U.S. patent application number 15/933442 was filed with the patent office on 2018-09-27 for microcell systems for delivering active molecules.
The applicant listed for this patent is E INK CALIFORNIA, LLC. Invention is credited to Renfu CHENG, Hui DU, Yih-Ming KANG, Lei LIU, Lin SHAO, Ming WANG.
Application Number | 20180271800 15/933442 |
Document ID | / |
Family ID | 63581387 |
Filed Date | 2018-09-27 |
United States Patent
Application |
20180271800 |
Kind Code |
A1 |
LIU; Lei ; et al. |
September 27, 2018 |
MICROCELL SYSTEMS FOR DELIVERING ACTIVE MOLECULES
Abstract
An active molecule delivery system whereby active molecules can
be released on demand and/or a variety of different active
molecules can be delivered from the same system and/or different
concentrations of active molecules can be delivered from the same
system. The active delivery system includes a plurality of
microcells, wherein the microcells are filled with a medium
including active molecules. The microcells include an opening, and
the opening is spanned by a porous diffusion layer. The microcell
arrays may be loaded with different active ingredients, thereby
providing a mechanism to deliver different, or complimentary,
active ingredients on demand.
Inventors: |
LIU; Lei; (Fremont, CA)
; CHENG; Renfu; (Fremont, CA) ; KANG;
Yih-Ming; (Fremont, CA) ; SHAO; Lin; (Fremont,
CA) ; DU; Hui; (Milpitas, CA) ; WANG;
Ming; (Fremont, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
E INK CALIFORNIA, LLC |
Fremont |
CA |
US |
|
|
Family ID: |
63581387 |
Appl. No.: |
15/933442 |
Filed: |
March 23, 2018 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
62475924 |
Mar 24, 2017 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 47/34 20130101;
A61K 31/465 20130101; A61K 47/32 20130101; A61K 9/7092 20130101;
A61K 9/0021 20130101 |
International
Class: |
A61K 9/70 20060101
A61K009/70; A61K 47/34 20060101 A61K047/34; A61K 47/32 20060101
A61K047/32 |
Claims
1. An active molecule delivery system comprising: a plurality of
microcells, including first and second microcells, wherein each
microcell includes an opening spanned by a porous diffusion layer,
wherein the first microcell includes a first active molecule, and
the second microcell includes a second active molecule different
from the first active molecule.
2. The active molecule delivery system of claim 1, further
comprising an adhesive layer adjacent the porous diffusion
layer.
3. The active molecule delivery system of claim 1, wherein the
porous diffusion layer comprises an acrylate, a methacrylate, a
polycarbonate, a polyvinyl alcohol, cellulose,
poly(N-isopropylacrylamide) (PNIPAAm), poly(lactic-co-glycolic
acid) (PLGA), polyvinylidene chloride, acrylonitrile, amorphous
nylon, oriented polyester, terephthalate, polyvinyl chloride,
polyethylene, polypropylene, polybutylene, polyisobutylene, or
polystyrene.
4. The active molecule delivery system of claim 1, wherein the
first or the second active molecule is distributed in a
biocompatible non-polar liquid.
5. The active molecule delivery system of claim 1, wherein the
first or the second active molecule is distributed in an aqueous
liquid.
6. The active molecule delivery system of claim 1, wherein the
first or the second active molecule is a pharmaceutical
compound.
7. The active molecule delivery system of claim 1, wherein each of
the plurality of microcells has a volume greater than 100 nL.
8. The active molecule delivery system of claim 1, wherein the
porous diffusion layer has an average pore size of between 10 nm
and 100 .mu.m.
9. The active molecule delivery system of claim 1, wherein the
portion of the porous diffusion layer spanning the opening of the
first microcell is thicker than the portion of the porous diffusion
layer spanning the opening of the second microcell.
10. The active molecule delivery system of claim 1, wherein the
portion of the porous diffusion layer spanning the opening of the
first microcell has a smaller average pore size than the portion of
the porous diffusion layer spanning the opening of the second
microcell.
11. The active molecule delivery system of claim 1, wherein the
volume of the first microcell is smaller than the volume of the
second microcell.
12. An active molecule delivery system comprising: a plurality of
microcells, including first and second microcells, wherein each
microcell includes an opening spanned by a porous diffusion layer,
wherein the first microcell includes an active molecule at a first
concentration, and the second microcell includes the active
molecule at a second concentration different from the first
concentration.
13. The active molecule delivery system of claim 12, further
comprising an adhesive layer adjacent the porous diffusion
layer.
14. The active molecule delivery system of claim 12, wherein the
porous diffusion layer comprises an acrylate, a methacrylate, a
polycarbonate, a polyvinyl alcohol, cellulose,
poly(N-isopropylacrylamide) (PNiPAAm), poly(lactic-co-glycolic
acid) (PLGA), polyvinylidene chloride, acrylonitrile, amorphous
nylon, oriented polyester, terephthalate, polyvinyl chloride,
polyethylene, polypropylene, polybutylene, polyisobutylene, or
polystyrene.
15. The active molecule delivery system of claim 12, wherein the
active molecules are distributed in a biocompatible non-polar
liquid.
16. The active molecule delivery system of claim 12, wherein the
active molecules are distributed in an aqueous liquid.
17. The active molecule delivery system of claim 12, wherein the
active molecule is a pharmaceutical compound.
18. The active molecule delivery system of claim 12, wherein each
of the plurality of microcells has a volume greater than 100
nL.
19. The active molecule delivery system of claim 12, wherein the
porous diffusion layer has an average pore size of between 10 nm
and 100 .mu.m.
20. The active molecule delivery system of claim 12, wherein the
portion of the porous diffusion layer spanning the opening of the
first microcell is thicker than the portion of the porous diffusion
layer spanning the opening of the second microcell.
21. The active molecule delivery system of claim 12, wherein the
portion of the porous diffusion layer spanning the opening of the
first microcell has a smaller average pore size than the portion of
the porous diffusion layer spanning the opening of the second
microcell.
22. The active molecule delivery system of claim 12, wherein the
volume of the first microcell is smaller than the volume of the
second microcell.
23. An active molecule delivery system comprising: a plurality of
microcells, each microcell containing a mixture comprising an
active molecule, and each microcell being sealed with a sealing
layer; a microneedle array comprising a plurality of microneedles;
and a compressible layer disposed between the microneedle array and
the plurality of microcells, wherein the microneedles are
configured to penetrate through a microcell, thereby piercing the
sealing layer and releasing the active molecule from the microcell.
Description
RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional
Application No. 62/475,924, filed Mar. 24, 2017, which is
incorporated herein in its entirety.
BACKGROUND
[0002] Transdermal delivery of pharmaceutical agents has proven
effective for drugs that are able to move across the skin barrier.
For example, small amounts of nicotine can be delivered over
extended periods with transdermal patches that suspend the nicotine
in an ethylene vinyl acetate (EVA) copolymer. See, e.g.,
Nicoderm-CQ.RTM. by GlaxoSmithKline (Brentford, UK). Most of the
commercially-available transdermal patches contain a matrix with
only one drug, or a combination of drugs that are compatible for
storage, such as oxycodone and tocopherol. See, e.g., TPM/Oxycodone
patch from Phosphagenics, Ltd. (Melbourne, AU). Nonetheless, the
efficacy of multi-component patches may degrade with time as the
components interact. See, e.g., reports of crystallization in
rotigotine transdermal patches (Nuepro.RTM., UCB, Inc., Smyrna,
Ga.).
[0003] Because there are a number of medications that are best
administered in combination, there is a need for a simple (and
inexpensive) delivery system that allows for the simultaneous
delivery of multiple active components from the same transdermal
system. Additionally, it would be beneficial if the delivery could
he accomplished on demand sometime after the transdermal patch has
been affixed to the skin.
SUMMARY
[0004] The invention addresses these needs by providing a
transdermal delivery system whereby combinations of active
molecules can be administered with the same device. Additionally,
the systems of the invention allow for the delivery of different
concentrations and/or different volumes of active molecules from
the same delivery system.
[0005] Thus, in one aspect the invention is an active molecule
delivery system including a plurality of microcells. The microcells
may be square, round, or polygonal, such as a honeycomb structure.
Each microcell includes an opening that is spanned by a porous
diffusion layer. The porous diffusion layer may be constructed from
a variety of materials, such acrylate, methacrylate, polycarbonate,
polyvinyl alcohol, cellulose, poly(N-isopropylacrylamide)
(PNIPAAm), polylactic-co-glycolic acid) (PLGA), polyvinylidene
chloride, acrylonitrile, amorphous nylon, oriented polyester,
terephthalate, polyvinyl chloride, polyethylene, polypropylene,
polybutylene, polyisobutylene, or polystyrene. Typically, each
microcell has a volume greater than 100 nL, and the porous
diffusion layer has an average pore size of between 1 nm and 100
nm.
[0006] In one embodiment, the system includes at least first and
second microcells, wherein the first microcell includes a first
active molecule and the second microcell includes a second active
molecule, which is different from the first active molecule. In
another embodiment, the system includes at least first and second
microcells, wherein the first microcell includes a first
concentration of an active molecule and the second microcell
includes a second concentration of the active molecule, which is
different from the first concentration. In another embodiment, the
system includes at least first and second microcells, wherein the
first microcell includes a first volume of a solution including an
active molecule and the second microcell includes a second volume
of the solution including the active molecule, wherein the two
volumes are different. In another embodiment, the system includes
at least first and second microcells, wherein the first microcell
includes a first thickness in the portion of the porous diffusion
layer over the opening of the first microcell and the second
microcell includes a second thickness in the portion of the porous
diffusion layer over the opening of the second microcell, wherein
the two thicknesses are different. In another embodiment, the
system includes at least first and second microcells, wherein the
average pore size of the porous diffusion layer over the opening of
the first microcell is different from the average pore size of the
porous diffusion layer over the opening of the second microcell. In
addition to varying the type and concentration of active molecules,
it is also possible to prepare a system including an active and
another useful compound such as a vitamin, adjuvant, etc. Other
combinations of active molecules, agents, and concentrations will
be evident to one of skill in the art.
[0007] In some embodiments, an active molecule is distributed in a
biocompatible non-polar liquid, such as an oil, such as vegetable,
fruit, or nut oil. In other embodiments, the active molecules are
distributed in an aqueous liquid, such as water or an aqueous
buffer. The mixtures may also include charge control agents,
surfactants, nutrients, and adjuvants. Typically, the active
molecule is a pharmaceutical compound, however systems of the
invention can be used to deliver hormones, nutraceuticals,
proteins, nucleic acids, antibodies, or vaccines.
[0008] In another aspect, a system is described including a
plurality of microcells sealed with a sealing layer and a
microneedle array including microneedles configured to penetrate
through a microcell, thereby piercing the sealing layer and
releasing an active molecule from the microcell. Such systems
additionally include a compressible layer disposed between the
microneedle array and the plurality of microcells. In some
embodiments, the delivery system additionally includes an adhesive
layer adjacent the sealing layer. The sealing layer may be, for
example, methylcellulose, hydroxymethylcellulose, an acrylate, a
methacrylate, a polycarbonate, a polyvinyl alcohol, cellulose,
poly(N-isopropylacrylamide) (PNIPAAm), poly(lactic-co-glycolic
acid) (PLGA), polyvinylidene chloride, acrylonitrile, amorphous
nylon, oriented polyester, terephthalate, polyvinyl chloride,
polyethylene, polypropylene, polybutylene, polyisobutylene, or
polystyrene. In some embodiments, the microneedles are at least 10
.mu.m in length to provide sufficient length to traverse all the
way though a microcell, for example at least 20 .mu.m in length, at
least 50 .mu.m in length, at least 70 .mu.m in length.
Additionally, the microneedles may be hollow to provide passage of
active molecules through the microneedles into a surface adjacent
the delivery system. In some embodiments, the compressible layer
includes a gas bladder, foam, or a hydrogel. In some embodiments
the active molecule delivery system also includes an encapsulating
backing to protect the system from physical disruption and to keep
the delivery system secure against a surface.
BRIEF DESCRIPTION OF THE DRAWINGS
[0009] FIG. 1 illustrates an embodiment of an active molecule
delivery system including a plurality of microcells including a
porous diffusion layer wherein different active molecules are
included in different microcells;
[0010] FIG. 2 illustrates an embodiment of an active molecule
delivery system including a plurality of microcells including a
porous diffusion layer wherein different microcells have different
volumes;
[0011] FIG. 3 illustrates an embodiment of an active molecule
delivery system including a plurality of microcells including a
porous diffusion layer wherein the opening to different microcells
is spanned by porous diffusion layers having different average pore
sizes;
[0012] FIG. 4 shows a method for making microcells for the
invention using a roll-to-roll process;
[0013] FIGS. 5A and 5B detail the production of microcells for an
active molecule delivery system using photolithographic exposure
through a photomask of a conductor film coated with a thermoset
precursor;
[0014] FIGS. 5C and 5D detail an alternate embodiment in which
microcells for an active molecule delivery system are fabricated
using photolithography. In FIGS. 5C and 5D a combination of top and
bottom exposure is used, allowing the walls in one lateral
direction to be cured by top photomask exposure, and the walls in
another lateral direction to be cured bottom exposure through the
opaque base conductor film;
[0015] FIGS. 6A-6D illustrate the steps of filling and sealing an
array of microcells to be used in an active molecule delivery
system;
[0016] FIGS. 7A and 7B illustrate the use of a system for
delivering active molecules that includes microcells, a
compressible layer; and an array of microneedles. The scale of the
microcells, compressible layer, and microneedles is exaggerated for
clarity. FIG. 7A shows the system before the microneedles pierce
the microcells and release the active molecules. FIG. 7B shows the
system after the microneedles have been driven into and through the
microcells, thereby releasing the active molecules into the surface
below;
[0017] FIG. 8 shows a prototypical microcell delivery system and a
microscope image of the porous diffusion layer that includes a
layer of polyisobutylene and a layer of an acrylic/methacrylic acid
copolymer (EUDRAGIT.RTM., Evonik, Essen, Del.);
[0018] FIG. 9 illustrates the use of a Franz cell for measuring
rates of diffusion through a double layer of dialysis film
(control) and a microcell assembly of the invention;
[0019] FIG. 10 shows nicotine release profiles through a double
layer of dialysis film (control) and a microcell assembly of the
invention.
DEATILED DESCRIPTION
[0020] The invention provides an active molecule delivery system
whereby active molecules can be released on demand and/or a variety
of different active molecules can be delivered from the same system
and/or different concentrations of active molecules can be
delivered from the same system. The invention is well-suited for
delivering pharmaceuticals to patients transdermally, however the
invention may be used to deliver active ingredients, generally. For
example, the invention can deliver tranquilizing agents to a horse
during transport. The active delivery system includes a plurality
of microcells, wherein the microcells are filled with a medium
including active molecules. The microcells include an opening, and
the opening is spanned by a porous diffusion layer. The microcell
arrays may be loaded with different active ingredients, thereby
providing a mechanism to deliver different, or complimentary,
active ingredients on demand.
[0021] In addition to more conventional applications, such as
transdermal delivery of pharmaceutical compounds, the active
molecule delivery system may be the basis for delivering
agricultural nutrients. For example, the microcell arrays can be
fabricated into large sheets that can be used in conjunction with
hydroponic growing systems, or the microcell arrays can be
integrated into hydrogel film farming. See, for example, Mebiol,
Inc. (Kanagawa, Japan). The active molecule delivery systems can
also be incorporated into the structural walls of smart packing.
Such delivery systems makes it possible to have long term release
of antioxidants into a package containing fresh vegetables. This
"smart" packaging will dramatically improve the shelf life of
certain foods, and it will only require the amount of antioxidant
necessary to maintain freshness until the package is opened. Thus,
the same packaging can be used for food that is distributed
locally, across the country, or around the globe.
[0022] The invention also provides a system for simple and low cost
delivery of "cocktails" of active molecules on demand. Such a
delivery system may be used, for example, as an emergency delivery
system for a person undergoing an allergic reaction. The system may
include epinephrine, as well as antihistamines. The device can be
applied and then triggered to cause the actives to be quickly
passed through the skin. The system may be particularly effective
as a back-up system for small children who may be exposed to
life-threatening allergens while on a field trip, etc. A parent can
affix the delivery system to the child with instructions to
activate the device in the event of, e.g., a bee sting. Because the
device is relatively simple, compliance with proper delivery
protocols will be greater than, e.g., an epipen.
[0023] An overview of an active molecule delivery system is shown
in FIG. 1. The system includes a plurality of microcells 11, each
microcell including a medium (a.k.a. internal phase), that includes
an active molecule 12a/b/c. As shown in FIG. 1, a first microcell
may include a first active 12a, while a second microcell includes a
second active 12b, while a third microcell includes a third active
12c. Each microcell 11 is part of an array that is formed from a
polymer matrix, which is described in more detail below. The active
molecule delivery system will typically include a backing barrier
13 to provide structural support and protection against moisture
ingress and physical interactions. The microcells are defined by
walls 14 that are at least 1 .mu.m high, although they can be much
higher depending upon the desired depth of the microcell. The
microcells may be arranged as squares, a honeycomb, circles, etc.
The microcell 11 will have an opening that is spanned by a porous
diffusion layer 15, which may be constructed from a variety of
natural or non-natural polymers, such as acrylates, methacrylates,
polycarbonates, polyvinyl alcohols, cellulose,
poly(N-isopropylacrylamide) (PNIPAAm), polylactic-co-glycolic acid)
(PLGA), polyvinylidene chloride, acrylonitrile, amorphous nylon,
oriented polyester, terephthalate, polyvinyl chloride,
polyethylene, polypropylene, polybutylene, polyisobutylene, or
polystyrene. Often the system will additionally include an adhesive
layer 16 that is also porous to the active molecule. The adhesive
layer 16 assists in keeping the active molecule delivery system
adjacent to the surface. Using picoliter injection with inkjet or
other fluidic systems, individual microcells can be filled to
enable a variety of different actives to be included in an active
molecule delivery system.
[0024] FIG. 2 shows an alternative construction of an active
molecule delivery system. In the construction of FIG. 2, the depth
of different microcells 27, 28, 29 is varied by increasing the
amount of polymer at the base of the microcell. This is easily
accomplished by using a mold with the desired depth and the
embossing technique described below. In other embodiments, the
width of a microcell can be larger or smaller depending upon the
volume of solution including an active that is desired to be
contained within a given microcell.
[0025] FIG. 3 shows yet another embodiment of an active molecule
delivery system in which the porosity of the diffusion layer is
varied for different microcells. This can be accomplished by using
different polymer materials and microinjection, e.g., using inkjet
during the sealing process (described below). Such systems allow a
single delivery system to administer varying concentrations of the
same or different active molecules over a period of time. For
example, a system of the invention may include three microcells 37,
38, 39 with nicotine at three different concentrations. However,
the dosage time will be controlled by the porosity of the diffusion
layer. For example, shortly after waking the most concentrated dose
may be delivered via the first microcell 37 via the most porous
diffusion layer 34, followed by a maintenance dose delivered from
the second microcell 38, and then during the nighttime, the least
concentrated dosage will be delivered via the third microcell 39
via the least porous diffusion layer 36.
[0026] Of course, a variety of combinations are possible, and
varying microcells might include pharmaceuticals, nutraceuticals,
adjuvants, vitamins, or vaccines. Furthermore, the arrangement of
the microcells may not be distributed. Rather the microcells may be
filled in clusters, which makes filling and sealing more
straightforward. In other embodiments, smaller microcell arrays may
be filled with the same medium, i.e., having the same active
molecule at the same concentration, and then the smaller arrays
assembled into a larger array to make a delivery system of the
invention.
[0027] Techniques for constructing microcells. Microcells may be
formed either in a batchwise process or in a continuous
roll-to-roll process as disclosed in U.S. Pat. No. 6,933,098. The
latter offers a continuous, low cost, high throughput manufacturing
technology for production of compartments for use in a variety of
applications including active molecule delivery and electrophoretic
displays. Microcell arrays suitable for use with the invention can
be created with microembossing, as illustrated in FIG. 4. A male
mold 20 may be placed either above the web 24, as shown in FIG. 4,
or below the web 24 (not shown) however alternative arrangements
are possible. See U.S. Pat. No. 7,715,088, which is incorporated
herein by reference in its entirety. A conductive substrate may be
constructed by forming a conductor film 21 on polymer substrate
that becomes the backing for a device. A composition comprising a
thermoplastic, thermoset, or a precursor thereof 22 is then coated
on the conductor film. The thermoplastic or thermoset precursor
layer is embossed at a temperature higher than the glass transition
temperature of the thermoplastics or thermoset precursor layer by
the male mold in the form of a roller, plate or belt.
[0028] The thermoplastic or thermoset precursor for the preparation
of the microcells may be multifunctional acrylate or methacrylate,
vinyl ether, epoxide and oligomers or polymers thereof, and the
like. A combination of multifunctional epoxide and multifunctional
acrylate is also very useful to achieve desirable
physico-mechanical properties. A crosslinkable oligomer imparting
flexibility, such as urethane acrylate or polyester acrylate, may
be added to improve the flexure resistance of the embossed
microcells. The composition may contain polymer, oligomer, monomer
and additives or only oligomer, monomer and additives. The glass
transition temperatures (or T.sub.g) for this class of materials
usually range from about -70.degree. C. to about 150.degree. C.,
preferably from about -20.degree. C. to about 50.degree. C. The
microembossing process is typically carried out at a temperature
higher than the T.sub.g. A heated male mold or a heated housing
substrate against which the mold presses may be used to control the
microembossing temperature and pressure.
[0029] As shown in FIG. 4, the mold is released during or after the
precursor layer is hardened to reveal an array of microcells 23.
The hardening of the precursor layer may be accomplished by
cooling, solvent evaporation, cross-linking by radiation, heat or
moisture. If the curing of the thermoset precursor is accomplished
by UV radiation, UV may radiate onto the transparent conductor film
from the bottom or the top of the web as shown in the two figures.
Alternatively, UV lamps may be placed inside the mold. In this
case, the mold must be transparent to allow the UV light to radiate
through the pre-patterned male mold on to the thermoset precursor
layer. A male mold may be prepared by any appropriate method, such
as a diamond turn process or a photoresist process followed by
either etching or electroplating. A master template for the male
mold may be manufactured by any appropriate method, such as
electroplating. With electroplating, a glass base is sputtered with
a thin layer (typically 3000 .ANG.) of a seed metal such as chrome
inconel. The mold is then coated with a layer of photoresist and
exposed to UV. A mask is placed between the UV and the layer of
photoresist. The exposed areas of the photoresist become hardened.
The unexposed areas are then removed by washing them with an
appropriate solvent. The remaining hardened photoresist is dried
and sputtered again with a thin layer of seed metal. The master is
then ready for electroforming. A typical material used for
electroforming is nickel cobalt. Alternatively, the master can be
made of nickel by electroforming or electroless nickel deposition.
The floor of the mold is typically between about 50 to 400 microns.
The master can also be made using other microengineering techniques
including e-beam writing, dry etching, chemical etching, laser
writing or laser interference as described in "Replication
techniques for micro-optics", SPIE Proc. Vol. 3099, pp. 76-82
(1997). Alternatively, the mold can be made by photomachining using
plastics, ceramics or metals.
[0030] Prior to applying a UV curable resin composition, the mold
may be treated with a mold release to aid in the demolding process.
The UV curable resin may be degassed prior to dispensing and may
optionally contain a solvent. The solvent, if present, readily
evaporates. The UV curable resin is dispensed by any appropriate
means such as, coating, dipping, pouring or the like, over the male
mold. The dispenser may be moving or stationary. A conductor film
is overlaid the UV curable resin. Pressure may be applied, if
necessary, to ensure proper bonding between the resin and the
plastic and to control the thickness of the floor of the
microcells. The pressure may be applied using a laminating roller,
vacuum molding, press device or any other like means. If the male
mold is metallic and opaque, the plastic substrate is typically
transparent to the actinic radiation used to cure the resin.
Conversely, the male mold can be transparent and the plastic
substrate can be opaque to the actinic radiation. To obtain good
transfer of the molded features onto the transfer sheet, the
conductor film needs to have good adhesion to the UV curable resin
which should have a good release property against the mold
surface.
[0031] Photolithography. Microcells can also be produced using
photolithography. Photolithographic processes for fabricating a
microcell array are illustrated in FIGS. 5A and 5B. As shown in
FIGS. 5A and 5B, the microcell array 40 may be prepared by exposure
of a radiation curable material 41a coated by known methods onto a
conductor electrode film 42 to UV light (or alternatively other
forms of radiation, electron beams and the like) through a mask 46
to form walls 41b corresponding to the image projected through the
mask 46. The base conductor film 42 is preferably mounted on a
supportive substrate base web 43, which may comprise a plastic
material.
[0032] In the photomask 46 in FIG. 5A, the dark squares 44
represent the opaque area and the space between the dark squares
represents the transparent area 45 of the mask 46. The UV radiates
through the transparent area 45 onto the radiation curable material
41a. The exposure is preferably performed directly onto the
radiation curable material 41a, i.e., the UV does not pass through
the substrate 43 or base conductor 42 (top exposure). For this
reason, neither the substrate 43, nor the conductor 42, needs to be
transparent to the UV or other radiation wavelengths employed.
[0033] As shown in FIG. 5B, the exposed areas 41b become hardened
and the unexposed areas (protected by the opaque area 44 of the
mask 46) are then removed by an appropriate solvent or developer to
form the microcells 47. The solvent or developer is selected from
those commonly used for dissolving or reducing the viscosity of
radiation curable materials such as methylethylketone (MEK),
toluene, acetone, isopropanol or the like. The preparation of the
microcells may be similarly accomplished by placing a photomask
underneath the conductor film/substrate support web and in this
case the UV light radiates through the photomask from the bottom
and the substrate needs to be transparent to radiation.
[0034] Imagewise Exposure. Still another alternative method for the
preparation of the microcell array of the invention by imagewise
exposure is illustrated in FIGS. 5C and 5D. When opaque conductor
lines are used, the conductor lines can be used as the photomask
for the exposure from the bottom. Durable microcell walls are
formed by additional exposure from the top through a second
photomask having opaque lines perpendicular to the conductor lines.
FIG. 5C illustrates the use of both the top and bottom exposure
principles to produce the microcell array 50 of the invention. The
base conductor film 52 is opaque and line-patterned. The radiation
curable material 51a, which is coated on the base conductor 52 and
substrate 53, is exposed from the bottom through the conductor line
pattern 52 which serves as the first photomask. A second exposure
is performed from the "top" side through the second photomask 56
having a line pattern perpendicular to the conductor lines 52. The
spaces 55 between the lines 54 are substantially transparent to the
UV light. In this process, the wall material 51b is cured from the
bottom up in one lateral orientation, and cured from the top down
in the perpendicular direction, joining to form an integral
microcell 57. As shown in FIG. 5D, the unexposed area is then
removed by a solvent or developer as described above to reveal the
microcells 57. The technique described in FIGS. 5C and 5D thus
allow the different walls to he constructed with different
porosity, as needed for the embodiment illustrated in FIG. 3.
[0035] The microcells may be constructed from thermoplastic
elastomers, which have good compatibility with the microcells and
do not interact with the electrophoretic media. Examples of useful
thermoplastic elastomers include ABA, and (AB)n type of di-block,
tri-block, and multi-block copolymers wherein A is styrene,
.alpha.-methylstyrene, ethylene, propylene or norbonene; B is
butadiene, isoprene, ethylene, propylene, butylene,
dimethylsiloxane or propylene sulfide; and A and B cannot be the
same in the formula. The number, n, is .gtoreq.1, preferably 1-10.
Particularly useful are di-block or tri-block copolymers of styrene
or oxmethylstyrene such as SB (poly(styrene-b-butadiene)), SBS
(poly(styrene-b-butadiene-b-styrene)), SIS
(poly(styrene-b-isoprene-b-styrene)), SEBS
(poly(styrene-b-ethylenelbutylenes-b-stylene))
poly(styrene-b-dimethylsiloxane-b-styrene),
poly((.alpha.-methylstyrene-b-isoprene),
poly(.alpha.-methylstyrene-b-isoprene-b-.alpha.-methylstyrene),
poly(.alpha.-methylstyrene-b-propylene
sulfide-b-.alpha.-methylstyrene),
poly(.alpha.-methylstyrene-b-dimethylsiloxane-b-.alpha.-methylstyrene).
Commercially available styrene block copolymers such as Kraton D
and C series (from Kraton Polymer, Houston, Tex.) are particularly
useful. Crystalline rubbers such as
poly(ethylene-co-propylene-co-5-methylene-2-norbomene) or EPDM
(ethylene-propylene-diene terpolymer) rubbers such as Vistalon 6505
(from Exxon Mobil, Houston, Tex.) and their grafted copolymers have
also been found very useful.
[0036] The thermoplastic elastomers may be dissolved in a solvent
or solvent mixture Which is immiscible with the display fluid in
the microcells and exhibits a specific gravity less than that of
the display fluid. Low surface tension solvents are preferred for
the overcoating composition because of their better wetting
properties over the microcell walls and the electrophoretic fluid.
Solvents or solvent mixtures having a surface tension lower than 35
dyne/cm are preferred. A surface tension of lower than 30 dyne/cm
is more preferred. Suitable solvents include alkanes (preferably
C.sub.6-12 alkanes such as heptane, octane or Isopar solvents from
Exxon Chemical Company, nonane, decane and their isomers),
cycloalkanes (preferably C.sub.6 cycloalkanes such as cyclohexane
and decalin and the like), alkylbezenes (preferably mono- or
di-C.sub.1-6 alkyl benzenes such as toluene, xylene and the like),
alkyl esters (preferably C.sub.2-5 alkyl esters such as ethyl
acetate, isobutyl acetate and the like) and C.sub.3-5 alkyl
alcohols (such as isopropanol and the like and their isomers).
Mixtures of alkylbenzene and alkane are particularly useful.
[0037] In addition to polymer additives, the polymer mixtures may
also include wetting agents (surfactants). Wetting agents (such as
the FC surfactants from 3M Company, Zonyl fluorosurfactants from
DuPont, fluoroacrylates, fluoromethacrylates, fluoro-substituted
long chain alcohols, perfluoro-substituted long chain carboxylic
acids and their derivatives, and Silwet silicone surfactants from
OSi, Greenwich, Conn.) may also be included in the composition to
improve the adhesion of the sealant to the microcells and provide a
more flexible coating process. Other ingredients including
crosslinking agents (e.g., bisazides such as
4,4'-diazidodiphenylmethane and
2,6-di-(4'-azidobenzal)-4-methylcyclohexanone), vulcanizers (e.g.,
2-benzothiazolyl disulfide and tetramethylthiuram disulfide),
multifunctional monomers or oligomers (e.g., hexanediol,
diacrylates, trimethylolpropane, triacrylate, divinylbenzene,
diallylphthalene), thermal initiators (e.g., dilauroryl peroxide,
benzoyl peroxide) and photoinitiators (e.g., isopropyl thioxanthone
(ITX), Irgacure 651 and Irgacure 369 from Ciba-Geigy) are also
highly useful to enhance the physico-mechanical properties of the
sealing layer by crosslinking or polymerization reactions during or
after the overcoating process.
[0038] After the microcells are produced, they are filled with
appropriate mixtures of active molecules. The microcell array 60
may be prepared by any of the methods described above. As shown in
cross-section in FIGS. 6A-6D, the microcell walls 61 extend upward
from the substrate 63 to form the open cells. The microcells may
include a primer layer 62 to passivate the mixture and keep the
macrocell material from interacting with the mixture containing the
actives 65. Prior to filling, the microcell array 60 may be cleaned
and sterilized to assure that the active molecules are not
compromised prior to use.
[0039] The microcells are next filled with a mixture 64 including
active molecules 65. As shown in FIG. 6B, different microcells may
include different actives. The microcells 60 are preferably
partially filled to prevent overflow and the unintentional mixing
of active ingredients. In systems for delivering hydrophobic active
molecules, the mixture may be based upon a biocompatible oil or
some other biocompatible hydrophobic carrier. For example, the
mixture may comprise a vegetable, fruit, or nut oil. In other
embodiments, silicone oils may be used. In systems for delivering
hydrophilic active molecules, the mixture may be based upon water
or another aqueous medium such as phosphate buffer. The mixture
need not be a liquid, however, as hydrogels and other matrices may
be suitable to deliver the active molecules 65.
[0040] The microcells may be filled using a variety of techniques.
In some embodiments, where a large number of neighboring microcells
are to be filled with an identical mixture, blade coating may be
used to fill the microcells to the depth of the microcell walls 61.
In other embodiments, where a variety of different mixtures are to
be filled in a variety of nearby microcell, inkjet-type
microinjection can be used to fill the microcells. In yet other
embodiments, microneedle arrays may be used to fill an array of
microcells with the coma mixtures. The filling may be done in a
one-step, or a multistep process. For example, all of the cells may
be partially filled with an amount of solvent. The partially filled
microcells are then filled with a second mixture including the one
or more active molecules to be delivered.
[0041] As shown in FIG. 6C, after filling, the microcells are
sealed by applying a polymer 66 that becomes the porous diffusion
layer. In some embodiments, the sealing process may involve
exposure to heat, dry hot air, or UV radiation. In most embodiments
the polymer 66 will be compatible with the mixture 64, but not
dissolved by the solvent of the mixture 64. The polymer 66 will
also be biocompatible and selected to adhere to the sides or tops
of the microcell walls 61. A suitable biocompatible adhesive for
the porous diffusion layer is a phenethylamine mixture, such as
described in U.S. patent application Ser. No. 15/336,841, filed
Oct. 30, 2016 and titled "Method for Sealing Microcell Containers
with Phenethylamine Mixtures," which is incorporated herein by
reference in its entirety. Accordingly, the final microcell
structure is mostly impervious to leaks and able to withstand
flexing without delamination of the porous diffusion layer.
[0042] In alternate embodiments, a variety of individual microcells
may be filled with the desired mixture by using iterative
photolithography. The process typically includes coating an array
of empty microcells with a layer of positively working photoresist,
selectively opening a certain number of the microcells by imagewise
exposing the positive photoresist, followed by developing the
photoresist, filling the opened microcells with the desired
mixture, and sealing the filled microcells by a sealing process.
These steps may be repeated to create sealed microcells filled with
other mixtures. This procedure allows for the formation of large
sheets of microcells having the desired ratio of mixtures or
concentrations.
[0043] After the microcells 60 are filled, the sealed array may he
laminated with a finishing layer 68 that is also porous to the
active molecules, preferably by pre-coating the finishing layer 68
with an adhesive layer which may be a pressure sensitive adhesive,
a hot melt adhesive, or a heat, moisture, or radiation curable
adhesive. The laminate adhesive may he post-cured by radiation such
as UV through the top conductor film if the latter is transparent
to the radiation. In some embodiments, a biocompatible adhesive 67
is then laminated to the assembly. The biocompatible adhesive 67
will allow active molecules to pass through while keeping the
device mobile on a user. Suitable biocompatible adhesives are
available from 3M (Minneapolis, Minn.).
[0044] Once the delivery system has been constructed, it may be
covered with an encapsulating hacking 79 to provide protection
against physical shock. Such an encapsulating backing 79 is shown
in FIGS. 7A-7B however the thickness of the encapsulating backing
79 has been exaggerated for clarity. The encapsulating backing may
also include adhesives to make sure that the active molecule
delivery system stays affixed, e.g., to a patient's back. The
encapsulating backing 79 may also include aesthetic coloring or fun
designs for children.
[0045] Microneedle array/microcell array systems. In other aspects,
it is beneficial to provide an inexpensive active molecule delivery
system that is shelf-stable and provides on-demand delivery of the
active molecules. An active molecule delivery system 70 including a
microneedle array 71 is shown in FIGS. 7A and 79. The microneedle
array 71 includes a plurality of microneedles 72 that are designed
to puncture the substrate 75 of the microcells in the assembly move
through the microcell 77, and finally to pierce a sealing layer 78
that retains the mixture containing the active molecule within the
microcell 77. The microneedles can be formed from polymers, metal,
or semiconductors, and the microneedles can be formed with contact
printing, grown with epitaxy, built up with photolithography, or
deposited with ion beam deposition. The microneedles can be solid
or hollow. The microneedles can be formed with openings that allow
the active molecules to pass from the side of the microneedles into
the lumen of the needle and out the tip into the surface to which
the delivery device is attached.
[0046] Between the microneedle array 71 and the substrate of the
microcells 75 is disposed a compressible material 74 that is
designed to deform and allow the microneedle assembly 71 to travel
to and into the microcells (compare FIGS. 7A and 7B). The
compressible material 74 may be a gel or a foam. The gel or foam
may include a polymer material, such as polyethylene.
Alternatively, the compressible material 74 may be a gas-filled
bladder that simply deforms or folds as pressure is put against the
back of the microcell assembly by a user. The microneedle array 71,
the compressible material 74, and the microcells are covered by an
encapsulating backing 79, which may be formed from an elastomeric
material to allow it to flex as the active molecule delivery system
is compressed and the microneedles 72 are driven through the
microcells.
[0047] The sealing layer 78 may be porous in some applications,
however, it will be more common for the sealing layer 78 to form a
barrier that prevents any fluid contained within the microcell 77
from escaping until the sealing layer 78 is pierced by the
microneedle 72. The sealing layer 78 may be constructed from any of
the materials listed above with respect to the porous diffusion
layer. In addition, the sealing layer 78 can also be constructed
from polyvinylpyrrolidone) and hydroxymethylcellulose. As depicted
in FIGS. 7A and 7B, the microcells 77 contain mixtures with
different active molecules, however, different rnicrocells may
contain different concentrations of the same active molecules, or
other combinations as discussed above. In fact, any of the active
delivery systems described above may be coupled with a microneedle
array to allow on-demand activation of the active delivery
system.
EXAMPLE
Nicotine Release from Microcell Delivery System
[0048] An active molecule delivery system including microcells and
a porous diffusion layer was developed to evaluate delivery of an
aqueous solution of nicotine. FIG. 8 shows the design of the
delivery system used for the test. The system 80 includes a
plurality of microcells formed with embossing as described above
with respect to FIG. 4. The microcells were filled with an aqueous
50 mg/ml solution of nicotine that included 5% of polyvinyl
alcohol. The filled microcells were then sealed with a two-part
porous diffusion layer that was deposited in two separate coatings.
The first layer (a.k.a. sealing layer) is formed from
polyisobutylene in xylene where the polyisobutylene has an average
molecular weight of 850 kD. Once the polyisobutylene has cured, a
final top coating is applied by spreading a methyl ethyl ketone
solution of copolymers derived from esters of acrylic and
methacrylic acid (Eudragit E100; EVONIC). The resulting two-part
diffusion layer was examined under a microscope to determine that
the polyisobutylene about 10 .mu.m thick and the
acrylic/methacrylic acid layer was about 15 .mu.m. (See microscope
image shown in FIG. 8)
[0049] The delivery rate of the microcell delivery system of FIG. 8
was evaluated using a Franz cell. The experimental setup is
illustrated in FIG. 9. In brief, a Pyrex Franz cell (PermeGear,
Inc., Hellertown, Pa.) was assembled as shown. As a control, two
layers of dialysis tubing (Thermo-Fisher, Waltham, Mass.) were cut
to fit across the opening at the joint of the Franz cell. 500 .mu.L
of a 1.3 mg/mL solution of nicotine in D.I. water was pipetted into
the top of the cell. This provided a total load of approximately
0.7 mg of nicotine on the donor side of the Franz cell. The
receptor cell was filled with 5 mL of D.I. water. After the
nicotine solution was introduced to the donor cell, samples were
removed from the receptor cell at various time points as indicated
in the graph in FIG. 10. The samples were later analyzed to
determine the total amount of nicotine that had passed through the
double layer barrier, thereby resulting in the data points
represented by the squares in FIG. 10.
[0050] The microcell delivery system described above (filled with
50 mg/ml of nicotine) was evaluated by removing the double layer of
dialysis tubing, cleaning the Franz cell, and placing the microcell
assembly at the neck joint. The total area of the microcell
assembly was about 0.8 cm.sup.2, resulting in a total volume of
about 1.4 .mu.L of the 50 mg/ml solution of nicotine, or a total
load of approximately 0.07 mg of nicotine. As before, the receptor
cell was filled with 5 mL of D.I. water, and samples were removed
from the receptor cell at various time points as indicated in the
graph in FIG. 10. The resulting data is represented by the circles
in FIG. 10.
[0051] As can be seen in FIG. 10, the microcell assembly released
its nicotine much faster and more efficiently than the dialysis
tubing (control). Regarding FIG. 10, it is clear that for the
microcell delivery system, the receptor cell achieved a steady
state concentration of nicotine in a few hours or less, while the
control had not leveled out after more than 24 hours. Furthermore,
despite having approximately one-tenth the amount of drug loading,
the microcell assembly delivered almost a third of the total
nicotine delivered by the control. That is, the microcell assembly
achieved approximately 90% efficiency in delivering nicotine into
the receptor cell while the control only achieved about 30%
efficiency after 24 hours. The speed and efficacy of the microcell
delivery system suggests that it may be very effective for
administering alkaloid pain medications with water solubility
similar to nicotine, such as morphine and oxycodone.
[0052] Thus the invention provides for an active molecule delivery
system including a plurality of microcells. The microcells may
include differing active molecules, or differing concentrations of
active molecules. The microcells include an opening that is spanned
by a porous diffusion layer. Microcell delivery systems may be
supplemented with microneedle arrays that provide a low-cost way to
have on-demand delivery of active molecules. This disclosure is not
limiting, and other modifications to the invention, not described,
but self-evident to one of skill in the art, are to be included in
the scope of the invention.
* * * * *