficient to reduce the barrier properties
thereof; (c) supplying the drug to said reservoir such that said
drug moves from the reservoir, through the channels and holes to
the site of the punctures of the skin or mucosa and thus into the
body.
44. The method of claim 43 further comprising applying pressure to
increase the rate of delivery of the drug to the body.
45. The method of claim 43 further comprising applying ultrasonic
vibrations to the skin or mucosa to increase the rate of delivery
of the drug to the body.
46. The method of claim 45 wherein said ultrasonic vibrations are
modulated in frequency, intensity, phase, or a combination
thereof.
47. The method of claim 45 wherein said ultrasonic vibrations are
in the range of about 2000 Hz to about 100 MHz.
48. The method of claim 43 wherein said drug in liquid form further
comprises an anti-irritant, antiseptic, or analgesic to reduce
trauma to the body due to the application of the device.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/021,212, filed Jul. 3, 1996.
BACKGROUND OF THE INVENTION
[0002] This invention relates to a device and method for puncturing
a selected layer or layers of the skin or mucosa. More
particularly, the invention relates a device and method for
puncturing the stratum corneum or mucosa to diminish the barrier
function thereof and permit a drug to be delivered to the body or
an analyte in the body to be withdrawn for monitoring. This
puncturing of the stratum corneum or mucosa is minimally is
invasive, and can be combined with various other methods, such as
use of chemical enhancers, pressure gradients, sonic gradients,
temperature gradients, and the like for selectively enhancing the
inward flux of a drug to the body or the outward flux of an analyte
from the body.
[0003] The stratum corneum is chiefly responsible for the
well-known barrier properties of skin. Thus, it is this layer of
the skin that presents the greatest barrier to transdermal flux of
drugs or other molecules into the body and of analytes out of the
body. Mucosal tissue also presents a barrier to flux of molecules
into and out of the body. The stratum corneum, the outer horny
layer of the skin, is a complex structure of compact keratinized
cell remnants separated by lipid domains. Compared to the oral or
gastric mucosa, the stratum corneum is much less permeable to
molecules either external or internal to the body. The stratum
corneum is formed from keratinocytes, which comprise the majority
of the epidermal cells, that lose their nuclei and become
corneocytes. These dead cells comprise the stratum corneum, which
has a thickness of about 10-30 .mu.m and, as noted above, is a very
resistant waterproof membrane that protects the body from invasion
by exterior substances and the outward migration of fluids and
dissolved molecules. The stratum corneum is continuously renewed by
shedding of corneum cells during desquamination and the formation
of new corneum cells by the keratinization process.
[0004] Various methods of enhancing the permeability of the stratum
corneum and mucosa have been described. For example, U.S. Pat. No.
5,458,140 and U.S. Pat. No. 5,445,611 disclose using ultrasonic
energy that is modulated in intensity, phase, or frequency or a
combination thereof. U.S. Pat. No. 4,775,361 discloses a method of
administering a drug by ablating the stratum corneum using pulsed
laser light without significantly damaging the underlying
epidermis. Numerous patents teach the use of chemical enhancers for
improving transdermal flux of a drug through the skin. E.g., U.S.
Pat. No. 4,863,970. It would be advantageous to develop additional
methods of permeating the stratum corneum or mucosa to enhance the
transport of drugs into the body or analytes out of the body,
particularly without the need for expensive or complicated
equipment.
[0005] In view of the foregoing, it will be appreciated that
providing a device and method of use thereof for introducing
multiple micropores or perforations in the stratum corneum or
mucosa for enhancing transport of molecules therethrough would be a
significant advancement in the art.
BRIEF SUMMARY OF THE INVENTION
[0006] It is an object of the present invention to provide a
simple, inexpensive device for puncturing the stratum corneum or
mucosa without significantly damaging the underlying tissues to
facilitate transport of molecules therethrough.
[0007] It is also an object of the invention to provide a method of
enhancing the passage of molecules through the stratum corneum or
mucosa.
[0008] It is another object of the invention to provide a method
for transdermally or transmucosally delivering a drug.
[0009] It is still another object of the invention to provide a
method for transdermally or transmucosally monitoring an
analyte.
[0010] These and other objects can be achieved by providing a
device for reducing the barrier properties of skin or mucosa to the
delivery of a substance into the body or the withdrawal of an
analyte from the body comprising:
[0011] (a) a base having a lower side and an upper side;
[0012] (b) a plurality of puncturing members extending from the
lower side of the base, the puncturing members configured for
puncturing the skin or mucosa to a depth sufficient to reduce the
barrier properties thereof without significantly damaging
underlying tissues;
[0013] (c) a plurality of holes extending from the lower side of
the base to the upper side of the base, the holes configured for
permitting a liquid to move therethrough by capillary action;
and
[0014] (d) a network of channels configured in the upper side of
the base to interconnect the holes.
[0015] Preferably, the device is fabricated by microlithography and
is composed of a material selected from the group consisting of
silicon, metal, and plastic. It is also preferred that the
puncturing member be in the shape of a pyramid or wedge. The
pyramid or wedge preferably have sharp edges having corner radii of
less than 1 .mu.m. The puncturing member is preferably configured
for puncturing the skin or mucosa to a depth of about 30-50 .mu.m,
and a dimension at a base thereof is preferably about 10-50 .mu.m.
The puncturing members preferably occupy up to about 50% of the
surface area of the lower surface of the base.
[0016] The device preferably further comprises a mechanism for
producing vibrations, the vibrations for facilitating efficient and
non-traumatic penetration of the puncturing members into the skin
or mucosa. A preferred vibration-producing mechanism comprises a
piezo-electric transducer. It is preferred that the mechanism for
producing vibrations produces vibrations in the range of about 2000
Hz to about 100 MHz.
[0017] In another illustrative embodiment of the device, an
external reservoir for holding a liquid drug composition to be
delivered to the body is provided. Still further, a mechanism for
limiting the rate of drug delivery is preferably included in the
device, the mechanism positioned between the external reservoir and
the puncturing members. Such rate-limiting mechanisms can include
selective permeability membranes and valve mechanisms. In another
preferred embodiment, the device is disposable.
[0018] A method for reducing the barrier function of skin or mucosa
to the delivery of substances into a body or withdrawal of analytes
out of the body, comprises:
[0019] (a) providing a device comprising:
[0020] a base having a lower side and an upper side;
[0021] a plurality of puncturing members extending from the lower
side of the base, the puncturing members configured for puncturing
the skin or mucosa to a depth sufficient to reduce the barrier
properties thereof without significantly damaging underlying
tissues;
[0022] a plurality of holes extending from the lower side of the
base to the upper side of the base, the holes configured for
permitting a liquid to move therethrough by capillary action;
and
[0023] a network of channels configured in the upper side of the
base to interconnect the holes;
[0024] (b) contacting the device with the skin or mucosa such that
the plurality of puncturing members puncture the skin or mucosa to
a depth sufficient to reduce the barrier properties thereof.
[0025] A method of transdermal or transmucosal monitoring of a
selected analyte in a body comprises:
[0026] (a) providing a device comprising:
[0027] a base having a lower side and an upper side;
[0028] a plurality of puncturing members extending from the lower
side of the base, the puncturing members configured for puncturing
said skin or mucosa to a depth sufficient to reduce the barrier
properties thereof without significantly damaging underlying
tissues;
[0029] a plurality of holes extending from the lower side of the
base to the upper side of the base, the holes configured for
permitting a liquid to move therethrough by capillary action;
and
[0030] a network of channels configured in the upper side of the
base to interconnect the holes, the network of channels including a
reservoir;
[0031] (b) contacting the device with the skin or mucosa such that
the plurality of puncturing members puncture the skin or mucosa to
a depth sufficient to reduce the barrier properties thereof
resulting in seepage of interstitial fluid to the surface of the
skin or mucosa such that interstitial fluid moves by capillary
action through the holes, through the channels, to the
reservoir;
[0032] (c) collecting the interstitial fluid from the reservoir;
and
[0033] (d) analyzing the interstitial fluid with respect to the
selected analyte.
[0034] In a preferred embodiment, the method further comprises
applying suction to increase the rate of collection of interstitial
fluid. Ultrasonic vibrations can also be applied to the skin or
mucosa to increase the rate of collection of the selected analyte.
The ultrasonic vibrations can be modulated in frequency, intensity,
phase, or a combination thereof, as disclosed in U.S. Pat. No.
5,458,140, hereby incorporated by reference. The ultrasonic
vibrations are preferably in the range of about 2000 Hz to about
100 MHz. The ultrasonic vibrations can also enhance the movement of
interstitial fluid by capillary action. In a preferred embodiment
of the invention, the selected analyte is glucose. It is also
preferred to apply an anticoagulant to inhibit obstruction of the
holes or channels.
[0035] A method of transdermally or transmucosally delivering a
drug in liquid form to a body comprises:
[0036] (a) providing a device comprising:
[0037] a base having a lower side and an upper side;
[0038] a plurality of puncturing members extending from the lower
side of the base, the puncturing members configured for puncturing
the skin or mucosa to a depth sufficient to reduce the barrier
properties thereof without significantly damaging underlying
tissues;
[0039] a plurality of holes extending from the lower side of the
base to the upper side of the base, the holes configured for
permitting a liquid to move therethrough by capillary action;
and
[0040] a network of channels configured in the upper side of the
base to interconnect the holes, the network of channels including a
reservoir;
[0041] (b) contacting the device with the skin or mucosa such that
the plurality of puncturing members puncture the skin or mucosa to
a depth sufficient to reduce the barrier properties thereof;
[0042] (c) supplying the drug to the reservoir such that said drug
moves from the reservoir, through the channels and holes to the
site of the punctures of the skin or mucosa and thus into the
body.
[0043] In a preferred embodiment, pressure is applied to increase
the rate of delivery of the drug to the body. Applying ultrasonic
vibrations to the skin or mucosa also increases the rate of
delivery of the drug to the body. The ultrasonic vibrations can be
modulated in frequency, intensity, phase, or a combination thereof,
as disclosed in U.S. Pat. No. 5,445,611, hereby incorporated by
reference. The ultrasonic vibrations are preferably in the range of
about 2000 Hz to about 100 MHz. The drug in liquid form can further
comprise an anti-irritant, antiseptic, or analgesic to reduce
trauma to the body due to the application of the device.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
[0044] FIG. 1 shows a perspective view of an illustrative
embodiment of the present invention.
[0045] FIG. 2 shows a cross section of a portion of another
illustrative embodiment according to the present invention.
[0046] FIG. 3 shows a perspective view of a portion of the
embodiment of FIG. 2.
[0047] FIG. 4 shows a top view of a portion of the embodiment of
FIG. 2.
[0048] FIG. 5 shows a schematic diagram of a device for making
multiple microporations in skin or mucosa and collecting
interstitial fluid.
[0049] FIG. 6 shows a schematic sectional diagram of a device for
making multiple microporations in skin or mucosa and delivering a
drug.
DETAILED DESCRIPTION
[0050] Before the present device and method for enhancing
permeability of skin or mucosa for drug delivery or analyte
monitoring are disclosed and described, it is to be understood that
this invention is not limited to the particular configurations,
process steps, and materials disclosed herein as such
configurations, process steps, and materials may vary somewhat. It
is also to be understood that the terminology employed herein is
used for the purpose of describing particular embodiments only and
is not intended to be limiting since the scope of the present
invention will be limited only by the appended claims and
equivalents thereof.
[0051] It must be noted that, as used in this specification and the
appended claims, the singular forms "a," "an," and "the" include
plural referents unless the context clearly dictates otherwise.
Thus, for example, reference to a device containing "a puncturing
member" includes a device containing two or more of such members,
reference to "a channel" includes reference to one or more of such
channels, and reference to "an ultrasound transducer" includes
reference to two or more ultrasound transducers.
[0052] It has been observed that forming a hole or micropore, 30
.mu.m across, in the stratum corneum yields a quick source of about
0.2 microliters of interstitial fluid seeping through the hole from
the underlying tissue without any additional pumping. Merely
increasing the number of holes introduced through the stratum
corneum would increases the amount of passively available fluid in
a linear fashion. That is, creating 100 holes should produce about
20 microliters of interstitial fluid. From a practical perspective,
using known approaches to create 100 holes in a controlled pattern
would be challenging and time-consuming. However, using the
mechanical puncturing capabilities of a mechanical microporation or
"bed-of-nails" device would allow an almost unlimited number of
micropores to be quickly created in any selected pattern.
Similarly, using conventional lancet and needle technologies would
make the needed depth control of the puncture very tricky and, if
the device were to create hundreds of these holes, the mechanical
challenge of building the device using conventional metal needle
technologies would be formidable. However, by fabricating
puncturing elements en masse such that they protrude from a
substantially planar surface, with sufficient spacing between each
to allow the stratum corneum to come in contact with this
intervening planar surface, the absolute length of the puncturing
elements themselves would act as an accurate limit for the depth of
the micropore. Also, using a microlithography approach to fabricate
these structures will allow an entire surface comprised of
puncturing elements and the interconnecting fluid management system
to be built very cost effectively.
[0053] One illustrative method would be to utilize the existing
base of manufacturing capabilities developed in the semiconductor
and micro-mechanical industries to dry-etch an entire 4 inch
silicon wafer with a network of these devices. This master could
then be used as the basis for an electroplated mold from which
thousands of copies could be produced. For a typical useable
surface area/per device application of 4 mm.times.4 mm, one 4-inch
wafer would yield more than 500 of the devices.
[0054] A device according to the present invention is made, for
example, by first preparing a master by a dry etch process on a
silicon wafer, as is well known in the art. Photolithographical
processes for etching micrometer-scale structures into silicon
waters and the like are described in A. T. Wooley & R. A.
Mathies, Ultra-high-speed DNA fragment separations using
microfabricated capillary array electrophoresis chips, 91
Biophysics 11348-52 (1994); C. S. Effenhauser et al., High-speed
separation of antisense oligonucleotides on a micromachined
capillary electrophoresis device, 66 Anal. Chem. 2949 (1994); C.
Effenhauser et al., 65 Anal. Chem. 2637 (1993); Z. H. Fan & D.
J. Harrison, Micromachining of capillary electrophoresis injectors
and separators on glass chips and evaluation of flow at capillary
intersections, 66 Anal. Chem. 177-84 (1994); W. H. Ko et al., in
Sensors: A Comprehensive Survey, T. Grandke, W. H. Ko, eds., VCH
Press: Weinheim, Germany, Vol. 1, pp. 107-68 (1989); K. E.
Petersen, 70 Proc. IEEE 420-57 (1982), which are hereby
incorporated by reference. The master silicon wafer is then used to
make an electroplated mold, and then the mold is used to make
copies of the device, all by processes well known in the art.
[0055] Also, by coupling the entire device to an ultrasonic
transducer, several known advantages can be realized
simultaneously. For example, ultrasound has been shown to enhance
the smooth cutting ability of scalpels and other surgical devices
and can be expected to facilitate the easy, painless penetration of
the puncturing elements into the stratum corneum with very little
pressure. The edges of the pyramidally shaped puncturing elements
shown in FIG. 1 can easily be fabricated such that the corner
radius is less than 10 nanometers, a sharpness similar to a
surgical scalpel. Second, ultrasound has also been shown to greatly
enhance capillary action, thus the amount of fluid that could be
collected in a device containing a capillary collection system
could be expected to be significantly greater than that provided by
mere passive means. Third, by using the entire body of the
puncturing elements to provide a conduit for the ultrasonic energy,
a simple method is presented wherein the sonic energy is placed
within the body where it can provide a positive pressure, and
streaming action on the interstitial fluid from within the body
outward towards a collection system of capillary channels coupling
all fluid harvested into a central reservoir.
[0056] FIG. 1 shows a perspective view of an illustrative device
according to the present invention. The device 10 comprises a base
14 with a plurality of puncturing members 18 extending therefrom.
In a preferred embodiment, the base is substantially planar. Each
puncturing member comprises a sharp point 22 or edge for puncturing
the stratum corneum or mucosa. Since the stratum corneum can be up
to about 30 .mu.m thick, it is preferred that the puncturing
element have a height of about 40-50 .mu.m to ensure that the
stratum corneum will be fully breached without significantly
damaging the underlying tissue. A pyramid or wedge shape is a
preferred shape for the puncturing member because of the ease with
which such a shape can be formed by microfabrication techniques
such as microlithography. In an illustrative puncturing element
having a pyramid shape, the base of the pyramid would preferably
have a square base about 30-40 .mu.m on a side.
[0057] It is also preferred that the base have a plurality of holes
26 extending therethrough from the lower side 30, on which the
puncturing element are disposed, to the upper side 34. Preferably,
each puncturing element is adjacent to and paired with at least one
hole for collecting the interstitial fluid that seeps out of the
puncture in the stratum corneum. These holes should be dimensioned
to permit the interstitial fluid to move by capillary action from
the lower side of the device to the upper side, where the
interstitial fluid can be collected. It is also preferred to
interconnect the holes with capillary channels 38 that are formed
in the upper side of the device. Preferably, such channels
intersect at a reservoir 42. The interstitial fluid moves by
capillarity from the micropore into the hole, through the channels,
and to the reservoir, where the interstitial fluid is collected,
such as with a micropipet. Additional fluid can be collected by
applying suction to the microporated area of skin or mucosa.
[0058] FIGS. 2-4 show another illustrative embodiment of the
invention. FIG. 2 shows a cross section of a portion of the device
50 comprising a base 54 with a puncturing member 58 extending
therefrom. The puncturing member is pyramid-shaped, as in FIG. 1.
The upper side 62 of the base is configured with a V-shaped channel
66 positioned such that the channel is directly over the puncturing
member and cuts into the volume circumscribed by the puncturing
member. FIG. 3 shows a perspective view of the device having the
V-shaped channels 66 and interconnecting shallower V-grooves 70.
The channels 66 cut through the lower side 74 of the base, and thus
form openings through which the interstitial fluid can be taken up
by capillary action. FIG. 4 shows how the V-grooves 70 interconnect
the V-channels for collecting the interstitial fluid. All of the
puncturing members, channels, and grooves shown in FIGS. 2,3, and 4
are designed to be wedge-shaped, compatible with being produced in
the crystalline structure of a silicon substrate with a
lithographic `dry-etch` type of process.
[0059] FIG. 5 shows an illustrative device 80 for collecting
interstitial fluid according to the present invention. The device
80 comprises a base 84 having a plurality of puncturing members 88
extending therefrom. V-shaped channels and grooves are configured
into the upper side 92 of the base for collecting the interstitial
fluid. A cover plate 96 fits over the base to cover the network of
channels and grooves and to inhibit evaporation of the interstitial
fluid. The network of channels and grooves leads the interstitial
fluid to a central area, where there is disposed a capillary tube
100 for receiving the interstitial fluid. Atop the cover plate is
disposed an ultrasonic transducer 104 and a backing 108 for the
tranducer.
[0060] The device is pressed against a selected area of skin or
mucosa, and the ultrasonic transducer is activated to aid in both
the puncturing of the tissue and in enhancing the seepage of the
interstitial fluid. The interstitial fluid is collected by the
network of openings in the base, and is conducted by the network of
channels and grooves to the capillary, which takes up the fluid by
capillary action. The fluid is then analyzed according to methods
known in the art. An illustrative analyte is glucose, which can be
quantified with various test strips that are available
commercially.
[0061] FIG. 6 shows an illustrative drug delivery device 120
comprising a base 124 having a plurality of puncturing members 128
extending therefrom. A network of grooves and channels (see FIGS.
2-4) is embedded in the base for distributing a drug composition
132 from a reservoir 136. The reservoir is bounded by a housing
138, the base, and a backing plate 144 including an O-ring 148. The
drug composition flows through the channels, grooves, and openings
in the base to the surface of the skin or mucosa for entry into the
body through the punctures or perforations. An ultrasound
transducer 140 lies over the drug composition for aiding in
delivery thereof. Above the transducer is the backing plate 144
including the O-ring for sealing the drug in the reservoir. A
spring 152 can advantageously bias the backing plate against the
transducer, which causes the transducer to be kept in fluid contact
with the drug.
[0062] The ultrasonic system is utilized not only to enhance the
slicing action of the edges of the puncturing elements as the
penetrate into the stratum corneum or mucosa, but is then utilized
to enhance the fluid flux of the therapeutic containing solution
through the micro-pores and into the underlying tissues. In this
case, large quantities of large molecular weight drugs could be
delivered transdermally with a programmable control of the flux
rate via variable activation of the ultrasonic pumping system. In
addition, the sonic energy can be utilized to create controlled
resonant vibrations in specifically shaped micro-structures such
that a micro-pump is created to facilitate driving the collected
fluid from one point to another within the entire structure.
Moreover, chemical enhancers, air pressure, and other methods known
in the art can be used to enhance the passage of the drug through
the micropores in the skin or mucosa into the body.
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