U.S. patent application number 17/255420 was filed with the patent office on 2021-09-09 for hybrid method of forming microstructure array molds, methods of making microstructure arrays, and methods of use.
The applicant listed for this patent is Corium, Inc.. Invention is credited to Wesley CHANG, Ashutosh SHASTRY, Parminder SINGH.
Application Number | 20210276228 17/255420 |
Document ID | / |
Family ID | 1000005655449 |
Filed Date | 2021-09-09 |
United States Patent
Application |
20210276228 |
Kind Code |
A1 |
SHASTRY; Ashutosh ; et
al. |
September 9, 2021 |
HYBRID METHOD OF FORMING MICROSTRUCTURE ARRAY MOLDS, METHODS OF
MAKING MICROSTRUCTURE ARRAYS, AND METHODS OF USE
Abstract
A method of forming a master mold (52), comprising: a) forming a
plurality of microstructure portions (42) in a substrate formed of
a first material by a first micromachining process, each
microstructure portion comprising a shaft (40) and a distal tip
(38); b) in preparing a negative mold (46) of the plurality of
microstructure portions, wherein the mold is formed of a second
material and comprises a plurality of cavities (48) corresponding
to each microstructure portion in the plurality of microstructure
portions (42); c) electroplating a metal (50) onto the negative
mold to fill each cavity in the plurality of cavities and to form
abase layer (54) extending from the negative mold; d) forming a
proximal section (56) for each of the microstructures in the base
layer using a second micromachining process (e.g. mechanical
micromachining); and e) before or after said step d), removing the
negative mold from the metal to form a master mold.
Inventors: |
SHASTRY; Ashutosh; (Santa
Clara, CA) ; CHANG; Wesley; (Fremont, CA) ;
SINGH; Parminder; (Union City, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Corium, Inc. |
Menlo Park |
CA |
US |
|
|
Family ID: |
1000005655449 |
Appl. No.: |
17/255420 |
Filed: |
June 25, 2019 |
PCT Filed: |
June 25, 2019 |
PCT NO: |
PCT/US2019/039028 |
371 Date: |
December 22, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62689640 |
Jun 25, 2018 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
G03F 7/0392 20130101;
A61M 2037/0053 20130101; G03F 7/2016 20130101; G03F 7/0015
20130101; G03F 7/0755 20130101; G03F 7/0382 20130101; B29L 2031/757
20130101; B29C 33/3857 20130101; A61M 37/0015 20130101; G03F 7/0002
20130101 |
International
Class: |
B29C 33/38 20060101
B29C033/38; G03F 7/00 20060101 G03F007/00; G03F 7/20 20060101
G03F007/20; G03F 7/039 20060101 G03F007/039; G03F 7/075 20060101
G03F007/075; G03F 7/038 20060101 G03F007/038; A61M 37/00 20060101
A61M037/00 |
Claims
1. A method of forming a master mold, comprising: a) forming a
plurality of microstructure portions in a substrate formed of a
first material by a first micromachining process, each
microstructure portion comprising a shaft and a distal tip; b)
preparing a negative mold of the plurality of microstructure
portions, wherein the mold is formed of a second material and
comprises a plurality of cavities corresponding to each
microstructure portion in the plurality of microstructure portions;
c) electroplating a metal onto the negative mold to fill each
cavity in the plurality of cavities and to form a base layer
extending from the negative mold; d) forming a proximal section for
each of the microstructures in the base layer using a second
micromachining process; and e) before or after said step d),
removing the negative mold from the metal to form a master
mold.
2. The method of claim 1, wherein the second micromachining process
is a mechanical micromachining process.
3. The method of claim 1, wherein the first material is selected
from silicon and a positive photoresist material.
4. The method of claim 1, wherein said first micromachining process
comprises a photolithography process.
5. The method of claim 4, wherein said photolithography comprises:
(i) applying a layer of photoresist on the first material; (ii)
applying a masking material onto the photoresist layer, wherein the
masking material covers at least a portion or the photoresist
layer; (iii) curing the portion of the photoresist layer not
covered by the masking material; (iv) isotropic etching the
substrate to create the distal tip section; (v) etching the
substrate to create the shaft portion; (vi) wet thermal oxidizing
the microstructures; and (vii) isotropic wet etching the
microstructures.
6. The method of claim 5, wherein the first material is silicon,
and the method further comprises forming a layer of silicon dioxide
on the silicon substrate using a thermal oxidation process prior to
step DI.
7. The method of claim 5, wherein the thermal oxidation process in
step DI is a wet thermal oxidation process.
8. The method of claim 5, wherein the photoresist material is an
epoxy-based negative photoresist.
9. The method of claim 8, wherein the photoresist material is
SUB.
10. The method of claim 5, wherein the masking material comprises a
plurality of apertures, wherein the photoresist layer exposed by
the apertures is cured in step (iii).
11. The method of claim 5, further comprising: removing the masking
material and any uncured photoresist material after step (iii).
12. The method of claim 11, wherein the masking material and
uncured photoresist are removed using a solvent.
13. The method of claim 5, wherein the etching of step (v)
comprises anisotropic etching.
14. The method of claim 5, wherein step (v) comprises deep
reactive-ion etching.
15. The method of claim 5, further comprising prior to step DI,
cleaning the polymeric material.
16. The method of claim 15, wherein said cleaning comprises
chemical cleaning.
17. The method of claim 16, wherein the chemical cleaning comprises
an RCA cleaning process.
18. The method of claim 5, wherein step (iv) and/or step (v)
comprises plasma etching.
19. The method of claim 18, wherein the plasma etching comprises a
plasma gas selected from SF.sub.6, carbon tetrachloride, oxygen,
and CHF.sub.3.
20. The method of claim 5, further comprising removing any
remaining photoresist from the first material after step (v).
21. The method of claim 1, wherein the second material is a
polymeric material.
22. The method of claim 1, wherein the second material is a
silicone material.
23. The method of claim 21, wherein the second polymeric material
is selected from the group consisting of polydimethylsiloxane
(PDMS), polycarbonate, polyetherimide, and polyethylene
terephthalate.
24. The method of claim 1, wherein the electroplating metal is
selected from copper, nickel, chromium, and gold.
25. The method of claim 1, wherein the proximal section is
micromachined to have a funnel or pyramidal shape.
26. A method of forming a casting mold comprising: preparing a
negative mold of the master mold formed in claim 1.
27. A method of preparing a microstructure array, comprising: (i')
dispensing a polymer matrix solution or suspension comprising at
least one therapeutic agent on a casting mold of claim 26; (ii')
drying the polymer matrix solution; (iii') dispensing a polymer
matrix backing solution on the casting mold; (iv') drying the
polymer matrix backing solution to form the microstructure array;
and (v') demolding the microstructure array.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application No. 62/689,640, filed Jun. 25, 2019, incorporated
herein by reference in its entirety.
TECHNICAL FIELD
[0002] The disclosure relates generally to methods for making or
fabricating molds for making microstructure arrays, methods of
using the molds for making microstructure arrays, and related
features thereof.
BACKGROUND
[0003] Arrays of microneedles were proposed as a way of
administering drugs through the skin in the 1970s, for example in
expired U.S. Pat. No. 3,964,482. Microneedle, microprojection or
microstructure arrays can facilitate the passage of drugs through
or into human skin and other biological membranes in circumstances
where ordinary transdermal administration is inadequate.
Microstructure arrays can also be used to sample fluids found in
the vicinity of a biological membrane such as interstitial fluid,
which is then tested for the presence of biomarkers.
[0004] In recent years it has become more feasible to manufacture
microstructure arrays in a way that makes their widespread use
financially feasible. U.S. Pat. No. 6,451,240 discloses some
methods of manufacturing microneedle arrays. If the arrays are
sufficiently inexpensive, for example, they may be marketed as
disposable devices. A disposable device may be preferable to a
reusable one in order to avoid the question of the integrity of the
device being compromised by previous use and to avoid the potential
need of sterilizing the device after each use and maintaining it in
controlled storage.
[0005] Despite much initial work on fabricating microneedle arrays
in silicon or metals, there are significant advantages to polymeric
arrays. U.S. Pat. No. 6,451,240 discloses some methods of
manufacturing polymeric microneedle arrays. Arrays made primarily
of biodegradable polymers also have some advantages. U.S. Pat. No.
6,945,952 and U.S. Published Patent Applications Nos. 2002/0082543
and 2005/0197308 have some discussion of microneedle arrays made of
biodegradable polymers. A further description of the fabrication of
a microneedle array made of polyglycolic acid is found in Jung-Hwan
Park et al., "Biodegradable polymer microneedles: Fabrication,
mechanics, and transdermal drug delivery," J. of Controlled
Release, 104:51-66 (2005).
[0006] Conventional micromolding techniques have been used to
fabricate molds for forming microprotrusion arrays (Park et al.,
Biomed Microdevices, 2007, 9(2):223-234). A method for fabricating
microneedles using photolithography and soft lithography techniques
is described is described in U.S. Pat. No. 7,763,203. However,
conventional micromolding and lithography techniques have
limitations when producing complicated microstructure structures
and shapes.
[0007] A method of forming microprotrusion arrays using solvent
casting methods is described in U.S. Publication No. 2008/0269685,
which is incorporated in its entirety herein by reference. These
arrays are formed using ceramic, metal, or polymer molds where the
material for the microprotrusion arrays are cast onto the
molds.
[0008] Despite these efforts, there is still a need to find simpler
and better methods for the manufacture of polymeric delivery
systems. One problem with the present molds is that it is difficult
to prepare molds having the desired shape for the microprotrusions.
One particular need is for manufacture of a simple method for
forming microstructure array molds. A further need is for the
manufacture and use of molds that reduce or eliminate the need for
extensive machining of arrays formed in the mold.
[0009] The foregoing examples of the related art and limitations
related therewith are intended to be illustrative and not
exclusive. Other limitations of the related art will become
apparent to those of skill in the art upon a reading of the
specification and a study of the drawings.
BRIEF SUMMARY
[0010] The following aspects and embodiments thereof described and
illustrated below are meant to be exemplary and illustrative, not
limiting in scope.
[0011] In one aspect, a method of forming a master mold is
provided. In some embodiments, a master mold for use in preparing
or forming a microstructure array is provided. In some embodiments,
the method comprises a) forming a plurality of microstructures each
comprising a shaft portion and a distal tip section in a substrate
formed of a first material by a first micromachining process; b)
preparing a mold of the plurality of microstructure portions formed
in a) such that the mold includes the negative of the plurality of
microstructure portions, wherein the mold is formed of a second
material; c) electroplating a metal onto the mold, to fill cavities
in the mold and to create a base layer; e) forming a proximal
section for each of the microstructures in the base layer using a
second micromachining process; and f) removing the second material
from the metal to form a master mold. In embodiments, the second
micromachining process is a mechanical micromachining process. In
some embodiments, the first micromachining process comprises a
photolithography process. In some embodiments, the first material
is selected from silicon and a positive photoresist material. In
some embodiments, the second material is a polymeric material. In
some embodiments, the polymeric material is selected from the group
consisting of polydimethylsiloxane (PDMS), polycarbonate,
polyetherimide, polyethylene terephthalate, or mixtures
thereof.
[0012] In some embodiments, the electroplating metal is selected
from copper, nickel, chromium, and/or gold.
[0013] In some embodiments, a photolithography method comprises 1)
applying a layer of photoresist on the first material; 2) applying
a masking material onto the photoresist layer, wherein the masking
material covers at least a portion or the photoresist layer; 3)
curing the portion of the photoresist layer not covered by the
masking material; 4) isotropic etching the substrate to create the
distal tip section; 5) etching the substrate to create the shaft
portion; 6) wet thermal oxidizing the microstructures; and 7)
isotropic wet etching the microstructures. In embodiments, the
first material is silicon. In some embodiments, the
photolithography method comprises forming a layer of silicon
dioxide on the silicon substrate using a thermal oxidation process
prior to step 1. In some embodiments, the thermal oxidation process
in step 1 is a wet thermal oxidation process. In some embodiments,
the photoresist material is an epoxy-based negative photoresist. In
some embodiments, the photoresist material is SUB. In some
embodiments, the masking material comprises a plurality of
apertures, wherein the photoresist layer exposed by the apertures
is cured in step 3.
[0014] In some embodiments, the photolithography method further
comprises removing the masking material and any uncured photoresist
material after step 3, e.g., after curing the portion of the
photoresist layer not covered by the masking material. In some
embodiments, the masking material and uncured photoresist are
removed using a solvent. In some embodiments, the etching is
anisotropic etching, deep reactive-ion etching, and/or plasma
etching. In some embodiments, plasma etching comprises a plasma gas
selected from at least one of SF.sub.6, carbon tetrachloride,
oxygen, and CHF.sub.3.
[0015] In another aspect, a method of forming a casting mold is
provided. In embodiments, a negative mold of a master mold is
prepared.
[0016] In another aspect, a method of preparing a microstructure
array is provided. In some embodiments, the method comprises
dispensing a polymer matrix solution or suspension comprising at
least one therapeutic agent on a casting mold, drying the polymer
matrix solution; dispensing a polymer matrix backing solution on
the casting mold; drying the polymer matrix backing solution to
form the microstructure array; and demolding the resulting
microstructure array.
[0017] Additional embodiments of the present molds,
microstructures, arrays, methods, apparatuses, devices, and the
like, will be apparent from the following description, drawings,
examples, and claims. As can be appreciated from the foregoing and
following description, each and every feature described herein, and
each and every combination of two or more of such features, is
included within the scope of the present disclosure provided that
the features included in such a combination are not mutually
inconsistent. In addition, any feature or combination of features
may be specifically excluded from any embodiment of the present
invention. Additional aspects and advantages of the present
invention are set forth in the following description and claims,
particularly when considered in conjunction with the accompanying
examples and drawings.
BRIEF DESCRIPTION OF DRAWINGS
[0018] FIGS. 1A-1K are illustrations of an embodiment of a method
of forming a mold useful to manufacture microstructure arrays.
[0019] FIG. 2 is an illustration of an embodiment of a method of
forming a mold useful to manufacture microstructure arrays.
[0020] FIGS. 3A-3D are illustrations of microstructure shapes,
according to some embodiments.
[0021] FIG. 5 is an illustration of a method of forming a
microstructure array using molds described herein, according to one
embodiment.
[0022] FIG. 3 is a flow chart of a method for preparing a
microarray mold and microprotrusion array from the mold, according
to one embodiment.
[0023] It will be appreciated that the thicknesses and shapes for
the various microstructures have been exaggerated in the drawings
to facilitate understanding of the device. The drawings are not
necessarily "to scale."
[0024] Various aspects now will be described more fully
hereinafter. Such aspects may, however, be embodied in many
different forms and should not be construed as limited to the
embodiments set forth herein; rather, these embodiments are
provided so that this disclosure will be thorough and complete, and
will fully convey its scope to those skilled in the art.
DETAILED DESCRIPTION
[0025] The practice of the present disclosure will employ, unless
otherwise indicated, conventional methods of chemistry,
biochemistry, and pharmacology, within the skill of the art. Such
techniques are explained fully in the literature. See, e.g.; A. L.
Lehninger, Biochemistry (Worth Publishers, Inc., current addition);
Morrison and Boyd, Organic Chemistry (Allyn and Bacon, Inc.,
current addition); J. March, Advanced Organic Chemistry (McGraw
Hill, current addition); Remington: The Science and Practice of
Pharmacy, A. Gennaro, Ed., 20.sup.th Ed.; Goodman & Gilman The
Pharmacological Basis of Therapeutics, J. Griffith Hardman, L. L.
Limbird, A. Gilman, 10th Ed.
[0026] Where a range of values is provided, it is intended that
each intervening value between the upper and lower limit of that
range and any other stated or intervening value in that stated
range is encompassed within the disclosure. For example, if a range
of 1 .mu.m to 8 .mu.m is stated, it is intended that 2 .mu.m, 3
.mu.m, 4 .mu.m, 5 .mu.m, 6 .mu.m, and 7 .mu.m are also explicitly
disclosed, as well as the range of values greater than or equal to
1 .mu.m and the range of values less than or equal to 8 .mu.m.
[0027] As used in this specification, the singular forms "a," "an,"
and "the" include plural referents unless the context clearly
dictates otherwise. Thus, for example, reference to "a polymer"
includes a single polymer as well as two or more of the same or
different polymers; reference to "an excipient" includes a single
excipient as well as two or more of the same or different
excipients, and the like.
[0028] In describing and claiming the present invention, the
following terminology will be used in accordance with the
definitions described below.
[0029] The word "about" when immediately preceding a numerical
value means a range of plus or minus 10% of that value, e.g.,
"about 50" means 45 to 55, "about 25,000" means 22,500 to 27,500,
etc., unless the context of the disclosure indicates otherwise, or
is inconsistent with such an interpretation. For example in a list
of numerical values such as "about 49, about 50, about 55, "about
50" means a range extending to less than half the interval(s)
between the preceding and subsequent values, e.g., more than 49.5
to less than 52.5. Furthermore, the phrases "less than about" a
value or "greater than about" a value should be understood in view
of the definition of the term "about" provided herein.
[0030] The terms "microprotrusion", "microprojection",
"microstructure" and "microneedle" are used interchangeably herein
to refer to elements adapted to penetrate or pierce at least a
portion of the stratum corneum or other biological membrane. For
example, illustrative microstructures may include, in addition to
those provided herein, microblades as described in U.S. Pat. No.
6,219,574, edged microneedles as described in U.S. Pat. No.
6,652,478, and microprotrusions as described in U.S. Patent
Publication No. U.S. 2008/0269685.
[0031] The term "microstructure array" for purposes herein is
intended to denote a two-dimensional or a three-dimensional
arrangement of microstructures, microprotrusions, microprojections,
or microneedles. The arrangement may be regular according to a
repeating geometric pattern or it may be irregular. A typical
"microstructure array", "microprojection array", or "microneedle
array" comprises microstructures, microprojections, or microneedles
projecting from a base or substrate of a particular thickness,
which may be of any shape, for example square, rectangular,
triangular, oval, circular, or irregular. An array typically
comprises a plurality of microstructures, microprojections, or
microneedles. The microstructures, microprojections, or
microneedles themselves may have a variety of shapes. While an
array could be pressed by hand into skin, a variety of devices may
be used to hold the array as it is being applied and/or to
facilitate, in one way or another, the process of application of
the array to the skin or other biological membrane. Such devices
may broadly be referred to as "applicators." Applicators may for
example reduce the variations in force, velocity, and skin tension
that occur when an array is pressed by hand into the skin.
Variations in force, velocity and skin tension can result in
variations in permeability enhancement.
[0032] In discussing the applicators and arrays described herein,
the term "downward" is sometimes used to describe the direction in
which microstructures are pressed into skin, and "upward" used to
describe the opposite direction. However, those of skill in the art
will understand that the applicators can be used where the
microstructures are pressed into skin at an angle to the direction
of the earth's gravity, or even in a direction contrary to that of
the earth's gravity. In many applicators, the energy for pressing
the microstructures is provided primarily by an energy-storage
member and so efficiency is not much affected by the orientation of
the skin relative to the earth's gravity.
[0033] "Biodegradable" refers to natural or synthetic materials
that degrade enzymatically, non-enzymatically or both to produce
biocompatible and/or toxicologically safe by-products which may be
eliminated by normal metabolic pathways. The term "biodegradable"
is intended to include the processes of erosion, dissolution,
disintegration, and degradation, as well as to include those
materials that are often referred to as being bioerodible or
biodegradable.
[0034] "Non-biodegradable" refers to natural or synthetic materials
that do not appreciably degrade when inserted into and/or contacted
with skin, mucosa, or other biological membrane for a period of
time associated with use of microstructure arrays. In some
embodiment, "non-biodegradable" refers to materials that do not
appreciably degrade when inserted into and/or contacted with skin,
mucosa or another biological membrane for a period of at least
about 5 minutes, about 10 minutes, about 15 minutes, about 20
minutes, about 30 minutes, about an hour or more. The term
"non-biodegradable" is also intended to include the processes of
erosion, dissolution, and disintegration.
[0035] "Optional" or "optionally" means that the subsequently
described circumstance may or may not occur, so that the
description includes instances where the circumstance occurs and
instances where it does not.
[0036] In this application reference is often made for convenience
to "skin" as the biological membrane which the microstructures
penetrate. It will be understood by persons of skill in the art
that in most or all instances the same inventive principles apply
to the use of microstructures to penetrate other biological
membranes such as, for example, those which line the interior of
the mouth or biological membranes which are exposed during
surgery.
[0037] "Substantially" or "essentially" means nearly totally or
completely, for instance, 90-95% or greater of some given
quantity.
[0038] "Transdermal" refers to the delivery of an agent into and/or
through the skin for local and/or systemic therapy. Administration
through other biological membranes, such as those which line the
interior of the mouth, gastro-intestinal tract, blood-brain
barrier, or other body tissues or organs or biological membranes
which are exposed or accessible during surgery or during procedures
such as laparoscopy or endoscopy, are also contemplated as surfaces
for which the microstructures described herein find use.
[0039] A material that is "water-soluble" intends a material
soluble or substantially soluble in aqueous solvents, such that the
material dissolves into, within or below the skin or other membrane
which is substantially aqueous in nature.
[0040] The compositions of the present disclosure can comprise,
consist essentially of, or consist of, the components
disclosed.
I. Methods of Making Microstructure Array Molds
[0041] Before describing the methods of manufacture in detail, it
is to be understood that the methods are not limited to specific
solvents, materials, or device structures, as such may vary. It is
also to be understood that the terminology used herein is for the
purpose of describing particular embodiments only, and is not
intended to be limiting.
[0042] In general, an array of microstructures, or a portion
thereof, is formed in a material such as silicon or photoresist
using semiconductor microfabrication techniques. Negative molds of
the microstructure array (portions) may be formed of silicones or
other suitable materials. The microfabricated portions are removed
and electroforming techniques are used to fill the cavities with a
suitable metal. An additional section of metal is electroformed to
create a base for preparing the proximal portion of the
microstructures. The additional section is micromachined to create
the desired shape for the proximal portion of the microstructures.
This positive mold may be used as a master mold suitable for use in
creating one or more negative molds. These negative molds may then
be used in casting microstructure arrays for use.
[0043] The molds used to form the arrays herein can be made using a
variety of methods and materials. In one general method, a master
mold for use in making microstructure arrays is prepared. The
master mold may be formed by creating a positive master mold, which
is then used to form negative molds. The master mold may be used to
prepare casting molds for preparing the microstructure arrays for
use. In an embodiment, the method comprises a hybrid method that
comprises (i) forming a positive mold of at least a portion of the
microstructure structure, (ii) forming a negative mold from the
positive mold of (i), (iii) preparing a second positive mold
including the microstructure structure; and (iv) micromachining the
second positive mold to form the master mold with the
microstructures having the desired shape. In one embodiment, the
step identified by (i), forming a positive mold of at least a
portion of the microstructure structure, comprises forming a
positive mold of the distal tip and of the shaft portion of a
microstructure. In one embodiment, the step identified by (iii),
preparing a second positive mold including the microstructure
structure, comprises electroforming the negative mold to fill the
cavities of the positive mold and to create a base layer that
extends from the negative mold. In one embodiment, the step
identified by (iv), micromachining the second positive mold,
comprises micromachining the base layer that extends from the
negative mold into a funnel shape or other shape that corresponds
to the desired shape of the base portion of each
microstructure.
[0044] In general, the method of fabricating the mold is a hybrid
method involving micromachining, lithography and mold casting to
form a master mold, casting molds and/or a microstructure array. In
general, microfabrication methods such as semiconductor
microfabrication methods are used to form at least a distal portion
of the microstructure mold. The semiconductor microfabrication is
used to form at least the distal portion or sharp tip of the
microstructures. One such microfabrication method is shown
generally in FIGS. 1A-1K. In general, semiconductor
microfabrication methods use combinations of photolithography and
etching to create a desired shape. It will be appreciated that
other methods and/or materials as known and/or used in the
fabrication of microelectronics including, but not limited to,
semiconductor fabrication may be used or incorporated into the
methods described below.
[0045] With reference to FIGS. 1A-1K, an exemplary semiconductor
micromachining process is shown for preparing the distal portion or
distal tip of the microstructure master mold. It will be
appreciated that other steps or steps in a different order may be
used to create the microstructure distal portion or tip.
[0046] A substrate 10 formed of a suitable material is provided.
The substrate may be formed of any material suitable for use with
photolithography techniques. In non-limiting embodiments, the
substrate is formed from silicon or a positive photoresist
material. In some embodiments, the substrate is formed from a glass
including, but not limited to a borosilicate glass such as
PYREX.RTM. (Corning) or a sapphire glass. In one embodiment,
positive photoresist materials become soluble to a photoresist
stripper or developer when exposed to light or a particular
wavelength of light. As an initial step, the substrate may be
cleaned using any methods known in the art. It will be appreciated
that the method of cleaning the substrate may depend on the
composition of the substrate. In one embodiment where the substrate
is formed of silicon, the substrate may be cleaned by the RCA clean
method as known in the art. In embodiments, the substrate may be
treated or coated with one or more materials. For example, the
substrate may be coated with a material that adjusts or aids the
photolithography or etching processes. In one embodiment, the
substrate is coated with an antireflective coating or a coating
that adjusts or improves the angle of light used in subsequent
steps. In another embodiment, where the substrate is a silicon
substrate, a layer of oxide such as silicon dioxide may be formed
on the substrate 10 by a suitable process prior to photoresist
coating. One exemplary process is a thermal oxidation procedure
such as wet thermal oxidation.
[0047] The microstructure tips may be formed using any suitable
photolithography techniques as known in the art. In one embodiment,
a layer of negative photoresist 12 is added to the upper or an
exposed surface of the substrate 10 (step (a)). One suitable
photoresist is an epoxy-based photoresist, such as SU-8
(Microchem). As a photoresist, SU-8 may produce a film thickness of
30 microns or greater (e.g. about 0.5 .mu.m to >200 .mu.m
thickness in a single coating). It will be appreciated that other
materials as known in the art may be used as the photoresist.
Further, other photoresist materials or otherwise light and/or
radiation sensitive materials may be used to create a thickness of
photoresist on the substrate of less than or greater than about 30
microns. The photoresist may be applied by spin-coating or may be
otherwise applied or spread over the substrate to a desired
thickness. In embodiments, the photoresist may be deposited or
applied to a thickness ranging from about 1 micron to about 300
microns, or from about 5 microns to about 500 microns, or from
about 10 microns to about 275 microns.
[0048] A masking material 14 is placed over at least a portion of
the photoresist material (step (b)). Any suitable masking material
as known in the art may be used. In embodiments, the masking
material may be photoresist that has been patterned using
photolithography techniques. In other embodiments, the masking
material may be a coated glass or quartz plate with a desired
pattern imprinted. In other embodiments, the masking material may
be a coating as known in the art including, but not limited to,
silicon dioxide or Si.sub.3N.sub.4. The masking material may
include one or more apertures, openings, patterns or features that
are used to create at least a portion of the microstructure shape.
In the example shown in FIG. 1B, the masking material includes a
plurality of openings or apertures 16 that approximately correspond
to the diameter of the microstructures to be formed in the
substrate. In some embodiments, the masking material is a stencil,
a planar sheet of material with desired shapes and patterns etched
out of the sheet. It will be appreciated that the apertures or
openings in the masking material may be any desired shape but will
generally correspond to the shape of the outer edge or a
cross-section of the microstructures formed. For example, masks
having polygonal apertures or openings (e.g. square or rectangular)
may result in microstructures having, for example, a square,
rectangular, or diamond shape or cross-section. The photoresist is
cured 18 such that the photoresist present below and exposed by the
apertures or openings 20 is cured (step (c)). The photoresist may
be cured by any suitable method or methods as known in the art.
Exemplary methods of curing the photoresist include, but are not
limited to exposure to radiation, including but not limited to UV
or near-UV radiation, deep UV radiation, e-beam radiation, or x-ray
radiation. Where SU-8 photoresist is used, the photoresist may be
cured by exposing the photoresist to light in the near UV spectrum
(e.g. 350-400 nm).
[0049] The masking material and the uncured photoresist material
are removed by suitable means known in the art 22 leaving the
substrate 10 and the cured photoresist 12 (step (d)). In
embodiments, a developer, stripper and/or other solvent as known in
the art is used to remove the uncured photoresist. In some
exemplary embodiments, the developer is specific for the
photoresist such as the SU-8 developer available from MicroChem. In
other embodiments, the developer may be a solvent-based developer
including, but not limited to ethyl lactate or diacetone alcohol.
The solvent is applied until dissolution of the uncured
photoresist. Solvent may be applied by any suitable means. In some
non-limiting embodiments, solvent is applied by at least one of
bath immersing the substrate, spray-coating the substrate, and/or
direct dispensing of solvent over the top surface of the substrate.
Generally, the substrate is incubated with the solvent for a period
of time to permit selective dissolution of the photoresist
material. In other embodiments, the photoresist may be removed by
an oxygen plasma etch process.
[0050] The substrate is etched using one or more etching steps. In
embodiments, an isotropic etchant 24 is initially used to produce
an inward portion 26 of the microstructure distal end and/or distal
tip (step (e)). In general, isotropic etchants etch uniformly in
all directions so that a portion of the substrate positioned
directly under the cured photoresist is etched away in both the
lateral as well as the vertical direction. Knowing the rate of
etching for the etchant, one skilled in the art can formulate the
appropriate time of etchant application to achieve a desired shape.
The isotropic etch may be a wet etch (e.g. via immersion in a
liquid etchant) and/or a dry (plasma) etch as known in the art. In
one embodiment, an isotropic wet etch is followed by an isotropic
plasma etch using, for example, SF.sub.6, carbon tetrachloride,
oxygen or CHF.sub.3 or a mixture of any of these gases.
[0051] In embodiments, the substrate is further subjected to
etching using an anisotropic etchant (step (f)). In one embodiment,
the substrate is subjected to deep reactive ion etching (DRIE).
Antistrophic etching is directionally dependent. Thus, the angle or
orientation of the etchant source with respect to the surface of
the substrate determines the angle of the etch. For example, as
shown in FIG. 1F, a DRIE etchant 28 is applied at an angle of about
90.degree. to the surface of the substrate. The resulting etch
creates structures in the substrate having a wall that is about
90.degree. to the bottom surface of the substrate. It will be
appreciated that the angle of application of the etchant may be
adjusted to create microstructures with desired configurations and
structures. The cured photoresist material is removed by any
immersion and/or soaking of the substrate with a suitable solvent
or stripper (liquid) suitable solvent or stripper as known in the
art (step (g)). It will be appreciated that the solvent or stripper
preferably does not significantly affect the shape of the
microstructures formed in the substrate. In some embodiments, the
cured photoresist may be removed by "dry" methods via plasma
treatment.
[0052] The microstructures are finished using suitable means as
known in the art. The finishing steps serve to refine and define
the desired shape of the microstructures for the mold as well as
the arrays formed therefrom. The finishing steps may include
refinement of the microstructure shapes, which includes adjusting
angles for the microstructures and/or finishing a surface of at
least a portion of the microstructures. Some exemplary etching
steps for finishing are shown in steps (h)-(j) of FIGS. 1H-1J. It
will be appreciated that one or more additional finishing steps may
be used. It will further be appreciated that not all of the
finishing steps depicted in FIGS. 1H-1J need be used. In one
embodiment one or more of a plasma etch, a wet thermal oxidation
step, and/or an isotropic wet etch may be used for finishing the
microstructure surfaces (steps (h)-(j)). In step (h), a plasma etch
is performed as described above using a suitable gas or mixture of
gases including, but not limited to, SF.sub.6. This plasma etch is
used to finish the surface and/or correct the angles for the distal
tip of the microstructures. When using an anisotropic etch, it will
be appreciated that the flow of the plasma may be adjusted to
create the desired angle and/or shape as depicted by 30 and 32. As
seen in steps (i)-(j), wet thermal oxidation is followed by an
isotropic etch to create a smooth surface for the microstructures
and/or the sharp tip. Wet thermal oxidation forms a layer of
silicon dioxide 34 in the outer surface of the silicon substrate.
This layer may be easily removed leaving a smooth surface. One
exemplary method of removing the silicon dioxide layer is isotropic
wet etching 36 as shown in step (j). Any suitable wet etching
process as known in the art may be used. Wet etching typically
involves contacting the material with a chemical etchant. In an
embodiment, the chemical etchant is an acid including, but not
limited to, hydrofluoric acid or phosphoric acid.
[0053] As seen in FIG. 1K, the resulting microstructure structures
42 have a shaft 40 and sharpened distal tip 38. The shaft length
should be of sufficient length to allow for penetration of the skin
to a desired depth.
[0054] As seen in FIG. 2, the positive mold with microstructure
structures 42 formed as above is then used to form a negative mold
46. The negative mold may be formed by any suitable methods and/or
materials as known in the art. In one embodiment, the negative mold
is formed by inserting the microstructure structures into a
negative mold material. In other embodiments, the negative mold is
formed by coating the positive mold microstructure structures with
a negative mold material. In embodiments, the negative mold
material is a polymer. In embodiments, the polymer is a soluble
polymer. In embodiments, the polymer is a silicone polymer. In
particular embodiments, the polymer is selected from
polydimethylsiloxane (PDMS) and polylactic-co-glycolyic acid
(PLGA). The microstructures are removed leaving the polymeric
negative mold 46 with cavities 48 in the shape of the
microstructure structures 42 of the positive mold.
[0055] With continued reference to FIG. 2, negative mold 46 is then
used to form a second positive mold, also referred to herein as a
master mold, formed of a durable material, such as a metal. In
embodiments, negative mold 46 is coated with a suitable durable
material 50. In non-limiting embodiments, the durable material is a
metal which is selected from copper, gold, nickel, chromium,
rhodium, platinum, or alloys thereof. The metal may be coated,
applied, or plated onto the negative mold using any suitable
methods including, but not limited to, electroplating, electron
beam deposition, and sputter coating. An excess portion of metal is
applied as shown by 52 to create a base or proximal region of the
microstructures. That is, the durable material is deposited in an
amount sufficient to entirely fill the cavities in the negative
mold and to form a layer or base layer 52 on the negative mold. The
base may be any suitable thickness 54 as needed for forming the
proximal portion of the microstructures. The metal positive mold is
removed from the negative mold 46. At this point, the positive mold
includes the shaft and distal tip of the microstructures with a
slab or base layer 52 having thickness 54. The base 52 is then
machined using suitable mechanical machining methods as known in
the art to create a desired shape of the proximal portion 56 of the
microstructures. In preferred embodiments, the proximal portion 56
has a funnel or pyramidal shape. Any remaining material from the
negative mold 46 is removed by a suitable solvent, such as
methylene chloride.
[0056] In one exemplary embodiment, a negative mold is formed from
a silicone such as polydimethylsiloxane. The negative mold is
typically formed casting a liquid mold material over the positive
master array. The negative mold casting solution material is
allowed to dry and harden. When the hardened material is peeled or
removed from the positive mater, created is a mold comprising
cavities corresponding to the microstructures of the positive
master array. It will be appreciated that the molds suitable for
use in the present methods may be prepared according to other
methods.
[0057] One exemplary master array mold includes a plurality of
microstructures projections having a height of about 100-500 .mu.m.
In general, the master array mold includes a plurality of
microstructures having a height of at least about 100 .mu.m, at
least about 150 .mu.m, at least about 200 .mu.m, at least about 250
.mu.m, or at least about 300 .mu.m. In general it is also preferred
that the microstructures of the master array mold have a height of
no more than about 1 mm, no more than about 500 .mu.m, no more than
about 300 .mu.m, or in some cases no more than about 200 .mu.m or
150 .mu.m. In embodiments, the microstructures of the master array
mold have a height of at least about 50-500 .mu.m. In other
embodiments, the microstructures of the master array mold have a
height of at least about 100-500 .mu.m, 100-400 .mu.m, 100-300
.mu.m, 100-200 .mu.m, 100-150 .mu.m, 150-500 .mu.m, 150-400 .mu.m,
150-300 .mu.m, 150-200 .mu.m, 200-500 .mu.m, 200-400 .mu.m, 200-300
.mu.m, 300-500 .mu.m, 300-400 .mu.m, or 400-500 .mu.m. It will be
appreciated that the microstructures within an array may have a
range of heights. The microstructures of the array master mold may
have any suitable shape including, but not limited to polygonal or
cylindrical. Particular embodiments include a combination of funnel
and cylinder shapes having a funnel tip and a cylindrical base, and
a cone with a polygonal bottom, for example hexagonal or
rhombus-shaped. Some particular shapes are shown in FIGS. 3A-3D.
Other possible microstructure shapes are shown, for example, in
U.S. Published Patent App. 2004/0087992 and in U.S. Application No.
2014/0180201. In one embodiment, a mold is created to form
microstructures shaped like an obelisk, where a distal portion of
the microneedle shaft is a pyramidion with four angled faces
joining and tapering to form a tip that penetrates the skin. The
needle shaft that bears the pyramidion has four planar or flat
sides.
[0058] In some particular embodiments, the master array includes a
plurality of microstructures having a height of about 200 .mu.m, a
base of about 70 .mu.m, and spacing between the projections of
about 200 .mu.m. In another exemplary embodiment, the master array
includes a plurality of hexagonal or other polygonal shaped
projections having a height of about 200 .mu.m, a base of about 70
.mu.m, and spacing between the projections of about 400 .mu.m. In
yet another embodiment, the master array includes a plurality of
cylindrical shaped projections having a height of about 400 .mu.m,
a diameter of about 100 .mu.m, and spacing between the projections
of about 200 .mu.m. It will be appreciated that the cylindrical
shaped projections may have a funnel shaped, pointed, or sharp
distal end.
[0059] The microstructures of the master mold may be spaced about
0-500 .mu.m apart. In specific, but not limiting embodiments, the
microstructures of the master mold are spaced about 0 .mu.m, about
50 .mu.m, about 100 .mu.m, about 150 .mu.m, about 200 .mu.m, about
250 .mu.m, about 300 .mu.m, about 350 .mu.m, about 400 .mu.m, about
450 .mu.m, or about 500 .mu.m apart. The space between the
microstructures may be measured from the base of the
microstructures (base to base) or from the tip (tip to tip). The
spacing of the microstructures of the master mold may be regular or
irregular.
[0060] This master mold may then be used to form multiple negative
molds of any suitable material. These negative molds may be used in
in the manufacture of microstructure arrays where each
microstructure comprises a therapeutic agent to be administered to
a subject for treatment. In one embodiment, the negative mold is
referred to as a casting mold as it received a casting solution or
suspension comprised of the therapeutic agent. An advantage of this
method for providing casting molds is that the casting molds do not
require machining to form the desired shapes of the distal and
proximal portions of the the microstructures. The casting molds may
be formed of any suitable material, including polymers and silicon.
In one embodiment, the polymer is PDMS, which has the advantages of
biocompatibility, viscoelasticity, high chemical inertness, and
ability to adhere to metals, among others. In other embodiments,
the casting mold is formed of any natural or synthetic rubber
(e.g., isoprene, natural rubber, butyl rubber) or polyurethane.
II. Methods of Making Microstructure Arrays
[0061] The methods and resulting molds described in Section I above
may be used in fabricating microstructure arrays. Exemplary methods
are described in U.S. Publication No. 2013/0292868 and
2014/0272101, which are incorporated herein by reference, wherein a
casting solution or suspension is deposited on a negative casting
mold. In one exemplary method, a microstructure array is prepared
by a casting a polymer matrix solution (or suspension) on or in a
negative casting mold. The solution is dried and a backing polymer
solution (or suspension) is cast on or in the negative casting
mold. The backing solution is dried. After drying, the casting mold
is removed. The microstructures formed from the dried polymer
matrix solution and the dried backing solution result in an array
of two-layer microstructures, particularly in embodiments where the
two solutions are different.
[0062] In one embodiment, a casting solution is formed by
dissolving or suspending one or more therapeutic agents, active
agents, drugs, active pharmaceutical ingredients (APIs), or other
substances to be delivered to a subject and one or more polymers in
a solvent to form a polymer matrix solution or suspension. The
terms active agent, therapeutic agent, agent, drug, and API are
used interchangeably herein and discussion or reference to one is
intended to include and apply to each and all terms. In one
embodiment, the casting solution is formed by dissolving or
suspending at least one agent and one or more polymers in an
aqueous buffer or solvent to form a solution or suspension
comprising the active agent and the polymer. In another embodiment,
at least one active agent is dissolved or suspended in a solvent to
form an active agent solution or suspension. At least one polymer
is separately dissolved in a solvent to form a polymer solution or
suspension. The suspension may be a liquid in liquid suspension or
a solid in liquid suspension depending on the nature of the active
agent and/or polymer. The solvent(s) used for the active agent
solution and the polymer solution may be the same or different. The
active agent solution and the polymer solution are mixed to form a
polymer matrix solution or suspension. It will further be
appreciated that a solvent mixture may be used to dissolve or
suspend the active agent and/or polymer.
[0063] Casting solvents are, in one embodiment, preferably aqueous
solvents. Suitable aqueous solvents include, but are not limited
to, water and mixtures of water and alcohols (for example, C1 to C8
alcohols such as propanol and butanol) and/or alcohol esters. In
other embodiments, the solvents are non-aqueous. Suitable
non-aqueous solvents include, but are not limited to, esters,
ethers, ketones, nitrites, lactones, amides, hydrocarbons and their
derivatives as well as mixtures thereof. In other non-limiting
embodiments, the solvent is selected from acetonitrile (ACN),
dimethyl sulfoxide (DMSO), water, or ethanol. It will be
appreciated that the choice of solvent may be determined by one or
more properties of the active agent and/or polymer. It will further
be appreciated that the casting solvent may comprise a mixture of
solvents.
[0064] Any suitable drug, therapeutic agent, API, or other active
agent may be dissolved or suspended in the solvent. The present
arrays are suitable for a wide variety of substances or agents.
Suitable active agents that may be administered include the broad
classes of compounds such as, by way of illustration and not
limitation: analeptic agents; analgesic agents; antiarthritic
agents; anticancer agents, including antineoplastic drugs;
anticholinergics; anticonvulsants; antidepressants; antidiabetic
agents; antidiarrheals; antihelminthics; antihistamines;
antihyperlipidemic agents; antihypertensive agents; anti-infective
agents such as antibiotics, antifungal agents, antiviral agents and
bacteriostatic and bactericidal compounds; antiinflammatory agents;
antimigraine preparations; antinauseants; antiparkinsonism drugs;
antipruritics; antipsychotics; antipyretics; antispasmodics;
antitubercular agents; antiulcer agents; anxiolytics; appetite
suppressants; attention deficit disorder and attention deficit
hyperactivity disorder drugs; cardiovascular preparations including
calcium channel blockers, antianginal agents, central nervous
system agents, beta-blockers and antiarrhythmic agents; caustic
agents; central nervous system stimulants; cough and cold
preparations, including decongestants; cytokines; diuretics;
genetic materials; herbal remedies; hormonolytics; hypnotics;
hypoglycemic agents; immunosuppressive agents; keratolytic agents;
leukotriene inhibitors; mitotic inhibitors; muscle relaxants;
narcotic antagonists; nicotine; nutritional agents, such as
vitamins, essential amino acids and fatty acids; ophthalmic drugs
such as antiglaucoma agents; pain relieving agents such as
anesthetic agents; parasympatholytics; peptide drugs; proteolytic
enzymes; psychostimulants; respiratory drugs, including
antiasthmatic agents; sedatives; steroids, including progestogens,
estrogens, corticosteroids, androgens and anabolic agents; smoking
cessation agents; sympathomimetics; tissue-healing enhancing
agents; tranquilizers; vasodilators including general coronary,
peripheral and cerebral; vessicants; and combinations thereof.
[0065] In embodiments, the active agent is a biological agent
including, but not limited to peptides, polypeptides, proteins, or
nucleic acids (e.g. DNA or RNA). In one embodiment, the active
agent is a polypeptide such as human parathyroid hormone (e.g.
hPTH(1-34)), a protein such as human growth hormone, or an
antibody. Examples of peptides and proteins which may be used with
the microstructure arrays include, but are not limited to,
parathyroid hormone (PTH), oxytocin, vasopressin,
adrenocorticotropic hormone (ACTH), epidermal growth factor (EGF),
prolactin, luteinizing hormone, follicle stimulating hormone,
luliberin or luteinizing hormone releasing hormone (LHRH), insulin,
somatostatin, glucagon, interferon, gastrin, tetragastrin,
pentagastrin, urogastrone, secretin, calcitonin, enkephalins,
endorphins, kyotorphin, taftsin, thymopoietin, thymosin,
thymostimulin, thymic humoral factor, serum thymic factor, tumor
necrosis factor, colony stimulating factors, motilin, bombesin,
dinorphin, neurotensin, cerulein, bradykinin, urokinase,
kallikrein, substance P analogues and antagonists, angiotensin II,
nerve growth factor, blood coagulation factors VII and IX, lysozyme
chloride, renin, bradykinin, tyrocidin, gramicidines, growth
hormones, melanocyte stimulating hormone, thyroid hormone releasing
hormone, thyroid stimulating hormone, pancreozymin,
cholecystokinin, human placental lactogen, human chorionic
gonadotropin, protein synthesis stimulating peptide, gastric
inhibitory peptide, vasoactive intestinal peptide, platelet derived
growth factor, growth hormone releasing factor, bone morphogenic
protein, and synthetic analogues and modifications and
pharmacologically active fragments thereof. Peptidyl drugs also
include synthetic analogs of LHRH, e.g., buserelin, deslorelin,
fertirelin, goserelin, histrelin, leuprolide (leuprorelin),
lutrelin, nafarelin, tryptorelin, and pharmacologically active
salts thereof. Administration of oligonucleotides is also
contemplated, and includes DNA and RNA, other naturally occurring
oligonucleotides, unnatural oligonucleotides, and any combinations
and/or fragments thereof. Therapeutic antibodies include Orthoclone
OKT3 (muromonab CD3), ReoPro (abciximab), Rituxan (rituximab),
Zenapax (daclizumab), Remicade (infliximab), Simulect
(basiliximab), Synagis (palivizumab), Herceptin (trastuzumab),
Mylotarg (gemtuzumab ozogamicin), CroFab, DigiFab, Campath
(alemtuzumab), and Zevalin (ibritumomab tiuxetan).
[0066] In other embodiments, at least a portion of the distal layer
comprises an agent suitable for use as a prophylactic and/or
therapeutic vaccine. In an embodiment, the vaccine comprises an
antigen epitope conjugated on or to a carrier protein. It will be
appreciated that vaccines may be formulated with our without an
adjuvant. Suitable vaccines include, but are not limited to,
vaccines for use against anthrax, diphtheria/tetanus/pertussis,
hepatitis A, hepatitis B, Haemophilus influenzae type b, human
papillomavirus, influenza, Japanese encephalitis,
measles/mumps/rubella, meningococcal diseases (e.g., meningococcal
polysaccharide vaccine and meningococcal conjugate vaccine),
pneumococcal diseases (e.g., pneumococcal polysaccharide vaccine
and meningococcal conjugate vaccine), polio, rabies, rotavirus,
shingles, smallpox, tetanus/diphtheria,
tetanus/diphtheria/pertussis, typhoid, varicella, and yellow
fever.
[0067] In another embodiment, at least a portion of the distal
layer comprises an agent suitable for veterinary uses. Such uses
include, but are not limited to, therapeutic and diagnostic
veterinary uses.
[0068] Polymers for use in the methods are typically biocompatible.
In one embodiment, at least some of the polymers are
biodegradable.
[0069] In an embodiment, the polymer is a structure-forming
polymer. In an embodiment, the polymer is a hydrophilic water
soluble polymer. Suitable polymers are known in the art and
described, for example, in U.S. Patent Application No.
2008/0269685. Exemplary biocompatible, biodegradable, or
bioerodible polymers include poly(lactic acid) (PLA), poly(glycolic
acid) (PGA), poly(lactic acid-co-glycolic acid)s (PLGAs),
polyanhydrides, polyorthoesters, polyetheresters, polycaprolactones
(PCL), polyesteramides, poly(butyric acid), poly(valeric acid),
polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polyethylene
glycol (PEG), block copolymers of PEG-PLA, PEG-PLA-PEG,
PLA-PEG-PLA, PEG-PLGA, PEG-PLGA-PEG, PLGA-PEG-PLGA, PEG-PCL,
PEG-PCL-PEG, PCL-PEG-PCL, copolymers of ethylene glycol-propylene
glycol-ethylene glycol (PEG-PPG-PEG, trade name of Pluronic.RTM. or
Poloxamer.RTM.), block copolymers of polyethylene
glycol-poly(lactic acid-co-glycolic acid) (PLGA-PEG), dextran,
hetastarch, tetrastarch, pentastarch, hydroxyethyl starches,
cellulose, hydroxypropyl cellulose (HPC), sodium carboxymethyl
cellulose (Na CMC), thermosensitive HPMC (hydroxypropyl methyl
cellulose), polyphosphazene, hydroxyethyl cellulose (HEC),
polysaccharides, polyalcohols, gelatin, alginate, chitosan,
hyaluronic acid and its derivatives, collagen and its derivatives,
polyurethanes, and copolymers and blends of these polymers. One
hydroxyethyl starch may have a degree of substitution of in the
range of 0-0.9. An exemplary polysaccharide is dextran including
dextran 70, dextran 40, and dextran 10.
[0070] The casting solution may further include one or more
excipients dissolved or suspended in the buffer or solvent.
Suitable excipients include, but are not limited to, one or more
stabilizers, plasticizers, surfactants, and/or anti-oxidants.
[0071] In one embodiment one or more sugars is added to the casting
solution. Sugars can stabilize the active ingredient and/or
plasticize at least one of the polymers. Sugars may also be used to
affect, moderate, or regulate degradation of the polymer(s).
Exemplary sugars include, but are not limited to, dextrose,
fructose, galactose, maltose, maltulose, iso-maltulose, mannose,
lactose, lactulose, sucrose, and trehalose, and sorbitol. In other
embodiments, a sugar alcohol as known in the art is included in the
casting solution. Exemplary sugar alcohols include, but are not
limited to, lactitol, maltitol, sorbitol, and mannitol.
Cyclodextrins can also be used advantageously in microstructure
arrays, for example .alpha., .beta., and .gamma.cyclodextrins.
Exemplary cyclodextrins include hydroxypropyl-.beta.-cyclodextrin
and methyl-.beta.-cyclodextrin. In other embodiments, where
Dextran, hetastarch and/or tetrastarch is used as a polymer in the
casting solution, sorbitol may preferably be included in the
casting solution. In this embodiment, sorbitol may not only
stabilize the active agent, but also plasticize the polymer matrix,
which reduces brittleness. The biodegradability or dissolvability
of the microstructure array may be facilitated by the inclusion of
sugars. Sugars and sugar alcohols may also be helpful in
stabilization of peptides, proteins, or other biological active
agents and in modifying the mechanical properties of the
microstructures by exhibiting a plasticizing-like effect. Where the
active agent is a biological agent including, but not limited to,
peptides, proteins, and antibodies, one or more sugars or sugar
alcohols may be used in the casting solution as a stabilizing
agent. The sugar may be added to (i) the therapeutic agent solution
or suspension, (ii) the polymer solution or suspension, or (iii)
the polymer matrix solution or suspension once (i) and (ii) have
been mixed.
[0072] One or more surfactants may be added to the casting solution
to change the solutions' surface tension and/or reduce the
hydrophobic interactions of proteins. Any suitable surfactant as
known in the art may be used. Exemplary surfactants include, but
are not limited to, emulsifiers such as Polysorbate 20 and
Polysorbate 80.
[0073] One or more antioxidants may be added to the casting
solution. Any suitable antioxidant as known in the art may be used.
Exemplary antioxidants include, but are not limited to, methionine,
cysteine, D-alpha tocopherol acetate, EDTA, and vitamin E.
[0074] In one embodiment, an optional backing layer, base layer, or
basement is further cast on the mold. A liquid backing formulation
is dispensed on the mold or into the cavities. The liquid backing
formulation is typically prepared by dissolving or suspending one
or more polymers in a suitable solvent. In a preferred embodiment,
the one or more polymers are biocompatible. Typically, but not
always, the polymers are non-biodegradable. In another embodiment,
the backing formulation may comprise one or more biodegradable
and/or non-biodegradable polymers. Suitable biodegradable polymers
are described above. Suitable non-biodegradable polymers are known
in the art and include, but are not limited to, amphiphilic
polyurethanes, polyether polyurethane (PEU), polyetheretherketone
(PEEK), poly(lactic-co-glycolic acid) (PLGA), polylactic acid
(PLA), polyethylene terephthalate, polycarbonate, acrylic polymers
such as those sold under the trade name Eudragit.RTM.,
polyvinylpyrrolidones (PVP), polyamide-imide (PAD, and/or
co-polymers thereof. Further suitable polymers are described in
U.S. Pat. No. 7,785,301, which is incorporated herein in its
entirety. In another embodiment, the backing layer is an adhesive
layer. One suitable adhesive is the Dymax.RTM. 1187-M UV medical
device adhesive. It will be appreciated that any biocompatible
adhesive is suitable for use with, in and/or as the backing layer.
This layer may also be a nonwoven or porous film double coated with
pressure sensitive adhesive. Liquid backing formulations may be
moved into the cavities by the same or similar methods as for the
active agent casting solution. Where a liquid backing layer
formulation is used, the solvent of the backing layer formulation
is removed by a drying process. The drying conditions for drying
the backing layer should be controlled so that the backing layer
solvent can be removed effectively without affecting the stability
of an active agent and/or to properly form (e.g. uniform) the
backing layer. In one embodiment, the mold is placed into a
compressed dry air (CDA) box under controlled air flow and then
placed in an oven at about 5-50.degree. C. In further embodiments,
the mold is placed in the oven at a temperature of about
5-50.degree. C. In embodiments, the temperature of the CDA and/or
oven is about 5.degree. C., about 10.degree. C., about 20.degree.
C., about 30.degree. C., about 40.degree. C., about 45.degree. C.,
or about 50.degree. C. In embodiments, the temperature of the CDA
and/or oven is about 5-45.degree. C., 5-40.degree. C., 5-30.degree.
C., 5-20.degree. C., 5-15.degree. C., 5-10.degree. C.,
10-50.degree. C., 10-45.degree. C., 10-40.degree. C., 10-30.degree.
C., 10-20.degree. C., 10-15.degree. C., 15-50.degree. C.,
15-45.degree. C., 15-40.degree. C., 15-30.degree. C., 15-20.degree.
C., 20-50.degree. C., 20-45.degree. C., 20-40.degree. C.,
20-30.degree. C., 30-50.degree. C., 30-45.degree. C., 30-40.degree.
C., 30-45.degree. C., 40-50.degree. C., 40-45.degree. C., or
45-50.degree. C. In embodiments, the oven uses convection,
conduction, or radiation for drying. In another embodiment, the
mold is placed in an oven at about 5-50.degree. C. without prior
time in a CDA box. In embodiments, the mold is placed in the CDA
and/or oven for at least about 0-120 minutes, about 30-120 minutes,
about 30-90 minutes, about 30-60 minutes, about 30-45 minutes,
about 45-120 minutes, about 45-90 minutes, about 45-60 minutes,
about 60-120 minutes, about 60-90 minutes, about 90-120 minutes, or
longer. Residual solvents in the backing layer can be measured to
determine the effectiveness of solvent removal under different
drying conditions. The backing layer connects and/or supports the
microstructure tips.
[0075] FIG. 4 is an illustration of a method of forming
microstructures having a drug-in-tip (DIT) and a backing layer. A
negative casting mold is created from the master mold described in
Section I. A liquid DIT casting solution is deposited into the
negative casting mold, which of course has at least one cavity in
the shape desired for the microstructures. The liquid DIT solution
is dried under controlled conditions to remove the solvent, thus
creating a solid DIT layer in the bottom or distal end of the
cavity. A backing layer is cast on the mold, over the solid DIT
layer, such that the remaining space in the cavity is filled and,
optionally, a layer of backing layer formulation extends between
adjacent cavities. The backing layer is dried such that the
resulting array has a backing layer with a plurality of
microstructures extending at an angle from the backing layer. The
backing layer with attached microstructures is demolded and
undergoes a final drying step to form the microstructure array
(MSA). It will be appreciated that the MSA may be demolded prior to
undergoing the final drying step.
[0076] The microstructures may be positioned on a base or substrate
to form the array. The substrate may be in addition to or used with
a backing layer. The microstructures may be attached to the
substrate by any suitable means. In one, non-limiting embodiment,
the microstructures are attached to the substrate using an
adhesive. Suitable adhesives include, but are not limited to,
acrylic adhesives, acrylate adhesives, pressure sensitive
adhesives, double-sided adhesive tape, double sided adhesive coated
nonwoven or porous film, and UV curable adhesives. One exemplary
double-sided tape is the #1513 double-coated medical tape available
from 3M. One exemplary, but non-limiting, UV curable adhesive is
the 1187-M UV light-curable adhesive available from Dymax. It will
be appreciated that any medical device adhesive known in the art
would be suitable. In one embodiment, the substrate is a breathable
nonwoven pressure sensitive adhesive. The substrate is placed on
the backing layer where present or a proximal surface of the
microstructures. The substrate is adhered or attached to the
microstructures. In another embodiment, the substrate is a UV cured
adhesive in a polycarbonate film. The UV adhesive is dispensed on
the top of the backing layer or the proximal surface of the
microstructures, covered with a polycarbonate (PC) film to spread
the adhesive and cured using a UV Fusion system. In one embodiment
a UV curing dose is about 1.6 J/cm.sup.2. After the substrate is
attached or adhered to the microstructures, the microstructure
array is removed from the mold. It will be appreciated where the
array includes a backing layer the substrate is attached or adhered
to the backing layer as described above for the
microstructures.
[0077] Cast microstructure arrays are removed from the mold by any
suitable means. In one embodiment, the microstructure array is
removed from the mold by using a de-mold tool. A double-sided
adhesive is placed on the back of microstructure array with one
side for adhering to the array and the other side for adhering to
the de-mold tool. The array is removed from the mold by gently
rolling the de-mold tool over the adhesive on the back of the
array. The microstructure array is then gently peeled off from the
de-mold tool. The arrays may be demolded after drying the backing
layer or after a final drying step.
[0078] Before or after the microstructure array is removed from the
mold a final drying step may be performed under vacuum. The final
drying may be at room temperature or at an elevated temperature. In
embodiments, the final drying is at about 5-50.degree. C. In
embodiments, the final drying is at about 5.degree. C., at about
10.degree. C., at about 20.degree. C., at about 25.degree. C., at
about 35.degree. C., at about 40.degree. C., at about 45.degree.
C., or at about 50.degree. C. Further suitable temperatures and
ranges are described above with reference to drying the backing
layer. In embodiments, the final drying is from about 1-24 hours or
longer, from about 4-20 hours, from about 6-10 hours, from about
8-16 hours, from about 8-12 hours, from about 8-10 hours, from
about 10-12 hours, from about 10-16 hours, from about 12-16 hours
or longer. In other embodiments, the final drying step is
overnight.
[0079] After the microstructure array is removed from the mold, it
may be cut to an appropriate size and/or shape. In one embodiment,
the microstructure array is die cut with an 11 or 16 mm punch.
[0080] FIG. 5 depicts an overall process that outlines steps for
preparing a master mold of a durable material and using the master
mold to form a negative casting mold that is used to prepare a
microstructure array.
III. Microstructure Arrays
[0081] General features of microstructure arrays suitable for use
in the instant arrays and methods are described in detail in U.S.
Patent Publication No. 2008/0269685, U.S. Patent Publication No.
2011/0006458, and U.S. Patent Publication No. 2011/0276028, the
entire contents of which are explicitly incorporated herein by
reference.
[0082] The microstructure arrays are preferably stable both during
the fabrication process as described above and have a stable shelf
life. Short-term stability of the arrays may be evaluated by
storing the arrays at various temperatures and/or humidities and
analyzing monomer content, composition purity, and deamidation of
proteins by SEC-HPLC, RP-HPLC, and IEX-HPLC, respectively at
specific time points. The liquid casting solution or formulation is
preferably stable during the fabrication process, which typically
lasts a few hours. Preferably, the liquid casting solution is
stable for a period of 30 minutes to 6 hours. In non-limiting
embodiments, the liquid casting solution is stable for a period of
at least from 30 minutes to 1 hour, from 30 minutes to 2 hours,
from 30 minutes to 3 hours, from 30 minutes to 4 hours, from 30
minutes to 5 hours, from 1-6 hours, from 1-5 hours, from 1-4 hours,
from 1-3 hours, from 1-2 hours, from 2-6 hours, from 2-5 hours,
from 2-4 hours, from 2-3 hours, from 3-6 hours, from 3-5 hours,
from 3-4 hours, from 4-6 hours, from 4-5 hours, or from 5-6 hours.
In specific, but not limiting embodiments, the liquid casting
solution is stable for at least about 30 minutes, about 45 minutes,
about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5
hours, about 6 hours, or longer. The microstructure arrays are
preferably stable for at least about one day when stored at about
room temperature (e.g. about 25.degree. C.). In other embodiments,
the arrays are shelf stable for at least a period of time after
fabrication. In some embodiments, the arrays are preferably stable
for at least about 1-12 weeks, about 1-16 weeks, or about 1-32
weeks when stored at about 5.degree. C. In other embodiments, the
arrays are stable when stored at an elevated temperature (e.g.
about 40.degree. C.) for at least about 1-12 weeks, about 1-16
weeks, or about 1-32 weeks. In other embodiments, the arrays are
stable when stored at about 5.degree. C. for at least about 1-52
weeks or 1-156 weeks. It will be appreciated that the shelf-life
may vary depending on the storage temperature. In embodiments, the
arrays are stable when stored at about 5.degree. C. for at least
about 1-156 weeks, about 1-12 weeks, about 1-2 weeks, about 1-3
weeks, about 1-4 weeks, about 1-5 weeks, about 2-6 weeks, about 2-5
weeks, about 2-4 weeks, about 2-3 weeks, about 3-6 weeks, about 3-5
weeks, about 3-4 weeks, about 4-6 weeks, about 4-5 weeks, or about
5-6 weeks. In embodiments, the arrays are stable when stored at
about 40.degree. C. for at least about 1-26 weeks, about 1-12
weeks, about 1-2 weeks, about 1-3 weeks, about 1-4 weeks, about 1-5
weeks, about 2-6 weeks, about 2-5 weeks, about 2-4 weeks, about 2-3
weeks, about 3-6 weeks, about 3-5 weeks, about 3-4 weeks, about 4-6
weeks, about 4-5 weeks, or about 5-6 weeks. In other embodiments,
the arrays are stable when stored at about 25.degree. C. for at
least about 1-14 days. In further embodiments, the arrays are
stable when stored at about 25.degree. C. for at least about 1-12
weeks, about 1-16 weeks, about 1-104 weeks, or about 1-156 weeks.
In specific, but not limiting, embodiments, the arrays are stable
when stored at about 5.degree. C. for at least about 5 days, at
least about 1 week, at least about 2 weeks, at least about 4 weeks,
at least about 5 weeks, at least about 6 weeks, or longer. In
embodiments, the arrays are stable when stored at about 25.degree.
C. for at least about 1-2 days, about 1-5 days, about 1-7 days,
about 1-10 days, about 2-5 days, about 2-7 days, about 2-10 days,
about 2-14 days, about 3-5 days, about 3-7 days, about 3-10 days,
about 3-14 days, about 5-14 days, about 5-10 days, about 5-14 days,
or about 10-14 days. In specific, but not limiting, embodiments,
the arrays are stable when stored at about 25.degree. C. for at
least about 12 hours, at least about 1 day, at least about 2 days,
at least about 3 days, at least about 4 days, at least about 5
days, at least about 6 days, at least about one week, or longer.
Stability is typically monitored by measuring the purity of the
active agent in the array after storage as compared to an array
before storage (time=0). In embodiments, the array has a purity of
at least about 80-100%, about 85-100%, about 90-100%, about
95-100%, about 80-95%, about 85-95%, about 90-95% about 80-90%,
about 85-90% or about 80-85% after storage. In non-limiting
embodiments, the array has a purity of at least about 80%, about
85%, about 90%, about 92%, about 93%, about 95%, about 96%, about
97%, about 98%, about 99%, or about 100% after storage.
[0083] Where the active agent is a protein, Methionine-oxidation
(Met-oxidation) is preferably less than or equal to 1-20% after
storage for about 1-6 weeks at about 5.degree. C.-40.degree. C. In
embodiments Met-oxidation is less than about 1-10%, about 1-5%,
about 1-6%, about 2-3%, about 2-4%, about 2-5%, 2-6%, about 3-5%,
or about 3-6%. In specific, but not limiting, embodiments,
Met-oxidation is less than about 1%, about 2%, about 3%, about 4%,
about 5%, about 6%, or about 10%.
[0084] The microstructure arrays should have sufficient mechanical
strength to at least partially penetrate the stratum corneum or
other membrane surface of a subject. It will be appreciated that
different mechanical strength will be required for application at
different sites. One method for assessing mechanical strength is a
skin-penetration efficiency (SPE) study as described in Example 7.
Preferably, the arrays have a SPE of about 50-100%. In other
embodiments, the arrays have a SPE of about 50-80%, about 50-85%,
about 50-90%, about 50-95%, about 60-80%, about 60-85%, about
60-90%, about 60-95%, about 60-100%, about 75-80%, about 75-85%,
about 75-90%, about 75-95%, about 75-100%, about 80-85%, about
80-90%, about 80-95%, about 80-100%, about 90-95%, and about
90-100%. In specific, non-limiting, embodiments, the arrays have a
SPE of about 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, and
100%.
[0085] Preferably, at least about 50-100% of the active agent is
delivered by the MSAs described herein. Delivery efficiency may be
determined by preparing the MSA and applying the MSA in vivo or in
vitro as described in Example 7. In embodiments, the MSA has a
delivery efficiency of at least about 50-60%, about 50-70%, about
50-75%, about 50-80%, about 50-90%, about 50-95%, about 50-99%,
about 60-70%, about 60-75%, about 60-80%, about 60-90%, about
60-95%, about 60-99%, about 70-75%, about 70-80%, about 70-90%,
about 70-95%, about 70-99%, about 75-80%, about 75-90%, about
75-95%, about 75-99%, about 80-90%, about 80-95%, about 80-99%,
about 90-95%, about 90-99%, or about 95-99%.
IV. Methods of Use
[0086] The methods, kits, microstructure arrays and related devices
described herein may be used for treating any condition. It will be
appreciated that the microstructure arrays may be used with any
appropriate applicator including the applicator described in U.S.
Publication No. 2011/0276027, as well as those described in U.S.
Publication No. 2014/0276580 and 2014/0276366, each of which are
incorporated herein in their entirety.
[0087] While a number of exemplary aspects and embodiments have
been discussed above, those of skill in the art will recognize
certain modifications, permutations, additions and sub-combinations
thereof. It is therefore intended that the following appended
claims and claims hereafter introduced are interpreted to include
all such modifications, permutations, additions and
sub-combinations as are within their true spirit and scope.
[0088] All patents, patent applications, and publications mentioned
herein are hereby incorporated by reference in their entireties.
However, where a patent, patent application, or publication
containing express definitions is incorporated by reference, those
express definitions should be understood to apply to the
incorporated patent, patent application, or publication in which
they are found, and not necessarily to the text of this
application, in particular the claims of this application, in which
instance, the definitions provided herein are meant to
supersede.
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