U.S. patent application number 11/071792 was filed with the patent office on 2005-06-30 for microneedle arrays and methods of manufacturing the same.
This patent application is currently assigned to 3M Innovative Properties Company. Invention is credited to Delmore, Michael D., Ferber, Richard H., Fleming, Patrick R., Huntley, Douglas A., Keister, Jamieson C., Thomas, Cristina U..
Application Number | 20050143713 11/071792 |
Document ID | / |
Family ID | 25485700 |
Filed Date | 2005-06-30 |
United States Patent
Application |
20050143713 |
Kind Code |
A1 |
Delmore, Michael D. ; et
al. |
June 30, 2005 |
Microneedle arrays and methods of manufacturing the same
Abstract
Microneedle arrays, methods of manufacturing microneedles and
methods of using microneedle arrays. The microneedles in the
microneedle arrays may be in the form of tapered structures that
include at least one channel formed in the outside surface of each
microneedle. The microneedles may have bases that are elongated in
one direction. The channels in microneedles with elongated bases
may extend from one of the ends of the elongated bases towards the
tips of the microneedles. The channels formed along the sides of
the microneedles may optionally be terminated short of the tips of
the microneedles. The microneedle arrays may also include conduit
structures formed on the surface of the substrate on which the
microneedle array is located. The channels in the microneedles may
be in fluid communication with the conduit structures. One manner
of using microneedle arrays of the present invention is in methods
involving the penetration of skin to deliver medicaments or other
substances and/or extract blood or tissue.
Inventors: |
Delmore, Michael D.; (Grant,
MN) ; Fleming, Patrick R.; (Lake Elmo, MN) ;
Huntley, Douglas A.; (Maplewood, MN) ; Keister,
Jamieson C.; (Lakeville, MN) ; Thomas, Cristina
U.; (Woodbury, MN) ; Ferber, Richard H.;
(Fridley, MN) |
Correspondence
Address: |
3M INNOVATIVE PROPERTIES COMPANY
PO BOX 33427
ST. PAUL
MN
55133-3427
US
|
Assignee: |
3M Innovative Properties
Company
|
Family ID: |
25485700 |
Appl. No.: |
11/071792 |
Filed: |
March 3, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11071792 |
Mar 3, 2005 |
|
|
|
09947195 |
Sep 5, 2001 |
|
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6881203 |
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Current U.S.
Class: |
604/506 ;
604/136; 604/173 |
Current CPC
Class: |
A61B 5/14514 20130101;
A61B 5/150022 20130101; A61M 2037/003 20130101; A61M 2037/0007
20130101; A61B 5/150358 20130101; A61B 5/150984 20130101; A61M
2037/0053 20130101; A61M 37/0015 20130101; A61B 5/150099 20130101;
A61B 5/150229 20130101; A61B 2562/0295 20130101; A61B 5/150969
20130101; A61B 5/150282 20130101; A61M 2037/0038 20130101 |
Class at
Publication: |
604/506 ;
604/173; 604/136 |
International
Class: |
A61M 031/00 |
Claims
What is claimed is:
1. A method of delivering a microneedle array to a skin impact
site, the method comprising: positioning a microneedle array
proximate a delivery site, the microneedle array comprising a
plurality of microneedles protruding from a surface; applying an
impact force to the microneedle array over a period of less than
about 1 second, wherein the plurality of microneedles are driven
through the stratum corneum at the skin impact site.
2. A method according to claim 1, wherein the period is less than
about 500 milliseconds.
3. A method according to claim 1, wherein the period is less than
about 300 milliseconds.
4. A method according to claim 1, wherein applying the impact force
to the microneedles array comprises accelerating the microneedle
array towards the skin impact site.
5. A method according to claim 1, wherein the microneedle array is
in contact with the skin impact site before applying the impact
force to the microneedle array.
6. A method according to claim 1, further comprising removing the
microneedle array from contact with the skin impact site within
about 1 second after the plurality of microneedles are driven
through the stratum corneum at the skin impact site.
7. A method according to claim 1, further comprising retaining the
microneedle array in contact with the skin impact site for about 2
seconds or more after the plurality of microneedles are driven
through the stratum corneum at the skin impact site.
8. A method according to claim 1, wherein the impact force has a
maximum of about 40 N/cm.sup.2 or less.
9. A method according to claim 1, wherein the impact force has a
maximum of about 20 N/cm.sup.2 or less.
10. A method according to claim 1, further comprising drawing a
vacuum at the skin impact site after the plurality of microneedles
are driven through the stratum corneum at the skin impact site.
11. A method according to claim 1, further comprising locating an
indicator in contact with the skin impact site after the plurality
of microneedles are driven through the stratum corneum at the skin
impact site.
12. A method according to claim 1, wherein the method further
comprises: locating an indicator in contact with the skin impact
site after the plurality of microneedles are driven through the
stratum corneum at the skin impact site; and drawing a vacuum at
the skin impact site after the plurality of microneedles are driven
through the stratum corneum at the skin impact site.
13. A microneedle array delivery device comprising: a microneedle
array comprising a plurality of microneedles protruding from a
surface; a driver operably connected to the microneedle array,
wherein the driver comprises stored energy; wherein release of the
stored energy results in application of an impact force to the
microneedle array over a period of less than about 1 second.
14. A device according to claim 13, wherein the driver comprises at
least one mechanical spring.
15. A method according to claim 13, wherein the driver comprises at
least one resilient member.
16. A method according to claim 13, wherein the driver comprises a
compressed fluid.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional U.S. Ser. No. 09/947,195,
filed Sep. 5, 2001, now allowed, the disclosure of which is herein
incorporated by reference.
FIELD OF INVENTION
[0002] The present invention relates to the field of microneedle
arrays.
BACKGROUND
[0003] Arrays of relatively small structures, sometimes referred to
as microneedles or micro-pins, have been disclosed for use in
connection with the delivery and/or removal of therapeutic agents
and other substances through the skin and other surfaces.
[0004] The vast majority of known microneedle arrays include
structures having a capillary or passageway formed through the
needle. Because the needles are themselves small, the passageways
formed in the needles must be limited in size. As a result, the
passageways can be difficult to manufacture because of their small
size and the need for accurate location of the passageways within
the needles.
[0005] Another potential problem of passageways small enough to fit
within the microneedles is that the passageways may become easily
obstructed or clogged during use.
[0006] As a result, a need exists for microneedle arrays that
include fluid passageways that are easier to manufacture and that
are resistant to obstruction or clogging during use.
[0007] Among the uses for microneedle arrays, penetration of skin
is one commonly-discussed application. Skin is a three-layer
protective barrier between the body and the outside world. At
approximately 200 um thick, the epidermis is the thinnest,
outermost layer of the skin and it contains many of the components
that give skin it barrier-like characteristics. The outermost layer
of the epidermis, the stratum corneum, is a thin layer (10-50 um)
of flattened, dead cells, water, and lipids that helps the body
retain water and prohibits the entrance of microorganisms and toxic
chemicals. The stratum corneum, sometimes called the "horny layer"
is both tough and flexible, with a significant degree of
elasticity. These characteristics make the stratum corneum an
effective barrier, resistant to penetration. There is significant
variability in the thickness and elasticity of the stratum corneum
associated with age and location on the body. For example, the
stratum corneum of the feet is over ten times thicker than that
found on the forearm of a typical human.
[0008] Beneath the epidermis is the dermis which houses blood
vessels and nerve endings, hair shafts and sweat glands. Thousands
of small capillaries (loop capillaries) feed the upper levels of
the dermis, beneath the epidermis. These capillaries extend just
above most of the nerve endings that also reside in the dermis. The
deepest layer of skin, the hypodermis, insulates the body from
extreme temperatures and provides a mechanical cushion from outside
assaults. The hypodermis contains larger blood vessels and arteries
and more nerves.
[0009] Delivery of substances into the skin or removal of fluids
through the skin may be facilitated by the use of microneedle
arrays. One problem associated with penetration of skin by
microneedle arrays is, however, the viscoelastic properties of
skin. When subjected to static or slow-moving loads, skin elongates
before rupture.
[0010] As a result, many situations requiring the extraction of
fluids, e.g., blood-glucose monitoring, required the use of sharp
instruments such as lancets that pierce the skin. Such devices are,
however, relatively painful to use and may pose a risk of
inadvertent piercing of skin. Further, the pierced site may
experience unnecessary bleeding.
SUMMARY OF THE INVENTION
[0011] The present invention provides microneedle arrays, methods
of manufacturing molds for microneedle arrays, and methods of
manufacturing microneedles from the molds. The microneedles in the
microneedle arrays are tapered structures that include at least one
channel formed in the outside surface of each microneedle. The
channels may assist in the delivery or removal of fluids using the
microneedle arrays.
[0012] In some embodiments, the microneedles include bases that are
elongated in one direction. Such a configuration may provide
microneedles with improved rigidity and structural integrity as
compared to microneedles that do not include elongated bases.
Further, the channels in microneedles with elongated bases may
extend from one of the ends of the elongated bases towards the tips
of the microneedles. That configuration may also provide channeled
microneedles with improved rigidity and structural integrity as
compared to channeled microneedles that do not include elongated
bases.
[0013] In other embodiments, the channels formed along the sides of
the microneedles may optionally be terminated short of the tips of
the microneedles to improve the structural integrity of the tips
and potentially improve their piercing ability.
[0014] The microneedle arrays of the present invention may also
include conduit structures formed on the surface of the substrate
on which the microneedle array is located. The channels in the
microneedles may preferably be in fluid communication with the
conduit structures to potentially assist with the delivery or
removal of fluids through the channels. The conduits may be formed
as depressions or grooves in the substrate surface or they may be
formed by barriers, similar to dikes, that protrude above the
substrate surface.
[0015] The microneedle arrays of the invention may be used in a
variety of different manners. One manner of using microneedle
arrays of the present invention is in methods involving the
penetration of skin to deliver medicaments or other substances
and/or extract blood or tissue. As discussed above, it may be
desired that the height of the microneedles in the microneedle
arrays be sufficient to penetrate the stratum corneum.
[0016] In addition to having a sufficient length, it may be
preferred to provide the microneedle arrays in combination with
devices that are capable of delivering the microneedle arrays to
the skin in a manner that results in effective piercing of the
stratum corneum. To do so, it may be preferred to apply a brief
impact force to the microneedle array such that the microneedles on
the array are rapidly driven into the stratum corneum.
[0017] It should be understood that impact delivery of microneedle
arrays as discussed herein may not necessarily be limited to
microneedle arrays that include microneedles with channels as
described in connection with FIGS. 1-4. The impact delivery devices
and methods described herein may be used with many different
microneedle arrays.
[0018] In one aspect, the present invention provides a microneedle
device that includes a plurality of microneedles projecting from a
substrate surface, wherein each of the microneedles has a tapered
shape with an outer surface, a base proximate the substrate
surface, and a tip distal from the base, and further wherein the
base is elongated along an elongation axis on the substrate surface
such that the base has opposing ends along the elongation axis.
Each microneedle also includes a channel formed in the outer
surface of each microneedle of the plurality of microneedles, each
channel extending from the base towards the tip of the
microneedle.
[0019] In another aspect, the present invention provides a
microneedle device that includes a plurality of microneedles
projecting from a substrate surface, wherein each of the
microneedles has a tapered shape with an outer surface, a base
proximate the substrate surface and a tip distal from the base.
Each of the microneedles also includes a channel formed in the
outer surface of each microneedle of the plurality of microneedles,
each channel extending from the base of the microneedle towards the
tip of the microneedle, wherein the channel terminates short of the
tip of the microneedle.
[0020] In another aspect, the present invention provides a method
of delivering a microneedle array to a skin impact site by
positioning a microneedle array proximate a delivery site, the
microneedle array including a plurality of microneedles protruding
from a surface; and applying an impact force to the microneedle
array over a period of less than about 1 second, wherein the
plurality of microneedles are driven through the stratum corneum at
the skin impact site.
[0021] In another aspect, the present invention provides a
microneedle array delivery device that includes a microneedle array
having a plurality of microneedles protruding from a surface; a
driver operably connected to the microneedle array, wherein the
driver has stored energy; wherein release of the stored energy
results in application of an impact force to the microneedle array
over a period of less than about 1 second.
[0022] These and other features and advantages of the invention may
be described below in connection with various illustrative
embodiments of the invention.
BRIEF DESCRIPTION OF THE FIGURES
[0023] FIG. 1 is a perspective view of one microneedle array
according to the present invention.
[0024] FIG. 2 is a partial cross-sectional view of two microneedles
in a microneedle array according to the present invention.
[0025] FIGS. 2A-2C are cross-sectional views of microneedles with
differently shaped bases according to the present invention.
[0026] FIGS. 2D and 2E are cross-sectional views of alternative
microneedles.
[0027] FIG. 3 is an enlarged cross-sectional view of one
microneedle of FIG. 2 taken along line 3-3 in FIG. 2.
[0028] FIG. 4 is a cross-sectional view of a microneedle including
a channel that terminates short of the tip of the microneedle.
[0029] FIG. 5 is a diagram of one process for manufacturing
microneedle arrays according to the present invention.
[0030] FIG. 6 illustrates one mask useful in manufacturing a
microneedle array according to the present invention.
[0031] FIG. 7 depicts use of a microneedle array in a manner
according to the present invention.
[0032] FIG. 8 depicts contact between the microneedle array and
skin as depicted in FIG. 7.
[0033] FIG. 9 is a schematic diagram of one device for delivering
microneedle arrays in accordance with methods of the present
invention.
[0034] FIG. 10 depicts application of vacuum in connection with
methods of the present invention.
DETAILED DESCRIPTION OF THE ILLUSTRATIVE EMBODIMENTS OF THE
INVENTION
[0035] The present invention provides a microneedle array that may
be useful for a variety of purposes. For example, the microneedles
may be used to deliver or remove fluids from the point at which
they are inserted. To accomplish that goal, the microneedles
include a channel formed in the outer surface of a tapered
structure. The channel extends from a base or near a base of the
microneedle towards the tip of the microneedle. The channel is
typically formed as a void running along the side of the
microneedle. In some embodiments, the channel may extend to the tip
of the microneedle and, in other embodiments, the channel may
terminate before reaching the tip.
[0036] The channels formed in microneedles of the present invention
can be distinguished from bores or vias formed in known
microneedles because they are open along substantially their entire
length, e.g., from the base of the microneedle to the terminus of
the channel. In contrast, bores or vias formed in known
microneedles typically are closed fluid pathways that have an
opening at the tip of the needle structure.
[0037] In some embodiments, the bases of the microneedles may be
elongated to improve the rigidity and structural integrity of the
microneedles. In the microneedles with bases that are elongated
along an elongation axis, it may be preferred that the channels
extend from one of the opposing ends located along the elongation
axis.
[0038] Additional features that may be included in the microneedle
arrays of the present invention are conduit structures in fluid
communication with the channels formed in the microneedles. The
conduit structure may be used to deliver fluids to the channels in
the microneedles or they may be used to remove fluids from the
channels of the microneedles. In some situations, the conduits and
channels may both deliver and remove fluids from microneedle
insertion sites.
[0039] The microneedle arrays of the present invention may be used
for a variety of purposes. For example, the microneedles may be
used to deliver drugs or other pharmacological agents through the
skin in a variation on transdermal delivery. Where the microneedles
are to be used for transdermal drug delivery, the height of the
microneedles is preferably sufficient to pass through the stratum
corneum and into the epidermis. It is also, however, preferable
that the height of the microneedles is not sufficiently large to
reach the dermis, thereby avoiding contact with nerves and the
corresponding potential for causing pain.
[0040] In addition to transdermal drug delivery, the microneedle
arrays of the present invention may also find use as a mechanical
attachment mechanism useful for attaching the microneedles arrays
to a variety of surfaces. For example, the microneedle arrays may
be used to affix a tape or other medical device to, e.g., the skin
of a patient.
[0041] As used in connection with the present invention, the term
"microneedle" (and variations thereof) refers to structures having
a height above the surface from which they protrude of about 500
micrometers or less. In some instances, microneedles of the present
invention may have a height of about 250 micrometers or less.
[0042] Referring now to FIG. 1, a portion of one array of
microneedles 20 is illustrated as arranged in rows extending in the
y direction on the surface 12 of a substrate 10. The microneedles
20 may preferably be arranged in successive rows that are, in the
depicted embodiment, uniformly spaced apart in the x direction. The
microneedles 20 each include a channel 22 formed in the outer
surface of the tapered microneedle.
[0043] Each of the channels 22 may be in fluid communication with
an optional conduit structure formed on the substrate surface 12
along each row of microneedles 20. The conduit structures include
branch arteries 32 in direct communication with the channels 22,
and the branch arteries 32 are in fluid communication with each
other through at least one main artery 34 of the conduit structures
as depicted in FIG. 1.
[0044] The conduit structure may be formed in any suitable manner
that defines fluid pathways on the substrate surface 12. The
conduit structure may, for example, be formed using barriers 36
that project from the substrate surface 12. One alternative for
forming conduit structure is to form depressions or grooves into
the substrate surface 12. In some instances, the conduit structure
may be formed by any suitable combination of protruding barriers
and depressions. In other instances, the conduit structure may, in
fact, include no structure, but rather be provided in the form of a
pattern of low surface energy on the substrate surface 12. The low
surface energy may be provided by, e.g., coatings, surface
treatments, etc.
[0045] Referring to FIGS. 1, 2 and 3, each of the microneedles 20
includes a base 26 on the substrate surface 12, with the
microneedle terminating above the substrate surface in a tip 24.
The base 26 may be formed in any suitable shape, although in some
embodiments the base 26 may have a shape that is elongated along an
elongation axis 11 on the substrate surface 12 as seen, e.g., in
FIG. 2. The elongated base 26 includes two opposing ends located
opposite from each other along the elongation axis 11. By providing
microneedles 20 with an elongated base 26, the microneedles 20 may
exhibit improved rigidity and/or structural integrity during use,
particularly when subjected to forces aligned along the elongation
axis 11.
[0046] In the depicted embodiment, the channel 22 is located in one
of the opposing ends of the microneedle 20, where the opposing ends
are located on opposing sides of the base 26 along the elongation
axis 11. Such a construction may enhance the ability of the
microneedle 20 to withstand shearing forces along the substrate
surface 12 in the elongated direction of the base 26.
[0047] Although the elongated microneedle base 26 illustrated in
FIG. 3 is oval in shape, it will be understood that the shape of
the microneedles 20 and their associated bases 26 may vary with
some bases, e.g., being elongated along one or more directions and
others being symmetrical in all directions.
[0048] For example, FIG. 2A depicts an alternative microneedle 120
with a egg-shaped base 126 defining an axis of elongation 111 that
is aligned between opposing ends of the elongated base 126. A
channel 122 extends from the base 126 towards the tip 124 of the
microneedle 120. It should be understood that the tip 124 is only
an illustration of the location of the tip projected onto the base
of the microneedle 120.
[0049] FIG. 2B depicts another microneedle 220 having a tip 224
(again, a projection of the tip) and an oval-shaped base 226 in
which the channel 222 is located at an intermediate location
between the opposing ends of the base 226 (as defined by the
elongation axis 211). This embodiment depicts a microneedle in
which the channel 222 is not located in one of the opposing ends of
the microneedle 220, rather, the channel 222 is located
intermediate, i.e., between the opposing ends of the base 226.
[0050] FIG. 2C depicts another microneedle 320 according to the
present invention in which the microneedle 320 has a tip 324
(again, a projection of the tip) and a circular base 326 with two
channels 322a and 322b formed in the microneedle 320. Microneedles
of the present invention may include only one channel (as depicted
in, e.g., FIGS. 1, 2, 2A, and 3B) or they may include more than one
channel as depicted in FIG. 2C.
[0051] The general shape of the microneedles of the present
invention is tapered. For example, the microneedles 20 have a
larger base 26 at the substrate surface 12 and extend away from the
substrate surface 12, tapering at a tip 24. It may be preferred,
e.g., that the shape of the microneedles be generally conical.
[0052] Although the microneedles depicted in FIG. 2 have a uniform
slope or wall angle (with respect to, e.g., a z axis normal to the
substrate surface 12), microneedles of the present invention may
have different wall angles. For example, FIG. 2D is a
cross-sectional view of one microneedle 420 including a lower
section 425 having steeper wall angles with respect to the
substrate surface 412, and an upper section 426 having shallower
wall angles proximate the tip 424 of the microneedle 420.
[0053] Another variation, depicted in FIG. 2E, is that the surface
of the microneedles of the present invention need not necessarily
be smooth. The sidewalls 527 of the microneedles 520 may, instead,
be stepped as seen in FIG. 2E as the sidewalls move from the
substrate surface 512 to the tip 524 of the microneedle 520.
[0054] One manner in which the microneedles of the present
invention may be characterized is by height. The height of the
microneedles 20 may be measured from the substrate surface 12 or
from the top surface of the barriers 32 forming conduits 30. It may
be preferred, for example, that the base-to-tip height of the
microneedles 20 be about 500 micrometers or less as measured from
the substrate surface 12. Alternatively, it may be preferred that
the height of the microneedles 20 the about 250 micrometers or less
as measured from the base 26 into the tip 24.
[0055] Other potentially preferred dimensions for the microneedles
20 may be discussed with reference to FIG. 3. It may be preferred
that the largest dimension of the base 26 of microneedles 20 with
an elongated oval base be approximately 100 micrometers or less,
while the shorter dimension of the base 26 of microneedle 20 be
about 65 micrometers or less. These dimensions apply to
microneedles with a base to tip height of approximately 220
micrometers.
[0056] Some exemplary dimensions for the channel 22 of microneedles
20 may also be described with reference to FIGS. 2 and 3. These
dimensions are provided as examples only, and are not intended to
limit the scope of the invention unless explicitly recited in the
claims. The width of the channel 22 (as measured along the shorter
dimension of the base 26) may, for example, be about 3 to about 40
micrometers.
[0057] Further, although the channels associated with microneedles
of the present invention are depicted as having relatively smooth
surfaces (see, e.g., FIGS. 2, 3, 2A-2C), the channels may
preferably have a surface that is not smooth, e.g., the surfaces of
the channels may be roughened, structured, etc. to enhance fluid
flow.
[0058] Another manner in which microneedles having an elongated
base may be characterized is in the relationship between the
dimensions of the base and the channel. Referring to FIG. 3, it may
be preferred that the channel 22 have a channel depth measured
along the elongation axis 11 at the base of the microneedle 20 that
is less than half of the dimension of the base 26 of the
microneedle 20 as measured along the elongation axis 11.
[0059] The length of the channel 22 along microneedles 20 may also
a vary. It may, for example, be preferred that the height of the
channel 22, i.e., its length from the base 26 to the point at which
the channel 22 terminates, may preferably be less than the base to
tip height of the microneedle 20. By terminating the channel 22
short of the microneedle tip 24, the integrity of the tip 24 may be
better maintained. In addition, the tip 24 of the microneedle 20
may be sharper, thereby potentially improving the ability of the
microneedle 20 to pierce a surface or material against which it is
pressed.
[0060] The microneedles 20 are each depicted with one channel 22
formed along a side the thereof. It should, however, be understood
that microneedles of the present invention may be formed with more
than one channel as discussed above. It will, also be understood
that in such circumstances, the size of the channels may be reduced
relative to the overall size of the microneedles to improve the
structural characteristics of the microneedle.
[0061] In addition to (or in place of) elongating the base of the
microneedles to improve their structural characteristics, that
channel or channels provided in the microneedles may be terminated
short of the tip of the microneedle. Doing so may improve the
structural characteristics of the microneedles and/or may also
improve the sharpness or penetration characteristics of the
microneedles. Referring to FIG. 4, one example of a microneedle 620
is depicted in cross-section. The microneedle 620 includes a
channel 622 that terminated short of the tip 624 of the microneedle
620. Although only one channel is depicted in the microneedle 620
of FIG. 4, it will be understood that more than one channel could
be provided.
[0062] Returning to FIG. 2, two of the barriers 36 used to form
conduit structure as seen in FIG. 1 are depicted in cross-section.
The barriers 36 are provided in the form of projections from the
substrate surface 12 similar to the microneedles 20. The barriers
36 that form the opposite sides of the branch arteries 32 of the
conduit structure are not depicted in FIG. 2 because they are
either outside the depicted view (on the left side) or hidden
behind the left-most microneedle.
[0063] As with the microneedles 20, the dimensions associated with
the barriers and conduit structure formed by the barriers 36 may
vary depending on the applications for which the microneedle arrays
are intended. For example, it may be preferred that the distance
between barriers 36 forming one of the branch arteries 32 in direct
fluid communication with the channels 22 in the microneedles be
spaced apart from each other by a distance that is equivalent to or
less than the smallest dimension of the channel 22 at the base 26
of the microneedle 20 as seen in, e.g., FIG. 3. In channel 22 of
FIG. 3, the smallest dimension of the channel 22 is transverse to
the axis 11.
[0064] By providing barriers 36 with that spacing, capillary action
between the channels 22 and the branch arteries 32 may be enhanced.
Such a relationship is depicted in, e.g. FIG. 3, where the distance
between the barriers 36 along axis 11 that form the branch artery
32 is less than the depth of the channel 22 along the axis 11.
[0065] In another manner of characterizing the barriers 36, it may
be preferred that the height of the barriers 36 above the substrate
surface 12 be selected such that the barriers 36 do not interfere
with penetration of a surface by the microneedles 20. In other
words, the barrier height should not prevent the microneedles from
reaching a desired depth.
[0066] A potential advantage of the barriers 36 forming the conduit
structures is that the barriers 36 may provide a sealing function
when the array is in position against, e.g., the skin of a patient.
By sealing the fluid paths into and/or out of the channels in the
microneedles 20, additional control over fluid flow within the
array may be achieved.
[0067] The microneedles 20 and conduit structure may preferably be
manufactured integrally with the substrate 10. In other words, the
microneedles 20, conduit structure 30, and substrate 10 are
preferably formed as a one piece, completely integral unit.
Alternatively, the microneedles and/or conduit structures may be
provided separately from the substrate 10.
[0068] The microneedle arrays may be manufactured from a variety of
materials. Material selection may be based on a variety of factors
including the ability of the material to accurately reproduce the
desired pattern; the strength and toughness of the material when
formed into the microneedles; the compatibility of the material
with, for example, human or animal skin; the compatibility of the
materials with any fluids to be delivered or removed by the
channels formed in the microneedles, etc. For example, it may be
preferred that the microneedle arrays of the present invention be
manufactured of one or more metals.
[0069] Regardless of the materials used for the microneedle arrays
of the present invention, it may be preferred that the surfaces of
the microneedle array that are likely to come into contact with
fluids during use have certain wettability characteristics. It may
be preferred that these surfaces are hydrophilic, e.g., exhibit a
static contact angle for water of less than 90 degrees (possibly
less than about 40 degrees), so that the fluid can be spontaneously
wicked via capillary pressure. The hydrophilic nature of the
surfaces may be provided by selection of materials used to
manufacture the entire microneedle array, surface treatments of the
entire array or only those portions likely to come into contact
with fluids, coatings on the entire array or only those portions
likely to come into contact with fluids, etc.
[0070] Microneedles in the microneedle arrays of the present
invention can be solid or porous. As used herein, the term "porous"
(and variations thereof) means having that the microneedles include
pores or voids through at least a portion of the structure, wherein
those pores or voids are sufficiently large and interconnected to
permit at least fluid passage.
[0071] One preferred process for forming microneedle arrays
according to the present invention is illustrated in FIG. 5.
Briefly, the method involves providing a substrate 40, forming a
structured surface in the substrate 42, the structured surface
including cavities having the shape of the desired microneedles and
any other features (e.g., barriers for the conduits). A metallic
microneedle array can then be electroformed on the structured
surface 44, followed by separation of the structured surface from
the metallic microneedle array 46.
[0072] FIG. 5 illustrates the formation of a structured surface in
a substrate as the initial activity. Although the preferred method
of manufacturing microneedle arrays according to the present
invention involves laser ablation of a mold substrate (using, e.g.,
an excimer laser) to provide cavities in the shape of the desired
microneedles, it should be understood that any suitable method of
forming cavities in the desired shape may be substituted for the
method described herein. For example, the cavities may be formed by
conventional photolithography, chemical etching, ion beam etching
etc. The preferred laser ablation lithography techniques constitute
only one method of forming the desired microneedles arrays.
[0073] The process of forming the structured surface begins with a
substrate having sufficient thickness to allow the formation of a
structured surface having needle cavities of the desired depth. The
depth of the needle cavities controls the height of the
microneedles. As a result, the substrate used to form the
structured surface must have a thickness that is at least equal to
or greater than the desired height of the microneedles. Preferably,
the substrate used to form the structured surface has a thickness
that is greater than the desired height of the microneedles.
[0074] Examples of suitable materials for mold substrates used in
connection with the present invention include, but are not limited
to, polyimide, polyester, polyurethane epoxy, polystyrene,
polymethylmethacrylate, and polycarbonate. Regardless of the exact
material or materials, it may be preferred that the mold substrate
be free of any inorganic fillers, e.g., silica, iron fibers,
calcium carbonate, etc. One preferred mold substrate material is a
polyimide, e.g., KAPTON H or KAPTON E from DuPont (Wilmington,
Del.), because of its ablation properties when exposed to energy
from excimer lasers.
[0075] In the case of films that are not thick enough to serve as a
mold substrate, two or more of the films may be laminated together
to provide a mold substrate of suitable thickness. If a bonding
agent (e.g., an adhesive) is used to laminate two films together,
it may be preferred that the bonding agent possess optical and/or
ablation properties similar to the films. Those material properties
may include, for example, energy absorption coefficient at a
selected wavelength, a uniform index of refraction; a low level of
crystallinity; etc. In addition, it may be preferred that the
bonding agent be free of inorganic components, e.g., silica, iron
fibers, calcium carbonate, etc.
[0076] The laminated substrate preferably contains no voids between
films and possesses good interlayer adhesion. As a result, it may
be preferred to laminate the films at elevated temperatures, under
some pressure, and/or in a vacuum. Further, it may be desirable to
treat the surface of one or more of the films to promote adhesion
and to limit void formation. One example of a potentially desirable
treatment is plasma etching, although many other surface treatments
may be used in place of, or in addition to, plasma etching.
[0077] One potentially preferred method of preparing a laminated
polyimide substrate includes laminating two polyimide films using
an epoxy (e.g., PR-500 available from Minnesota Mining and
Manufacturing Company, St. Paul, Minn.). Prior to application of
the epoxy, the surfaces of the films are plasma etched. The epoxy
may preferably be coated in a solvent solution to, e.g., enhance
uniformity of the epoxy layer after evaporation of the solvent.
Following drying of the epoxy/solvent solution, the films are
laminated together under heat and pressure, preferably in a
sub-atmospheric pressure environment. The temperature at which the
lamination is carried out is preferably high enough to melt the
epoxy (i.e., at or above the T.sub.m of the epoxy), thereby
enhancing bubble removal and uniform thickness of the epoxy
layer.
[0078] After a substrate of sufficient thickness has been obtained
(through lamination or otherwise), it may be desirable to laminate
the substrate to a base layer to support the substrate during laser
ablation or other techniques used to form the structured surface.
The base layer preferably maintains the substrate in a
substantially planar configuration during processing to hold the
substrate within, e.g., the object plane of the laser ablation
system during ablation. The base layer may, for example, be glass
or any other suitable material. It may further be preferred that
the surface of the base layer to which the substrate is laminated
have a flatness on the order of 10 micrometers. The substrate may
be laminated to the base layer using any suitable technique
including, but not limited to, adhesives, curable resins, etc.
[0079] After the substrate is attached to the base layer, it is
processed to form a structured surface including needle cavities in
the shape of the desired microneedles. As discussed above, one
preferred process of forming the cavities is laser ablation using a
mask. A method of using such mask in connection with laser energy
will be described below, although it should be understood that,
unless otherwise indicated, preparation of the structured surface
is not to be limited to the use of laser energy.
[0080] One example of a mask pattern useful for forming a
structured surface for the eventual production of an array of
microneedles with channels and conduits in fluid communication with
the channels is depicted in FIG. 6. The mask pattern includes one
row of needle apertures 350 aligned in the x direction as seen in
FIG. 6. The row of needle apertures 350 is interconnected by one
set of barrier apertures 354 corresponding to the barriers in the
conduit structures. The barrier apertures 354 extend in both the x
and y directions, i.e., along the row of needle apertures 350 and
in the y direction at the ends of the barrier apertures. The
portions of the barrier apertures 354 that extend in the y
direction are used to form the barriers of the main arteries (see,
e.g., FIG. 1).
[0081] In addition, each of the needle apertures 350 includes a
channel feature 352 corresponding to the desired location of the
channel on the microneedle corresponding to the needle
aperture.
[0082] The mask itself may, e.g., be manufactured using standard
semiconductor lithography mask techniques. The patterned portions
of the mask are opaque to the laser energy used to pattern the
substrate, e.g., ultraviolet light in the case of excimer laser
energy. The mask may include a support substrate that is
transparent to the laser energy. For example, the patterned
portions may be formed of aluminum while the support substrate is
fused silica. One alternative for the aluminum may be a dielectric
stack that is opaque for light of the desired wavelengths.
[0083] The needle apertures 350 in the mask are preferably arranged
in successive rows that are uniformly spaced apart (along the x
axis). It is further preferred that the spacing between the needle
apertures along the rows are also uniform (along the y axis). With
uniform spacing between the needle apertures and associated conduit
apertures, laser ablation processes similar in many respects to
those described in International Publication No. WO 96/33839
(Fleming et al.) and its U.S. priority applications, can be used to
form cavities in the substrate.
[0084] One of the ways in which the preferred laser ablation
process differs from that disclosed in WO 96/33839 is that a
telecentric imaging system is used to deliver laser energy to the
mask. The telecentric imaging system provides principal rays that
are parallel to the optical axis. As a result, the image does not
change size when out of focus. In addition, projected features at
the center of the mask are the same size as those found at the
edges of the mask.
[0085] By providing both the needle apertures and the barrier
apertures in the same mask, the present invention provides a number
of advantages. Among those advantages is the ability to provide
microneedles and the associated conduit structures in registration
with each other because the features can be imaged at the same
time. This can be particularly important in producing devices such
as microneedle arrays in which the features are spaced apart in
distances measured in micrometers.
[0086] Control over the depth of the different cavities formed in
the substrate (corresponding to the different heights of the
microneedles and barriers on the microneedle arrays) can be
obtained by, e.g., selectively covering or masking the different
features on the mask while ablating the underlying substrate
through the apertures that are not covered or masked. That process
can be used, e.g., to obtain barrier cavities that are shallower
than the microneedle cavities.
[0087] Use of the mask pattern depicted in FIG. 6, for example, may
proceed with a first exposure of the substrate located beneath
portion A of the mask pattern, i.e., the row of needle apertures
350 interconnected by the barrier apertures 354. As a result, the
substrate is exposed during the first exposure in a pattern
corresponding to portion A of the mask pattern.
[0088] Movement of the mask pattern and the substrate being exposed
relative to each other in the y direction can then be used to align
the mask apertures 350 in the uppermost row of portion B with the
parts of the substrate exposed by the needle apertures 350 in
portion A during the first exposure. A second exposure then results
in another exposure through the needle apertures to ablate more of
the substrate, thereby increasing the depth of the needle cavities
in the substrate without also increasing the depth of the barrier
cavities. Step-wise movement and exposure can then be repeated
until the needle cavities and the barrier cavities are formed to
the desired depth in the substrate.
[0089] Control over the wall angles of the needle cavities may be
achieved by any suitable technique or combination of techniques.
Examples of suitable techniques may be described in, e.g., T.
Hodapp et el., "Modeling Topology Formation During Laser Ablation,"
J. Appl. Physics, Vol. 84, No. 1, pp. 577-583 (Jul. 1, 1998).
[0090] When processing a polyimide mold substrate through laser
ablation, it may be preferred that the mold substrate be located in
an oxygen atmosphere to improve subsequent plating of the cavities
thus formed.
[0091] After completion of the structured surface, the substrate
provides a negative of the desired microneedle array structure,
with needle cavities corresponding to the shape of the microneedles
and conduit cavities corresponding to the desired shape of the
conduit structures. As for the needle cavities, they are preferably
generally tapered in shape, with a channel structure extending into
the tapered shape of the needle cavity.
[0092] The resulting mold substrate is then preferably
electroplated to form a metallic positive of the microneedle array.
Before electroplating, however, the substrate may preferably be
cleaned to remove any debris that is, e.g., associated with the
laser ablation processing used to form the negative image in the
substrate. One suitable cleaning process may include locating the
substrate in an ultrasonic bath of detergent and water, followed by
drying.
[0093] After cleaning the mold substrate, a seed layer of one or
more conductive metals is preferably first deposited to provide a
conductive surface, followed by heavier electroplating in, e.g., a
nickel bath. The seed layer may be deposited by sputtering,
chemical vapor deposition, a silver bath, or any other suitable
method. To enhance proper filling of the cavities and fidelity of
the resulting microneedles to the shape of the cavities, it may be
preferred that the seeding be continued until a thicker seed layer
is deposited. For example, it may be preferred that the seed layer
be deposited with a thickness of about 0.5 micrometers or more,
possibly even about 1 micrometer.
[0094] Following formation of the seed layer, the seeded mold
substrate can then be electroformed with a thicker layer of, e.g.,
nickel, to form a metallic microneedle array. After filling the
cavities in the mold substrate, the plating process is preferably
continued until a backplate is formed on the mold substrate with a
thickness sufficient to support the microneedle array. For example,
a backplate with a thickness of about 0.5 millimeters to about 3
millimeters or more may be formed. If desired, the surface of the
backplate opposite the microneedle structures may be polished. That
polishing may preferably be carried out while the substrate is
still attached to a base layer as described above.
[0095] After the metallic microneedle array is formed, the mold
substrate can be removed from the microneedle array by any suitable
technique or combination of techniques. Some suitable techniques
include, but are not limited to, chemical etching, shock freezing,
laser ablation, etc. For example, a polyimide substrate may be
removed from a microneedle array using an etchant, e.g., potassium
hydroxide (KOH).
[0096] Because the needle cavities in the structured surface may
have a relatively high aspect ratio, it may be desirable to use an
electroplating process capable of accurately filling the high
aspect ratio cavities. For example, it may be desirable to carry
out the electroplating process in the presence of ultrasonic energy
for at least a portion of the electroplating. Examples of some
suitable systems for and processes of electroplating in the
presence of ultrasonic energy may be described in e.g., U.S. Pat.
No. 6,746,590 (H. Zhang et al.).
[0097] The microneedle arrays of the invention may be used in a
variety of different manners. One manner of using microneedle
arrays of the present invention is in methods involving the
penetration of skin to deliver medicaments or other substances
and/or extract blood or tissue. As discussed above, it may be
desired that the height of the microneedles in the microneedle
arrays be sufficient to penetrate the stratum corneum.
[0098] Microneedle Array Delivery
[0099] In addition to having a sufficient length, it may be
preferred to provide the microneedle arrays in combination with
devices that are capable of delivering the microneedle arrays to a
skin impact site in a manner that results in effective piercing of
the stratum corneum by the microneedles on the array. Delivery of a
microneedle array in accordance with the methods of the present
invention will involve application of an impact force to the
microneedle array over a short period of time (typically less than
about 1 second) such that the microneedles of the array are driven
through the stratum corneum at the skin impact site. Application of
the impact force may rapidly accelerate the microneedle arrays of
the present invention such that impact delivery of the microneedle
array with the skin is achieved.
[0100] It should be understood that impact delivery of microneedle
arrays as discussed herein may not necessarily be limited to
microneedle arrays that include microneedles with channels as
described above in connection with FIGS. 1-6. The impact delivery
devices and methods described herein may be used with many
different microneedle arrays.
[0101] Referring to FIG. 7, one method of forcing a microneedle
array 60 including microneedles 62 is depicted, with the
microneedle array 60 being forced against the skin 70 (with stratum
corneum 72) by an impact force 64. FIG. 8 depicts the microneedle
array 60 in contact with the skin 70, such that the microneedles 62
penetrate the stratum corneum 72.
[0102] The impact force magnitude and duration period are selected
to provide effective penetration of the stratum corneum by the
microneedles. It may be preferred that the period of time over
which the impact force is applied be less than about 500
milliseconds, in some instances, the period may preferably be about
300 milliseconds or less.
[0103] The impact force may be applied in a variety of manners. For
example, the microneedle array 60 may be positioned a distance from
the skin impact site, such that application of the impact force 64
results in acceleration of the microneedle array 60 towards the
skin impact site until the microneedle array contacts the skin
impact site. In another example, the microneedle array may be
positioned in contact with the skin impact site before the impact
force is applied to the microneedle array, such that application of
the force does not result in acceleration as would be achieved if
the microneedle array is positioned away from the skin.
[0104] After application of the impact force and subsequent driving
of the microneedles through the stratum corneum, it may be desired
to remove the microneedle array from contact with the skin impact
site within about 1 second or less. In other instances, it may be
desirable to retain the microneedle array in contact with the skin
impact site for a longer period of time, e.g., about 2 seconds or
more.
[0105] The maximum magnitude of the impact force may preferably be
limited to, e.g., control the pain associated with impact delivery
of microneedles arrays in connection with the present invention.
For example, it may be preferred to provide impact delivery of the
microneedle arrays of the present invention with a maximum impact
force about 40 N/cm.sup.2 or less, more preferably about 20
N/cm.sup.2.
[0106] At the other end of the force spectrum, the minimum impact
force may vary depending on a variety of factors such as the size
of the microneedle array, the size and/or shape of the
microneedles, etc.
[0107] A wide variety of devices may be used to provide the desired
impact delivery of microneedle arrays with the skin of a subject.
One such device 68 is illustrated schematically in FIG. 9 as
including a microneedle array 60 and a driver 66. The device 68 may
be a single-use disposable design, it may be designed for using a
single microneedle array 60, or it may be designed to use multiple
different microneedles arrays 60.
[0108] The driver 66 may be provided by any mechanism capable of
applying the desired impact force needed to drive the microneedles
into the stratum corneum as discussed above. The driver 66 may be
in the form of any device capable of releasing stored energy in the
form of the impact force over the durations discussed above, i.e.,
over a period of less than about 1 second. For example, the driver
66 may include a mechanical spring (e.g., a coil spring, leaf
spring, etc.), compressed resilient member (e.g., rubber, etc.),
compressed fluids (e.g., air, liquids, etc.), piezoelectric
structure, electromagnetic structure, hammer device, etc.
[0109] One example of a potentially suitable device 68 may include
a lancet driver incorporating a mechanical spring which may be
modified, if needed, to provide the desired force to the
microneedle array. Typically, a lancet driver may also require some
modifications to ensure that the microneedle array is forced
against the skin in a manner such that substantially all of the
microneedles contact the skin.
[0110] Following impact delivery of a microneedle array according
to the present invention, it may be desirable to provide vacuum
over the surface of the skin impacted by the microneedle array.
Application of vacuum to the impact site can be used to extract
blood or fluid from the skin penetrated by the microneedles.
[0111] Referring to FIG. 10, a vacuum cup 90 is depicted over the
skin impact site as depicted in, e.g., FIG. 8. The vacuum cup 90
may preferably include a port 94 that allows for evacuation of the
volume 92 defined by the vacuum cup 90. As used in connection with
the present invention, "vacuum" is defined as a pressure below the
ambient atmospheric pressure surrounding the vacuum cup. The vacuum
may be provided by any suitable source, e.g., a pump, syringe,
etc.
[0112] The microneedles driven into the stratum corneum at the skin
delivery site may provide fluid pathways through the stratum
corneum. A vacuum applied over the skin delivery site after the
microneedles have been driven into the stratum corneum may enhance
the passage of fluids through the stratum corneum within the skin
delivery site.
[0113] The ability of the vacuum drawn within volume 92 to draw
fluids through the skin in the skin impact site may be used for a
variety of purposes. For example, an indicator 80 capable of
detecting the presence or absence of substances or materials in
fluids drawn out from the skin impact site may be located on the
skin impact site. The indicator 80 may be placed in contact with
the skin delivery site before drawing the vacuum over that site or
after drawing the vacuum over the skin impact site.
[0114] For example, a blood glucose monitoring strip 80 may be
placed over the skin impact site with the fluid drawn through the
impact site activating the strip to provide a glucose reading. In
such a method, sufficient fluid may be drawn under, e.g.,
conditions of 0.5 atm of vacuum for less than 1 minute.
[0115] In addition to indicators for determining blood-glucose
levels, the device and methods of the present invention may be used
to extract fluid for other indicators such as those capable of
determining the presence, absence or amounts of a variety of
materials in fluids (e.g., blood) such as dissolved oxygen, carbon
dioxide, lactic acid, illicit drugs, etc.
[0116] Additionally, the demonstration of effective penetration of
the stratum corneum may provide a useful pathway for localized,
painless administration of pharmaceuticals. Topically applied
pharmaceuticals may be more effectively delivered through the skin
after penetration of the stratum corneum by the microneedle arrays
of the present invention. In other variations, the microneedle
array penetration may be coupled with an electrical or ultrasonic
device to deliver larger drugs through the skin more rapidly that
is possible through uncompromised tissue.
[0117] Where used for the delivery of medicaments or other
substances (or the removal of fluids), it may be desirable to
include one or more reservoirs in fluid communication with the
conduit structures formed in the microneedle arrays. Examples of
such reservoirs may be described in, e.g., U.S. Pat. No. 3,964,482
(Gerstel et al.). The reservoirs may be in fluid communication with
the conduit structures on the front side of the microneedle arrays
(i.e., the side from which the microneedles project) or they may be
in fluid communication with the conduit structure from the back
side (i.e., the side opposite the front side) through vias or other
fluid pathways.
[0118] All patents, patent applications, and publications cited
herein are each incorporated herein by reference in their entirety,
as if individually incorporated by reference. Various modifications
and alterations of this invention will become apparent to those
skilled in the art without departing from the scope of this
invention, and it should be understood that this invention is not
to be unduly limited to the illustrative embodiments set forth
herein.
* * * * *