U.S. patent application number 12/853876 was filed with the patent office on 2010-12-02 for tissue conforming microneedle device for drug delivery or biological fluid collection.
Invention is credited to Vadim V. Yuzhakov.
Application Number | 20100305473 12/853876 |
Document ID | / |
Family ID | 39471822 |
Filed Date | 2010-12-02 |
United States Patent
Application |
20100305473 |
Kind Code |
A1 |
Yuzhakov; Vadim V. |
December 2, 2010 |
TISSUE CONFORMING MICRONEEDLE DEVICE FOR DRUG DELIVERY OR
BIOLOGICAL FLUID COLLECTION
Abstract
Microneedle arrays are provided for use on a contoured or
flexible tissue surface. In one embodiment, the microneedle array
includes a plurality of microneedles, each having a base portion, a
tip end portion distal to the base portion, and body portion
therebetween; and a flexible substrate which comprises a plurality
of apertures, each of which are defined by (i) a plurality of
substrate elements which are integral with the base portions of the
microneedles, and (ii) at least one spring element connecting at
least two of the substrate elements. The spring element may include
a curved element, such as a C-shaped, U-shaped, or S-shaped
element. Apertures may be defined, for example, by two substrate
elements, which connected to three or four spring elements. A skin
patch is provided for therapeutic or diagnostic applications, which
includes the microneedle array and an adhesive material.
Inventors: |
Yuzhakov; Vadim V.;
(Alameda, CA) |
Correspondence
Address: |
SUTHERLAND ASBILL & BRENNAN LLP
999 PEACHTREE STREET, N.E.
ATLANTA
GA
30309
US
|
Family ID: |
39471822 |
Appl. No.: |
12/853876 |
Filed: |
August 10, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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11563892 |
Nov 28, 2006 |
7785301 |
|
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12853876 |
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Current U.S.
Class: |
600/575 ; 29/428;
604/173; 604/506 |
Current CPC
Class: |
A61M 37/0015 20130101;
A61M 2037/003 20130101; A61M 2037/0046 20130101; Y10T 29/49826
20150115 |
Class at
Publication: |
600/575 ;
604/173; 29/428; 604/506 |
International
Class: |
A61M 5/00 20060101
A61M005/00; A61B 5/00 20060101 A61B005/00; B23P 17/04 20060101
B23P017/04 |
Claims
1. A device for administration of a drug to a contoured or flexible
tissue surface, the device comprising: a microneedle array which
comprises a plurality of microneedles, each microneedle having a
base portion, a tip end portion distal to the base portion, and
body portion between the base portion and the tip end portion, and
an elastically stretchable substrate which comprises a plurality of
apertures, each of which are defined by both (i) a plurality of
substrate elements which are integral with the base portions of the
microneedles, and (ii) at least one spring element integral with
and connecting at least two of the substrate elements; and at least
one drug storage element, which contains a drug formulation,
disposed adjacent to the microneedle array.
2. The device of claim 1, wherein the drug storage element is
attached to a first surface of the substrate, the first surface
being opposed to a second surface of the substrate of the
microneedle array, wherein the microneedles project from said
second surface.
3. The device of claim 1, wherein the drug storage element is
coated onto an outer surface of the microneedles.
4. The device of claim 1, wherein the drug storage element can flex
and deform with substrate of the microneedle array.
5. The device of claim 1, further comprising a release mechanism
for releasing the drug formulation from the drug storage element to
permit the drug formulation to pass through the apertures of the
substrate of the microneedle array.
6. The device of claim 1, wherein the drug storage element
comprises a porous material, wherein the drug formulation is stored
in pores of the porous material.
7. The device of claim 1, further comprising an adhesive surface
suitable for securing the device to the skin of a patient during
administration of the drug formulation to the patient.
8. The device of claim 1, further comprising a removable release
liner, which covers the microneedles and apertures prior to use of
the device.
9. The device of claim 1, wherein at least one of the spring
elements of the substrate comprises a curved element.
10. The device of claim 9, wherein the curved element is C-shaped,
U-shaped, or S-shaped.
11. The device of claim 1, wherein at least one of the apertures of
the substrate is defined by two substrate elements.
12. The device of claim 1, wherein at least one of the substrate
elements is connected to three or four spring elements.
13. The device of claim 1, wherein at least one of the plurality of
microneedles has a channel extending substantially from the base
portion through at least a part of the body portion, the channel
being open along at least part of the body portion and in fluid
communication with at least one of the apertures in the
substrate.
14. The device of claim 13, wherein the base portion of the at
least one of the microneedles is untapered and has a substantially
rectangular cross-sectional shape in a plane parallel to the
substrate.
15. The device of claim 14, wherein the at least one channel is
open to two opposing surfaces of the microneedle.
16. The device of claim 13, wherein the tip end portion of the at
least one of the microneedles is tapered.
17. The device of claim 16, wherein the at least one channel
extends into the tapered tip end portion.
18. The device of claim 1, wherein the elastically stretchable
substrate and the microneedles are both formed of a biocompatible
metal or polymer.
19. The device of claim 1, wherein the microneedles have a length
between 100 .mu.m and 500 .mu.m.
20. A device for transdermal sampling of a biological fluid, the
device comprising: comprising: a microneedle array which comprises
a plurality of microneedles, each microneedle having a base
portion, a tip end portion distal to the base portion, and body
portion between the base portion and the tip end portion, and an
elastically stretchable substrate which comprises a plurality of
apertures, each of which are defined by both (i) a plurality of
substrate elements which are integral with the base portions of the
microneedles, and (ii) at least one spring element integral with
and connecting at least two of the substrate elements; and at least
one collection reservoir for retaining a biological fluid sample
drawn through the microneedle array.
21. The device of claim 20, further comprising a sensor for testing
the biological fluid retained in the collection reservoir.
22. A method for manufacturing a microneedle array comprising: (a)
forming an elastically stretchable substrate which comprises a
plurality of apertures, each of which are defined by (i) a
plurality of substrate elements, and (ii) at least one spring
element connecting at least two of the substrate elements; and (b)
forming a plurality of microneedles, each having a base portion, a
tip end portion distal to the base portion, and body portion
therebetween, wherein the base portions of the microneedles are
integral with the substrate elements.
23. The method of claim 22, which comprises forming in a planar
substrate material the plurality of apertures, the plurality of
substrate elements, and the plurality of spring elements, by
removing selected portions of the substrate material.
24. The method of claim 23, wherein the removal process comprises
embossing, injection molding, casting, photochemical etching,
electrochemical machining, electrical discharge machining,
precision stamping, high-speed computer numerically controlled
milling, Swiss screw machining, soft lithography, directional
chemically assisted ion etching, laser cutting, or a combination
thereof.
25. The method of claim 22, wherein at least one of the plurality
of microneedles has a channel extending substantially from the base
portion through at least a part of the body portion, the channel
being open along at least part of the body portion and in fluid
communication with at least one of the apertures in the
substrate.
26. A method of administering a drug to a patient in need thereof,
comprising: inserting the microneedles of the device of claim 1
into the skin of the patient to form holes in the stratum corneum;
and causing a fluid drug formulation to be transported through the
apertures of the substrate of the microneedle array and then
through the holes in the stratum corneum, while the microneedles
are positioned in the holes.
27. The method of claim 26, wherein at least one of the plurality
of microneedles has a channel extending substantially from the base
portion through at least a part of the body portion, the channel
being open along at least part of the body portion and in fluid
communication with at least one of the apertures in the
substrate.
28. A method of transdermally collecting a biological fluid sample
from a patient, comprising: inserting the microneedles of the
device of claim 20 into the skin of the patient to form holes in
the stratum corneum; and causing the biological fluid to be
withdrawn from the patient through the holes in the stratum corneum
and then through the apertures of the substrate of the microneedle
array, while the microneedles are positioned in the holes.
29. The method of claim 28, wherein at least one of the plurality
of microneedles has a channel extending substantially from the base
portion through at least a part of the body portion, the channel
being open along at least part of the body portion and in fluid
communication with at least one of the apertures in the substrate.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. application Ser.
No. 11/563,892, filed Nov. 28, 2006, which is incorporated herein
by reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] This invention is generally in the field of devices for the
administration of drugs to patients and devices for biological
sample collection through the skin. More particularly, this
invention relates to microneedle array devices and methods for
transdermal drug delivery, for transdermal diagnostic sampling of
biological fluids, or for a combination thereof.
[0003] Microneedles and microneedle arrays have been disclosed for
use in the fields of transdermal drug delivery and biological
sample collection. Transdermal drug delivery provides several
advantages over other routes for administering a drug formulation
to a patient. For example, oral administration of some drugs may be
ineffective because the drug is destroyed in the gastrointestinal
tract or eliminated by the liver, both of which are avoided by
transdermal drug delivery. Parenteral injection with a conventional
hypodermic needle also has its drawbacks, as it is painful and
inconvenient. It would, however, be advantageous to provide
improved microneedle devices and methods for transdermal drug
delivery. Analyte concentration determination in biological samples
withdrawn transdermally is important for a variety of diagnostic
applications. For example, collection of blood or interstitial
fluids is often necessary, for example, to measure glucose for
diabetes management, or to measure cholesterol for monitoring
cardiovascular conditions. Conventional devices and methods may
involve cumbersome and complicated devices and procedures, or may
be painful. It would be advantageous to provide devices and
diagnostic methods that are relatively simple to use and pain free,
in order to improve patient compliance with diagnostic monitoring
and disease management.
[0004] In both transdermal drug delivery and transdermal biological
sampling using microneedle arrays, particularly in patch-type
devices, it would be particularly desirable for the microneedles to
remain in their precise, penetrated position through the stratum
corneum to maintain the fluid communication between a drug or
sample collection reservoir and the tissues beneath the stratum
corneum for an extended period. However, the skin of a patient is
contoured and quite flexible. Thus, it may be difficult for a
conventional microneedle array having a rigid, planar substrate to
maintain the desired microneedle penetration, particularly where
the microneedle array is part of a patch device and the patient
(and consequently, his or her skin) ordinarily moves about and
flexes throughout the extended period of microneedle array (e.g.,
patch) application. For example, a microneedle array having base
made of silicon is flat and inflexible, and even though a polymeric
or metal microneedle base can be slightly bent in one direction,
such arrays of microneedles cannot readily be applied to convex or
concave skin surfaces or stretched in different directions. Thus, a
patch having such a microneedle array may tend to fall off the skin
surface as the patient moves, particularly for patches designed to
be continuously worn even on relatively flat areas of a patient's
skin, due to the significant stretching of the skin that occurs
during normal movement. It therefore would be desirable to provide
a microneedle array that can improve penetration control into
contoured skin surfaces and lessen premature movement of
microneedles out of optimum penetrated position. It also would be
desirable to provide a better microneedles array, and patch, for
transdermal drug delivery or transdermal biological sample
collection over an extended period.
SUMMARY OF THE INVENTION
[0005] In one aspect, microneedle arrays are provided for use on a
contoured or flexible tissue surface. In one embodiment, the
microneedle array includes a plurality of microneedles, each having
a base portion, a tip end portion distal to the base portion, and
body portion therebetween; and a flexible substrate which comprises
a plurality of apertures, each of which are defined by (i) a
plurality of substrate elements which are integral with the base
portions of the microneedles, and (ii) at least one spring element
connecting at least two of the substrate elements. The spring
element may include a curved element, such as a C-shaped, U-shaped,
or S-shaped element. In one embodiment, at least one of the
apertures is defined by two substrate elements. In one embodiment,
each substrate element is connected to three or four spring
elements.
[0006] In one embodiment of the microneedle array, at least one of
the plurality of microneedles has a channel extending substantially
from the base portion through at least a part of the body portion,
the channel being open along at least part of the body portion and
in fluid communication with at least one of the apertures in the
substrate. The base portion of the at least one of the microneedles
may be untapered and have a substantially rectangular
cross-sectional shape in a plane parallel to the substrate. The at
least one channel may be open to two opposing surfaces of the
microneedle. The tip end portion of the at least one of the
microneedles may be tapered, and, in one embodiment, the at least
one channel extends into the tapered tip portion.
[0007] In one embodiment, the flexible substrate and the
microneedles may be formed of a biocompatible metal, such as a
stainless steel, or formed of a polymer. In one embodiment, the
length of the plurality of microneedles may be between 100 .mu.m
and 500 .mu.m.
[0008] In one aspect, a device is provided for transdermal
administration of a drug. In one embodiment, the device includes a
microneedle array that has a plurality of microneedles, each having
a base portion, a tip end portion distal to the base portion, and
body portion therebetween; a flexible substrate which comprises a
plurality of apertures, each of which are defined by (i) a
plurality of substrate elements which are integral with the base
portions of the microneedles, and (ii) at least one spring element
connecting at least two of the substrate elements; and at least one
drug storage element, which contains a drug formulation, disposed
adjacent to the microneedle array. The drug delivery device may
further include a release mechanism for releasing the drug
formulation from the drug storage element to permit the drug
formulation to pass through the apertures of the substrate of the
microneedle array. The drug storage element may be attached to a
first surface of the substrate, the first surface being opposed to
a second surface of the substrate of the microneedle array, wherein
the microneedles project from said second surface. The drug storage
element may be in the form of a coating on the surfaces of the
microneedles, on the substrate, or on both the microneedles and
substrate. The drug storage element, in one embodiment, can flex
and deform with substrate of the microneedle array. In one
embodiment, the drug storage element comprises a porous material,
wherein the drug formulation is stored in pores of the porous
material. The device may further include an adhesive surface
suitable for securing the device to the skin of a patient during
administration of the drug formulation to the patient, and/or a
removable release liner, which covers the microneedles and
apertures prior to use of the device.
[0009] In another aspect, a device is provided for transdermal
sampling of a biological fluid. In one embodiment, the device
includes a microneedle array that has a plurality of microneedles,
each having a base portion, a tip end portion distal to the base
portion, and body portion therebetween; a flexible substrate which
comprises a plurality of apertures, each of which are defined by
(i) a plurality of substrate elements which are integral with the
base portions of the microneedles, and (ii) at least one spring
element connecting at least two of the substrate elements; and at
least one collection reservoir for retaining a biological fluid
sample drawn through the microneedle array adjacent thereto. The
device may further include a sensor for testing a biological fluid
retained in the collection reservoir.
[0010] In yet another aspect, a method is provided for
manufacturing a microneedle array. The method includes (a) forming
a flexible substrate which comprises a plurality of apertures, each
of which are defined by (i) a plurality of substrate elements, and
(ii) at least one spring element connecting at least two of the
substrate elements; and (b) forming a plurality of microneedles,
each having a base portion, a tip end portion distal to the base
portion, and body portion therebetween, wherein the base portions
of the microneedles are integral with the substrate elements. In
one embodiment, the method includes forming in a planar substrate
material the plurality of apertures, the plurality of substrate
elements, and the plurality of spring elements, by removing
selected portions of the substrate material. The removal process
may include embossing, injection molding, casting, photochemical
etching, electrochemical machining, electrical discharge machining,
precision stamping, high-speed computer numerically controlled
milling, Swiss screw machining, soft lithography, directional
chemically assisted ion etching, laser cutting, or a combination
thereof.
[0011] In one particular embodiment, a skin patch is provided for
therapeutic or diagnostic applications. In one case, the patch
includes (a) a microneedle array which comprises a plurality of
microneedles, each having (i) a base portion, a tip end portion
distal to the base portion, and body portion therebetween, and (ii)
a channel extending substantially from the base portion through at
least a part of the body portion, the channel being open along at
least part of the body portion; (b) a flexible substrate which
comprises a plurality of apertures, each of the apertures being
defined by (i) two or more substrate elements which are integral
with the base portions of the microneedles, and (ii) at least two
spring elements connected to the two or more substrate elements,
wherein the channels of the microneedles are in fluid communication
with at least one of the apertures in the substrate; and (c) an
adhesive material for securing the microneedle array to a patient's
skin with the microneedles inserted into the stratum corneum.
[0012] In another aspect, a method is provided for administering a
drug to a patient in need thereof. The method may include inserting
into the skin of the patient the microneedles of the microneedle
array described herein, to form holes in the stratum corneum; and
then causing a fluid drug formulation to be transported through the
apertures of the substrate of the microneedle array and then
through the holes in the stratum corneum, while the microneedles
remain positioned in the holes. In still another aspect, a method
is provided for transdermally collecting a biological fluid sample
from a patient. The method may include inserting into the skin of
the patient the microneedles of the microneedle array described
herein, to form holes in the stratum corneum; and causing the
biological fluid to be withdrawn from the patient through the holes
in the stratum corneum and then through the apertures of the
substrate of the microneedle array, while the microneedles remain
positioned in the holes. In either of these methods, the area of
the skin where the microneedles are inserted may be in a body area
that is routinely moved or highly flexed, such as the back, neck,
knee, etc.
BRIEF DESCRIPTION OF THE FIGURES
[0013] FIG. 1 is a close-up, perspective view of part of one
embodiment of a microneedle array as described herein.
[0014] FIGS. 2A-D are perspective views of one embodiment of a
microneedle array as described herein, illustrating how the array
can be elastically deformed to conform to contoured surfaces or
elastically stretched in different directions.
[0015] FIG. 3 is a close-up view, perspective view of an
intermediate structure made in forming one embodiment of the
microneedle array.
[0016] FIGS. 4A-B are perspective views of one embodiment of a drug
delivery patch which comprise a microneedle array as described
herein.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0017] Microneedle arrays have been developed which can be
elastically stretched and deformed to better conform with contoured
and flexible tissue surface. The substrate of the array is flexible
and elastically deformable (i.e., stretchable). Continuous wear
devices (e.g., a skin patch) incorporating these microneedle arrays
advantageously can be stretched or compressed in essentially any
direction as a patient's skin stretches and changes contours during
normal movement, beneficially maintaining the microneedles in their
inserted position during extended transdermal drug delivery or
diagnostic applications. That is, in one embodiment, the
microneedle array comprises one or more spring elements configured
to allow the substrate to stretch when the microneedle array is
attached to and worn on the tissue surface.
[0018] The flexibility of the microneedle array is provided by a
substrate design having a network of interconnected spring
elements. In one embodiment, apertures in the substrate are defined
by (i) a plurality of substrate elements which are integral with
the base portions of the microneedles, and (ii) at least one spring
element connecting at least two of the substrate elements. Each
spring element essentially functions as a microspring or hinge. The
spring element is capable of absorbing and storing mechanical
energy when stretched, compressed, bent, and/or twisted by an
external load so that the spring element will regain its original
shape once the load is removed. The array of spring elements impart
flexibility to at least a portion of the substrate so as to allow
the microneedle array to conform to contours of the skin surface
structure.
[0019] In a preferred embodiment, the microneedle array
advantageously includes microneedles having a strong, small solid
tip capable of piercing the stratum corneum into the patient's
lower skin tissues (e.g., epidermis, dermis, or subcutaneous skin
layers), while the flexible substrate enables the microneedles to
both conform to the contoured skin surface during initial
penetration of the microneedles and to remain in this inserted
position as the contoured skin surface changes during natural
movements of the patient. Moreover, the ability of the microneedle
array to flexibly or elastically deform reduces the likelihood that
the array is bent or broken while being worn by the patient because
it is capable of yielding to forces that would otherwise break a
rigid microneedle array. Thus, any dangers that may be posed by a
broken microneedle array are lessened or avoided. A still further
advantage of the present microneedle array is that it may be
fabricated using relatively easy and relatively inexpensive
techniques, since the flexible structures can be formed from the
substrate material.
[0020] As used herein, the terms "comprise," "comprising,"
include," and "including" are intended to be open, non-limiting
terms, unless the contrary is expressly indicated.
Microneedle Array
[0021] In one embodiment, the microneedle array includes a
plurality of microneedles, each having a base portion, a tip end
portion distal to the base portion, and body portion therebetween;
and a flexible substrate which comprises a plurality of apertures,
each of which are defined by (i) a plurality of substrate elements
which are integral with the base portions of the microneedles, and
(ii) at least one spring element connecting at least two of the
substrate elements. In various embodiments, the spring element may
include a curved element, such as a C-shaped, U-shaped, or S-shaped
element, or a combination thereof. Each of the apertures may be
defined by one, two, or more substrate elements, and by two, three,
four, or more spring elements.
[0022] The material of construction and dimensions of the spring
element can be tailored to control where/how the spring element
flexes. The number, arrangement, and orientation of the spring
elements with the substrate elements can be used to control how the
whole substrate flexes. A substantially planar substrate formed of
a rigid material can be made substantially flexible and/or
stretchable by creating arrays of the spring elements, e.g., a
network of flexible structures, in the substrate. The shape and
thickness of these spring elements can be tailored each material of
construction and each array device. The interconnected network of
spring elements desirably extends over a substantial area of the
substrate, in order to maximize the area of flexibility in the
whole substrate, enhancing the ability of the array to conform to
and stretch with a variety of contoured tissue surfaces.
[0023] It is also envisioned that apertures may be defined by
substrate elements (which have microneedles extending therefrom),
spring elements, and tertiary elements that neither are spring
elements nor have a microneedle extending therefrom. The substrate
also may include areas with no apertures, areas with apertures but
no spring elements or substrate elements, or both of these types of
areas as long as there is sufficient flexibility/stretchability
imparted to the whole substrate by the remaining area having spring
element-defined apertures.
[0024] Each microneedle projects at an angle from the substrate
element. Typically, the microneedle is perpendicular to the
substrate element. The base portion of the microneedle may include
a curved portion transitioning the change in orientation of the
microneedle from the substrate element. One, two, or more
microneedles may extend from a single substrate element. The
substrate element may also include one or more springs or otherwise
is designed to flex.
[0025] Representative, non-limiting embodiments of the microneedle
array are illustrated in FIGS. 1 and 2. FIG. 1 shows a microneedle
array 10 includes a substantially planar substrate 12 and a
plurality of microneedles 14 extending from the substrate 12. The
substrate 12 includes substrate elements 16 and spring elements 18,
which define apertures 20. The surface 13 of substrate 12
optionally may be coated with an adhesive material (not shown) to
enhance securement of the inserted microneedle array to the outer
skin or other tissue surface. The base portion 22 of the
microneedle 14 integrally connected to the substrate element 16.
The microneedle also includes a tip end portion 26 distal to the
base portion 22, and a body portion 24 therebetween. The body
portion 24 of the microneedle 14 has a substantially rectangular
cross-sectional shape in a plane parallel to the substrate 12. The
microneedle 14 also has an elongated channel 28 extending from the
base portion 22 through the body portion 24, and optionally into
the tip end portion 22. The channel 28 is open through two opposing
surfaces of the body portion, and the channel 28 is in fluid
communication with aperture 20 in the substrate 12. The tip end
portion 26 and body portion 24 of the microneedle 14 are
substantially perpendicular to the substrate 12, and the base
portion 22 of the microneedle 14 includes a curved portion that is
integral with the substrate element 16. It is understood, however,
that in other embodiments, the microneedle may be of essentially
any other design (e.g., in a different shape, with or without
channels or bores, etc.).
[0026] FIGS. 2A-D illustrate the conformability and stretchability
of the microneedle array 10. FIG. 2A shows the array as it would
conform to microneedles inserted into a concave surface (not
shown), and FIG. 2B shows the array as it would conform to
microneedles inserted into a convex surface (not shown). FIG. 2C-D
show the microneedle array as it would elastically deform if
stretched in two different directions in the plane of the
substrate.
[0027] The apertures in the substrate may be in essentially any
shape, which is dictated in part by the shape of the substrate
elements and spring elements. In various embodiments, the apertures
may be approximately square, circular, hexagonal, semi-circular,
oval, diamond, triangular, or a combination thereof. In a preferred
embodiment, the apertures occupy a substantial area of the
substrate, in order to maximize the contact of the drug reservoir
with skin and to facilitate adhesion of the microneedle patch
device to the skin. As used herein, the term "substantial area of
the substrate" means that in a plan view of the substrate of the
microneedle device, the apertures compose more than about 40%
(e.g., between 50% and 95%, between 60% and 85%) of the total area
of the substrate from which the microneedles extend.
The Microneedles
[0028] Generally, the microneedle can be in any elongated shape
suitable for providing the skin piercing and fluid conduit
functions, with minimal pain to the patient. In various
embodiments, the microneedle is substantially cylindrical,
wedge-shaped, cone-shaped, or triangular (e.g., blade-like). The
cross-sectional shape (cut along a plane approximately parallel to
the plane in which the substrate substantially lies or
approximately perpendicular to the longitudinal axis of the
microneedle) of the microneedle, or at least the portion of
microneedle that is penetrable into the skin, may take a variety of
forms, including rectangular, square, oval, circular, diamond,
triangular, elliptical, polygonal, U-shaped, or star-shaped.
[0029] In one embodiment, the base portion of the at least one of
the microneedles has a substantially rectangular cross-sectional
shape in a plane parallel to the substrate. Preferably, this base
portion is untapered and the tip end portion which extends from the
base portion is tapered, the combination of which is believed to
provide a good combination of strength, manufacturing ease, and
fluid transport performance.
[0030] The tip portion of the microneedle is designed to pierce a
biological barrier, e.g., to pierce the stratum corneum of the skin
of a patient, to form a conduit through which a fluid can be
transported into or out of the patient's tissue. To provide minimal
pain to the patient, the tip portion of the microneedle should be
sufficiently small and sharp to enable piercing and penetration of
the skin with minimal pain. In a preferred embodiment, the tip end
portion of the microneedle is tapered from the body portion toward
the tip end portion, defining a point or apex at the end of the
microneedle. In various embodiments, the tapered tip portion may be
in the form of an oblique angle at the tip, or a pyramidal or
triangular shape.
[0031] In one embodiment, at least one of the microneedles has at
least one channel extending substantially from the base portion
through at least a part of the body portion, the channel being open
along at least part of the body portion and in fluid communication
with at least one of the apertures in the substrate. The channel
desirably extends from the substrate through the base portion and
into the tip portion, to facilitate delivery of the drug well
beneath the skin surface or to facilitate collection of the
biological sample from beneath the skin surface. In one specific
variation of this embodiment, the channel is open to two opposing
surfaces of the microneedle.
[0032] In one embodiment, a proximal end of the at least one
channel extends to or into the at least one of the interior side
surfaces of the substrate. In a preferred embodiment, the channel
extends from the substrate through the body portion and into the
tip end portion. In an alternative embodiment, the channel may
terminate in the body portion of the microneedle and not extend
into the tapered tip portion.
[0033] In one embodiment, each microneedle in an array has a
rectangular cross-sectional shape, an untapered base portion, a
tapered tip end portion, and a channel which is open to two
opposing surfaces of the microneedle and extends from an aperture
in the substrate, through the body portion, and into the tapered
tip portion. See FIG. 1. Drug delivery rates and biological sample
collection rates can be maintained relatively constant because the
created pores are kept open by the microneedles inserted into the
patient's stratum corneum, and pain from insertion of the
microneedles can be minimized since the tip portion of the
microneedles in such an embodiment can be made to have a smaller
cross-section and sharper tip than drug-coated solid microneedles
or hollow microneedles with a central bore. In addition, mass
transport using the microneedles can be increased relative to
similarly dimensioned hollow tipped or solid microneedles.
[0034] In another embodiment, the microneedles may be solid
microneedles. In one embodiment, the microneedle may have at least
one channel extending from the base portion through the body
portion to the tip end portion, the channel having an opening at
the base portion and an opening at the tip end portion. For
example, in one embodiment, the microneedle may have a central
hollow bore.
[0035] The dimensions of the microneedles may vary depending on a
variety of factors such as the type of drug to be delivered, the
dosage of the drug to be delivered, the type of biological sample
to be collected, the skin site where the microneedles are inserted,
the amount of biological sample to be collected, and the desired
penetration depth. Generally, the microneedles are constructed to
provide skin-piercing and fluid delivery and/or collection
functions and thus will be designed to be sufficiently robust to
withstand insertion into and withdrawal from the skin. Each
microneedle has a length of about 1 micrometer (.mu.m) to about
5000 micrometers (.mu.m). More preferably, each microneedle has a
length of about 1 .mu.m to about 500 .mu.m. Still more preferably,
each microneedle has a length of about 100 .mu.m to about 500
.mu.m. The penetration length of the microneedles into the
biological barrier is about 50 .mu.m to about 200 .mu.m. In
addition, each of the microneedles has a maximum thickness
dimension of 500 .mu.m. The thickness of the microneedle may vary
along its length. For instance, the base portion may be wider
(thicker) than the body portion, or the body portion may have a
slight taper approaching the tip portion.
[0036] In one embodiment, the microneedle includes one or more
channels. The one or more channels in each microneedle provide a
path for a drug formulation to flow from the substrate through/into
the biological barrier or for a biological fluid to flow from the
biological tissue through/into the substrate at the site of
piercing. The channel preferably extends from the substrate toward
the tip through a substantial portion of a length dimension of the
microneedles. In some embodiments, the channel may not extend all
the way to the tip of the microneedle if it is not a central bore.
The channel may comprise an opening through two surfaces of the
microneedle. In alternate embodiments, the channel may comprise any
shape suitable to deliver fluid proximal to the microneedle tip.
For example, the channel may comprise a groove on one surface of
the microneedle that is only open to the outside environment on one
side of the microneedle. In addition, the channel may be
dimensioned to provide a capillary force or effect upon the fluid
to be delivered such that the capillary effect draws or wicks fluid
into the base portion of the microneedle from the substrate,
through the body portion of the microneedle, and toward the tip
portion of the microneedle. In other embodiments, the channel may
be dimensioned to provide a capillary force or effect upon the
fluid to be collected such that the capillary effect draws or wicks
fluid on or into the microneedle from the biological barrier,
through the body portion of the microneedle, and toward the
substrate. In other embodiments, each microneedle may have more
than one channel, for example, two narrower channels in
parallel.
[0037] The width of the channel may be constant along its length or
may vary. The length of the channel will vary depending on a
variety of factors. In a preferred embodiment, the length of the
channel may be about 50 to 99% of the length of the microneedle,
and preferably is about 70 to 99% of the length of the microneedle.
Nevertheless, it is possible that in certain embodiments the length
of the channel will be between 1 to 50% of the length of the
microneedle. As such, the length of the tip portion beyond the
channel may vary, but usually is about 1 to 50% of the length of
the microneedle, and more usually is about 1 to 30% of the length
of the microneedle. The width of the channel, the length of the
channel, and the length of the microneedle may be varied to
increase or decrease the flow rate of the drug or the flow rate of
the biological fluid.
[0038] In one embodiment, the body portion of the microneedle is
rectangular with a centrally located channel extending through the
opposed longer sides of the body portion. In one particular
embodiment, the rectangular body portion has a long side
cross-sectional dimension between 1 .mu.m and 500 .mu.m and a short
side cross-sectional dimension between 1 .mu.m and 200
[0039] In a preferred embodiment, the microneedle has an untapered,
rectangular-shaped base portion having a longer side width of
between 50 .mu.m and 500 .mu.m and a shorter side width of between
20 .mu.m and 200 .mu.m. The channel is centrally located in the
microneedle and extends from an aperture in the substrate, through
the base portion, and into a tapered tip portion, and is open to
both of the longer sides of the base portion. In one embodiment,
the width of the channel is substantially constant along its length
in the base portion. In one case, the width of the channel is
between about 40 .mu.m and about 400 .mu.m, e.g., between 100 and
250 .mu.m.
[0040] Materials of Construction and Other Details
[0041] In preferred embodiments, the substrate, the microneedles,
or both, are formed of, or coated with, a biocompatible material.
The microneedles may be formed from the substrate material, or
alternatively, the microneedles can include a material different
from the substrate material. Representative examples of suitable
materials of construction include metals and alloys such as
stainless steels, palladium, titanium, and aluminum; and polymers
such as polyetherimide, polycarbonate, polyetheretherketone,
polyimide, polymethylpentene, polyvinyl idene fluoride,
polyphenylsulfone, liquid crystalline polymer, polyethylene
terephthalate (PET), polyethylene terephthalate-glycol modified
(PETG), polyimide, and polycarbonate. In a preferred embodiment,
the microneedles and substrate consist of a metal or alloy. In
another embodiment, the microneedles comprise a biocompatible
thermoplastic polymer. In a preferred embodiment, the substrate and
the microneedles are formed of the same material.
[0042] The microneedle material of construction preferably is
selected such that the microneedle is strong enough at its designed
dimensions for the microneedle to effectively pierce the stratum
corneum or other biological barrier without significant bending or
breaking of the microneedle. The microneedle and substrate
materials should be non-reactive with any drug formulation being
delivered or any analyte sampled.
[0043] The substrate, the microneedles, or both, optionally may
further include secondary materials of construction embedded
therein or coated thereon. For example, microparticles,
nanoparticles, fibers, fibrids, or other particulate materials may
be included. Examples of such materials include metals, carbon
siliceous materials, glasses, and ceramics. These secondary
materials may enhance one or more physical or chemical
characteristics of the microneedle array. For example, the
secondary material may be insulating layer or may improve the flow
or transport of the drug formulation through the apertures and
channels of the array. Representative examples of suitable
insulating materials include PET, PETG, polyimide, polycarbonate,
polystyrene, silicon, silicon dioxide, ceramic, glass, and the
like. In a preferred embodiment, a channel of the microneedle may
include one or more agents to facilitate fluid flow. For example,
one or more hydrophilic agents may be present on the interior
surfaces defining the channel. Examples of such hydrophilic agents
include, but are not limited to, surfactants. Exemplary surfactants
include MESA, Triton, Macol, Tetronic, Silwet, Zonyl, and
Pluronic.
[0044] The surface of the substrate that is in contact with the
surface of the biological barrier (e.g., the stratum corneum) may
be coated, in whole or in part, with a bonding substance that can
secure the microneedle patch to the biological barrier for an
extended period of time, e.g., for a duration required to release
all of the drug formulation to the biological barrier. Examples of
such bonding agents include adhesives and bioactive films, which
are activated by pressure, heat, light (UV, visible, or laser),
electric, magnetic fields, biochemical and electrochemical
reactions, or a combination thereof.
Microneedle Drug Delivery Device
[0045] In one embodiment, the microneedle array described herein is
included as part of a drug delivery device. The device may include
a drug storage element, which is a means for containing a drug
formulation for release to and through the microneedle array, for
transdermal administration of the formulation via the microneedle
array. In another embodiment, the drug formulation may be provided
as a coating, applied onto the surfaces of the microneedles and/or
the substrate of the microneedle array. Preferably, the drug
delivery device is in the form of a transdermal drug delivery
patch.
[0046] In a preferred embodiment, the drug storage element is
positioned adjacent to the substrate. For example, the drug storage
element may be attached to a first surface of the substrate,
wherein the first surface is opposed to a second surface of the
substrate from which the microneedles project. In a preferred
embodiment, the drug delivery device is in the form of a patch that
can be secured to the skin during transdermal administration of a
drug formulation through the microneedle array. In one embodiment,
the device includes a backing structure and adhesive surface
suitable for securing the device to the skin of a patient with the
microneedles in an inserted position in the skin. In a preferred
embodiment, the drug formulation comprises an adhesive compound.
The inserted microneedles may be secured by non-adhesive means
known in the art, such as an elastic band or a strap with
hook-and-loop fasteners, which can be wrapped around a patient's
limb over the microneedle patch. In a preferred embodiment, the
microneedles, drug storage element, and/or adhesive surface are
protected by a release liner which is removed before administration
of the drug delivery patch to the skin.
[0047] FIGS. 4A-B illustrate one embodiment of a transdermal drug
delivery patch device 50. As shown in FIG. 4A, the device 50
includes substrate 52, from which an array of microneedles 54
perpendicularly extends. The device 50 also includes a drug storage
element 70, which can release drug through apertures 60 in the
substrate 52. FIG. 4B shows device 50 with a release liner 80
partially removed to expose the microneedles and drug storage
element.
[0048] In a preferred embodiment, the drug storage element is
flexible and can conform to a contoured, or curved, surface. In one
embodiment, the drug storage element can be stretched or compressed
in a direction parallel to the plane in which the substrate
substantially lies.
[0049] In one embodiment, the drug formulation may be contained in
a drug storage element and also in the apertures and/or channels of
the microneedles. For example, the drug storage element may be
applied to the microneedle array and deformed to fill the apertures
in the substrate. In another instance, the drug storage element may
be applied to the microneedle array with the drug formulation in a
liquid form to fill the apertures in the substrate and/or
microneedles and then the drug formulation may be dried to a solid
or semisolid state.
[0050] In one embodiment, the drug storage element completely fills
the apertures and contacts the skin upon patch application. In one
embodiment, the drug storage element includes an adhesive material
and contains a drug formulation, wherein the adhesive material is
adapted to adhere to a patient's skin through the apertures, and
the drug formulation flows from the drug storage element, through
the apertures and the microneedles into the skin tissues beneath
the stratum corneum. In variations of this device, the adhesive may
adhere to the skin through a portion of the apertures and drug
formulation flows through a different portion of the apertures. The
apertures may occupy a substantial area of the substrate sufficient
to maintain securement of the microneedle array patch on the skin
for an extended period.
[0051] In a preferred embodiment, the drug storage element has at
least one sealed reservoir, which can be selectively punctured or
otherwise breached in a controlled manner to release a drug
formulation contained therein. In one embodiment, the drug storage
element includes a porous material, wherein the drug formulation is
stored in pores of the porous material. Representative examples of
suitable porous materials include open cell polymeric foams,
sheets/mats of woven or non-woven fibers, combinations thereof, and
the like. In another example, the drug storage element may be in
the form of one or more substantially flat pouches, for example,
made of two sheets of flexible thermoplastic polymeric film, sealed
along the edges to define a reservoir therebetween.
[0052] The "drug formulation" refers to essentially any therapeutic
or prophylactic agent known in the art (e.g., an active
pharmaceutical ingredient, or API), and typically includes one or
more biological acceptable carriers or excipients to facilitate
transdermal administration of the drug formulation. In one
embodiment, the drug formulation is a fluid drug formulation,
wherein the formulation can flow through apertures and/or channels
in the microneedle array; it may be a solution, suspension,
emulsion, or a combination thereof. In another embodiment, the drug
formulation comprises a solid formulation, wherein the transport of
drug through apertures and/or channels in the microneedle array, or
from the surface of the microneedles, involves diffusional
transport mechanisms, with little or no bulk flow. The drug
delivery device may include a drug formulation that includes a
combination of liquid and solid components, wherein transport of
the drug formulation involves both flow and mass diffusion.
[0053] The drug delivery device may include a means for causing a
drug formulation to be released from the drug storage element,
permitting the drug formulation to flow through the apertures in
the substrate, through apertures in the stratum corneum formed by
the microneedles, and into tissues of the patient, for local,
regional, or systemic therapeutic or prophylactic effect. In one
embodiment, the release is to and through the apertures in the
planar substrate and thus to the base end of the microneedle or
channel in the microneedle. In another embodiment, the release is
to and through a central bore in the microneedles. A wide variety
of release mechanisms for releasing the drug formulation from the
drug storage element can be envisioned by those skilled in the art.
These release mechanisms may utilize a mechanical force, heat, a
chemical reaction, an electric field, a magnetic field, a pressure
field, ultrasonic energy, vacuum, pressure, or a combination
thereof. In one embodiment, the release mechanism includes a means
for applying a compressive force to a porous material to expel the
drug formulation from the pores in the porous material. The means
for applying a compressive force can be in the form of a
spring-biased piston or button that can be manually depressed to
apply a direct or leveraged force onto the back of the drug storage
element. The same force optionally may cause the microneedles to be
inserted into the skin of a patient and/or cause a
pressure-sensitive adhesive surface on the device (e.g., inside the
apertures and on the periphery of a backing material) to become
adhered to the surface of the skin. In another embodiment, the drug
delivery device includes at least one puncturing barb extending
from the surface of the planar substrate (opposite the
microneedle), wherein the puncturing barb can be used to puncture
the sealed reservoir, e.g., upon application of a compressive force
to the reservoir. This barb could be one or more microneedles bent
in the opposite direction from the microneedles intended for skin
insertion.
[0054] The flow of the drug formulation through the channels or on
the microneedles into the biological barrier may be passive, e.g.,
the result of capillary and gravitational forces. Drug transport
may also involve molecular diffusion. Alternatively, the flow may
be actively assisted. In one embodiment, the drug delivery device
may include means for actively driving the drug formulation through
the microneedle channels and/or on the microneedles and into the
skin. For example, the flow of the drug formulation through the
channels into the biological barrier may be aided by application of
heat (e.g., generated by a series of microfabricated resistors), an
electric field, a magnetic field, a pressure field, a concentration
gradient, or any other physical force or energy. The application of
an electric field can comprise electrophoresis, iontophoresis,
electroosmosis, electroporation, or the like. The application of a
magnetic field can comprise magnetophoresis or the like. The
application of a pressure field can comprise pumping, applying
ultrasonic energy, applying vacuum, pressure, or the like.
[0055] The optional release liner of the transdermal drug delivery
patch is applied to the microneedle to protect the microneedles
and/or the drug storage element during manufacture, storage, and/or
handling of the patch device. The release liner is removed prior to
the application of the microneedle patch to the skin to expose the
microneedles and drug storage element. The release liner may be
designed to be removed manually or by an applicator device. The
release liner is typically thicker that the length of the
microneedles. The release liner may be flexible. In one embodiment,
the release liner is applied to the microneedle array onto the
microneedle side, and then a drug storage element applied to the
opposing side of the microneedle array as needed, e.g., immediately
before the microneedle array is applied to the skin. The
microneedle array and release liner may be rolled up, e.g., for
manufacturing, storage, or packaging, without the drug storage
element.
Microneedle Device for Fluid Withdrawal
[0056] In one embodiment, the microneedle array described herein is
included as part of a device for withdrawal of a biological fluid
from a patient, such as a diagnostic sensing device. The device
includes a collection reservoir for containing a withdrawn sample
of a biological fluid from holes in a patient's tissue formed by
the microneedle array. Preferably, the fluid withdrawal device is
in the form of a transdermal patch. The term "biological sample" or
"biological fluid" refers to blood, interstitial fluid, or another
biological fluid, or component thereof which may be withdrawn from
a biological tissue of a patient in an amount useful in diagnostic
analyses. For example, the biological sample may comprise a blood
sample for monitoring glucose, potassium, cholesterol, or other
analyte levels indicative of or relating to a medical condition of
the patient. As used herein, the term "patient" refers to animals,
particularly mammals, and especially humans.
[0057] In one embodiment, the collection reservoir is located
adjacent to the substrate. The collection reservoir preferably is
flexible and able to conform to a contoured surface, along with the
microneedle array. The reservoir may be attached to a first surface
of the substrate, wherein the first surface is opposed to a second
surface of the substrate from which the microneedles project. The
biological sample collection device may be in the form of a patch
that can be secured to the skin during transdermal
withdrawal/collection of a biological fluid sample over an extend
period. In one embodiment, the device, or patch, includes a backing
structure and an adhesive surface suitable for securing the device
to the skin of a patient with the microneedles in an inserted
position in the skin. The adhesive surface and/or microneedles of
the patch may be protected by a release liner, which is removable
before application of the microneedle array patch to the skin.
[0058] In one embodiment, the collection device includes an
adhesive material adapted to adhere to a patient's skin through the
apertures. In variations of this device, the adhesive may adhere to
the skin through a portion of the apertures and withdrawn
biological fluid flows through a different portion of the
apertures. The apertures may occupy a substantial area of the
substrate sufficient to maintain securement of the microneedle
array patch on the skin for an extended period.
[0059] In one embodiment, the biological sample collection device
may include one or more sensors in communication with the
collection reservoir, one or more of the microneedles, one or more
of the apertures, or combinations thereof. The sensor may be a
biosensor known in the art, such as an analyte sensor. The sensor
may be used to continuously or intermittently monitor an analyte
concentration during any period of time during which the
microneedle array patch is worn. In one embodiment, the sensor may
transmit collected data to an external device for further analysis
and/or display to a patient or healthcare provider.
[0060] The flow of the biological sample through the holes in the
biological tissue barrier (e.g., stratum corneum) made by the
microneedles (whether through a channel or bore therein or along
the outer surface of the microneedle) may be passive, e.g., the
result of capillary and gravitational forces, or may be actively
assisted. In one embodiment, the biological sample collection
device may include a means for actively driving transport of the
biological fluid. The transport assist means may utilize local heat
application (e.g., generated by a series of microfabricated
resistors), an electric field, a magnetic field, a pressure field,
a concentration gradient, or any other physical force or energy.
The application of an electric field can comprise electrophoresis,
iontophoresis, electroosmosis, electroporation, or the like. The
application of a magnetic field can comprise magnetophoresis or the
like. The application of a pressure field can comprise pumping,
applying ultrasonic energy, applying vacuum, pressure, or the
like.
Making the Microneedle Arrays
[0061] The microneedle arrays described herein can be made by using
or adapting a variety of fabrication techniques known in the art,
depending upon the particular materials of construction and the
particular microneedle/array design selected. In one embodiment,
the microneedle array is made using one or more conventional
microfabrication techniques. The microneedles may be formed
individually or the whole array of microneedles and substrate may
be formed in a single process. In a preferred embodiment, the
microneedle arrays are formed in mass (i.e., commercial scale)
quantities using inexpensive fabrication processes available in the
art.
[0062] In one embodiment, the microneedle array is made by a method
that includes (a) forming a flexible substrate which comprises a
plurality of apertures, each of which are defined by (i) a
plurality of substrate elements, and (ii) at least one spring
element connecting at least two of the substrate elements; and (b)
forming a plurality of microneedles, each having a base portion, a
tip end portion distal to the base portion, and body portion
therebetween, wherein the base portions of the microneedles are
integral with the substrate elements. Steps (a) and (b) may be
conducted simultaneously. In one embodiment, the method includes
forming in a planar substrate material the plurality of apertures,
the plurality of substrate elements, and the plurality of spring
elements, by removing selected portions of the substrate material.
The removal process may include embossing, injection molding,
casting, photochemical etching, electrochemical machining,
electrical discharge machining, precision stamping, high-speed
computer numerically controlled milling, Swiss screw machining,
soft lithography, directional chemically assisted ion etching,
laser cutting, or a combination thereof.
[0063] The forming of the microneedles may include forming the
microneedles in-plane with the substrate and then bending the
plurality of microneedles out-of-plane with the substrate, for
example, to a position substantially perpendicular to the substrate
surface. Alternatively, the microneedles may be fabricated
originally out-of-plane with the substrate (i.e., with no
intermediate in-plane structure). In a preferred embodiment,
photochemical etching can be used to fabricate the metal
microneedles that are initially out-of-plane with the substrate.
These various microneedle fabrication options allow the microneedle
arrays to be fabricated from any type of substrate material.
[0064] In a preferred embodiment, microneedles may be formed
in-plane or out-of-plane with the substrate using a
microreplication technique known in the art. Representative
examples of suitable microreplication techniques include embossing,
injection molding and casting processes. Such microreplication
techniques, and in particular embossing techniques, may provide low
cost manufacturing and also may advantageously enable the tip of
the microneedle to be extremely small (near infinitesimally small
cross-sectional area) and sharp. Furthermore, embossing techniques
allow precise, consistent fabrication of the microneedles.
[0065] In a preferred embodiment, an embossing technique is used.
In one process using an embossing technique, a planar substrate
material, such as a suitable thermoplastic precursor material, is
placed into an embossing apparatus, where such an apparatus
includes a mold having features of a microneedle array as described
herein. (The mold may have a negative image of the features of the
microneedles, substrate elements, and spring elements) The
precursor material is then compressed by the mold under heat and a
suitable compression force. In one embodiment, the substrate
material has a thickness in the range of about 25 .mu.m to about
650 .mu.m, preferably from about 50 .mu.m to about 625 .mu.m, and
more preferably from about 75 .mu.m to about 600 .mu.m. In one
embodiment, the substrate material is heated temperature in the
range of about 20.degree. C. to 1500.degree. C., preferably from
about 100.degree. C. to 1000.degree. C., more preferably from about
200.degree. C. to 500.degree. C. The heat is usually applied to the
substrate material for about 0.1 seconds to 1000 seconds,
preferably for about 0.1 seconds to 100 seconds, and more
preferably about 0.1 seconds to 10 seconds. The compression force
may range from about 1 GPa to 50 GPa, preferably from about 10 GPa
to 40 GPa, and more preferably from about 20 GPa to 30 GPa. The
compression force may be applied for about 0.01 seconds to 100
seconds, preferably for about 0.01 seconds to 10 seconds, and more
preferably about 0.01 seconds to 1 second. The heat and compression
force may be applied at the same time or different times. After the
substrate material is cooled, it is removed from the embossing
apparatus, yielding an embossed array of microneedles, which may be
in-plane or out-of-plane. If the microneedles of the embossed array
are in-plane with the substrate, then the microneedles subsequently
are subjected to a bending step to fix them into an out-of-plane
orientation relative to the substrate.
[0066] The step of bending in-plane microneedles of an intermediate
structure into an out-of-plane position to form a microneedle array
can be done using a variety of different methods, to effect
application of a direct or indirect force that causes plastic
and/or elastic deformation of the microneedles, preferably limited
to the base portion thereof. In one example, the bending of the
microneedles out-of-plane with the substrate may be facilitated by
the use of a mold (e.g., a metal mold) having protrusions
corresponding to the number and position of the microneedles in the
intermediate structure, whereby the mold can be engaged (e.g.,
compressed) with the intermediate structure, the compressive force
between the protrusions and the microneedles causing all of the
microneedles to bend (at their base portions) simultaneously
out-of-plane. In another example, the microneedle array can be
pressed between a thick elastic film (e.g., rubber or polyurethane)
and a mold having cavities corresponding to the number and position
of the microneedles to bend the microneedles out-of-plane with the
substrate simultaneously. The compressive force squeezes the thick
elastic film into the cavities on the opposite side of the
substrate, and the thick elastic film consequently bends the
microneedles out-of-plane with the substrate and into the
cavities.
[0067] Heat and/or various auxiliary pressures can be used in
conjunction with the bending force to facilitate the bending of the
microneedles. For example, a heated high-speed liquid or gas can be
flowed in a direction substantially perpendicular to the plane of
the substrate comprising plastic microneedles. The plastic
microneedles are heated by the flowing fluid, undergo a plastic
transition, and then are bent out-of plane with the substrate by
the force of the high-speed fluid. In other embodiments, the step
of bending the in-plane microneedles may include directly or
indirectly applying an electric field or a magnetic field to
microneedles.
[0068] FIG. 3 illustrates a close-up view of one embodiment of an
intermediate microneedle structure 30. The intermediate structure
30 includes a planar substrate 32 and a plurality of microneedles
34, which lie in the plane of the substrate. The structure 30
includes apertures 40, each of which are defined by one microneedle
34, the long side of two elongated substrate elements 36 (the base
portion 42 of the microneedle being integral with one of these
substrate elements), the short side of two other elongated
substrate elements 36, and four spring elements 38. Each
microneedle 34 has an elongated through channel 48, which extends
from the substrate element 36 into the tip portion of the
microneedle. To complete the microneedle array from this
intermediate structure, the microneedles 34 will be bent
out-of-plane from the substrate 32. This bending desirably will
form a curve segment in the base portion 42 of the microneedle
adjacent the substrate element.
[0069] The microneedle arrays and drug storage elements or
collection reservoir can be made separately and then assembled
using techniques known in the art for adapting a conventional
microneedle array into a drug delivery or fluid withdrawal device.
This assembly and packaging preferably is done in an aseptic or
sterile environment.
Use of Devices Which Include the Microneedle Array
[0070] Drug delivery devices and biological sample collection
devices which include the microneedle arrays described herein may
be used to administer a drug formulation to, or withdraw a
biological fluid sample from, a patient across a biological
barrier. The biological barrier typically is human or other
mammalian skin, although other tissue surfaces may be
envisioned.
[0071] The transdermal administration of a drug to a patient in
need thereof may include the steps of (a) inserting into the skin
of the patient the microneedles of a drug delivery device that has
a drug storage element containing a drug formulation, and then (b)
causing the drug formulation to be transported from the drug
storage element, and through holes (made by the inserted
microneedles) in the stratum corneum of the patient's skin. In one
embodiment of a drug delivery device, a drug formulation is
released from a drug storage element, and flows to the microneedle
array, where it passes through the apertures in the substrate of
the array and then enters the channels (or bores, or grooves) in
the microneedles at the base of the microneedles. The drug
formulation is transported through the channel (or bore or groove),
traversing the stratum corneum and then entering the epidermis,
dermis, and/or subcutaneous skin tissues. The drug formulation may,
in addition or in the alternative, travel along on the outside of
the inserted microneedles, to traverse the stratum corneum. After
administration of the drug formulation is complete, the
microneedles are removed from the skin.
[0072] The transport of the drug formulation from the device and
through the biological barrier can be passively or actively
assisted. In various embodiments, the drug formulation is
transported under the influence or assistance of capillary forces,
gravitational forces, overpressure, vacuum, an electric field, a
magnetic field, iontophoresis, a molecular concentration gradient,
or a combination thereof. One skilled in the art can utilize or
readily adapt any of these means using technology known in the
art.
[0073] The transdermal withdrawal of a biological fluid sample from
a patient may include the steps of (a) inserting into the skin of
the patient the microneedles of a biological sample collection
device that has a reservoir, and then (b) causing the biological
fluid to be transported from the stratum corneum of the skin, into
and through at least one channel of at least one of the
microneedle, and to the reservoir. In one embodiment of a
biological fluid sampling device, blood or interstitial fluid flows
from the epidermis, dermis, and/or subcutaneous skin tissues to the
inserted microneedles. The fluid enters the channels (or bores, or
grooves) in the microneedles, and/or travels along on the outside
of the inserted microneedles, to traverse the stratum corneum,
where it passes through the apertures in the substrate of the array
and then into a collection reservoir. After withdrawal of an
appropriate sample size, or upon completion of an extended
diagnosis or sensing period, the microneedles are removed from the
skin.
[0074] The transport of the biological fluid can be passively or
actively assisted. In various embodiments, the biological fluid is
transported under the influence or assistance of capillary forces,
gravitational forces, overpressure, vacuum, an electric field, a
magnetic field, iontophoresis, a molecular concentration gradient,
or a combination thereof. One skilled in the art can utilize or
readily adapt any of these means using technology known in the
art.
[0075] The microneedles of the disclosed devices can be inserted
into the skin by a variety of means, including direct manual
application or with the aid of an applicator device to insure
uniform and proper microneedle penetration, consistently within a
single array and across different arrays. The applicator device may
be completely mechanical or it may be electromechanical. The
applicator device may include pressure sensors in communication
with an electronically controlled release mechanism, to insure that
a device is applied to the skin with the desired force each time.
Optionally, the applicator device may include hardware, software,
and power source components to provide heat, electrical field,
magnetic field, pressure, or other drug delivery assistance means
known in the art. In addition, the applicator device may also
automatically remove the release liner from the microneedle patch
before or during the application of the microneedle patch to the
skin. The applicator device may include one or more rollers for use
in applying an even pressure to the patches described above to
ensure that it is completely secured to the skin. The roller may,
for example, further secure a pressure sensitive adhesive surface
around the periphery of the patch.
[0076] Publications cited herein are incorporated by reference. The
foregoing description of various embodiments of the present
invention is presented for purposes of illustration and
description. The description is not intended to be exhaustive or to
limit the invention to the precise form disclosed. The embodiments
were chosen and described in order to best illustrate the
principles of the invention and its practical application to
thereby enable one of ordinary skill in the art to best utilize the
invention and various embodiments with various modifications as are
suited to the particular use contemplated. Modifications and
variations of the methods and devices described herein will be
obvious to those skilled in the art from the foregoing detailed
description. Such modifications and variations are intended to come
within the scope of the appended claims.
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