U.S. patent application number 10/681777 was filed with the patent office on 2004-06-03 for microneedle array patch.
Invention is credited to Gonnelli, Robert R., McAllister, Devin V..
Application Number | 20040106904 10/681777 |
Document ID | / |
Family ID | 32093895 |
Filed Date | 2004-06-03 |
United States Patent
Application |
20040106904 |
Kind Code |
A1 |
Gonnelli, Robert R. ; et
al. |
June 3, 2004 |
Microneedle array patch
Abstract
Microneedle devices for transport of molecules, including drugs
and biological molecules, across tissue, are provided. The
microneedle devices permit drug delivery or removal of body fluids
at clinically relevant rates across skin or other tissue barriers,
with minimal or no damage, pain, or irritation to the tissue.
Microneedles can be formed of biodegradable or non-biodegradable
polymeric materials or metals. In a preferred embodiment, a
microneedle device includes a plugging element comprising a
platform including a plurality of microneedle plugs for preventing
skin or other tissue barriers from entering the hollow
microneedles. In another preferred embodiment, a microneedle device
includes a plurality of bioerodible elements for temporarily
plugging the hollow microneedles, thereby preventing skin or other
tissue barriers from entering the hollow microneedles.
Inventors: |
Gonnelli, Robert R.;
(Mahwah, NJ) ; McAllister, Devin V.; (Shrewsbury,
MA) |
Correspondence
Address: |
ROPES & GRAY LLP
ONE INTERNATIONAL PLACE
BOSTON
MA
02110-2624
US
|
Family ID: |
32093895 |
Appl. No.: |
10/681777 |
Filed: |
October 7, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60416740 |
Oct 7, 2002 |
|
|
|
Current U.S.
Class: |
604/173 |
Current CPC
Class: |
A61M 2037/0053 20130101;
A61B 17/205 20130101; A61M 2037/0038 20130101; A61M 2037/0046
20130101; A61M 37/0015 20130101; B33Y 80/00 20141201 |
Class at
Publication: |
604/173 |
International
Class: |
A61M 005/00 |
Claims
1. A delivery device for introducing a substance into or below the
stratum corneum of a patient, comprising a microneedle having a
distal end and an interior channel that extends to the distal end,
a pin dimensioned for slidably extending into the interior channel
and out the distal end, and an adhesive patch of the type capable
of adhering to biological tissue.
2. A delivery device according to claim 1, wherein the pin has an
arcuate distal end for piercing biological tissue.
3. A delivery device according to claim 1, comprising means for
sliding the pin into and out of the interior channel.
4. A delivery device according to claim 1, further comprising a
reservoir for storing a fluid substance to be introduce into the
biological tissue.
5. A delivery device according to claim 1, further comprising a
reservoir having a plurality of chambers.
6. A delivery device according to claim 1, further comprising a
pump for pumping a fluid through the interior channel.
7. A delivery device according to claim 6, further comprising a
flow controller for controlling the rate at which fluid flows
through the interior channel.
8. A delivery device according to claim 1, further comprising a
plug for insertion into a distal end of the channel to prevent
tissue from entering the channel.
9. A delivery device according to claim 8, wherein the plug
comprises a bioerodible material.
10. A delivery device according to claim 8, wherein the plug
comprises a barb for gripping to biological tissue.
11. A delivery device according to claim 1, wherein the microneedle
comprises an array of microneedles formed on a substrate.
12. A delivery device according to claim 1, wherein the pin
comprises an array of pins fixed to a substrate and arranged to be
co-axial with the interior channels of the array of
microneedles.
13. A delivery device according to claim 12, further comprising a
spring assembly for moving the springs axially within the interior
channels.
14. A delivery device according to claim 1, further comprising a
flange for coupling to the microneedle to an external device.
15. A delivery device according to claim 1, further comprising a
pump for drawing a sample through the interior channel.
16. A transdermal patch, comprising at least one microneedle having
an interior channel, a removable plug disposed at a distal end of
the interior channel, as an adhesive patch for adhering at least
one microneedle to biological tissue.
17. A method for introducing a substance into or below the stratum
corneum of a patient, comprising inserting into tissue of a patient
a microneedle having a distal end and an interior channel that
extends to the distal end, and sliding a pin dimensioned into the
interior channel and out the distal end.
18. A method according to claim 17, further comprising inserting a
plurality of microneedles into the tissue of a patient.
19. A method according to claim 17, further comprising pumping a
fluid through the microneedle.
20. A method according to claim 18, further comprising operating a
syringe for pumping the fluid.
Description
RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional
Application 60/416,740 entitled Microneedle Array Patch, the
contents of which are herein incorporated by reference.
BACKGROUND
[0002] This invention relates to injection devices, such as
microneedle devices having an array of microneedles for placing on
the skin.
[0003] Conventional methods of biological fluid sampling and
non-oral drug delivery are normally invasive. That is, the skin is
lanced to extract blood and measure various components when
performing fluid sampling, or a drug delivery procedure is normally
performed by injection, which causes pain and requires special
medical training. Alternatives to drug delivery by injection have
been disclosed, for example, by Henry, McAllister, Allen, and
Prausnitz, of Georgia Institute of Technology (in a paper titled
"Micromachined Needles for the Transdermal Delivery of Drugs"),
U.S. Pat. No. 3,964,482, WO 98/00193, WO 97/48440, WO 97/48441, and
WO 97/48442.
[0004] The use of microneedles has great advantages in that
intracutaneous drug delivery can be accomplished without pain,
leading to increased patient compliance, and without bleeding.
Further, patients may apply the drug delivery devices themselves
without extensive training. As used herein, the term "microneedles"
refers to a plurality of elongated structures that are sufficiently
long to penetrate through the stratum corneum skin layer and into
the epidermal layer, yet are also sufficiently short to not
penetrate to the dermal layer. However, if the dead cells have been
completely or mostly removed from a portion of skin, then a very
minute length of microneedle could be used to reach the viable
epidermal tissue.
[0005] However, technical problems exist in the use of such
microneedles. Among them is the plugging of hollow microneedles
with skin or other tissues, thus, preventing the flow of
therapeutic through the microneedle. This may have an impact on the
amount of therapeutic actually delivered to the patient, which can
be important for proper dosing.
SUMMARY OF THE INVENTION
[0006] Microneedle devices for transport of molecules, including
drugs and biological molecules, across tissue, are provided. The
microneedle devices permit drug delivery or removal of body fluids
at clinically relevant rates across skin or other tissue barriers,
with minimal or no damage, pain, or irritation to the tissue.
Microneedles can be formed of a variety of materials, including
biodegradable or non-biodegradable polymeric materials or metals.
The microneedle devices described herein include a hollow
microneedle capable of penetrating the stratum corneum. The
microneedle has a movable barrier located at a distal end of the
microneedle. The moveable barrier prevents or reduces tissue from
blocking an interior channel that extends though the microneedle.
In one particular embodiment, the microneedle device include a
platform or substrate having a plurality of microneedles each with
plugs disposed at their distal ends for preventing skin or other
tissue barriers from entering the hollow microneedles. In another
embodiment, a microneedle device includes a plurality of
bioerodible elements for temporarily plugging the hollow
microneedles, thereby preventing skin or other tissue barriers from
entering the hollow microneedles. The bio erodible elements may be
plugs that are fitted within the distal end of a channel extending
through the microneedle. The plugs may be frangible and optionally
may have a seam that allows the plug to separate from the
microneedle. Once separated the plug may dissolve over time.
[0007] In a further optional embodiment, the devices described
herein may include moveable barriers that comprise pins or pistons
that fit within the interior channels of the mcironeedle and may be
moved through the channel so that a distal portion of the pin or
piston sits within the distal end of the channel and prevents
tissue from blocking the microneedle. In a further optional
embodiment, the pin or piston may be capable of pushing tissue from
the channel to dislodge any tissue blocking the channel.
[0008] Additional advantages and other novel features of the
invention will be set forth in part in the description that follows
and in part will become apparent to those skilled in the art upon
examination of the following or may be learned with the practice of
the invention. As will be realized, the invention is capable of
other different embodiments, and its several details are capable of
modification in various, aspects all without departing from the
invention. Accordingly, the drawings and descriptions will be
regarded as illustrative in nature and not as restrictive.
BRIEF DESCRIPTION OF THE DRAWINGS
[0009] FIG. 1 depicts a microneedle surface of one embodiment of
the invention.
[0010] FIG. 2A depicts a cross-sectional view of the microneedle
device of FIG. 1 in its resting state.
[0011] FIG. 2B depicts a cross-sectional view of the microneedle
device of FIG. 1 when pressure is applied to back of the patch.
[0012] FIG. 3 depicts a microneedle surface of a different
embodiment of the invention.
[0013] FIG. 4A depicts a cross-sectional view of the microneedle
device of FIG. 3 prior to its application to skin.
[0014] FIG. 4B depicts a cross-sectional view of the microneedle
device of FIG. 3 during its application to skin.
[0015] FIG. 4C depicts a cross-sectional view of the microneedle
device of FIG. 3 after its application to skin.
[0016] FIG. 4D depicts a cross-sectional view of a microneedle and
plug.
[0017] FIGS. 5A and 5B depict a process for clearing tissue from
the channel of a microneedle and pumping fluid through the
channel.
DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS
[0018] The systems and methods described herein are, in one aspect,
directed to transdermal devices, including an intraepidermal
delivery devices for administering a substance to a patient. More
particularly, the invention is directed to devices and to methods
for establishing fluid communication for administering agents and
monitoring a patent's condition. In one exemplary embodiment the
systems and methods provide delivery devices for administering a
substance into or below the stratum corneum of the skin of a
patient. As used herein, the term penetrate refers to entering a
layer of the skin without necessarily passing completely through.
Piercing refers to passing completely through a layer of the skin.
As used herein, transdermal refers to the exchange of a substance,
such as blood, a pharmaceutical, a biological agent or a vaccine,
through one or more layers of skin. Intradermal refers to one or
more layers within the skin and not limited to the dermis layer of
the skin.
[0019] The devices and methods are particularly suitable for use in
administering various substances, including pharmaceutical agents,
to a patient, and notably to a human patient. A pharmaceutical
agent includes a substance having biological activity that can be
delivered through the body membranes and surfaces, and particularly
the skin. Examples include antibiotics, antiviral agents,
analgesics, anesthetics, anorexics, antiarthritics,
antidepressants, antihistamines, anti-inflammatory agents,
antineoplastic agents, vaccines, including DNA vaccines, adjuvants,
biologics, and the like. Other substances which can be delivered
intradermally to a patient include proteins, peptides and fragments
thereof. The proteins and peptides can be naturally occurring,
synthesized or recombinantly produced.
[0020] In some embodiments, a vaccine is administered using the
device and method. The multipuncture devices of described herein
are believed in addition to have a unique immunological advantage
in the delivery of vaccines with the potential of increasing the
vaccine's clinical value. The insertion of the multiple needle
points into the tissue is suggested as having an adjuvant-like
stimulatory effect. The needle stick response from multiple
microneedle points is believed more than a simple acute
inflammatory response. Needle sticks can cause damage to a variety
of cells and cellular architecture, causing the appearance of
polymorphonuclear neutrophil (PMN) and microphages as well as the
release of cytokines, including IL1, tumor necrosis factor (TNF)
and other agents, which can lead to a number of other immunological
responses. The soluble stimulatory factors influence the
proliferation of lymphocytes and are central to the immune response
to vaccines. The immune stimulation is proportional to the direct
needle-cell interaction.
[0021] The microneedle device is valuable in promoting significant
immune response to a vaccine by delivering a vaccine below the
stratum corneum and into the cells of the tissue. Some of the
microneedles can have a length selected to penetrate and pass
through the stratum corneum without penetrating the dermis to
minimize absorption of the vaccine into the bloodstream. The small
intracellular depots created by the microneedle array are believed
to increase the availability of the vaccine antigen for interaction
with antigen presenting cells more than would a vaccine deposited
by standard needles in a larger depot quantity. In further
embodiments, some or all of the microneedles can have a length to
penetrate, but not pierce, the stratum corneum.
[0022] The microneedle array is believed to magnify several-fold
the trivial or inconsequential immune stimulatory impact of a
single needlestick independent of the route of delivery and
vaccine. The microneedle delivery device facilitates and enhances
vaccine immunogenicity by an adjuvant-like immune stimulation.
[0023] The primary barrier properties of the skin including the
resistance to drug penetration reside in the outermost layer of the
skin, referred to as the stratum corneum. The inner layers of the
epidermis generally include three layers, commonly identified as
the stratum granulosum, the stratum malpighii, and the stratum
germinativum. Once a drug or other substance penetrates below the
stratum corneum, there is substantially less resistance to
permeation into the subsequent layers of the skin and eventual
absorption by the body. Thus, delivery of a substance below the
stratum corneum can be an effective system for administering some
substances, and particularly some vaccines, to the body. The
devices and methods described herein will, among other things, for
deliver a substance, and particularly a pharmaceutical agent, into
or below the stratum corneum for administering the substance or
pharmaceutical agent to the patient. Preferably, the device and
method pierce the stratum corneum substantially without penetrating
the dermis to target the tissue layers below the stratum corneum.
It is of potential benefit for vaccines to target presentation of
antigen to various antigen presenting cells and other
immunostimulatory sites, such as Langerhans cells and
intraepithelial cells, as well as proximal delivery of
adjuvants.
[0024] FIG. 1 depicts one embodiment of a microneedle device.
Microneedle device 1 shows microneedle surface 10, including
microneedles 20 with microneedles openings 30. As shown, the
microneedle device may comprise an array of microneedles, each of
which is hollow and each of which can penetrate the stratum
corneum. In this embodiment, the microneedle array may be used as
part of a transdermal patch that transdermally delivers a substance
to the patient or transdermally collects a sample from the patient.
To this end the device 1 may include a reservoir that can store a
fluid substance or substances to deliver to the patient or that was
collected from the patient. In either case, and as will be
described in more detail herein, the microneedle device 1 includes
a distal barrier over or within one or more of the microneedles 20,
and typically, the barrier is disposed over or within the distal
end of the channel 30 to prevent tissue from blocking the channel
openings 30 when the patient or doctor applies pressure to device 1
to force the mcironeedles 20 through the tissue.
[0025] FIG. 2A depicts a cross-sectional view of microneedle device
1 in its resting state. Drug reservoir 70 is loaded with a
predetermined amount of a therapeutic in liquid form. Platform 60
includes microneedle plugs 61 which are arrayed to fit into
microneedles 20 in order to prevent punctured skin from entering
and plugging microneedles 20, and preventing the release of
therapeutic. Platform 60 rests on springs 50 which hold platform 60
and microneedle plugs 61 above microneedles 20.
[0026] FIG. 2B depicts a cross-sectional view of microneedle device
1 when pressure (represented by three arrows) is applied to device
surface 40 while microneedle device 1 is being applied to skin.
Microneedle device 1 is applied to skin with microneedle surface 10
in contact with the skin. The pressure pushes down platform 60
depresses springs 50, and forces microneedle plugs 61 into
microneedles 20, preventing skin from entering and plugging
microneedles 20. After pressure is released from device surface 40,
device 1 returns to the formation shown in FIG. 2A. Springs 50
re-extend to lift platform 60 and microneedle plugs 61 from
microneedles 20. At this point, microneedles 20 are embedded into
skin and the therapeutic in a liquid composition or form escapes
from drug reservoir 70 through microneedles openings 30. Thus the
plugs 61 act as moveable barriers that prevent tissue from blocking
the openings 30 of microneedles 20.
[0027] Platform 60 is depicted in FIGS. 2A-2B as solid, however,
other embodiments are contemplated. For example, platform 60 may
include a plurality of openings, in the areas surrounding platform
plugs 61, through which a therapeutic may flow from drug reservoir
70 through microneedles 20. Further, FIGS. 2A-2B depict the
interior microneedles 61 (as being sized to fit within the interior
of microneedles 20. However, in other embodiments, the microneedles
20 may have narrow interior channels and in this embodiment
microneedles 61 may be narrow pin shaped elements that may slide
into, and optionally extend from, the distal opening of the
microneedles 20. In either case the microneedles 61 do not need to
have interior channels for passing fluid as microneedles may be
slid out of, at least partially, the interior channel of the
microneedle 20. In such embodiments, the conical shape of the
microneedle interior channel will provide space between the
microneedle 61 and the interior wall of the conical channel,
thereby providing a space through which the therapeutic fluid may
flow. In further optional embodiments, the microneedle 61 may have
an exterior surface that is grooved or scored to provide a path
through which liquid may flow. Optionally, the wall of the interior
channel may be similarly grooved or scored. Other techniques for
increasing fluid flow may be practiced with the systems described
herein without departing from the scope of the invention.
[0028] FIG. 3 depicts an alternative embodiment of a microneedle
device. Microneedle device 101 shows microneedle surface 110,
including microneedles 120 with microneedle plugs 130. An optional
adhesive patch 112 secures the device 101 to the tissue of the
patient.
[0029] FIG. 4A depicts a cross-sectional view of microneedle device
101 prior to its application to skin. In this embodiment, drug
reservoir 170 is loaded with a predetermined amount of a
therapeutic in liquid form. The microneedle openings 121 of
microneedles 120 are blocked by microneedle plugs 130. Microneedle
plugs 130 have an accurate shape with shoulders 132 that extend
beyond the diameter of microneedles 120. In this embodiment, the
plugs 130 have a shape adapted to act as a barb and catch
biological tissue. The plugs 130 may have a frangible seam that
fractures when the microneedle device 101 is applied to the
patient's tissue. This allows the plug 130 to separate from the
needle 120, and thereby facilitates the flow of agent through the
needle 120.
[0030] FIG. 4B depicts a cross-sectional view of the microneedle
device 101 during its application to skin. Microneedle device 101
is applied to skin with microneedle surface 110 in contact with the
skin. Microneedle plugs 130 block microneedles openings 121,
preventing skin from entering and plugging microneedles 120,
thereby preventing the release of therapeutic. Microneedle device
101 is pressed into skin to a deeper level than when the pressure
applied to microneedle device 101 is released. When the pressure is
released, microneedle device 101 rises from the level it has been
pushed to and rests on the surface of the skin. However, shoulders
132 of microneedle plugs 130 anchor microneedle plugs 130 at the
level to which microneedle plugs 130 have been pushed. Thus, as
microneedle device 101 rises to rest on the surface of the skin,
microneedle plugs 130 are pulled out of microneedle openings 121
and microneedles 120.
[0031] FIG. 4C depicts a cross-sectional view of microneedle device
101 after its application to skin and microneedle plugs 130 are
anchored in skin. The therapeutic in a liquid composition or form
escapes from drug reservoir 170 through microneedles openings 121.
The anchored plugs 130 may be comprised of a biologically erodible
material that over time will dissolve. Optionally and
alternatively, the plugs 130 may comprise a therapeutic material
that caries a medicant into the patient's tissue to provide a time
release dose that may work in cooperation with the fluidic medicant
delivered through the microneedles 120.
[0032] FIG. 4D depicts a cross-sectional view of the microneedle
120 having a plug 130 disposed therein. Specifically, FIG. 4D
depicts that the microneedle 120 may have an interior channel 122
that is conically shaped. The plug 130 may have a lower accurate
section 132 and an upper conical section 134. The upper conical
section 134 mates up with the interior wall of the channel 122 to
form a mechanical stop that prevents the plug 130 from sliding out
of the distal end of the interior channel 122. In a further
optional embodiment, the plug 130 may include a proximal end that
secures to the exterior surface of the microneedle 120. In such an
embodiment, the plug 130 does not enter into the microneedle
channel, or does not enter a substantial amount. Instead the plug
130 includes a frangible collar that wraps around and secures to
the exterior distal surface of the microneedle 120. Such an
embodiment is depicted in FIG. 4A which shows one of the
microneedles 130 having a proximal collar 132. The proximal collar
132 may be formed of the same material as the plug 130, or
optionally of a different material. A frangible seam 134, which may
be a perforated seam, may be disposed between the collar 132 and
the distal end of the plug 130. The frangible seam 134 may
facilitate the separation of the distal end of the plug 130 from
the device 101. In these embodiments, the plug 130 may be formed of
a bioerodible material. Such materials include polymers of hydroxy
acid and are enumerated in more detail below. In other embodiment,
the plug 130 may be made of other materials, including materials
that carry a medicant for delivering medicant to the patient.
Still, in other embodiments, the plug 130 may include a combination
of materials. In any case, the material or materials selected will
depend upon the application at hand and all are understood to fall
within the scope of the invention.
[0033] Microneedle device 1 or 101 can be used as a Continuous
non-invasive medical device that continuously delivers a fluidic
drug through the skin and into the body. Microneedle device 1 or
101 is applied to the skin such that microneedles 20 or 120
penetrate through the stratum corneum and enter the viable
epidermis so that the tip of microneedles 20 or 120 at least
penetrates into the viable epidermis. For one example, insulin
could be delivered to the blood stream via microneedles 20 or 120
through the stratum corneum and epidermis, and also into the dermis
where the insulin would be absorbed into the capillaries (not
shown).
[0034] FIG. 5A depicts a microneedle system 200 that may be
employed for delivering a fluid medicant to a patient. More
particularly, FIG. 5A depicts a microneedle system 200 that
includes a silicon substrate 210, an adhesive patch 212, a
microneedle 214, and a pin 218 having an arcuate distal end
220.
[0035] As discussed above, the microneedle 200 may be employed by
applying the adhesive patch 212 to the skin of a patient. The
needle 214 can penetrate through the outer layer of the patient's
skin to provide a drug delivery channel. As also discussed above,
the distal end 222 of the microneedle 214 may become obstructed,
either in part or in whole, by tissue, fluid, or some other
material that travels up into an interior channel (not shown) that
extends through the microneedle 214. To this end, the microneedle
system 200 includes a pin 218 that provides a moveable barrier that
is dimensionally adapted for sliding through the interior channel
of the microneedle 214 and applying a force to tissue located at
the distal end 222 such that the tissue is dislodged from the
distal end 222 of the microneedle 214. In the embodiment depicted
in FIG. 5A, the pin 218 includes an arcuate tip 220. The arcuate
tip 220 is optional and is there to provide the ability to
penetrate more deeply into the patient's tissue and thereby move
any blocking or obstructing tissue from the distal end 222 of the
microneedle into a position that is further away from the
microneedle 214. As discussed above the pin 218 may be extendable
past the opening of the microneedle to dislodge tissue from the
mcironeedle. However, as discussed above, the pin 218 may also be
placed at the distal end of the microneedle 214 as the microneedle
is applied to the patient's tissue to block tissue from entering
into the interior of the microneedle. In this embodiment, the
microneedle 214 is formed as a tube and the pointed distal end 220
of the pin 218 provides the cutting edge that penetrates through
the patient's tissue. Optionally however the microneedle 214 may
independently have a pointed distal end for penetrating the
patient's tissue.
[0036] Turning to FIG. 5B, there is depicted another step in the
process for delivering the fluid to the patient through the
microneedle system 200. Specifically, as shown therein, the pin 218
is removed from the microneedle 214. Once removed, the interior
channel is available and may be attached to a pump 224. The pump
224 could be a fluidic piston or pump of a kind commonly employed
for delivering a low dosage of medicine to a patient. As depicted
in FIG. 5B, the pump 224 can connect to a proximal end of the
microneedle 214 to allow for the delivery of fluid through the
interior channel and into the patient. In experiments Dosage is
delivered through the microneedle 214 as shown in Table 1.
1TABLE 1 Flow Vol- Time rate ume (min: (ul/min) (ul) sec) Comments
1 50 50:00 Some pain during insertion; slight stinging be- gins 6
minutes into the experiment and gradu- ally becomes more painful up
until about the 20 min mark, then decreases until it disappears at
.about.32 min; piston moved .about.50 ul; minor leaking upon
removal .about.1 ul; site does not appear raised immediately after
removal, observed after two minutes - skin was slightly raised in
1-2 mm region as evidenced by touch 2 50 25:00 No insertion pain;
very little sensation during infusion; piston moved .about.50 ul;
minor leaking upon removal <1 ul (probably spilled from tube);
site does not appear raised immediately after removal, site after 2
min was slightly raised, .about.2 mm diam, reddened 5 50 10:00 Some
insertion pain; some stinging during in- fusion, big pain increase
at 8 min, strong stinging/burning sensation; no leaking; site does
not appear raise immediately after removal, after 2 min site was
slightly raised, .about.2 mm diam region, reddened 10 50 5:00 No
insertion pain; slight infusion pain starts at 2 min; no leaking;
site does not appear raised immediately after removal, 2 min after
removal site was slightly raised, 2 mm diam, reddened 20 50 2:30
Relatively pain free insertion; very low infusion sensation, some
pain a few seconds before end of the run; piston moved .about.50
ul; no leaking; site is reddened over a 2 mm diam area, but doesn't
appear to be raised 40 50 1:15 Low pain; no infusion sensation;
piston moved .about.50 ul; no leaking; site is raised immediately
after removal just less than a 1 cm diam region, reddened zone
.about.1 mm diam. 80 50 0:37. Painless insertion; stinging during
infusion; 5 piston moved .about.50 ul; no leaking; site is raised
.about.1 cm diam 160 50 0:18. Relatively pain free insertion;
stinging and cold 75 sensation, .about.2 ul leaked when removed
tubing from tube; piston moved .about.50 ul; site raised to a
height .about.500 um over an .about.1 cm diam region
[0037] Materials:
[0038] The above experiment was conducted with a system constructed
as depicted in FIGS. 5A and 5B and applied to the underside of a
forearm. The data collected and recorded is set out in Table 1
above. The experimental setup was constructed using the following
materials, however other materials and components may be
substituted by those skill in the art without substantially
detracting from the results achieved.
[0039] Microneedle Pin insert 218-0.12 mm Diam Seirin Accupuncture
Needle; J Type; No. 2; Sterilized with ETO; Lot 0121505; expiration
12/03; Seirin Corp., Shizuoka, JP
[0040] Microneedle 214 (30 G tube)-304 SS; ID=0.0055"/0.0065"; OD
0.0120"/0.0125"; L=0.155"/0.165"; Micro Tube 30 Ga; Eagle Stainless
Tube & Manufacturing, Inc., Franklin, Mass.
[0041] Silicone substrate 210--60 mil thick; Die cut 3/8" diam.;
Class VI Medical Grade; 60 Shore A; Part No. 87315k65;
McMaster-Carr Supply Co.
[0042] Adhesive tape 212-- Medical Tape 1513; 3M Transparent
Polyester 3.4 Mil Double Coated Medical Tape
[0043] Liquid adhesive--RP 30; Advanced Performance Instant
Adhesive; USP Class 6; exp. Aug. 27, 2003; Adhesive Systems Inc.,
Franklin, Ill.
[0044] Tygon tubing--Tygong Flexible Plastic Tubing; ID=0.010";
OD=0.030"; Formulation S-54-HL for surgical and hospital use;
Norton Performance Plastics, Akron, Ohio; Lot # 133341;
Saint-Gobain PPL Corp.
[0045] Syringe pump 224-- BD 1 ml disposable plastic syringe with
hypodermic needle; Becton, Dickinson and Co., Franklin Lakes,
N.J.
[0046] Saline --100 ml bag of 0.9% Sodium Chloride Injection USP;
Lot PS 114900; Exp. Apr. 03; Baxter Healthcare Corp., Deerfield,
Ill.
[0047] Syringe pump 224--Model KDS100; Ser. No. 4736; kdScientific
Inc., New Hope, Pa.
[0048] Accordingly, as shown in FIGS. 5 and 5B the systems and
methods described herein may be employed to increase the amount of
medicant or fluid delivered to the patient. In one embodiment, the
pump 224 includes a valve and a controller for regulating the flow
of fluid through the interior channel and into the patient. Any
suitable pump, valve and controller may be employed and the devices
selected will depend at least in part on the application. In one
embodiment, the pump may be a manually operated pump, such as a
syringe. In other embodiments the pump may include a motorized
pumping mechanism.
[0049] 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.
[0050] 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.
[0051] The microneedle device disclosed herein is typically applied
to skin. The skin consists of multiple layers. The stratum corneum
is the outer layer (comprising dead cells), generally between 10
and 50 cells for humans, or between 10 and 20 .mu.m thick. 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. The dermis contains a rich capillary network close to
the dermal/epidermal junction, and once a drug reaches the dermal
depth it diffuses rapidly to deep tissue layers (such as hair
follicles, muscles, and internal organs), or systemically via blood
circulation.
[0052] The microneedle devices disclosed herein include a
substrate; one or more microneedles; a reservoir for delivery of
drugs; an element for plugging each of the one or more
microneedles; and optionally, pump(s), sensor(s), and/or
microprocessor(s) to control the interaction of the foregoing.
[0053] 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. The
substrate includes a reservoir for drugs and/or biological
molecules.
[0054] 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, polytetrafluorethylene
(TEFLON.TM.), and polyesters.
[0055] 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. The microneedles
should be sterilizable using standard methods.
[0056] The microneedles of the device may be constructed as
described in U.S. Pat. No. 6,312,612 and U.S. Pat. No. 6,334,856.
For example, U.S. Pat. No. 6,312,612 describes a microneedle array
constructed of silicon and silicon dioxide compounds using MEMS
(i.e., Micro-Electro-Mechanical-- Systems) technology and standard
microfabrication techniques. The microneedle array may be
fabricated from a silicon die which can be etched in a
microfabrication process to create hollow cylindrical individual
microneedles. One process for manufacturing microneedles described
by U.S. Pat. No. 6,312,612 comprises providing a mold comprising a
plurality of micropillars that are mounted to a base and
differentially melting a thin lay of plastic onto the micropillars,
such that the plastic coats the micropillars to form hollow
microneedles.
[0057] Another example, U.S. Pat. No. 6,334,856 describes
microfabrication processes for manufacturing microneedles such as
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).
[0058] The microneedles of the invention may be hollow. As used
herein, the tern "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. One of skill in the art can select the
appropriate bore features required for specific applications. For
example, one can adjust the bore diameter to permit passage of the
particular material to be transported through the microneedle
device.
[0059] 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 tern "microneedle" includes both
microtubes and tapered needles unless otherwise indicated. In a
preferred embodiment, the diameter of the microneedle is greatest
at the base end of the microneedle and tapers to a point at the
distal end of the microneedle. The microneedle can also be
fabricated to have a shaft that includes both a straight
(untapered) portion and a tapered portion.
[0060] 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 .mu.m 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.
[0061] The length of the microneedles typically is between about 1
.mu.m and 1 mm, preferably between 10 microns and 500 microns, and
more preferably between 30 and 200 .mu.m. 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 spacings
between the microneedles.
[0062] 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 can be provided. An array
of microneedles can include a mixture of microneedle orientations,
heights, or other parameters.
[0063] In a preferred embodiment of the device, the substrate
and/or microneedles, as well as other components, are formed from
flexible materials to allow the device to fit the contours of the
biological barrier, such as the skin, vessel walls, or the eye, to
which the device is applied. A flexible device will facilitate 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.
[0064] The microneedle devices of the invention also include a
reservoir in fluid communication with the microneedles. The
reservoir is formed in the substrate in a space below the base (to
which the microneedles are attached). Typically, the reservoir will
accommodate about 0.2-10.0 ml of a solution or a suspension
containing a therapeutic agent (e.g., the reservoir can contain
about 0.4, 0.5, 1.0, 2.5, 5.0 or 7.5 ml of such a solution). The
reservoir and therapeutic agent may be chosen such that the device
contains not more than 1, 2, 3, 5, or 10 days supply of the
agent.
[0065] 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.
[0066] 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.
[0067] In a preferred embodiment, the reservoir should be in fluid
communication with the microneedles so that the therapeutic in a
fluid composition or form could exit the reservoir and flow into
the hollow microneedles.
[0068] The microneedle devices of the invention also include one or
more elements for plugging each of the one or more microneedles
(the plugging element). The plugging element of the device can be
constructed from a variety of materials, including metals,
ceramics, semiconductors, organics, polymers, and composites.
Generally, the plugging element should have the mechanical strength
to prevent skin or other tissue from enter the hollow microneedles
when the microneedle device is applied to the skin. In a preferred
embodiment, the plugging element may comprise a platform, held up
by springs, including a plurality of protuberances (microneedle
plugs) sized to fit into the hollow microneedles to prevent slain
or other tissue barriers from entering the hollow microneedles. As
the inner diameter of the microneedles is typically between about 3
.mu.m and about 80 .mu.m, the outer diameter of the microneedle
plugs will typically be between about 3 .mu.m and about 80 .mu.m,
depending oil the diameter of the microneedles. The length of the
microneedles typically is between about 1 .mu.m and about 1 mm. The
length of the microneedle plugs will also be between about 1 .mu.m
and about 1 mm. The microneedle plug may, however, extend past the
length of the microneedles. The microneedle plugs also may mimic
the perpendicular, cross-sectional shape of microneedles, for
example, the perpendicular cross-section of the microneedle plug
can be polygonal (e.g. star-shaped, square, triangular), oblong, or
another shape best able to fit the microneedle.
[0069] In another preferred embodiment, a microneedle device
includes a plurality of bioerodible elements (microneedle plugs)
for temporarily plugging the hollow microneedles, thereby
preventing skin or other tissue barriers from entering the hollow
microneedles. The microneedle plug is comprised of a continuous
piece of bioerodible polymer having a portion inside and a portion
outside the distal end of the microneedle. The portion inside the
distal end of the microneedle is held in place by friction or by a
small amount of biocompatible adhesive. The microneedle plug also
may mimic the perpendicular, cross-sectional shape of microneedle,
for example, the perpendicular cross-section of the microneedle
plug can be polygonal (e.g. star-shaped, square, triangular),
oblong, or another shape best able to fit the microneedle. The
portion inside the distal end of the microneedle may be from about
1 .mu.m to about 500 .mu.m in length, preferably from about 1 m to
about 250 .mu.m, more preferably from about 5 .mu.m to about 100
.mu.m. The cross-sectional dimensions of the portion inside the
distal end of the microneedle may be from about 10 nm to about 1
mm, preferably from about 1 .mu.m to about 200 .mu.m, more
preferably from about 3 .mu.m to about 80 .mu.m.
[0070] The portion outside the distal end of the microneedle may
have a cone shape with the base (widest portion) of the cone
attached to the polymer portion inside the microneedle. The outside
portion may be from about 1 .mu.m up to about 500 .mu.m in length
and have a diameter at the base from about 1 .mu.m up to about 1.2
mm in diameter. The diameter of the base of the cone will be
greater than the diameter of the microneedle to which it is fitted.
The outside portion may have an arrowhead shape, the barbed ends of
the arrowhead shape extending past the sides of the microneedle.
The width of the arrowshead across the barbed ends should be wider
than the diameter of the microneedle.
[0071] The microneedle devices of the invention also must be
capable of transporting material across the barrier at a useful
rate. For example, a microneedle device must be capable of
delivering drug across the skin at a rate sufficient to be
therapeutically useful. A 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.
[0072] 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 polymer 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 a microneedle and into the tissue.
[0073] 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.
[0074] 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, viruses, pH, heat
and/or light.
[0075] 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, the physical surface properties of the
microneedle could be manipulated to either promote or inhibit
transport of material along the microneedle surface, such as by
controlling hydrophillicity or hydrophobicity.
[0076] 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."
[0077] 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.
[0078] The microneedle devices of the invention can further include
sensors. 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 amperoimetric sensor monitors currents generated
when electrons are exchanged between a biological system and an
electrode. Blood glucose sensors frequently are of this type.
[0079] 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.
[0080] 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 remove 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.
[0081] The microneedle devices can further include a collar or
flange, for example, around the periphery of the substrate or the
base. It preferably is attached to the device, but alternatively
can be formed as 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.
[0082] The device may be attached to the patient by a belt, strap,
or adhesive (e.g., it can be attached to the patient's skin by an
adhesive patch). In some instances, an adhesive and a second
security device (e.g., a belt or strap) can be used.
[0083] In a preferred embodiment, a 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.
[0084] The microneedle devices of the present invention 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.
[0085] 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. The 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 and the microneedles
are plugged with bioerodible elements. 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.
[0086] 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. A preferred drug is insulin.
Representative agents include anti-infectives, hormones, growth
regulators, drugs regulating cardiac action or blood flow,
vaccines, chemotherapy agents, pain relief agents, dialysis-related
agents, blood thinning agents, 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 the drug is
used to treat, or the drug's mode of action: 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 1 a (multiple sclerosis), lidocaine (local
anesthesia), somatropin (growth hormone), sumatriptan (migraine
headaches), vaccines towards tumors, and vaccines towards
infectious diseases.
[0087] It will be understood that the microneedle device of the
present invention can be used in many applications, including as a
painless and convenient transdermal drug-delivery system for
continuous and controlled outpatient therapies. Another use of the
microneedle device of the present invention is to form a portable
drug delivery system for outpatient delivery of the following drugs
and therapeutic agents, for example: central nervous system therapy
agents, psychic energizing drugs, tranquilizers, anticonvulsants,
muscle relaxants and anti-parkinson agents, smoking cessation
agents, analgesics, antipyretics and anti-inflammatory agents,
antispasmodics and antiulcer agents, antimicrobials, antimalarias,
sympathomimetric patches, antiparasitic agents, neoplastic agents,
nutritional agents, and vitamins.
[0088] The devices may contain a predetermined dosage of
therapeutic which may be dependent on the disease or disorder being
treated, the size of the individual to be treated, the effective
dose of the therapeutic, etc.
[0089] 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 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.
[0090] 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.
[0091] 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).
[0092] 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.
[0093] 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.
[0094] 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. 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.
[0095] The microneedle devices disclosed herein also should be
useful for controlling transport across tissues other than skin.
For example, microneedles could 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 could 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 would 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.
[0096] It will also be understood that the length of the individual
microneedles is by far the most important dimension with regard to
providing a painless and bloodless drug-dispensing system, or a
painless and bloodless body-fluids sampling system using the
opposite direction of fluid flow. While the dimensions discussed
hereinabove are preferred, and the ranges discussed are normal for
human skin, it will further be understood that the microneedle
arrays of the present invention can be used on skin of any other
form of living (or even dead) creatures or organisms, and the
preferred dimensions may be quite different as compared to those
same dimensions for use with human skin, all without departing from
the principles of the present invention.
[0097] While the invention has been disclosed in connection with
the preferred embodiments shown and described in detail, various
modifications and improvements thereon will become readily apparent
to those skilled in the art. It should be understood that all
matter contained in the above description or shown in the
accompanying drawings shall be interpreted as illustrative, and not
in a limiting sense, and that the following claims should be
interpreted in the broadest sense allowable by law.
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