U.S. patent application number 11/917705 was filed with the patent office on 2008-09-04 for coated microstructures and methods of manufacture thereof.
This patent application is currently assigned to GEORGIA TECH RESEARCH CORPORATION. Invention is credited to Harvinder Singh Gill, Mark R. Prausnitz.
Application Number | 20080213461 11/917705 |
Document ID | / |
Family ID | 37571292 |
Filed Date | 2008-09-04 |
United States Patent
Application |
20080213461 |
Kind Code |
A1 |
Gill; Harvinder Singh ; et
al. |
September 4, 2008 |
Coated Microstructures and Methods of Manufacture Thereof
Abstract
Coated microneedle devices and methods of making such devices
are provided. In one aspect, a method for coating includes
providing a microstructure having at least one surface in need of
coating; and applying a coating liquid, which comprises at least
one drug, to the at least one surface of the microstructure,
wherein the surface energy of the coating liquid is less than the
surface energy of the surface of the microstructure. The coating
liquid may include a viscosity enhancer and surfactant.
Microneedles having heterogeneous coatings, pockets, or both are
also provided.
Inventors: |
Gill; Harvinder Singh;
(Atlanta, GA) ; Prausnitz; Mark R.; (Atlanta,
GA) |
Correspondence
Address: |
SUTHERLAND ASBILL & BRENNAN LLP
999 PEACHTREE STREET, N.E.
ATLANTA
GA
30309
US
|
Assignee: |
GEORGIA TECH RESEARCH
CORPORATION
Atlanta
GA
|
Family ID: |
37571292 |
Appl. No.: |
11/917705 |
Filed: |
June 19, 2006 |
PCT Filed: |
June 19, 2006 |
PCT NO: |
PCT/US2006/023814 |
371 Date: |
December 14, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60691857 |
Jun 17, 2005 |
|
|
|
60732267 |
Nov 1, 2005 |
|
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Current U.S.
Class: |
427/2.3 ;
604/46 |
Current CPC
Class: |
B05D 1/32 20130101; A61M
2037/0046 20130101; A61M 2037/0053 20130101; A61K 9/0021 20130101;
A61M 37/0015 20130101; B05D 5/00 20130101; A61K 9/0097
20130101 |
Class at
Publication: |
427/2.3 ;
604/46 |
International
Class: |
B05D 5/00 20060101
B05D005/00; A61M 37/00 20060101 A61M037/00 |
Goverment Interests
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0002] This invention was made with U.S. government support under
Contract No. 8 RO1 EB00260-03 awarded by the National Institute of
Health. The U.S. government has certain rights in the invention.
Claims
1. A microneedle device for insertion of a drug into a biological
tissue comprising: at least one microneedle having a base, a tip
end, and a shaft portion therebetween; and a coating on at least a
portion of the surface of the at least one microneedle, the coating
comprising at least one drug and a viscosity enhancer.
2. The microneedle device of claim 1, wherein the coating further
comprises a surfactant.
3. The microneedle device of claim 1, wherein the viscosity
enhancer comprises cellulose, a cellulose derivative, hyaluronic
acid, xanthan gum, alginic acid, alginic acid derivative,
polyvinylpyrollidone, acacia, guar gum, or a carbohydrate
4. The microneedle device of claim 1, wherein the coating has a
heterogeneous composition.
5. The microneedle device of claim 4, wherein the coating comprises
discrete particles.
6. The microneedle device of claim 4, wherein the coating comprises
two or more discrete layers.
7. The microneedle device of claim 4, wherein the coating comprises
at least two different phases.
8. The microneedle device of claim 1 wherein the shaft portion of
the at least one microneedle comprises one or more pockets
therein.
9. The microneedle device of claim 8, wherein the coating is
located substantially only in the one or more pockets.
10. The microneedle device of claim 8, wherein the one or more
pockets contain at least a portion of the coating and the coating
comprises a liquid, gel, microparticles, or a combination
thereof.
11. The microneedle device of claim 1, wherein the coating further
comprises a hydrogel.
12. The microneedle device of claim 11, wherein the hydrogel
coating is in a dried state.
13. The microneedle device of claim 1, wherein all of the coating
is adapted to come off of the microneedle following insertion into
a biological tissue.
14. The microneedle device of claim 13, wherein the coating is
adapted to come off of the microneedle in fifteen minutes or less
following insertion into a biological tissue.
15. The microneedle device of claim 14, wherein the coating
comprises drug dispersed in a matrix material which provides
controlled release of the drug.
16. The microneedle device of claim 14, wherein the drug is a
hydrophobic molecule and the coating further comprises an
amphiphilic material.
17. The microneedle device of claim 1, wherein at least a portion
of the coating is adapted to remain on the microneedle following
insertion into a biological tissue.
18. The microneedle device of claim 17, wherein substantially all
of the coating is adapted to remain on the microneedle, which may
be a sensor, following insertion into a biological tissue.
19. The microneedle device of claim 1, further comprising a precoat
material disposed between at least a portion of the at least one
microneedle and the coating which comprises the drug.
20. The microneedle device of claim 19, wherein the precoat
material alters the surface energy of the microneedle.
21. A microneedle device for insertion of a drug into a biological
tissue comprising: at least one microneedle having a base, a tip
end, and a shaft portion therebetween; and a coating on at least a
portion of the surface of the at least one microneedle, the coating
comprising at least one drug, wherein the coating has a
heterogeneous composition.
22. The microneedle device of claim 21, wherein the coating
comprises discrete particles, two or more discrete layers, two
different phases, or a combination thereof.
23. The microneedle device of claim 21, wherein the shaft portion
of the at least one microneedle comprises one or more pockets
therein.
24. A microneedle device for insertion of a drug into a biological
tissue comprising: at least one microneedle having a base, a tip
end, and a shaft portion therebetween; and a coating on at least a
portion of the surface of the at least one microneedle, the coating
comprising at least one drug, wherein the shaft portion of the at
least one microneedle comprises one or more pockets therein.
25. The microneedle device of claim 24, wherein the coating is
located substantially only in the one or more pockets.
26. The microneedle device of claim 24, wherein the one or more
pockets contain at least a portion of the coating and the coating
is in the form of a liquid, gel, microparticles, or a combination
thereof.
27. The microneedle device of claim 1, wherein the at least one
microneedle is formed of stainless steel, titanium, or another
metal.
28. The microneedle device of claim 27, wherein the microneedles
are electropolished.
29. The microneedle device of claim 1, which comprises two or more
of the microneedles.
30. (canceled)
31. A method for coating a microstructure comprising: providing a
microstructure having at least one surface in need of coating; and
applying a coating liquid, which comprises at least one drug, to
the at least one surface of the microstructure, wherein the surface
energy of the coating liquid is less than the surface energy of the
surface of the microstructure.
32-46. (canceled)
47. A method for coating at least one microneedle comprising:
providing a coating liquid disposed in one or more reservoirs, the
coating liquid comprising at least one drug; providing a physical
mask having one or more apertures, each aperture having
cross-sectional dimensions larger than the at least one microneedle
to be coated; aligning the at least one microneedle with at least
one of the one or more apertures; inserting the at least one
microneedle through the aligned aperture and into the coating
liquid, thereby coating at least a portion of the microneedle; and
removing the coated microneedle from the coating liquid and from
the aperture.
48. The method of claim 47, wherein the physical mask comprises a
plurality of holes or slits which closely circumscribe each
microneedle or a single row of microneedles.
49. The method of claim 48, wherein the physical mask is in the
form of a rigid plate secured to the reservoir.
50. The method of claim 47, wherein the one or more reservoirs are
defined in a secondary structure.
51. The method of claim 47, wherein the physical mask has a
plurality of the reservoirs defined in the physical mask.
52. The method of claim 47, wherein the step of inserting the
microneedle through the aligned aperture is done before moving both
the physical mask and the microneedle in a manner to cause the
microneedle to be dipped into the coating liquid.
53. The method of claim 47, further comprising inserting the at
least one microneedle into the same or a different coating liquid
and then removing the microneedle from said same or different
coating liquid.
54. The method of claim 47, wherein the at least one microneedle
comprises one or more pockets therein.
55-62. (canceled)
63. A method of making a microneedle device comprising: forming one
or more microneedles from a metal; and electropolishing the one or
more microneedles to smooth the surfaces of the microneedles.
64. (canceled)
65. A microneedle patch comprising: an array two or more
microneedles extending out of plane from a substrate; and an
adhesive material disposed between the two or more microneedles,
the adhesive material comprising an adhesive suitable for removably
securing the microneedle patch to a patient's skin.
66-67. (canceled)
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims benefit of U.S. Provisional
Application No. 60/691,857, filed Jun. 17, 2005, and U.S.
Provisional Application No. 60/732,267, filed Nov. 11, 2005. Those
applications are incorporated herein by reference in their
entirety.
BACKGROUND OF THE INVENTION
[0003] This invention is generally in the field of microneedles
useful in medical applications, and more particularly to coated
microneedles for drug delivery and sensing, such as
transdermally.
[0004] Biopharmaceuticals, such as peptides, proteins, and future
uses of DNA and RNA, represent a rapidly growing segment of
pharmaceutical therapies (Walsh, Trends Biotechnol 23:553-58
(2005)). These drugs are delivered almost exclusively by the
parenteral route, as the oral route is generally unavailable due to
poor absorption, drug degradation, and low bioavailability.
However, conventional parenteral administration with hypodermic
needles undesirably requires expertise for delivery, can lead to
accidental needle sticks, and causes pain, which results in reduced
patient compliance. Given these problems, efforts have been made to
develop alternate drug delivery routes to replace hypodermic
needles (Orive et al., Curr Opin Biotechnol 14:659-64 (2003)). It
would be desirable to provide drug delivery methods and devices
that avoid the limitations and disadvantages associated with the
use of conventional hypodermic needles.
[0005] Transdermal drug delivery is an especially attractive
alternative to conventional hypodermic needles, because it is
usually easy to use, safe, and painless (Prausnitz et al., Nat Rev
Drug Discov 3:115-24 (2004)). The tough barrier posed by the skin's
outer layer of stratum corneum has limited the applicability of
this method to drugs that are hydrophobic, low molecular weight,
and potent, as the stratum corneum's barrier properties severely
limit passive delivery of most drugs, especially macromolecules and
microparticles.
[0006] The use of micron-scale needles assembled on a transdermal
patch has been proposed as a hybrid between hypodermic needles and
transdermal patches that can overcome the problems of both
injections and patches (Prausnitz et al., Microneedles In
Percutaneous Penetration Enhancers (Smithand & Maibach, eds),
pp. 239-55, CRC Press, Boca Raton, Fla., 2005)). Microneedles have
been shown to be painless in human subjects relative to hypodermic
needles (Mikszta et al., Nat. Med. 8:415-19 (2002); Kaushik et al.,
Anesth Analg 92:502-04 (2001). Unlike transdermal patches,
microneedles also have been successfully used to deliver a variety
of compounds into the skin, including macromolecules. In vitro skin
permeability enhancement of two to four orders of magnitude has
been observed for small molecules (e.g., calcein) and large
compounds (e.g., proteins and nanoparticles) (Henry et al., J Pharm
Sci 87:922-25 (1998); McAllister, et al., Proc Natl Acad Sci USA
100:13755-60 (2003)). In vivo delivery has been shown for peptides,
such as insulin and desmopressin (Martanto et al., Pharm. Res.
21:947-52 (2004); Cormier, et al., J Control Release 97:503-11
(2004)); genetic material, including plasmid DNA and
oligonucleotides (Lin et al., Pharm. Res. 18:1789-93 (2001); Chabri
et al., Br J Dermatol 150:869-77 (2004)); and vaccines directed
against hepatitis B and anthrax (Mikszta et al., Nat. Med. 8:415-19
(2002); Mikszta et al., J Infect Dis 191:278-88 (2005)).
[0007] Four different modes of microneedle-based drug delivery have
been primarily investigated (Prausnitz, Adv Drug Deliv Rev
56:581-87 (2004); Prausnitz et al., Microneedles In Percutaneous
Penetration Enhancers (Smithand & Maibach, eds), pp. 239-55,
CRC Press, Boca Raton, Fla., 2005). These modes are (1) piercing an
array of solid microneedles into the skin followed by application
of a drug patch at the treated site (Henry, J. Pharm. Sci.
87:922-25 (1998)); (2) coating drug onto microneedles and inserting
them into the skin for subsequent dissolution of the coated drug
within the skin (Cormier et al., J Control Release 97:503-11
(2004)); (3) encapsulating drug within biodegradable, polymeric
microneedles followed by insertion into skin for controlled drug
release (J-H Park, et al., Pharma. Res. 23:1008-19 (2006)); and (4)
injecting drug through hollow microneedles (Zahn et al., Biomed
Microdevices 2:295-303 (2000)).
[0008] Among these approaches, coated microneedles are attractive
for rapid bolus delivery of high molecular weight molecules into
the skin, which can be implemented as a simple `Band-Aid`-like
system for self-administration. Furthermore, storing a drug in a
solid phase coating on microneedles may enhance long-term stability
of the drug, even at room temperature. For instance, desmopressin
coated onto microneedles has been shown to maintain 98% integrity
after six months storage under nitrogen at room temperature
(Cormier et al.,. J Control Release 97:503-11 (2004)). Coated
microneedles are also particularly attractive for vaccine delivery
to the skin, because antigens can be targeted to epidermal
Langerhans cells and dermal dendritic cells for a more potent
immune response. For example, a strong immune response against a
model ovalbumin antigen delivered from coated microneedles has been
shown in guinea pigs (Matriano et al., Pharm Res 19:63-70
(2002)).
[0009] While the microneedle itself can be fabricated by adapting
the tools of the microelectronics industry for inexpensive, mass
production (Reed & Lye, Proc IEEE 92:56-75 (2004)), precise
coating of microneedles presents technical challenges. Among the
various conventional coating processes, such as dip coating, roll
coating and spray coating (Bierwagen, Electrochim. 37:1471-78
(1992)), dip coating is particularly appealing for coating
microneedles because of its apparent simplicity and ability to coat
complex shapes. A conventional dip-coating process typically
involves submerging and withdrawing an object from a coating
solution, and then drying the continuous liquid film adhering to
the surface of the object to yield a solid coating. However, such
dip coating to coat microneedles by simply dipping and withdrawing
them from an aqueous solution of a compound (e.g., calcein,
sulforhodamine or vitamin B) results in non-uniform coatings with
frequent spreading of the solution to the substrate from which the
microneedles extend. Moreover, predictions of dip-coating theory to
produce uniform coatings from different coating solutions mostly
apply to static equilibrium systems; dynamic systems as in the case
of dip coating are more complex. In addition, because surface
tension-driven phenomena often take place on the micron scale,
conventional dip-coating methods have difficulty coating specified
sections of micron-dimensioned structures, especially when those
structures are closely spaced. For instance, bridging of liquid
coating material between closely spaced microneedles is
problematic. It therefore would be desirable to provide a
micron-scale, dip coating process to coat microneedles with uniform
and spatially controlled coatings using methods suitable for a
breadth of drugs and biopharmaceuticals.
[0010] U.S. Pat. No. 6,855,372 to Trautman et al. discloses
processes and apparatus for coating skin-piercing microprojections,
in which dipping is done by moving the microprojections
tangentially across and through a thin film of liquid on a rotating
drum. Usefulness of the process would appear to be limited due to
the tendency of ripple formation in the film while dipping
microprojections. Ripples would cause liquid to touch and coat the
substrate that carries the microprojections or would cause
differences in coating length of microprojections on the leading
and trailing edge of the array. The method also would appear be
restricted to certain dip lengths and to certain microprojection
spacings, given that wicking of liquid up between closely spaced
microprojections and onto the base of the device would still be
expected to be a problem. It therefore would be desirable to
provide microneedle coating processes that reduces or eliminates
between-needle wicking and offers better coating uniformity and
better control of dip/coating length on each microneedle. It would
also be desirable to provide improved methods for precisely coating
microneedles or other microstructures with a variety of materials,
including materials other than homogeneous liquid solutions.
SUMMARY OF THE INVENTION
[0011] Coated microneedle devices and methods of making such
devices are provided. In one aspect, a method for coating includes
providing a microstructure having at least one surface in need of
coating; and applying a coating liquid, which comprises at least
one drug, to the at least one surface of the microstructure,
wherein the surface energy of the coating liquid is less than the
surface energy of the surface of the microstructure. The method may
further include precoating the at least one surface of the
microstructure with a material to increase the surface energy of
said surface, and/or modifying the coating liquid to decrease the
surface tension of said coating liquid. The coating liquid may be
aqueous, may include a viscosity enhancer and/or a surfactant. The
method may include volatilizing at least a portion of a solvent, if
used in the coating liquid, to form a solid coating. The coating
liquid may comprises a molten material having a melting temperature
greater than 25.degree. C., which is then cooled to for a solid
coating. In a preferred embodiment, the microstructure is a single
microneedle or an array of two or more microneedles. In a preferred
embodiment, a physical mask is utilized during application of the
coating liquid to the microstructure.
[0012] In one embodiment, a method for coating at least one
microneedle includes the steps of providing a coating liquid
disposed in one or more reservoirs, the coating liquid comprising
at least one drug; providing a physical mask having one or more
apertures, each aperture having cross-sectional dimensions larger
than the at least one microneedle to be coated; aligning the at
least one microneedle with at least one of the one or more
apertures; inserting the at least one microneedle through the
aligned aperture and into the coating liquid, thereby coating at
least a portion of the microneedle; and removing the coated
microneedle from the coating liquid and from the aperture. The
physical mask may include a plurality of holes or slits which
closely circumscribe each microneedle or a single row of
microneedles. The one or more reservoirs may be defined in a
secondary structure, or the physical mask may have a plurality of
the reservoirs defined therein. In one embodiment, the physical
mask is in the form of a rigid plate secured to the reservoir. The
coating liquid in the reservoir preferably is agitated or flowed to
maintain composition uniformity.
[0013] In one embodiment, the step of inserting the microneedle
through the aligned aperture is done before moving both the
physical mask and the microneedle in a manner to cause the
microneedle to be dipped into the coating liquid.
[0014] In another embodiment, the method further includes inserting
the at least one microneedle into the same or a different coating
liquid and then removing the microneedle from said same or
different coating liquid.
[0015] In another aspect, a microneedle device for insertion of a
drug into a biological tissue is provided that includes at least
one microneedle having a base, a tip end, and a shaft portion
therebetween; and a coating on at least a portion of the surface of
the at least one microneedle, the coating comprising at least one
drug and a viscosity enhancer. The coating may further include a
surfactant. The viscosity enhancer may include cellulose, a
cellulose derivative, hyaluronic acid, xanthan gum, alginic acid,
alginic acid derivative, polyvinylpyrollidone, acacia, guar gum, or
a carbohydrate. The coating may have a heterogeneous composition,
which may include discrete particles, two or more discrete layers,
or two or more different phases. The coating may include a
hydrogel, and the hydrogel coating may be in a dried state or
hydrated state.
[0016] In one embodiment, all of the coating is adapted to come off
of the microneedle following insertion into a biological tissue.
For example, the coating may be adapted to come off of the
microneedle in fifteen minutes or less following insertion into a
biological tissue.
[0017] In one case, the coating comprises drug dispersed in a
matrix material which provides controlled release of the drug. In
another case, the drug is a hydrophobic molecule and the coating
further comprises an amphiphilic material.
[0018] In another embodiment, at least a portion of the coating is
adapted to remain on the microneedle following insertion into a
biological tissue. In still another embodiment, substantially all
of the coating is adapted to remain on the microneedle, which may
be a sensor, following insertion into a biological tissue.
[0019] In another aspect, a microneedle device is provided for
insertion of a drug into a biological tissue, which includes at
least one microneedle having a base, a tip end, and a shaft portion
therebetween; and a coating on at least a portion of the surface of
the at least one microneedle, the coating comprising at least one
drug, wherein the coating has a heterogeneous composition. The
coating may include discrete particles, two or more discrete
layers, two different phases, or a combination thereof.
[0020] In another aspect, a microneedle device for insertion of a
drug into a biological tissue is provided which includes at least
one microneedle having a base, a tip end, and a shaft portion
therebetween; and a coating on at least a portion of the surface of
the at least one microneedle, the coating comprising at least one
drug, wherein the shaft portion of the at least one microneedle
comprises one or more pockets therein. The coating may be located
substantially only in the one or more pockets. The one or more
pockets may contain at least a portion of the coating where the
coating is in the form of a liquid, gel, microparticles, or a
combination thereof.
[0021] The at least one microneedle of these devices is formed of
stainless steel, titanium, or another metal. In a preferred
embodiment, the microneedles are electropolished. In preferred
embodiments, the microneedle device includes two or more of the
microneedles. The drug preferably is a therapeutic, diagnostic, or
prophylactic agent.
[0022] In another aspect, a method is provided for making a
microneedle device, which includes forming one or more microneedles
from a metal; and electropolishing the one or more microneedles to
smooth the surfaces of the microneedles. The step of forming may
include laser cutting.
[0023] In still another aspect, a microneedle patch is provided
which includes an array two or more microneedles extending out of
plane from a substrate; and an adhesive material disposed between
the two or more microneedles, the adhesive material comprising an
adhesive suitable for removably securing the microneedle patch to a
patient's skin. The adhesive material may include a double-sided
adhesive tape. It may be a pressure sensitive adhesive. In another
embodiment, the adhesive material results from application of a
liquid adhesive material to the substrate.
BRIEF DESCRIPTION OF THE DRAWINGS
[0024] FIG. 1A is a cross-sectional view of one embodiment of an
in-plane microneedle row-coating device showing the coating
solution reservoir with the microneedle row aligned with the dip
holes. FIG. 1B is a perspective view of the in-plane microneedle
row-coating device having x, y and z-micropositioners and a
stereomicroscope objective. One embodiment of a coating device for
coating an array of microneedles is shown in FIGS. 1C-1E, which
includes a first portion (FIG. 1C) that includes a rectangular
etched channel to hold coating solution, a feeding port, and
alignment holes, and a second portion (FIG. 1D) that includes a
physical mask with dip holes apertures and alignment holes. FIG. 1E
shows a plan view of the two portions assembled.
[0025] FIGS. 2A-B show one embodiment of individual microneedles
imaged by a scanning electron microscope after cleaning with
powdered detergent and after electropolishing, respectively.
[0026] FIGS. 3A-D are scanning electron microscope images showing
different microneedle geometries including different lengths and
widths with a tip angle of 55.degree., pockets of different shapes
and sizes in microneedles, and different grooved surfaces,
respectively in FIGS. 3A-C, and an out-of-plane array (FIG.
3D).
[0027] FIGS. 4A-B show examples of microneedles having good coating
results using brightfield microscopy using a vitamin B coating
solution. FIG. 4C shows various embodiments of microneedles having
different coating lengths.
[0028] FIGS. 5A-G show a variety of molecules and particles coated
onto certain embodiments of single microneedles as seen using
fluorescence or brightfield microscopy.
[0029] FIGS. 6A-F show the effect of the surface tension and
viscosity of different coating formulations on microneedle coating
uniformity.
[0030] FIGS. 7A-B are graphs indicating the mass of vitamin B
coated on different microneedles in various embodiments.
[0031] FIGS. 8A-B illustrate one embodiment of a process for
assembling a microneedle patch including coated in-plane
microneedle rows as described herein.
[0032] FIGS. 9A-B illustrate another embodiment of a process for
assembling a microneedle patch including coated out-of-plane
microneedle arrays as described herein.
[0033] FIGS. 10A-B are cross-sectional views of microneedles in a
microneedle array which are dipped into a coating liquid using a
physical mask to control deposition of coating, with mask having
multiple closed dip holes built into the mask (FIG. 10A) or a
single reservoir in fluid communication with open dip holes (FIG.
10B).
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0034] Coated microneedle devices and methods of coating
microneedles have been developed to produce microneedles and
microneedle arrays having a variety of coatings improvements,
enabling a wide range of drug materials to be controllably coated
onto microneedles and then delivered into biological tissues,
particularly for transdermal drug delivery. The methods provide for
uniform coatings, for coatings of particles or other heterogeneous
coatings. The microneedle shafts may include pockets for containing
coating materials, particularly liquid, gel, and particle coatings.
In a preferred embodiment, these microneedle coating includes a
solid coating that contains or consists of at least one drug. The
coated microneedles may be incorporated into a transdermal drug
delivery patch or other drug delivery device.
[0035] The coating process can reproducibly produce uniform,
substantially continuous coatings on precise portions of the
microneedles' shafts without bridging or patchiness, thereby
providing enhanced dosage control in the manufacturing of drug
coated microneedles. This is accomplished by various means of
providing that the coating liquid precisely contacts the
microneedle or selected portion thereof. In one embodiment, devices
and methods have been developed to limit deposition of the coating
to the microneedle. By avoiding deposition of the coatings onto the
substrates having the microneedles, dosage control is improved and
product loss during coating is minimized.
[0036] As used herein, the term "biological tissue" includes
essentially any cells, tissue, or organs, including the skin or
parts thereof, mucosal tissues, vascular tissues, lymphatic
vessels, ocular tissues (e.g., cornea, conjunctiva, sclera), and
cell membranes. The biological tissue can be in humans or other
types of animals (particularly mammals), as well as in plants,
insects, or other organisms, including bacteria, yeast, fungi, and
embryos. Human skin and sclera are biological tissues of particular
use with the present microneedle devices and methods of use
thereof.
[0037] As used herein, the terms "comprise," "comprising,"
"include," and "including" are intended to be open, non-limiting
terms, unless the contrary is expressly indicated.
Coated-Microneedle Devices
[0038] In one aspect, a microneedle device is provided for
insertion of a drug into a biological tissue. In a preferred
embodiment, the device includes at least one microneedle having a
base, a tip end, and a shaft portion therebetween, and a coating on
at least a portion of the surface of the microneedle, wherein the
coating comprises a drug and a viscosity enhancer.
[0039] In another aspect, a microneedle device is provided which
includes at least one microneedle having a base, a tip end, and a
shaft portion therebetween, and a coating on at least a portion of
the surface of the microneedle, wherein the coating includes at
least one drug and is a heterogeneous composition. For instance,
the coating may have discrete particles, two or more discrete
layers, two different phases, or a combination thereof. The drug
may be in the particles, one or more of the layers, or one or more
of the different phases.
[0040] In yet another aspect, a microneedle device is provided
which includes at least one microneedle having a base, a tip end,
and a shaft portion therebetween, and a coating on at least a
portion of the surface of the microneedle, wherein the coating
includes at least one drug and the shaft portion of the microneedle
has one or more pockets therein.
[0041] Microneedles
[0042] The microneedle can be formed/constructed of different
biocompatible materials, including metals, glasses, semi-conductor
materials, ceramics, or polymers. Examples of suitable metals
include pharmaceutical grade stainless steel, gold, titanium,
nickel, iron, tin, chromium, copper, and alloys thereof. In one
embodiment, stainless steel is an attractive material for
microneedle fabrication because it is FDA approved for medical
devices and is inexpensive.
[0043] In another embodiment, the microneedle may include or be
formed of a polymer. The polymer can be biodegradable or
non-biodegradable. Examples of suitable biocompatible,
biodegradable polymers include polylactides, polyglycolides,
polylactide-co-glycolides (PLGA), polyanhydrides, polyorthoesters,
polyetheresters, polycaprolactones, polyesteramides, poly(butyric
acid), poly(valeric acid), polyurethanes and copolymers and blends
thereof. Representative non-biodegradable polymers include
polyacrylates, polymers of ethylene-vinyl acetates and other acyl
substituted cellulose acetates, non-degradable polyurethanes,
polystyrenes, polyvinyl chloride, polyvinyl fluoride, poly(vinyl
imidazole), chlorosulphonate polyolefins, polyethylene oxide,
blends and copolymers thereof. Biodegradable microneedles can
provide an increased level of safety compared to non-biodegradable
ones, such that they are essentially harmless even if inadvertently
broken off into the biological tissue. This applies whether the
microneedles contain molecules for delivery or serve merely as
vehicle for transporting a drug coating.
[0044] In one embodiment, the microneedle device includes a
substantially planar foundation from which one or more microneedles
extend, typically in a direction normal (i.e., perpendicular or
`out-of-plane`) to the foundation. Alternatively, microneedles may
be fabricated on the edge of a substrate `in-plane` with the
substrate. In another embodiment, a single microneedle can be
fabricated on a substrate surface or edge. In one embodiment,
microneedles are fabricated on a flexible base substrate. It would
be advantageous in some circumstances to have a base substrate that
can bend to conform to the shape of the tissue surface. In another
preferred embodiment, the microneedles are fabricated on a curved
base substrate. The curvature of the base substrate typically would
be designed to conform to the shape of the tissue surface.
[0045] The microneedles may be solid or hollow. The microneedles
can be porous or non-porous. The microneedles may be planar,
cylindrical, or conical. The microneedles can have a straight or
tapered shaft. In one embodiment, the diameter of the microneedle
is greatest at the base end of the microneedle and tapers to a
point at the end distal the base. The microneedles can also be
fabricated to have a shaft that includes both a straight (i.e.,
untapered) portion and a tapered portion. The microneedles can be
formed with shafts that have a circular cross-section in the
perpendicular, or the cross-section can be non-circular.
[0046] The tip portion of the microneedles can have a variety of
configurations. The tip of the microneedle can be symmetrical or
asymmetrical about the longitudinal axis of the shaft. The tips may
be beveled, tapered, squared-off, or rounded. The tip portion
generally has a length that is less than 50% of the total length of
the microneedle.
[0047] The dimensions of the microneedle, or array thereof, are
designed for the particular way in which it is to be used. The
length typically is selected taking into account both the portion
that would be inserted into the biological tissue and the (base)
portion that would remain uninserted. The cross-section, or width,
is tailored to provide, among other things, the mechanical strength
to remain intact for the delivery of the drug or for serving as a
conduit for the withdrawal of biological fluid, while being
inserted into the skin, while remaining in place during its
functional period, and while being removed (unless designed to
break off, dissolve, or otherwise not be removed). In various
embodiments, the microneedle may have a length of between about 50
.mu.m and about 5000 .mu.m, preferably between about 100 .mu.m and
about 1500 .mu.m, and more preferably between about 200 .mu.m and
about 1000 .mu.m. In one embodiment, the length of the microneedle
is about 750 .mu.m. In various embodiments, the base portion of the
microneedle has a width or cross-sectional dimension between about
20 .mu.m and about 500 .mu.m, preferably between about 50 .mu.m and
about 350 .mu.m, more preferably between about 100 .mu.m and 250
.mu.m. For a hollow microneedle, the outer diameter or width may be
between about 50 .mu.m and about 400 .mu.m, with an aperture
diameter of between about 5 .mu.m and about 100 .mu.m. The
microneedle may be fabricated to have an aspect ratio
(width:length) between about 1:1 and 1:10. Other lengths, widths,
and aspect ratios are envisioned.
[0048] In a preferred embodiment, the microneedle includes one or
more pockets. As used herein, the term "pocket" refers to an
aperture extending crosswise into the microneedle shaft (e.g.,
perpendicular to the direction of microneedle movement during the
process of insertion into biological tissue). The pocket preferably
extends through the shaft, but it is envisioned that it
alternatively may be closed at one end, distal the opening in the
shaft. This is distinct from a hollow bore wherein a concentric
space extends substantially through the axial length of the shaft.
As used herein, the pockets are considered to be part of the
surface of the microneedle. The pocket preferably contains coating
material, which may be particularly advantageous in certain
embodiments where the coating material needs to be protected from
mechanical forces during the insertion process, e.g., when the
coating comprises a liquid or particles. It has been found that
such coating materials are more likely than others to be
prematurely dislodged or wiped off of the microneedle during
insertion into skin, diminishing the complete delivery of the
complete dosage of the coating. However, the pockets of the
microneedles advantageously function to shield the coating material
therein from the mechanical forces of insertion. The pockets may be
made in various shapes (e.g., circular, square, rectangular) and of
various numbers and dimensions and different spacings within the
microneedle.
[0049] In various embodiments, the microneedle device includes a
single microneedle or an array of two or more microneedles. The
microneedles can be fabricated as, or combined to form microneedle
arrays. For example, the device may include an array of between 2
and 1000 (e.g., between 2 and 100) microneedles. In one embodiment,
a device may include between 2 and 10 microneedles. An array of
microneedles may include a mixture of different microneedles. For
instance, an array may include microneedles having various lengths,
base portion diameters, tip portion shapes, spacings between
microneedles, drug coatings, etc.
[0050] Fabrication of Microneedles
[0051] The microneedle can be fabricated by a variety of methods
known in the art or as described in the Examples below. Details of
possible manufacturing techniques are described, for example, in
U.S. Patent Application Publication No. 2006/0086689 A1 to Raju et
al., U.S. Patent Application Publication No. 2006/0084942 to Kim et
al., U.S. Patent Application Publication No. 2005/0209565 to
Yuzhakov et al., U.S. Patent Application Publication No.
2002/0082543 A1 to Park et al., U.S. Pat. No. 6,334,856 to Allen et
al., U.S. Pat. No. 6,611,707 to Prausnitz et al., U.S. Pat. No.
6,743,211 to Prausnitz et al., all of which are incorporated herein
by reference.
[0052] In a preferred embodiment, the microneedles are cut from
stainless steel or other metal sheets using a laser (e.g., an
infrared laser) or other techniques known in the art. Microneedles
of different lengths and widths from sheets up to 125 .mu.m have
been successfully fabricated by this method.
[0053] In a preferred embodiment, an electropolishing technique is
used to produce clean, smooth, and sharp microneedle surfaces.
Electropolishing can remove slag deposits from the microneedles, as
laser-cutting of metals such as stainless steel may produce
microneedles with rough edges covered with slag deposits. In one
non-limiting embodiment, laser cut stainless steel microneedles can
be electropolished in a solution that includes glycerin,
ortho-phosphoric acid (85%), and water in a ratio of 6:3:1 by
volume. In one example, a copper plate is used as the cathode and
the metal microneedles serve as the anode. The anode may be
vibrated using means known in the art to help remove gas bubbles
generated at the anodic surface during electropolishing.
Electropolishing is believed to be especially effective, because
current density (i.e., etching rate) is largest at sites of high
curvature, which inherently targets sites of surface roughness for
removal. In some embodiments, the electropolishing process has an
output rate of finished microneedle arrays of one 50-needle array
every 30 minutes using a single laser. This rate can be increased
by process optimization and use of multiple lasers.
[0054] Coating/Drug Formulation
[0055] The microneedles include at least one drug-containing
coating over at least part of the surface of the microneedle. In a
preferred embodiment, the coating is applied in a manner such that
the surface energy (or surface tension) of the coating liquid is
less than the surface energy of the microneedle. This facilitates
effective coating of the microneedle. As detailed herein, this
surface energy differential may be achieved by modifying the
coating liquid, modifying the microneedle surface properties, or a
combination of such modifications.
[0056] In one aspect, the microneedle coating may be a
heterogeneous composition. For example, the coating may include two
or more phases (e.g., solid/liquid, solid/solid, emulsion, gel) two
or more discrete layers, discrete particles, or a combination
thereof. In one embodiment, the microneedle includes one or more
pockets which are coated to contain a drug formulation which is in
the form of a liquid, gel, particles, or a combination thereof.
[0057] The coating may consist of only the one or more drugs or it
may include one or more non-volatile components (i.e., the
components remaining after the solvent of the coating liquid has
been volatilized) to modify the surface energy properties of the
coating, to modify release characteristics of the drug, or to do
both. Components may also be added to improved adhesion of wet or
dry coating to the microneedle. Such non-volatile components are
described below in discussing the coating liquid.
[0058] In one embodiment, all of the coating is adapted to come off
of the microneedle following insertion into a biological tissue. In
a preferred embodiment, the coating is adapted to come off of the
microneedle rapidly. Rapid dissolution is equal to or less than 15
minutes, preferably less than 5 minutes, more preferably less than
5 minutes, and more preferably less than 10 sec. This embodiment
would be particularly useful to deliver vaccines, local anesthetics
(e.g., lidocaine), cosmetic formulations (e.g., botox, tattoos),
and drugs suitable for bolus delivery. In one case, the coating
comprises drug dispersed in a matrix material (e.g.,
microencapsulated) which provides controlled release of the drug.
In another case, the drug is a hydrophobic molecule and the coating
further comprises an amphiphilic material, which facilitates
dissolution/release of the coating from the microneedle.
[0059] In another embodiment, the coating is adapted for slow
release (e.g., dissolution) when inserted into a biological tissue.
Slow dissolution is more than 15 minutes, and may range, for
example, from a few hours to a day or two, or a week. This
embodiment would be particularly useful to deliver clonidine (e.g.,
to treat hypertension), testosterone (e.g., for replacement
therapy), insulin (e.g., for basal diabetic therapy), and other
drugs suitable for long-term therapy, particularly drugs with
relatively narrow therapeutic windows. In still another embodiment,
the coating comprises a material which is substantially insoluble
when inserted into a biological tissue.
[0060] In one embodiment, at least a portion of the coating is
adapted to remain on the microneedle following insertion into a
biological tissue. For example, the coating may include a matrix
material or layer that serves to modulate release of a drug, which
may be dispersed therein, which may be located in an underlying
layer, or both.
[0061] In still another embodiment, all or substantially all of the
coating is adapted to remain on the microneedle following insertion
into a biological tissue. For example, the microneedle may be part
of a sensor, and the coating material may aid in operation of the
sensor without being released.
[0062] In one embodiment, the coating may include a plurality of
discrete microparticles or other particles. The coating may consist
only of these particles, packed together to form a coating once the
solvent of the coating liquid has been volatilized. Alternatively,
these particles may be dispersed within a continuous matrix
material. Examples of the particles or microparticles that may form
part or all of the coating include solid or gel-like organic or
inorganic compounds in a non-dissolving solvent (e.g., barium
sulfate suspension in water), liposomes, proteins, cells, virus
particles, prions, and combinations thereof. In one case, drug
molecules are incorporated into a microparticle or nanoparticles
form. As used herein, the term "microparticle" encompasses
microspheres, microcapsules, microparticles, and beads, having a
number average diameter of 1 to 100 .mu.m, most preferably 1 to 25
.mu.m. The term "nanoparticles" are particles having a number
average diameter of 1 to 1000 nm. Microparticles may or may not be
spherical in shape. "Microcapsules" are defined as microparticles
having an outer shell surrounding a core of another material, in
this case, drug. The core can be liquid, gel, solid, gas, or a
combination thereof. "Microspheres" can be solid spheres, can be
porous and include a sponge-like or honeycomb structure formed by
pores or voids in a matrix material or shell, or can include
multiple discrete voids in a matrix material or shell. The
microparticle or nanoparticles may further include a matrix
material. The shell or matrix material may be a polymer, amino
acid, saccharride, or other material known in the art of
microencapsulation.
[0063] In another embodiment, the microneedle coating includes
multiple, discrete (distinct) layers. This may be achieved, for
example, by using multiple dipping and drying steps, into the same
or different coating liquids.
[0064] In a preferred embodiment, the microneedle is first coated
with a precoat material, which is disposed between at least a
portion of the at least one microneedle and the coating which
comprises the drug. Such a precoat material preferably is used to
alter or improve the surface properties (e.g., hydrophilicity or
hydrophobicity) of the microneedle surface to enhance adhesion and
uniformity of the drug-containing coating. The use of a precoat may
enable one to omit surfactant from the primary, drug-containing
coating liquid. The precoat may be substantially soluble or
insoluble in vivo. In non-limiting examples, the precoat may
consist of silicon dioxide or a biocompatible polyester,
polyethylene glycol (PEG), PLGA or polyanhydride. Deposition of
silicon dioxide or other precoat material may be achieved using
vapor deposition or other techniques known in the art.
[0065] In still other embodiments, an exterior, secondary coating
may be used to alter release kinetics of a drug from an underlying
coating layer. For example, the exterior coating may include a
material known in the art that dissolves or biodegrades relatively
solely in vivo to provide delayed or slow release of drug. In one
example, the exterior coating could include a hydrogel or other
water swellable material to provide controlled drug release. In
another variation, an exterior layer could provide for rapid (e.g.,
bolus) release of drug. An underlying layer could provide bolus or
controlled release of the same or another drug.
[0066] Optionally, additional drug can be integrated into the
microneedle structure, passed through bores or channels in the
microneedle, or a combination thereof.
[0067] A wide range of drugs may be formulated for delivery with
the present microneedle devices and methods. As used herein, the
terms "drug" or "drug formulation" are used broadly to refer to any
prophylactic, therapeutic, or diagnostic agent, or other substance
that may be suitable for introduction to biological tissues,
including pharmaceutical excipients and substances for tattooing,
cosmetics, and the like. The drug can be a substance having
biological activity. The drug formulation may include various
forms, such as liquids, liquid solutions, gels, hydrogels, solid
particles (e.g., microparticles, nanoparticles), or combinations
thereof The drug may comprise small molecules, large (i.e., macro-)
molecules, or a combination thereof. In a preferred embodiment, the
drug formulation is solid at ambient temperatures so that the
coating on the microneedle is solid. A solid coating may increase
the shelf life of certain active agents and can provide better ease
of handling of the coated microneedles.
[0068] In representative, non-limiting, embodiments, the drug can
be selected from among amino acids, vaccines, antiviral agents,
DNA/RNA, gene delivery vectors, interleukin inhibitors,
immunomodulators, neurotropic factors, neuroprotective agents,
antineoplastic agents, chemotherapeutic agents, polysaccharides,
anti-coagulants, antibiotics, analgesic agents, anesthetics,
antihistamines, anti-inflammatory agents, and vitamins. The drug
may be selected from suitable proteins, peptides and fragments
thereof, which can be naturally occurring, synthesized or
recombinantly produced. In one embodiment, the drug formulation
includes insulin.
[0069] A variety of other pharmaceutical agents known in the art
may be formulated for administration via the microneedle devices
described herein. Examples include .beta.-adrenoceptor antagonists
(e.g., carteolol, cetamolol, betaxolol, levobunolol, metipranolol,
timolol), miotics (e.g., pilocarpine, carbachol, physostigmine),
sympathomimetics (e.g., adrenaline, dipivefrine), carbonic
anhydrase inhibitors (e.g., acetazolamide, dorzolamide),
prostaglandins, anti-microbial compounds, including anti-bacterials
and anti-fungals (e.g., chloramphenicol, chlortetracycline,
ciprofloxacin, framycetin, fusidic acid, gentamicin, neomycin,
norfloxacin, ofloxacin, polymyxin, propamidine, tetracycline,
tobramycin, quinolines), anti-viral compounds (e.g., acyclovir,
cidofovir, idoxuridine, interferons), aldose reductase inhibitors,
anti-inflammatory and/or anti-allergy compounds (e.g., steroidal
compounds such as betamethasone, clobetasone, dexamethasone,
fluorometholone, hydrocortisone, prednisolone and non-steroidal
compounds such as antazoline, bromfenac, diclofenac, indomethacin,
lodoxamide, saprofen, sodium cromoglycate), local anesthetics
(e.g., amethocaine, lignocaine, oxbuprocaine, proxymetacaine),
cyclosporine, diclofenac, urogastrone and growth factors such as
epidermal growth factor, mydriatics and cycloplegics, mitomycin C,
and collagenase inhibitors.
Coating Methods
[0070] Methods have been developed for coating microneedles. It
also is envisioned that the present coating methods and devices can
be used or readily adapted to coat other microstructures,
particularly structures having micron-scale dimensions where
surface tension issues impact coating location, coating thickness,
and coating processibility. Representative examples of other
microstructures include microfluidic devices, microarrays,
microelectrodes, AFM probes, microporous materials, microactuators,
microsensors, and the like.
[0071] The Coating Liquid
[0072] The coating liquid is the material applied to coat the one
or more microneedles. The coating liquid includes the coating/drug
formulation material(s) described above that ultimately intended to
serve as the microneedle coating. As used herein, the term "coating
liquid" includes pure solutions, suspensions (e.g., solid
particles-dispersed-in-liquid), emulsions, and combinations
thereof, as well as molten materials. The molten material may be
the active drug or it may act as the dissolving or suspending
medium for the drug and/or additives or particles or a combination
thereof. It is essentially any non-gas material or combination of
materials having a viscosity suitable for use in a coating process
to coat microneedles. The coating liquid may be homogeneous or
heterogeneous. In a preferred embodiment, the coating liquid is
aqueous. In one embodiment, the coating liquid comprises particles
suspended in a solvent.
[0073] The surface energy (or surface tension) of the coating
liquid preferably is less than the surface energy of the
microneedle. Depending on the drug, and the solvent if any, the
coating liquid may need to include one or more additives to alter
the surface energy of the coating liquid. For example, the surface
energy of stainless steel is 53.3 mN/m and the surface energy of
water is 72.8 mN/m. Therefore, an aqueous coating solution may need
to include one or more additives to reduce the surface tension of
the coating solution to less than 53.3 mN/m--preferably while
increasing the viscosity of the coating solution so that thicker
rather than thin coatings will be formed.
[0074] Representative examples of additives include viscosity
modifiers, surfactants, pH modifiers, diluents, or other
pharmaceutically acceptable excipients known in the art. Such
additives preferably are water soluble, FDA approved as injectable
excipients (for safety), solid at room temperature (to convert into
a solid phase upon drying), and possess high surfactant or
viscosity enhancement activity per unit mass (to provide minimal
usage of additives and thereby increase drug percentage in the dry
coatings).
[0075] The coating liquid may include a solvent. As used herein,
the term "solvent" is used generically and broadly to refer to any
volatile component in the coating liquid, whether solvent or
non-solvent for the drug in the coating liquid. The solvent is the
component, if any, in the coating liquid that is volatilized (e.g.,
evaporates) during/following application of the coating liquid onto
the microneedle, thereby causing the non-volatile coating materials
to solidify and adhere to the microneedle. The solvent may be
aqueous, organic, inorganic, or a combination thereof.
Representative examples of the suitable solvents include water,
ethanol, ethyl acetate, isopropanol, propylene glycol, and benzyl
alcohol.
[0076] In a preferred embodiment, the coating liquid includes one
or more surfactants in an amount/concentration effective to spread
the coating liquid onto the microneedle and a viscosity enhancer in
an amount/concentration effective to produce a coating having a
desired thickness. For example, the thickness desired is
determined, in part, by the dosage of drug needed per microneedle,
the surface area of the microneedle expected to penetrate the
biological tissue, and the number of microneedles per array.
Examples of suitable surfactants include nonionic surfactants, such
as Poloxamers (e.g., Lutrol F-68) and polyoxyethylene sorbitan
fatty acid esters (e.g., Tween 20). Examples of suitable viscosity
enhancers include cellulose and derivatives thereof (e.g., sodium
salt of carboxymethylcellulose (low viscosity), hydroxylpropyl
cellulose) hyaluronic acid, xanthan gum, alginic acid and
derivatives thereof (e.g., sodium alginate, propylene glycol
alginate), polyvinylpyrollidone, acacia, guar gum, or carbohydrates
such as sucrose or maltose. The concentrations of these additives
in the coating liquid may range from 0.1% to 70% (weight/volume %).
In one embodiment, the coating liquid comprises a drug, 1%
carboxymethylcellulose, an 0.5% Lutrol F-68 NF. It is understood,
however, that the particular additives and concentrations chosen
for each formulation will depend, in part, upon the coating
requirements as well as any interaction among the particular drug
and the additives selected.
[0077] Anionic, cationic or nonionic surfactants can be used.
Representative examples and concentration ranges of anionic
surfactants include docusate sodium (e.g., 0.01% to 1% wt/vol %)
and sodium lauryl sulfate (e.g., 0.1% to 3% wt/vol %). A
representative example and concentration range of a cationic
surfactant includes benzalkonium chloride (e.g., 0.01% to 1% wt/vol
%). Representative examples and concentration ranges of nonionic
surfactants include polyoxyethylene sorbitan fatty acid esters
(e.g., polysorbates 20, 40 and 60 at 0.1% to 3% wt/wt %), sorbitan
fatty acid esters (0.1% to 3% wt/wt %), poloxamers (e.g. Lutrol F68
0.1% to 5% wt/vol %), and polyoxyethylene alkyl ethers (0.05% to 1%
wt/vol %).
[0078] Certain drugs and certain coating liquids can be effectively
and uniformly coated onto the microneedles without the need for
surfactants or without the need for any additives. In one
embodiment, certain hydrophobic drugs can be coated onto
microneedles for quick release (e.g., between one and ten minutes)
in vivo, where the coating liquid includes an amphiphilic viscosity
enhancer without surfactant. Examples of suitable hydrophobic drugs
include doxyrubicin, estradiol, testosterone, fentanyl, clonidine,
oxybutynin, dexamethasone, indomethacin, and the like.
[0079] In one embodiment, the process is used where the surface
energy of the coating liquid is less than the surface energy of the
microneedle (either the material of construction or after surface
modification). In an alternative embodiment, the coating liquid may
have surface energy greater than the microneedle. This coating
liquid will enable filling and coating of pockets in the
microneedle surface without coating the remainder of the
microneedle surface. The coating liquid may contain dissolved solid
additives or drugs, or maybe devoid of any dissolved solids with
even the drug being liquid at room temperature. In either case, the
result will be a pocket filled with a solid (after drying) or a
liquid phase, respectively. Particles may additionally be
introduced into either of these formulations causing particles to
be filled into the pockets. Relatively slow speeds of microneedle
withdrawal, on the order of more than a second, from the
microneedle immersed state to outside the coating liquid, have been
found to be useful to facilitate the coating of only the
pockets.
[0080] In another embodiment, the coating liquid is free of
excipients all together. For instance, some drugs can remain stable
at their melting point, and microneedles can be coated by dipping
them into molten drug and then allowing the drug to cool and
solidify, thereby forming the coating. In one embodiment, the
coating liquid comprises a molten material having a melting
temperature greater than 25.degree. C. Such embodiments
advantageously enable delivery of pure drug and provide high drug
mass loading per microneedle. An example of a suitable drug for use
in this coating method is lidocaine, clonidine, and the like.
[0081] Apart from molten liquid existing in a pure liquid state,
multi-component molten coating also may be formulated.
Multi-component molten coating liquids generally consist of a
dissolving medium created by heating a solid above its melting
point to form a liquid state, into which a drug is dissolved. For
example, PEG (MW 1500) may be heated to 55.degree. C. and then
dexamethasone dissolved into it. The dissolving medium may be
hydrophilic or hydrophobic. Representative examples of hydrophilic
dissolving medium include to polyethylene glycols (PEGs) (melting
point greater than 25.degree. C.), sugars (especially low
melting-point sugars such as xylitol (melting point 92-96.degree.
C.), dextrose (melting point 146-150.degree. C.), maltose (melting
point 102.degree. C.), and sorbitol (melting point 110-112.degree.
C.), water soluble polyoxyethylene derivatives (e.g., Brijs, Brij
72, melting point 44-45.degree. C.), polyethylene-propylene glycol
copolymers (Poloxamers, e.g., Pluronic F-68, melting point
52.degree. C.), poly(ethyleneoxide) (PEO) derivatives, PEG
derivatives, PEG-PEO derivatives, or various combinations thereof.
Representative examples of hydrophobic dissolving media include to
glyceryl monostearate (melting point 55-60.degree. C.), glyceryl
palmitostearate (melting point 52-55.degree. C.), cetyl alcohol
(melting point 56.degree. C.), stearyl alcohol (melting point
56-60.degree. C.), bees wax (melting point 56-60.degree. C.) and
other wax and combinations thereof. Additives other than drugs may
be included as dissolvable solids or liquid to the molten liquid
coating solution to alter or improve the surface energy or
viscosity of the molten coating liquid. Molten liquid coating
liquids provide an alternative to solvent-based coating solutions
to help satisfy surface energy or viscosity or other
physicochemical properties required for a particular coating
application.
[0082] Dip Coating Method and Apparatus
[0083] In one aspect, a method is provided for coating a
microstructure, which method includes providing a microstructure
having at least one surface in need of coating, and applying a
coating liquid, which comprises at least one drug, to the at least
one surface of the microstructure, wherein the surface energy of
the coating liquid preferably is less than the surface energy of
the surface of the microstructure. In one case, this method
includes precoating the at least one surface of the microstructure
with a material to increase the surface energy of said surface, or
otherwise modifying the surface energy properties of the
microneedle. In another case, the method includes modifying the
coating liquid to decrease the surface tension of the coating
liquid. In preferred embodiments, the microstructure comprises at
least one microneedle.
[0084] In another aspect, a method is provided for coating at least
one microneedle, which method includes the steps of (i) providing a
coating liquid disposed in a reservoir, the coating liquid
comprising at least one drug; (ii) providing a physical mask having
one or more apertures therethrough, each aperture having
cross-sectional dimensions larger than the at least one microneedle
to be coated; (iii) aligning the at least one microneedle with at
least one of the one or more aperture; (iv) inserting the at least
one microneedle through the aligned aperture; (v) inserting the at
least one microneedle into the coating liquid, thereby coating at
least a portion of the microneedle; and (vi) removing the coated
microneedle from the coating liquid and from the aperture. The one
or more reservoirs may be defined in a secondary structure or the
physical may have a plurality of the reservoirs defined in the
physical mask.
[0085] Steps (iv) and (v) can be done in two discrete steps or in a
single step. For example, the step of inserting the microneedle
through the aligned aperture may be done before moving the
physically masked microneedles to cause the microneedle to be
dipped into the coating liquid; alternatively, the physical mask
can be in a fixed position relative to the reservoir of coating
liquid, so that only the microneedles are moved.
[0086] By utilization of a physical mask, access of the coating
liquid is restricted only to the microneedle shaft, thereby
preventing contamination of the substrate from which the
microneedles extend. That is, any meniscus rise or capillary action
that may cause contact of the coating liquid to an adjacent
microneedle or with the substrate is advantageously avoided.
Furthermore, this "micro-dip coating" process is particularly
advantageous for use with relatively smaller coating liquid
volumes, such as might the case when coating microneedles with
highly potent or expensive substances, such as DNA/RNA.
[0087] In a preferred embodiment, the physical mask is in the form
of a plate having a one or more discrete apertures therethrough.
These apertures preferably are the form of one or more holes or
slits which closely circumscribe each microneedle or a single row
of microneedles. As used herein, the term "closely circumscribe"
means that the physical mask is effective to restrain, by surface
tension forces, the coating liquid to the reservoir and apertures,
preventing it from "climbing up" the microneedle shaft
substantially beyond the dipped portion of the microneedle which it
is desired to coat. Surface energy properties of the coating system
(physical mask, microneedle, and coating fluid) and operating
conditions (e.g., temperature, dipping/withdrawal speed) impact the
selection of appropriate dimensions for the holes and slits.
[0088] In one embodiment, the physical mask is in the form of a
substantially rigid plate secured to the reservoir (see e.g., FIG.
10A). The plate includes an array of micron-sized holes
corresponding to the microneedles in a microneedle array to be
coated. When properly aligned, for example using micropositioners
or pre-aligned parts moving on a rail, each of the microneedles can
be simultaneously inserted through the micron sized holes and into
the coating liquid, resulting in a controlled micro-dip-coating
process. The use of one or more micropositioners can be used to
provide control over the microneedle length being coated, that is
how much of the microneedle length is actually coated. Physical
stops in the form of think sheets or protruding cylinders in
between the physical mask and microneedles may also be used to
control the microneedle length being coated. The coating device can
be configured to coat single microneedles, in-plane rows of
microneedles (see, e.g., FIGS. 1A-B), and out-of-plane arrays of
microneedles (see, e.g., FIG. 1C).
[0089] In another embodiment, the physical mask may be designed to
act as a coating liquid reservoir or reservoirs. For instance, the
physical mask may include reservoirs, closed at one end, that can
be filled with the coating liquid (see, e.g., FIG. 10B). Single
microneedles or multiple microneedles of an array can be dipped
into each reservoir or groove. Typically, the apertures of the mask
have a closed bottom, the coating liquid is filled in these
apertures from the open top. These can be periodically or
continually refilled to maintain a constant amount of coating
liquid in the reservoir.
[0090] To reduce propensity of air bubbles in the reservoir and/or
apertures in the plate, the device may include vent holes designed
to release entrapped air. To prevent evaporation of coating liquid
(or solvent thereof) from the coating liquid, a pumping device
(e.g., an automated or manually pulsated syringe plunger) can be
included with the coating apparatus to fill the coating liquid
reservoir and to oscillate/mix the coating liquid in dip-coating
holes. The coating liquid in the reservoir may be flowed or
agitated to facilitate maintenance of a uniform coating liquid
composition during the dipping process. Alternatively or in
addition, the coating process may be performed at a reduced
temperature (relative to ambient) to reduce the rate of evaporation
of the coating liquid or solvent portion thereof.
[0091] In one embodiment, the method further includes the step of
volatilizing at least a portion of the solvent to form a solid
coating. This may be referred to as "drying" the coating or coating
liquid. A similar step may be included when using molten coating
liquids, wherein the coated liquid is permitted to (or actively
caused to) cool the molten material sufficiently to cause it to
solidify, forming a solid coating on at least a portion of the
microneedle.
[0092] The coating method may further includes inserting the at
least one microneedle into the same or a different coating liquid
and then removing the microneedle from said same or different
coating liquid. The composition of the coating liquid may include a
solvent to dissolve part of the previous coating, if desired. In
another embodiment, the method may further include the step of
applying a second coating liquid onto the solid coating or onto a
second surface of the microneedle in need of coating. The
composition of the second coating liquid may include a second drug.
Multiple such dippings into the same or a different coating liquid
may be repeated.
[0093] The process optionally may include an intervening dip into a
cleaning solvent, e.g., to thin or remove part of a prior coating
layer. This may be useful to build complete coating structures,
e.g., where one coating composition is located on one part of the
microneedle (e.g., a first pocket) and a second coating composition
is located on another part of the microneedle (e.g., a second
pocket).
[0094] While the present coating method using a physical mask has
been described as applied to coat microneedles, it is envisioned
that the process could be used or readily adapted to coat other
microprotrusion type structures in other microstructures.
[0095] Coating Process Considerations
[0096] Based on thermodynamics, to obtain uniform coatings on
microneedle surfaces, generally the surface tension of the coating
liquid should be lower than the surface energy of the microneedle
surface material (material of construction or overcoat deposition).
A slow (taking more than a second) or rapid (taking less than a
second or more preferably less than a tenth of a second or more
preferably less than a hundredth of a second) withdrawal of the
microneedle from the immersed state to outside the coating liquid
will provide a uniform coating on the microneedle. Addition of a
viscosity enhancer will increase the coating thickness by
increasing the film thickness of the entrained liquid during
withdrawal. However, the requirement of coating liquid surface
tension being lower than the microneedle material can be overcome
by conducting the coating process at a rate faster than is needed
to achieve thermodynamic equilibrium. For instance, by increasing
the viscosity and withdrawing at a rapid speed, the microneedle
will entrain a significant volume of the liquid on the surface. If
the solvent then evaporates before the liquid film can contract to
form an island in the middle of the microneedle surface, the solid
coating will become uniformly deposited onto the microneedles.
Another way to overcome the surface tension barrier to obtain
uniform coatings is to use a non-aqueous solvent that has lower
surface tension, possibly lower than the microneedle material.
Similarly, while coating only the pockets, advantage can be made of
the kinetic effect by utilizing a high surface energy
liquid/solution that will not wet the microneedle surface but will
fill the pockets. Again, the speed must be sufficiently slow so
that liquid does not entrain on the surface, but only gets into the
pockets.
[0097] One factor for liquid `pocket` coatings is that the all of
the liquid formulation must have sufficient viscosity and low vapor
pressure so that it can remain in the pockets for a sufficient
duration to permit packaging and storage (e.g., under inert
atmosphere and overpressure conditions) to substantially prevent
vaporization. In another embodiment, the liquid coating may contain
dissolved solids, which again must be sufficient to form a
continuous film once the volatile solvent has evaporated.
[0098] Microneedle Array Patches
[0099] The microneedle device may be in the form of a patch for
application to the skin of a patient. The patch may include one, or
more preferably an array of tens or hundreds of microneedles (e.g.,
between 50 and 500) and an adhesive component to secure the patch
to the skin. The patches may be fabricated using either multiple
linear rows of in-plane microneedles, individual arrays of
out-of-plane microneedles, or combinations thereof.
[0100] The adhesive component may be in the form of a flexible or
rigid substrate which includes a pressure sensitive adhesive as
known in the art.
[0101] In one embodiment, the microneedles and adhesive component
are configured such that the microneedles extend through apertures
in the adhesive layer. Individual microneedles or subgroups of
microneedles (e.g., rows) can extend through a single aperture. By
having the adhesive surface adjacent the microneedles, the adhesive
is able to better hold the microneedles down and to compensate for
the recoiling-tendency of skin and/or a rigid substrate for
out-of-plane microneedles.
[0102] In one embodiment, in-plane microneedles are fabricated with
a uniform adhesive layer in between the microneedles. For example,
rows of microneedles can be assembled into a patch by forming slits
(equal to the length of an in-plane row) in a material, such as
polyethylene medical foam tape. Such cutting can be performed by
any suitable technique, such as laser cutting. The microneedle rows
can be manually inserted into each slit from the non-adhesive side
of the foam tape and glued to the foam tape using a medical grade
adhesive. The adhesive is then allowed to cure. Optionally, a
polyethylene medical foam tape of sufficient thickness (e.g., 0.8
mm) can then be cut into a disc and affixed onto the dried glue
area to provide a cushioned backing to facilitate pressing the
patch during insertion. See FIG. 8.
[0103] In another embodiment, a microneedle patch can be assembled
using a complete microneedle array of out-of plane microneedles, a
circular disc of a single-sided medical foam tape and a think
double-sided medical tape. In the middle of the disc, a rectangular
piece of adhesive release liner equal in dimensions to the
periphery of the array can be cut out and peeled off. The stainless
steel microneedle array can then be attached to this exposed
adhesive. To provide a layer of pressure-sensitive adhesive on the
stainless steel substrate of the affixed array itself, a
double-sided, polyethylene terephthalate (PET) carrier tape first
perforated with holes corresponding to the microneedles can be
attached by slipping it over the microneedles using an alignment
device. See FIG. 9.
[0104] The present coating methods and apparatus can be readily
adapted for commercial production. For instances, automated systems
are known, which can be used or readily adapted to sequentially
grasp, position, dip, and release small parts, such as microneedles
or microneedle arrays in an assembly-line fashion.
Uses of the Microneedle Devices and Patches
[0105] The microneedle devices described herein may be used to
deliver substances into and through the various biological tissues.
In a preferred application, the microneedle devices are used to
deliver a drug, particularly a therapeutic, prophylactic, or
diagnostic agent into the skin, sclera, or other biological tissue
of a patient. As used herein, the term "patient" refers to a human,
animal, or other living organism in need of therapeutic,
diagnostic, or prophylactic intervention. In one embodiment, the
drug formulation is one which undergoes a phase change upon
administration. For instance, a solid drug formulation may be
dissolved within tissue, where it then diffuses out for bolus or
controlled release. In a preferred embodiment, the drug coating is
highly soluble at the physiological pH of the patient to promote
rapid delivery.
[0106] In one application, the coated microneedles are used for
vaccination. For example, the drug can be targeted to Langerhans
cells residing in the epidermis for a more potent immune response.
Advantageously, the solid phase of the antigen in the coatings may
help eliminate the cold-chain (storage/transportation) requirement,
because the solid phase antigen may be more stable.
[0107] In one embodiment, the delivery of drug particles or
drug-containing particles can be effectively delivered into a
patient's skin using the present coated microneedles. Successful
delivery of microparticles or other particles (e.g., up to 20 .mu.m
in diameter) may be enhanced by using insertion rates of at least 1
to 2 cm/s, by using microneedles with pockets, or a combination
thereof. The dosage delivered may be controlled, for example, by
controlling the size of the particles, the number of pockets per
microneedle, the total number of microneedles, or a combination
thereof.
[0108] The dissolution time maybe controlled from seconds to
minutes to hours to days to weeks based on how the coating is
formulated. In one example, the coating may be substantially
insoluble and swell (e.g., hydrogels) to release the drug by
diffusion. In another example, the coating may dissolve rapidly
(e.g., in 10 to 20 seconds) after insertion in a patient's skin or
sclera.
[0109] The amount of drug delivered within the tissue may be
controlled, in part, by the type of microneedle used and how it is
used. In a preferred embodiment, a coated microneedle is inserted
into the biological tissue to allow the microneedle coating to
dissolve and be delivered into a biological fluid. In a preferred
embodiment, the microneedle is coated along a length equal to or
less than the insertion depth so that no microneedle coating, and
therefore no drug, is precluded from being delivered within the
tissue.
[0110] The present methods for delivering a drug to a biological
tissue include the step of inserting at least one coated
microneedle into the biological tissue. The initial insertion depth
of the microneedle may be between 200 .mu.m and 5000 .mu.m (e.g.,
more than 250 .mu.m, 500 .mu.m, 800 .mu.m, or 1000 .mu.m, and e.g.,
less than 4000 .mu.m, 3000 .mu.m, 2500 .mu.m, 2000 .mu.m, 1800
.mu.m, or 1500 .mu.m). In one embodiment, the insertion depth is
between 200 and 1500 .mu.m. As used herein, the terms "insertion
depth" and the process of "inserting" the microneedle into
biological tissue refer to the movement of the microneedle into the
surface of the skin, and this depth includes both the distance the
tissue is deformed (by the microneedle) and the distance the tissue
is penetrated by the microneedle. The term "penetration depth"
refers to the non-deformative incursion of the microneedle into the
tissue. In other words, insertion depth equals penetration distance
plus deformation distance under the tip of the microneedle.
[0111] There are various methods to control the insertion depth. In
one embodiment, the microneedles are designed to have a length
equal to the desired penetration depth. In another embodiment, the
microneedles are designed to have a length longer than the desired
penetration depth, but the microneedles are only inserted part way
into the tissue. Partial insertion may be controlled by the
mechanical properties of the tissue, which bends and dimples during
the microneedle insertion process. In this way, as the microneedle
is inserted into the tissue, its movement partially bends the
tissue and partially penetrates into the tissue. By controlling the
degree to which the tissue bends, the depth of microneedle
penetration into the tissue can be controlled. In one embodiment,
the microneedles are inserted into the tissue using a drilling or
vibrating action. In this way, the microneedles can be inserted to
a desired depth by, for example, drilling the microneedles a
desired number of rotations, which corresponds to a desired depth
into the tissue. See, e.g., U.S. Patent Application Publication No.
20050137525 A1 to Wang et al., which is incorporated herein by
reference in its entirety.
[0112] In another embodiment, the microneedle insertion depth may
be controlled by mechanical means. For example, the insertion of a
longer microneedle may be physically limited to insert only up to a
pre-specified length by encasing the microneedle (or microneedles
or array) in a sheath with only part of the microneedle protruding
out for tissue insertion. Alternatively, the microneedle or array
may be secured onto a micropositioner which can control the depth
of tissue insertion. The depth of insertion also may be controlled
by the geometry of the microneedle, such as a widening of the
needle, by by the speed of insertion, where more rapid insertion
generally results in deeper insertion depth, and/or by controlling
skin mechanics, e.g., by stretching the skin which generally
facilitates deeper insertion.
[0113] The microneedles may be vibrated following insertion or
during retraction to facilitate separation of the coating from the
microneedle.
[0114] In various embodiments, the methods may be adapted to
deliver the drug formulation specifically to the epidermis, dermis,
or subcutaneous tissue. The method may include essentially any
means known for controlling deformation of the biological barrier
during the microneedle insertion process. For instance, deformation
of the biological tissue may be intentionally reduced by performing
the insertion step with control of microneedle velocity,
microneedle vibration, microneedle rotation, tissue stretching, or
a combination thereof.
[0115] The microneedle devices also may be adapted to use the one
or more microneedles as a sensor to detect analytes, electrical
activity, and optical or other signals. The sensor may include
sensors of pressure, temperature, chemicals, and/or electromagnetic
fields (e.g., light). 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). The microneedle biosensor can be any of the
four classes of principal transducers: potentiometric,
amperometric, optical, and physiochemical. In one embodiment, a
microneedle is coated with a drug formulation 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 on at least a portion of
the surface of the microneedle. In another embodiment, a wave guide
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 for diagnostic purposes. In one example, the microneedle
coating may release a diagnostic agent and the microneedle detects
a reaction product following reaction of the diagnostic agent with
an analyte in vivo. In another example, the microneedle may be dual
functional, delivering a drug via the coating and serving as a
sensor not directly related to the drug delivered.
[0116] The present invention may be further understood with
reference to the following non-limiting examples.
EXAMPLE 1
Fabrication of Coated Microneedles
[0117] Metal microneedles were laser cut, electropolished, and then
coated with various coating materials. Coated single microneedles
and coated microneedle arrays were produced.
[0118] Forming the Microneedle Structures
[0119] Solid microneedles were cut from stainless steel sheets
(Trinity Brand Industries, SS 304, 75 .mu.m thick; McMaster-Carr,
Atlanta, Ga., USA) using an infrared laser (Resonetics Maestro,
Nashua, N.H., USA), guided by CAD/CAM design, using techniques
known in the art. Microneedles were prepared as single
microneedles, individual rows of microneedles, or as
two-dimensional arrays of microneedles.
[0120] Microneedles were also made with a variety of shapes in
increasingly complex geometries using laser etching. First,
microneedles of different lengths and widths with a constant tip
angle of 55.degree. were created (FIG. 3A). Next, microneedles were
made with small through-holes (i.e., "pockets") of different shapes
and sizes in the shafts of the microneedles (FIG. 3B). Microscopic
examination showed that the inside surfaces of these pockets were
smooth and clean. Microneedles with grooved surfaces in the form of
valleys and ridges were also made. Different patterns of valleys
were successfully fabricated with uniform cleanliness and
smoothness (FIG. 3C). The out-of-plane microneedles were prepared
by manually pushing out at a 90.degree. angle the microneedles that
had been cut into stainless steel sheets (FIG. 3D).
[0121] Electropolishing
[0122] Because laser-cutting stainless steel produced microneedles
with rough edges covered with slag deposits (FIG. 2A), an
electropolishing technique was used to remove slag from the
microneedles. The microneedles were electropolished in a solution
containing glycerin, ortho-phosphoric acid (85%) and water in a
ratio of 6:3:1 by volume (Fisher Chemicals, Fair Lawn, N.J., USA).
A copper plate was used as the cathode, while the microneedles
served as the anode. The anode was vibrated at a frequency of 10 Hz
throughout the electropolishing process (current density of 1.8
mA/mm.sup.2) using a custom built vibrating device to help remove
gas bubbles generated at the anodic surface during
electropolishing. The electropolishing process yielded microneedles
with smooth surfaces and sharp tips (tip radius 0.5 to 1 .mu.m)
(FIG. 2B). The electropolishing process reduced the thickness of
the microneedles to 50 .mu.m.
[0123] Microneedle Coating
[0124] The electropolished microneedles were then coated with
different molecules using a custom micron-scale, dip-coating
process and specially formulated coating solutions. The
micro-dip-coating devices and methods were used to localize
coatings to only microneedle shafts for both single microneedles
(FIG. 4A) and microneedle arrays (FIG. 4B).
[0125] Single microneedles were dip-coated by horizontally dipping
the microneedle into 20-30 .mu.l of coating solution held as a
droplet on the tip of a 200 .mu.l large-orifice pipette tip
(Catalogue #21-197-2A, Fisher Scientific). The large-orifice
pipette tip was mounted horizontally in a clamp and the microneedle
was mounted opposite to it on a manual linear micropositioner
(A1506K1-S1.5 Unislide, Velmex, Bloomfield, N.Y., USA). Immersion
and withdrawal of the microneedle into the liquid droplet was
performed manually by moving the microneedle while viewing under a
stereomicroscope (SZX12, Olympus America).
[0126] Linear rows of microneedles were dip coated using a custom
designed coating device, which included a coating solution
reservoir and a micropositioning dip coater. As illustrated in FIG.
1A, the coating-solution reservoir of the micro-dip coating device
consisted of two laminated parts: a `bottom plate` and a `cover
plate`, both of which were made of polymethylmethacrylate
(McMaster-Carr). The two plates (bottom and cover plates) were
aligned and adhered to each other using methylene chloride solvent
bonding. The bottom plate had a central feeding channel (1 mm
deep.times.0.5 mm wide) machined into one of its faces, with a
through-hole drilled across to the other face, which acted as the
inlet port to fill the channel with coating solution. The cover
plate had five holes (400 .mu.m diameter) drilled with the same
spacing as the microneedles in the linear microneedle row. These
"dip-holes" acted as individual dipping reservoirs to coat each of
the microneedles in the row.
[0127] To enable three-dimensional alignment and dipping of
microneedle rows into the dip-holes, three linear-micropositioners
were assembled on a flat acrylic plate (FIG. 1B). The first
micropositioner (x-micropositioner: A1503K1-S1.5 Unislide, Velmex)
was used to position the linear microneedle array. The other two
micropositioners were assembled stacked on one another on the
acrylic plate to create a composite y-z motion micropositioner (two
A1503K1-S1.5 Unislides, Velmex) that positioned the coating
solution reservoir. Together, the three micropositioners permitted
the alignment of the linear microneedle array to the dip-holes. The
x-micropositioner was used to horizontally move the microneedles
into and out of the dip-holes. The coating process was performed
manually while viewing under a stereomicroscope (SZX12, Olympus).
Control over the coating length on the microneedle shaft was
exercised manually using the x-micropositioner. Tolerance for
misalignment was included by designing the dip-hole diameter to be
twice the width of the microneedles. Five in-plane microneedles
containing five microneedles each were coated to predetermined
lengths of 30%, 50%, 75% and 100% length coverage (FIGS. 4C.sub.1
to 4C.sub.5).
[0128] Microneedle arrays were dip-coated using a method and
dipping device similar to that used to coat linear rows of
microneedles. The coating-solution reservoir and the
microneedle-array holder were pre-aligned opposite to each other on
a vertical rod. The cover plate of the coating-solution reservoir
contained 50 dip-holes at the same spacing as the microneedles in
the array. The coating-solution reservoir was stationary, while the
microneedle-array holder could be slid up and down the rod. Pins
were provided on the microneedle-array holder to position a
microneedle array on the holder in alignment with the dip-holes,
and held in place using a magnet. To coat the microneedles, the
microneedle-array holder was manually slid down the rod to dip the
microneedles of the array into the 50 dip-holes below.
[0129] The coating solution included 1% (weight/volume %)
carboxymethylcellulose sodium salt (low viscosity, USP grade,
CarboMer, San Diego, Calif., USA), 0.5% (weight/volume %)) Lutrol
F-68 NF (BASF, Mt. Olive, N.J., USA), and a model drug. The surface
tension and viscosity of the coating solutions were modified with
additives in order to deposit (more) uniform coatings on the
microneedles. The model drugs tested included 0.01% sulforhodamine
(Molecular Probes, Eugene, Oreg.), 0.01% calcein (Sigma, St. Louis,
Mo., USA), 3% vitamin B (Fisher Chemicals), 1% bovine serum albumin
conjugated to Texas Red (Molecular Probes), 0.05% gWiz.TM.
luciferase plasmid DNA (6732 base pairs, Aldevron, Fargo, N. Dak.,
USA), 2.times.10.sup.9 plaque forming units per ml of modified
vaccinia virus--Ankara (Emory University Vaccine Center, Atlanta,
Ga., USA), 10% barium sulfate (1 .mu.m diameter particles, Fisher
Chemicals), 1.2% 10-.mu.m diameter latex beads (PN 6602796, Beckman
Coulter, Miami, Fla., USA) and 8.2% 20-.mu.m diameter latex beads
(PN 6602798, Beckman Coulter), all w/v %. DNA and virus were made
fluorescent by incubating with YOYO-1 (Molecular Probes) at a
dye:base pair/virus ratio of 1:5 for 1 h at room temperature in the
dark. These drug materials selected for coating ranged in size from
small molecules (calcein-0.6 nm) to larger microparticles (20 .mu.m
latex beads) and included inorganic materials (barium sulfate),
organic materials (latex), and materials of biological origin
(protein-bovine serum albumin, plasmid DNA-luciferase plasmid, and
virus-modified vaccinia). All were reproducibly coated onto the
microneedles, with coatings uniform across the entire microneedle
length (representative images, FIG. 5).
EXAMPLE 2
Assembly of Coated Microneedle Patches
[0130] Coated microneedle arrays, made as in Example 1, were
assembled into transdermal patches containing pressure-sensitive
adhesive to adhere to the skin. To secure microneedles in the skin
at all times until ready to be removed, microneedles were
integrated into a Band-Aid-like patch. This patch had
pressure-sensitive adhesive on one complete side, with microneedles
protruding therefrom. The adhesive secured the microneedles and
compensated for the recoiling tendency of the skin and the rigid
stainless steel substrate of out-of-plane microneedles. These
patches were fabricated using either multiple linear rows of
in-plane microneedles or individual arrays of out-of-plane
microneedles.
[0131] Microneedle Patches Using Multiple Rows of Microneedles
[0132] In-plane microneedles were fabricated with a uniform
adhesive layer in between the microneedles. In this example, a set
of ten rows of microneedles, containing five microneedles each, was
assembled into a patch of 50 microneedles. First, ten slits, each
75 .mu.m wide and 7.7 mm long (i.e., equal to the length of an
in-plane row) were laser cut into a 1.6 mm-thick, single-sided
polyethylene medical foam tape (TM9716, MACtac, Stow, Ohio) using a
CO.sub.2 laser (LS500XL, New Hermes, Duluth, Ga., USA). The ten
microneedle rows were then manually inserted into each slit from
the non-adhesive side of the foam tape and glued to the foam tape
using a medical grade adhesive (Loctite 4541, Rocky Hill, Conn.,
USA). The adhesive was allowed to cure for 24 hours. A polyethylene
medical foam tape (0.8 mm thick; TM9942, MACtac) was then cut into
a disc of 16 mm diameter and affixed onto the dried glue area to
provide a cushioned backing to facilitate pressing the patch during
insertion.
[0133] Microneedle Patches Using Complete Microneedle Arrays
[0134] To assemble a microneedle patch using a complete microneedle
array of out-of plane microneedles, a circular disc of 20 mm
diameter was first cut from a 0.8 mm-thick, single-sided medical
foam tape (TM9942, MACtac) using a CO.sub.2 laser. In the middle of
this disc, a rectangular piece of the adhesive release liner equal
in dimensions to the periphery of the array (i.e., 12 mm.times.12
mm) was cut out using the CO.sub.2 laser and peeled off. The
stainless steel microneedle array was then attached to this exposed
adhesive. To provide a layer of pressure-sensitive adhesive on the
stainless steel substrate of the affixed array itself, a
double-sided, polyethylene terephthalate (PET) carrier tape (63.5
.mu.m thick; T04314A, MACtac) was attached as follows. The PET film
was first perforated with holes of 400 .mu.m diameter at the same
spacing as the microneedles using a CO.sub.2 laser. The tape was
then slipped over the microneedles using a custom-built alignment
device and pressed to stick against the stainless steel
substrate.
EXAMPLE 3
In Vitro Dissolution of Microneedle Coating
[0135] To assess the in vitro dissolution time, single microneedles
(n=3) coated with vitamin B, calcein, or sulforhodamine, made as in
Example 1, were inserted into pig cadaver skin for 10 s or 20 s.
Upon removal, these microneedles were imaged by fluorescence
microscopy to detect residual coating. After 10 s insertion, a
majority of the coating was dissolved. After 20 s insertion, the
microneedle coating was completely dissolved. A
sulforhodamine-coated microneedle showed similar dissolution and
release into skin.
EXAMPLE 4
Delivery of Molecules and Particles By Coated Microneedles
[0136] Delivery from Individual Microneedles in vitro
[0137] To further determine if the drug materials coated on the
microneedles are actually delivered into the skin, single
microneedles (n=3) coated with calcein or sulforhodamine, made as
in Example 1, were inserted into pig cadaver skin for 20 s and
removed. After removing the microneedles, fluorescence micrographs
of coated microneedles and histological skin sections were
collected using an Olympus IX70 fluorescent microscope with a CCD
camera (RT Slider, Diagnostic Instruments). Brightfield micrographs
were collected using an Olympus SZX12 stereomicroscope with a CCD
camera (Leica DC 300, Leica Microsystems, Bannockburn, Ill., USA).
Histological examination of pig cadaver skin was conducted on
frozen sections. Pig cadaver skin was pierced with microneedles for
20 s, frozen in OCT compound (Tissue-Tek, 4583, Sakura Finetek,
Torrance, Calif., USA), and cut into 10 .mu.m-thick sections using
a cryostat (Cryo-Star HM 560MV, Microm, Waldorf, Germany).
[0138] No residue was observed on the skin after insertion, and
examination of histology sections of the pig skin revealed
distribution of calcein along the periphery of the insertion point.
Similar results were also observed for sulforhodamine, suggesting
that the results are generally applicable to different
molecules.
[0139] Delivery of Microparticles
[0140] For particle delivery assessment, single microneedles coated
with barium sulfate particles (1 .mu.m diameter, as measured by
scanning electron microscopy), or latex beads (10 or 20 .mu.m
diameter), made as in Example 1, were inserted into pig cadaver
skin for 1 min (n=3 microneedles for each insertion). After
removing the microneedles, micrographs of coated microneedles and
histological skin sections were collected. Digital X-ray imaging to
detect barium sulfate was done using a Faxitron MX20 cabinet X-ray
(Faxitron X-Ray, Wheeling, Ill., USA).
[0141] At a slow speed of approximately 0.5 to 1 mm/s, barium
sulfate particles were delivered into pig skin without wiping-off
on the surface, while latex beads 10 and 20 .mu.m in diameter were
wiped off on the skin surface. At a higher insertion speed of
approximately 1 to 2 cm/s, the momentum of the microneedles was
able to carry the 10 .mu.m diameter beads coated on microneedles
into the skin. However, the 20 .mu.m diameter beads were still
found as residue on the skin surface. The 20 .mu.m diameter latex
beads were delivered into the skin after loading them into the
hollow protective cavity of the `pockets` (400 .mu.m long.times.50
.mu.m wide.times.50 .mu.m deep) and delivering at 1 to 2 cm/s.
Delivery of microparticles into the skin from particle-coated
microneedles was achieved.
EXAMPLE 5
In vivo and In vitro Insertion of Microneedle Arrays into Human
Skin
[0142] For in vitro testing, out-of-plane microneedle arrays (n=3)
were coated and assembled into patches as in Example 2, and then
manually inserted into human cadaver skin for 1 min. After 1 min,
the patch was removed and visually examined by brightfield
microscopy to qualitatively assess the amount of residual coating
left on the microneedles. The human cadaver skin was also imaged by
brightfield microscopy to assess release and delivery of coatings
into the skin. Visual examination of the coated patch after
insertion into the skin in vitro showed as light streaks along the
length of the microneedles that approximately 10% of the coating
remained on the microneedles. Surface examination of the treated
skin showed an array of blue dots corresponding to microneedle
penetration and coating deposition from the array.
[0143] For in vivo analysis, out-of-plane arrays of non-coated
microneedles, made in Example 1, were autoclaved and manually
applied onto the forearms of human subjects (n=3) for 30 s. Gentian
violet was then applied to the treated site for 1 min and wiped
away using isopropanol swabs. The gentian violet selectively
stained the sites of skin perforation, which identified the sites
of microneedle insertion. Dot arrays corresponding to array of
microneedle penetrations were observed on the forearms. The
subjects (n=3) did not report any discomfort upon insertion of the
arrays.
[0144] One may reasonably infer from the results that arrays of
microneedles can be coated with a solid drug formulation and
integrated into a patch, which subsequently may be applied to human
skin for delivery of drug into the skin without patient
discomfort.
EXAMPLE 6
Fabrication of Microneedles with Various Coating Compositions
[0145] Stainless steel single microneedles, in-plane microneedle
rows, or out-of-plane microneedle arrays were fabricated as
described in Example 1. Various microneedle geometries were drafted
in AutoCAD software (Autodesk, Cupertino, Calif., USA) and then cut
into microneedles: single microneedles without pockets, single
microneedles with three circular pockets each 90 .mu.m in diameter,
or single microneedles with a single rectangular pocket 400 .mu.m
long.times.50 .mu.m wide; in-plane microneedle rows containing five
microneedle shafts; or out-of-plane microneedle arrays with fifty
microneedles. All needles were 730 .mu.m in length and 180 .mu.m in
width. In-plane microneedle rows were fabricated, each with five
rectangular (400 .mu.m long.times.50 .mu.m wide) pockets in the
microneedle shafts.
[0146] Microneedle Coating
[0147] Using the custom designed dip-coating devices as in Example
1, the microneedles described in the preceding paragraph were
uniformly coated, with spatial control over the length being
coated. Single dips were made unless otherwise specified. The
coated microneedles were allowed to air-dry at least 24 h before
use.
[0148] The following aqueous formulations (weight/volume % unless
specified otherwise) were prepared and used to coat the
microneedles:
TABLE-US-00001 Formulation A1 0.1% sulforhodamine Formulation A2 1%
carboxymethylcellulose sodium salt (CMC, low viscosity, USP grade,
CarboMer, San Diego, CA, USA), 0.5% Lutrol F-68 NF (BASF, Mt.
Olive, NJ, USA), 0.1% sulforhodamine (Molecular Probes, Eugene, OR,
USA) Formulation A3 52% (wt/wt %) sucrose, 0.2% (wt/wt %) Tween 20,
0.1% sulforhodamine Formulation A4 0.1% sulforhodamine, 0.5% Lutrol
F-68 NF, 0.5% hyaluronic acid Formulation A5 0.1% sulforhodamine,
0.5% Lutrol F-68 NF, 0.5% xanthan gum Formulation A6 0.1%
sulforhodamine, 0.5% Lutrol F-68 NF, 1% sodium alginate Formulation
A7 0.1% sulforhodamine, 0.5% Lutrol F-68 NF, 5%
polyvinylpyrrolidone Formulation A8 0.1% sulforhodamine, 0.5%
Lutrol F-68 NF, 52% (wt/wt %) sucrose Formulation A9 25% sucrose,
0.1% sulforhodamine Formulation A10 80% (vol/vol %) glycerol, 20%
(vol/vol %) of 0.1% sulforhodamine Formulation A11 1%
carboxymethylcellulose sodium salt, 0.5%, Lutrol F-68 NF, 0.2%,
sodium fluorescein Formulation A12 80% (vol/vol %) glycerol, 20%
(vol/vol %) green food dye Formulation A13 80% (vol/vol %)
glycerol, 20% (vol/vol %) amber food dye Formulation A14 80%
(vol/vol %) glycerol, 20% (vol/vol %) red food dye
[0149] In addition, the following organic solvent formulations
(weight/volume % unless specified otherwise) were prepared and used
to coat the microneedles:
TABLE-US-00002 Formulation O1 5% poly(lactic-co-glycolic acid)
(PLGA) in acetonitrile Formulation O2 5% polyvinylpyrrolidone, 0.1%
curcumin in ethanol Formulation O3 5% PLGA, 0.03% sulforhodamine in
acetonitrile
[0150] Effect of Viscosity and Surface Tension
[0151] To identify the effect of surface tension and viscosity on
coating uniformity, two surfactant and viscosity enhancer systems
were used to coat single microneedles (n=3) individually and then
both combined using sulforhodamine as the model drug to help
visualize the coatings. Dipped microneedles were air-dried for 24
hours and examined under Olympus IX70 fluorescent microscope with a
CCD camera (RT Slider, Diagnostic Instruments, Sterling Heights,
Mich., USA) to assess coating uniformity.
[0152] Attempts to coat with sulforhodamine in water (Formulation
A1) did not produce a coating. Using sodium salt of
carboxymethylcellulose or Lutrol F-68 NF, the coatings were found
to be very thin (FIG. 6A) or localize away from the microneedle
periphery towards the center (FIG. 6B), respectively. However, the
combination (Formulation A2) produced good thick uniform coatings
(FIG. 6C). A similar trend was observed for Formulation A3, as a
thick uniform coating across the entire needle surface (FIG. 6F)
was formed. A coating with only Tween 20 (a polyoxyethylene
sorbitan monolaurate) solution containing sulforhodamine resulted
in a very thin layer on the microneedle surface (FIG. 6D), while
coating with only sucrose produced a coating which was more
centralized on the microneedle shaft (FIG. 6E). The contraction of
coating upon drying towards the center of the microneedle was more
prominent in the case of sucrose as compared to carboxymethyl
cellulose. Therefore, the presence of a surfactant was found to
help spread the coating evenly across the microneedle surface,
while the viscosity enhancer provided a thicker film of
coating.
[0153] Drug-excipient interaction can lead to drug aggregation or
decreased solubility. Scratching of Tween 20/sucrose based coatings
on stainless steel microneedles with a hypodermic needle revealed a
waxy characteristic which was not observed for Lutrol
F-68/carboxymethylcellulose based coatings, apparently because
Lutrol F-68 is a solid at room temperature while Tween 20 is a
liquid. Therefore, the present formulations were based on Lutrol
F-68 as the surfactant, and different viscosity enhancers were
tested. Thick uniform coatings were formed using hyaluronic acid
(Formulation A4), xanthan gum (Formulation A5), sodium alginate
(Formulation A6), polyvinylpyrollidone (Formulation A7) and sucrose
(Formulation A8) as the viscosity enhancers. From this information,
one may envision that concentrations of these or other viscosity
enhancers or combinations thereof may be tailored using routine
experimentation to produce coating solution characteristics
specific for a wide variety different drug molecules.
EXAMPLE 7
Surface Modification of Microneedles by Precoating
[0154] In an effort to enhance the application of an aqueous
coating solution to microneedles in a coating process without the
use of a surfactant in the coating solution, the surface properties
of the stainless steel microneedles produced in Example 6 were
modified by (pre)coating the microneedles with a thin silicon
dioxide layer (0.1 .mu.m), in order to render the microneedle
surface more hydrophilic. Silicon dioxide was deposited using a
conventional vapor deposition method. Then, the microneedles were
coated with an aqueous sulforhodamine solution. This resulted in a
uniform but thin coating (less than 1 to 2 .mu.m).
[0155] In another test, the stainless steel microneedles were
(pre)coated with PLGA by dipping the microneedles in Formulation
O1, in order to make the microneedles hydrophobic. After drying,
these surface modified microneedles were dipped into Formulation
A1, dried, and examined under a fluorescent microscope to check for
coating uniformity. Unexpectedly, this surface modification also
resulted in a uniform coating using just water and sulforhodamine
solution. The coating was relatively thin (less than 1 to 2 .mu.m),
presumably because the coating solution did not include a viscosity
enhancer, which it is would have yielded a thicker film and
coating.
[0156] These results indicate that, for coating processes, the
dynamic contact angle is more important than the static equilibrium
contact angle. That is, during withdrawal of the microneedle from
the coating solution, a liquid film becomes entrained on the PLGA
surface. As the entrainment volume is small, the aqueous solvent
rapidly evaporates to yield the solid coating. Surface modification
of microneedles is a useful tool for controlling coating
uniformity, and may be particularly well suited for sensitive
protein solutions, given that protein solutions are often
inherently viscous and will itself provide the necessary viscosity
enhancement for thicker coatings.
EXAMPLE 8
Release of Hydrophobic Coating Materials From Microneedles
[0157] Single microneedles were coated with Formulation O2, as in
Example 6, and examined under a fluorescent microscope for coating
uniformity. A uniform coating of the microneedle surfaces resulted.
The microneedles dipped in Formulation O2 were immersed in
deionized (DI) water for 15 s and checked for loss of coating from
the microneedle surface by visualization under the fluorescent
microscope. After the water dipping, the coating was completely
removed from the microneedles. Even though curcumin has negligible
solubility in water, dissolution of the polyvinylpyrrolidone (the
matrix of the solid coating) resulted in the microneedle coating
coming off of the microneedle surface. PLGA coating (Formulation
O3) also resulted in a uniform coating.
EXAMPLE 9
Coating Microneedles Using Molten Materials
[0158] Pocketed and unpocketed microneedles, made in Example 6,
were dip coated into molten lidocaine and polyethylene glycol
(PEG). Single microneedles with or without rectangular pockets (400
.mu.m long.times.50 .mu.m wide) were dipped in liquid molten
solutions, which did not contain any solvent or additives, of
lidocaine at 100.degree. C. or PEG (MW 1500) at 55.degree. C. each
containing less than 0.01% sulforhodamine (added solely to help in
coating visualization), cooled and air dried for 24 h, and examined
under a fluorescent microscope for coating uniformity. The
lidocaine molten solution was relatively viscous, and the resulting
coatings covered the entire surface in both unpocketed and pocketed
microneedles. PEG, however, produced coating only in the
microneedle pocket. This phenomenon occurred because molten PEG has
high surface tension. Using the molten liquid approach,
microneedles can be coated with a variety of drugs in their pure
state (e.g., lidocaine) or with drug-containing matrix materials
without solvent by using a molten liquid as a dissolution medium
for a solid drug (e.g., dexamathasone drug dissolved in molten
PEG).
EXAMPLE 10
Coating Microneedles Having Pockets
[0159] Single microneedles having rectangular pockets (400 .mu.m
long and 50 .mu.m wide) made as described in Example 6 were dipped
into Formulation A2, Formulation A9, or Formulation A10. The
process for coating the microneedles with Formulation A2 consisted
of six dips with a temporal space of 6 s between dips. Coated
microneedles were examined under a fluorescent microscope after
drying for 24 hours.
[0160] With Formulation A2, both the pockets and the solid surface
of microneedles were coated. However, with Formulation A9, which
omits the surfactant from and increases the solids content in the
coating solution, only the pockets of the microneedle were coated.
Similarly, dipping microneedles in the viscous glycerol solution
(Formulation A10) helped to fill the pockets without coating the
microneedle surfaces. The liquid in the pockets completely
evaporated in approximately 24 hours at ambient conditions.
[0161] In a similar process, microneedles were coated with
propylene glycol, producing microneedles having liquid-filled
pockets. These liquid pockets could be made more stable by storing
under pressure in a nitrogen atmosphere. In one application of
liquid-filled pocket microneedles, the liquid based drug
formulations could deliver hydrophobic drugs from an organic
solvent, such as polypropylene glycol.
EXAMPLE 11
Composite Coatings on Microneedles
[0162] Single microneedles with or without pockets were dipped in
different formulations, as described in Example 6, in sequences to
produce coatings of multiple molecules to generate different drug
release profiles. Four different composite coating schemes were
evaluated:
[0163] (1) pocketed microneedles with three circular pockets (90
.mu.m diameter each) dipped into Formulation A12, DI water,
Formulation A13, DI water, and Formulation A14 in that sequence. At
each DI water step in Step (1), the portion of the microneedle
dipped was decreased by one pocket to retain the formulation in it
from the previous dip, while cleaning the water-dipped pockets.
This procedure allowed sequential filling of each pocket with a
different formulation. Between each dip and after completion of
composite coatings, microneedles were allowed to dry and imaged
under a fluorescent microscope;
[0164] (2) unpocketed microneedles dipped six times into
Formulation O.sub.3 and then dipped six times into Formulation A11,
which was intended to produce a device that can provide a release
profile of a burst release followed by slow release;
[0165] (3) unpocketed microneedles dipped into Formulation A2,
Formulation O1, and Formulation A11 in that sequence; and
[0166] (4) microneedles with a rectangular pocket (400
.mu.m.times.50 .mu.m) dipped into Formulation A9, Formulation O1,
and Formulation A11 in sequence.
[0167] After fabrication of the composite coated microneedles was
completed, the microneedles were dipped into DI water for 1 min to
assess dissolution/drug release. The dipping process caused the
water-soluble layers to dissolve, leaving the PLGA layers intact on
the microneedles. These composite coatings can therefore be
tailored to meet drug delivery requirements either for bolus
delivery or controlled delivery of single or multiple drugs.
EXAMPLE 12
Mass of Coating on Microneedles
[0168] To identify parameters important to controlling the total
mass of coating (in order to control dosage), four coating
parameters were varied in preparing coating microneedles, which
were made as in Example 6. The parameters were (a) concentration of
drug in the coating solution, (b) number of dips during coating,
(c) number of microneedles in the array, and (d) pocketed or
unpocketed microneedles for drug coated onto microneedles, with
vitamin B as the model drug.
[0169] In-plane rows of microneedles were dipped into a solution
containing 1% sodium salt of carboxymethyl cellulose, 0.5% Lutrol
F-68 NF, and different concentrations of vitamin B. For parameter
(a), vitamin B was used at 0.01%, 0.1%, 1%, 2%, 3%, and 4%
concentrations (n=5 rows for each concentration) with 6 dips at 8 s
interval. For parameter (b), a 3% vitamin B concentration was used
with 1, 3, 6, 12, or 24 dips at 8 s intervals (n=5 rows for each
dip number). For parameter (c), a 3% vitamin B concentration was
used with out-of-plane arrays having 5 or 50 needles (n=3 arrays
for each row number). For parameter (d), in-plane rows each with
five microneedles having a rectangular pocket (400 .mu.m.times.50
.mu.m) were dipped into a formulation containing 1% or 3% vitamin B
and 25% sucrose. All coated microneedles were allowed to dry for at
least 24 hr and imaged using brightfield microscopy.
[0170] The mass of vitamin B in the coatings was then determined by
dissolving the vitamin B containing coatings off of the
microneedles and then measuring vitamin B concentration using
fluorescence spectroscopy. The mass of vitamin B in the coatings
was then calculated from the knowledge of the volume of DI water
used to dissolve the coatings.
[0171] An increase in the concentration of vitamin B in the coating
solution and in the number of coating dips was found to increase
the mass of vitamin B coated onto microneedles and the thickness of
coating, as illustrated in FIGS. 7A and 7B, respectively, with
image insets showing thickness. At the maximum concentration of
vitamin B used (i.e., 4%) with six dips, 2.6 .mu.g of vitamin B was
coated per microneedle. At the maximum number of dips used (i.e.,
24) using a 3% solution concentration, the mass was 6.4 .mu.g
vitamin B per microneedle. Changing the number of microneedles from
five to fifty increased the mass on the array proportionately,
which suggests a consistent and uniform coating across the needles
of the array. The use of pockets alone for microneedle coatings,
led to vitamin B loading of 0.066 .mu.g per microneedle.
[0172] Using either a single parameter or their combination, a
pre-determined mass of vitamin B can be coated on the
microneedles.
EXAMPLE 13
In vitro Delivery of Coating Materials from Microneedles into Pig
Skin
[0173] Single non-pocketed microneedles (n=3) coated with
Formulation A2, and single pocketed (rectangular pocket--400
.mu.m.times.50 .mu.m) microneedles (n=3) coated with Formulation
A10, as described in Example 6, were inserted into pig cadaver skin
for 20 s and removed. After removing the microneedles, the skin
surface was examined for coating residue using brightfield
microscopy. In addition, the pig skin was examined histologically
to assess the extent of delivery of microneedle coatings into the
skin. Histological sections of pig skin after insertion of
microneedles coated with Formulation A2 or Formulation A10 contain
a tear in the skin corresponding to the penetration of the coated
microneedles. The punctured spots are surrounded by a bright region
around their periphery which indicates that the sulforhodamine was
released from the solid coating or liquid in the pockets.
EXAMPLE 14
In vivo Insertion of Microneedle Arrays into Human Skin
[0174] Arrays of non-coated, out-of-plane microneedles were
assembled into adhesive patches as described in Example 2,
sterilized using ethylene oxide, and manually applied onto the
forearms of human subjects (n=3). After removing the adhesive
patch, Gentian violet was applied on the treated site for 1 min.
and wiped away using isopropanol swabs. Gentian violet selectively
stained the sites of skin perforation. Brightfield imaging of the
skin surface after staining showed dark dots which correspond to
insertion points of individual microneedles of the fifty needle
array. The results of this example and the preceding one suggest
that coated microneedle arrays will penetrate human skin and
deliver their payload coatings.
[0175] Publications cited herein and the materials for which they
are cited are specifically incorporated by reference. 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.
* * * * *