U.S. patent application number 10/856691 was filed with the patent office on 2005-06-23 for devices and methods for enhanced microneedle penetration of biological barriers.
Invention is credited to Ackley, Donald E., Allen, Mark G., Henry, Sebastian, Jackson, Thomas, McAllister, Devin V., Prausnitz, Mark R..
Application Number | 20050137531 10/856691 |
Document ID | / |
Family ID | 32326693 |
Filed Date | 2005-06-23 |
United States Patent
Application |
20050137531 |
Kind Code |
A1 |
Prausnitz, Mark R. ; et
al. |
June 23, 2005 |
Devices and methods for enhanced microneedle penetration of
biological barriers
Abstract
Microneedle devices and methods of use thereof are provided for
the enhanced transport of molecules, including drugs and biological
molecules, across tissue by improving the interaction of
microneedles and a deformable, elastic biological barrier, such as
human skin. The devices and methods act to (1) limit the
elasticity, (2) adapt to the elasticity, (3) utilize alternate ways
of creating the holes for the microneedles to penetrate the
biological barrier, other than the simply direct pressure of the
microneedle substrate to the barrier surface, or (4) any
combination of these methods. In preferred embodiments for limiting
the elasticity of skin, the microneedle device includes features
suitable for stretching, pulling, or pinching the skin to present a
more rigid, less deformable, surface in the area to which the
microneedles are applied (i.e. penetrate). In a preferred
embodiments for adapting the device to the elasticity of skin, the
device comprising one or more extensions interposed between the
substrate and the base end of at least a portion of the
microneedles.
Inventors: |
Prausnitz, Mark R.;
(Decatur, GA) ; Allen, Mark G.; (Atlanta, GA)
; Henry, Sebastian; (Ay, FR) ; McAllister, Devin
V.; (Holley, NY) ; Ackley, Donald E.;
(Cardiff, CA) ; Jackson, Thomas; (La Jolla,
CA) |
Correspondence
Address: |
FISH & NEAVE IP GROUP
ROPES & GRAY LLP
ONE INTERNATIONAL PLACE
BOSTON
MA
02110-2624
US
|
Family ID: |
32326693 |
Appl. No.: |
10/856691 |
Filed: |
May 28, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10856691 |
May 28, 2004 |
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09448107 |
Nov 23, 1999 |
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6743211 |
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Current U.S.
Class: |
604/173 |
Current CPC
Class: |
A61M 5/422 20130101;
A61B 5/150076 20130101; A61M 2037/003 20130101; A61B 5/150984
20130101; A61B 5/150083 20130101; B33Y 80/00 20141201; A61B
5/150022 20130101; A61B 5/150229 20130101; A61B 5/150213 20130101;
A61B 5/150412 20130101; A61B 5/151 20130101; A61B 5/150389
20130101; A61M 2037/0053 20130101; A61B 5/14532 20130101; A61M
5/425 20130101; A61B 5/150099 20130101; A61B 5/150503 20130101;
A61B 5/14514 20130101; A61B 5/150068 20130101; A61B 17/205
20130101; A61M 37/0015 20130101; A61M 2037/0023 20130101 |
Class at
Publication: |
604/173 |
International
Class: |
A61M 005/00 |
Claims
1. A device for transport of material or energy across or into an
elastic biological barrier comprising: a microneedle having a tip
end and a base end, a substrate connected to the base end of the
microneedle, and a means for improving penetration of the
biological barrier by the microneedle.
2. The device of claim 1 wherein the biological barrier is human or
other mammalian skin.
3. The device of claim 1 wherein the means comprises one or more
extensions (i) interposed between the substrate and the base end of
the microneedle, or (ii) extending from the side of the substrate
distal to the base end of the microneedle.
4. The device of claim 3 wherein the extension is between about 500
.mu.m and about 10 mm in height.
5. The device of claim 3 wherein the extension has a
cross-sectional dimension of at least about 200 .mu.m.
6. The device of claim 3 wherein the extension includes an array of
microneedles extending therefrom.
7. The device of claim 3 wherein the extension is composed of a
material which is different from the material forming the
microneedles.
8. The device of claim 3 wherein the microneedle is hollow and
wherein the extension includes at least one aperture in
communication with the bore of the microneedle.
9. The device of claim 3 further comprising a rigid surface
positioned apart from an array of the microneedles and oriented to
contact an elastic biological barrier substantially at the same
time as the microneedles when the microneedles are applied to the
barrier.
10. The device of claim 1 wherein the substrate is curved.
11. The device of claim 1 comprising a plurality of microneedles of
varying lengths.
12. The device of claim 11 comprising four or more microneedles
wherein the tip ends of the microneedles collectively define a
curvilinear surface.
13. The device of claim 1 comprising a plurality of hollow
microneedles in a linear array, wherein the substrate is mounted on
a holder having one or more apertures through the holder in
communication with the microneedles.
14. The device of claim 1 wherein the substrate is flexible.
15. The device of claim 14 wherein the substrate is deformable by
fluid pressure or mechanical means.
16. The device of claim 15 wherein the substrate is mounted onto a
flexible membrane bubble.
17. The device of claim 16 further comprising a second membrane
bubble positioned to define a chamber between the flexible membrane
bubble and the second membrane bubble.
18. The device of claim 17 wherein the chamber contains molecules
which flow through the microneedle.
19. The device of claim 18 wherein the molecules are drug
molecules.
20. The device of claim 1 wherein the means reduces the elasticity
of the biological barrier.
21. The device of claim 20 wherein the means physically manipulates
the biological barrier to present a more rigid surface in the area
of the biological barrier to be penetrated by the microneedle.
22. The device of claim 21 wherein the manipulation is selected
from the group consisting of stretching, pulling, pinching, and a
combination thereof.
23. The device of claim 22 wherein the manipulation includes
pulling by reducing the atmospheric pressure over the area of the
biological barrier to be penetrated by the microneedles.
24. The device of claim 23 further comprising a body portion
defining a first vacuum region and a second vacuum region, wherein
an array of microneedles separates the first and second
regions.
25. The device of claim 24 wherein the body portion comprises an
annular ring which holds the microneedles.
26. The device of claim 25 wherein the microneedle is hollow and
wherein the body portion further comprises a means for attachment
to a syringe, a conduit for connection to a vacuum pump, or
both.
27. The device of claim 22 wherein the means comprises a stretching
cone or expandable ring around the microneedles.
28. The device of claim 22 wherein the means comprises a body
portion from which a plurality of stretching elements are pivotally
attached.
29. The device of claim 28 wherein the stretching elements have
ends provided with a non-slip feature for engagement with the
biological barrier.
30. The device of claim 22 wherein the means comprises jaws for
pinching a portion of the biological barrier for contact with the
microneedles.
31. The device of claim 21 wherein the means comprises an adhesive
film applied over the area of the biological barrier to be
penetrated by the microneedle.
32. The device of claim 2 wherein the means for improving
penetration creates holes in the stratum corneum, wherein the
microneedle can be inserted into the holes.
33. The device of claim 32 wherein the means for creating holes is
selected from the group consisting of thermal ablation, high
pressure fluid puncturing, cryoablation, and application of
degradation agents.
34. The device of claim 1 wherein the means for improving
penetration accelerates the tips of the microneedles into the
biological barrier, accelerates the biological barrier into contact
with the tips of the microneedles, or a combination thereof.
35. The device of claim 34 wherein the means for accelerating the
tip of the microneedle comprises releasing a spring or gas under
compression.
36. The device of claim 1 wherein a lubricating material is
incorporated into or coated onto the microneedle.
37. The device of claim 1 further comprising a collar to limit the
depth of microneedle penetration.
38. The device of claim 1 further comprising a means for attaching
the device to the skin of a patient, wherein the means is not the
microneedle.
39. The device of claim 38 wherein the means is an adhesive
film.
40. The device of claim 38 wherein the means is an arm band.
41. The device of claim 1 wherein the microneedle is hollow and
wherein the device further comprises a reservoir selectably in
communication with the hollow microneedle.
42. The device of claim 1 wherein the means for enhancing
penetration comprises an apparatus for vibrating the
microneedle.
43. The device of claim 42 wherein the apparatus comprises a
piezoelectric transducer or an electromechanical actuator.
44. A kit of parts for use in transport of material or energy
across or into an elastic biological barrier, comprising (i) a
device comprising one or more microneedles having a tip end and a
base end, and a substrate connected to the base end of the
microneedle, and (ii) an adhesive film or barrier-tightening
chemical, either of which can be applied over an area of the
biological barrier to be penetrated by the microneedle.
45. A method for transport of material or energy across or into an
elastic biological barrier, comprising using the device of claim 1.
Description
BACKGROUND OF THE INVENTION
[0001] This invention is generally in the field of devices for the
transport of therapeutic or biological molecules across tissue
barriers, such as for drug delivery or sampling of biological
fluids.
[0002] Numerous drugs and therapeutic agents have been developed in
the battle against disease and illness. However, a frequent
limitation of these drugs is their delivery: how to transport drugs
across biological barriers in the body (e.g., the skin, the oral
mucosa, the blood-brain barrier), which normally do not transport
drugs at rates that are therapeutically useful or optimal.
[0003] Drugs are commonly administered orally as pills or capsules.
However, many drugs cannot be effectively delivered in this manner,
due to degradation in the gastrointestinal tract and/or elimination
by the liver. Moreover, some drugs cannot effectively diffuse
across the intestinal mucosa. Patient compliance may also be a
problem, for example, in therapies requiring that pills be taken at
particular intervals over a prolonged time.
[0004] Another common technique for delivering drugs across a
biological barrier is the use of a needle, such as those used with
standard syringes or catheters, to transport drugs across (through)
the skin. While effective for this purpose, needles generally cause
pain; local damage to the skin at the site of insertion; bleeding,
which increases the risk of disease transmission; and a wound
sufficiently large to be a site of infection. The withdrawal of
bodily fluids, such as for diagnostic purposes, using a
conventional needle has these same disadvantages. Needle techniques
also generally require administration by one trained in its use.
The needle technique also is undesirable for long term, controlled
continuous drug delivery.
[0005] Similarly, current methods of sampling biological fluids are
invasive and suffer from the same disadvantages. For example,
needles are not preferred for frequent routine use, such as
sampling of a diabetic's blood glucose or delivery of insulin, due
to the vascular damage caused by repeated punctures. No alternative
methodologies are currently in use. Proposed alternatives to the
needle require the use of lasers or heat to create a hole in the
skin, which is inconvenient, expensive, or undesirable for repeated
use.
[0006] An alternative delivery technique is the transdermal patch,
which usually relies on diffusion of the drug across the skin.
However, this method is not useful for many drugs, due to the poor
permeability (i.e. effective barrier properties) of the skin. The
rate of diffusion depends in part on the size and hydrophilicity of
the drug molecules and the concentration gradient across the
stratum corneum. Few drugs have the necessary physiochemical
properties to be effectively delivered through the skin by passive
diffusion. Iontophoresis, electroporation, ultrasound, and heat
(so-called active systems) have been used in an attempt to improve
the rate of delivery. While providing varying degrees of
enhancement, these techniques are not suitable for all types of
drugs, failing to provide the desired level of delivery. In some
cases, they are also painful and inconvenient or impractical for
continuous controlled drug delivery over a period of hours or days.
Attempts have been made to design alternative devices for active
transfer of drugs, or analyte to be measured, through the skin.
[0007] For example, U.S. Pat. No. 5,879,326 to Godshall et al. and
PCT WO 96/37256 by Silicon Microdevices, Inc. disclose a
transdermal drug delivery apparatus that includes a cutter portion
having a plurality of microprotrusions, which have straight
sidewalls, extending from a substrate that is in communication with
a drug reservoir. In operation, the microprotrusions penetrate the
skin until limited by a stop region of the substrate and then are
moved parallel to the skin to create incisions. Channels in the
substrate adjacent to the microprotrusions allow drug from the
reservoir to flow to the skin near the area disrupted by the
microprotrusions. Merely creating a wound, rather than using a
needle which conveys drug through an enclosed channel into the site
of administration, creates variability in dosage.
[0008] U.S. Pat. No. 5,250,023 to Lee et al. discloses a
transdermal drug delivery device, which includes a plurality of
needles having a diameter in the range of 50 to 400 .mu.m. The
needles are supported in a water-swellable polymer substrate
through which a drug solution permeates to contact the surface of
the skin. An electric current is applied to the device to open the
pathways created by the needles, following their withdrawal from
the skin upon swelling of the polymer substrate.
[0009] PCT WO 93/17754 by Gross et al. discloses another
transdermal drug delivery device that includes a housing having a
liquid drug reservoir and a plurality of tubular elements for
transporting liquid drug into the skin. The tubular elements may be
in the form of hollow needles having inner diameters of less than 1
mm and an outer diameter of 1.0 mm.
[0010] While each of these devices has potential use, there remains
a need for better drug delivery devices, which make smaller
incisions, deliver drug with greater efficiency (greater drug
delivery per quantity applied) and less variability of drug
administration, and/or are easier to use. In view of these needs,
microneedle devices have been developed, which are described in
U.S. Ser. No. 09/095,221, filed Jun. 10, 1998, and Ser. No.
09/316,229, filed May 21, 1999, both by Prausnitz et al., which are
hereby incorporated by reference. Certain embodiments of the device
were found to readily penetrate skin samples in in vitro
experiments, but not always provide uniform or complete insertion
of the microneedles into some areas of the skin in vivo, as the
stratum corneum and underlying tissues are highly deformable and
elastic over much of the body.
[0011] It is therefore an object of the present invention to
provide methods and devices for improving the control of
microneedle insertion into the body of a patient.
[0012] It is another object of the present invention to provide a
microneedle device producing improved microneedle insertion for
relatively painless, controlled, safe, convenient transdermal
delivery of drugs.
[0013] It is a further object of the present invention to provide a
microneedle device producing improved microneedle insertion for
controlled sampling of biological fluids in a minimally-invasive,
painless, and convenient manner.
SUMMARY OF THE INVENTION
[0014] Microneedle devices and methods of use thereof are provided
for the enhanced transport of molecules, including drugs and
biological molecules, across tissue by improving the interaction of
an array of microneedles and a deformable, elastic biological
barrier, such as human skin. The devices and methods act to (1)
limit the elasticity, (2) adapt to the elasticity, (3) utilize
alternate ways of creating the holes for the microneedles to
penetrate the biological barrier, other than the simply direct
pressure of the microneedle substrate to the barrier surface, or
(4) any combination of these methods.
[0015] In preferred embodiments for limiting the elasticity of
skin, the microneedle device includes features suitable for
stretching, pulling, or pinching the skin to present a more rigid,
less deformable, surface in the area to which the microneedles are
applied (i.e. penetrate). For example, a vacuum can be applied to
the area of the skin at the site of microneedle application to pull
it taut and/or pull the skin onto the tips of the microneedles.
Alternatively or in addition, the elasticity of skin can be reduced
by applying a thin film or membrane over the skin surface at the
site of application, so as to keep the skin tight, limiting the
ability of the skin to stretch at the application site. The
microneedles are then pushed through the film or membrane and into
the skin.
[0016] In preferred embodiments for adapting the device to the
elasticity of skin, the microneedles of the device include
individual extensions or are provided in a curved three dimensional
array, for example, by using a flexible substrate and/or varying
the height of the microneedles in the array. In another embodiment,
the microneedles are applied to the skin surface at an increased
velocity, thereby reducing the time available for the stratum
corneum and underlying tissues to deform from contact with the tips
or entire length of the microneedles.
[0017] In a preferred embodiment for creating holes in the skin for
microneedles, tiny holes are burned into the skin, for example, by
heating of the tips of the microneedles and/or by using a laser. In
another embodiment, a focused blast of high pressure gas is used to
create the holes.
[0018] Essentially all of the microneedle devices and methods
described herein can be adapted to vibrate the microneedles and/or
the skin to further enhance penetration. In a preferred embodiment,
the microneedles include a lubricating material coated onto or
incorporated into the microneedles.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] FIGS. 1a-e are side cross-sectional views of a method for
making hollow microneedles.
[0020] FIGS. 2a-g are side cross-sectional views of a method for
making a hollow microneedle.
[0021] FIGS. 3a-d are side cross-sectional views illustrating a
preferred method for making hollow microneedles.
[0022] FIGS. 4a-d are side cross-sectional views illustrating a
preferred method for making hollow silicon microtubes.
[0023] FIGS. 5a-e are side cross-sectional views illustrating a
preferred method for making hollow metal microtubes.
[0024] FIGS. 6a-d are side cross-sectional views illustrating a
preferred method for making tapered metal microneedles.
[0025] FIGS. 7a-d are side cross-sectional views illustrating a
method for making tapered microneedles using laser-formed
molds.
[0026] FIGS. 8a-f are side cross-sectional views illustrating a
second method for making tapered microneedles using laser-formed
molds.
[0027] FIG. 9 is a side elevational view of a schematic of an
embodiment of the microneedle device inserted into undeformed
skin.
[0028] FIGS. 10a-d are illustrations of microneedle devices having
various embodiments of microneedle extensions.
[0029] FIGS. 11a-c are cross-sectional views illustrating
microneedle devices having curved substrates (11a), varying
microneedle height (11b), and linear microneedle arrays (11c).
[0030] FIGS. 12a-c are cross-sectional views illustrating preferred
microneedle devices inserted into skin with altered elasticity.
[0031] FIGS. 13a-c are cross-sectional views illustrating preferred
embodiments of microneedle devices which can apply suction to skin
at the site of insertion.
[0032] FIGS. 14a-c are cross-sectional (14a-b) and perspective
(14c) views illustrating preferred embodiments of microneedle
devices which stretch the skin at the site of insertion.
[0033] FIGS. 15a-c are cross-sectional views illustrating examples
of microneedle devices which pinch the skin at the site of
insertion.
[0034] FIG. 16 is a cross-sectional view of a preferred embodiment
of a microneedle device for use in localized heating of skin.
[0035] FIG. 17 is a cross-sectional view of a preferred embodiment
of a microneedle device having a microneedle reinforcing layer.
[0036] FIGS. 18a-b are cross-sectional views of a preferred
embodiment of a microneedle device having a flexible substrate in
an unactivated position (18a) and an activated position (18b).
[0037] FIG. 19 is a cross-sectional view a preferred embodiment of
a microneedle device having arrays of microneedles with spaces
between the arrays.
DETAILED DESCRIPTION OF THE INVENTION
[0038] 1. Biological Barriers
[0039] The devices disclosed herein are useful in transport of
material into or across biological barriers including the skin (or
parts thereof); the blood-brain barrier; mucosal tissue (e.g.,
oral, nasal, ocular, vaginal, urethral, gastrointestinal,
respiratory); blood vessels; lymphatic vessels; or cell membranes
(e.g., for the introduction of material into the interior of a cell
or cells). The biological barriers can be in humans or other types
of animals, as well as in plants, insects, or other organisms,
including bacteria, yeast, fungi, and embryos. The microneedle
devices can be applied to tissue internally with the aid of a
catheter or laparoscope. For certain applications, such as for drug
delivery to an internal tissue, the devices can be surgically
implanted.
[0040] In a preferred embodiment, the microneedle device disclosed
herein is applied to skin. The stratum corneum is the outer layer,
generally between 10 and 50 cells, or between 10 and 20 .mu.m
thick. Unlike other tissue in the body, the stratum corneum
contains "cells" (called keratinocytes) filled with bundles of
cross-linked keratin and keratohyalin surrounded by an
extracellular matrix of lipids. It is this structure that is
believed to give skin its barrier properties, which prevents
therapeutic transdermal administration of many drugs. Below the
stratum corneum is the viable epidermis, which is between 50 and
100 .mu.m thick. The viable epidermis contains no blood vessels,
and it exchanges metabolites by diffusion to and from the dermis.
Beneath the viable epidermis is the dermis, which is between 1 and
3 mm thick and contains blood vessels, lymphatics, and nerves.
[0041] As used herein, references to using the microneedle devices
on "skin" also include using the microneedle devices with other
biological barriers unless expressly limited to only skin.
[0042] 2. The Microneedle Device
[0043] The microneedle devices disclosed herein include a
substrate; one or more microneedles; and, optionally, a reservoir
for delivery of drugs or collection of analyte, as well as pump(s),
sensor(s), and/or microprocessor(s) to control the interaction of
the foregoing. The microneedle device preferably includes
penetration enhancing features to alter or adapt to deformable and
elastic biological barriers, such as the skin over much of the
human body.
[0044] a. Substrate
[0045] The substrate of the device can be constructed from a
variety of materials, including metals, ceramics, semiconductors,
organics, polymers, and composites. The substrate includes the base
to which the microneedles are attached or integrally formed. A
reservoir may also be attached to the substrate.
[0046] In one embodiment of the device, the substrate is formed
from a thin, rigid material that is sufficiently stiff so as to
force the attached microneedles through the biological barrier in
such areas where the barrier resists deformation by the
microneedles.
[0047] In a preferred embodiment of the device, the substrate is
formed from flexible materials to allow the device to fit the
contours of the biological barrier, and to adapt to barrier
deformations that may occur when the microneedle device is applied.
A flexible device further facilitates more consistent penetration
during use, since penetration can be limited by deviations in the
attachment surface. For example, the surface of human skin is not
flat due to dermatoglyphics, i.e. tiny wrinkles, and hair, and is
highly deformable. The flexible substrate can be deformed
mechanically (for example, using an actuator or simply by fluid
pressure) in order to pierce the biological barrier.
[0048] b. Microneedle
[0049] The microneedles of the device can be constructed from a
variety of materials, including metals, ceramics, semiconductors,
organics, polymers, and composites. Preferred materials of
construction include pharmaceutical grade stainless steel, gold,
titanium, nickel, iron, gold, tin, chromium, copper, alloys of
these or other metals, silicon, silicon dioxide, and polymers.
Representative biodegradable polymers include polymers of hydroxy
acids such as lactic acid and glycolic acid polylactide,
polyglycolide, polylactide-co-glycolide, and copolymers with PEG,
polyanhydrides, poly(ortho)esters, polyurethanes, poly(butyric
acid), poly(valeric acid), and poly(lactide-co-caprolactone).
Representative non-biodegradable polymers include polycarbonate,
polymethacrylic acid, ethylenevinyl acetate,
polytetrafluoroethylene (TEFLON.TM.), and polyesters.
[0050] Generally, the microneedles should have the mechanical
strength to remain intact for delivery of drugs, or serve as a
conduit for the collection of biological fluid, while being
inserted into the skin, while remaining in place for up to a number
of days, and while being removed. In embodiments where the
microneedles are formed of biodegradable polymers, however, this
mechanical requirement is less stringent, since the microneedles or
tips thereof can break off, for example in the skin, and will
biodegrade. Nonetheless, even a biodegradable microneedle still
needs to remain intact at least long enough for the microneedle to
serve its intended purpose (e.g., its conduit function). Therefore,
biodegradable microneedles can provide an increased level of
safety, as compared to nonbiodegradable ones.
[0051] The microneedles can be formed of a nonporous solid, a
porous solid (with or without a sealed coating or exterior
portion), or hollow. As used herein, the term "porous" means having
pores or voids throughout at least a portion of the microneedle
structure, sufficiently large and sufficiently interconnected to
permit passage of fluid and/or solid materials through the
microneedle. As used herein, the term "hollow" means having one or
more substantially annular bores or channels through the interior
of the microneedle structure, having a diameter sufficiently large
to permit passage of fluid and/or solid materials through the
microneedle. The annular bores may extend throughout all or a
portion of the needle in the direction of the tip to the base,
extending parallel to the direction of the needle or branching or
exiting at a side of the needle, as appropriate. A solid or porous
microneedle can be hollow. One of skill in the art can select the
appropriate porosity and/or bore features required for specific
applications. For example, one can adjust the pore size or bore
diameter to permit passage of the particular material to be
transported through the microneedle device. The inner surface of
the bore of hollow microneedles can be made rough to enhance cell
membrane disruption for those applications in which cell disruption
is useful.
[0052] The microneedles can have straight or tapered shafts. A
hollow microneedle that has a substantially uniform diameter, which
needle does not taper to a point, is referred to herein as a
"microtube." As used herein, the term "microneedle" includes both
microtubes and tapered needles unless otherwise indicated. In one
embodiment, the diameter of the microneedle is greatest at the base
end of the microneedle and tapers to a point at the end distal the
base. The microneedle can also be fabricated to have a shaft that
includes both a straight (untapered) portion and a tapered
portion.
[0053] The microneedles can be formed with shafts that have a
circular cross-section in the perpendicular, or the cross-section
can be non-circular. For example, the cross-section of the
microneedle can be polygonal (e.g. star-shaped, square,
triangular), oblong, or another shape. The shaft can have one or
more bores. The cross-sectional dimensions typically are between
about 10 nm and 1 mm, preferably between 1 micron and 200 microns,
and more preferably between 10 and 100 .mu.m. The outer diameter is
typically between about 10 .mu.m and about 100 .mu.m, and the inner
diameter is typically between about 3 .mu.m and about 80 .mu.m.
[0054] The length of the microneedles typically is between about 1
.mu.m and 1 mm, preferably between 10 microns and 500 microns. The
length is selected for the particular application, accounting for
both an inserted and uninserted portion. An array of microneedles
can include a mixture of microneedles having, for example, various
lengths, outer diameters, inner diameters, cross-sectional shapes,
and spacing between the microneedles.
[0055] The microneedles can be oriented perpendicular or at an
angle to the substrate. Preferably, the microneedles are oriented
perpendicular to the substrate so that a larger density of
microneedles per unit area of substrate is provided. An array of
microneedles can include a mixture of microneedle orientations,
heights, or other parameters.
[0056] c. Reservoir
[0057] The microneedle device may include a reservoir in
communication with the microneedles. The reservoir can be attached
to the substrate by any suitable means. In a preferred embodiment,
the reservoir is attached to the back of the substrate (opposite
the microneedles) around the periphery, using an adhesive agent
(e.g., glue). A gasket may also be used to facilitate formation of
a fluid-tight seal.
[0058] In a preferred embodiment, the reservoir contains drug, for
delivery through the microneedles. The reservoir may be a hollow
vessel, a porous matrix, or a solid form including drug which is
transported therefrom. The reservoir can be formed from a variety
of materials that are compatible with the drug or biological fluid
contained therein. Preferred materials include natural and
synthetic polymers, metals, ceramics, semiconductors, organics, and
composites. In one embodiment, the reservoir is a standard
syringe.
[0059] The microneedle device can include one or a plurality of
chambers for storing materials to be delivered. In the embodiment
having multiple chambers, each can be in fluid connection with all
or a portion of the microneedles of the device array. In one
embodiment, at least two chambers are used to separately contain
drug (e.g., a lyophilized drug, such as a vaccine) and an
administration vehicle (e.g., saline) in order to prevent or
minimize degradation during storage. Immediately before use, the
contents of the chambers are mixed. Mixing can be triggered by any
means, including, for example, mechanical disruption (i.e.
puncturing or breaking), changing the porosity, or electrochemical
degradation of the walls or membranes separating the chambers. In
another embodiment, a single device is used to deliver different
drugs, which are stored separately in different chambers. In this
embodiment, the rate of delivery of each drug can be independently
controlled.
[0060] In a preferred embodiment, the reservoir should be in dire
contact with the microneedles and have holes through which drug
could exit the reservoir and flow into the interior of hollow or
porous microneedles. In another preferred embodiment, the reservoir
has holes which permit the drug to transport out of the reservoir
and onto the skin surface. From there, drug is transported into the
skin, either through hollow or porous microneedles, along the sides
of solid microneedles, or through pathways created by microneedles
in the skin.
[0061] d. Transport Control Components
[0062] The microneedle device also must be capable of transporting
material across the barrier at a useful rate. For example, the
microneedle device must be capable of delivering drug across the
skin at a rate sufficient to be therapeutically useful. The device
may include a housing with microelectronics and other micromachined
structures to control the rate of delivery either according to a
preprogrammed schedule or through active interface with the
patient, a healthcare professional, or a biosensor. The rate can be
controlled by manipulating a variety of factors, including the
characteristics of the drug formulation to be delivered (e.g., its
viscosity, electric charge, and chemical composition); the
dimensions of each microneedle (e.g., its outer diameter and the
area of porous or hollow openings); the number of microneedles in
the device; the application of a driving force (e.g., a
concentration gradient, a voltage gradient, a pressure gradient);
and the use of a valve.
[0063] The rate also can be controlled by interposing between the
drug in the reservoir and the opening(s) at the base end of the
microneedle polymeric or other materials selected for their
diffusion characteristics. For example, the material composition
and layer thickness can be manipulated using methods known in the
art to vary the rate of diffusion of the drug of interest through
the material, thereby controlling the rate at which the drug flows
from the reservoir through the microneedle and into the tissue.
[0064] Transportation of molecules through the microneedles can be
controlled or monitored using, for example, various combinations of
valves, pumps, sensors, actuators, and microprocessors. These
components can be produced using standard manufacturing or
microfabrication techniques. Actuators that may be useful with the
microneedle devices disclosed herein include micropumps,
microvalves, and positioners. In a preferred embodiment, a
microprocessor is programmed to control a pump or valve, thereby
controlling the rate of delivery.
[0065] Flow of molecules through the microneedles can occur based
on diffusion, capillary action, or can be induced using
conventional mechanical pumps or nonmechanical driving forces, such
as electroosmosis or electrophoresis, or convection. For example,
in electroosmosis, electrodes are positioned on the biological
barrier surface, one or more microneedles, and/or the substrate
adjacent the needles, to create a convective flow which carries
oppositely charged ionic species and/or neutral molecules toward or
into the biological barrier. In a preferred embodiment, the
microneedle device is used in combination with another mechanism
that enhances the permeability of the biological barrier, for
example by increasing cell uptake or membrane disruption, using
electric fields, ultrasound, chemical enhancers, vacuum viruses,
pH, heat and/or light.
[0066] Passage of the microneedles, or drug to be transported via
the microneedles, can be manipulated by shaping the microneedle
surface, or by selection of the material forming the microneedle
surface (which could be a coating rather than the microneedle per
se). For example, one or more grooves on the outside surface of the
microneedles can be used to direct the passage of drug,
particularly in a liquid state. Alternatively, the physical surface
properties of the microneedle can be manipulated to either promote
or inhibit transport of material along the microneedle surface,
such as by controlling hydrophilicity or hydrophobicity.
[0067] The flow of molecules can be regulated using a wide range of
valves or gates. These valves can be the type that are selectively
and repeatedly opened and closed, or they can be single-use types.
For example, in a disposable, single-use drug delivery device, a
fracturable barrier or one-way gate may be installed in the device
between the reservoir and the opening of the microneedles. When
ready to use, the barrier can be broken or gate opened to permit
flow through the microneedles. Other valves or gates used in the
microneedle devices can be activated thermally, electrochemically,
mechanically, or magnetically to selectively initiate, modulate, or
stop the flow of molecules through the needles. In a preferred
embodiment, flow is controlled by using a rate-limiting membrane as
a "valve."
[0068] The microneedle devices can further include a flowmeter or
other means to monitor flow through the microneedles and to
coordinate use of the pumps and valves.
[0069] e. Sensors
[0070] Useful sensors may include sensors of pressure, temperature,
chemicals, and/or electromagnetic fields. Biosensors can be located
on the microneedle surface, inside a hollow or porous microneedle,
or inside a device in communication with the body tissue via the
microneedle (solid, hollow, or porous). These microneedle
biosensors can include four classes of principal transducers:
potentiometric, amperometric, optical, and physiochemical. An
amperometric sensor monitors currents generated when electrons are
exchanged between a biological system and an electrode. Blood
glucose sensors frequently are of this type.
[0071] The microneedle may function as a conduit for fluids,
solutes, electric charge, light, or other materials. In one
embodiment, hollow microneedles can be filled with a substance,
such as a gel, that has a sensing functionality associated with it.
In an application for sensing based on binding to a substrate or
reaction mediated by an enzyme, the substrate or enzyme can be
immobilized in the needle interior, which would be especially
useful in a porous needle to create an integral needle/sensor.
[0072] Wave guides can be incorporated into the microneedle device
to direct light to a specific location, or for detection, for
example, using means such as a pH dye for color evaluation.
Similarly, heat, electricity, light or other energy forms may be
precisely transmitted to directly stimulate, damage, or heal a
specific tissue or intermediary (e.g., tattoo removal for dark
skinned persons), or diagnostic purposes, such as measurement of
blood glucose based on IR spectra or by chromatographic means,
measuring a color change in the presence of immobilized glucose
oxidase in combination with an appropriate substrate.
[0073] f. Attachment Features
[0074] A collar or flange also can be provided with the device, for
example, around the periphery of the substrate or the base. It
preferably is attached to the device, but alternatively can be
formed as an integral part of the substrate, for example by forming
microneedles only near the center of an "oversized" substrate. The
collar can also emanate from other parts of the device. The collar
can provide an interface to attach the microneedle array to the
rest of the device, and can facilitate handling of the smaller
devices.
[0075] In a preferred embodiment, the microneedle device includes
an adhesive to temporarily secure the device to the surface of the
biological barrier. The adhesive can be essentially anywhere on the
device to facilitate contact with the biological barrier. For
example, the adhesive can be on the surface of the collar (same
side as microneedles), on the surface of the substrate between the
microneedles (near the base of the microneedles), or a combination
thereof.
[0076] In one embodiment, the microneedle device is incorporated
into an arm (e.g., wrist) band. The arm band can be conveniently
worn by a patient for drug delivery, sampling of biological fluids,
or both over a prolonged period of time, such as several hours.
[0077] g. Transdermal Microneedle Device
[0078] FIG. 9 is a side elevational view of a schematic of an
embodiment of the microneedle device inserted into undeformed skin.
The device 10 includes an upper portion or substrate 11 from which
a plurality of microneedles 12 protrude. The height of the upper
portion 11 is between about 1 .mu.m and 1 cm, and the width of the
upper portion is between about 1 mm and 10 cm. The upper portion 11
of the device can be solid or hollow, and may include multiple
compartments. In a preferred embodiment for drug delivery, the
upper portion 11 contains one or more drugs to be delivered. It is
also preferred that the upper portion include one or more sensors
and/or an apparatus (e.g., pump or electrode) to drive
(provide/direct the force) transport of the drug or other
molecules.
[0079] The height (or length) of the microneedles 12 generally is
between about 1 .mu.m and 1 mm. The diameter and length both affect
pain as well as functional properties of the needles. In one
embodiment for transdermal applications, the "insertion depth" of
the microneedles 12 is less than about 100 .mu.m, more preferably
about 30 .mu.m, so that insertion of the microneedles 12 into the
skin through the stratum corneum 14 does not penetrate through the
epidermis 16 into the dermis 18 (as described below), thereby
avoiding contacting nerves and reducing the potential for causing
pain. In such applications, the actual length of the microneedles
may be longer, since the portion of the microneedles distal the tip
may not be inserted into the skin; the uninserted length depends on
the particular device design and configuration. The actual
(overall) height or length of microneedles 12 should be equal to
the insertion depth plus the uninserted length. Other embodiments
using sufficiently small microneedles may penetrate into the dermis
without causing pain.
[0080] The diameter of each microneedle 12 generally is between
about 10 nm and 1 mm, and preferably leaves a residual hole
(following microneedle insertion and withdrawal) of less than about
1 .mu.m, to avoid making a hole which would allow bacteria to enter
the penetration wound. The actual microneedle diameter should be
larger than 1 .mu.m, since the hole likely will contract following
withdrawal of the microneedle. The diameter of microneedle 12 more
preferably is between about 1 .mu.m and 100 .mu.m. Larger diameter
and longer microneedles are acceptable, so long as the microneedle
can penetrate the biological barrier to the desired depth and the
hole remaining in the skin or other tissue following withdrawal of
the microneedle is sufficiently small, preferably small enough to
exclude bacterial entry. The microneedles 12 can be solid or
porous, and can include one or more bores connected to upper
portion 11.
[0081] h. Microneedle Penetration Enhancing Features
[0082] In a preferred embodiment, the microneedle devices include
features which improve penetration of the microneedles into
deformable, elastic biological barriers, such as human skin. As
used herein, "improved penetration" refers to providing more
uniform, better controlled insertion of microneedles, for example,
as compared to manual insertion of a microneedle or array of
microneedles into skin without compensation (in the device design
or site preparation or both) for deformation of the skin at the
intended site of insertion. This is particularly critical for
devices which include a three dimensional array of the
microneedles. These features typically function to (1) adapt to the
deformation, (2) limit the deformation, and/or (3) utilize
alternate ways of creating the holes in the biological barrier for
the microneedles to enter. These penetration enhancing techniques
generally can be used with solid, porous, or hollow microneedles.
Examples of penetration enhancing features include the
following:
[0083] i. Microneedle Extensions
[0084] In a preferred embodiment for adapting the device to the
elasticity of skin, the microneedles of the device include
extensions, also called protrusion enhancers. One solution to
enhance microneedle penetration would be to make the microneedles
much longer. However, very tall, small diameter microneedles would
tend to be structurally fragile. Therefore, a relatively wider, yet
tall base is provided between the substrate and the microneedle to
increase the length while maintaining structural integrity of the
microneedles. The extensions can be fabricated using the same
microfabrication techniques described herein or other conventional
fabrication techniques, and typically are made integrally with the
substrate and microneedles. The extensions can be of any
cross-sectional shape, are typically between about 500 .mu.m and 10
mm in height, and generally are at least about 200 .mu.m in
diameter for a single needle/single extension configuration. A
single extension can support one or more microneedles.
[0085] The extensions also can be designed to function as a
penetration stop or limiter, to limit the depth of microneedle
penetration.
[0086] FIGS. 10a-c illustrate several non-limiting embodiments of
the extensions. Device 110 includes substrate 112, extension 114,
and microneedle(s) 116. The figures show a single needle/single
extension configuration (10a), a multiple needle/single extension
configuration (10b), and a multiple needle/multiple extension
configuration (10c). The microneedle devices can include arrays of
microneedles and extensions in essentially any combination and
number.
[0087] FIG. 10d illustrates an embodiment of a microneedle device
180 having extension 182 terminating in microneedle array 184. The
device also includes shoulder 186 and key (cutout) 188, which serve
to control stretching of the skin at the site of microneedle
insertion to enhance penetration. Specifically, the skin stretches
in the key 188 as the microneedle device 180 is pushed in, while
shoulder 186 simultaneously limits the area of skin being
stretched.
[0088] ii. Optimized Microneedle Spacing
[0089] In another embodiment to adapt to the deformability of skin,
the microneedle device includes arrays of microneedles having
spaces between the microneedles or between arrays of microneedles,
wherein the spacings permit areas of the skin to fill the spaces in
order to enhance microneedle contact with adjacent areas of the
skin. The spacing is designed to adapt to the skin's radius of
curvature to overcome the penetration problem.
[0090] FIG. 19 illustrates a microneedle device 300 having arrays
of microneedles 302 with spaces 304 between the arrays. Spaces 304
have a size between about one and ten times, preferably between
about one and two times, the size of the arrays 302. This spacing
effect can be achieved using some configurations of the microneedle
extensions described above.
[0091] iii. Linear and Curved Arrays of Microneedles
[0092] In another embodiment for adapting the device to the
elasticity of skin, the microneedles are provided in a curved three
dimensional array. For example, the microneedle device can have a
rigid substrate which forms a curved, rather than planar, surface.
The substrate can be, for example, hemispherical or elliptical. The
device, by presenting the needles with a curved surface, can
provide improved uniformity of penetration among the microneedles
of an array, as illustrated in FIG. 11a. This same effect also can
be achieved by varying the height of the microneedles in the array
having a planar substrate, as shown in FIG. 11b.
[0093] In a preferred embodiment, two dimensional (i.e. linear)
arrays are used. A preferred embodiment of a linear array
microneedle device is shown in FIG. 11c. Device 220 includes
substrate 222, which is formed into a U-shape, and an array of
microneedles 224 at the apex of substrate 222. The
substrate/microneedle portion is mounted over the end of a slotted
holder 226. Molecules for transport through the microneedles 224
flow through one or more slots 228 positioned at the end of the
slotted holder 226. The device also includes a fitting portion 230
which is integral with or attached to the slotted holder 226. The
fitting portion 230 can be, for example, a female Luer lock for
attachment to a conventional syringe. The use of a linear array
such as in this device readily deforms the skin at a sharp radius
over the tips of the microneedles 224, greatly facilitating their
penetration into the skin.
[0094] In a variation of this embodiment, several linear arrays of
microneedles can be combined onto a single fitting portion or
holder in order to increase the area of injection. By spacing the
arrays on the holder widely enough, the correct skin deformation
can be maintained. The spacing is selected to be sufficient to
allow the skin or other barrier to reach a relaxed state in the
region between the arrays, thus facilitating the correct
deformation over each needle array in a manner independent of other
arrays.
[0095] These microneedle devices are fabricated using or adapting
the same microfabrication techniques described herein. In one
embodiment, microneedle arrays can be fabricated on flexible
substrates, which then are mounted onto rigid spherical,
cylindrical, or elliptical surfaces.
[0096] iv. Flexible Substrates
[0097] The substrate also can be flexible so that it deforms with
the skin or other barrier upon application of the microneedle
array.
[0098] FIGS. 18a-b illustrate a preferred embodiment of a
microneedle device having a flexible substrate. In this case,
device 250 include microneedles 252, which are fabricated on a
flexible substrate 254. The substrate is laminated to a preformed
membrane bubble 256, such as those which are used as a membrane
switch. This laminated structure is attached to holder 258.
[0099] The molecules to be delivered, e.g., drug, are contained in
a chamber 260 formed between the membrane bubble 256 and the
substrate 254. The molecules are sealed inside the chamber either
at the laminating step or are filled after lamination, for example,
by injection through the membrane. A sponge or similar device (not
shown) may be incorporated into the chamber 260 to contain the
molecules before insertion and delivery. The sponge device is
compressed by the bubble membrane as it turns to its downward
position (see FIG. 18b).
[0100] In operation, the device 250 is pressed against the skin,
wherein the holder 258 positions the microneedles 252 against the
skin, as shown in FIG. 18a. Then, force is applied to the membrane
bubble 256, flipping it through its transition state to the down
position. This action applies pressure to the molecules in the
chamber 260, expanding the substrate 254 of the microneedle array
and pushing the microneedles 252 through the skin. Subsequently,
the pressure forces the molecules through the microneedles 252 and
into the skin. It The change in pressure upon the membrane bubble
must occur faster and be larger than can be relieved by the flow of
molecules through the microneedles, in order to achieve effective
delivery.
[0101] In an alternative embodiment, the chamber 260 may include an
intermediate septum or equivalent divider (not shown) which can be
ruptured or moved to permit the molecules to flow through the
microneedles 252. For example, the user applies pressure to the
membrane bubble, which pressure first forces the microneedles into
the skin, as shown in FIG. 18b, and then ruptures the septum to
deliver drugs through the needle and into the skin.
[0102] v. High Velocity Insertion
[0103] In another embodiment, the microneedles are applied to the
skin surface at an increased velocity, thereby reducing the time
available for the stratum corneum and underlying tissues to deform
from contact with the tips of the microneedles. The insertion can
be by forcing the microneedles into the skin, forcing the skin into
the microneedles, or a combination thereof. This more rapid
microneedle/skin contact can occur, for example, by releasing a
compressed spring or other elastic device that pushes or pulls the
microneedles, or by a rapid burst release of compressed gas against
the back of the substrate. Alternatively, the skin could be forced
by rapidly pulling a vacuum or pushing the skin from the sides
(pinching) at the site of microneedle administration to cause the
skin to be pulled up against an array of microneedles. Various
combinations of these mechanisms can be used together. The
mechanisms typically are integrated into the microneedle
device.
[0104] vi. Limiting Biological Barrier Elasticity
[0105] In preferred embodiments for limiting the
elasticity/deformation of tissue, the microneedle device includes
features suitable for stretching, pulling, or pinching the tissue,
particularly skin, to present a more rigid surface in the area to
which the microneedles are applied (i.e. penetrate) as illustrated
in FIGS. 12a-c.
[0106] It may also be useful to cool the stratum corneum to reduce
its elasticity and/or to apply chemicals to the skin surface to
"tighten" the skin and reduce its elasticity. For example, the skin
surface may be cooled by directing a flow of cold gas through the
microneedles onto the skin surface. The flow of cold gas can be
generated, for example, from a liquefied gas source such as
nitrogen, carbon dioxide, or a refrigerant such as FREON.TM.. The
skin also can be cooled by contact with a cooling (e.g.,
refrigerated) element, such as a plate, or the microneedles
themselves can function as the cooling element. The cooling element
should provide sufficient local cooling of the stratum corneum so
as to stiffen the stratum corneum in the vicinity of each needle
sufficiently to enhance penetration. These cooling means can be
used independently or in combination with chemical means to tighten
the skin. Examples of chemical means include biocompatible organic
solvents, such as isopropanol or acetone, which tend to dry out and
stiffen the skin surface, or such astringent chemicals that can be
topically applied to the skin before microneedle insertion.
[0107] a. Suction
[0108] Suction can be used to hold the skin in place during the
insertion of the microneedle, limiting the deflection and
deformation of skin in contact with the tips of the microneedles.
Suction also can be used to bring skin in contact with stationary
microneedles, and if sufficiently great, can cause the skin to be
pierced by the microneedles. The suction may also enhance systemic
delivery of drug by increasing blood flow in the area of
administration via the microneedles, or may enhance withdrawal of
interstitial fluid or blood for analysis/sensing. The suction
typically is induced by creating a vacuum on the skin at the site
of microneedle application. The vacuum induced is between about 10
and 2000 mm Hg, preferably between about 50 and 300 mm Hg, at the
site of application. The suction typically can occur before,
simultaneously with, or following insertion of the
microneedles.
[0109] Examples of microneedle devices adapted to create a vacuum
are shown in FIGS. 13a-c. FIG. 13a shows device 120 which includes
substrate 122, microneedle array 124, and reservoir 126, which is
partially enclosed by outer chamber 128. Outer chamber 128 includes
a port 127 through which air or other fluids within the chamber are
withdrawn following, and/or before, contact of the opening rim 129
to the skin surface. The outer chamber 128 can be made of flexible
or rigid material, and generally is gas impermeable. A source of
vacuum, e.g., a vacuum pump, typically is adapted to be in fluid
communication with port 127. A micro-battery-powered vacuum pump
can be integrated into the device to provide this function. In
another embodiment, device 128 can be evacuated, so that when
triggered, the skin at the site of administration is exposed to the
vacuum and is pulled up into the device. This embodiment effects a
short pulse of vacuum, without requiring extra equipment. In
another embodiment, a tool can be used to mechanically create the
necessary vacuum upon manual activation.
[0110] FIG. 13b is a variation of the device shown in FIG. 13a,
wherein device 130 includes two coaxial cylinders, outer cylinder
132 and inner cylinder 134. Vacuum is induced in the space between
the cylinders. Inner cylinder 134 terminates with reservoir 136,
substrate 138, and microneedles 140. Outer cylinder 132 and its rim
139 function as the outer chamber 128 and opening rim 129 in FIG.
13a. Optionally, an overpressure can be applied in the inner
cylinder 134 to facilitate flow, e.g. of drug, from reservoir 136
through the microneedles 140. The device can be designed to have
the inner cylinder 134 and microneedles 140 in a position fixed or
movable with respect to the outer cylinder 132, as appropriate. In
other embodiments, the device can have a non-cylindrical shape.
[0111] A preferred embodiment of a suction device for use with a
microneedle array is shown in FIG. 13c. The suction device 200
includes body portion 202 having an inner vacuum ring 204 and an
outer vacuum ring 206, separated by a ring-shaped microneedle array
(not shown). The use of coaxial suction rings provides a uniform
deformation force on the skin. The amount of deformation can be
controlled by varying the absolute and relative sizes of the
annular vacuum rings, and by controlling the amount of vacuum
pulled, for example, by a suction pump. The relative height of the
inner and outer rings, and their height relative to the microneedle
array, can be varied to change the skin deformation and consequent
pressure onto the microneedle array. In the device shown,
molecules, typically as a fluid, are delivered through a port 208
in the annular ring holding the microneedles, and to the whole
ring-shaped array through a circular fluidics channel 210 adjacent
the substrate of the microneedles. The device shown includes a
female Luer lock 212 for attachment to a conventional syringe, as
well as tubing section 214 that can be used to connect the device
to a vacuum pump of some kind, either manually or power driven.
[0112] b. Stretching
[0113] Stretching can also be used to limit the deflection and
deformation of skin in contact with the tips of the microneedles.
The stretching can be effected by a separate device or incorporated
as a feature of the microneedle device itself.
[0114] FIGS. 14a-b shows one embodiment of a microneedle device
that includes a stretching component. Microneedle device 150
includes flexible stretching cone 152, which includes circular
outer rim 156 and surrounds microneedles 154. FIG. 14a shows device
150 with the stretching cone 152 in its normal, relaxed form and
shape (i.e. no net forces applied to it) resting on the skin
surface, with the tips of microneedles 154 terminating inside
stretching cone 152. FIG. 14b shows device 150 following
application of pressure (e.g., manual pressure) on device 150
toward the skin. As the force is applied, outer rim 156 begins to
"flatten" and frictionally engages the skin surface, stretching the
skin away from and perpendicular to the central axis of the
stretching cone 152, while the microneedles 154 move into contact
with and then penetrate the skin. The outer rim 156 should be
roughened, knurled, have teeth, or be formed of or coated with a
sticky or non-slippery material so as to provide the necessary
engagement between the surfaces. Examples of suitable materials
include rubbers and synthetic polymers.
[0115] In another embodiment, the device includes an aperture or
other means of allowing gas trapped between the barrier and the
device to escape. Examples of such apertures include one or more
vent holes or slits, for example, through the side of the
stretching cone 152.
[0116] A preferred embodiment is shown in FIG. 14c, wherein
stretching cone 152 is replaced with a plurality of, e.g., four,
hinged stretching elements 153. The stretching elements stretch the
skin laterally as device 150 is pressed down against the skin. The
skin deflection is determined by the length of the stretcher
element 153 relative to the length of the central cylinder 155.
Like outer rim 156, the ends of the stretching elements 153 (distal
the hinge end) preferably are roughened or knurled, have teeth, or
are formed of or coated with a sticky or non-slippery material so
as to control the friction between the skin and the stretching
elements 153, thereby providing an additional means of controlling
the stretching force. The device shown in FIG. 14c is connected to
a standard female Luer lock 157, for attachment to a standard
syringe. In a preferred embodiment, microneedles 154 are aligned in
columns and rows substantially parallel to the stretching element
153, so as to optimize the stretching force fore effective
microneedle penetration.
[0117] In another embodiment, stretching of the skin is
accomplished using a separate ring device, which can be pressed
against the skin and then concentrically expanded to stretch the
skin within the ring. For example, the ring device can be a
rubber-coated metal band (having diameter x), which is compressed
into a coil (having a diameter less than x). The coiled ring is
then pressed against the skin and allowed to uncoil (i.e. expand to
diameter x again), while frictionally engaging the skin, thereby
stretching it. In a further embodiment, the ring device is
configured as an iris that expands to stretch the skin upon
mechanical actuation by engaging an actuation lever or rotary
motion.
[0118] c. Pinching
[0119] Pinching can also be used to limit the deflection and
deformation of skin in contact with the tips of the microneedles.
In a preferred embodiment, the microneedle device includes jaws,
typically one or more pair, which can be pressed against the skin
surface and triggered to close against a segment of skin, as
illustrated in FIGS. 15a-b. The size of the jaw opening can be
selected based on the area of skin to be pinched to facilitate
penetration of the microneedle array selected for use.
[0120] In FIGS. 15a-b, microneedle device 160 includes a pair of
jaws 164 having flex or hinge points 168 and tips 166, positioned
around microneedles 162. FIG. 15a shows the jaws 164 in the open
position, and FIG. 15b shows the jaws 164 in the closed position,
pinching an area of skin which is drawn against the microneedle
162, causing the microneedles to penetrate the skin.
[0121] An alternative embodiment of the clamping device and method
is illustrated in FIG. 15c. In this embodiment, a clamping device
170 is used to pinch the skin and provide a rigid support 172
behind a pinched section of skin, in order to present a surface of
limited deformability for insertion of the microneedles 174. The
clamping device 170 can be a separate device from the microneedle
device 176, or the devices can be integrated into a single
unit.
[0122] d. Adhesive Film Assist
[0123] The deformation of skin can be reduced by applying a thin,
adhesive film over the skin surface at the site of application. The
film keeps the skin taut and limits deformation at the site of
microneedle insertion as the microneedles are pushed through the
film and into the skin. This is analogous to the use of a surgical
tape that is applied to the skin before making a surgical
incision.
[0124] The adhesive film can include an expandable or shrinkable
material that is triggered to change size or shape prior to
microneedle application, so as to stretch the skin thereby further
limiting its deformability. For example, the material can be
water-swellable, and wetted (triggering event) prior to microneedle
application. In another example, the material can change form in
response to a change in temperature (triggering event).
[0125] The adhesive film must be thin enough for the microneedles
to penetrate both the film and the stratum corneum. If hollow
microneedles are used, then the film should fracture upon
penetration without substantial clogging of the hollow bore of the
microneedles. Alternatively, the film could be formed of a woven or
porous material so that the microneedles substantially penetrate
gaps or pores in the adhesive film rather than the fibers or matrix
of the film material. Examples of suitable films include
ethylene-tetrafluoroethylene (ETFE) copolymer mesh (available from
Goodfellow PLC) and porous films such as GORETEX.TM. (available
from William H. Gore, Inc.) coupled with an appropriate acrylic
adhesive.
[0126] vii. Creating Holes for the Microneedles
[0127] Another method of improving the penetration of biological
barriers with microneedles involves producing holes or pathways in
the barrier through which the microneedles can traverse, other than
the pathway created solely by forcing the microneedle into barrier.
A variety of techniques can be adapted for use with the microneedle
devices described herein. For example, U.S. Pat. No. 5,885,211 to
Eppstein, et al. discloses several methods of selectively removing
the stratum corneum to enhance permeability of human skin. Some of
these so-called microporation techniques disclosed can be adapted
to promote penetration of microneedles into the viable epidermis.
In a preferred embodiment, holes are created by vaporizing the
stratum corneum, for example, by using a laser or by heating of the
tips of the microneedles.
[0128] Laser techniques are described, for example, in U.S. Pat.
No. 5,885,211 to Eppstein, et al. and U.S. Pat. No. 4,775,361 to
Jacques et al. The laser, or pulsed light source, preferably is
used in conjunction with a dye which substantially absorbs over the
emission range of the light. The dye is applied to the skin and the
laser or light is focused on the dye, heating it. Then, the stratum
corneum adjacent to the dye is heated by conduction, elevating the
temperature of tissue-bound water and other vaporizable substances
in the selected area above the vaporization point of the water and
other vaporizable substances. This vaporization results in
degradation of the stratum corneum at one or more select, i.e.
pinpoint, areas, through which the microneedles can readily
penetrate. One of skill in the art can readily select the
appropriate dye, laser (e.g., Helium-Neon) or light source, and
parameters of use, based, in part, on the particular microneedle
array, drug to be delivered, and/or analyte to sample. In one
embodiment, the light is focused, in part, by passing the light
through the internal bore of a hollow microneedle.
[0129] Thermal ablation of the stratum corneum can be achieved by
radiant heating (using a light/laser as described above) or by
using conductive heating. For example, U.S. Pat. No. 5,885,211 to
Eppstein, et al. describes contacting human skin with a heat source
(conductive heating) ablate the stratum corneum. The microneedle
devices described herein can be applied to the ablated skin and/or
can be configured to provide the ablation of the stratum corneum,
in particularly by heating the microneedles to serve as the heat
source which contacts the skin. Heating of the microneedles can be
accomplished, for example, by (1) contacting the needles with an
ohmic heating element, (2) providing microneedles formed of or
coated with a conductive material, through which a modulated
electrical current is passed to induce resistive heating of the
microneedles, or (3) providing microneedles positioned in a
modulatable alternating magnetic field of an excitation coil such
that energizing the excitation coil with alternating current
produces eddy currents sufficient to heat the microneedles by
internal ohmic losses. The microneedles should be able to rapidly
heat the skin surface at select spots to above 100.degree. C.,
preferably above 123.degree. C., to induce flash vaporization of
the water content of the stratum corneum, as described in U.S. Pat.
No. 4,775,361 to Jacques et al. The heating preferably is done
using an on/off cycling technique and/or adjacent cooling to
minimize damage to tissues adjacent the target area. In embodiments
in which the microneedles are heated, the substrate preferably
includes an insulating material, as shown in FIG. 16, which
illustrates two hollow microneedles and substrate in
cross-section.
[0130] Other embodiments include applying a jet or focused blast of
high pressure fluid to hydraulically puncture the stratum corneum
and form a micropore into which the microneedle is inserted. The
micropore preferably is slightly larger than the diameter of the
microneedle. The microneedle device can be designed to utilize
hollow microneedles to direct the jet of high pressure fluid.
Various devices and techniques for high velocity introduction of
fluids and particles into skin for delivery of drugs or genes are
described, for example, in U.S. Pat. No. 5,919,159 and U.S. Pat.
No. 5,599,302 to Lilley, et al. (Medi-Ject, Inc.), U.S. Pat. No.
5,899,880 to Bellhouse, et al. (PowderJect Research Ltd.), and U.S.
Pat. No. 5,865,796 to McCabe (PowderJect Vaccines, Inc.).
[0131] Creation of the holes and penetration can be enhanced by
select cooling/freezing of the surface of the skin, e.g.,
cryoablation (see U.S. Pat. No. 5,147,355 to Friedman, et al.). For
example, the microneedle device can be adapted to create a local
Joule-Thompson effect (see U.S. Pat. No. 5,758,505 to Dobak III, et
al.).
[0132] In another embodiment, chemical agents, such as certain
keratin reducing agents (see U.S. Pat. No. 5,911,223 to Weaver et
al.), can be applied at the site of administration to degrade the
keratin of the skin's stratum corneum, rendering it more porous.
Examples of suitable chemicals include sodium thiosulfate and
urea.
[0133] viii. Lubricated Microneedles
[0134] In one embodiment, the microneedles include a lubricating
material, such as TEFLON.TM. (polytetrafluoroethylene), coated onto
the microneedles. In a preferred embodiment, the lubricating
material is incorporated into metal microneedles, for example, by
plating the lubricating material with the metal during the
manufacture of the microneedles.
[0135] ix. Vibrating the Microneedles
[0136] Essentially all of the microneedle devices and methods
described herein can be adapted to vibrate the microneedles and/or
the skin to further facilitate penetration. The vibration can be
effected to move the microneedles perpendicular and/or parallel to
the surface of the biological barrier, and/or at an orientation
thereinbetween. The vibration motion can be induced using known
techniques, the most common of which is coupling the microneedle or
array thereof to a piezoelectric transducer that can provide the
vibratory motion. Such a transducer can be bonded directly to the
array or can be bonded to a reservoir, thereby utilizing the
acoustic transmission properties of the reservoir contents (e.g.,
an aqueous drug solution) to transmit vibration to the
microneedles. Alternatively, electromechanical actuation can be
used to vibrate the microneedles, such electromechanical actuation
means include miniature motors and speaker coils.
[0137] 3. Methods of making Microneedle Devices
[0138] The microneedle devices are made by microfabrication
processes, by creating small mechanical structures in silicon,
metal, polymer, and other materials. These microfabrication
processes are based on well-established methods used to make
integrated circuits, electronic packages and other microelectronic
devices, augmented by additional methods used in the field of
micromachining. The microneedle devices can have dimensions as
small as a few nanometers and can be mass-produced at low per-unit
costs.
[0139] a. Microfabrication Processes
[0140] Microfabrication processes that may be used in making the
microneedles disclosed herein include lithography; etching
techniques, such as wet chemical, dry, and photoresist removal;
thermal oxidation of silicon; electroplating and electroless
plating; diffusion processes, such as boron, phosphorus, arsenic,
and antimony diffusion; ion implantation; film deposition, such as
evaporation (filament, electron beam, flash, and shadowing and step
coverage), sputtering, chemical vapor deposition (CVD), epitaxy
(vapor phase, liquid phase, and molecular beam), electroplating,
screen printing, lamination, stereolithography, laser machining,
and laser ablation (including projection ablation). See generally
Jaeger, Introduction to Microelectronic Fabrication (Addison-Wesley
Publishing Co., Reading Mass. 1988); Runyan, et al., Semiconductor
Integrated Circuit Processing Technology (Addison-Wesley Publishing
Co., Reading Mass. 1990); Proceedings of the IEEE Micro Electro
Mechanical Systems Conference 1987-1998; Rai-Choudhury, ed.,
Handbook of Microlithography Micromachining & Microfabrication
(SPIE Optical Engineering Press, Bellingham, Wash. 1997).
[0141] The following methods are preferred for making
microneedles.
[0142] i. Electrochemical Etching of Silicon
[0143] In this method, electrochemical etching of solid silicon to
porous silicon is used to create extremely fine (on the order of
0.01 .mu.m) silicon networks which can be used as piercing
structures. This method uses electrolytic anodization of silicon in
aqueous hydrofluoric acid, potentially in combination with light,
to etch channels into the silicon. By varying the doping
concentration of the silicon wafer to be etched, the electrolytic
potential during etching, the incident light intensity, and the
electrolyte concentration, control over the ultimate pore structure
can be achieved. The material not etched (i.e. the silicon
remaining) forms the microneedles. This method has been used to
produce irregular needle-type structures measuring tens of
nanometers in width.
[0144] ii. Plasma Etching
[0145] This process uses deep plasma etching of silicon to create
microneedles with diameters on the order of 0.1 .mu.m or larger.
Needles are patterned directly using photolithography, rather than
indirectly by controlling the voltage (as in electrochemical
etching), thus providing greater control over the final microneedle
geometry.
[0146] In this process, an appropriate masking material (e.g.,
metal) is deposited onto a silicon wafer substrate and patterned
into dots having the diameter of the desired microneedles. The
wafer is then subjected to a carefully controlled plasma based on
fluorine/oxygen chemistries to etch very deep, high aspect ratio
trenches into the silicon. See, e.g., Jansen, et al., "The Black
Silicon Method IV: The Fabrication of Three-Dimensional Structures
in Silicon with High Aspect Ratios for Scanning Probe Microscopy
and Other Applications," IEEE Proceedings of Micro Electro
Mechanical Systems Conference, pp. 88-93 (1995). Those regions
protected by the metal mask remain and form the needles. This
method is further described in Example 1 below.
[0147] iii. Electroplating.
[0148] In this process, a metal layer is first evaporated onto a
planar substrate. A layer of photoresist is then deposited onto the
metal to form a patterned mold which leaves an exposed-metal region
in the shape of needles. By electroplating onto the exposed regions
of the metal seed layer, the mold bounded by photoresist can be
filled with electroplated material. Finally, the substrate and
photoresist mold are removed, leaving the finished microneedle
array. The microneedles produced by this process generally have
diameters on the order of 1 .mu.m or larger. See, e.g., Frazier, et
al., "Two dimensional metallic microelectrode arrays for
extracellular stimulation and recording of neurons", IEEE
Proceedings of the Micro Electro Mechanical Systems Conference, pp.
195-200 (1993).
[0149] iv. Other Processes
[0150] Another method for forming microneedles made of silicon or
other materials is to use microfabrication techniques such as
photolithography, plasma etching, or laser ablation to make a mold
form (A), transferring that mold form to other materials using
standard mold transfer techniques, such as embossing or injection
molding (B), and reproducing the shape of the original mold form
(A) using the newly-created mold (B) to yield the final
microneedles (C). Alternatively, the creation of the mold form (A)
could be skipped and the mold (B) could be microfabricated
directly, which could then be used to create the final microneedles
(C).
[0151] Another method of forming solid silicon microneedles is by
using epitaxial growth on silicon substrates, as is utilized by
Containerless Research, Inc. (Evanston, Ill., USA) for its
products.
[0152] b. Hollow or Porous Microneedles
[0153] In a preferred embodiment, microneedles are made with pores
or other pathways through which material may be transported. The
following descriptions outline representative methods for
fabricating either porous or hollow microneedles.
[0154] i. Porous Microneedles
[0155] Rather than having a single, well-defined hole down the
length of the needle, porous needles are filled with a network of
channels or pores which allow conduction of fluid or energy through
the needle shaft. It has been shown that by appropriate
electrochemical oxidation of silicon, pore arrays with high aspect
ratios and a range of different pore size regimes can be formed;
these pore regimes are defined as (1) microporous regime with
average pore dimensions less than 2 nm, (2) mesoporous regime with
average pore sizes of between 2 nm and 50 nm, and (3) macroporous
regime with pores greater than 50 nm. The mesoporous and
macroporous regimes are expected to be most useful for drug
delivery. Two approaches to porous needles are generally available,
either (a) the silicon wafer is first made porous and then etched
as described above to form needles or (b) solid microneedles are
etched and then rendered porous, for example, by means of
electrochemical oxidation, such as by anodization of a silicon
substrate in a hydrofluoric acid electrolyte. The size distribution
of the etched porous structure is highly dependent on several
variables, including doping kind and illumination conditions, as
detailed in Lehmann, "Porous Silicon--A New Material for MEMS",
IEEE Proceedings of the Micro Electro Mechanical Systems
Conference, pp. 1-6 (1996). Porous polymer or metallic microneedles
can be formed, for example, by micromolding a polymer containing a
volatilizable or leachable material, such as a volatile salt,
dispersed in the polymer or metal, and then volatilizing or
leaching the dispersed material, leaving a porous polymer matrix in
the shape of the microneedle.
[0156] ii. Hollow Needles
[0157] Three-dimensional arrays of hollow microneedles can be
fabricated, for example, using combinations of dry etching
processes (Laermer, et al., "Bosch Deep Silicon Etching: Improving
Uniformity and Etch Rate for Advanced MEMS Applications," Micro
Electro Mechanical Systems, Orlando, Fla., USA, (Jan. 17-21, 1999);
Despont et al., "High-Aspect-Ratio, Ultrathick, Negative-Tone
Near-UV Photoresist for MEMS", Proc. of IEEE 10.sup.th Annual
International Workshop on MEMS, Nagoya, Japan, pp. 518-22 (Jan.
26-30, 1997)); micromold creation in lithographically-define- d
and/or laser ablated polymers and selective sidewall
electroplating; or direct micromolding techniques using epoxy mold
transfers.
[0158] One or more distinct and continuous pathways are created
through the interior of microneedles. In a preferred embodiment,
the microneedle has a single annular pathway along the center axis
of the microneedle. This pathway can be achieved by initially
chemically or physically etching the holes in the material and then
etching away microneedles around the hole. Alternatively, the
microneedles and their holes can be made simultaneously or holes
can be etched into existing microneedles. As another option, a
microneedle form or mold can be made, then coated, and then etched
away, leaving only the outer coating to form a hollow microneedle.
Coatings can be formed either by deposition of a film or by
oxidation of the silicon microneedles to a specific thickness,
followed by removal of the interior silicon. Also, holes from the
backside of the wafer to the underside of the hollow needles can be
created using a front-to-backside infrared alignment followed by
etching from the backside of the wafer.
[0159] a. Silicon Microneedles
[0160] One method for hollow needle fabrication is to replace the
solid mask used in the formation of solid needles by a mask that
includes a solid shape with one or more interior regions of the
solid shape removed. One example is a "donut-shaped" mask. Using
this type of mask, interior regions of the needle are etched
simultaneously with their side walls. Due to lateral etching of the
inner side walls of the needle, this may not produce sufficiently
sharp walls. In that case, two plasma etches may be used, one to
form the outer walls of the microneedle (i.e., the `standard`
etch), and one to form the inner hollow core (which is an extremely
anisotropic etch, such as in inductively-coupled-plasma "ICP"
etch). For example, the ICP etch can be used to form the interior
region of the needle followed by a second photolithography step and
a standard etch to form the outer walls of the microneedle. FIG. 1a
represents a silicon wafer 82 with a patterned photoresist layer 84
on top of the wafer 82. The wafer 82 is anisotropically etched
(FIG. 1b) to form a cavity 86 through its entire thickness (FIG.
1c). The wafer 82 is then coated with a chromium layer 88 followed
by a second photoresist layer 90 patterned so as to cover the
cavity 86 and form a circular mask for subsequent etching (FIG.
1d). The wafer 82 is then etched by a standard etch to form the
outer tapered walls 92 of the microneedle (FIG. 1e).
[0161] Alternatively, this structure can be achieved by
substituting the chromium mask used for the solid microneedles
described in Example 1 by a silicon nitride layer 94 on the silicon
substrate 95 covered with chromium 96, deposited as shown in FIG.
2a and patterned as shown in FIG. 2b. Solid microneedles are then
etched as described in Example 1 as shown FIG. 2c, the chromium 96
is stripped (FIG. 2d), and the silicon 95 is oxidized to form a
thin layer of silicon dioxide 97 on all exposed silicon surfaces
(FIG. 2e). The silicon nitride layer 94 prevents oxidation at the
needle tip. The silicon nitride 94 is then stripped (FIG. 2f),
leaving exposed silicon at the tip of the needle and oxide-covered
silicon 97 everywhere else. The needle is then exposed to an ICP
plasma which selectively etches the inner sidewalls of the silicon
95 in a highly anisotropic manner to form the interior hole of the
needle (FIG. 2g).
[0162] Another method uses the solid silicon needles described
previously as `forms` around which the actual needle structures are
deposited. After deposition, the forms are etched away, yielding
the hollow structures. Silica needles or metal needles can be
formed using different methods. Silica needles can be formed by
creating needle structures similar to the ICP needles described
above prior to the oxidation described above. The wafers are then
oxidized to a controlled thickness, forming a layer on the shaft of
the needle form which will eventually become the hollow
microneedle. The silicon nitride is then stripped and the silicon
core selectively etched away (e.g., in a wet alkaline solution) to
form a hollow silica microneedle.
[0163] In a preferred embodiment, an array of hollow silicon
microtubes is made using deep reactive ion etching combined with a
modified black silicon process in a conventional reactive ion
etcher, as described in Example 3 below. First, arrays of circular
holes are patterned through photoresist into SiO.sub.2, such as on
a silicon wafer. Then the silicon can be etched using deep reactive
ion etching (DRIE) in an inductively coupled plasma (ICP) reactor
to etch deep vertical holes. The photoresist was then removed.
Next, a second photolithography step patterns the remaining
SiO.sub.2 layer into circles concentric to the holes, leaving ring
shaped oxide masks surrounding the holes. The photoresist is then
removed and the silicon wafer again deep silicon etched, such that
the holes are etched completely through the wafer (inside the
SiO.sub.2 ring) and simultaneously the silicon is etched around the
SiO.sub.2 ring leaving a cylinder.
[0164] This latter process can be varied to produce hollow, tapered
microneedles. After an array of holes is fabricated as described
above, the photoresist and SiO.sub.2 layers are replaced with
conformal DC sputtered chromium rings. The second ICP etch is
replaced with a SF.sub.6/O.sub.2 plasma etch in a reactive ion
etcher (RIE), which results in positively sloping outer sidewalls.
Henry, et al., "Micromachined Needles for the Transdermal Delivery
of Drugs," Micro Electro Mechanical Systems, Heidelberg, Germany,
pp. 494-98 (Jan. 26-29, 1998).
[0165] b. Metal Microneedles
[0166] Metal needles can be formed by physical vapor deposition of
appropriate metal layers on solid needle forms, which can be made
of silicon using the techniques described above, or which can be
formed using other standard mold techniques such as embossing or
injection molding. The metals are selectively removed from the tips
of the needles using electropolishing techniques, in which an
applied anodic potential in an electrolytic solution will cause
dissolution of metals more rapidly at sharp points, due to
concentration of electric field lines at the sharp points. Once the
underlying silicon needle forms have been exposed at the tips, the
silicon is selectively etched away to form hollow metallic needle
structures. This process could also be used to make hollow needles
made from other materials by depositing a material other than metal
on the needle forms and following the procedure described
above.
[0167] A preferred method of fabricating hollow metal microneedles
utilizes micromold plating techniques, which are described as
follows and in Examples 4 and 5. In a method for making metal
microtubes, which does not require dry silicon etching, a
photo-defined mold first is first produced, for example, by spin
casting a thick layer, typically 150 .mu.m, of an epoxy (e.g.,
SU-8) onto a substrate that has been coated with a thin sacrificial
layer, typically about 10 to 50 nm. Arrays of cylindrical holes are
then photolithographically defined through the epoxy layer, which
typically is about 150 .mu.m thick. (Despont, et al.,
"High-Aspect-Ratio, Ultrathick, Negative-Tone Near-UV Photoresist
for MEMS," Proc. of IEEE 10.sup.th Annual International Workshop on
MEMS, Nagoya, Japan, pp. 518-522 (Jan. 26-30, 1997)). The diameter
of these cylindrical holes defines the outer diameter of the tubes.
The upper surface of the substrate, the sacrificial layer, is then
partially removed at the bottom of the cylindrical holes in the
photoresist. The exact method chosen depends on the choice of
substrate. For example, the process has been successfully performed
on silicon and glass substrates (in which the upper surface is
etched using isotropic wet or dry etching techniques) and
copper-clad printed wiring board substrates. In the latter case,
the copper laminate is selectively removed using wet etching. Then
a seed layer, such as Ti/Cu/Ti (e.g., 30 nm/200 nm/30 nm), is
conformally DC sputter-deposited onto the upper surface of the
epoxy mold and onto the sidewalls of the cylindrical holes. The
seed layer should be electrically isolated from the substrate.
Subsequently, one or more electroplatable metals or alloys are
electroplated onto the seed layer. Representative suitable metals
and alloys include Ni, NiFe, Au, Cu, Cr, Pt, Pd, and Ti. The
surrounding epoxy is then removed, leaving microtubes which each
have an interior annular hole that extends through the base metal
supporting the tubes. The rate and duration of electroplating is
controlled in order to define the wall thickness and inner diameter
of the microtubes. In one embodiment, this method was used to
produce microtubes having a height of between about 150 and 250
.mu.m, an outer diameter of between about 40 and 120 .mu.m, and an
inner diameter of between about 30 and 110 .mu.m (i.e., having a
wall thickness of 10 .mu.m). In a typical array, the microtubes
have a tube center-to-center spacing of about 150 .mu.m, but can
vary depending on the desired needle density.
[0168] A variation of this method is preferred for forming tapered
microneedles. As described above, photolithography yields holes in
the epoxy which have vertical sidewalls, such that the resulting
shafts of the microneedles are straight, not tapered. This vertical
sidewall limitation can be overcome by molding a preexisting 3D
structure, i.e., a mold-insert. The subsequent removal of the
mold-insert leaves a mold which can be surface plated similarly to
the holes produced by photolithography described above.
[0169] Alternatively, non-vertical sidewalls can be produced
directly in the polymeric mold into which electroplating will take
place. For example, conventional photoresists known in the art can
be exposed and developed in such as way as to have the surface
immediately adjacent to the mask be wider than the other surface.
Specialized greyscale photoresists in combination with greyscale
masks can accomplish the same effect. Laser-ablated molds can also
be made with tapered sidewalls, e.g., by optical adjustment of the
beam (in the case of serial hole fabrication) or of the reticle or
mold during ablation (in the case of projection ablation).
[0170] To form hollow tapered microneedles, the mold-insert is an
array of solid silicon microneedles, formed as described in Henry,
et al., "Micromachined Needles for the Transdermal Delivery of
Drugs," Micro Electro Mechanical Systems, Heidelberg, Germany,
January 26-29, pp. 494-498 (1998). First, a layer of a material,
such as an epoxy (e.g., SU-8 or a polydimethylsiloxane ("PDMS")),
is spin cast onto the array of silicon microneedles to completely
blanket the entire array. The epoxy settles during pre-bake to
create a planar surface above the silicon needle tips; the material
is then fully pre-baked, photolithographically cross-linked, and
post-baked.
[0171] The upper surface of the epoxy is then etched away, for
example with an O.sub.2/CHF.sub.3 plasma, until the needle tips are
exposed, preferably leaving between about 1 and 5 .mu.m of tip
protruding from the epoxy. The silicon is then selectively removed,
for example by using a SF.sub.6 plasma or a HNO.sub.3/HF solution.
The remaining epoxy micromold is the negative of the microneedles
and has a small diameter hole where the tip of the microneedle
formerly protruded.
[0172] After the removal of the silicon, a seed layer, such as
Ti--Cu--Ti, is conformally sputter-deposited onto the epoxy
micromold. Following the same process sequence described for hollow
metal microtubes, one or more electroplatable metals or alloys,
such as Ni, NiFe, Au, or Cu, are electroplated onto the seed layer.
Finally, the epoxy is removed, for example by using an
O.sub.2/CHF.sub.3 plasma, leaving an array of hollow metal
microneedles. An advantage of using PDMS in this application is
that the micromold can be physically removed from the silicon mold
insert by mechanical means, such as peeling, without damaging the
silicon mold insert, thus allowing the silicon mold insert to be
reused. Furthermore, the electroplated microneedles can be removed
from the PDMS mold by mechanical means, for example by peeling,
thereby allowing the PDMS to also be reused. In a preferred
embodiment, this method is used to produce microneedles having a
height of between about 150 and 250 .mu.m, an outer diameter of
between about 40 and 120 .mu.m, and an inner diameter of between
about 50 and 100 .mu.m. In a typical array, the microtubes have a
tube center-to-center spacing of about 150 .mu.m, but can vary
depending on the desired needle density. The microneedles are 150
.mu.m in height with a base diameter of 80 .mu.m, a tip diameter of
10 .mu.m, and a needle-to-needle spacing of 150 .mu.m.
[0173] c. Silicon Dioxide Microneedles
[0174] Hollow microneedles formed of silicon dioxide can be made by
oxidizing the surface of the silicon microneedle forms (as
described above), rather than depositing a metal and then etching
away the solid needle forms to leave the hollow silicon dioxide
structures. This method is illustrated in FIGS. 3a-d. FIG. 3a shows
an array 24 of needle forms 26 with masks 28 on their tips. In FIG.
3b, the needle forms 26 have been coated with a layer 30 of metal,
silicon dioxide or other material. FIG. 3c shows the coated needle
forms 26 with the masks 28 removed. Finally, in FIG. 3d, the needle
forms 26 have been etched away, leaving hollow needles 30 made of
metal, silicon dioxide, or other materials.
[0175] In one embodiment, hollow, porous, or solid microneedles are
provided with longitudinal grooves or other modifications to the
exterior surface of the microneedles. Grooves, for example, should
be useful in directing the flow of molecules along the outside of
microneedles.
[0176] d. Polymer Microneedles
[0177] In a preferred method, polymeric microneedles are made using
microfabricated molds. For example, the epoxy molds can be made as
described above and injection molding techniques can be applied to
form the microneedles in the molds (Weber, et al., "Micromolding--a
powerful tool for the large scale production of precise
microstructures", Proc. SPIE--International Soc. Optical Engineer.
2879:156-67 (1996); Schift, et al., "Fabrication of replicated high
precision insert elements for micro-optical bench arrangements"
Proc. SPIE--International Soc. Optical Engineer. 3513:122-34
(1998)). These micromolding techniques are preferred over other
techniques described herein, since they can provide relatively less
expensive replication, i.e. lower cost of mass production. In a
preferred embodiment, the polymer is biodegradable.
[0178] Microneedles, particularly hollow ones and ones formed of
relatively brittle materials, may break at the juncture of the
microneedle and substrate due to mechanical stresses at the sharp
angle formed there. It has been found that the integrity of such
microneedles can be improved by reinforcing the base of the
microneedles with an additional layer of material (e.g., silicon)
applied onto the face of the substrate face adjacent the base end
of the microneedles as shown in FIG. 17.
[0179] 4. Microneedle Device Applications
[0180] The device may be used for single or multiple uses for rapid
transport across a biological barrier or may be left in place for
longer times (e.g., hours or days) for long-term transport of
molecules. Depending on the dimensions of the device, the
application site, and the route in which the device is introduced
into (or onto) the biological barrier, the device may be used to
introduce or remove molecules at specific locations.
[0181] As discussed above, FIG. 9 shows a side elevational view of
a schematic of a preferred embodiment of the microneedle device 10
in a transdermal application. The device 10 is applied to the skin
such that the microneedles 12 penetrate through the stratum corneum
and enter the viable epidermis so that the tip of the microneedle
at least penetrates into the viable epidermis. In a preferred
embodiment, drug molecules in a reservoir within the upper portion
11 flow through or around the microneedles and into the viable
epidermis, where the drug molecules then diffuse into the dermis
for local treatment or for transport through the body.
[0182] To control the transport of material out of or into the
device through the microneedles, a variety of forces or mechanisms
can be employed. These include pressure gradients, concentration
gradients, electricity, ultrasound, receptor binding, heat,
chemicals, and chemical reactions. Mechanical or other gates in
conjunction with the forces and mechanisms described above can be
used to selectively control transport of the material.
[0183] In particular embodiments, the device should be
"user-friendly." For example, in some transdermal applications,
affixing the device to the skin should be relatively simple, and
not require special skills. This embodiment of a microneedle may
include an array of microneedles attached to a housing containing
drug in an internal reservoir, wherein the housing has a
bioadhesive coating around the microneedles. The patient can remove
a peel-away backing to expose an adhesive coating, and then press
the device onto a clean part of the skin, leaving it to administer
drug over the course of, for example, several days.
[0184] a. Drug Delivery
[0185] Essentially any drug or other bioactive agents can be
delivered using these devices. Drugs can be proteins, enzymes,
polysaccharides, polynucleotide molecules, and synthetic organic
and inorganic compounds. Representative agents include
anti-infectives, hormones, such as insulin, growth regulators,
drugs regulating cardiac action or blood flow, and drugs for pain
control. The drug can be for local treatment or for regional or
systemic therapy. The following are representative examples, and
disorders they are used to treat:
[0186] Calcitonin, osteoporosis; Enoxaprin, anticoagulant;
Etanercept, rheumatoid arthritis; Erythropoietin, anemia; Fentanyl,
postoperative and chronic pain; Filgrastin, low white blood cells
from chemotherapy; Heparin, anticoagulant; Insulin, human,
diabetes; Interferon Beta 1a, multiple sclerosis; Lidocaine, local
anesthesia; Somatropin, growth hormone; and Sumatriptan, migraine
headaches.
[0187] In this way, many drugs can be delivered at a variety of
therapeutic rates. The rate can be controlled by varying a number
of design factors, including the outer diameter of the microneedle,
the number and size of pores or channels in each microneedle, the
number of microneedles in an array, the magnitude and frequency of
application of the force driving the drug through the microneedle
and/or the holes created by the microneedles. For example, devices
designed to deliver drug at different rates might have more
microneedles for more rapid delivery and fewer microneedles for
less rapid delivery. As another example, a device designed to
deliver drug at a variable rate could vary the driving force (e.g.,
pressure gradient controlled by a pump) for transport according to
a schedule which was pre-programmed or controlled by, for example,
the user or his doctor. The devices can be affixed to the skin or
other tissue to deliver drugs continuously or intermittently, for
durations ranging from a few seconds to several hours or days.
[0188] One of skill in the art can measure the rate of drug
delivery for particular microneedle devices using in vitro and in
vivo methods known in the art. For example, to measure the rate of
transdermal drug delivery, human cadaver skin mounted on standard
diffusion chambers can be used to predict actual rates. See
Hadgraft & Guy, eds., Transdermal Drug Delivery: Developmental
Issues and Research Initiatives (Marcel Dekker, New York 1989);
Bronaugh & Maibach, Percutaneous Absorption,
Mechanisms--Methodology--Drug Delivery (Marcel Dekker, New York
1989). After filling the compartment on the dermis side of the
diffusion chamber with saline, a microneedle array is inserted into
the stratum corneum; a drug solution is placed in the reservoir of
the microneedle device; and samples of the saline solution are
taken over time and assayed to determine the rates of drug
transport.
[0189] In an alternate embodiment, biodegradable or
non-biodegradable microneedles can be used as the entire drug
delivery device, where biodegradable microneedles are a preferred
embodiment. For example, the microneedles may be formed of a
biodegradable polymer containing a dispersion of an active agent
for local or systemic delivery. The agent could be released over
time, according to a profile determined by the composition and
geometry of the microneedles, the concentration of the drug and
other factors. In this way, the drug reservoir is within the matrix
of one or more of the microneedles.
[0190] In another alternate embodiment, these microneedles may be
purposefully sheared off from the substrate after penetrating the
biological barrier. In this way, a portion of the microneedles
would remain within or on the other side of the biological barrier
and a portion of the microneedles and their substrate would be
removed from the biological barrier. In the case of skin, this
could involve inserting an array into the skin, manually or
otherwise breaking off the microneedles tips and then remove the
base of the microneedles. The portion of the microneedles which
remains in the skin or in or across another biological barrier
could then release drug over time according to a profile determined
by the composition and geometry of the microneedles, the
concentration of the drug and other factors. In a preferred
embodiment, the microneedles are made of a biodegradable polymer.
The release of drug from the biodegradable microneedle tips can be
controlled by the rate of polymer degradation. Microneedle tips can
release drugs for local or systemic effect, or other agents, such
as perfume, insect repellent and sun block.
[0191] Microneedle shape and content can be designed to control the
breakage of microneedles. For example, a notch can be introduced
into microneedles either at the time of fabrication or as a
subsequent step. In this way, microneedles would preferentially
break at the site of the notch. Moreover, the size and shape of the
portion of microneedles which break off can be controlled not only
for specific drug release patterns, but also for specific
interactions with cells in the body. For example, objects of a few
microns in size are known to be taken up by macrophages. The
portions of microneedles that break off can be controlled to be
bigger or smaller than that to prevent uptake by macrophages or can
be that size to promote uptake by macrophages, which can be
desirable for delivery of vaccines.
[0192] b. Diagnostic Sensing of Body Fluids (Biosensors)
[0193] One embodiment of the devices described herein may be used
to remove material from the body across a biological barrier, i.e.
for minimally invasive diagnostic sensing. For example, fluids can
be transported from interstitial fluid in a tissue into a reservoir
in the upper portion of the device. The fluid can then be assayed
while in the reservoir or the fluid can be removed from the
reservoir to be assayed, for diagnostic or other purposes. For
example, interstitial fluids can be removed from the epidermis
across the stratum corneum to assay for glucose concentration,
which should be useful in aiding diabetics in determining their
required insulin dose. Other substances or properties that would be
desirable to detect include lactate (important for athletes),
oxygen, pH, alcohol, tobacco metabolites, and illegal drugs
(important for both medical diagnosis and law enforcement).
[0194] The sensing device can be in or attached to one or more
microneedles, or in a housing adapted to the substrate. Sensing
information or signals can be transferred optically (e.g.,
refractive index) or electrically (e.g., measuring changes in
electrical impedance, resistance, current, voltage, or combination
thereof). For example, it may be useful to measure a change as a
function of change in resistance of tissue to an electrical current
or voltage, or a change in response to channel binding or other
criteria (such as an optical change) wherein different resistances
are calibrated to signal that more or less flow of drug is needed,
or that delivery has been completed.
[0195] In one embodiment, one or more microneedle devices can be
used for (1) withdrawal of interstitial fluid, (2) assay of the
fluid, and/or (3) delivery of the appropriate amount of a
therapeutic agent based on the results of the assay, either
automatically or with human intervention. For example, a sensor
delivery system may be combined to form, for example, a system
which withdraws bodily fluid, measures its glucose content, and
delivers an appropriate amount of insulin. The sensing or delivery
step also can be performed using conventional techniques, which
would be integrated into use of the microneedle device. For
example, the microneedle device could be used to withdraw and assay
glucose, and a conventional syringe and needle used to administer
the insulin, or vice versa.
[0196] In an alternate embodiment, microneedles may be purposefully
sheared off from the substrate after penetrating the biological
barrier, as described above. The portion of the microneedles which
remain within or on the other side of the biological barrier could
contain one or more biosensors. For example, the sensor could
change color as its output. For microneedles sheared off in the
skin, this color change could be observed through the skin by
visual inspection or with the aid of an optical apparatus.
[0197] The microneedles can also be used for aerosolization or
delivery for example directly to a mucosal surface in the nasal or
buccal regions or to the pulmonary system.
[0198] The microneedle devices disclosed herein also should be
useful for controlling transport across tissues other than skin.
For example, microneedles can be inserted into the eye across, for
example, conjunctiva, sclera, and/or cornea, to facilitate delivery
of drugs into the eye. Similarly, microneedles inserted into the
eye can facilitate transport of fluid out of the eye, which may be
of benefit for treatment of glaucoma. Microneedles may also be
inserted into the buccal (oral), nasal, vaginal, or other
accessible mucosa to facilitate transport into, out of, or across
those tissues. For example, a drug may be delivered across the
buccal mucosa for local treatment in the mouth or for systemic
uptake and delivery. As another example, microneedle devices may be
used internally within the body on, for example, the lining of the
gastrointestinal tract to facilitate uptake of orally-ingested
drugs or the lining of blood vessels to facilitate penetration of
drugs into the vessel wall. For example, cardiovascular
applications include using microneedle devices to facilitate vessel
distension or immobilization, similarly to a stent, wherein the
microneedles/substrate can function as a "staple-like" device to
penetrate into different tissue segments and hold their relative
positions for a period of time to permit tissue regeneration. This
application could be particularly useful with biodegradable
devices. These uses may involve invasive procedures to introduce
the microneedle devices into the body or could involve swallowing,
inhaling, injecting or otherwise introducing the devices in a
non-invasive or minimally-invasive manner.
[0199] c. Delivery of Energy
[0200] Other than transport of drugs and biological molecules, the
microneedles may be used to transmit or transfer other materials
and energy forms, such as light, electricity, heat, or pressure.
The microneedles, for example, could be used to direct light to
specific locations within the body, in order that the light can
directly act on a tissue or on an intermediary, such as
light-sensitive molecules in photodynamic therapy.
[0201] The present invention will be further understood with
reference to the following non-limiting examples.
EXAMPLE 1
Fabrication of Solid Silicon Microneedles
[0202] A chromium masking material was deposited onto silicon
wafers and patterned into dots having a diameter approximately
equal to the base of the desired microneedles. The wafers were then
loaded into a reactive ion etcher and subjected to a carefully
controlled plasma based on fluorine/oxygen chemistries to etch very
deep, high aspect ratio valleys into the silicon. Those regions
protected by the metal mask remain and form the microneedles.
[0203] <100>-oriented, prime grade, 450-550 .mu.m thick,
10-15 .OMEGA.-cm silicon wafers (Nova Electronic Materials Inc.,
Richardson, Tex.) were used as the starting material. The wafers
were cleaned in a solution of 5 parts by volume deionized water, 1
part 30% hydrogen peroxide, and 1 part 30% ammonium hydroxide (J.
T. Baker, Phillipsburg, N.J.) at approximately 80.degree. C. for 15
minutes, and then dried in an oven (Blue M Electric, Watertown,
Wis.) at 150.degree. C. for 10 minutes. Approximately 1000 .ANG. of
chromium (Mat-Vac Technology, Flagler Beach, Fla.) was deposited
onto the wafers using a DC-sputterer (601 Sputtering System, CVC
Products, Rochester, N.Y.). The chromium layer was patterned into
20 by 20 arrays of 80 .mu.m diameter dots with 150 .mu.m
center-to-center spacing using the lithographic process described
below.
[0204] A layer of photosensitive material (1827 photoresist,
Shipley, Marlborough, Mass.) was deposited onto the chromium layer
covering the silicon wafers. A standard lithographic mask (Telic,
Santa Monica, Calif.) bearing the appropriate dot array pattern was
positioned on top of the photoresist layer. The wafer and
photoresist were then exposed to ultraviolet (UV) light through the
mask by means of an optical mask aligner (Hybralign Series 500,
Optical Associates, Inc., Milpitas, Calif.). The exposed
photoresist was removed by soaking the wafers in a liquid developer
(354 developer, Shipley, Marlborough, Mass.) leaving the desired
dot array of photoresist on the chromium layer. Subsequently, the
wafers were dipped into a chromium etchant (CR-75; Cyanteck
Fremont, Calif.), which etched the chromium that had been exposed
during the photolithography step, leaving dot arrays of chromium
(covered with photoresist) on the surface of the silicon wafer. The
photoresist still present on the chromium dots formed the masks
needed for fabrication of the microneedles, described below.
[0205] The microneedles were fabricated using a reactive ion
etching techniques based on the Black Silicon Method developed at
the University of Twente. The patterned wafers were etched in a
reactive ion etcher (700 series wafer/batch Plasma Processing
System, Plasma Therm, St. Petersburg, Fla.) with means for ensuring
good thermal contact between the wafers and the underlying platen
(Apiezon N, K. J. Lesker, Clairton, Pa.). The wafers were etched
using the following gases and conditions: SF.sub.6 (20 standard
cubic centimeters per minute) and O.sub.2 (15 standard cubic
centimeters per minute) at a pressure of 150 mTorr and a power of
150 W for a run time of approximately 250 minutes. These conditions
caused both deep vertical etching and slight lateral underetching.
By controlling the ratio of flow rates of the SF.sub.6 and O.sub.2
gases used to form the plasma, the aspect ratio of the microneedles
could be adjusted. The regions protected by the chromium masks
remained and formed the microneedles. Etching was allowed to
proceed until the masks fell off due to underetching, resulting in
an array of sharp silicon spikes.
EXAMPLE 2
Transdermal Transport Using Solid Microneedles
[0206] To determine if microfabricated microneedles could be used
to enhance transdermal drug delivery, arrays of microneedles were
made using a deep plasma etching technique. Their ability to
penetrate human skin without breaking was tested and the resulting
changes in transdermal transport were measured.
[0207] Arrays of microneedles were fabricated having extremely
sharp tips (radius of curvature less than 1 .mu.m), and are
approximately 150 .mu.m long. Because the skin surface is not flat
due to dermatoglyphics and hair, the full length of these
microneedles will not penetrate the skin. All experiments were
performed at room temperature (23.+-.2.degree. C.).
[0208] The ability of the microneedles to pierce skin without
breaking was then tested. Insertion of the arrays into skin
required only gentle pushing. Inspection by light and electron
microscopy showed that more than 95% of microneedles within an
array pierced across the stratum corneum of the epidermis samples.
Moreover, essentially all of the microneedles that penetrated the
epidermis remained intact. On those very few which broke, only the
top 5-10 .mu.m was damaged. Microneedle arrays could also be
removed without difficulty or additional damage, as well as
re-inserted into skin multiple times.
[0209] To quantitatively assess the ability of microneedles to
increase transdermal transport, calcein permeability of human
epidermis with and without inserted microneedle arrays was
measured. Calcein crosses skin very poorly under normal
circumstances and therefore represents an especially difficult
compound to deliver. As expected, passive permeability of calcein
across unaltered skin was very low, indicating that the epidermis
samples were intact.
[0210] Insertion of microneedles into skin was capable of
dramatically increasing permeability to calcein. When microneedles
were inserted and left embedded in the skin, calcein permeability
was increased by more than 1000-fold. Insertion of microneedles for
10 s, followed by their removal, yielded an almost 10,000-fold
increase. Finally, insertion of a microneedle array for 1 h,
followed by its removal, increased skin permeability by about
25,000-fold. Permeabilities for skin with microneedles inserted and
then removed are higher than for skin with microneedles remaining
embedded probably because the microneedles themselves or the
silicon plate supporting the array may block access to the
microscopic holes created in the skin. Light microscopy showed that
the holes which remained in the skin after microneedles were
removed were approximately 1 .mu.m in size.
[0211] To confirm in vitro experiments which showed that skin
permeability can be significantly increased by microneedles,
studies were conducted with human volunteers. They indicated that
microneedles could be easily inserted into the skin of the forearm
or hand. Moreover, insertion of microneedle arrays was never
reported to be painful, but sometimes elicited a mild "wearing"
sensation described as a weak pressure or the feeling of a piece of
tape affixed to the skin. Although transport experiments were not
performed in vivo, skin electrical resistance was measured before
and after microneedle insertion. Microneedles caused a 50-fold drop
in skin resistance, a drop similar to that caused by the insertion
of a 30-gauge "macroneedle." Inspection of the site immediately
after microneedle insertion showed no holes visible by light
microscopy. No erythema, edema, or other reaction to microneedles
was observed over the hours and days which followed. This indicates
that microneedle arrays can permeabilize skin in human subjects in
a non-painful and safe manner.
EXAMPLE 3
Fabrication of Silicon Microtubes
[0212] Three-dimensional arrays of microtubes were fabricated from
silicon, using deep reactive ion etching combined with a modified
black silicon process in a conventional reactive ion etcher. The
fabrication process is illustrated in FIGS. 4a-d. First, arrays of
40 .mu.m diameter circular holes 32 were patterned through
photoresist 34 into a 1 .mu.m thick SiO.sub.2 layer 36 on a two
inch silicon wafer 38 (FIG. 4a). The wafer 38 was then etched using
deep reactive ion etching (DRIE) (Laermer, et al., "Bosch Deep
Silicon Etching: Improving Uniformity and Etch Rate for Advanced
MEMS Applications," Micro Electro Mechanical Systems, Orlando,
Fla., USA (Jan. 17-21, 1999)). in an inductively coupled plasma
(ICP) reactor to etch deep vertical holes 40. The deep silicon etch
was stopped after the holes 40 are approximately 200 .mu.m deep
into the silicon substrate 38 (FIG. 4b) and the photoresist 34 was
removed. A second photolithography step patterned the remaining
SiO.sub.2 layer 36 into circles concentric to the holes, thus
leaving ring shaped oxide masks 34 surrounding the holes (FIG. 4c).
The photoresist 34 was then removed and the wafer 38 was again deep
silicon etched, while simultaneously the holes 40 were etched
completely through the wafer 38 (inside the SiO.sub.2 ring) and the
silicon was etched around the SiO.sub.2 ring 38 leaving a cylinder
42 (FIG. 4d). The resulting tubes were 150 .mu.m in height, with an
outer diameter of 80 .mu.m, an inner diameter of 40 .mu.m, and a
tube center-to-center spacing of 300 .mu.m.
EXAMPLE 4
Micromold Fabrication of Metal Microtubes
[0213] Hollow metal microtubes were prepared without dry silicon
etching, using a thick, photo-defined mold of epoxy. The sequences
are illustrated in FIGS. 5a-e. First, a thick layer of SU-8 epoxy
44 was spin cast onto a silicon or glass substrate 46 that had been
coated with 30 nm of titanium 48, the sacrificial layer. Arrays of
cylindrical holes 49 were then photolithographically defined
through an epoxy layer 44, typically 150 .mu.m thick (FIG. 5a). The
sacrificial layer then was partially removed using a wet etching
solution containing hydrofluoric acid and water at the bottom of
the cylindrical holes in the SU-8 photoresist 46 (FIG. 5b). A seed
layer of Ti/Cu/Ti (30 nm/200 nm/30 nm) 39 was then conformally DC
sputter-deposited onto the upper surface of the epoxy mold and onto
the sidewalls of the cylindrical holes 49 (FIG. 5c). As shown in
FIG. 5c, the seed layer 39 was electrically isolated from the
substrate. Subsequently, NiFe was electroplated onto the seed layer
39 (FIG. 5d), the epoxy 44 was removed from the substrate, and the
surrounding epoxy 44 was removed (FIG. 5e). The resulting
microtubes are 200 .mu.m in height with an outer diameter of 80
.mu.m, an inner diameter of 60 .mu.m, and a tube center-to-center
spacing of 150 .mu.m. The holes in the interior of the microtubes
protrude through the base metal supporting the tubes.
EXAMPLE 5
Micromold Fabrication of Tapered Microneedles
[0214] A micromold having tapered walls was fabricated by molding a
preexisting 3-D array of microneedles, i.e. the mold-insert, and
subsequently removing the mold insert. The micromold was then
surface plated in a manner similar to that for the microtubes
described in Example 4. The fabrication sequence is illustrated in
FIGS. 6a-d.
[0215] First, an array of solid silicon microneedles 50 were
prepared as described in Henry, et al., "Micromachined Needles for
the Transdermal Delivery of Drugs," Micro Electro Mechanical
Systems, Heidelberg, Germany, January 26-29, pp. 494-98 (1998).
Then, a layer of epoxy 52 (SU-8) was spin cast onto the microneedle
array to completely blanket the array (FIG. 6a). The epoxy 52
settled during pre-bake to create a planar surface above the tips
of the microneedles 50. The epoxy 52 was then fully pre-baked,
photolithographically cross-linked, and post-baked.
[0216] Then, the upper surface of the epoxy 52 was etched away
using an O.sub.2/CHF.sub.3 plasma until approximately 1 to 2 .mu.m
of the needle tips 54 were exposed, protruding from the epoxy 52
(FIG. 6b). The silicon was then selectively removed by using a
SF.sub.6 plasma (FIG. 6c). The remaining epoxy mold 52 provided a
negative of the microneedles with a small diameter hole where the
tip of the silicon needle protruded. After the removal of the
silicon, a seed layer of Ti--Cu--Ti 54 was conformally
sputter-deposited onto the top and sidewalls of the epoxy micromold
52. Following the same process sequence as described in Example 4,
NiFe was then electroplated onto the seed layer 54 (FIG. 6c).
Finally, the epoxy was removed using an O.sub.2/CHF.sub.3 plasma,
leaving a 20.times.20 array of NiFe hollow metal microneedles 54
(FIG. 6d). The microneedles 54 were 150 .mu.m in height with a base
diameter of 80 .mu.m, a tip diameter of 10 .mu.m, and a
needle-to-needle spacing of 150 .mu.m.
[0217] Micromold-based microneedles also have been successfully
manufactured using a process in which the epoxy mold material was
replaced with PDMS. In this case, it was possible to remove the
mold from the mold insert, as well as the microneedles from the
mold, using only physical techniques such as peeling. This approach
advantageously requires no dry etching and allows one to reuse both
the mold and the mold insert.
EXAMPLE 6
Micromold Fabrication of Tapered Microneedles using Laser-Formed
Molds
[0218] A micromold having tapered walls was fabricated by use of
laser ablation techniques, as shown in FIGS. 7a-d. A
laser-ablatable polymer sheet 60 such as KAPTON.TM. polyimide
approximately 150 microns in thickness was optionally laminated to
a thin (10-30 micron) metal sheet 62 such as titanium (FIG. 7a). A
tapered hole 64 was formed in the metal/polymer laminate 60/62
using a laser technique such as excimer laser ablation (FIG. 7b).
The entry hole of the laser spot was on the metal side 62, and a
through hole was made through both the metal sheet and the polymer
film. The through hole 64 was tapered in combination with either
defocusing or appropriate substrate motion to create a taper such
that the wide end of the hole 64 (typically 40-50 microns) was on
the metal side 62 and the narrow end of the hole 64 (typically
10-20 microns) was on the polymer 60 side. A thin layer of metal
66, e.g. titanium, of thickness 0.1 micron was then deposited,
e.g., using a sputter-deposition technique, in such a way that the
metal 66 deposited on the metal film side and coated the polymer
sidewalls, but did not coat the polymer 60 side of the laminate
(FIG. 7c). Electrodeposition of metal 68, e.g., gold, to a
thickness of 1 to 5 microns was then performed on the
titanium-coated metal surface 66, and polymer sidewalls curved
section of 60 next to 64. Finally, the polymer 60 was removed,
using e.g. an oxygen plasma, to form the completed microneedles
(FIG. 7d).
[0219] Alternate polymer removal methods, such as thermal, solvent,
aqueous, or photo-degradation followed by solvent or aqueous
removal, are also possible if the polymer material is chosen
appropriately (e.g., a photoresist resin).
EXAMPLE 7
Formation of Microneedles by Embossing
[0220] Formation of a microneedle by embossing is shown in FIGS.
8a-f. A polymeric layer 70 (FIG. 8a) is embossed by a solid
microneedle or microneedle array 72 (FIG. 8b). The array 72 is
removed (FIG. 8c), and the layer 70 is etched from the non-embossed
side 74 until the embossed cavity 76 is exposed (FIG. 8d). A
metallic layer 78 is then deposited on the embossed side and the
sidewalls, but not on the non-embossed side 74 (FIG. 8e). This
layer 78 is optionally thickened by electrodeposition of an
additional metal layer 80 on top of it (FIG. 8e). The polymer layer
70 is then removed to form the microneedles 78/80 (FIG. 8f).
EXAMPLE 8
Transdermal Application of Hollow Microneedles
[0221] The bore of hollow microneedles must provide fluid flow with
minimal clogging in order to be suitable to transport material,
such as in transdermal drug delivery. Therefore, microneedles and
microtubes were evaluated to determine their suitability for these
functions.
[0222] Hollow metal and silicon microneedles, produced as described
in Examples 3-5, were inserted through human skin epidermis with no
apparent clogging of the needle bores. Scanning electron microscopy
of a hollow metal (NiFe) microneedle penetrating up through the
underside of human epidermis showed the microneedle remains intact,
with the tip free of debris. Similarly, silicon microneedles, metal
microneedles, and metal microtubes were successfully inserted
through human skin. Also, the hollow microneedles were shown to
permit the flow of water through their bores.
EXAMPLE 9
Drug Transport Through Microneedles Inserted into Skin
[0223] Studies were performed with solid and hollow microneedles to
demonstrate transport of molecules and fluids. As shown in Table 1,
transport of a number of different compounds across skin is
possible using microneedles. These studies were performed using
either solid silicon microneedles or using hollow silicon
microneedles made by methods described in this patent. Transport
was measured across human cadaver epidermis in vitro using Franz
diffusion chambers at 37.degree. C. using methods described in
Henry, et al., "Microfabricated microneedles: A novel method to
increase transdermal drug delivery" J. Pharm. Sci. 87: 922-25
(1998).
[0224] The transdermal delivery of calcein, insulin, bovine serum
albumin ("BSA"), and nanoparticles was measured. Delivery refers to
the ability to transport these compounds from the stratum corneum
side of the epidermis to the viable epidermis side. This is the
direction of transport associated with delivering drugs into the
body. Removal of calcein was also measured. Removal refers to the
ability to transport calcein from the viable epidermis side of the
epidermis to the stratum corneum side. This is the direction of
transport associated with removing from the body compounds found in
the body, such as glucose.
[0225] In all cases shown in Table 1, transport of these compounds
across skin occurred at levels below the detection limit when no
needles were inserted into the skin. Intact skin provides an
excellent barrier to transport of these compounds. In all cases
examined, when solid microneedles were inserted into the skin and
left in place, large skin permeabilities were measured, indicating
that the microneedles had created pathways for transport across
the-skin. Furthermore, in all cases, when solid microneedles were
inserted into the skin and then removed, even greater skin
permeabilities resulted. Finally, when hollow microneedles were
inserted into the skin and left in place, still greater skin
permeabilities resulted for those compounds tested. These studies
show that microneedles can dramatically increase skin permeability
and can thereby increase transport of a number of different
compounds across the skin. They also shows that when solid
microneedles are used, a preferred embodiment involves inserting
and then removing microneedles, rather than leaving them in place.
They also shows that using hollow microneedles are a preferred
embodiment over the use of solid microneedles.
[0226] In Table 2, the flow rate of water through hollow silicon
microneedles is shown as a function of applied pressure. These data
demonstrate that significant flow rates of water through
microneedles can be achieved at modest pressures.
1TABLE 1 Transport of Drugs Through Microneedles Inserted Into Skin
Solid needles Hollow No Solid needles inserted and needles Compound
needles inserted removed inserted Calcein ** 4 .times. 10.sup.-3 1
.times. 10.sup.-2 1 .times. 10.sup.-1 delivery Calcein ** 2 .times.
10.sup.-3 1 .times. 10.sup.-2 n.a. removal Insulin ** 1 .times.
10.sup.-4 1 .times. 10.sup.-2 n.a. delivery BSA delivery ** 9
.times. 10.sup.-4 8 .times. 10.sup.-3 9 .times. 10.sup.-2
Nanoparticle ** n.a. 3 .times. 10.sup.-5 n.a. delivery **means that
the transport was below the detection limit. n.a. means that the
data are not available. Nanoparticles were made of latex with a
diameter of approximately 100 nm.
[0227]
2TABLE 2 Flow Rate of Water Through Hollow Silicon Microneedles as
a Function of Applied Pressure Pressure Flow rate (psi) (ml/min)
1.0 16 1.5 24 2.0 31 2.5 38 3.0 45
[0228] Publications cited herein and the material for which they
are cited are specifically incorporated by reference. Nothing
herein is to be construed as an admission that the invention is not
entitled to antedate such disclosure by virtue of prior
invention.
[0229] Modifications and variations of the methods and devices
described herein will be obvious to those skilled in the art from
the foregoing detailed description. Such modifications and
variations are intended to come within the scope of the appended
claims.
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